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Volume 16(6)
November 2004
1.
Editorial introductions. [Editorial introductions]
2.
Making sure the treatment of myositis does not get "lost in translation".
Isenberg, David[Myositis and myopathies: EDITORAL OVERVIEW]
pg. 665-667
3.
Clinical assessment in adult onset idiopathic inflammatory myopathy.
Sultan, S M[Myositis and myopathies]
pg. 668-672
4.
Clinical assessment in juvenile idiopathic inflammatory myopathies and the
development of disease activity and damage tools.
Pilkington, Clarissa[Myositis and myopathies]
pg. 673-677
5.
Use of imaging to assess patients with muscle disease.
Scott, David L a,b; Kingsley, Gabrielle H a,c[Myositis and myopathies]
pg. 678-683
6.
Is it really myositis? A consideration of the differential diagnosis.
Nirmalananthan, Niranjanan a; Holton, Janice L b; Hanna, Michael G a,c[Myositis and
pg. 684-691
myopathies]
7.
Myositis specific autoantibodies: changing insights in pathophysiology and clinical
associations.
Hengstman, Gerald J.D a; van Engelen, Baziel G.M a; van Venrooij, Walther J
b[Myositis and myopathies]
pg. 692-699
8.
Myositis: an update on pathogenesis.
Christopher-Stine, Lisa a; Plotz, Paul H b[Myositis and myopathies]
pg. 700-706
9.
Have recent immunogenetic investigations increased our understanding of disease
mechanisms in the idiopathic inflammatory myopathies?
Chinoy, Hector; Ollier, William E.R; Cooper, Robert G[Myositis and myopathies]
pg. 707-713
10.
Illness and art: the legacy of Paul Klee.
Varga, John[Raynaud phenomenon, scleroderma, overlap syndromes, and other fibrosing
pg. 714-717
syndromes: EDITORIAL OVERVIEW]
11.
Raynaud phenomenon and the vascular disease in scleroderma.
Kahaleh, M Bashar[Raynaud phenomenon, scleroderma, overlap syndromes, and other fibrosing
pg. 718-722
syndromes]
12.
Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and
relevance.
Cepeda, Eduardo J; Reveille, John D[Raynaud phenomenon, scleroderma, overlap syndromes,
pg. 723-732
and other fibrosing syndromes]
13.
Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic
sclerosis.
Postlethwaite, Arnold E a,b; Shigemitsu, Hidenobu b,c; Kanangat, Siva a,c[Raynaud
pg. 733-738
phenomenon, scleroderma, overlap syndromes, and other fibrosing syndromes]
14.
Recent advances in fibroblast signaling and biology in scleroderma.
Pannu, Jaspreet; Trojanowska, Maria[Raynaud phenomenon, scleroderma, overlap syndromes,
pg. 739-745
15.
Animal models of systemic sclerosis: insights into systemic sclerosis pathogenesis and
potential therapeutic approaches.
Christner, Paul J; Jimenez, Sergio A[Raynaud phenomenon, scleroderma, overlap syndromes,
pg. 746-752
16.
Erratum. [Raynaud phenomenon, scleroderma, overlap syndromes, and other fibrosing syndromes]
17.
Bibliography Current World Literature. [Current World Literature]
18.
List of journals scanned. [List of journals scanned]
19.
Cumulative index to authors for volume 16. [Cumulative index to authors for volume 16: PDF
pg. 753
pg. 754-778
pg. i-ii
Only]
20.
Cumulative index to subjects for volume 16. [Cumulative index to subjects for volume 16: PDF
pg. iii-xi
Only]
21.
Cumulative contents for volume 16. [Cumulative contents for volume 16: PDF Only]
pg. I-VI
Editorial introductions
Current Opinion in Rheumatology was launched in 1989. It
is one of a successful series of review journals whose
unique format is designed to provide a systematic and
critical assessment of the literature as presented in the
many primary journals. The field of rheumatology is divided into 15 sections that are reviewed once a year.
Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important
topics at that time. Here we are pleased to introduce the
Journal’s Section Editors for this issue.
Section Editors
David Isenberg, MD, FRCP
Dr. Isenberg trained at St. Bartholomew’s Hospital, graduating
in 1973. He undertook a variety
of training posts in various North
London hospitals before becoming a Sir Jules Thorn research
fellow at University College and
the Middlesex Hospitals, based
in part in Ivan Riott’s Immunology Department. Subsequently,
he undertook a further period of
research as a Stanley Thomas Johnston research fellow in
the Department of Haematology and Oncology at the
New England Medical Centre, Tufts University, Boston,
Massachusetts. These experiences led to the development of one of his major research interests: the link between structure, function, and origin of autoantibodies.
His research laboratory, established at University College London in 1984, has pursued these topics ever
since. Another major research interest has been seeking
to improve the means of assessing disease activity in
patients with autoimmune rheumatic diseases, notably
lupus, myositis, and Sjögren syndrome.
He has been Chairman of the British Isles Lupus Assessment Group (BILAG) for the past ten years, headed the
Systemic Lupus International Collaborating Clinics
group for five years, and is currently President of the
British Society of Rheumatology.
John Varga, MD
Dr. Varga was born in Budapest,
Hungary. He received his undergraduate training at Columbia University in New York, McGill University in Montreal, and
Glasgow University in Scotland.
He received his medical degree
at New York University, and
completed a residency in international medicine at Rhode Island Hospital, Brown University
in Providence, Rhode Island, followed by a rheumatology fellowship at Boston University, Boston, Massachusetts.
Dr. Varga was a post-doctoral research fellow of the Arthritis Foundation in the laboratory of Sergio Jimenez at
the University of Pennsylvania. He joined the faculty of
Jefferson Medical College in Philadelphia, Pennsylvania,
in 1987. In 1995, he was appointed Director of Rheumatology at the University of Illinois College of Medicine,
and in 2004, he was named The Gallgher Professor of
Medicine at Northwestern University Feinberg School
of Medicine in Chicago.
Dr. Varga is Chair of the Scientific and Medical Advisory
Board of the Scleroderma Foundation, and of the Abbott
Scholar Advisory Board. He has served on National Institutes of Health Study Section panels in 1998. He has
published over 120 peer-reviews articles, along with 60
reviews and book chapters, and two books. Dr. Varga
directs an NIH-supported scleroderma research program
focusing on basic, translational, and clinical aspects of
this disease. He has trained over 20 clinical and research
fellows.
EDITORAL OVERVIEW
Making sure the treatment of myositis does not get
“lost in translation”
David Isenberg
Centre for Rheumatology, University College London, The Middlesex Hospital,
London, UK
Correspondence to David Isenberg, Centre for Rheumatology, University College
London, The Middlesex Hospital, 4th Floor, Arthur Stanley House, 40-50
Tottenham Street, London W1T 4NJ, UK
E-mail: D.Isenberg@ucl.ac.uk
Current Opinion in Rheumatology 2004, 16:665–667
Separate tools need to be developed to distinguish
these two items. To complete the understanding of
the totality of the effect of the disease upon a patient and, by implication, the effect of a drug upon
disease outcome, the patients’ own assessment of
their health status is required.
© 2004 Lippincott Williams & Wilkins
1040–8711
At a recent meeting at the Royal College of Physicians in
London attended by senior members of the Department
of Health, senior academics, and representatives of several major pharmaceutical companies the question of the
future of clinical research was considered. Amongst the
questions posed at this symposium was the critical issue
of what has changed to make major pharmaceutical companies more interested in treating patients with autoimmune and other related diseases. From the perspective
of autoimmunity there seem to be three critical changes:
(1) The recognition that even for somewhat uncommon
diseases such as systemic lupus erythematosus and
scleroderma the number of patients who suffer from
them worldwide is substantial. The number of patients with systemic lupus erythematosus (SLE) in
the United States of America alone has been estimated at close to 250,000 [1].
(2) The huge amount of basic research undertaken into
the etiopathogenesis of autoimmune diseases in the
past twenty years is now paying dividends. A number of key molecules thought to be critical to the
development of these disorders have been identified and agents that block or interfere with their
function in some way have become available.
(3) The ‘tools’ to assess patients with autoimmune diseases have been developed and many have been
validated and shown to be reliable. An essential element in devising these tools has been the recognition that the distinction must be made between
disease activity (implying ongoing active inflammation) and damage (implying permanent change).
The lupus community has led the way in developing the
different type of tools (for review, see references [2,3]).
For those interested in myositis it is essential that, even
though this disease has a much lower prevalence compared with related conditions such as lupus, Sjögren’s
and scleroderma, an opportunity is not lost to undertake
adequately controlled, reasonably sized trials of the more
recently developed therapeutic agents. These agents
suppress key molecules, as likely to be important in the
development of myositis, as in the development of other
autoimmune rheumatic diseases. In this brief review I
will highlight some of the important international collaborative efforts that have been undertaken in the past
three years to agree assessment tools for use in clinical
trials of patients with myositis and briefly discuss some
of the agents that might warrant a close examination of
their therapeutic potential.
Disease assessment in patients
with myositis
Following initial discussions at the European League
against Rheumatism (EULAR) conference in Glasgow in
1999 the International Myositis Assessment and Clinical
Studies (IMAC) group has formed and has actively explored the development of valid sensitive, reliable, and
practical outcome measures that will be of use in randomized control trials for patients with myositis. Two
disease activity tools have been devised, namely, the
myositis intention to treat index (MITAX) and the myositis disease activity assessment visual analogue scale
(MYOACT). The MITAX index is, in essence, a modification of the British Isles Lupus Assessment Group
(BILAG) tool for assessing the disease activity in patients with lupus [4]. It is based on the principle of the
physician’s intention to treat. Disease activity is divided
665
666 Myositis and myopathies
into constitutional, dermatological, gastrointestinal, pulmonary, cardiac, and muscle organs/systems. Individual
clinical features or combinations of features that were
deemed likely to lead to the prescription of large doses of
corticosteroids and/or immunosuppressive drugs define a
grade A—the most active score in any organ or system.
Those patients with known disease activity that is evident but requires somewhat lower doses of immunosuppression and/or drugs such as antimalarials or topical steroids sets the criteria we used to define a B grade. C
grade in each organ or system defines patients with mild
persistent activity. The D grade implies that the organ or
system was once active but is no longer active and the E
grade indicates that the organ or system has never been
active. In contrast, the MYOACT consists of a series of
10-cm visual analogue scales completed by the physician
reviewing the patients. The scales have been modified
from those proposed in the assessment of patients with
vasculitis [5].
The myositis damage index (MDI) is a comprehensive
tool aimed at assessing the extent and severity of damage
developing in different organs and systems. The first
part of the index simply aims to count the items of developing in different organs or systems. This portion is,
in essence, a modification of the Systemic Lupus International Collaborating Clinics/American College of
Rheumatology damage index [6]. The other part, the
myositis damage score (MYODAM), consists of a series
of 10-cm visual analogue scales that aim to quantitate the
severity of damage in the same organs or systems.
ing in patients with myositis was considered in detail
[9•]. Although some more recently described general immunosuppressives such as tacrolimus [10] and mycophenolate [11] have been tried in a few patients with myositis there is increasing interest in attempts to block more
specific groups of cells or individual cytokines. For example anti-T lymphocyte globulin (ATG) appeared to
increase muscle strength in one small study [12] and
there are ongoing attempts to utilize antibodies to CD20positive B cells ([13•] Sultan S and Edwards JCW, personal communication). The first attempts to block the
overexpression of tumor necrosis factor-␣ (TNF-␣) in
patients with myositis have also been described [14].
In summary, the Oscar-winning film Lost in Translation
describes the attempts of an American actor to make
sense of a job opportunity that presents itself in Japan.
Distractions are placed in his way but somehow he overcomes them. By analogy, there is an international consensus amongst rheumatologists and neurologists that we
must make sensible attempts to assess both the effects of
myositis and explore new opportunities to treat it. Some
distractions lie ahead. There is for example a clear difference of opinion amongst interested parties about the
utility of the current classification system for myositis
[9•] but these obstacles must be overcome so that we
may successfully translate our better understanding of
the etiopathogenesis of myositis into more successful
treatment for this seriously disabling disease.
References and recommended reading
Although no major international attempt has been made
to develop a disease-specific tool for patient perception,
use of the Short-Form 36 (SF36) in a group of patients
with myositis has been reported [7]. As this tool has been
used in a variety of diseases and is readily available in
different translations it seems probable that it will be
widely used in many control trials of patients with myositis.
Papers of particular interest, published within the annual period of review,
have been highlighted as:
To start the process of determining the validity and reliability of the MITAX and MYOACT disease activity
tools and the MYODAM disease damage measure, two
‘real patient’ exercises involving adult patients with
myositis have been undertaken [8•]. The intraclass correlation coefficient among the physicians and the interrater reliability as assessed by a variation in the physicians rating of patients was generally good for most
aspects of these tools. More extensive assessments are
currently being undertaken to confirm their validity and
reliability.
•
Of special interest
••
Of outstanding interest
1
Rus V, Hochberg MC: The epidemiology of lupus erythematosus. In Dubois’
Lupus Erythematosus, edn 6. Edited by Wallace DJ, Hahn BH. Philadelphia:
Lippincott Williams and Wilkins; 2002: 65–83.
2
Isenberg DA, Ramsey-Goldman R: Assessing patients with lupus: towards a
drug-responder index. Rheumatology 1999, 38:1045–1049.
3
Ramsey-Goldman R, Isenberg DA: Systemic lupus erythematosus measures.
Arthritis Care Res 2003, 49:S225–S233.
4
Hay EM, Bacon PA, Gordon C, et al.: The BILAG index: a reliable and valid
instrument for measuring clinical activity in systemic lupus erythematosus. Q
J Med 1993, 86:447–458.
5
Whiting-O’Keefe QE, Stone J, Hellman DB: Validity of a vasculitic index for
systemic narcotising vasculitis. Arthritis Rheum 1999, 42:2365–2371.
6
Gladman DD, Ginzler E, Goldsmith C, et al.: The development and initial validation of the Systemic Lupus International Collaborating Clinics/America
College of Rheumatology damage index for systemic lupus erythematosus.
Arthritis Rheum 1996, 39:363–369.
7
Sultan S, Ioannou Y, Moss K, Isenberg DA: Outcome in patients with inflammatory myositis: morbidity and mortality. Rheumatology 2002, 41:22–26.
8
•
Isenberg DA, Allen L, Farewell V, et al.: International consensus outcome
measures for patients with idiopathic inflammatory myopathies. Development
and initial validation of myositis activity and damage indices in patients with
adult onset disease. Rheumatology 2004, 43:49–54.
New agents
At a recent international workshop at the European Neuromuscular Center Clinical Trials Network the questions
of trial design and agents that might be suitable for test-
Editorial overview: Myositis and myopathies Isenberg 667
9
•
Hoogendijk JE, Amato AA, Lecky BR, et al.: The 119th ENMC international
workshop: trial design in adult idiopathic inflammatory myopathies, with the
exception of inclusion body myositis. Neuromuscul Disord 2004, 14:337–
345.
10
Oddis CV, Sciurba FC, Abu Elmgad K, Starzl TE: Tacrolimus in refractory
polymyositis with interstitial lung disease. Lancet 1999, 353:1762.
11
Tousche AK, Mever M: Mycophenolate mofetil for dermatomyositis. Dermatology 2001, 202:341–343.
12
Lindberg C, Trysberg E, Tarkowski A, Oldfars A: Anti-T lymphocyte globulin
treatment in inclusion body myositis. A randomised pilot study. Neurology
2003, 61:260–262.
13
•
Edwards JCW, Szcepanski L, Szechinski J, et al.: Efficacy of B cell targeted
therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med
2004, 350:24–533.
14
Hengstman GJ, van den Horagen FH, Barrera P, et al.: Successful treatment
of dermatomyositis and polymyositis with anti-tumour necrosis factor alpha.
Preliminary observations. Eur Neurol 2003, 50:10–15.
Clinical assessment in adult onset idiopathic
inflammatory myopathy
S.M. Sultan
Purpose of review
Outcome measures have been developed and validated for
many rheumatic diseases and used in clinical trials. The clinical
assessment and measures of improvement in clinical trials of
patients with idiopathic inflammatory myopathy (IIM) has varied
to date and over the past few years an attempt has been made
to reach a consensus in defining this improvement.
Recent findings
The IMACS group (International Myositis Outcome
Assessment Collaborative Study) has proposed core set
measures for disease activity and damage assessment in
adults. Distinguishing between activity and damage can be
difficult and measures to ascertain this are discussed.
Summary
Significant progress has been made in developing international
consensus in the assessment of IIM. Further developments are
underway to assess the reliability and validity of measures that
should capture the multisystem nature of this disease.
Keywords
idiopathic inflammatory myopathy, muscle strength, health
related quality of life
Introduction
The assessment of disease activity and damage are
clearly fundamental for the care of patients with idiopathic inflammatory myopathy (IIM) to optimize therapy
and long-term prognosis. It is apparent that a fine line
exists between under-treating a patient, which may lead
to an increase in disease activity, and over-treating a patient, with the risk of serious morbidity from inappropriate therapy.
It is generally accepted that to capture the totality of the
effect of a disease on a patient, three aspects of the
disease must be assessed:
(1) Disease activity (which is potentially reversible with
treatment)
(2) Damage (defined as irreversible changes in
anatomy, physiology, or function) accumulated
since the onset of disease, albeit from the disease
itself, comorbid conditions, or as a result of therapy
(3) The patient’s own perception of the disease, as this
is frequently different from the physician’s perception of the disease.
Curr Opin Rheumatol 16:668–672. © 2004 Lippincott Williams & Wilkins.
However, until a few years ago there was no agreement
as to what set of measures should be included in the
assessment of outcome of therapeutic trials in patients
with IIM.
Centre for Rheumatology, The Middlesex Hospital, University College Hospital,
London, UK
The clinical assessment and measures of improvement in
clinical trials of patients with IIM has varied to date and
over the past few years an attempt has been made to
reach a consensus in defining this improvement. Measures are needed that capture the multisystem nature of
the disease in patients with IIM. The patients frequently
have cardiac, respiratory, cutaneous, skeletal (joints), and
gastrointestinal involvement. In fact disease activity and
damage in extramuscular organs may not necessarily be
synchronous with the muscle involvement. With the
prospect of new therapies, there is an urgency to develop
a consensus on the assessment of patients with IIM.
Correspondence to S.M. Sultan, Centre for Rheumatology, The Middlesex Hospital,
University College Hospital, Arthur Stanley House, 40-50 Tottenham Street,
London W1T 4NJ, UK
Tel: 02073809230; fax: 02073809278; e-mail: ssultan@doctors.org.uk
1040–8711
This review highlights recent advances in the clinical
assessment of myositis disease activity and damage.
Current measures used to assess disease
activity and damage
Muscle strength testing
Current evaluation of the extent of muscle involvement
is most often accomplished through manual muscle
668
Adult onset idiopathic inflammatory myopathy Sultan 669
strength testing (MMT) and serial muscle enzyme measurements. The MMT is based on the manual muscle
strength testing (MMT), based on the Medical Research
Council War Memorandum scale, and is widely used in
routine clinical care and clinical trials. Both the 6 point
(0–5 scale) and the 12 point (0–10 scale) have been used
and been shown to be sensitive in detecting change in
strength when the muscles are moderately weak. However, the MMT is insensitive with lesser degrees of
muscle weakness when using the 0 to 5 scale [1]. The
total MMT score, rather than the score of individual
muscles, appears to be most accurate for sequential
monitoring [2]. The grading system is subjective and to
an extent varies with the strength of the examiner. Error
may be introduced due to the comprehension of the subject, motivation, and difference in stature of the subject
relative to the tester. The use of MMT has been comprehensively reviewed by Harris-Love in a Workshop
Report [3••].
More objective and sensitive measures of muscle
strength are available, such as the hand-held dynamometry and fixed dynamometry [2,4]. However, they are
time consuming and there is a lack of correlation with
MMT, and these measures are therefore limited to research protocols [5].
However, neither manual MMT nor dynometers distinguish between active disease and damage although a significant improvement with treatment would suggest that
the weakness was due to disease activity.
Muscle enzymes
Serum creatine kinase (CK) levels often do not correlate
particularly well with muscle strength or physical function [6] although on an individual level they may be
helpful in monitoring disease activity. Also, they do not
assess extramuscular involvement and may be normal in
some adults despite active disease (more often dermatomyositis). Lactate dehydrogenase (LDH) and alanine
transferase (ALT) may also be elevated and correlate
with disease activity, but are less sensitive than CK [6].
Elevation of the MB fraction of CPK and cardiac troponin T may be seen in the presence of regenerating myoblasts or myocarditis [7]. Serum cardiac troponin I is cardiac specific and is not produced by regenerating
myoblasts, and may be useful in detecting myocarditis
[8].
Assessment of extramuscular disease
Idiopathic inflammatory myopathies are systemic diseases and assessment of constitutional symptoms, cutaneous, articular, gastrointestinal, respiratory, and cardiac
systems are needed. Organ-specific measures currently
used are valuable in the assessment of an individual patient but have not been developed into quantitative
measures that could be used in clinical trials.
Evaluation of cutaneous features and the activity and
chronicity of individual lesions as well as assessment of
periungual abnormalities has been shown to be sensitive
in serial assessment of disease activity in patients with
JDM [9].
Pulmonary involvement from underlying interstitial lung
disease may be due to active inflammation, which is potentially reversible with treatment or from fibrosis, which
is irreversible. Early in the disease, lung function tests
may show a restrictive defect with a decreased diffusing
capacity and hypoxemia with exercise and this can be
used to monitor progress. The rate of decline may give
some indication of the activity of the disease. However,
high resolution computed tomography (HRCT) scanning
[10], bronchoalveolar lavage, and occasionally lung biopsy [11] may be required to differentiate between activity and damage. A ground glass appearance on HRCT
scanning is suggestive of an alveolitis or consolidation as
part of an organizing pneumonia in active disease
whereas honeycombing or diffuse alveolar damage occurs in the chronic, irreversible phase [11]. Bronchoalveolar lavage (BAL) is more invasive and may demonstrate an above-normal percentage of activated cytotoxic
T cells [12] with a decrease in the CD4:CD8 ratio in the
BAL fluid.
Muscle imaging
Muscle biopsy
Magnetic resonance imaging (MRI) can demonstrate areas of muscle inflammation, edema suggesting active
disease, and areas of fibrosis and calcification (ie, damage) [13]. It can be repeated sequentially and can be
useful for guiding areas from which to take biopsies.
T1-weighted images show muscle atrophy and fatty
infiltration and T2-weighted images, which show
increased water content as increased intensity best demonstrate areas of active muscle inflammation. Gadolinium enhancement is not helpful. MRI may show increased intensity in active disease, even when enzymes
and other tests are normal [14]. Conversely false negatives do occur, even when there is ongoing muscle inflammation documented by muscle biopsy [15].
This is certainly useful at the time of diagnosis, but it is
occasionally helpful in assessing clinical activity late in
the course of the disease to determine activity versus
damage. The yield may be further increased if it is MRI
guided or at the very least a clinically weak muscle is
biopsied.
Magnetic resonance spectroscopy (MRS) provides a view
of muscle metabolism comparing the ratio of muscle
phosphorus contained in phosphocreatine to the level of
inorganic phosphorous. This ratio is decreased in abnormal muscle. MRS is very sensitive (while not very spe-
cific) and has been used to detect muscle abnormalities
in the amyopathic variant of DM [14].
Although this form of imaging is not widely used in routine clinical practice this is due to the limitation in availability and cost. It is likely that the use of imaging will
become a routine part of the evaluation of disease activity and damage in patients with IIM both at the time of
diagnosis and follow-up. Certainly at present, it is still
useful in the assessment of patients deemed refractory to
treatment, where the distinction between damage and
activity would mean reduction or discontinuation of immunosuppressive therapy.
Recent developments in defining and
assessing disease activity
With the hope of new therapies on the horizon (eg, antiTNF ␣ drugs), there is an urgent need for tools that are
reliable and validated for the assessment of disease activity and damage for the use in clinical trials. In clinical
trials to date, various combinations of measures of disease activity have been used; it is important that a consensus is achieved to allow comparison of clinical trial
data. A recent effort of an international group of specialists with expertise in these disorders has allowed substantial progress to be made. The IMACS group (International Myositis Outcome Assessment Collaborative
Study) has focused on the development and validation of
several measures to capture the totality of the effect of a
disease on an individual. Three important domains have
been recommended: disease activity, damage, and health
related quality of life.
Assessment of disease activity
The IMACS have proposed core set measures for disease activity assessment in adults (Table 1) [16]. When
making these assessments the physician takes into account information obtained from history, examination,
and laboratory examination to create an overall impresTable 1. Proposed preliminary core set measure for disease
activity assessment [16]
Domain
Global activity
Muscle strength
Physical function
Laboratory
assessment
Extraskeletal
muscle
disease
Core set measure (as proposed by the IMACS
group)
Physician global disease activity assessed by
Likert or VAS
Parent/patient global disease activity assessed by
Likert or VAS
MMT by a 0–10 scale or expanded 0–5 scale to
include Proximal, distal, and axial muscles
Validated patient/parent questionnaire of ADL
(HAQ/CHAQ)
Validated observational tool of function, strength,
and endurance (CMAS)
At least two serum muscle enzyme activities: CK,
aldolase, LD, AST, or ALT
A validated approach that is comprehensive and
assesses cutaneous, gastrointestinal, joint,
cardiac, and pulmonary activity must be
developed
sion of disease activity. The amount of clinical improvement deemed clinically significant is summarized in
Table 2 [3].
Global disease activity as measured by Likert or visual
analogue scale
In the workshop report [3••] the use of a visual analogue
scale (VAS) has been reviewed and it is suggested that
physician global assessments correlate best with extramuscular activity, muscle strength, and physical function
and is sensitive to change. Global measures can discriminate between active disease and damage [17].
Manual muscle strength testing
Manual muscle strength testing has been selected by
IMACS as the preferred method to assess muscle
strength as one of the core set measures of IIM disease
activity and damage [3••]. The reasons are that it has
been partially validated, it is easily accessible, its costs
are low, and it is easy to use. A total MMT score of 24
proximal, distal, axial muscles demonstrated good interrater and intrarater reliability, moderate sensitivity to
change. A subset of eight axial and proximal muscles has
been widely used as a primary endpoint in several adult
PM/DM trials [3••].
Assessment of physical function
The impact of the disease on the patient physical function and ability to self-care also must be assessed. Selfreported questionnaires such as the Stanford Health Assessment Questionnaire (HAQ) (developed in 1980)
have been used widely. Assessment of eight domains is
made: dressing, arising, eating, walking, hygiene, reach,
grip, and social activities. It also consists of pain assessment, global severity, fatigue, and sleep VAS. The Medical Outcomes Study 36-item Short Form (SF-36) has
been proposed for use in adult patients with myositis as
a generic QOL measure. We have previously shown that
the SF-36 scores differed between patients and controls
in all domains, although there was no difference in the
scores of the domains in patients with active disease
compared with patients who had inactive disease [18].
Laboratory assessment
In the workshop report by the IMACS group [3••] measurement of two muscle enzymes (CK, LDH, AST,
ALT, aldolase) has been suggested. Inconsistent correTable 2. Consensus on the minimum percentage change in the
myositis core set measures to classify a patient as clinically
improved [3••]
Core set domain
Global activity assessment
Patient global activity assessment
Muscle strength
Physical function
Muscle-associated enzymes
Extramuscular activity assessment
Adult specialists,
Median % change
(25th, 75th percentile)
20 (20, 25)
20 (20, 25)
15 (10, 20)
15 (10, 20)
30 (20, 50)
20 (20, 28)
Adult onset idiopathic inflammatory myopathy Sultan 671
lation of CK with muscle histology or muscle activity is
multifactorial and is in part due to suppression of CK by
corticosteroid therapy loss of intrinsic CK activity in the
presence of muscle atrophy. However, in an individual
patient CPK remains a helpful guide in predicting clinical relapse. LDH may be the most clinically useful
muscle enzyme in patients with longstanding disease [6].
patients with underlying OA. The low agreement in
muscle assessment when using the MITAX appears to
be difficulty in attributing weakness due to activity and
that due to damage when scoring ‘loss of function’. This
aspect will need further investigation and possibly modification of the assessment tool. The face validity of the
tool is also being evaluated.
Extraskeletal muscle disease
Consensus approach to the assessment of
disease damage
Two comprehensive quantitative measures have been
developed by the IMACS group to assess the disease
activity in target organs other than muscle [19•]: The
Myositis Intention to Treat Index (MITAX) and the
Myositis Activity Assessment by Visual Analogue Scales
(MYOACT). The MITAX is in fact based upon the
BILAG lupus activity index and is an intention-to-treat
index. It represents the physicians’ judgment of how
active the patients’ disease has been in the previous 2
weeks. Seven target organs are assessed: constitutional,
mucocutaneous, joints, gastrointestinal (GI), respiratory
(RS), cardiovascular (CV), and muscle. Also a physician
global VAS is obtained for the disease activity. Each
clinical feature is scored as not present, improving, the
same, worse, or new. Scores for each system range from
category A score (implying very active disease with the
requirement for high levels of steroids and/or immunosuppressive drugs), category B (active but controlled disease), category C (stable, relatively mild disease), category D (disease that was once active but is no longer so),
and category E (organ never affected by the disease).
In the first test of its performance (a ‘real patient’ exercise involving seven patients and seven physician assessors), the interrater reliability of the MITAX was shown
to be good except for the skeletal and muscle assessments. The MYOACT was considered good for mucocutaneous, average for GI, CV, RS, and muscle [18].
A further interreliability exercise has been undertaken as
part of a multicenter effort (unpublished data). Six centers have participated to date: University College London, St. Georges Hospital (London), Manchester, Pittsburgh, Sweden, and Prague. The activity indices were
filled in both by the local physician and myself (SS)
independently of one another. To date a total of 105
patients have been seen with the local physician. Correlation between physicians has been reported as Intraclass
Correlation Coefficients (ICC). An ICC > 0.65 has been
used as indicating a high level of agreement.
Again there appears to be good agreement in the assessment of most systems. The agreement was low in the
assessment of skeletal and muscle involvement when
using the MITAX and low in constitutional, mucocutaneous, and gastrointestinal assessment for the MYOACT. In the assessment of the skeletal system disagreement occurred when the patient had overlap RA or
To date there is limited information as how best to define or assess damage. MRI as discussed earlier certainly
may have a greater role to play in the future in differentiating between inflammation, fibrosis, and atrophy.
The IMACS group has suggested that further investigation is required as to what measures should be used in
clinical trials [3••]. At present the following have been
suggested: the physician global damage assessments (as
measured by a VAS); the HAQ/CHAQ as measures of
physical function—this has been shown to measure a
cumulative decline in function in adult patients and the
Myositis Damage Index (MDI) [3••]. The MDI has
been devised to assess the extent and severity of damage
developing in different organs and systems. The MDI is
an assessment of accumulation of damage since the onset
of the disease. No distinction is made as to whether this
is as a result of the disease itself, comorbid conditions, or
as a result of therapy as not infrequently it is difficult to
differentiate between these. It has been agreed that for
changes to constitute damage they must have been present for at least 6 months (or the pathology that lead to the
feature must have been present for at least 6 months). A
comprehensive organ-based assessment is made including: muscle, skeletal (joints and damage as a result of
osteoporosis), mucocutaneous, pulmonary, cardiovascular, peripheral vascular, gastrointestinal, endocrine, ocular, and infection. Malignancy and death are also recorded.
We have also assessed the interrater reliability of this tool
(unpublished). The between rater reliability for the
damage index was fair. In most systems, the ICC was >
0.7. The agreement in the cardiovascular, peripheral vascular disease, malignancy was relatively low. The agreement for the VAS for the damage index was generally
good except for peripheral vascular disease. The agreement for the global VAS for the damage index was very
good ICC > 0.8.
Assessment of health related quality of life
No disease outcome assessment would be complete
without an assessment of the patients’ perception of
their disease. Various health related quality of life (HRQOL) measures are available, but none have been validated in IIM. The Nottingham Health Profile [20] and
the Short Form-36 [18] have been used in IIM. The
IMACs group has suggested using the SF-36 as it has
been extensively validated in other rheumatic diseases
and its use has been widespread.
8
White GH, Tideman PA: Increased Troponin I in a patient with dermatomyositis. Clin Chem 2001, 47:1130–1131.
9
Pachman LM, Sundberg J, Maduzia , et al.: Sequential studies of nailfold capillaries vessels in 10 children with juvenile dermatomyositis: correlation with
disease activity score but not von Willebrand factor antigen. Arthritis Rheum
1996, 38(suppl):360.
10
Akira M, Hara H, Sakatani M: Interstitial lung disease in association with polymyositis-dermatomyositis: long-term follow-up CT evaluation in seven patients. Radiology 1999, 210:333–338.
11
Tazelaar HD, Viggiano RW, Pickersgill J, et al.: Interstitial lung disease in
polymyositis and dermatomyositis: clinical features and prognosis as correlated with histologic findings. Am Rev Respir Dis 1990, 141:727–733.
12
Kourakata H, Takada T, Suzuki E, et al.: Flow cytometric analysis of bronchoalvelar lavage fluid cells in polymyositis/dermatomyositis with interstitial pneumonia. Respirology 1999, 4:223–228.
13
Park JH, Olsen NJ, King L, et al.: MRI and P-31 magnetic resonance spectroscopy detect and quantify muscle dysfunction in the amyopathic and myopathic variants of dermatomyositis. Arthritis Rheum 1995, 38:68–77.
14
Pachman LM, Crawford S, Morrelo F, et al.: MRI directed muscle biopsy for
assessment of juvenile dermatomyositis response to therapy: comparison on
initial and follow up biopsies using histological rating scale evaluating disease
severity/chronicity. Arthritis Rheum 1996, 38(suppl):360.
Conclusion
In conclusion, much progress has been made in developing a consensus as to the combination of assessments
that would best define disease activity and damage in
patients with IIM. Further studies are underway to assess the validity and reliability of these assessment tools.
•
Of special interest
••
1
Kendall FP, McCreary EK, Povance PG: In Muscles: Testing and Function,
edn 4. Baltimore: Williams and Wilkins: 1993.
2
Hinder KA, Hinderer SR: Muscle strength development and assessment in
children and adolescents. In Muscle Strength. Edited by Harms-Ringdahl K.
Edinburgh: Churchill Livingstone; 1993: 93–140.
15
Dorph C, Nennesmo I, Lundberg I: Percutaneous conchotome muscle biopsy: a useful diagnostic and assessment tool. J Rheumatol 2001, 60:423–
426.
3
Rider LG, Giannini EH, Harris-Love M, et al.: Defining clinical improvement in
adult and juvenile myositis. J Rheumatol 2003, 30:603–617.
••
An excellent and comprehensive review of measures used to define disease activity
and damage to date. It ties together the evidence for the current use of measures
and efforts to standardize these outcome measures for use in clinical trial.
16
Miller FW, Rider LG, Chung YL, et al.: Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies. Rheumatol 2001, 40:1262–1273.
17
Rider LG: Outcome assessment in the adult and juvenile idiopathic inflammatory myopathies. Rheum Dis Clin North Am 2002, 28:935–977.
Sultan SM, Ioannou Y, Moss K, Isenberg DA: Outcome in patients with idiopathic inflammatory myositis: morbidity and mortality. Rheumatology 2002,
41:22–26.
4
Escolar DM, Henricson EK, Mayhew J, et al.: Clinical evaluator reliability for
quantitative and manual muscle testing measures of strength in children.
Muscle Nerve 2001, 24:787–793.
18
5
Watkins MP, Harris BA: Evaluation of skeletal muscle performance. In Muscle
Strength. Edited by Harms-Ringdahl K. Edinburgh: Churchill Livingstone;
1993: 19–36.
19
•
6
Rider LG, Miller FW: Laboratory evaluation of the inflammatory myopathies.
Clin Diagn Lab Immunol 1995, 2:1–9.
7
Bodor GS, Survant L, Voss EM, et al.: Cardiac troponin T composition in
normal and regenerating human skeletal muscle. Clin Chem 1997, 43:476–
484.
Isenberg DA, Allen E, Farewell V, et al.: International consensus outcome
adult onset disease. Rheumatology 2004, 43:49–54.
A remarkable international effort to standardize the reporting of outcome in IIM. The
first workshop report assessing the reliability of the activity and damage index.
20
Chung YL, Houssien DA, Scott DL: Health status in inflammatory muscle
disease. Arthritis Rheum 1997, 40(suppl):S115.
Clinical assessment in juvenile idiopathic inflammatory
myopathies and the development of disease activity and
damage tools
Clarissa Pilkington
Purpose of review
In the past few years, adult and pediatric experts in the field
have combined their skills to achieve major advances in clinical
research on pediatric inflammatory myopathies. As rare
diseases, it has become recognized that international trials are
needed to assess drug treatments and their long-term
sequelae. Tools for assessing specific aspects of disease are
available and have been studied to better understand their
performance strengths and limitations. These tools have been
incorporated into disease activity and damage scores that
have been developed by international consensus and are now
being evaluated.
Recent findings
This review focuses on the tools whose evaluations have been
published in the past year and includes methods to assess
muscle strength and function in children with myositis. Two
international collaborative efforts have focused on disease
activity and damage assessments, and their findings are
discussed. Some papers highlighting further diagnostic
investigations are also reviewed.
Summary
The standardization of assessment tools has enormous
implications for future clinical practice: (1) Clinicians who are
not experienced in these rare disorders will be able to evaluate
their patients appropriately and highlight important clinical
signs that are of prognostic importance. (2) International drug
trials can be undertaken and thus improve our understanding
of the impact of medication on the disease process. (3)
Follow-up studies can be undertaken with sufficient numbers
of patients to answer questions about the long-term sequelae
of the disease and its treatments.
Keywords
inflammatory myopathies, juvenile dermatomyositis, disease
activity, disease damage
Great Ormond Street and University College London Hospitals and Juvenile
Dermatomyositis Research Centre, Institute of Child Health, London, United
Kingdom
The author thanks the Cathal Hayes Research Foundation for supporting her
involvement in this international work.
Correspondence to Clarissa Pilkington, MD, Institute of Child Health, Department
of Rheumatology (JDRC), 30 Guilford Street, London WC1N 1EH, UK
Tel: 0207905 2667; fax: 0207905 2672; e-mail: c.pilkington@ich.ucl.ac.uk
Abbreviations
CHAQ
CMAS
JDM
Childhood Health Assessment Questionnaire
Childhood Myositis Assessment Scale
juvenile dermatomyositis
1040–8711
Introduction
Juvenile dermatomyositis (JDM) is the most common of
the juvenile-onset inflammatory myopathies. Even so, it
is a rare disease with a reported incidence of approximately three cases per million children [1•,2]. Most general pediatricians in a district general hospital may only
see two cases during their working lives, and many pediatric rheumatology centers will only see three or four
new cases in a year. This makes it difficult for doctors to
gain enough expertise through clinical experience of
their own patients to further the understanding of this
“orphan disease.” As such, it is impossible for research to
move forward without collaboration.
In the past few years, there has been an increasing collaborative effort between adult and pediatric rheumatologists, neurologists, and dermatologists to pool expertise and develop assessment tools. Over the past year,
there have been several papers published as a result of
these collaborations.
Inflammatory myopathies in childhood include JDM
overlap syndromes (such as JDM- scleroderma overlap)
and the extremely rare polymyositis. The prognosis for
JDM before the introduction of steroids was a 33% mortality rate, with 33% of the survivors being left with a
severe disability [3]. There have been no double-blind
trials on the use of corticosteroids, but the mortality rate
has been reduced to less than 10% [4]. More aggressive
treatment is associated with improved outcomes [5].
However, there are still patients who do not respond to
first-line treatments and continue to have active disease.
Newer treatments are available, but physicians need to
be able to evaluate outcome data to select which treatments are most suitable for individual cases. To compare
the effectiveness of drug treatments, there needs to be
a standardized set of tools for measuring and assessing
disease activity. The hope of all physicians is to control
673
disease activity, reduce the length of the disease process,
and prevent accumulation of damage from the disease or
its treatments. Outcome studies are needed to allow physicians to evaluate the risks and benefits of differing
treatments: these need standardized disease damage assessment indices to allow multicenter research.
Another element in the process of researching rare diseases is the need to “collect” sufficient numbers for
studying. Again, there has been an increase in the collaborative efforts of clinicians caring for these diseases,
and registries have been set up. In the United States,
there is the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Juvenile Dermatomyositis Research Registry; and in the United Kingdom
and Ireland, there is the Juvenile Dermatomyositis National Registry and Repository.
Incidence of juvenile dermatomyositis
The reported incidence of JDM varies from 1.9 to 4.2
cases per million children [6,7]. These reports have been
derived by extrapolating from the study of cases from
referral centers, apart from the 1995 United Kingdom
study, which was a nationwide study over the course of 1
year [7]. However, the incidence may vary from one year
to another and between different racial groups. The National Institute of Arthritis and Musculoskeletal and Skin
Diseases study [1•] used two registries in a two-source
capture–recapture analysis to estimate as accurately as
possible the annual incidence of JDM in the United
States between 1995 and 1998. It also looked at the incidence within different racial groups. Their findings are
reproduced in Table 1. This demonstrates that the incidence rate varies between years with an average of 3.2
per million children per year. Breakdown by ethnicity
showed that Hispanics had a slightly lower incidence (2.7
per million) than white non-Hispanics (3.4 per million)
and African-American non-Hispanics (3.3 per million).
Therefore, future epidemiologic studies will need to
take race and variations between years into account.
Pediatric rheumatology assessment tools
Classic JDM has a characteristic rash and symmetric
proximal muscle weakness [8]. It may have an associated
vasculitis that can affect multiple organs and result in
skin ulceration and calcinosis. In the assessment of JDM,
there needs to be assessments of multiple systems
Table 1. Juvenile dermatomyositis (2–17 years of age)
incidence estimates in the United States
Year
1995
1996
1997
1998
Average
Adapted from [1].
Incidence per million
95% CI
4.1
2.5
2.7
3.4
3.2
3.1–5.1
2.1–2.9
2.5–3.0
2.6–4.3
2.9–3.4
(muscle strength, skin, pulmonary function, gastrointestinal disease) and the effect of the disease on the child’s
overall function.
The assessment of muscle strength in children using
manual muscle testing has been previously reviewed as
part of a review of clinical assessment and investigation
of JDM [9]. There is no recognized tool for comprehensively assessing skin disease, although it is a recognized
component in the disease activity scores. It is recognized
that ulcerative skin disease is a sign associated with a
poor prognosis [10]. Some centers use this as one of the
criteria for more aggressive treatment regimens such as
the use of cyclophosphamide [11]. There has been debate about nailfold capillaroscopy in childhood rheumatic disease and the meaning of the findings in relation
to disease activity [12], but more work needs to be done
before its routine use in clinical assessments can be recommended.
Assessment of pulmonary involvement
The strength of muscles affecting speech, swallowing,
and respiration also needs to be assessed. Abnormalities
cannot always be elicited by questioning: swallowing
problems may result in severe aspiration on videofluoroscopy and yet be asymptomatic (personal experience)
[9]. Aspiration can lead to secondary lung changes that
can be seen early on a high-resolution CT scan. Later,
changes become apparent on chest x-ray. Chest CT
scans will also pick up signs of interstitial lung disease,
and lung function tests with carbon monoxide diffusion
measurements are helpful [13].
MRI scan
Muscle biopsies and electromyographies are considered
too invasive or painful by many pediatricians, and MRI
scans are used instead (Brown, Personal communication,
June 2004). MRI scans do pick up muscle inflammation
and demonstrate the patchy nature of the inflammation
seen within muscles. It has a predictive power similar to
that of muscle biopsies [14] and can distinguish between
active disease and inactive disease [15]. Muscle biopsy is
still considered the gold standard, but it is not always
positive, even in cases in which the diagnosis is not in
doubt. Recent studies have suggested that the use of
immunologic stains for increased expression of the major
histocompatibility complex class I protein may reduce
the false-negative rate in adults [16] and children [17].
Childhood Health
Assessment Questionnaire
The child’s function can be assessed using the Childhood Health Assessment Questionnaire (CHAQ) [18].
This has been validated in both juvenile idiopathic arthritis [19] and JDM [18]. It is one of the most widely
used health questionnaires in pediatric rheumatology
and has been translated into many languages.
Assessment in juvenile idiopathic inflammatory myopathies Pilkington 675
Validation of the Childhood Myositis
Assessment Scale
The Childhood Myositis Assessment Scale (CMAS) was
developed to assess muscle strength and endurance in
children with myositis [20]. It is a 14-item observational
tool that is easy to use, gives a numerical score out of a
total of 52, and takes approximately 10 to 15 minutes to
complete. It does not require sophisticated equipment.
It measures a child’s muscle strength, physical function,
and endurance. Its limitations are that it is difficult to
perform in young children younger than 4 years old. It
can also be limited by contractures, which make some of
the maneuvers difficult even when the muscle strength
is normal. It has been validated in JDM [21] and has
become widely used by the pediatric rheumatology community. However, more needs to be known about its
properties if it is to be used as one of the standardized
assessment tools by specialists and nonspecialists. Recent work has been undertaken to validate the CMAS by
the Juvenile Dermatomyositis Disease Activity Collaborative Study Group, which includes pediatric rheumatologists from Canada and the United States [22••]. In
this multicenter study, 108 juvenile idiopathic inflammatory myopathy patients (98 JDM, six juvenile polymyositis, and four myositis with connective tissue diseases)
were assessed twice at an interval of 7 to 9 months.
Within this group, 26 patients were evaluated on the
same day by two examiners. The results showed that the
CMAS had very good interrater reliability (intraclass correlation of 0.89) and good construct validity.
Childhood Myositis Assessment
Scale correlations
The CMAS correlated well with the CHAQ and manual
muscle testing, as was predicted: all three measure
muscle strength or a function of muscle strength. The
CMAS correlated moderately with assessments of overall
disease activity (physician Visual Analogue Score, parental Visual Analogue Score), again as was predicted, because muscle strength does not always correlate directly
with muscle inflammation or extraskeletal manifestations of disease. In fact, the data suggested that the
CMAS and manual muscle testing were nonredundant
(i.e., did not measure exactly the same properties),
whereas the CMAS and CHAQ measure very similar
properties (i.e., function), and thus one of the two may be
redundant.
In practice, most clinicians would expect to use all three
as the CHAQ includes the parent/patient perception of
well-being, and this does not always correlate directly
with the clinician’s view. Parents may not realize the
severity of their child’s condition at the time of diagnosis
or may have difficulties in separating psychological problems from disease activity during convalescence. Conversely, clinicians may underestimate the effect of the
disease on an individual child and his or her family. The
CHAQ is also known to have limitations with a “floor
effect”: children with no disease and children with mild
disease either score 0 or close to 0. For these reasons, all
three need to be included in an assessment of a patient
with JDM.
Whenever a unit or center takes up a new tool, it takes
time for the assessors to become familiar with it and to be
able to interpret what the final score actually means clinically and what constitutes a clinically meaningful
change. An important aspect of this work was to look at
the “minimum clinically important difference,” and to
evaluate the correspondence between scores and physical dysfunction. This was only preliminary work, but it
suggested that a change in CMAS score of 1.5 correlated
with a change in CHAQ score of 0.13. The corresponding
CHAQ values and disability levels taken from a juvenile
idiopathic arthritis study [23] are shown in Table 2.
Disease activity tools
Disease Activity Score
A disease activity tool needs to evaluate all the organs
that can be affected by the disease. In both adults and
children, dermatomyositis primarily affects the muscles
and the skin. However, it can be a multisystem disease
with widespread vasculopathy including the gastrointestinal tract, lungs, and central nervous system. This diversity is seen more often in children than in adult patients. Until recently, there were no widely available
disease activity assessment tools. Some centers developed their own, and the one used by the Chicago group
(Division of Immunology/Rheumatology at Northwestern’s Children’s Memorial Hospital) was published in
early 2003 [24•]. This has been called the Disease Activity Score and gives a score from 0 to 20. The items
evaluating muscle and skin disease are given equal
weighting. The score does not include any serologic
markers or any evaluation of gastrointestinal, pulmonary,
or neurologic problems. It can be done in any clinical
setting because it does not require any investigative
equipment.
Three pediatric rheumatologists assessed 44 patients
with a total of 58 visits. At one visit, two of the three
clinicians separately assessed 29 patients, and on a further visit, one of the original two clinicians and a third
Table 2. Relationship between CHAQ values and physical
disability in JIA and corresponding CMAS values in JDM
CHAQ values
(95% CI)
Physical disability
in JIA
Equivalent CMAS
scores (95% CI)
0.00 (−0.07, 0.07)
0.24 (0.14, 0.35)
0.71 (0.52, 0.91)
1.53 (0.96, 2.10)
None
Mild
Mild-moderate
Moderate
48 (47.2–48.8)
45 (43.7–46.3)
39 (36.4–41.6)
30 (22.8–37.2)
CHAQ, Childhood Health Assessment Questionnaire; CMAS,
Childhood Myositis Assessment Scale; JIA, juvenile idiopathic arthritis.
clinician again assessed 29 patients (some patients being
present at both visits). The estimated disease activity
measures were affected by the sensitivity of the individual raters to the presence or absence of skin signs.
This suggests the need for clearer descriptions of the
skin indicators to improve interrater reliability.
International Myositis Assessment and Clinical
Studies Group
The International Myositis Assessment and Clinical
Studies Group brought together international experts
from the adult and pediatric arenas to develop disease
activity and damage tools for myositis using the experience gained from the development of similar tools in
patients with lupus erythematosus. Two activity and two
damage tools [25•,26] were produced: the Myositis Intention to Treat Activity Index and the Myositis Disease
Activity Assessment (by Visual Analogue Scale) for disease activity, with the Myositis Damage Index and the
Myositis Disease Damage Assessment (by Visual Analogue Scale) for damage. The disease activity tools assess
the presence and extent of activity in seven systems:
constitutional, articular, cardiac, pulmonary, gastrointestinal, cutaneous, and skeletal muscle. The damage tools
identify the presence and severity of damage within the
systems. The reliability of the tools and interrater reliability were assessed as fair to good for initial real patient
exercises involving experts in myositis and patients with
myositis. These tools are now undergoing further multicenter validation studies.
Paediatric Rheumatology International
Trials Organisation
A different approach was taken to produce core sets of
measures for disease activity and damage [27••] for JDM
by the Paediatric Rheumatology International Trials Organisation in collaboration with the Pediatric Rheumatology Collaborative Study Group (an American and Ca-
nadian group). Two questionnaire surveys were sent to
267 clinicians from 46 countries asking them to select
and rank response variables that they used for assessing
clinical response. Forty experienced pediatric rheumatologists from 34 countries then attended a consensus
conference. They selected the domains and variables to
be included in the preliminary disease activity and damage core sets for JDM and juvenile systemic lupus erythematosus [28].
• The domains for disease activity included the physician’s global assessment (Visual Analogue Scale or
Likert Scale), muscle strength assessment (CMAS or
manual muscle testing), functional ability assessment
(CHAQ), muscle enzymes, global assessment by
parents/patients, and a global JDM disease activity
tool (Disease Activity Score or Myositis Intention to
Treat Index/Myositis Disease Activity Assessment
Visual Analogue Scale).
• The domains for disease damage included the physician’s global assessment (Visual Analogue Scale or
Likert Scale), muscle strength assessment development, and a global JDM disease damage tool (Myositis Intention to Treat Index/Myositis Disease Damage Assessment Visual Analogue Scale).
The activity core set is very similar to that proposed by
the International Myositis and Clinical Studies Group
(Table 3). However, both the activity and damage core
sets include both muscle strength and functional assessments: they cannot by themselves distinguish between
the two. Previous damage (such as contractures) can interfere with activity assessments [28], and clinicians can
have difficulty separating activity from damage. This difficulty was thought to make a parent’s global assessment
of damage too unreliable. A further complicating factor is
that many features considered by adult physicians to be
damage (e.g., calcinosis) are reversible in children. There-
Table 3. Comparison of proposed sets of measures for disease activity in juvenile dermatomyositis from two
international collaborative efforts
Target population
Domain
Physician’s assessment
Muscle strength
Laboratory measurement
Functional ability
Patient/parent assessment
Global disease activity tool
Extramuscular disease
PRINTO [27••]
IMACS [25,26]
JDM
All pediatric IIM
Physician’s global assessment of disease activity by
VAS or Likert Scale
CMAS, MMT
CK, LDH, aldolase, ALT, AST
CHAQ
Patient/parent global assessment of overall well-being
using VAS or Likert Scale
DAS or MDAA
—
Physician’s global assessment of disease activity by VAS
or Likert Scale
MMT
At least 2 of CK, LDH, aldolase, ALT, AST
CHAQ, and CMAS
—
—
MDAA
PRINTO, Paediatric Rheumatology International Trial Organisation; IMACS, International Myositis Assessment and Clinical Studies Group; JDM,
juvenile dermatomyositis; IIM, idiopathic inflammatory myopathies; VAS, Visual Analogue Scale; CMAS, Childhood Myositis Assessment Scale;
MMT, manual muscle testing; CK, creatine kinase; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; AST, aspartate aminotransferase;
CHAQ, Childhood Health Assessment Questionnaire; DAS, Disease Activity Score; MDAA, Myositis Disease Activity Assessment (which
combines the Myositis Disease Activity Assessment by VAS and the Myositis Intention to Treat Activity Index tools).
Published with permission [29•].
Assessment in juvenile idiopathic inflammatory myopathies Pilkington 677
fore, a slightly different definition of damage is needed
in pediatric cases.
The same groups through a large-scale international collection from the follow-up of patients with JDM are now
prospectively validating these core sets.
Conclusion
The willingness of the international community to collaborate is allowing clinical research on JDM to progress
at an exciting rate. Validating assessment tools for standardized rating of the different aspects of disease activity
will allow multicenter studies to flourish. Building these
into tools assessing disease activity and disease damage
will allow international drug trials to be undertaken.
Once these tools have been validated, it will be important to move forward and conduct these studies because
they will determine which treatments are the most effective and so will directly benefit patient care.
11
Riley P, Maillard SM, Wedderburn LR, et al.: Intravenous cyclophosphamide
pulse therapy in juvenile dermatomyositis. A review of efficacy and safety.
Rheumatology Oxford) 2004, 43:491–496.
12
Dolezalova P, Young SP, Bacon PA, et al.: Nailfold capillary microscopy in
healthy children and in childhood rheumatic diseases: a prospective single
blind observational study. Ann Rheum Dis 2003, 62:444–449.
13
Kobayashi I, Yamada M, Takahashi Y, et al.: Interstitial lung disease associated with juvenile dermatomyositis: clinical features and efficacy of cyclosporin A. Rheumatology Oxford) 2003, 42:371–374.
14
Kimball AB, Summers RM, Turner M, et al.: Magnetic resonance imaging detection of occult skin and subcutaneous abnormalities in juvenile dermatomyositis: implications for diagnosis and therapy. Arthritis Rheum 2000,
43:1866–1873.
15
Maillard SM, Jones R, Owens C, et al.: Quantitative assessment of MRI T2
relaxation time of thigh muscles in juvenile dermatomyositis. Rheumatology
2004, 43:603–608.
16
Civatte M, Schleinitz N, Krammer P, et al.: Class I MHC detection as a diagnostic tool in non-informative muscle biopsies of patients suffering from dermatomyositis. Neuropathol Appl Neurobiol 2003, 29:546–552.
17
Li CK, Varsani H, Holton JL, et al.: MHC class I overexpression on muscles in
early juvenile dermatomyositis. J Rheumatol 2004, 31:605–609.
18
Feldman BM, Ayling-Campos A, Luy L, et al.: Measuring disability in juvenile
dermatomyositis: validity of the childhood health assessment questionnaire.
J Rheumatol 1995, 22:326–331.
19
Singh G, Athreya BH, Fries JF, et al.: Measurement of health status in children
with juvenile rheumatoid arthritis. Arthritis Rheum 1994, 37:1761–1769.
20
Lovell DJ, Lindsley CB, Rennebohm RM, et al.: Development of validated
disease activity and damage indices for the juvenile idiopathic inflammatory
myopathies. II. The Childhood Myositis Assessment Scale (CMAS): a quantitative tool for the evaluation of muscle function. The Juvenile Dermatomyositis Disease Activity Collaborative Study Group. Arthritis Rheum 1999,
42:2213–2219.
21
Lovell DJ, Giannini EH, Rider L, et al.: Validation and rater reliability of the
childhood myositis assessment scale for the juvenile myositis collaborative
study group [abstract]. Arthritis Rheum 1996, 38(suppl):S183.
22
••
Huber AM, Feldman BM, Rennebohm RM, et al.: Validation and clinical significance of the Childhood Myositis Assessment Scale for assessment of
muscle function in the juvenile idiopathic inflammatory myopathies. Arthritis
Rheum 2004, 50:1595–1603.
A good paper on clinical functions of CMAS.
23
Dempster H, Porepa M, Young N, et al.: The clinical meaning of functional
outcome scores in children with juvenile arthritis. Arthritis Rheum 2001,
44:1768–1774.
24
•
Bode RK, Klein-Gitelman MS, Miller ML, et al.: Disease activity score for children with juvenile dermatomyositis: reliability and validity evidence. Arthritis
Rheum 2003, 49:7–15.
Acknowledgment
The author thanks Dr. L. Wedderburn and S. Arscott for their careful reading of the
manuscript, V. Brown and A. Juggins for their help in preparing this manuscript, and
international colleagues for their invaluable cooperation.
•
Of special interest
••
1
•
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and Musculoskeletal and Skin Diseases Registry. Arthritis Rheum 2003,
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2
Cassidy JT, Petty RE: Juvenile dermatomyositis. In Textbook of Pediatric
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Bitnum S, Daeschner CW Jr, Travis LB, et al.: Dermatomyositis. J Pediatr
1964, 64:101–131.
4
Spencer CH, Hanson V, Singsen BH, et al.: Course of treated juvenile dermatomyositis. J Pediatr 1984, 105:399–408.
25
•
5
Fisler RE, Liang MG, Fuhlbrigge RC, et al.: Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence
of calcinosis. J Am Acad Dermatol 2002, 47:505–511.
Isenberg DA, Allen E, Farewell V, et al.: International consensus outcome
adult onset disease. Rheumatology Oxford) 2004, 43:49–54.
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Oddis CV, Conte CG, Steen VD, et al.: Incidence of polymyositis-dermatomyositis: a 20-year study of hospital diagnosed cases in Allegheny County,
PA 1963–1982. J Rheumatol 1990, 17:1329–1334.
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9
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Wedderburn LR, Li CK: Paediatric idiopathic inflammatory muscle disease.
Best Pract Res Clin Rheumatol 2004, 18:345–358.
A good review of JDM.
Use of imaging to assess patients with muscle disease
David L. Scotta,b and Gabrielle H. Kingsleya,c
Purpose of review
A variety of imaging modalities can be used in muscle
diseases. These range from plain x-rays to conventional
magnetic resonance imaging (MRI) and phosphate magnetic
resonance spectroscopy (MRS). This review places these
imaging methods into their relevant clinical contexts on the
basis of the best available research evidence.
Recent findings
Plain x-rays have limited roles in imaging patients with muscle
disease. An exception is identifying calcinosis in patients with
myositis; there is some evidence that effective early treatment
may reduce its frequency and severity. Scintigraphy has been
used in several centers but it appears to have limited value.
Ultrasound, though successfully used in a number of units, is
relatively little used, though the evidence suggests it would be
sensible if this method were adopted more widely. MRI is
currently the key imaging modality. It is useful in diagnosing
pyomyositis, diabetic muscle infarction, and inflammatory
myositis. Its main proven value is identifying the best sites for
biopsy in early myositis, though it can help differentiate
between different forms of muscle disease when there is
diagnostic uncertainty. The area of most intense ongoing
original research is MRS, which can show the bioenergetics of
normal and abnormal muscles. Changes in the ratios of
inorganic phosphate and phosphocreatine, particularly during
exercise provide insights into the metabolic consequences of
muscle diseases and may, in the future, suggest alternative
therapeutic approaches.
Summary
Magnetic resonance imaging is a useful adjunct when
diagnosing muscle diseases. It is particularly useful to identify
suitable sites for muscle biopsy. Ultrasound may be equally
helpful, though there is less supporting evidence from existing
research. MRS is the area in which most current novel
research is focused.
Keywords
dermatomyositis, polymyositis, ultrasound, magnetic resonance
imaging, magnetic resonance spectroscopy
a
Department of Rheumatology, GKT School of Medicine, Weston Education
Centre, Kings College, London, UK; bDepartment of Rheumatology, Kings College
Hospital, Denmark Hill, London, UK; and cDepartment of Rheumatology, University
Hospital Lewisham, Lewisham High Street, London, UK
Correspondence to David Scott, Department of Rheumatology, GKT School of
Medicine, Weston Education Centre, Kings College, 10 Cutcombe Road, London
SE5 9RS, UK
Tel: 44 (0)207 848 5215; fax: 44 (0) 207 848 5202;
e-mail janice.jimenez@kcl.ac.uk
678
1040–8711
Introduction
Imaging methods currently only have subsidiary roles in
the diagnosis and assessment of muscle diseases. Such
limited roles contrast with their central importance in
other forms of musculoskeletal disease, in particular inflammatory synovitis. This situation is likely to change in
the future as technical developments in imaging methods increase their scope and value.
A range of imaging methods has been used in muscle
disease. Some methods, including plain x-rays, computerized tomography (CT), and scintiscans, have circumscribed roles, which are unlikely to develop significantly
in the foreseeable future. Other methods, in particular
ultrasound scans, magnetic resonance imaging (MRI),
and the associated technique of magnetic resonance
spectroscopy (MRS) are of relatively intense research interest and they are likely to develop substantially in future years. This review highlights the main uses of imaging in muscle diseases and places the most recent
research into an historical context.
Range of muscle diseases
Myositis ossificans
This disorder is characterized by muscle calcification,
and usually follows trauma [1]. It mainly involves thighs
and upper arms, with pain, loss of movement, and swelling. One rare variant is myositis ossificans progressiva [2],
a hereditary disorder of unknown cause.
Pyomyositis
Abscess formation deep within large muscles [3] spreads
from soft tissue infections or through the blood. It is
especially a problem in immunocompromised patients. It
mainly involves quadriceps and upper arms causing pain,
edema, and fever. In the initial nonsuppurative phase,
pyomyositis responds to antibiotics alone. When pus is
present, drainage is mandatory.
Muscle infarction
Occasional patients with diabetes mellitus develop
muscle infarction [4], especially if poorly controlled. It is
characterized by sudden, severe muscle pain and tender-
Imaging and muscle disease Scott and Kingsley 679
ness, sometimes with a palpable mass; the thighs are
mainly involved. Treatment is symptomatic and conservative because most cases resolve spontaneously.
Idiopathic inflammatory myositis
Polymyositis and dermatomyositis are characterized by
inflammatory and degenerative changes in the muscles
and skin in dermatomyositis [5]. They result in symmetrical weakness and muscle atrophy, principally of the
limb girdles. Their onset varies from acute to insidious.
The first symptom is often proximal muscle weakness or
rash. Muscle tenderness and pain are less marked. Rash,
polyarthralgias, Raynaud’s phenomenon, dysphagia, pulmonary disease, and constitutional complaints such as
fatigue often occur. Muscle weakness is only obvious
when there is substantial destruction of muscle fibers.
Diagnosis depends on proximal muscle weakness, the
characteristic rash, elevated serum muscle enzymes,
muscle biopsy changes, and electromyographic abnormalities.
Inclusion body myositis is a chronic disorder of unknown
cause characterized by progressive muscle weakness and
wasting that usually affects older people [6,7]. Unlike
dermatomyositis and polymyositis it also affects distal
muscles, with weakness of wrist and finger muscles. The
pathology includes inflammatory infiltrates, intracellular
degenerative changes, and abnormal mitochondria,
which include the presence of ragged red fibers, paracrystalline inclusions, and heterogeneous deletions of
mitochondrial DNA [8,9]. The inflammation usually
does not respond to conventional immunotherapy.
Plain x-rays
Calcinosis
Subcutaneous calcinosis is uncommon; a recent survey of
35 patients with juvenile dermatomyositis identified five
(14%) patients with radiologic calcinosis [10]. A retrospective review of juvenile dermatomyositis [11] showed
that calcinosis was associated with delays in starting
treatment, prolonged elevations of muscle enzymes,
and long disease durations. Aggressive treatment that
achieved rapid and complete control of muscle inflammation reduced the risk of developing calcinosis. Calcification in myositis is not just subcutaneous; one recent
report described periarticular calcification in early polymyositis [12].
Myositis ossificans
As imaging is an inherent part of diagnosis, it is often
mentioned in case reports. Examples include the development of myositis ossificans presenting as groin pain in
soccer players [13] and the apparently successful use of
alendronate to treat a young man who developed myositis ossificans after strenuous physical activity [14].
Scintigraphy
Several units have evaluated scintigraphy in myositis; all
initially reported encouraging results. Several techniques
were described including 99mTc-MDP (methylendiphosphate) scintigraphyl [15], 111-indium altumomab
pentetate-labeled antimyosin [16], and 99mtechnetiumpyrophosphate muscle. However, this approach has not
developed greatly. Although a further recent report describes an alternative scintigraphic approach—using Ga67 scintigraphy to evaluate polymyositis—no technique
has yet been widely adopted.
Ultrasound
Kane et al. [17•] reviewed ultrasound in muscle diseases
and other musculoskeletal conditions. They concluded it
is useful in diagnosing inflammatory muscle disease,
though MRI is more sensitive in detecting edema. Ultrasound is also able to image myositis ossificans, pyomyositis, and infarction in diabetes mellitus [18] together
with calcium deposits in dermatomyositis. One report
compared ultrasound with MRI in 12 children with pyomyositis [19•]. Both modalities showed characteristic
changes of pyomyositis. Ultrasound was preferable for
imaging the extremities, but in the pelvis, MRI was better. It was also best for differentiating pyomyositis from
osteomyelitis.
Magnetic resonance imaging
and spectroscopy
Proton-based MRI methods are standard and a few centers also use phosphate imaging. MRI shows inflammation, edema, fibrosis, fatty infiltration, and calcification.
Degeneration of muscle fibers themselves cannot be
shown directly on MRI. Muscle edema and inflammation give relatively normal appearances in T1 and protondensity weighted images and high-signal intensities on
T2-weighted fat- or non-fat-saturated sequences. It may
be difficult to differentiate edema from inflammation on
MRI. Magnetic resonance spectroscopy (MRS) records
similar data to MRI but presents it in a different manner,
indicating the amount of specific chemical entities by
their resonance in a defined volume of tissue.
Pyomyositis
One recent review [20] concluded ultrasound, CT, and
MRI are all valuable in diagnosis and directing therapy,
including drainage. CT is better for monitoring progress;
in advanced disease, it shows the extent of destructive
changes. Case reports highlight the value of CT; for example, a young boy with complement deficiency who
developed pyomyositis of the psoas [21] and a teenager
in the early stage of pyomyositis in whom CT showed
inflammation in the sternocleidomastoid muscle [22].
Tuberculous myositis is a rare and challenging problem,
and a recent review of 35 cases [23] showed that CT or
MRI were identified features suggestive of tuberculous
myositis in 15 patients (43%).
Muscle infarction
Kapur et al. [24•] reported one case and reviewed over
100 other reports, describing clinical experience in 116
cases and pathology in 78 cases of diabetic muscle infarction (Table 1). MRI findings are not pathognomonic,
but there are several characteristic features. These include extensive muscle edema, muscle enlargement,
subcutaneous edema, and interfascial edema. Muscle infarction is a risk in patients with diabetes who have other
disorders. Lentine and Guest [25] describe it as a complication in dialysis patients with diabetic nephropathy.
In these cases isolated skeletal muscle infarction was
shown on MRI.
Myositis
Magnetic resonance imaging defines the extent of anatomic changes. In the acute phase edema is seen using
T2-weighted and/or short tau inversion recovery (STIR)
imaging, and there are normal images using T1-weighted
imaging [26,27]. In chronic disease, when muscular atrophy and fatty infiltration within atrophied muscles are
the dominant features, a combination of T1-weighted
and fat-suppressed images are most relevant. MRI findings in myositis were first described in 13 patients by
Kaufman et al. [28] over 15 years ago. Subsequent studies
in adults [29–31] and children [32–34] confirmed the
specificity of MRI changes. There is one recent report
recommending whole body MRI in myositis [35].
Occasional patients with amyopathic dermatomyositis
have clinical features of dermatomyositis but no clinically detectable myopathy. MRI shows some of these
cases have muscle involvement. In one study of 40 Chinese patients presenting with dermatomyositis, 10 had
amyopathic dermatomyositis [36]; MRI showed abnormal signal intensity in muscles on both T2- and fat suppression sequences in three cases.
Schweitzer et al. [37] examined the cost effectiveness of
MRI as a biopsy guide in 25 patients with suspected
polymyositis; 14 had preoperative MR imaging. In the
patients whose biopsy site was selected using MRI find-
ings there was only one false-negative biopsy compared
with five false-negative biopsies in patients without imaging. Pre-biopsy MRI was associated with reduced
medical costs—$14,000 compared with $20,000—and appeared cost effective.
Recent case series illustrate the benefits of MRI in myositis. Keily et al. [38] described four cases from a series of
78 patients with myositis seen at a single UK center.
They all highlighted the complexities in the presentation and natural history and showed the important and
growing role of MRI in routine care. Maillard et al. [39••]
evaluated MRI in children, studying 10 children with
active dermatomyositis, 10 with inactive disease and 20
healthy controls. MRI T2 relaxation times were increased in active dermatomyositis and MRI scores correlated with muscle strength and function, though they
were unrelated to muscle enzymes.
Dion et al. [40] developed diagnostic imaging criteria for
polymyositis and sporadic inclusion body myositis in a
series of 25 patients each with polymyositis and inclusion
body myositis. MRIs were abnormal in all patients. Fatty
infiltration and atrophy were frequent in inclusion body
myositis. Inflammation as the sole abnormality was preferentially seen in polymyositis. Involvement of the anterior group, an asymmetric distribution, and a distal predominance were all more frequent in inclusion body
myositis. These changes are summarized in Table 2.
This work attracted some subsequent criticism, mainly
related to the limitations of the available diagnostic criteria [41].
Mastaglia et al. [42] in a recent review concluded that
MRI is helpful in confirming the diagnosis and selecting
appropriate biopsy sites, though its diagnostic sensitivity
is not fully evaluated. However, another review by Dalakas and Hohlfeld [43] made little mention of MRI, and
relegated it to having a minor role in occasional cases to
identify inflammatory sites and select the area for biopsy.
It is, at present, uncertain exactly what role MRI should
play in assessing myositis [44].
Table 1. MRI and pathological findings of DMI
Assessment
Findings
MRI
T2 Hyperintense signal of
infarcted muscle
T2 Muscle enlargement
T2 Subcutaneous edema
T2 Subfascial edema
Muscle fiber necrosis
Inflammatory cell infiltrate
Microvascular abnormality
Edema
Hemorrhage
Fibrosis/granulation
Tissue-regenerating
muscle fibers
Histopathology
Adapted from [24].
Number of cases (%)
78/78 (100%)
47/47 (100%)
38/42 (90%)
34/38 (90%)
73/75 (97%)
48/56 (86%)
54/65 (83%)
27/55 (49%)
27/56 (48%)
36/60 (60%)
33/59 (56%)
Magnetic resonance spectroscopy in myositis
Pfleiderer et al. [45••] reported in vivo MRS studies in 10
patients with dermatomyositis and 18 healthy controls.
They evaluated short-term alterations of metabolic parameters in short cycles of submaximal exercise. Pi/PCr
(inorganic phosphate/phosphocreatine) ratios increased
in both patients and controls during exercise. In controls
they rapidly returned to baseline values. However, the
subsequent decrease during the break period was incomplete in patients with dermatomyositis (Fig. 1). Consequently, in dermatomyositis, Pi/PCr did not return to
baseline levels and subsequent rises decreased with each
exercise cycle.
Table 2. MRI evaluation of 22 patients with polymyositis and 25 patients with
inclusion body myositis
Fatty infiltration
Atrophy
Inflammation
Global analysis
Presence of fatty infiltration
Anterior group exclusively
Anterior group (Grade 3 or 4)
All three groups involved
Fascial pattern
Widespread pattern
Asymmetrical
Distal predominance
Presence of atrophy
Anterior group atrophy
Undulating fascia
Presence of inflammation
Inflammation in posterior group
Fascial pattern
Widespread pattern
Asymmetrical
Isolated inflammation
Polymyositis
Inclusion
body
myositis
Significance
68
4
20
44
28
28
4
12
64
16
32
72
32
40
16
8
20
96
40
76
44
8
88
44
64
92
60
64
72
8
20
44
10
0
<0.03
0.0021
0.001
NS
NS
0.0001
0.0009
0.0002
0.02
0.0014
0.02
NS
0.03
NS
0.03
NS
0.05
Adapted from [40].
Magnetic resonance spectroscopy was used to measure
urinary creatine levels in myositis by Chung et al. [46].
Urinary creatine was detected using MRS in 26 of 35
patients with myositis, 4 of 60 cases with other medical
disorders, and 10 of 50 healthy controls. Urinary
Figure 1. Typical Pi/PCr curves for a control case and a
dermatomyositis patient in contrast to controls
creatine/creatinine ratios exceeded 0.4 in 20 patients
with PM/DM but were not seen in any controls.
Future work
Magnetic resonance spectroscopy studies of high energy
phosphate metabolism are being used to understand the
biology of normal muscle, and this may soon impact on
imaging muscle disease. Brosseau et al. [47] studied anaerobic exercise in the dominant and nondominant forearms of sedentary subjects. MRS showed timedependent changes in Pi and PCr concentrations.
Metabolic kinetics in the dominant forearms improved
during repetitive high-intensity exercise compared with
the nondominant forearm muscles. Their findings provide a way of investigating how training may improve
muscle bioenergetics in muscle disease.
Schocke et al. [48] showed PCr hydrolysis during incremental exercises in normal muscles enters a steady state
at different workload levels. In normal subjects creatine
ingestion reduces the initial PCr resynthesis rate after
brief exercise and increases the initial PCr resynthesis
rate after exhaustive exercise, probably as a consequence
of mitochondrial respiration [49]. This work starts to create a rationale for using creatine supplements in muscle
diseases.
In myositis there was a marked increase in Pi/PCr only observed during the first
exercise cycle. The subsequent decrease during the break was incomplete.
Adapted from [45••].
Quantitative phosphate MRS was used to investigate
muscle metabolism in vivo in 9 patients with dermatomyositis and five patients with polymyositis. Postexercise MRS showed muscle oxidative metabolism was impaired in myositis. The phosphocreatine and adenosine
diphosphate recovery half-times were almost twice as
long as in controls. The impairment of high-energy phosphate recovery indices in myositis patients was similar to
that found in cases with a primary mitochondrial disorder
[50].
Conclusion
Conventional imaging currently has a relatively minor
role in imaging muscle disease. In patients with a suspected muscle disease in whom there is diagnostic uncertainty either MRI or ultrasound provides useful
screening tools. In early myositis the balance of evidence
favors obtaining an MRI, particularly as a guide to the
best site for a biopsy. In the future MRS and understanding muscle bioenergetics represent important areas in
which advances are likely to occur.
•
Of special interest
••
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••
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••
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Is it really myositis? A consideration of the
differential diagnosis
Niranjanan Nirmalananthana, Janice L. Holtonb and Michael G. Hannaa,c
Purpose of review
The idiopathic inflammatory myopathies are an important and
treatable group of disorders. However, the potential toxicity
associated with the immune therapeutic regimens used to treat
these disorders may be significant; therefore, accurate
diagnosis before such treatment is essential. The differential
diagnosis is potentially large. Accurate diagnosis usually
depends on a combination of careful clinical assessment in
conjunction with detailed laboratory investigations. Muscle
biopsy remains essential in achieving an accurate diagnosis
that will then guide treatment. This review describes the
diagnostic approach used.
Recent findings
There has been debate over the requirements for an accurate
diagnosis of inflammatory myopathy (i.e., polymyositis and
dermatomyositis). It is increasingly recognized that there can
be clinical and muscle histopathologic overlap between the
features of inflammatory myopathies and those of other muscle
disorders, in particular, the genetic muscular dystrophies.
Pathologic findings of inflammation and major
histocompatibility complex upregulation, although typical of
inflammatory myopathies, have been shown to occur in some
muscular dystrophies, complicating the diagnostic process.
Inclusion body myositis is much less responsive to
immunotherapy and is now recognized as the most common
acquired muscle disease in those older than 50 years of age. It
is likely that genetic muscular dystrophies and inclusion body
myositis account for some cases of apparently
“treatment-resistant” myositis.
Summary
A thorough clinical assessment, including a detailed family
history, complemented by electromyography and creatine
kinase measurements, should be undertaken in any patient
with presumed idiopathic inflammatory myopathy. In addition, a
muscle biopsy remains essential in all cases. A precise tissue
diagnosis confirming features of an active inflammatory
process should be achieved before immunosuppressive
treatment is commenced. An increasing array of
immunocytochemical and histioenzymatic stains now allows a
full analysis and will help to confirm or exclude virtually all the
differential diagnostic possibilities considered in this review.
Electron microscopy may also be valuable in selected cases.
Close collaboration between clinicians and muscle
pathologists is essential in allowing the most accurate
interpretation of myopathologic findings in the clinical context.
Keywords
myositis, inflammatory myopathies, muscular dystrophies,
diagnosis
684
a
Neurogenetics Group, bDivision of Neuropathology, cCentre for Neuromuscular
Disease; Department of Molecular Neuroscience, Institute of Neurology; and
National Hospital for Neurology and Neurosurgery, London, United Kingdom
Correspondence to Michael G. Hanna, MD, Centre for Neuromuscular Disease,
National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N
3BG, UK
Tel: 020 7837 3611; fax: 020 7692 1208; e-mail: m.hanna@ion.ucl.ac.uk
Abbreviations
BMD
CK
DM
DMD
IBM
IIM
LGMD
MHC
PM
Becker muscular dystrophy
creatine kinase
dermatomyositis
Duchenne muscular dystrophy
inclusion body myositis
idiopathic inflammatory myopathy
limb-girdle muscular dystrophy
major histocompatibility complex
polymyositis
1040–8711
Introduction
Myositis is strictly a term that is used to describe infection or inflammation of skeletal muscle. In clinical practice, the term is often used synonymously with the socalled idiopathic inflammatory myopathies (IIMs), a
group of disorders characterized clinically by muscle
weakness (principally proximal) and fatigue and pathologically by mononuclear inflammatory infiltrates in
muscle [1]. The main clinical entities in the group are
dermatomyositis (DM) and polymyositis (PM) [2]. They
are, by definition, considered primary autoimmune diseases directed at as yet unidentified antigens within
skeletal muscle. Inclusion body myositis (IBM) had previously been considered another member of the group of
IIMs, but most investigators now consider this to be a
primary degenerative disease of muscle in which there
may be secondary inflammatory changes [3•].
Making a diagnosis of PM and DM is essential because
of the treatability of these disorders, their association
with malignancy and autoimmune rheumatic disorders,
and the frequency of multisystem involvement. There
are, however, a number of myopathic and neurogenic
disorders that may cause diagnostic difficulty. It is essential that these disorders be differentiated from IIM,
particularly in view of the potential toxicity of immunosuppressive therapy.
This review summarizes the clinical features of IIM, discusses common pitfalls in diagnosis, and briefly considers some of the conditions that may cause diagnostic
confusion.
Is it really myositis? Nirmalananthan et al. 685
Clinical features of
inflammatory myopathies
The clinical features of the inflammatory myopathies
have been reviewed elsewhere [4,5,6••]. PM and DM
are typically of subacute onset and are characterized by
the development of progressive, symmetric, and usually
painless, predominantly proximal muscle weakness. The
weakness generally occurs earlier and is more severe in
the pelvic girdle than the shoulder girdle. IBM is a more
chronic disease, and diagnosis can be delayed by a number of years after symptom onset.
The diagnosis of DM is established by the presence of
weakness associated with a rash on sun-exposed parts,
elevation of creatine kinase (CK) activity, myopathic
electromyographic findings, and a distinctive histopathologic picture. Although the onset is typically subacute,
it can sometimes develop acutely over days. Presentation
without a rash or with a typical rash but no apparent
muscle pathology may occur rarely. The presence of the
rash, however, is virtually pathognomonic of the condition. In children with the rash and muscle weakness, it
may be reasonable not to consider a muscle biopsy in
favor of an MRI scan, but we always perform muscle
biopsies in our adult [older than 16 years] population.
Inclusion body myositis has a more chronic course, and a
selective and asymmetric pattern of muscle involvement
not usually seen in PM or DM may be helpful diagnostically. Patients typically develop wasting of the long
finger flexors and the quadriceps, resulting in frequent
falls. CK elevation is relatively modest and histology is
distinctive. It is also resistant to therapy with conventional immunosuppressive treatments [6••].
Polymyositis is often the most diagnostically challenging
because it lacks characteristic cutaneous manifestations
(compared with DM), a unique distribution of weakness
(compared with IBM) or a completely specific myopathologic appearance. There has recently been much
debate regarding its diagnosis and differentiation from
IBM [4,7••].
The most widely used criteria for the diagnosis of PM
and DM are those of Bohan and Peter [8]. However, in
the 1977 study of Bohan et al. [9], proximal muscle weakness was the presenting symptom in only 69% of patients, CK levels were normal in 5%, and more than 10%
had a normal electromyogram, with many more lacking
the typical triad of features described below. Furthermore, 12.5% of muscle biopsy samples revealed no abnormalities and were atypical in many other patients.
Other more specific criteria have recently been proposed
[4,10].
Depending on the individual case, the history should be
directed to exclude specific alternative diagnoses, with
particular attention to the family history and medication
history. The standard supportive laboratory investigations merit further consideration.
Serologic tests
Although aspartate and alanine aminotransferases, lactate dehydrogenase, and aldolase levels are elevated in
IIM, the most widely used muscle enzyme assay is CK.
This can be elevated as much as 50-fold in PM and DM
but rarely much higher; serum CK that is elevated more
than 100-fold should call the diagnosis into question. In
IBM, the CK is more mildly elevated, as much as fivefold. CK levels may, however, rarely be normal in IIMs,
even in the presence of inflammatory changes found on
biopsy. The explanation for this is unclear but emphasizes the importance of undertaking muscle biopsy and
not relying on CK for diagnostic purposes [11,12]. CK
levels may also fluctuate from day to day (increasing
significantly after major exercise), even in the absence of
any intervention. Furthermore, CK elevation is nonspecific, merely indicating the presence of muscle damage,
and should never be regarded as a diagnostic test. CK is
elevated in muscular dystrophies and in some metabolic
myopathies (particularly if there is any degree of rhabdomyolysis) and although the degree of elevation can be
informative, there is considerable overlap.
A search for autoantibodies may be diagnostically useful
in PM and DM and provide a clue to disease subtype.
Indeed, the absence of a positive antinuclear antibody
and an anti-Jo antibody should also raise doubts about
the diagnosis. Although autoantibodies have been found
in IBM [13,14], they are unusual. They are not associated
with muscular dystrophies or metabolic myopathies, although their presence should not exclude these diagnoses [15]. The presence of acetylcholine receptor antibodies points to a diagnosis of myasthenia gravis.
Electromyography
Electromyographic findings in IIM are not specific and
are useful only insofar as they confirm an active myopathic process. In PM and DM, there is evidence of
increased membrane irritability such as positive sharp
waves, fibrillation potentials, and complex repetitive discharges. Myopathic motor unit action potentials that are
polyphasic and of short duration and low amplitude are
seen. Finally, there is early or rapid recruitment of motor
unit action potentials.
In IBM, there may be additional evidence of neurogenic
changes with prolonged, large-amplitude motor unit action potentials. This can lead to diagnostic confusion
with motor neuron disease [16].
Muscle biopsy
A definitive diagnosis of IIM relies on muscle biopsy,
and erroneous interpretation of a muscle biopsy specimen is probably the most common cause of a clinical
misdiagnosis of IIM [17]. There are many pitfalls in both
the analysis and interpretation of a muscle biopsy specimen, and these have been reviewed [17].
The key myopathologic feature of PM is considered to
be endomysial lymphocytic infiltration. However, similar
infiltration has been reported in Duchenne muscular
dystrophy (DMD) and Becker muscular dystrophy
(BMD) [18], facioscapulohumeral dystrophy [19], limbgirdle muscular dystrophy (LGMD) type 2B [20], and
congenital muscular dystrophy with primary merosin deficiency [21] as well as in IBM. It is therefore very important to also perform appropriate immunocytochemical
staining in all cases to assess for deficiency of any of the
known proteins that cause muscular dystrophies. In addition, genetic testing can be very helpful, such as the
genetic test that is now widely available for facioscapulohumeral dystrophy. In IBM, there are additionally
Congo red–positive amyloid deposits and rimmed vacuoles that represent an important diagnostic clue, and filamentous inclusions are usually present on electron microscopy.
The key myopathologic feature in DM is perivascular B
cell–predominant inflammation associated with microinfarcts and perifascicular atrophy. Muscle inflammation
can, however, be patchy and is affected by the early use
of steroids [22]. In cases in which typical changes are not
found, particular care must be taken to exclude other
possible diagnoses, and immunohistochemistry and enzyme studies should be undertaken on biopsy samples.
Major histocompatibility complex (MHC) class I proteins are not usually expressed on muscle fibers. However, in IIM, MHC class I is detectable by immunohistochemistry [23,24]. MHC class I is present not only on
degenerating fibers but also in apparently normal fibers
and in areas without overt inflammation. For this reason,
it has been suggested that immunohistochemical evidence of MHC upregulation be included in the diagnostic criteria for IIM [4]. Although MHC upregulation is
very helpful, it is not specific for IIMs. MHC class I
upregulation, together with inflammatory infiltration,
may also be found in muscle from patients with dysferlinopathies and DMD, and, as in IIM, MHC is present
on normal as well actively degenerating fibers [25•]. Interestingly, it has been observed that conditional upregulation of MHC class I in mouse skeletal muscle is sufficient to cause autoimmune myositis [26].
Examples of histopathologic findings in IIMs, IBM, and
muscular dystrophy are shown in Figure 1.
Figure 1. Inflammatory changes can be found in muscle biopsy specimens from patients with a number of
conditions including the idiopathic inflammatory myopathies and some types of muscular dystrophy
In polymyositis, the inflammatory cell infiltrate is
predominantly endomysial (A) with infiltration of intact
myofibers (arrow). CD8-positive T lymphocytes are the
dominant cell type (B) and can be seen within nonnecrotic
fibers (arrow). There is widespread expression of major
histocompatibility complex (MHC) class I at the periphery
of myofibers (C). Inclusion body myositis is characterized
by the presence of rimmed vacuoles (D, arrow) that on
ultrastructural examination are found to contain whorled
membranous material (E) and randomly oriented 12- to
18-nm diameter fibrils (F). In dermatomyositis, the
lymphocytic infiltrate is often perivascular in distribution
(G, arrow), although it extends into the endomysium.
Ultrastructural examination shows a variety of pathologic
findings in the capillaries including empty loops of basal
lamina indicating capillary loss (H) and the characteristic
tubuloreticular inclusions in endothelial cells (I).
Inflammation may be a feature of dysferlinopathy (J) in
which the normal sarcolemmal distribution of dysferlin
immunohistochemical staining (K) is absent (L).
Hematoxylin and eosin (A, D, G, J); CD8
immunohistochemistry (B); MHC class I
immunohistochemistry (C); electron microscopy (E, F, H,
I); dysferlin immunohistochemistry (K, L). Original
magnifications: ×40 (A, G, J); ×80 (B, C, D, K, L); ×5000
(E, H); ×1600 (F); ×12,000 (I).
Consideration of the differential diagnosis
A broad differential diagnosis is presented in Table 1. In
the presence of a typical rash in association with the
other clinical features of DM, the diagnosis is often
straightforward. Difficulties arise in patients with suspected PM or with DM without dermatitis. It is also
important to review the diagnosis in patients who were
considered to have an IIM but who have not responded
to immunotherapy and are often labeled as having treatment-resistant PM or DM.
Alternative diagnoses should also be systematically excluded in patients with atypical investigation results, especially in patients with normal muscle biopsy specimens. A few specific disorders are briefly considered
here.
Muscular Dystrophies
Limb-girdle muscular dystrophy
The LGMDs are a heterogeneous group of disorders
presenting with a face-sparing, predominantly proximal,
progressive muscular weakness associated with elevated
muscle enzyme levels and dystrophic features on biopsy
specimens (i.e., degeneration and regeneration of muscle
fibers) [27]. In recent years, there have been many gene
discoveries [28•,29••]. There are at least 10 recessive
forms, classed as type 2 LGMD, constituting 90% of
cases [29••]. The proteins implicated are diverse and
include sarcolemmal components responsible for membrane stabilization, proteases, nuclear membrane proteins, and others.
The distribution of weakness is often similar to that of
IIM [30], and dysphagia may also occur [31]. Specific
clinical features vary between subtypes [29••]; for example, the sarcoglycanopathies (LGMDs 2C to 2F) pre-
Table 1. Differential diagnosis of inflammatory myopathy
Muscular dystrophies, in particular:
Limb-girdle muscular dystrophy, especially type 2B (dysferlinopathy)
Miyoshi myopathy (dysferlinopathy)
Dystrophinopathy (Becker muscular dystrophy, isolated female
manifesting carriers of dystrophinopathy)
Facioscapulohumeral dystrophy
Metabolic myopathies, in particular:
Myophophorylase deficiency (McArdle disease)
Phosphofructokinase deficiency
Acid maltase deficiency
Mitochondrial myopathy
Endocrine myopathies
Drug-induced myopathy
D-penicillamine
Quinidine
Procainamide
␤-hydroxy-␤-methylglutaryl-coenzyme A reductase inhibitors (statins)
Interferon alpha
Interleukin-2
Motor neuron disease
Spinal muscular atrophy (late-onset forms)
Myasthenia gravis
sent very much like the dystrophinopathies, with cardiomyopathy and calf hypertrophy.
Dysferlinopathy: limb-girdle muscular dystrophy 2B
and Miyoshi myopathy
LGMD2B and Miyoshi myopathy are caused by mutations in the dysferlin gene. Dysferlin is an integral sarcolemmal protein believed to be involved in membrane
fusion and repair [32••,33]. Dysferlinopathy is an autosomal recessive condition that is clinically heterogeneous
[34], even in cases with identical genetic defects [35]. It
usually presents in early adulthood with weakness in a
proximal (LGMD2B), proximal-distal, or distal (Miyoshi
myopathy) distribution.
Miyoshi myopathy starts distally in the legs, particularly
in gastrocnemius and soleus muscles. Proximal progression to the pelvic girdle and the upper limbs then occurs,
although the small muscles of the hand are spared.
LGMD2B also usually affects the lower limbs years before the upper limbs and, as in IBM, the quadriceps
muscle is often weaker than the hip muscles. Clinical
clues include the fact that periscapular muscles are usually relatively spared.
Creatine kinase levels are always elevated, even in the
preclinical stages, and can often be much higher than in
IIM with levels in the tens of thousands. Electromyography is myopathic. Muscle histology can also be confusing. Patients with both LGMD2B and Miyoshi myopathy may have significant inflammation demonstrated on
muscle biopsy samples [36,37] both endomysially and
perivascularly [25•]. Muscle fibers also aberrantly express MHC class I, as in IIM [25•]. The key to diagnosis
is immunohistochemistry findings that demonstrate an
absence of sarcolemmal dysferlin. Genetic diagnosis is
difficult due to the very large size of the gene (150 kb
over 55 exons). Interestingly, the SJL/J mouse, which
has been used as a model of autoimmune myositis [38],
has been found to have a mutation in dysferlin, resulting
in greatly reduced dysferlin expression [39].
Dystrophinopathy
Duchenne muscular dystrophy is the most common of
the dystrophies and results from mutations in the plasma
membrane–associated protein dystrophin [40••]. DMD
rarely poses diagnostic problems, but other presentations
of dystrophinopathy may be more difficult to differentiate from IIM.
Becker muscular dystrophy usually results from dystrophin mutations that result in abnormal but at least partly
functional protein, whereas in DMD, there is loss of dystrophin expression. The age at onset in BMD is later
than that in DMD, usually between the ages of 5 and 15
years, although it can present as late as the fourth de-
cade. The pattern of wasting is very similar to that of
DMD, but the severity is usually much less. Pelvic girdle
and thigh muscles are involved first, with relatively early
calf pseudohypertrophy. As with LGMD2B, confusion
can arise with IBM due to frequent prominent involvement of the quadriceps muscle. Shoulder girdle weakness usually develops subsequently. Cardiac disease and
mental retardation are rarer than in DMD, and this
makes differentiation from IIM more difficult. Dystrophinopathies may be responsive to corticosteroids [41],
and muscle biopsy sample can show mononuclear infiltrates, giving rise to further diagnostic difficulty.
The family history of X-linked inheritance can help
clarify the diagnosis, but approximately one third of
cases represent new mutations. Ninety-eight percent of
mutations can be detected by a multiplex polymerase
chain reaction screening 19 exons of the dystrophin
gene, one of the largest in the genome [40••]. Diagnosis
can also be confirmed by immunostaining muscle biopsy
specimens for dystrophin. The protein is absent in
DMD, but in BMD, although it is present, there is usually only partial sarcolemmal staining. The immunohistochemistry findings may, however, be normal. Western
blot for dystrophin in muscle allows the determination of
both the quantity and size of the molecule, reduced in
80% of patients with BMD and increased in approximately 5%. Fifteen percent of BMD patients have normal-size protein of reduced quantity.
Female carriers of dystrophinopathy
Because of lyonization (the random inactivation of one X
chromosome during early development), most female
carriers of a dystrophin mutation will switch off production of the mutant gene in 50% of chromosomes and
express enough normal dystrophin from the remainder to
prevent phenotypic expression. In some cases, however,
nonrandom inactivation results in significantly reduced
dystrophin levels and phenotypic expression [42].
Muscle weakness in female carriers occurs in approximately 19% of families with DMD and 14% of families
with BMD [43].
Manifesting female carriers present from their late teens
onward, with progressive proximal weakness of variable
severity. The inflammation seen in DMD and BMD is,
however, usually absent, and muscle biopsy samples reveal scattered muscle fibers with dystrophin levels reduced or absent on immunohistochemistry.
Facioscapulohumeral dystrophy
Facioscapulohumeral dystrophy is the third most common muscular dystrophy after DMD and myotonic dystrophy. Selective weakness is the main distinguishing
feature. Patients commonly present with onset in the
face, and subsequent periscapular and humeral weakness. Later progression to the lower limbs is seen, par-
ticularly distally, the reverse of the progression in the
IIMs. A significant minority of muscle biopsy specimens from patients with facioscapulohumeral dystrophy
show inflammatory change [19]. Almost all patients
with facioscapulohumeral dystrophy harbor deletions of a
tandem repeat, termed D4Z4, on chromosome 4q, and
genetic diagnosis is available. Interestingly, there is no
gene known at this locus, and it appears that the deletion
modulates expression of more proximal genes on chromosome 4, an effect termed positional variegation [44].
Metabolic myopathies
Defects in many aspects of cellular metabolism can cause
myopathy. Genetic metabolic myopathies present from
anytime in childhood to adulthood and tend to be slowly
progressive. It is unusual for the metabolic myopathies to
show the classic electromyographic triad described for
PM and DM. Furthermore, a biopsy specimen does not
demonstrate inflammation, and with appropriate histioenzymatic staining, a specific metabolic defect can often
be identified. Sometimes there is diagnostic confusion if
there has been rhabdomyolysis. In this setting, the biopsy specimen may appear to show an inflammatory infiltrate, but careful analysis usually reveals that it is only
necrotic fibers that are surrounded by inflammatory cells
and macrophages. In contrast, in IIMs, nonnecrotic fibers
are the subject of inflammatory attack.
Several metabolic myopathies present with fixed or progressive proximal muscle weakness. The main classes
are muscle glycogenoses, lipid storage disorders, and mitochondrial myopathies.
Muscle glycogenoses
The glycogenoses (glycogen storage diseases) are autosomal recessive enzyme deficiencies impairing glycogen
metabolism. They may present with either a hepatic or
muscle phenotype.
The most common of the muscle glycogenoses is
McArdle disease (type 5 glycogenosis) caused by a deficiency of myophosphorylase. Onset is usually in early
adulthood, typically with myalgia occurring soon after
starting exercise. Extreme exertion may result in myoglobinuria. Some patients present late with a relatively
fixed proximal myopathy, usually with a history of fatigue and exercise intolerance. Screening is by the forearm lactate test in which the normal increase in muscle
lactate levels caused by repeated exercise is abolished.
The nonischemic version of the test has been shown to
be as effective as the ischemic lactate test and is less
painful [45]. False positives are frequent, so the result
must be confirmed by biochemical analysis of muscle
enzyme activity or histochemical staining for myophosphorylase on muscle biopsy. A genetic test is also available.
Muscle phosphofructokinase deficiency (Tarui
disease/type 7 glycogenosis) usually causes exerciseinduced myalgia similar to McArdle disease, but a minority of patients present with a late-onset proximal myopathy [46,47], sometimes with no history of exercise
intolerance.
The adult-onset form of acid maltase deficiency (type 2
glycogenosis) causes proximal muscle weakness that is
greater in the pelvic than the shoulder girdle and can be
mistaken clinically for PM or LGMD. CK levels are elevated in almost all cases. Electromyography shows nonspecific myopathic changes but may be normal in as
many as 25% of patients, and the muscle biopsy specimen usually shows lysosomal vacuolation but again may
be normal in as many as 25% of patients [48]. Clinically,
a major clue is relatively early diaphragmatic involvement [49]. The rarer brancher deficiency glycogenosis
(type 4 glycogenosis) may also present as progressive
proximal myopathy [50], although this is usually a rapidly
progressive juvenile disease with marked hepatic involvement.
Lipid storage disorders
Carnitine palmitoyl transferase II deficiency is the most
common of the lipid storage disorders. It usually manifests as muscle pain induced by prolonged exercise.
Myoglobinuria is frequent. However, some patients present with a painless proximal myopathy. Muscle biopsy
specimens show abnormal lipid accumulations, and
muscle tissue can be used for specific enzyme assays.
Other rarer lipid storage disorders can also present with
proximal myopathy, including primary carnitine deficiency [51], which is easily treatable with carnitine
supplementation.
Mitochondrial myopathies
Mitochondrial disease is very heterogeneous and can
present in many ways including ophthalmoplegia, stroke,
and epilepsy [52]. Mitochondrial myopathy usually
presents as a symmetric proximal myopathy associated
with fatigue, much like IIM.
Clinical clues prompting investigation of mitochondrial
disease are few, and a detailed history and examination
are relied on to find associated features such as diabetes
or evidence of a family history of features consistent with
those of mitochondrial disease such as deafness, diabetes, and developmental delay. Pedigrees may demonstrate maternal inheritance in the case of mitochondrial
DNA disorders, but nuclear mitochondrial diseases are
inherited in a Mendelian fashion. The electromyogram is
often normal. Diagnosis relies on a combination of clinical findings, muscle histology, biochemical studies, and
molecular genetics [53•]. Muscle biopsy is the crucial
part of the investigation, both for positive identification
and for differentiation from other proximal myopathies.
However, classic histologic features such as the presence
of ragged red fibers are not entirely specific and may be
seen in IBM or acid maltase deficiency, nor does their
absence exclude mitochondrial myopathy.
Endocrine myopathies
A number of endocrinopathies are associated with proximal myopathy [54]. The features are summarized in
Table 2. Thyroid and parathyroid dysfunction is easily
screened by checking T4, thyroid-stimulating hormone,
calcium, and phosphate levels. Cushing syndrome is usually clinically obvious from other stigmata by the time
significant myopathy is evident, as is acromegaly. A history of exogenous steroid administration should always
lead one to suspect steroid myopathy. In all these cases,
myopathy resolves with treatment of the underlying endocrine disorder. Hypothyroidism is the most likely to
mimic myositis clinically, with significantly elevated CK
and inflammation in as many as 12.5% of biopsy samples
[55].
Specific considerations in the differential
diagnosis of inclusion body myositis
Although the most common condition that IBM is mistaken for is PM, there are a number of other differential
diagnostic considerations [7••].
The early-adult onset distal myopathy with rimmed
vacuoles (Nonaka myopathy) is an autosomal recessive
disorder that is allelic with hereditary IBM, both of
which are owing to mutations in the GNE gene [56].
Initial weakness occurs in the distal leg anterior compartment, and serum CK is moderately elevated, usually no
Table 2. Features of endocrinopathies associated with proximal myopathy
Endocrine disorder
Distribution
CK
Notes
Hypothyroidism
Hyperthyroidism
Cushing syndrome/steroid myopathy
Hypoparathyroidism
Proximal
Proximal + distal ± bulbar
Proximal
Proximal
↑/↑↑
N/↓
N
N/mild ↑
Hyperparathyroidism
Osteomalacia
Acromegaly
Proximal
N
N
N/↑
Myoedema; type II atrophy on Bx, occasionally inflammatory
Weakness > wasting; frequent myalgia; Bx sample normal
Fibrillation potentials absent on EMG
Very rarely causes myopathy; usually tetany; EMG/Bx
sample normal
Hyperreflexia
Type II atrophy on Bx
Late in disease course, when clinically obvious
Proximal
Bx, biopsy; EMG, electromyogram; N, normal.
more than five times normal. The quadriceps muscle,
often prominently affected in sporadic IBM, is typically
spared. However, there is much overlap. Furthermore, in
addition to the typical vacuolation of fibers found on
muscle biopsy, endomysial inflammation can also be
seen in distal myopathy with rimmed vacuoles [57•].
Vacuolar myopathy similar to sporadic IBM but without
inflammation is also seen in distal myopathies, including
Welander distal myopathy and tibial muscular dystrophy.
Proximal involvement is, however, rare in Welander distal myopathy and occurs very late in tibial muscular dystrophy, and onset of both disorders typically begins in
the long finger extensors (compare with finger flexor involvement in IBM). Miyoshi myopathy was discussed
previously. A recent pathologic study of three cases of
X-linked Emery-Dreifuss muscular dystrophy revealed
an inflammatory process very similar to that of IBM [58].
However, in general X-linked Emery-Dreifuss muscular
dystrophy poses little diagnostic challenge because early
contractures, mainly of the elbows and ankles, are a
prominent feature, and patients develop limitation of
spinal flexion.
Conclusion
An accurate diagnosis of IIM is important because of the
treatability of these conditions. Furthermore, misdiagnosis may lead to unnecessary exposure of patients to toxic
immunotherapies.
Many neuromuscular disorders, in particular the genetic
muscular dystrophies and metabolic myopathies, may
potentially mimic the myositides. Usually a detailed
clinical and myopathologic evaluation will allow the correct diagnosis to be made. Lack of response to immunotherapy should always lead to a review of the diagnosis
before considering further and often increasingly toxic
immunotherapies. Close collaboration between clinicians and muscle pathologists is essential to achieve the
optimal management in patients with IIMs.
•
Of special interest
••
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203.
Myositis specific autoantibodies: changing insights in
pathophysiology and clinical associations
Gerald J.D. Hengstmana, Baziel G.M. van Engelena and Walther J. van Venrooijb
Purpose of review
Defined autoantibodies are found in about half of the patients
with myositis. Traditionally, these autoantibodies have been
divided into myositis specific autoantibodies (MSAs) and
myositis associated autoantibodies. Several studies have
shown that MSAs are associated with specific clinical
characteristics and can aid our understanding of the
pathophysiology of myositis.
Recent findings
Recent studies suggest that some MSAs are markers of
specific inflammatory muscle diseases (e.g., anti-SRP for an
immune-mediated necrotizing myopathy) and not just of
myositis in general. Furthermore, new insights are emerging
about the pathophysiology of MSAs, in particular anti-Jo-1.
Based on these new insights, an alternative hypothesis of the
formation of anti-Jo-1 autoantibodies is presented in which the
immune system itself rather than muscle is the site of antigen
presentation.
Summary
The recognition that some MSAs are markers of specific
disease entities that were once commonly referred to as
(poly)myositis, aids the development of better disease
definitions. The changing insights in the function of the Jo-1
antigen and the emergence of new hypotheses on the
formation of the Jo-1 antibody, open new avenues for future
research aimed at unraveling the mystery of myositis.
Keywords
myositis, antibodies, autoantibodies, pathophysiology,
Curr Opin Rheumatol16:692–699. © 2004 Lippincott Williams & Wilkins.
a
Neuromuscular Centre Nijmegen, Department of Neurology, University Medical
Centre Nijmegen, Nijmegen, The Netherlands and bNijmegen Centre for Molecular
Life Sciences, Department of Biochemistry, University of Nijmegen, Nijmegen, The
Netherlands
This work was supported by NWO-MW, grant 940-37-009.
Correspondence to Gerald J.D. Hengstman, Neuromuscular Centre Nijmegen,
Department of Neurology, University Medical Centre Nijmegen, Internal mail
number 326, PO Box 9101, 6500 HB Nijmegen, The Netherlands
Tel: +31 24 3613396; fax: +31 24 3541122; e-mail: g.hengstman@neuro.umcn.nl
1040–8711
692
Introduction
Autoantibodies can be found in the sera of most patients
with myositis [1]. Defined autoantibodies are detected in
about 50% of myositis patients and are traditionally divided into myositis specific autoantibodies (MSAs) and myositis associated autoantibodies (MAAs), the latter also occurring in autoimmune diseases without the presence of
myositis [2]. Most MSAs are directed against cytoplasmic
RNA-protein complexes involved in the process of protein synthesis [3–11]. The best-characterized MSAs are
directed to several tRNA-synthetases and their cognate
tRNAs, to components of the signal recognition particle
(SRP), and to components of a nucleosome remodeling
complex called Mi-2 [3–11]. Several clinical and epidemiologic studies have shown that MSAs are associated
with specific clinical characteristics [12,13]. Table 1 gives
an overview of the most common MSAs, their antigens,
their frequency of occurrence in myositis patients, and
their clinical associations.
In the past couple of years, several studies have changed
our insights about the MSAs. It is now becoming clear
that some MSAs, in particular anti-Jo-1 and anti-signal
recognition particle (anti-SRP) antibodies, are markers of
very specific disease entities and not just of myositis in
general. Furthermore, new ideas are emerging about the
pathophysiology of MSAs, in particular anti-Jo-1.
Changing diagnostic criteria
Many studies have described the association of MSAs
with specific subtypes of myositis and several extramuscular complications. Essential to the validity of these
observed associations are the definitions used for diagnosis and identification of clinical signs and symptoms.
Traditionally, most of the articles describing the MSA
associations have used the Bohan and Peter criteria [14].
However, recent papers, especially in the neurologic literature, have challenged the concept of polymyositis
(PM) [15–17]. The advocates for a more detailed histologic definition of PM state that inflammatory infiltrates
in skeletal muscle tissue are not only present in PM but
also in other myopathies including facioscapulohumeral
dystrophy (FSHD), dysferlinopathies, etc. (Table 2)
[15,16]. Bohan and Peter excluded only some of these
diseases [14]. With present knowledge, it is probably
best to state that all diseases mentioned in Table 2
should be excluded (on clinical grounds or histologically)
MSAs: changing insights Hengstman et al. 693
Table 1. Overview of most common myositis specific autoantibodies
Antibody
Anti-ARS
Anti-Jo-1
Anti-PL-7
Anti-PL-12
Anti-EJ
Anti-OJ
Anti-KS
Anti-tRNA
Anti-tRNAhis
Anti-tRNAala
Miscellaneous
Anti-SRP
Anti-Mi-2
Antigen
His-tRNA synthetase
Thr-tRNA synthetase
Ala-tRNA synthetase
Gly-tRNA synthetase
Ile-tRNA synthetase
Asp-tRNA synthetase
tRNAhis
tRNAala
SRP-complex
Nuclear helicase
Frequency
Clinical association
11–20%
2%
1%
1–3%
1%
<1%
Anti-synthetase syndrome
7%
1%
4%
4–14%
“Aggressive” PM
Classic DM
Anti-ARS, anti-aminoacyl-tRNA synthatase; SRP, signal recognition particle; PM,
polymyositis; DM, dermatomyositis.
in patients suspected of having PM. It is because of these
ongoing changes in diagnostic criteria that associations
we thought were once clear (eg, anti-SRP is only seen in
PM) are now being reconsidered (eg, anti-SRP is specific
for a type of necrotizing myopathy).
Anti-aminoacyl-tRNA synthetases
The most prevalent MSAs are directed against aminoacyl-tRNA synthetases (ARS). The presence of anti-ARS
antibodies is strongly associated with the anti-synthetase
syndrome, consisting of myositis, idiopathic interstitial
lung disease (ILD), nonerosive arthritis, and Raynaud’s
phenomenon [12,18–21].
Anti-Jo-1 and interstitial lung disease
A recent prospective study performed by Fathi et al. [22]
confirmed the association of anti-Jo-1 with ILD and arthritis. A small group of 17 newly diagnosed dermatomyositis (DM)/PM patients were investigated for the
presence of ILD defined as the occurrence of radiographic signs of ILD on chest X-ray or high-resolution
CT scan (HRCT) and/or restrictive ventilatory defect.
Eleven patients were diagnosed with ILD, four of whom
had the anti-Jo-1 autoantibody. Of the six patients without ILD, none was anti-Jo-1 positive.
Another retrospective study also examined the presence
of ILD in DM/PM and compared ILD in patients with
Table 2. Myopathies with inflammatory infiltrates on
muscle biopsy
Immune-mediated myopathies
Dermatomyositis
Inclusion body myositis
Polymyositis
Muscular dystrophies
Facioscapulohumeral muscular dystrophy (FSHD)
Dysferlinopathies
Necrotizing myopathies
Toxic myopathies
and without anti-Jo-1 [23]. In a group of 156 patients,
ILD was diagnosed in 23.1%. The anti-Jo-1 autoantibody was found in only 15 patients (9%), a remarkably
low number of patients raising some questions on the
methodology of the study, especially since the authors
do not describe the serological tests used. The prevalence of ILD in the anti-Jo-1 group was 73%, again confirming the association of this antibody with ILD. The
only differences found between the anti-Jo-1 positive
and anti-Jo-1 negative group were that the anti-Jo-1 positive group were less likely to have a symptomatic form of
ILD and bronchiolitis obliterans organizing pneumonia
(BOOP). The authors noticed that patients with antiJo-1 had similar ILD outcome, compared with those
without this antibody, with respect to resolution, improvement, or deterioration of ILD and mortality rate
related to ILD complications. They concluded that patients with and without anti-Jo-1 require similar management and follow-up of ILD.
Specificity of anti-Jo-1
Although it has been shown that anti-Jo-1 is specific for
DM/PM compared with other inflammatory autoimmune rheumatic disorders, few studies have investigated
its specificity compared with other neuromuscular disorders [19,24–26]. In a small study of 17 patients with Duchenne muscular dystrophy, anti-Jo-1 was not found [25].
In another study, Tanimoto et al. [26] were unable to
detect the anti-Jo-1 autoantibody in sera from 33 patients
with a neuromuscular disorder other than myositis. Unfortunately, they did not describe their serological technique nor specify the type of neuromuscular disorders
examined. In a recent study, we were unable to detect
anti-Jo-1 in sera from 18 patients with FSHD, a muscular
dystrophy with marked inflammation on muscle biopsy
[27]. Based on these findings, it can be concluded that
the anti-Jo-1 autoantibody is highly specific for DM/PM
and that the formation of anti-Jo-1 is not merely the
result of muscle inflammation but is closely linked to the
pathophysiology of DM/PM.
The anti-synthetase syndrome
Because earlier studies only looked for anti-ARS antibodies in patients with myositis and other autoimmune
rheumatic tissue diseases, and only found them in myositis patients, it was thought that anti-ARS antibodies are
myositis specific. Based on more recent work, it became
clear that anti-ARS antibodies are specific for their own
disease entity of which myositis may be a component:
the anti-synthetase syndrome (Table 3) [28,29]. Histologic studies confirmed that the anti-synthetase syndrome is a separate disease entity within the spectrum of
myositis [30]. Mozaffar and Pestronk [30] demonstrated
that the myopathological changes in the anti-synthetase
syndrome include perimysial connective tissue fragmentation and inflammation, with muscle fiber pathology in
neighboring perifascicular regions. Based on their findings they suggested that myositis in the anti-synthetase
syndrome may result from an immune-mediated disorder
of connective tissue. This hypothesis can explain more
easily why ILD is such a prominent feature of the antisynthetase syndrome.
Kamei [35•] examined the cellular localization of Jo-1
tagged with green fluorescent protein in transfected T24
cells. The tagged-Jo-1 localized solely and diffusely in
the cytoplasm of almost all cells. Occasionally though,
small aggregates or spots could be seen in or near the
nucleus. The author subsequently demonstrated that
these seemingly nuclear spots coincide with cytoplasmic
invaginations of the nuclear membrane, indicating that
tagged-Jo-1 is not localized in the nucleus but solely in
the cytoplasm.
Anti-Jo-1 antibody formation
Ever since its first description almost 25 years ago, researchers have hoped that the anti-Jo-1 autoantibody
would provide a better understanding of the pathogenesis of myositis. To elucidate the role of anti-Jo-1 in
myositis, two questions must be answered: why are they
formed and what do they do? Neither question can be
fully answered but new insights are emerging based on
recent studies casting a different light on the Jo-1 antigen.
Earlier work has shown that the anti-Jo-1 autoantibody
response is antigen-driven and very closely linked to the
disease process [36]. There are several hypotheses as to
why anti-Jo-1 is the subject of antibody targeting. One is
that anti-Jo-1 autoantibodies result from a direct interaction of Jo-1 with RNA from picornaviruses, thus rendering it foreign to the immune system [6]. Another hypothesis proposes that the immune response is primarily
directed against picornaviral proteins with regions homologous to regions present in Jo-1, thus causing autoantibody formation via the mechanism of molecular
mimicry [37]. A third hypothesis is based on the formation of anti-idiotypic antibodies, again triggered by a presumed viral protein [38]. A more recent model hypothesizes that certain self-proteins become modified (e.g.,
during apoptosis or as a result of inflammatory or infectious processes) and are subsequently recognized as nonself by the immune system [39]. The immune response
might then, via epitope spreading, evolve into a fullblown immune reaction directed to the whole protein,
including the nonmodified parts.
Cellular localization of Jo-1
Jo-1 and the immune system
Knowledge of the cellular localization of an autoantigen
is important for the understanding of its cellular function
and for gaining further insight in the pathogenesis of the
disease studied. Anti-Jo-1 autoantibodies are directed
against His-tRNA-synthetase, an enzyme with a cytoplasmic function and therefore a presumably cytoplasmic
localization. However, contradictory results have been
reported regarding the cellular localization of Jo-1. Cytoplasmic, nuclear, nucleolar, and all forms of combinations of these localizations have been reported [1,31–34].
Jo-1 has traditionally been seen as a ubiquitously expressed intracellular protein catalyzing the binding between the amino acid histidine and its tRNA. But why is
Jo-1 the target of a disease-specific antibody response?
Because anti-Jo-1 antibodies were thought to occur only
in patients with myositis, most studies have looked at the
muscle as the site of antigen expression. This notion led
to the development of a hypothesis in which a presumably altered Jo-1 is expressed by muscle tissue thus eliciting an immune reaction directed against muscle tissue
along with a specific antibody response (Fig. 1A). Others
have postulated that necrosis or apoptosis of muscle fibers causes modifications of Jo-1, which are subsequently exposed to the immune system as the muscle
fibers disintegrate (Fig. 1B). Recent studies, however,
showed that fragments of several tRNA synthetases
function as chemokines with a potential role in the immune response of myositis [40,41••]. It is thus conceivable that anti-Jo-1 antibodies are not directed to the entire Jo-1 antigen but initially only against its chemokinefragment. Through epitope-spreading, antibodies can
eventually be formed against other components of Jo-1.
Immunopathogenesis of the
anti-Jo-1 autoantibody
Table 3. Characteristics of the anti-synthetase syndrome
Clinical
Laboratory
Biopsy
Treatment
Myositis
Interstitial lung disease
Nonerosive arthritis
Raynaud phenomenon
Anti-ARS antibodies
Fragmentation of perimysial connective tissue
Macrophage predominant perimysial inflammation
Perifascicular myopathic changes
Normal capillary density
Normal response of interstital lung disease to treatment
Moderate response of myositis to treatment
Figure 1. Hypotheses on the role of the Jo-1 antigen and the formation of anti-Jo-1 autoantibodies in myositis
(A) Initiated by a factor X (step 1), altered Jo-1 is formed
(step 2) and presented by MHC class I molecules on the
sarcolemma (step 3) to the immune system (step 4)
with subsequent formation of anti-Jo-1 antibodies.
(B) Inflammation of muscle tissue (step 1) results in
necrosis/apoptosis of muscle cells. In this process of
necrosis/apoptosis, Jo-1 is altered (posttranslational
modification) (step 2). As the cell disintegrates, the altered
Jo-1 antigen is phagocytized (step 3 and 4) and
subsequently presented to the immune system by
antigen-presenting cells (step 5), resulting in formation of
anti-Jo-1 antibodies (step 6). (C) Initiated by factor X,
immune cells form the chemokine-fragment of Jo-1 (step
1), which is subsequently secreted together with other
pro-inflammatory molecules (step 2) resulting in
inflammation of muscle tissue and induction of aberrant
MHC class I expression on the sarcolemma (step 3).
If the chemokine-fragment is the actual antigen, it becomes more likely that the immune system rather than
muscle is the site where the initial antigen is expressed
(Fig. 1C).
The latter hypothesis is attractive for several reasons.
First, one can now understand better why myositis is a
multisystem disorder. If the muscle is the initial site of
the immune response, it is hard to understand why the
lung, or the joints, or the skin become involved. Several
studies have shown that patients with the anti-Jo-1 autoantibody do not always have myositis at the time of the
detection of the antibody [28,29]. Cases like these cannot be explained by anti-Jo-1 formation in muscle tissue.
But why are antibodies formed against a chemokine?
Several explanations are possible. First, the immune response is always a battlefield between proinflammatory
and antiinflammatory components. As part of the antiinflammatory reaction, antibodies may be formed, which
suppress the function of proinflammatory molecules, like
chemokines. The formation of anti-Jo-1 antibodies may
thus be a consequence of the immune system trying to
suppress the immune response. Secondly, the immune
response in myositis may be abnormal with formation of
abnormal chemokines, which are foreign to the immune
system. Thirdly, apoptosis of inflammatory cells plays an
important role in the regulation of the immune response.
Through abnormal apoptotic cleavage, unique fragments
of Jo-1 may be formed and presented to the immune
system, causing the formation of anti-Jo-1 antibodies.
Jo-1–induced T-cell proliferation
In an interesting study, Ascherman et al. [42] looked at
antigen-presenting cells (APCs) and their role in eliciting
a T-cell response to the Jo-1 antigen. Using recombinant
full-length Jo-1 (generated from the RNA of a healthy
control subject) and four fragments of this recombinant
antigen, T-cells from the peripheral blood of anti-Jo-1–
positive myositis patients and from healthy controls were
stimulated in the presence of PBMC-derived APCs and
dendritic cells (DCs). In anti-Jo-1–positive patients and
in healthy controls T-cell proliferation was found to both
full-length Jo-1 and to its individual fragments in a dosedependent manner. An absolute dependence on DCs
was found for the productive presentation of Jo-1 fragments, and this was not the case for the productive presentation of full-length Jo-1. It was further shown,
through antibody-blocking experiments, that the T-cell
proliferation driven by full-length Jo-1 as well as by Jo-1
fragments is MHC class II dependent. Although the authors demonstrated elegantly that Jo-1 and its fragments
can induce a T-cell proliferation, they failed to identify
differences between healthy controls and anti-Jo-1–
positive patients. A potential explanation for this is that
they used a recombinant Jo-1 product that does not con-
tain protein modifications. Based on the hypothesis that
Jo-1 might be altered in anti-Jo-1 positive myositis patients (eg, through posttranslational modifications), it
would have been of interest to see whether their experiments would have rendered different results if they had
used Jo-1 isolated from biopsies of anti-Jo-1–positive patients.
Anti-signal recognition particle
Several studies have shown that anti-signal recognition
particle (anti-SRP) autoantibodies are mainly found in
PM (defined by the Bohan and Peter criteria), and only
occasionally in DM and inclusion body myositis (IBM)
[2,8,12,14,18,19,43–46]. Although few patients were
studied, an association between the antibodies and an
acute and severe myositis, cardiac involvement, a poor
response to treatment, and an increased mortality rate
[12,18,19,44] was noted. As we have pointed out previously, many of these presumed associations of anti-SRP
autoantibodies are weak [39]. A recent study confirmed
the presence of a relatively aggressive disease characterized by severe myalgia and arthralgia, high levels of serum creatine kinase, and a moderate response to immunosuppressive treatment in patients with the anti-SRP
antibody [43]. Cardiac involvement, however, was not
found [43].
Anti-signal recognition particle myopathy
Recent studies have shown that anti-SRP autoantibodies
are markers for a specific immune-mediated myopathy
other than PM. In an excellent paper Miller et al. [47]
described the clinical and pathologic features of seven
patients with anti-SRP autoantibodies as detected by
two different techniques: immunoprecipitation and immunodiffusion. The onset of weakness in all patients
was between August and January. All patients progressed
relatively rapidly to severe weakness with a mean time
from onset to maximum weakness of 5 months. Most
patients complained of fatigue or pain, but this was never
the primary complaint. Physical examination revealed a
severe symmetric proximal weakness of the upper and
lower extremities. None of the patients had clinical signs
or symptoms suggestive of cardiac involvement. Serum
creatine kinase levels were markedly elevated with a
mean of 12.900 U/l and electromyography showed myopathic features with very prominent spontaneous activity. Six of the seven patients improved on corticosteroids,
but only partially. Three patients relapsed after tapering
of the corticosteroids.
The histopathology in the seven patients was remarkable. All biopsies showed myopathic features with regenerating fibers. Mononuclear inflammatory infiltrates
were uncommon and there was no marked MHC-I staining of the sarcolemma. Necrotic muscle fibers and increased endomysial connective tissue were noticed in
Table 4. Characteristics of the anti-SRP myopathy
Clinical
Laboratory
EMG
Biopsy
Treatment
Rapidly progressive disease
Severe weakness
Symmetric proximal weakness of arms and legs
Marked atrophy of proximal muscles
High levels of serum CK
Marked spontaneous activity on EMG
Absence of inflammatory infiltrates
Absence of HLA-ABC class antigens on the sarcolemma
Responsive to treatment, but only partial
most biopsies as well as a reduced endomysial capillary
density. Furthermore, the mean diameter of the endomysial capillaries was increased with deposition of membrane attack complex (MAC). The histopathology Miller
et al. found in their anti-SRP patients strongly differs
from the histopathology of PM in which mononuclear
inflammatory infiltrates and MHC-class I staining of the
sarcolemma are usually present, the diameter of endomysial capillaries is not altered, and deposition of MAC
in the capillaries is absent [30,47,48].
Miller et al. thus concluded that the anti-SRP autoantibodies identify a specific immune- mediated myopathy
characterized by a rapidly progressive severe proximal
muscle weakness with an incomplete response to corticosteroids and no clinical signs or symptoms suggestive
of multi-organ involvement. Based on the histopathological features, the authors hypothesized that the disease
referred to as “myopathy with anti-SRP autoantibodies”
is caused by a humoral immune mechanism primarily
directed against the endomysial capillaries with subsequent multifocal ischemic pathology of the muscle tissue. Where the formation of antibodies directed against
components of the SRP complex fits into the picture
remains unknown.
Second clinical study on anti- signal recognition
particle myopathy
In another study, Kao et al. [49•] determined the longterm outcome and associated clinical, serological, and
pathologic features of 19 patients with the anti-SRP autoantibody. Sera from 263 patients with DM/PM, 790
patients with systemic sclerosis (SSc), and 109 patients
with an overlap syndrome were examined. Sixteen sera
tested positive for anti-SRP in the myositis group, two in
the SSc group, and one in the overlap syndrome group.
All patients in the myositis group were diagnosed with
PM according to the Bohan and Peter criteria [14]. The
authors subsequently compared the anti-SRP positive
PM patients with the anti-SRP negative PM patients. No
differences were observed with regard to demographic
features (no clear seasonal onset, although the authors do
not state how they identified the month of onset), cardiac
involvement (defined as echocardiographic evidence of
biventricular cardiomyopathy or electrocardiographic
evidence of ventricular arrhythmias attributable to PM
and not to coronary heart disease), or 5-year cumulative
survival rate (86%). The patients with anti-SRP autoantibodies had more frequently severe proximal weakness
at presentation, higher levels of serum CK at diagnosis,
and more severe muscle atrophy at presentation. Three
anti-SRP–positive PM patients were diagnosed with
ILD and two with arthritis. The authors noticed that the
anti-SRP–positive PM patients exhibited persistent
muscle weakness and resistance to treatment, with a favorable response being achieved in only one third. Unfortunately, no clear data are presented on which these
conclusions are based. The muscle biopsy specimens of
10 PM patients with anti-SRP autoantibodies were compared with those of 17 PM patients without the antibody.
Compatible with the findings by Miller et al., the authors
Figure 2. Different disease entities within the spectrum of myositis, past and present
More than 25 years ago, myositis was roughly divided into DM and PM. With the present day knowledge, we are able to identify several distinct disease entities that
were formerly included in dermatomyositis (DM) and polymyositis (PM). Several of these disease entities are characterized by certain specific autoantibodies, as
indicated. anti-SRP, anti-signal recognition particle antibodies; anti-ARS, anti-aminoacyl-tRNA synthetase antibodies.
did not find extensive endomysial inflammation, but unlike Miller et al. they also did not notice marked necrosis
[47]. The authors state that the two patients with SSc
and the one patient with an overlap syndrome (suffering
from the anti-synthetase syndrome) had no features of
myositis, without mentioning what they mean with “features” (are these clinical signs and symptoms, or an elevated serum CK or muscle biopsy abnormalities?).
Based on their study, the authors conclude that anti-SRP
is not specific for PM, that severe muscle weakness and
atrophy are prominent features whereas cardiac involvement is less common, and survival is better than previously reported.
In conclusion, the contours of a specific myopathy are
emerging that can be identified by the presence of antiSRP autoantibodies (Table 4). However, several questions remain unanswered including the presence of necrotic fibers and the predilection of the disease to start in
the fall.
Conclusion
In conclusion, the MSAs have aided in the identification
of several distinct disease entities within the spectrum of
myositis. More than 25 years ago, PM was defined as an
acquired muscle weakness with the presence of inflammatory infiltrates in skeletal muscle, usually responsive
to immunosuppression. Today we recognize several different diseases that once were included under the heading PM (Fig. 2). Besides histology and accurate clinical
descriptions, MSAs have played an important role in this
process. As several authors have pointed out, PM is most
frequently a component of an overlap syndrome and with
current knowledge, we are able to diagnose most of these
patients correctly [15,16]. These changes in disease definitions will aid research in unraveling the pathogenesis
of these diseases and in performing better therapeutic
trials.
Furthermore, the increasing insights in the function of
the Jo-1 antigen and the emergence of new hypotheses
on the formation of the anti-Jo-1 antibody, open new
avenues for future research aimed at unraveling the mystery of these disabling diseases.
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•
Of special interest
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•
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••
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involvement.
49
•
Myositis: an update on pathogenesis
Lisa Christopher-Stinea and Paul H. Plotzb
Purpose of review
The etiology and much about the pathogenesis of the
inflammatory myopathies remain a mystery. In this review, we
investigate recent research efforts to understand the
pathogenesis of the diverse entities of polymyositis (PM),
dermatomyositis (DM), and inclusion body myositis (IBM),
diseases that result from interactions between environmental
risk factors and genetic susceptibility.
Recent findings
Over the past year, there has been considerable progress
toward better understanding of IBM, with relatively few
developments toward understanding PM and DM. Although
these diseases may share some common clinical phenotypic
and serologic components, they differ on a molecular and
cellular level.
Summary
The need for definitive, safer therapies in these diseases
makes vital the search for defining detailed pathogenesis of
inflammation and muscle fiber damage at the molecular level.
Keywords
inflammatory myopathy, polymyositis, dermatomyositis,
inclusion body myositis, pathogenesis
Curr Opin Rheumatol16:700–706. © 2004 Lippincott Williams & Wilkins.
a
Instructor in Medicine, Division of Rheumatology, Johns Hopkins University
School of Medicine, Baltimore, Maryland, USA and bChief, Arthritis and
Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin
Diseases, National Institutes of Health, Bethesda, Maryland, USA
Correspondence to Paul H. Plotz, Chief, Arthritis and Rheumatism Branch,
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National
Institutes of Health, Clinical Center 9N244, Bethesda, MD 20892-1820, USA
Tel: 301 496 9904; fax: 301 402 0012; e-mail: plotzp@mail.nih.gov
1040–8711
700
Introduction
The etiology and much about the pathogenesis of the
inflammatory myopathies remain elusive. We review
here recent scientific endeavors exploring the pathogenesis of the diverse entities of polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM),
diseases that are held to result from interactions between
environmental risk factors and genetic susceptibility.
There have been relatively few developments toward
understanding PM and DM pathogenesis in the past
year, but considerable progress toward better understanding of IBM.
Polymyositis and dermatomyositis
Experimental models
A Swedish study examined the skeletal muscle changes
in an experimental model of Chagas disease and compared its muscle inflammation pattern with that of the
human inflammatory myopathies [1••]. Female CBA/J
mice were injected with the Tulahuen strain of T. cruzi,
and the inflammatory phenotype was characterized. The
predominant muscle cell types in the model were macrophages and T cells, with CD4+ cells near blood vessels
and CD8+ cells present within the perimysium; almost
no B cells were present; no vacuolar fibers were noted.
Thus, the model most closely approximates PM. This
may be a useful animal model for PM, particularly as it
relates to understanding the order of events that lead to
inflammation and muscle damage in association with Tcell infiltration.
Clinical aspects
Potential association with viral illness
Attempts to find evidence of a direct role of viral infection in myositis have continued, though again without
really credible success.
A rare example of a viral myopathy seen in conjunction
with the West Nile Virus was noted in one case report
[2]. Symptoms in addition to the neurologic manifestations included a myositis characterized by a T-lymphocyte infiltration of nerve fibers, leading the authors to
conclude that the virus may reach the central nervous
system via peripheral nerves. There was muscle fiber
necrosis, atrophy, and inflammation with an exclusive Tcell infiltration with a slight predominance of CD4+ over
CD8+ cells and with scattered CD68+ cells. There were
no inflammatory changes seen in blood vessels and
muscle septa, and WNV antigens were not detected
Myositis Christopher-Stine and Plotz 701
by immunohistochemistry. This appearance suggests
that the myalgia often reported with a self-limited WNV
illness [3] might be a viral myositis rather than evidence
of neurologic involvement.
Douche-Aourik et al. [4] reported the persistence of enterovirus RNA in muscle samples of patients with inflammatory myopathies and fibromyalgia. There was no
evidence of VP-1 protein in the samples positive for putative viral RNA. These findings must be read with
skepticism. The authors fail to cite the strongest evidence that enteroviral sequences are absent from myositis samples—a study in which the potential technical
problems that they name, and others they missed, had
been carefully anticipated and excluded [5].
A French [6] study was unable to detect B19 DNA by
PCR in 7 of 8 muscle biopsy samples obtained from
patients with inflammatory myopathy, and viral capsid
protein expression was not demonstrated by immunohistochemistry. One patient had a transiently positive viral
capsid protein that became negative even in the absence
of disease flare. Parvovirus B19 was unable to induce
IL-6 production by myoblasts in vitro.
Fathi et al. [7•] investigated the prevalence and disease
predictors for ILD in 17 patients newly diagnosed with
PM or DM in Sweden. Sixty-five percent had evidence
of pulmonary involvement, even in the absence of symptoms. Arthritis and anti-Jo-1 antibodies were predictors
of concomitant pulmonary involvement. We agree with
the authors’ suggestion that chest x-ray, HRCT, PFTs,
and anti-Jo-1 antibodies should be included in the initial
investigation of PM and DM patients. Schnabel et al. [8•]
screened 63 consecutive PM/DM patients for lung disease. They found evidence of ILD in 32% of subjects
screened. Those patients who progressed were distinguished by evidence of ground-glass opacities on HRCT
and by BAL neutrophilia. Cyclophosphamide provided
stabilization, and sometimes improvement, in all members of this group. Those patients without rapidly progressive disease had stable lung disease on moderateintensity immunosuppressives during the mean of 35
months of follow-up. This study suggests that treatment
for ILD in future clinical trials for PM/DM-associated
lung disease should stratify patients.
Nonspecific interstitial pneumonia was the most common observed histologic pattern in patients with clinically amyopathic dermatomyositis in a retrospective multicenter study performed in France [9]. A recent case
report reminds us that fatal interstitial fibrosis may be
present in the presence of clinically amyopathic dermatomyositis, even if there is no evidence of anti-Jo-1 or
other antisynthetase antibodies [10].
Necrotizing myopathy
On occasion, patients presenting with a clinically apparent idiopathic inflammatory myopathy may lack mononuclear cell infiltrate on muscle biopsy despite the presence of a necrotizing myopathy [11]. This subset of
patients may still be steroid responsive, as evidenced by
this report, thus suggesting that clinicians not delay steroid therapy despite lack of a monocellular infiltrate
when the rest of the clinical picture suggests acute myositis. De Bleecker et al. [12•] report a case of a patient
with an ill-defined overlap syndrome including a
chronic-steroid responsive necrotizing myopathy in the
absence of a malignancy. The muscle biopsy demonstrated little inflammation, but there was MAC deposition on the mural elements of the vessel wall, and MHC
class I was present on the surface of all muscle fibers.
Thus, virtual absence of inflammatory changes need not
exclude the diagnosis of a potentially treatable autoimmune inflammatory myopathy. The pathogenesis in this
interesting disease subset needs study.
Environmental risk factors
In the most interesting and persuasive evidence of an
environmental contribution to the expression of an autoimmune rheumatic disease, Okada et al. [13••] demonstrated that among 13 geoclimatic variables studied in
a population of 919 consecutive myositis patients from 15
locations surface ultraviolet radiation intensity was the
strongest contributor to DM and was strongly related to
the proportion of anti-Mi2 antibodies. These data suggest that ultraviolet radiation exposure may modulate the
expression of autoimmune diseases such as myositis both
immunologically and clinically in different populations
around the world. This may be related to the observation
that, at least in DM, increased numbers of ultraviolet
light-induced apoptotic cells in the skin can lead to a
supra-threshold concentration of antigenic peptides [14].
Cellular immune mechanisms
Tumor necrosis factor-␣
Kuru et al. [15] studied the expression of TNF-␣ and its
receptor in PM, DM, and Duchenne Muscular Dystrophy (DMD) using in situ hybridization and immunohistochemistry. They demonstrated that TNF-␣ mRNA
and protein were present in muscle fibers in all three
disease entities but were rare or absent in neurologic
disorders or normal controls. The proportion of TNF-␣–
positive fibers correlated with the proportion of regenerating fibers (those that were positive for the developmental form of myosin heavy chain, MHC-d) suggesting
that TNF-␣ is produced and expressed by muscle fibers
and is associated with regeneration.
Although the role of TNF in the pathogenesis of inflammatory myopathies remains uncertain, anecdotal evidence of the efficacy of anti-TNF therapy in inflammatory myopathies has appeared. We believe that such
evidence must be heavily discounted because of a very
strong reporting bias towards positive outcomes in the
early application of almost any new therapy [16]. The
apparent development of clinical polymyositis in a patient with long-standing RA who underwent infliximab
therapy merits notice. Although the patient was clinically
asymptomatic with respect to polymyositis, anti-Jo-1 antibodies were present before the initiation of antiTNF-␣ therapy [17]. Thus anti-TNF-␣ agents should be
administered with caution in patients with myositisspecific as well as antinuclear antibodies even in the
absence of a clinical myopathy.
Co-stimulatory molecules
One of the most exciting recent discoveries is the finding
of the co-stimulatory molecule B7-H1 expression in cultured human myoblasts in the presence of INF-␥ as well
as its presence in inflammatory myopathy muscle specimens. Weindl et al. [18•] examined the pathophysiologic
significance of B7-H1 by examining muscle biopsies
from patients with IIM as well as those with a noninflammatory myopathy and normal controls for B7-H1
expression by immunohistochemistry. MHC Class I expression and anti-CD28 were assessed as well. Nonmyopathic and noninflammatory myopathy specimens had
no evidence of B7-H1 expression, whereas B7-H1 expression was detected in almost all inflammatory myopathy specimens. The B7-H1 positive muscle fibers were
in direct contact with T cells, and they were found at the
juxtaposition of inflammatory cells and non-necrotic
damaged muscle fibers. The authors contend that the
role of B7-H1 may be a protective mechanism activated
in response to damage of MHC-expressing target cells
provoked by INF-␥.
Human cells express inducible co-stimulator ligand
(ICOSL), another functional co-stimulatory member of
the B7 family. ICOSL interacts with its receptor, ICOS,
on activated T cells to regulate CD4 and CD8 T-cell
responses. Wiendl et al [19•] showed that normal fibers
constitutively expressed low levels of ICOSL while
muscle fibers in patients with inflammatory myopathies
demonstrated markedly increased ICOSL expression.
The ICOSL-ICOS interactions may play a part in antigen presentation in the pathogenesis of inflammatory
myopathies.
Myosin heavy chain
The utility of MHC Class I staining in evaluating myopathies is receiving considerable attention. Van der Pas
et al. [20] proposed to determine whether MHC Class I
antigen expression is upregulated in the sarcolemma in
patients with IIM, and if so, whether this upregulation
could be used as an additional diagnostic tool. They concluded that detection of sarcolemmal MHC Class I is a
valid test for IIM and is not affected by immunosuppressive therapy used for less than 4 weeks. About 4% of
biopsies from patients with a dystrophy were positive. In
a smaller study, Civatte et al. [21] further investigated the
value of MHC Class I detection in muscle biopsies of
patients believed to have DM clinically despite having
noninformative muscle biopsies. They found abnormal
sarcolemmal expression of class I MHC regardless of
whether or not the muscle biopsy demonstrated histopathology consistent with DM. In patients with typical biopsy features, class I expression was observed in nearly
all muscle fibers but was strongest in perifascicular areas
or was restricted to perifascicular atrophic fibers. In all
muscle biopsies of DM patients without typical DM features, only some perifascicular fibers expressed class I
MHC. They concluded that abnormal perifascicular
MHC class I expression may aid in diagnosis in patients
with clinical DM in the absence of conclusive histopathologic evidence of the disease.
Cytokine/cell adhesion/signaling
molecules/chemokines/receptors
Both angiogenesis and leukocyte recruitment play a critical role in chronic inflammation, and chemokines have
an essential function in these processes. De Paepe et al.
[22] hypothesized that the CXCR4/SDF-1 interaction
represented a regulatory system involved in the accumulation, migration, and activation of lymphocytes important in the immunopathogenesis of IIM. They demonstrated that CXCR chemokine receptors levels are
elevated in IIM, suggesting either that the CXCR4positive cells are selectively recruited to sites of inflammation via local SDF-1 secretion or that membranous
CXCR4 secretion is locally upregulated. Thus the SDF1/CXCR4 interaction may be a useful therapeutic target.
Autoreactive T cells are important mediators of tissue
injury and potential targets for intervention in human
autoimmune diseases including polymyositis. In a technically fascinating and impressive paper, Hofbauer et al.
[23••] successfully characterized the TCR of autoaggressive T cells over time in biopsies of patients with myositis. This important technique has applicability to other
autoimmune inflammatory disorders as well.
Lindvall’s group showed that the LFA-1/VLA-4 ratio
was lower in patients with PM compared with patients
with noninflammatory myopathy or normal controls [24].
They suggest that the VLA-4/VCAM-1 system is an important part of chronic T-cell inflammation of the
muscle.
S-protein and CD-59 are complement regulators that
bind to and inactivate the complement membrane attack
complex (MAC). In addition to the deposition of MAC in
necrotic fibers, MAC has been found in non-necrotic
muscle fibers in inflammatory myopathies and muscular
dystrophies where it is believed that MAC deposition
may play a role in muscle damage [25]. Louboutin et al.
[26] characterized the putative role of S-protein and CD59 in DMD and PM—two diseases where MAC deposition has been found. They showed that CD59 disappears
from the sarcolemma when fiber necrosis occurs; thus, it
cannot inhibit the formation of MAC as it usually does.
Secondly, their results suggested that S-protein was not
able to prevent the full assembly of MAC in necrotic
fibers of DMD and PM patients; rather it could inactivate MAC deposition inside necrotic fibers or clear the
MAC-targeted muscle fibers.
Oxidative stress
Oxidative stress has been implicated in the pathogenesis
of inflammatory and noninflammatory muscle diseases.
Semicarbazide-sensitive amine oxidase (SSAO) deaminates aromatic and aliphatic primary amines. In the catalytic reaction, oxygen is consumed, and hydrogen peroxide, aldehydes, and ammonia are the final products.
SSAO is present in plasma and associated with mammalian tissue membranes, but it is found in very low levels
in human skeletal muscle [27•]. Testing the idea that
deamination is enhanced in inflammatory myopathies
and that SSAO’s contribution results in an additional
source of oxidative stress in myopathies, Olive et al. [28]
demonstrated the overexpression of SSAO in diseased
skeletal muscle.
Transglutaminase 2 overexpression
Knowing that transglutaminase 2 (TGase 2) is overexpressed in sporadic inclusion body myositis (sIBM), Choi
et al. [29] concluded from their prior work with sIBM that
an increase in transglutaminase 2 may also be present in
other inflammatory myopathies, such as PM and DM.
Choi, who had previously shown aberrant expression of
TGAse 2 is associated with inclusion body formation in
sIBM, considered that overexpression of TGase 2 might
be a universal feature of IIM. Immunocytochemistry and
quantitative RT-PCR on the muscle tissue of patients
with Duchenne muscular dystrophy (DMD) and normal
controls as well as patients with PM and DM uncovered
an increased level of TGAse 2 expression only in PM and
DM tissues. The jump to the conclusion that TGase 2
inhibition might open a therapeutic avenue in the idiopathic inflammatory myopathies seems premature.
Autoimmunity: Jo-1
Anti-Jo-1, directed against the ubiquitous intracellular
enzyme, histidyl tRNA synthetase, is the most common
myositis-specific antibody. Although it is often described
in concert with interstitial lung disease, it has rarely been
described with concomitant malignancy. A recent report
of a case of poorly differentiated adenocarcinoma in a
patient who was anti-Jo-1 positive [30] raises new possibilities about the source of the antigens driving myositisspecific autoantibodies, the relation of the myopathy to
the associated tumor, and the order of events, since the
autoantibodies and the tumor both antedate the onset of
clinical myopathy.
Genetic susceptibility
Specific HLA subtypes are believed to confer increased
risk for developing PM and DM. These include HLADRB1*03 in Caucasians and HLA-DRB1*14 in Koreans
[31,32]. It is not known, however, whether this association is primary or merely represents an association with
other genes in the HLA region. Hassan et al. [33] conducted a study in 65 adult patients with PM or DM to
analyze associations between individual genotypes in the
HLA region as well as various haplotypes including the
following genetic markers: SNPs in HLA-DRB1 and
TNF genes as well as microsatellite markers in TNF and
MICA genes. Their observations suggested that the ancestral haplotype (A1;B8;DRB1*03) along with the
TNF2 allele, as opposed to the HLA-DR3 gene itself, is
an important susceptibility factor for the development of
PM and DM.
Lampe et al. [34] found a significant increase in frequency of the following HLA alleles in patients with
sIBM compared with normal controls: A*03, B*08,
DRB1*03, and DQB1*05, with DRB1*03 having the
most statistically significant increase as compared with
normals. The authors contend, as others have before,
that HLA typing may help to distinguish between IBM
subtypes and perhaps may predict who will benefit from
future therapeutic interventions.
Because of the similarities observed in the skin and
muscle of patients with chronic graft versus host disease
(cGVHD) and dermatomyositis, particularly juvenile
DM, the pathogenesis is thought to be similar. Microchimerism—the presence of cells acquired by transplacental transfer from fetus to mother or mother to fetus—
has been observed in both peripheral blood and muscle
cells of patients with IIM. HLA-DQA1*0501 is believed
to confer increased risk for these diseases in some populations. Although HLA-DQA1*0501 has been associated
with microchimerism [35], Artlett et al. [36] were unable
to show that DQA1*0501 was associated with microchimerism in T lymphocytes or whole blood DNA in patients with SSc, juvenile IIM, or healthy controls. Thus,
the HLADQA1 alleles do not appear to play a role in the
persistence of microchimerism inpatients with autoimmune myopathies.
Autoimmunity
It is debated whether sIBM is primarily immunemediated; some experts, particularly neurologists, prefer
the name inclusion body myopathy. A recent case describing the concomitant findings of anti-PM-SCl antibodies in a patient with IBM supports a role for autoimmunity pathogenesis of IBM [37]. In addition, IBM has
been described in concert with autoimmune rheumatic
diseases, albeit rarely. Most recently, the combination of
SLE, Sjogren syndrome, and IBM was reported for the
first time [38]. The patient had SLE for over a decade
when she presented with muscle weakness. Electron microscopy demonstrated intranuclear and intracytoplasmic
tubulofilamentous inclusions; the patient improved with
high-dose methotrexate therapy.
Muntzing et al. [39] demonstrated the presence of clonal
restriction of TCR expression in muscle-infiltrating lymphocytes in IBM. Identical T-cell clones predominate in
different muscles and exist for many years, suggesting an
antigen-driven inflammatory reaction in IBM.
Protein folding and trafficking
The “unfolded protein response” (UPR) is a functional
mechanism whereby cells protect themselves from endoplasmic reticulum (ER) stress by assuring proper folding and preventing buildup of unfolded proteins in the
ER. This is accomplished with the help of molecular
chaperones such as calnexin, calreticulin, GRP94,
BiP/GRP78, and ERp72. Expression and immunolocalization of these proteins was studied in patients with
sIBM and controls, and in amyloid-␤-precursor protein
(AßPP) overexpressing cultured human muscle fibers
[40]. All five ER chaperones physically associated with
A␤lPP in sIBM muscle, implying that they may play a
role in AßPP folding and processing.
The lysosomal system of muscle fibers may also play a
critical role in rimmed vacuole formation [41]. Work by
Kumamoto et al. [42] showed that the transport of newly
synthesized lysosomal enzymes via the Golgi apparatus
and autophagic vacuole formation in the lysosome system is activated in sIBM. This was demonstrated by the
observation of clathrin and M6PR, which facilitate receptor-mediated intracellular transport inside rimmed
vacuoles and in the sarcoplasm of vacuolated or nonvacuolated fibers, but not in control specimens. PrPSc, a
hallmark of prion diseases such as spongiform encephalopathies, was demonstrated to be a prominent constituent in sporadic IBM muscle tissue of a patient with concomitant Creutzfeldt-Jakob Disease (CJD)[43]. The
existence of muscle disease in subtypes of CJD may
deserve further systematic investigation, as distinct glycotyopes of PrSc may be present in muscle and brain.
The muscle glycotype in this case report resembled that
found in vCJD brain.
Although it is attractive to connect vacuolar trafficking
abnormalities of glycoproteins to IBM because of the
known genetic lesion in one type of hereditary IBM (see
below), for the moment, it seems safest to consider these
observations as evidence of yet another group of proteins
being trapped in IBM inclusions.
UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) mutation
The genetic absence of GNE activity leads to muscle
weakness in hereditary inclusion body myositis (HIBM),
perhaps by interfering with the trafficking of glycoproteins. Huizing et al. [44•] examined the glycosylation
status of ␣-dystroglycan (a central protein of skeletal
muscle dystrophin) in muscle biopsies of four HIBM
patients and found absent or markedly reduced ␣-dystroglycans using antibodies specific for ␤-dystoglycan
and laminin ␣-2. They suggest that HIBM may therefore
be a “dystroglycanopathy,” similar to the process in congenital muscular dystrophies—perhaps providing one
mechanism for the muscle weakness of HIBM patients.
In an important series of observations, inflammation has
now been clearly recognized in hereditary IBM. Yabe et
al. [45••] reported two cases of distal myopathy with
rimmed vacuoles (DMRV) in a Japanese family in which
inflammation (an unusual feature of DMRV) was present
as well as a compound heterozygous mutation in their
GNE gene. Mutations associated with DMRV in this
study were localized to the kinase domain. An additional
novel homozygous mutation was discovered in a nonJewish Iranian population with quadriceps-sparing myopathy
consistent with adult onset hIBM: G-to-A mutation in
exon 7 changing valine to isoleucine in the epimerase
domain of GNE [46]. Muscle inflammation was present
in this case as well.
These important observations blur the boundary between purely hereditary and sporadic IBM, in particular
by raising the possibility that the inflammation seen in
apparently sporadic IBM might be a downstream secondary event following damage induced by as-yet unrecognized genetic mutations.
The Middle East cluster of hIBM is the result of a
founder mutation with incomplete penetrance and is not
limited only to the Jewish population. One hundred
twenty-nine patients in 55 families with a known history
of hIBM were homozygous for the M712T mutation,
initially described as the “Persian Jewish Mutation” [47].
Argov et al. [47] have found that the phenotypic spectrum is wider than initially thought. In a study by Del Bo
et al., genetic analysis of the GNE gene in an Italian
family with autosomal recessive h-IBM demonstrated
two novel mutations: a heterozygous deletion involving
exons 1–9 and the missense R162C mutation [48]. The
quadriceps weakness was apparently distinct from that
found in the quadriceps sparing nonPersian Jewish families with a different GNE mutation.
Hereditary IBM with early-onset Paget disease of bone
and frontotemporal dementia (IBMPFD) is a rare form of
hereditary myopathy. Its clinical attributes distinguish it
from the other forms of hIBM linked to chromosome 9.
Watts et al. [49] found no relation of GNE mutations with
IBMPFD, confirming genetic heterogeneity with IBM2.
lungs and the skeletal muscle to account for the high prevalence of concomitant
pathology and the autoantibodies—directed to aminoacyl-tRNA synthetases—found
in patients with both lung and muscle involvement.
9
Cottin V, Thivolet-Bejui F, Reynaud-Gaubert M, et al.: Interstitial lung disease
in amyopathic dermatomyositis, dermatomyositis and polymyositis. Eur
Respir J 2003, 22:245–250.
10
High WA, Cohen JB, Murphy BA, Costner MI: Fatal interstitial pulmonary
fibrosis in anti-Jo-1-negative amyopathic dermatomyositis. J Am Acad Dermatol 2003, 49:295–298.
11
Bronner IM, Hoogendijk JE, Wintzen AR, et al.: Necrotising myopathy, an
unusual presentation of a steroid-responsive myopathy. J Neurol 2003,
250:480–485.
Other genetic evidence
The muscle morphology in X-EDMD is not pathognomonic; rather, there are nonspecific myopathic changes
including endomysial connective tissue proliferation, fiber splitting, type II fiber predominance, and type I fiber
atrophy. A recent paper reported the co-existence of
x-linked Emery-Dreifuss muscular dystrophy (EDMD)
and IBM [50]. Thus typical IBM morphologic features
may be found in other neuromuscular disorders.
Conclusion
Although the pathogenesis of the inflammatory myopathies remains obscure, great strides over the past year
have placed us closer to understanding the etiologies of
these diverse disease entities. We have deepened our
understanding that although these diseases may share
some components of the clinical phenotype as well as
some serologic similarities, they differ on a molecular
and cellular level. The inflammatory myopathies result
from a combination of interactions between environmental and genetic risk factors, and the need for definitive,
safer therapeutic options in inflammatory myopathies
makes the search for defining detailed pathogenesis of
inflammation and muscle fiber damage at the molecular
level essential.
De Bleecker J, Vervaet V, Van den Bergh P: Necrotizing myopathy with microvascular deposition of the complement membrane attack complex. Clin
Neuropathol 2004, 23:76–79.
The papers of Bronner [11] and De Bleecker resemble earlier observations on the
necrotizing myopathy with little or no inflammation seen in patients with anti-SRP
autoantibodies.
12
•
Okada S, Weatherhead E, Targoff IN, et al.: Global surface ultraviolet radiation intensity may modulate the clinical and immunologic expression of autoimmune muscle disease. Arthritis Rheum 2003, 48:2285–2293.
A group of clinicians from around the around the world with expertise in myositis
joined together by Dr. Fred Miller and his colleagues in the National Institute of
Environmental Health Sciences at NIH have made an excellent advance in providing a plausible model for how an environmental factor might influence the phenotype of a disease with a strong genetic component. Their success depended upon
starting with a good hypothesis.
13
••
14
Werth VP, Bashir M, Zhang W: Photosensitivity in rheumatic diseases. J Investig Dermatol Symp Proc 2004, 9:57–63.
15
Kuru S, Inukai A, Kato T, et al.: Expression of tumor necrosis factor-alpha in
regenerating muscle fibers in inflammatory and non-inflammatory myopathies.
Acta Neuropathol (Berl) 2003, 105:217–224.
16
Hengstman GJ, van den Hoogen FH, Barrera P, et al.: Successful treatment
of dermatomyositis and polymyositis with anti-tumor-necrosis-factor-alpha:
preliminary observations. Eur Neurol 2003, 50:10–15.
17
Musial J, Undas A, Celinska-Lowenhoff M: Polymyositis associated with infliximab treatment for rheumatoid arthritis. Rheumatology (Oxford) 2003,
42:1566–1568.
•
Of special interest
••
Andersson J, Englund P, Sunnemark D, et al.: CBA/J mice infected with Trypanosoma cruzi: an experimental model for inflammatory myopathies. Muscle
Nerve 2003, 27:442–448.
Despite the apparent remoteness of this parasite-induced disease from the apparently autoimmune pathology of human idiopathic inflammatory myopathy, this
model mimics the pathologic picture closer than most others. It may, however,
prove too remote and unfamiliar to be attractive to other investigators.
1
••
Wiendl H, Mitsdoerffer M, Schneider D, et al.: Human muscle cells express a
B7-related molecule, B7-H1, with strong negative immune regulatory potential: a novel mechanism of counterbalancing the immune attack in idiopathic
inflammatory myopathies. FASEB J 2003, 17:1892–1894.
This is a follow-up of important earlier observations on this newly recognized costimulatory path.
18
•
Wiendl H, Mitsdoerffer M, Schneider D, et al.: Muscle fibres and cultured
muscle cells express the B7.1/2-related inducible co-stimulatory molecule,
ICOSL: implications for the pathogenesis of inflammatory myopathies. Brain
2003, 126:1026–1035.
Another possibly important co-stimulatory pair identified by this group adds expected complexity to the picture of pathogenesis.
19
•
20
van der Pas J, Hengstman GJ, ter Laak HJ, et al.: Diagnostic value of MHC
class I staining in idiopathic inflammatory myopathies. J Neurol Neurosurg
Psychiatry 2004, 75:136–139.
Petersen LR, Marfin AA: West Nile virus: a primer for the clinician. Ann Intern
Med 2002, 137:173–179.
21
4
Douche-Aourik F, Berlier W, Feasson L, et al.: Detection of enterovirus in
human skeletal muscle from patients with chronic inflammatory muscle disease or fibromyalgia and healthy subjects. J Med Virol 2003, 71:540–547.
Civatte M, Schleinitz N, Krammer P, et al.: Class I MHC detection as a diagnostic tool in noninformative muscle biopsies of patients suffering from dermatomyositis (DM). Neuropathol Appl Neurobiol 2003, 29:546–552.
22
5
Leff RL, Love LA, Miller FW, et al.: Viruses in idiopathic inflammatory myopathies: absence of candidate viral genomes in muscle. Lancet 1992,
339:1192–1195.
De Paepe B, Schroder JM, Martin JJ, et al.: Localization of the alphachemokine SDF-1 and its receptor CXCR4 in idiopathic inflammatory myopathies. Neuromuscul Disord 2004, 14:265–273.
2
Smith RD, Konoplev S, DeCourten-Myers G, Brown T: West Nile virus encephalitis with myositis and orchitis. Hum Pathol 2004, 35:254–258.
3
6
Chevrel G, Borsotti JP, Miossec P: Lack of evidence for a direct involvement
of muscle infection by parvovirus B19 in the pathogenesis of inflammatory
myopathies: a follow-up study. Rheumatology (Oxford) 2003, 42:349–352.
Fathi M, Dastmalchi M, Rasmussen E, et al.: Interstitial lung disease, a common manifestation of newly diagnosed polymyositis and dermatomyositis.
Ann Rheum Dis 2004, 63:297–301.
A fine report of a large experience with a remarkably high proportion of patients with
lung involvement.
7
•
Schnabel A, Reuter M, Biederer J, et al.: Interstitial lung disease in polymyositis and dermatomyositis: clinical course and response to treatment. Semin
Another nicely studied series with a relatively high incidence of lung involvement. It
seems likely that there will turn out to be common microenvironmental factors in the
8
•
Hofbauer M, Wiesener S, Babbe H, et al.: Clonal tracking of autoaggressive
T cells in polymyositis by combining laser microdissection, single-cell PCR,
and CDR3-spectratype analysis. Proc Natl Acad Sci USA 2003, 100:4090–
4095.
An impressive array of highly sensitive techniques have been brought together to
explore important questions about individual immune cells that inhabit the inflammatory lesions in myositis. A tour de force.
23
••
24
Lindvall B, Dahlbom K, Henriksson KG, et al.: The expression of adhesion
molecules in muscle biopsies: the LFA-1/VLA-4 ratio in polymyositis. Acta
Neurol Scand 2003, 107:134–141.
25
Sewry CA, Dubowitz V, Abraha A, et al.: Immunocytochemical localisation of
complement components C8 and C9 in human diseased muscle. The role of
complement in muscle fibre damage. J Neurol Sci 1987, 81:141–153.
26
Louboutin JP, Navenot JM, Rouger K, Blanchard D: S-protein is expressed in
necrotic fibers in Duchenne muscular dystrophy and polymyositis. Muscle
Nerve 2003, 27:575–581.
Andres N, Lizcano JM, Rodriguez MJ, et al.: Tissue activity and cellular localization of human semicarbazide-sensitive amine oxidase. J Histochem Cytochem 2001, 49:209–217.
This is an intriguing new window on the very local events where the damage is
occurring.
27
•
28
Olive M, Unzeta M, Moreno D, Ferrer I: Overexpression of semicarbazidesensitive amine oxidase in human myopathies. Muscle Nerve 2004, 29:261–
266.
29
Choi YC, Kim TS, Kim SY: Increase in transglutaminase 2 in idiopathic inflammatory myopathies. Eur Neurol 2004, 51:10–14.
30
Watkins J, Farzaneh-Far R, Tahir H, et al.: Jo-1 syndrome with associated
poorly differentiated adenocarcinoma. Rheumatology (Oxford) 2004,
43:389–390.
31
Hausmanowa-Petrusewicz I, Kowalska-Oledzka E, Miller FW, et al.: Clinical,
serologic, and immunogenetic features in Polish patients with idiopathic inflammatory myopathies. Arthritis Rheum 1997, 40:1257–1266.
32
Rider LG, Shamim E, Okada S, et al.: Genetic risk and protective factors for
idiopathic inflammatory myopathy in Koreans and American whites: a tale of
two loci. Arthritis Rheum 1999, 42:1285–1290.
33
Hassan AB, Nikitina-Zake L, Sanjeevi CB, et al.: Association of the proinflammatory haplotype (MICA5.1/TNF2/TNFa2/DRB1*03) with polymyositis and
34
Lampe JB, Gossrau G, Kempe A, et al.: Analysis of HLA class I and II alleles
in sporadic inclusion-body myositis. J Neurol 2003, 250:1313–1317.
35
clonal expansions of muscle-infiltrating T cells persist over time. Scand J Immunol 2003, 58:195–200.
40
Vattemi G, Engel WK, McFerrin J, Askanas V: Endoplasmic reticulum stress
and unfolded protein response in inclusion body myositis muscle. Am J Pathol
2004, 164:1–7.
41
Tsuruta Y, Furuta A, Furuta K, et al.: Expression of the lysosome-associated
membrane proteins in myopathies with rimmed vacuoles. Acta Neuropathol
(Berl) 2001, 101:579–584.
42
Kumamoto T, Ueyama H, Tsumura H, et al.: Expression of lysosome-related
proteins and genes in the skeletal muscles of inclusion body myositis. Acta
Neuropathol (Berl) 2004, 107:59–65.
43
Kovacs GG, Lindeck-Pozza E, Chimelli L, et al.: Creutzfeldt-Jakob disease
and inclusion body myositis: abundant disease-associated prion protein in
muscle. Ann Neurol 2004, 55:121–125.
Huizing M, Rakocevic G, Sparks SE, et al.: Hypoglycosylation of alphadystroglycan in patients with hereditary IBM due to GNE mutations. Mol
Genet Metab 2004, 81:196–202.
This study is an imaginative approach to make the connection between a known
genetic lesion and a distant clinical symptom.
44
•
45 Yabe I, Higashi T, Kikuchi S, et al.: GNE mutations causing distal myopathy
with rimmed vacuoles with inflammation. Neurology 2003, 61:384–386.
••
An interesting and welcome complexity that suggests that it is highly likely that
inflammation in many circumstances in muscle disease will one day be discovered
to be a secondary event.
46
Krause S, Schlotter-Weigel B, Walter MC, et al.: A novel homozygous missense mutation in the GNE gene of a patient with quadriceps-sparing hereditary inclusion body myopathy associated with muscle inflammation. Neuromuscul Disord 2003, 13:830–834.
Lambert NC, Evans PC, Hashizumi TL, et al.: Cutting edge: persistent fetal
microchimerism in T lymphocytes is associated with HLA-DQA1*0501: implications in autoimmunity. J Immunol 2000, 164:5545–5548.
47
Argov Z, Eisenberg I, Grabov-Nardini G, et al.: Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. Neurology 2003, 60:1519–
1523.
36
Artlett CM, O’Hanlon TP, Lopez AM, et al.: HLA-DQA1 is not an apparent risk
factor for microchimerism in patients with various autoimmune diseases and
in healthy individuals. Arthritis Rheum 2003, 48:2567–2572.
48
Del Bo R, Baron P, Prelle A, et al.: Novel missense mutation and large deletion
of GNE gene in autosomal-recessive inclusion-body myopathy. Muscle Nerve
2003, 28:113–117.
37
Selva-O’Callaghan A, Mijares-Boeckh-Behrens T, Labrador-Horrillos M, et al.:
Anti-PM-Scl antibodies in a patient with inclusion body myositis. Rheumatology (Oxford) 2003, 42:1016–1018.
49
Watts GD, Thorne M, Kovach MJ, et al.: Clinical and genetic heterogeneity in
chromosome 9p associated hereditary inclusion body myopathy: exclusion of
GNE and three other candidate genes. Neuromuscul Disord 2003, 13:559–
567.
38
Derk CT, Vivino FB, Kenyon L, Mandel S: Inclusion body myositis in connective tissue disorders: case report and review of the literature. Clin Rheumatol
2003, 22:324–328.
50
39
Muntzing K, Lindberg C, Moslemi AR, Oldfors A: Inclusion body myositis:
Fidzianska A, Rowinska-Marcinska K, Hausmanowa-Petrusewicz I: Coexistence of X-linked recessive Emery-Dreifuss muscular dystrophy with inclusion
body myositis-like morphology. Acta Neuropathol (Berl) 2004, 107:197–
203.
Have recent immunogenetic investigations increased
our understanding of disease mechanisms in the
idiopathic inflammatory myopathies?
Hector Chinoy, William E.R. Ollier and Robert G. Cooper
Purpose of review
The idiopathic inflammatory myopathies (IIM) continue to
provide a challenge given the variable effectiveness of the
available treatments, and immunogenetic studies are ongoing
to further elucidate IIM disease mechanisms. This review
examines how recent research has improved our
understanding of the mechanisms that lead to IIM.
Recent findings
HLA-DRB1 studies in a large homogenous cohort of UK
Caucasian patients have confirmed that polymyositis (PM) and
dermatomyositis (DM) are not genetically identical diseases
while other studies have shown that tumor necrosis factor
alpha is genetically implicated in disease susceptibility. Some
remarkable results from an international collaboration,
correlating gene-environment interactions, clearly suggest that
ultraviolet light is capable of modulating both clinical and
immunologic features of IIMs. Studies on microchimerism are
unraveling interesting associations in juvenile DM patients, and
bolstering the hypothesis that myositis may be an ‘allo-immune’
disease. mRNA gene expression profiling is helping to
increase our understanding of myositis pathogenesis, whilst
animal models have provided new information on the roles of
Th1 responses and nitric oxide synthase in muscle disease.
New candidate genes have been examined in inclusion body
myositis (IBM), and a novel gene transfer experiment has been
conducted, which led to significant changes in expression of
the IBM phenotype.
Summary
Improving the understanding of the immunogenetics and
immunopathogenesis of the IIMs may in the future provide
novel therapeutic targets, and thus improve outcomes in these
difficult diseases.
Keywords
idiopathic inflammatory myopathies, immunogenetics,
polymyositis, dermatomyositis, inclusion body myositis, HLA,
haplotypes, microchimerism
Rheumatic Diseases Centre, Hope Hospital, Salford, UK
Correspondence to Robert G. Cooper, Rheumatic Diseases Centre, Hope Hospital,
Salford M6 8HD, UK
Tel: +44 (0)161 206 4367; e-mail: rcooper@fs1.ho.man.ac.uk
1040–8711
Introduction
The idiopathic inflammatory myopathies (IIMs) are a
heterogeneous group of potentially serious rare diseases,
defined by the presence of acquired muscle inflammation and weakness. Polymyositis (PM) and dermatomyositis (DM) are the subtypes most often seen by rheumatologists. Although corticosteroids, immunosuppressive
agents, and intravenous immunoglobulins can all be effective in managing PM/DM, the response to these
therapies is variable, and often disappointing. Patients
thus occasionally die from their disease, while survivors
frequently remain disabled through persisting weakness
or lung fibrosis. Given the limited effectiveness of available agents, new and more potent therapies are clearly
needed. However, to facilitate the development of novel
therapies, the etiopathogenic mechanisms underlying
these conditions require further elucidation. The IIMs
are rare diseases, with an annual incidence ranging 2.18
to 7.7 cases per million [1]; so research into these mechanisms has proved difficult.
It is becoming increasingly obvious that genetic factors
are involved [2]. The previous evidence for a genetic
basis in IIMs, as extensively reviewed in 2000 by Shamim et al. [3], has largely come from candidate gene
studies, as the rarity of IIMs has precluded the use of
more robust genetic methods, such as twin studies,
whole genome scans, and transmission disequilibrium
testing [4]. However, multiple case reports where two or
more members are affected in one family [3], clearly
suggest a familial predisposition for developing IIMs.
Indeed, Rider et al. [5] confirmed that HLA-DRB1*0301
and homozygosity of HLA-DQA1 represent risk factors
for developing familial IIMs. Candidate gene studies in
nonfamilial IIM have mainly concentrated on the HLA
class II region, confirming that HLA-DRB1*0301 and
the linked allele HLA-DQA1*0501 are risk factors for
developing IIMs in Caucasians, but not in Mesoamerican
Mestizos, Koreans, or Japanese populations [6–10]. Gene
polymorphisms other than HLA class II are also associ707
ated with IIMs, including those of the IL-1 receptor
antagonist [11], tumor necrosis factor alpha (TNF␣) [12],
and Gm/Km allotypes [8].
HLA-related differences
in polymyositis/dermatomyositis
Most previous IIM candidate gene studies have analyzed
adult and juvenile PM/DM patient results together, and
some studies even included results from patients with
inclusion body myositis (IBM) [3]. Such ‘pooling’ reflects the sample size problems outlined, and was presumably undertaken to gain power during statistical
comparisons of IIM patients with control subjects. Given
the phenotypic differences (ie, of clinical, serological, and
pathologic features) between IIM subtypes, a more logical approach would be to compare and contrast, rather
than group, these diseases. To get over the sample size
problems, and thus to address the question of whether
PM and DM are genetically the same with respect to
HLA class II, we recently coordinated a nationwide collaborative study of 59 physicians, constituting the UK
‘Adult Onset Myositis Immunogenetic Collaboration’
(AOMIC), which recruited 110 PM and 98 DM UK Caucasian patients over 4 years (Chinoy et al, unpublished
data). These patients’ HLA-DRB1 data were compared
with those of 537 ethnically matched controls. The results confirmed that HLA-DRB1*03 was a risk factor for
PM (odds ratio [OR] 4.0, 95% confidence interval [CI]
2.6–6.1) (Table 1). However, there was also a significant
protective effect of HLA-DRB1*07 in PM versus controls (OR 0.3, 95% CI 0.4–0.6). The results for DM patients were different, as the association with HLADRB1*03 was considerably weaker than for PM (OR 2.0,
95% CI 1.3–3.1) and, by contrast with PM, DRB1*07
represented a risk factor versus controls (OR 1.8, 95% CI
1.2–2.9). These results suggest that, at least in a UK
Caucasian population, HLA-DRB1 not only plays a role
in governing PM/DM disease susceptibility, through association with DRB1*03, but may also govern myositis
disease phenotype, through association with DRB1*07.
These alleles may be a marker for another contributory
factor (eg, a different allele in linkage disequilibrium
forming part of a broader haplotype, or an autoantibody).
Autoantibodies and ‘elemental disorders’
It was previously thought that genetically predisposed
individuals may only develop their autoimmune disease
after certain interactions with environmental triggers
[13,14], so is there any recent evidence to support this?
Two previous studies suggested that decreasing latitude
exerts an influence on the proportion of a myositis population with DM rather than PM [8,15]. The findings of a
more recent paper by Okada et al. [16••] are thus of great
interest. In studying 919 IIM patients in 15 global locations for 13 different climatic variables, surface ultraviolet (UV) light intensity proved the strongest contributor
to the relative proportion of DM compared with PM (r =
0.939, P < 4 × 107), and to the relative proportion of
anti-Mi-2 antibodies (r = 0.69, P = 0.02) (Fig. 1). It thus
appears that the greater an individual’s exposure to sunlight, the greater the likelihood that, if that individual
did develop myositis, it would be of anti-Mi-2 positive
DM in type. These remarkable results suggest that an
environmental factor may be capable of modulating the
expression of both the clinical and immunologic features
of the resulting myositis. The authors speculated that
sunlight achieves this by playing an etiological role in the
development of Mi-2 antibodies, and thus DM, via
mechanisms of UV-induced immune dysregulation
[16••]. The presence of anti-Mi-2 antibodies in DM patients are very strongly associated with HLA-DRB1*0701,
with Mierau et al. [17] demonstrating an OR of 22 versus
controls, in a Caucasian population, and Shamim et al. [8]
demonstrating an association in Caucasians and Mexican
Mestizos. Miller describes the concept of ‘elemental disorders’, where autoimmune diseases as we understand
them, are the result of a specific pathogenesis due to
interactions between genetic and elemental environmental risk factors to produce unique sign-symptom
complexes [18].
Nonclassical HLA and cytokine genes
TNF␣ is a pro-inflammatory cytokine that plays a major
role in immune response regulation, and is encoded
within the MHC class III region. The TNF␣ promoter
single nucleotide polymorphism (SNP) at position −308,
resulting from a G to an A substitution, is termed TNF2
(−308A), and associations with this allele are found in
juvenile DM (JDM) [12] and adult DM [19]. A recent
JDM gene expression profile study led to the proposal of
a novel JDM pathogenesis model, which encompasses
antiviral, ischemic, and degeneration/regeneration cascades, in which TNF␣ is thought to be a key molecule
[20]. Certainly, in JDM, TNF2 (−308A) is associated
with disease chronicity, pathologic calcification [19],
and increased circulating concentrations of an anti-
Table 1. Immunogenetic risk factors in UK AOMIC cohort
Controls
(n = 537)
HLA
DRB1*03
DRB1*07
n (%)
151 (28.1)
129 (24.0)
Polymyositis
(n = 110)
n (%)
67 (60.9)
9 (8.2)
p
Dermatomyositis
(n = 98)
pcorr
−11
3 × 10
1 × 10−04
−10
4 × 10
0.001
OR (95%CI)
n (%)
p
pcorr
OR (95%CI)
4.0 (2.6–6.1)
0.3 (0.4–0.6)
43 (43.9)
36 (36.7)
0.002
0.008
0.022
0.100
2.0 (1.3–3.1)
1.8 (1.2–2.9)
OR, odds ratio; CI, confidence interval; p, probability; pcorr, corrected for multiple comparisons using Bonferroni adjustment.
Disease mechanisms in IIM Chinoy et al. 709
Figure 1. Depiction of correlations
in normal muscle, but is found in muscle fibers, inflammatory cells, and capillaries in PM, DM, and IBM [24].
Through alternative splicing of transcripted HLA-G
mRNA, at least seven different isoforms have been identified, labeled HLA-G1 to -G7. HLA-G binds CD8+ cells
and antigenic peptides, is thought to play an important
role in immunotolerance, and more specifically, may
help prevent maternal lymphocytes from attacking fetal
tissue. Using in vitro models of human myoblasts and
TE671 muscle rhabdomyosarcoma cells, two isoforms,
transmembranous HLA-G1 and soluble HLA-G5, have
been investigated recently [25•]. The HLA-G isoforms
inhibited the primary alloreactive response to muscle
cells, and inhibited alloreactive lysis mediated by CD4+,
CD8+, and natural killer cells. Priming of cytotoxic T
cells was also inhibited, and muscle cells were protected
from antigen-specific cytotoxic T cell lysis. HLA-G1 and
-G5 are therefore powerful inhibitors of the primary and
secondary immune responses, and in the future these
results could form the basis for developing a novel
muscle cell protective agent for reducing IIM cellmediated injury.
Microchimerism
Correlations between the weighted surface ultraviolet (UV) intensity at each of
the global locations and the proportion of DM/DM & PM, and the proportion of
anti-Mi-2 autoantibodies/all myositis-specific autoantibodies (MSAs). Reprinted
with permission [16••]. Arthritis & Rheumatism © 2003. Reprinted by permission
of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
angiogenic factor, thrombospondin-1 [21]. TNF2
(−308A) is thought to be part of the common extended
haplotype A1;B8;DR3;DQ2, which has been associated
with autoimmunity [12]. A recent study compared 65
PM/DM patients to a matched control population, examining the associations of HLA-DRB1*03 and TNF2
(−308A) with two microsatellite markers, MICA5.1 and
TNFa2 [22]. The TNF2 (−308A) allele (OR 2.75, 95%
CI 1.35–5.61), and the haplotype MICA5.1/TNF2/
TNFa2/DRB1*03 (OR 3.48, 95% CI 1.71–7.09) were both
associated with PM/DM compared with controls. In line
with other autoimmune diseases, the ancestral haplotype
together with the TNF2 (−308A) allele, rather than
HLA-DRB1*03 alone, may be an important susceptibility
factor for the development of PM/DM [22•].
Muscle fibers in biopsies from IIM patients in vivo, and
in cultured muscle cells, express intracellular (cytoplasmic) HLA-G, a nonclassical MHC class I molecule,
which exhibits a highly restricted tissue distribution under physiologic conditions [23]. HLA-G is undetectable
Microchimerism refers to the low-level persistence of
nonself cells due to bidirectional trafficking of
fetal/maternal cells during pregnancy [26]. Maternal microchimeric cells (ie, nonhost cells) have been found in
the peripheral blood and muscle lesions of juvenile IIM
patients (Table 2) [27–33••]. In a recent study of HLA
and maternal microchimerism in JDM [33••], maternal
chimeric cells were identified in 60 of 72 (83%) JDM
patients, versus 5 of 29 (17%) healthy male controls (OR
24, 95% CI 6.9–93.0). All healthy siblings with microchimerism were either HLA-DQA1*0501 positive, or had
noninherited (maternal) DQA1*0501 cells present. Maternally derived chimeric cells from JDM patients produced high levels of interferon-gamma (IFN-␥) secreting
T cells when exposed to JDM lymphocytes, suggesting
an antihost immune response. A further study examined
microchimerism in 87 systemic sclerosis (SSc) and 28
JDM patients [32], and demonstrated an increased frequency of maternal microchimerism in SSc (33/47
[70.2%] patients, OR 2.5, 95% CI 0.9–7.6) and JDM
(20/28 [71.4%] patients, OR 33.7, 95% CI 5.7–329.8)
compared with controls. An increase in HLA-DQA1*0501
was observed in JDM patients positive for maternal microchimerism, although this effect did not reach statistical significance. HLA-DQA1*0501 is also strongly associated with fetal microchimerism in maternal T cells
[34], although this has not been demonstrated to date in
juvenile IIM. The risk for JDM and other autoimmune
diseases may be determined by the HLA genotype of
the mother, providing a ‘second hit’ to trigger disease in
genetically susceptible individuals [33••]. The inherited
HLA genotype may therefore contribute to loss of toler-
Table 2. Associations of maternal microchimerism with juvenile IIM patients
Sample
Method
PBMC
PBMC
PBMC
Muscle
PBMC†
Muscle
PBMC
NTMA
NTMA
FISH
FISH
FISH
FISH
NTMA
PBMC
FISH
Muscle
PBMC
PBMC
FISH
NTMA/Cw
NTMA
Frequencies of disease
vs comparison group
Comparison group
Associations
3/3 vs 2/7
13/15 vs 5/35
11/15 vs 5/17
12/15 vs 2/10
8/9 vs 0/9
10/10 vs 2/10
25/30 vs 7/39
7/100
22/30 vs 12/39
8/40
16/20 vs 1/10
20/28 vs 2/29
60/72 vs 11/48
5/29
Sibling
Sibling
Control
Control
Control
Control
Sibling
Control
Sibling
Control
Control
Control
Sibling
Control
p = 0.2*
OR 39.0 (5.6–406.8)
OR 6.6 (1.1–41.6)
OR 16.0 (1.7–202.9)
p = 0.0004*
p = 0.0007*
OR 22.9 (5.7–99.6)
OR 66.4 (17.1–278.1)
OR 6.1 (1.9–20.6)
OR 11.0 (3.2–39.4)
OR 36.0 (2.9–1671.8)
OR 33.8 (5.7–329.8)
OR 16.8 (6.2–46.7)
OR 24.0 (6.9–93.0)
References
[27]
[28]
[28]
[28]
[29]
[29]
[30]
[30]
[30]
[30]
[30]
[31,32]
[33••]
[33••]
Where odds ratios were not calculated in respective papers cited, the values shown in the table are those derived from data presented in each
paper.
*Odds ratios not possible as cells have zero values; †CD4+ and CD8+ cells used.
OR, odds ratio; PBMC, peripheral blood mononuclear cell; NTMA, nontransmitted maternal HLA-DQA1 allele; FISH, fluorescent in situ
hybridization; NTMA/Cw, non-transmitted maternal Cw allele.
ance and activation of chimeric cells, thereby initiating
the disease process and inflammation.
The finding of loss of tolerance is in contrast to other
situations where chimerism may be beneficial, such as
pregnancy or organ transplantation. An interesting analogy of microchimerism is that of chronic graft-versushost disease (GVHD), where donor cells infiltrate the
skin and mucous membranes [35]. Recently, a large cohort of patients undergoing hematopoietic stem cell
transplantation over a 30-year period were retrospectively reviewed [36••]. Of the 1859 patients who developed GVHD, 12 also developed a myositis syndrome
(GVHD-PM), resembling idiopathic PM in many clinical
and laboratory aspects. Not one of the stem cell transplant patients without GVHD developed myositis. As
the host’s immune system had been eliminated, the lymphocytic infiltration in the muscle of GVHD-PM patients was assumed to consist of donor cells [35]. The
cases of GVHD-PM, and their resemblance to IIM, suggest a common underlying pathogenesis in both conditions, with microchimeric cells in IIM forming the role of
donor cells, and bolsters the hypothesis that myositis
represents an allo-immune mediated disease [37].
As IBM usually presents with distal, rather than proximal, muscle weakness, and thus mimicking peripheral
neuropathy, it is rarely seen by rheumatologists. However, due to presence of inflammation in muscle biopsies, sporadic IBM is considered one of the IIMs and is
therefore included in this update. Several HLA and nonHLA loci are already known risk factors for sporadic IBM
[3]. HLA class I and II associations have recently been
examined in 47 sporadic IBM patients and 29,670 controls [38]. HLA-A*03 (OR 2.6, 95% CI 1.6–4.1), B*08 (OR
2.8, 95% CI 1.6–4.6), DRB1*03 (OR 3.5, 95% CI 2.1–5.6),
and DQB1*05 (2.0, 95% CI 1.2–3.3) alleles were all significantly increased compared with controls, even after
adjustment for multiple comparisons. The ethnicity of
the cases in this study was not stated and these results
should thus be interpreted with caution. There are currently no clinical or biochemical parameters that predict
the outcome of IBM or response to treatment, and HLA
typing may help subgroup IBM patients and predict such
parameters.
Sporadic IBM muscle biopsies possess structural abnormalities similar to those in brain tissue plaques from Alzheimer’s disease patients, including amyloid-␤ precursor
protein (A␤PP), amyloid-␤ (A␤), and apolipoprotein E
(apoE) [39]. Using an adenovirus vector, A␤ gene transfer into normal cultured human muscle fibers induced
phenotypic abnormalities similar to those found in IBM,
suggesting the likelihood of a key role of A␤PP/A␤ in
IBM pathogenesis [40]. The same gene was transferred
into muscle fibers from a patient with known sporadic
IBM and associated cardiac amyloidosis in whom a
Val122Ile transthyretin (TTR) mutation was also expressed [41•]. The resulting overexpression of the A␤
gene amplified the abnormalities found in this patient’s
cultured muscle fibers, including accelerated degeneration, inclusions, and vacuole formation, which were over
and above those seen in the normal muscle. The TTR
mutation could either be a genetic risk factor, or perpetuate the existing IBM. Polymorphisms of two further intracellular amyloid deposits, ApoE and ␣(1)-antichymotrypsin, have been tested in the peripheral blood of 35
sporadic IBM patients [42], but no significant associations or correlations with age of onset were found. An
important gene expression profiling study has also found
increased expression of amyloid-␤ and ApoE in IBM, but
significantly elevated levels of the same genes were also
demonstrated in PM and DM, suggesting that accumu-
lation of such proteins in IBM may be due to posttranscriptional events [43].
T cell receptors
Immunohistochemistry studies of biopsies from patients
with PM have demonstrated a predominance of CD8+ T
lymphocytes invading non-necrotic muscle fibers that
express HLA class I on their cell surface [44]. Previous
studies have demonstrated clonally expanded T cell receptor (TCR) families in muscle fibers of patients with
PM. To characterize the role of these T cells further, a
process of CDR3 spectratyping was combined with laser
microdissection and single-cell polymerase chain reaction (PCR), to select individual pathogenically relevant
T cells from PM muscle biopsies [45]. After examining
repeat biopsies in one patient, it was shown that T cell
clones could persist for many years. In another patient,
several T cells had minor nucleotide changes in the
CDR3 region of the T cell receptor, which did not alter
the amino acid sequences, thus suggesting the presence
of different T cell clones driving a common antigendriven response. Oligoclonal CDR3 spectratype peaks
disappeared during immunosuppressive treatment. Recent TCR expression work has also been performed in
IBM, again suggesting only a limited number of antigens
drive the inflammatory reaction [46]. These pathogenically relevant T cells may represent future epitopes for
targeted immunotherapy.
Animal models
Myositis is thought to be predominantly Th1 driven,
initiated by an (unknown) antigen and MHC interaction,
leading to T cell expansion, maturation, and subsequent
cytokine proliferation (eg, IFN-␥, IL-1, IL-18). Theoretically, dampening down of the Th1 cell response, and
switching to a Th2-driven system, producing alternative
cytokines (eg, IL-4, IL-6, IL-10), could dampen down
the pathogenicity of autoreactive T cells [47]. A strain of
nonobese diabetic (NOD) mice has been developed,
rendered Th1-deficient by a CD2 promoter driven
IFN-␥ receptor ␤-chain transgene [47]. An unexpected
consequence was the development of an early lethal myopathy due to a CD8+ T cell-dependent myositis syndrome, characterized by a massive leukocyte inflammatory response in the muscle fibers. By interacting with
other genetic components in the NOD model, the inhibition of Th1 responses may conversely have exacerbated certain autoimmune responses.
Another way of influencing the inflammatory response in
muscle is through nitric oxide (NO), which can be pro- or
anti-inflammatory depending on its concentration and
locality. A further transgenic mouse model has been developed with muscle-specific overexpression of neuronal
nitric oxide synthase (nNOS), driven by a human skeletal muscle actin promoter [48]. Using a rodent hindlimb
unloading/reloading model, overexpression of nNOS in-
hibited neutrophil production, and prevented any increases in muscle membrane damage. Muscle-derived
NO evidently functions as an anti-inflammatory molecule, and may provide a future potential therapeutic
target.
New and future approaches
The work done by Okada et al. [16••] and ourselves
demonstrates the advantages, and indeed necessity, of
undertaking national/international genetic collaborations. The results of these larger studies illustrate the
importance during genetic testing of treating IIM subtypes as discrete, rather than grouped, diagnoses. Due to
the rarity of IIMs, only further collaboration is likely to
elucidate the complex interactions between genetic and
environmental factors. Recently doubt has been cast on
the diagnostic category PM, as some patients have been
shown to have IBM or muscular dystrophy [49]. mRNA
microarray gene expression profiling studies may assist in
a more robust molecular reclassification of the IIMs [43],
whilst also providing novel molecular insights into the
role of genes in IIM subtypes (reviewed in [50•]). It is
relatively easy to obtain muscle biopsies, allowing ready
analysis of target tissue in IIM patients. Measurements
of mRNA levels allow the demonstration of which genes
are upregulated or downregulated (albeit without establishing cause and effect), and clarification of which genes
to analyze in further candidate gene studies. A recent
landmark study examined the molecular profiles of patients with IIMs, showing distinct changes from normal
muscle and differing between the IIMs [43]. An important distinguishing feature of DM, compared with PM
and IBM, was the increased expression of interferoninducible genes, and this finding was reproduced in a
JDM study [20], raising the hypothesis that DM has an
antigen-driven pathogenesis, and again supporting the
idea that PM and DM are genetically different. In the
future, improved techniques and reduced costs may allow the use of powerful high-density SNP arrays to conduct whole genome scans by association [50•–52].
Research continues worldwide into our understanding of
the underlying pathogenesis of the IIMs. A basic science
approach led to the elucidation of the key role of TNF␣
in RA, and the subsequent use of anti-TNF␣ therapy.
By analogy, ongoing collaborative genetic work may help
identify key hierarchical molecules implicated in IIM
pathology.
Acknowledgments
The authors thank the Arthritis Research Campaign and the Myositis Support
Group (UK), which provided the funds necessary to undertake the AOMIC genetic
analysis. We also wish to thank the 59 physicians who contributed to AOMIC.
•
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••
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An elegant gene transfer experiment upregulating the IBM phenotype in muscle
fibers of a patient expressing the TTR mutation.
41
•
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Neurol 2004, 51:215–220.
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50 Hoffman EP, Brown KJ, Eccleston E: New molecular research technologies in
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•
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EDITORIAL OVERVIEW
Illness and art: the legacy of Paul Klee
John Varga
Division of Rheumatology, Northwestern University Feinberg School of Medicine,
Chicago, Illinois, USA
Correspondence to John Varga, MD, Division of Rheumatology, Northwestern
University Feinberg School of Medicine, McGaw 2300, 240 E. Huron Street,
Chicago, IL 60611, USA
Tel: 312 503 8003; fax: 312 503 0994, e-mail: j-varga@northwestern.edu
1040–8711
Introduction
Along with Pablo Picasso and Henri Matisse, Paul Klee
was a dominant figure of 20th century art. His works,
characterized by brilliant color, breathtaking inventiveness, spectacular versatility, and unmatched productivity, have had a profound influence on all major graphic
artists to follow, and they have fundamentally shaped our
sensibility of art. At his untimely death in 1940, Klee left
a staggering 10,000 paintings, drawings, and etchings.
When he was 56 years old, Klee came down with scleroderma, the illness that was to progressively disable and
ultimately kill him. Although its onset had an initially
devastating impact, during the remaining 5 years of his
life Klee’s struggle with his illness energized him, emboldened his vision, and led him to new insight. It is with
his late work that Klee created his artistic manifesto.
Klee’s life and art
Klee was a complex and enigmatic painter, working with
infinite styles and techniques, equally comfortable with
abstract and representative art. He was also a gifted musician and composer, a passionate teacher, a poet and
philosopher, and an artist who had the courage to stand
firmly by his convictions in the face of grave danger. He
was a calm self-contained man who spoke little; his art
spoke for him. Klee was born in 1879 in Switzerland. His
father was a music teacher, and young Klee grew up in a
richly cultured and happy home. His childhood was
dominated equally by music and art. As a young man he
supported himself as a violinist in a chamber orchestra
and as a music critic. Except during his final illness, he
played the violin every morning for an hour before he got
down to work. Throughout his life, Klee’s dedication to,
and love for, musical forms informed his drawings and
paintings. As reflected in his writings (he left 4000 pages
of diary entries, analytical texts, and lecture notes from
his years as a teacher), he viewed art through the prism
of music. Klee left home at the age of 19 to study painting in Munich. There, he married the concert pianist
714
Lily Stumpf, and their only child, Felix, was born in
1906.
Klee’s youthful work is characterized by vitality, a whimsical light touch, and irrepressible humor. He favored
prints, etchings, and pen-and-ink drawings that revealed
a fondness for the satiric, the grotesque, and the surreal.
He gave his pictures evocative and satirical titles such as
“Two Men Meet, Each Believing the Other to Be of
Higher Rank” (Fig. 1). In 1912, Klee met and exhibited
with Vasily Kandinsky and other members of the influential Blaue Reiter Expressionist group. A trip to Tunis
in 1914 had an enormous impact on his art. During this
trip, Klee experienced North African architecture and
intense light; he discovered color. He wrote, “Color has
taken possession of me; no longer do I have to chase after
it. I know that it has hold of me forever…Color and I are
one. I am a painter.” The result was his “square paintings,” which began as squares of sun-splashed colors,
often accompanied by triangles or domes, as in “Red and
White Domes” (Fig. 2). Although these images are described as abstract, for Klee the meaning of abstraction
lay in the opposite direction to the intellectual effort of
abstracting. As he famously wrote, “Art does not reproduce the visible; it makes visible.”
Although close friends were killed in the World War I,
Klee, who was drafted into the German Army at the age
of 36, managed to spend two relatively quiet years in a
Bavarian garrison, painting airplane wings. With the collapse of Germany, he returned to his family deeply disillusioned by war. In 1925, he was invited to join the
faculty of the Bauhaus, the newly established State
School of Art and Design in Weimar. During the next 16
years, he taught arts and craft, painting, drawing, bookbinding, stained glass, and textile design. It was a happy
and fertile period, with growing complexity of his square
paintings and bold experiments with color paralleled by
his increasing international reputation. Klee’s 50th birthday was celebrated with a large exhibition in Berlin.
With the rise of the Nazis, this tranquil phase of Klee’s
life came to an end. Already suspect and accused of being non-Aryan, Klee refused to declare loyalty to the
Nazi regime and was dismissed from his job. As his persecution intensified, his works were removed from private and public German collections. In the fall of 1933,
Klee decided to leave Germany and settled in his native
Bern. In 1937, seventeen of his paintings were included
Editorial overview: Raynaud phenomenon, scleroderma, overlap syndromes, and other fibrosing syndromes Varga 715
Figure 1. “Two Men Meet, Each Believing the Other to Be of
Higher Rank,” 1903
Etching, black and white.
Photographs taken during Klee’s last years attest to the
progressive ravages of his illness. The pictures show curling of his fingers, sclerodactyly, hollow cheeks, and taut
facies with drawn lips and prominent nose. He appears
increasingly thin and is wearing a sweater in his studio,
suggesting intolerance to cold. Although no medical records survive, there can be little doubt in retrospect that
Klee had scleroderma. Although the “measles” diagnosed at age 56 is difficult to explain (perhaps it was
telangiectasia, perceptible in a later photograph of Klee’s
face), his exhaustion, stiff hands, dysphagia and weight
loss, dyspnea, and ultimately heart failure represent a
characteristic clinical picture of progressive scleroderma.
Seventy years ago, little could be offered to alleviate the
misery of scleroderma or to halt its progression.
in Joseph Goebbels’ infamous “Entartete Kunst”
(Degenerate Art) show. The exhibition, including also
works by Picasso, Edvard Munch, Marc Chagall,
Oskar Kokoschka, and others, was designed to ridicule
and denigrate creative art that did not uphold “correct”
National Socialist virtues, and was seen by millions of
Germans. Two years later, much of the “Degenerate
Art” was burned in the courtyard of a Berlin fire station,
and others were auctioned off to the highest bidders.
Although in poor health, and shaken by the recent death
of his father, in 1940 Klee mounted a final exhibition in
Zurich, featuring more than 300 pieces. The exhibition
was badly received, with negative allusions to the artist’s
mental state. Exhausted, he entered a sanitarium for several weeks. In May 1940, feeling that the end was near,
Klee was accompanied by his wife to a nursing home in
Locarno. In order not to upset him, no one talked about
the war or the fall of Paris. He died on the morning of
June 29. His death was attributed to heart failure.
Klee’s flight and illness
The impact of illness on Klee’s art
The flight from Germany had shaken Klee severely; he
lost his home, his professorship, his culture. Although his
name was already famous around the world, few people
in his native town had heard of him. Worse, all the
money he had earned and banked in Germany was lost;
he was back once more in the financial state he had been
when he first left Bern 30 years before. Ironically, he
never became a citizen of Switzerland, the country of his
birth; his application, initially turned down by the authorities, was finally granted only after his death.
How did his illness influence Klee’s art, productivity,
creativity, composition, and technique? The numbers are
telling. Klee, who was Germanic in his passion for cata-
On top of his isolation in his new surroundings, Klee
started to feel exhausted. Although he was characteristically stoic and kept his concerns largely to himself, his
wife made reference to his fatigue in her correspondence. In 1935, Klee experienced a skin rash that was
diagnosed as measles. According to his son, he never
fully recovered, and the “measles” was followed by a
succession of illnesses. He had difficulty swallowing, and
eventually he could only take a liquid diet. Because of
his embarrassment, he ate his meals alone. An avid hiker,
he experienced exertional shortness of breath. In his letters, he described having arthritic pain in his hands, making it difficult to hold the paintbrush. He visited several
doctors and health spas. Finally, the diagnosis of scleroderma was made in 1936. As his health declined his doctors ordered him to stop smoking. Around this time, he
had also to give up playing the violin. His friends
Picasso and Georges Braque came to pay homage.
Figure 2. “ Red and White Domes,” 1914
Watercolor.
716 Raynaud phenomenon, scleroderma, overlap syndromes, and other fibrosing syndromes
loguing his artistic output, recorded that in 1936, after
the onset of his illness, he produced only 25 works. This
was a dramatic fall in productivity. However, subsequent
years saw a progressive increase, with a staggering 1253
pieces completed in 1939, the last full year of his life! It
is as if the struggle to come to grips with his mortality
allowed Klee to draw on enormous stores of creative energy, imagination, and power.
And what about the nature of his later work? A gradual
but profound evolution took place. These changes are
marked by greater simplicity and greater intensity. Klee
began to use coarser mediums like poster paints, and
rough materials such as burlap and newspaper. He abandoned his intricate, small-scale compositions for much
larger pieces, some longer than 2 meters. The late pictures are bolder; abstract figures are painted with simple,
heavy black lines; some seem childish or primitive. The
lightheartedness and wit of the early works now gives
way to introspection and despair. The mood is somber,
the colors are dull, the subjects become symbols; gone
are the whimsy and buoyancy, the exuberant yellows,
greens, and blues, of 20 years before. The titles (“Forgetful Angel,” “Gloomy Cruise,” “Hurt,” “The Sick
One in the Boat”) reflect the themes of suffering, destruction, and death, signifying Klee’s anguish over his
illness and no doubt also his gloom over the inevitability
of another world war. Figures of angels and devils betray
the artist’s fear of death. As Gunter Wolf noted, in many
late pictures we see the reflection of the profound
changes in Klee’s own face and body. “Maske” (The
Mask, 1940) and “Durchhalten!” (Endure! 1940) show a
disfigured face resembling the artist. Bars of thick brushstrokes, menacing and emblematic, make their appearance, often with a skeletal figure behind a grid of bars.
Art historians have puzzled over the meaning of the recurrent bars; but it is not hard to look at “The Captive”
(Fig. 3) and see the artist trapped in the prison of scleroderma, the steel cage of his own physical immobility.
Like his favorite composer, Mozart, Klee created his own
disturbing requiem, “Tod und Feuer” (Death and Fire,
1940). The painting, one of his last, is dominated by a
gleaming white skull, with the word “Tod” (Death)
forming the features of the face. A solitary stick figure
walks toward the skull; deep shades of red and orange
signify burning, a combustion, in contrast to a cool graygreen domain of death below. The featureless man with
a body of no substance (Klee?) walks forward without
hesitation, even though his next step is into his own
grave. Klee now knew that the end was approaching. He
was now unafraid of death: requiem, not despair.
Klee’s body was cremated, and his ashes were interred in
Berne. On his grave are inscribed these words from his
diary:
Figure 3. “The Captive,” 1940
Oil on burlap.
I cannot be grasped in the here and now
For I live as well with the dead
As with the yet unborn.
A little nearer to the heart of creation than is normal
But still not close enough.
Klee’s legacy
Klee’s artistic output was staggering, and his legacy as a
writer and philosopher equally copious. He worked in all
mediums and moved freely between abstraction and representation. Unlike other graphic artists, Klee’s reputation is not tied to a single, easily identifiable masterpiece; rather, his approach to art was oriented toward a
lifelong process of reexamining and redefining themes
and form. His career was one of ceaseless experimentation with new techniques, styles, and colors. His creative
genius remained undiminished throughout his life and
was fundamentally shaped by his final illness. After a
period of despair following his flight from Germany and
the onset of scleroderma, during which he almost ceased
artistic activity altogether, he showed a remarkable turnabout. Even as his health deteriorated and his physical
energy declined, his art and creativity mysteriously
soared. This paradox ultimately remains Klee’s personal
triumph and lasting legacy.
Editorial overview: Raynaud phenomenon, scleroderma, overlap syndromes, and other fibrosing syndromes Varga 717
Bywater EGL: Paul Klee: the effect of scleroderma on his painting. Rheumatic
Disease in Visual Arts. 1997: 49–50.
Grohmann W. Klee. New York: Harry N. Abrams, 1985.
•
Of special interest
••
Bridget Riley, Hayward Gallery Exhibit, February 2002.
Silver R: Paul Klee and scleroderma. Bull Rheum Dis 1995, 45:4–6.
Klee: Gualtieri di San Lazzarro. New York: Praeger, 1964.
Paul Klee at the Guggenheim Museum. New York: Guggenheim Museum, 1993.
The diaries of Paul Klee: Edited by Felix Klee. Berkeley: University of California
Press, 1964.
Keller C, Dotz W, Varga J: Scleroderma of Paul Klee. Dermatopathology 1999,
5:19–22.
Wolf G: Endure!: how Paul Klee’s illness influenced his art. Lancet 1999,
353:1516–1518.
Raynaud phenomenon and the vascular disease
in scleroderma
M. Bashar Kahaleh
Purpose of review
Raynaud phenomenon is the earliest and most common
clinical manifestations of scleroderma (systemic sclerosis).
Therefore, Raynaud phenomenon offers the best window into
the investigation of the early steps in the pathogenesis of
systemic sclerosis. This review focuses on the differential
diagnosis of Raynaud phenomenon, the transition of Raynaud
phenomenon to systemic sclerosis, mechanisms and
consequences of vascular injury and dysfunction in systemic
sclerosis, and therapeutic options.
Recent findings
Careful clinical evaluation using a simple definition of Raynaud
phenomenon is the most reliable and reproducible method in
the diagnosis. Although the assessment of vascular function by
noninvasive methods is still not sensitive enough for the
evaluation and follow-up of individual patients, it helps in the
differential diagnosis and in population studies. Progressive
deficiency in vasodilatory capacity of the vessels is proposed
as a mechanism of Raynaud phenomenon, particularly in
systemic sclerosis. In addition, decreased fibrinolysis and
enhanced coagulation pathways undoubtedly contribute to
vascular dysfunction. The mechanism of endothelial injury is
still elusive, yet endothelial apoptosis mediated by
antiendothelial antibodies is the most attractive hypothesis
now. Therapies directed at the vascular disease continue to
focus on the alleviation of vascular spasm. However,
immunosuppressive therapy may influence the levels of
vascular injury markers and thus may have an effect on the
vascular disease itself.
Summary
Continued progress in the investigation of the vascular
aspects of scleroderma is described in this review. Immune
involvement in the early stages of the disease and mechanism
of vascular repair in advance cases are some of the highlights
of last year’s progress.
Keywords
Raynaud phenomenon, endothelial cells, vascular disease
Division of Rheumatology, Department of Medicine, Medical College of Ohio,
Toledo, Ohio, USA
Correspondence to M. Bashar Kahaleh, MD, Professor of Medicine, Chief, Division
of Rheumatology, Medical College of Ohio, 1321 Glendale Avenue, Toledo, OH
43617, USA
Tel: 419 383 4271; fax: 419 383 6244; e-mail: bkahaleh@mco.edu
718
Abbreviation
CTD
connective tissue disease
1040–8711
Introduction
Raynaud phenomenon is an exceedingly important component of systemic sclerosis because it symbolizes the
generalized and progressive nature of the vascular dysfunction in the disease. The histopathologic bases for the
vascular dysfunction are well described and involve signs
of injury to the microcirculation and small blood vessels.
A core set variables for the assessment of vascular involvement in systemic sclerosis was proposed [1].
Raynaud phenomenon and digital ulcers were identified
as the two parameters that represent the minimal requirements for the documentation of vascular involvement in systemic sclerosis. Attacks of Raynaud phenomenon should be characterized by duration, frequency,
severity, and the Raynaud condition score. The assessment of digital ulcers should include frequency, size,
severity, number of involved digits, and the VAS score.
Relevant studies published last year are reviewed and
grouped in sections related to the transition of Raynaud
phenomenon to connective tissue disease, the noninvasive evaluation of primary and secondary Raynaud phenomenon, etiologic factors in Raynaud phenomenon, and
vascular disease and proposed therapeutic options.
Transition to connective tissue disease
One of the most difficult clinical challenges faced when
evaluating patients with Raynaud phenomenon is the
assessment of risk for transition to connective tissue disease (CTD). DeAngelis et al. [3] reported the outcome of
118 consecutive patients with Raynaud phenomenon attending a rheumatology specialty clinic. Thirty-five patients were classified as having primary Raynaud phenomenon, 20 were unclassifiable, and 63 patients had
secondary Raynaud phenomenon. After an average follow-up of 3 years, none of the primary group developed
secondary condition, and only 10% of the unclassifiable group developed systemic sclerosis. This report
documents the rare transition from primary Raynaud
phenomenon to CTD even in patients with suspected
CTD. In contrast, Ziegler et al. [4•] reported a 9% tran-
Raynaud phenomenon and the vascular disease in scleroderma Kahaleh 719
sition from primary Raynaud phenomenon and 30% from
possible secondary Raynaud phenomenon after a 12.4year mean follow-up. This study suggests that there is a
continuum in transition to CTD and that clinicians
should not confidently assure patients with primary
Raynaud phenomenon of the benign nature of their
symptoms.
as in the carotid arteries. Duplex determination of the
carotid elasticity or stiffness was significantly different in
the two groups [10]. The same investigators reported in
a subsequent study more reduction in elastic properties
of the carotid artery in the dSSc subset than in lSSc [11].
The two studies document the frequent, but often neglected, large vessel involvement in systemic sclerosis.
The value of positive ANA in predicting future development of CTD was examined by Myckatyn and Russell
[5], who described the outcome of patients with positive
ANA using the clinical database at the University of Alberta Hospital. After a mean follow-up of 5.4 years, 91%
remained ANA-positive, and 6% progressed to CTD.
The study emphasized the long-term persistence of positive serology and the low rate of transition to CTD.
Etiologic and pathogenetic factors in Raynaud
phenomenon and systemic sclerosis
vascular disease
Genetic factors
Childhood Raynaud phenomenon is rare and not well
characterized. One of the largest series of children with
Raynaud phenomenon was elegantly described [2•].
The mean age at onset was 12 years (range, 1–19 years).
Seventy percent were classified as having primary
Raynaud phenomenon, and 30% were associated with
other diseases. One of the surprising findings in this
study was the presence of antiphospholipid antibodies in
more than 20% of children with Raynaud phenomenon.
Evaluation of Raynaud phenomenon
The diagnostic value of nailfold capillaroscopy was
evaluated in 447 patients with CTD. The results again
confirmed the specificity of systemic sclerosis capillary
pattern [6]. A comparison of thermography and laser
Doppler imaging in the assessment of Raynaud phenomenon demonstrated poor correlation between the two
methods. The lack of correlation suggests that one technique is not a good substitute for the other [7]. The
authors suggested that Doppler imaging is more sensitive to changes than thermography.
Ultrasound examination of the microcirculation was performed with newly developed multi-D linear array transducer that improves resolution [8]. Thirty-three patients,
14 with primary Raynaud phenomenon and 19 with systemic sclerosis, were examined. Differences in the diameters of the digital arteries allowed the differentiation of
primary Raynaud phenomenon from systemic sclerosisassociated Raynaud phenomenon. Primary Raynaud
phenomenon can also be distinguished from systemic
sclerosis-associated Raynaud phenomenon by the assessment of skin perfusion pressure at rest and after cold
presser [9]. Significant reduction in perfusion pressure
was noted in the systemic sclerosis group that may be
related to the obstructive arteriolar lesion in systemic
sclerosis microcirculation.
Differences between primary and secondary Raynaud
phenomenon can also be shown in the large circulation,
The link of genetic factors to Raynaud phenomenon was
suggested in a case report describing primary Raynaud
phenomenon in 16-year-old monozygotic twins [12]. The
concordance rate for Raynaud phenomenon in monozygotic twins is unknown. Nonetheless, significant familial
aggregation of primary Raynaud phenomenon is well described. Investigation of large series of twins and multicase families is needed to explore the role of genetics in
the pathogenesis of Raynaud phenomenon.
Endothelial-dependent relaxation
Defective endothelial dependent vasodilatation in systemic sclerosis is well described. Schlez et al. [22] extended these observations by evaluating blood flow velocity and the diameter of skin capillaries before and
after the microinjection of acetylcholine (endothelialdependent) or sodium nitroprusside (endothelial-independent) in 10 systemic sclerosis and control subjects.
No difference in respond to nitroprusside was noted;
however, significant defect in response to acetylcholine
was noted in patients with systemic sclerosis. Moreover,
the response to acetylcholine returned to normal in two
patients with systemic sclerosis after 1 week of prostacyclin infusion. Although this is a limited observation,
the potential for prostacyclin as a vascular modifying
agent in systemic sclerosis has been long suggested.
Coagulation and fibrinolysis
The status of the coagulation and fibrinolytic systems in
systemic sclerosis is not well described. Mattuci-Cerinic
et al. [13•] examined the coagulation/fibrinolysis system
in 29 patients with systemic sclerosis. Significant activation of the coagulation system and reduction in fibrinolysis activities was noted. The conclusions in this study
are in agreement with the histologic findings in systemic
sclerosis, in which excessive fibrin deposits are commonly seen in association with thrombosis in the microvessels. Still, no controlled trial using anticoagulation
or fibrinolytic enhancing therapy in systemic sclerosis
has been accomplished to date.
Atherosclerosis and hyperlipidemia
van Vugt et al. [14] reported a higher than expected incidence of arteriosclerotic disease and hyperlipidemia in
patients with primary Raynaud phenomenon who under-
went upper extremity angiograms. Of 103 patients with
primary Raynaud phenomenon, the angiograms were
compatible with vasospasm in 42 patients, atherosclerotic vascular disease in 44 patients, peripheral embolism in
eight patients, and vasculitis and Buerger disease in six
patients. Moreover, 47% of patients had hyperlipidemia.
The high frequency of atherosclerotic vascular disease in
patients with Raynaud phenomenon noted in this study
should serve as a reminder of the epidemic nature of
atherosclerosis and should encourage the search for hyperlipidemia in patients with Raynaud phenomenon.
Endothelial apoptosis
The bulk of published studies suggest a pathogenetic
role for antiendothelial antibodies in systemic sclerosis.
This conclusion was reinforced by Worda et al. [15••],
who described the induction of endothelial apoptosis in
the chicken model of systemic sclerosis (UCD-200) by
directly transferring UCD-200 serum into normal chicken
embryos. Binding of antiendothelial antibodies to the
microvascular EC in the chorioallantoic membrane in association with EC apoptosis was unmistakably seen.
However, the cell and target antigen specificity of antiendothelial antibodies is still unknown. Moreover, standarized detection methods are badly needed. A new assay for antiendothelial antibodies that used indirect
immunofluorescence technique with rodent lung preparations and fluorescinated human anti-IgG has been introduced [16]. Positive testing was recorded in 42 of 45
patients with systemic sclerosis. It is not clear whether
this method detects ANAs in addition to antiendothelial
antibodies, because the reported staining patterns were
nuclear or nucleolar in location. Moreover, it is not clear
whether antiendothelial antibodies are truly endothelialspecific and whether they react with the same antigens.
Indeed, Western blot analysis of EC protein extracts
showed an average of 10 reacting bands in each antiendothelial antibody-positive serum, and in most examples,
extracts from fibroblast reacted with antiendothelial antibodies, sometimes even more so than with EC.
Vasculogenesis and angiogenesis
The vascular changes in systemic sclerosis affect predominantly the microcirculation and arterioles, with capillary necrosis and intimal proliferation of arterioles resulting in occlusion of blood vessels, decreased organ
blood flow, and a state of progressive chronic organ ischemia. This underperfused state (ischemia, acidosis)
should be a fertile ground for neoangiogenesis, but new
capillaries are rare, and broad avascular areas are common, suggesting defective pathways in angiogenesis and
vascular repair.
Konttinen et al. [17•] reported an immunohistochemical
study of systemic sclerosis skin that showed rare and
sporadic expression of ␣v␤3 integrin in the blood vessels,
suggesting unsuccessful attempts at new vessel formation. The expression of ␣v␤3 integrin receptor is associated with VEGF-mediated angiogenesis and is used as a
histologic marker for new vessel formation.
Circulating endothelial cells
The recent innovations in cell isolation and immunohistochemical evaluation allowed the isolation of circulating
fully differentiated EC and bone marrow-derived endothelial progenitor cells. Del Papa et al. [18••] observed
increased circulating EC and bone marrow-derived endothelial progenitors in 46 patients with systemic sclerosis. The circulating number of ECs correlated with the
overall disease activity score and with pulmonary hypertension.
Gene expression profile in systemic sclerosis skin
Analysis of general and cell type-specific gene expression patterns in systemic sclerosis skin demonstrated upregulation of genes related to endothelial cells (VEcadherin, Thy 1, von Wilbrand factor, and CD31), B and
T cells, and extracellular matrix [19••]. The upregulated
genes were detected in involved and clinically uninvolved systemic sclerosis skin. It is interesting to note
that histologic evidence for fibrosis was seen in clinically
unaffected skin. Moreover, no clear differences in patterns of gene expression among fibroblasts derived from
systemic sclerosis, morphia, and normal skin were noted,
suggesting that fibroblasts in vitro are not a suitable starting sample for examining systemic sclerosis-specific
gene expression patterns.
Immune involvement
Lymphocyte transendothelial migration
Enhanced expression of adhesion molecules in systemic
sclerosis vessels is widely documented and presumed to
result in inflammatory cell trafficking in the vessel wall
and surrounding tissue. The role of lymphocyte in this
process was examined by Stummvoll et al. [20], who investigated the transendothelial migrating capacity of
control and systemic sclerosis peripheral lymphocytes
in an in vitro system. Increased migration of systemic
sclerosis cells was seen mainly by the CD3+ CD4+ cell
subset. Among migrating systemic sclerosis CD4+ T lymphocytes, the frequency of HLA-DR+ cells was increased, and cells were in an activated state, as reflected
by enhanced expression of the adhesion molecules
CD11a, CD49d, CD29, and CD44. It is important to
note that this cell type is frequently seen in the perivascular spaces in the early stages of systemic sclerosis.
Cytokines
An increased circulating level of interleukin-13 (a cytokine that promotes fibrosis and inflammation) in systemic sclerosis was described in 1997. A study by Riccieri
et al. [21] confirmed this observation and correlated circulating levels with parameters of microvascular injury
Raynaud phenomenon and the vascular disease in scleroderma Kahaleh 721
assessed by nailfold capillaroscopy. Thus, interleukin-13
levels correlated with an active capillary pattern, the
presence of hemorrhages, sludging of blood, and larger
total loops and arterial diameters. This observation hints
at a possible vascular effect for this cytokine.
Therapeutic interventions
Therapy of the vascular disease in systemic sclerosis is
directed mostly at alleviation of vasospasm.
Sildenafil
A case report described improved digital perfusion and
reduced frequency and severity of Raynaud attacks after
sildenafil treatment [23].
effect for L-arginine in primary and secondary Raynaud
phenomenon.
Ascorbic acid
The hypothesis that a potent water-soluble antioxidant
can reverse endothelial dysfunction was tested in 11 patients with systemic sclerosis and 10 healthy subjects
[28]. The study was a double-blind, randomized, crossover, placebo-controlled trial using 2 g ascorbic acid or
placebo. No clear effect for ascorbic acid on endothelialdependent vasodilatation was seen. The authors suggested that the use of different antioxidants or different
dosing of ascorbic acid may be required to show beneficial effects for antioxidants on endothelial vasodilatory
function.
PGE1
Similar findings were noted using transdermal PGE1
ethylester [24]. This study showed improved skin perfusion and reduced frequency of Raynaud phenomenon
attacks after the transdermal PGE1 treatment (10 hours
daily for 2 weeks).
Iloprost
The efficacy and safety of intravenous iloprost in the
treatment of ischemic digits in pediatric patients with
connective tissue diseases who failed to respond to conservative treatment was reported in a retrospective study
[25]. Healing of ischemic ulcer and improved blood flow
were noted in most patients.
Cilostazol
Cilostazol (Pletal), a synthetic phosphodiesterase III inhibitor that reversibly inhibits platelet aggregation and is
used for the treatment of intermittent lower extremity
claudication, was tested in a 6-week, double-blind, placebo-controlled trial of patients with primary and secondary Raynaud phenomenon. Treatment was associated with vasodilation of the brachial arteries and conduit
vessels [26]. However, the drug had no effects on microvascular blood flow or on the frequency and severity of
Raynaud phenomenon attacks in both primary and secondary Raynaud phenomenon. Still, a multicenter control trial is currently underway to evaluate the effect of
cilostazol in children with primary and secondary
Raynaud phenomenon (http://www.ClinicalTrials.gov).
Cyclophosphamide and prednisone
The circulating levels of the endothelial injury markers
E-selectin and thrombomodulin were examined in patients with early diffuse systemic sclerosis after 1-year
therapy with oral cyclophosphamide and prednisolone
[29]. Significant reduction of the circulating levels was
noted in association with improved skin scores and pulmonary function at the end of the follow-up period. This
intriguing observation suggests a possible role for immunosuppression in the therapy of systemic sclerosis vascular disease.
Conclusion
Vascular disease is the leading cause of complications
and mortalities in systemic sclerosis. Humeral and cellular immunity is important in the development of the
early events of vascular disease. Failure of vascular repair
in established disease is highlighted. Unfortunately,
medical therapy still focuses on the elevation of vasospasm. Better understanding of the mechanisms of endothelial injury and vascular dysfunction will undoubtedly lead to better therapeutic approaches to the vascular
aspects of systemic sclerosis.
•
Of special interest
••
1
L-arginine
Defective EDRF (nitric oxide) pathway in Raynaud
phenomenon has been suggested, but it has been difficult to overcome therapeutically. L-arginine supplementation has been suggested as a potentially successful
strategy. Success in reversing digital ischemia was reported in two patients, and significant improvement in
symptoms of Raynaud phenomenon was noted in an additional two patients [27]. L-arginine may be considered
for the acute management of digital ischemia; however,
numerous previous studies failed to show a long-term
Kahaleh B, Meyer O, Scorza R: Assessment of vascular involvement. Clin Exp
Rheumatol 2003, 21:S9–14.
2
Nigrovic PA, Fuhlbrigge RC, Sundel RP: Raynaud’s phenomenon in children:
a retrospective review of 123 patients. Pediatrics 2003, 111:715–721.
•
Well-described large series of children with Raynaud phenomenon. Girls were
more affected than boys; the majority of cases were primary Raynaud phenomenon.
Positive ANA and nailfold capillary pattern correlated with secondary causes. Surprisingly, antiphospholipid antibodies were found in > 20% of children with
Raynaud phenomenon.
3
DeAngelis R, Del Medico R, Blasetti P, et al.: Raynaud’s phenomenon: clinical
spectrum of 118 patients. Clin Rheumatol 2003, 22:279–284.
Ziegler S, Brunner M, Eigenbauer E, et al.: Long-term outcome of primary
Raynaud’s phenomenon and its conversion to connective tissue disease: a
12-year retrospective patient analysis. Scand J Rheumatol 2003, 32:343–
347.
The frequency of connective tissue disease development in patients considered to
4
•
have idiopathic Raynaud phenomenon for > 10 years was examined. Overall, 14%
progressed to a definite CTD, 10 from primary Raynaud phenomenon and 10 from
possible secondary Raynaud phenomenon. The initial presence of antinuclear antibodies, thickening of fingers, higher age at onset of Raynaud phenomenon, and
female sex seemed to be important determinants for a possible transition to a CTD.
5
Myckatyn SO, Russell AS: Outcome of positive antinuclear antibodies in individuals without connective tissue disease. J Rheumatol 2003, 30:736–
739.
6
Nagy Z, Czirjak L: Nailfold digital capillaroscopy in 447 patients with connective tissue disease and Raynaud’s disease. J Eur Acad Dermatol Venereol
2004, 18:62–68.
7
Clark S, Dunn G, Moore T, et al.: Comparison of thermography and laser
Doppler imaging in the assessment of Raynaud’s phenomenon. Microvasc
Res 2003, 66:73–76.
8
Cazalets C, Cador B, Rolland Y, et al.: Digital flow exploration by color Doppler ultrasound in patients with Raynaud’s disease or systemic sclerosis. J Mal
Vasc 2004, 29:12–20.
9
Kanetaka T, Komiyama T, Onozuka A, et al.: Laser Doppler skin perfusion
pressure in the assessment of Raynaud’s phenomenon. Eur J Vasc Endovasc
Surg 2004, 27:414–416.
Del Papa N, Colombo G, Fracchiolla N, et al.: Circulating endothelial cells as
a marker of ongoing vascular disease in systemic sclerosis. Arthritis Rheum
2004, 50:1296–1304.
Not long ago, new vessel formation was believed to be caused by expansion of the
existing vascular tree by angiogenesis. Now it is known that bone marrow-derived
endothelial progenitors mediate vasculogenesis, and these cells have been shown
to be of enormous therapeutic potential in the management of ischemic disorders.
This study showed an increase in endothelial progenitors and fully differentiated
endothelial cells in systemic sclerosis circulation. Still, new vessel formation is uncommon in systemic sclerosis. Examination of steps in vasculogenesis in systemic
sclerosis is clearly needed.
18
••
Whitfield ML, Finlay DR, Murray JI, et al.: Systemic and cel type-specific gene
expression patterns in scleroderma skin. Proc Natl Acad Sci USA 2003,
100:12319–12324.
Large-scale gene expression study that showed what appears to be consistent
differences in gene expression between systemic sclerosis and control skin biopsies irrespective of the clinical appearance of the skin at the biopsy site, suggesting
a systemic nature of disease. Moreover, no obvious differences in patterns of gene
expression among fibroblasts derived from systemic sclerosis, morphia, and normal
skin were noted.
19
••
20
Stummvoll GH, Aringer M, Grisar J, et al.: Increased transendothelial migration of scleroderma lymphocytes. Ann Rheum Dis 2004, 63:569–574.
10
Cheng KS, Tiwari A, Boutin A, et al.: Differentiation of primary and secondary
Raynaud’s disease by carotid arterial stiffness. Eur J Vasc Endovasc Surg
2003, 25:336–341.
21
Riccieri V, Rinaldi T, Spadaro A, et al.: Interleukin-13 in systemic sclerosis:
relationship to nailfold capillaroscopy abnormalities. Clin Rheumatol 2003,
22:102–106.
11
Cheng KS, Tiwari A, Boutin A, et al.: Carotid and femoral arterial wall mechanics in scleroderma. Rheumatology (Oxford) 2003, 42:1299–1305.
22
Schlez A, Kittel M, Braun S, et al.: Endothelium-dependent regulation of cutaneous microcirculation in patients with systemic scleroderma. J Invest Dermatol 2003, 120:332–334.
23
Rosenkratz S, Diet F, Weibrauch J, et al.: Sildenafil improved pulmonary hypertension and peripheral blood flow in a patient with sclerodermaassociated lung fibrosis and the Raynaud phenomenon. Ann Med 2003,
139:871–873.
24
Schuzl A, Hufner HM, Kittel M, et al.: Systemic scleroderma patients have
improved skin perfusion after the transdermal application of PGE1 ethyl ester.
Vasa 2003, 32:83–86.
25
Zulian F, Corona F, Gerloni V, et al.: Safety and efficacy of iolprost for the
treatment of ischaemic digits in paediatric connective tissue. Rheumatology
(Oxford) 2003, 43:229–233.
26
Rajagopalan S, Pfenninger D, Somers E, et al.: Effects of cilostazol in patients
with Raynaud’s syndrome. Am J Cardiol 2003, 92:1310–1315.
27
Rembold CM, Ayers CR: Oral L-arginine can reverse digital necrosis in
Raynaud’s phenomenon. Mol Cell Biochem 2003, 244:139–141.
28
Mavrikakis ME, Lekakis JP, Papamichael CM, et al.: Ascorbic acid does not
improve endothelium-dependent flow-mediated dilatation of the brachial artery in patients with Raynaud’s phenomenon secondary to systemic sclerosis.
Int J Vitam Nutr Res 2003, 73:3–7.
29
Apras S, Ertenli I, Ozbalkan Z, et al.: Effects of oral cyclophosphamide and
prednisolone therapy on the endothelial functions and clinical findings in patients with early diffuse systemic sclerosis. Arthritis Rheum 2003, 48:2256–
2261.
12
Oskay T, Olmez U: Primary Raynaud’s phenomenon in monozygotic twins.
Ann Rheum Dis 2004, 63:219.
Mattuci-Cerinic M, Valentinie G, Sorano GG, et al.: Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin
Comprehensive study that examined coagulation and fibrinolysis parameters and
levels of endothelial injury markers in patients with systemic sclerosis. The results
clearly demonstrate reduced fibrinolytic potential and increased coagulation pathway markers along with increased markers of vascular injury.
13
•
14
van Vugt RM, Kater L, Dijkstra PF, et al.: The outcome of angiography in
patients with Raynaud’s phenomenon: an unexpected role for atherosclerosis
and hypercholesterolemia. Clin Exp Rheumatol 2003, 21:445–450.
Worda M, Sgonc R, Dietrich H, et al.: In vivo analysis of the apoptosisinducing effect of anti-endothelial cell antibodies in systemic sclerosis by the
chorionallantoic membrane assay. Arthritis Rheum 2003, 48:2605–2614.
This excellent study is the first to demonstrate the in vivo apoptosis-inducing effects of antiendothelial antibodies. These findings support a primary pathogenetic
role for the antibodies in systemic sclerosis.
15
••
16
Wusirika R, Ferri C, Marin M, et al.: The assessment of anti-endothelial cell
antibodies in scleroderma-associated pulmonary fibrosis. Am J Clin Pathol
2003, 120:596–606.
17 Konttinen YT, Mackiewicz Z, Ruuttila P, et al.: Vascular damage and lack of
angiogenesis in systemic sclerosis skin. Clin Rheumatol 2003, 22:196–202.
•
Although some patients with systemic sclerosis showed a high degree of ␣v␤3
integrin receptor expression, the majority did not, suggesting defective angiogenesis potentials in systemic sclerosis.
Autoantibodies in systemic sclerosis and fibrosing
syndromes: clinical indications and relevance
Eduardo J. Cepeda and John D. Reveille
Purpose of review
Systemic sclerosis, or scleroderma, is associated with a variety
of autoantibodies, each of them having their own clinical
associations. The fibrosing disorders, other than systemic
sclerosis, represent a diverse group of diseases with systemic
or localized effect and with limited understanding of their
pathogenesis. The purpose of this review is to analyze the
literature on the clinical usefulness of examining serum
autoantibodies in patients with known or suspected
scleroderma and fibrosing disorders.
Recent findings
Studies on autoantibodies within the past year highlight their
clinical utility in systemic sclerosis. Anticentromere antibodies
are most often seen with limited cutaneous involvement and
lower frequency of pulmonary fibrosis and lower mortality
(despite an increased risk for pulmonary hypertension)
compared with anti-Scl-70 and antinucleolar antibodies.
Anti-Scl-70 antibodies are associated with diffuse cutaneous
involvement, increased frequency of pulmonary fibrosis, and
higher mortality. The anti-polymyositis-scleroderma
autoantibody is associated with the polymyositis-scleroderma
overlap syndrome. Anti-Th/To antibodies are associated with
milder skin and systemic involvement but with more severe
pulmonary fibrosis and overall worse prognosis.
Anti-RNA-polymerase family antibodies and antifibrillarin
antibodies are predictive of diffuse cutaneous and systemic
involvement and greater mortality. Less specific autoantibodies
for systemic sclerosis and limited data on some other
autoantibodies limit their clinical utility in patients with systemic
sclerosis. For the most part, the association between
autoantibodies and fibrosing disorders other than systemic
sclerosis remains inconclusive.
Summary
Autoantibodies in systemic sclerosis provide important and
prognostic information and are useful in defining clinical
subsets of the disease. When used appropriately, they can be
a useful instrument in the management of scleroderma.
Keywords
autoantibodies, systemic sclerosis, Raynaud phenomenon,
overlap syndrome, fibrosing disorders
Division of Rheumatology, The University of Texas-Houston Health Science
Center at Houston, Houston, Texas, USA
Correspondence to John D. Reveille, The University of Texas-Houston Health
Science Center, MSB 5.270, 6431 Fannin, Houston, TX 77030, USA
Tel: 713 500 6900; fax: 713 500 0580; e-mail: john.d.reveille@uth.tmc.edu
Abbreviations
ACA
aCL
AFA
ANoA
aPL
ELISA
LAC
MHC
RNAP
SLE
SSc
TNF
anticentromere antibodies
anticardiolipin antibodies
antifibrillarin antibodies
antinucleolar antibodies
antiphospholipid antibodies
enzyme-linked immunosorbent assay
lupus anticoagulant
major histocompatibility complex
RNA polymerase
systemic lupus erythematosus
systemic sclerosis, scleroderma
tumor necrosis factor
1040–8711
Introduction
Patients with systemic sclerosis (scleroderma, SSc) express a variety of autoantibodies that have their own
clinical associations. Whether these autoantibodies play a
direct role in the pathogenesis of SSc or are merely epiphenomena, they carry significant value in both diagnosis and prognosis. Moreover, autoantibodies in SSc are
clearly influenced by hereditary factors, as evidenced by
their higher concordance in identical twins and their associations with major histocompatibility complex (MHC)
genes [1•,2].
The autoantibodies classically associated with SSc include anticentromere antibodies (ACA) and anti-Scl-70
(anti-topoisomerase-I). In addition to these are the less
commonly occurring components of the antinucleolar antibody (ANoA) system, which comprises a mutually exclusive heterogeneous group of autoantibodies that produce nucleolar staining by indirect immunofluorescence
on cells from a variety of species [3]. The most widely
recognized of these include anti-PM-Scl, antifibrillarin/anti-U3-ribonucloprotein (AFA), anti-Th/To, and
the anti-RNA-polymerase family (anti-RNAP), including
anti-RNAP I, II, and III (although anti-RNAP frequently
do not produce nucleolar staining on immunifluorescence) [4–9]. In addition to these disease-specific antibodies, other autoantibodies are also found in patients
with SSc, with varying clinical significance.
The purpose of this review is to describe the pathogenic
significance and clinical utility of determining various
723
autoantibodies associated with SSc, Raynaud phenomenon, overlap syndromes with SSc, and fibrosing disorders.
one recent study, ACA positivity correlated with longerduration Raynaud phenomenon before the diagnosis of
SSc was made [17].
Anticentromere antibodies
Anticentromere antibodies are most often seen in the
presence of limited cutaneous SSc and are associated
with a higher risk for calcinosis and ischemic digital loss
in patients with SSc [10••,18–21,22•,23]. Likewise,
there is a significantly lower frequency of interstitial pulmonary fibrosis in SSc with ACA [10••,20,21].
Anticentromere antibodies have been most typically determined by their characteristic staining pattern on immunofluorescence, giving rise to a speckled appearance
on Hep-2 cells. More recent techniques, including enzyme-linked immunosorbent assay (ELISA) and immunoblotting have been developed and are being used increasingly in clinical practice. They have been shown to
perform with satisfactory accuracy when compared with
indirect immunofluorescence [10••]. Thus far, six centromeric nucleoproteins, CENP-A through CENP-F, are
known to be bound by sera from patients with SSc
[10••]. However, these distinctions have not been shown
to have clinical relevance. All sera containing ACA react
with CENP-B. A solid-phase ELISA has been established by using a cloned fusion protein of CENP-B as
antigen. More recently, this ELISA has been refined and
has been found to have adequate sensitivity and specificity for clinical use (Table 1) [10••].
The frequency of ACA in patients with SSc has been
reported to be 20 to 30% overall, but it varies in different
ethnic groups. They occur most frequently in Caucasians, where they are found in approximately a third of
SSc patients, compared with a significantly lower frequency in Hispanic, African-American, and Thai patients
[11,12,13•]. ACA are rarely found in healthy individuals
or in patients with other connective tissue diseases [10].
When found in patients evaluated for Raynaud phenomenon, ACA have predictive value for those at risk for the
future development of SSc [10•,14–16]. Conversely, in
By contrast, patients with ACA do have an increased risk
of pulmonary hypertension, though this is not due to
abnormalities in coronary circulation [21,24•]. A recent
study investigated whether determination of coronary
flow reserve, as evaluated by transthoracic Doppler echocardiography, might represent a potential method of detecting early dysfunction of the cardiovascular system in
patients with SSc without clinical signs or symptoms of
cardiac impairment [24•]. Twenty-four out of 44 SSc
patients showed reduced coronary flow reserve in comparison with a normal range of age- and sex-matched
healthy subjects, especially those with diffuse cutaneous
SSc, although no correlation was found with ACA.
Patients who are ACA positive have a lower mortality
than those with positive anti-Scl-70 autoantibodies or
ANoA [20,25]. However, the relation of cancer to SSc is
controversial. Although several studies have suggested
an increased frequency of cancer in patients with SSc
contributing to increased mortality, and two have correlated this risk with ACA, a more recent case-control
study in a large cohort of patients with SSc was unable to
replicate these findings [26–32,33•].
Table 1. Diagnostic and prognostic associations of autoantibodies
Autoantibody
Technique
Predictive of
Compared with
ACA
ACA
ACA
ACA
ACA
Anti-Scl-70
Anti-Scl-70
Anti-Scl-70
Anti-Scl-70
Anti-Scl-70
Anti-Scl-70
Anti-Scl-70
Anti-Scl-70
Anti-Scl-70
Anti-Scl-70
AFA
Anti-RNAP
PM-Scl
IIF
IIF
IIF
IIF
IIF
ID
ID
ID
IB
IB
ELISA
ELISA
ID
ID
IP, ELISA, IB
IB, IP
IP, IB
ID
SSc
SSc
lcSSc
Pulm. fibrosis
SSc
SSc
SSc
SSc
SSc
SSc
SSc
SSc
dcSSc
Pulm. fibrosis
Pulm. fibrosis
dcSSc
dcSSc
SSc/myositis overlap
Healthy individuals
Other CTDs
Healthy individuals
Healthy individuals
RP
Healthy individuals
Other CTDs
RP
Healthy individuals
Other CTDs
Healthy individuals
Other CTD
Healthy individuals
Healthy individuals
Healthy individuals
Healthy individuals
Healthy individuals
Healthy individuals
Sensitivity %
Specificity %
Pos LR
44
31
44
12
24
20
26
28
41
40
43
43
37
45
43
12
38
50
99.9
97
93
71
90
100
99.5
98
99.4
99
100
90
82
81
83
97
94
98
327
12.5
6.1
0.41
2.3
> 25
52
10
68
40
> 55
4.3
2.0
2.3
2.5
4.0
6
31
ACA, anticentromere antibody; AFA, antifibrillarin antibody; RNAP, RNA polymerase; IIF, indirect immunofluorescence; ID, immunodiffusion; IB,
immunoblotting; ELISA, enzyme-linked immunosorbent assay; IP, immunoprecipitation; SSc, systemic sclerosis; lcSSc, limited cutaneous systemic
sclerosis; dcSSc, diffuse cutaneous systemic sclerosis; CTD, connective tissue disease; RP, Raynaud phenomenon; Pos LR, positive likelihood
ratio.
Published with permission [10].
Autoantibodies in systemic sclerosis Cepeda and Reveille 725
Once a patient is found to be ACA positive, there is no
clinical utility in serial measurements. ACA-positive patients tend to remain positive over time, whether tested
by indirect immunofluorescence or by immunoblotting
[10••,34–36].
HLA-DRB1*01, HLA-DRB1*04, and HLA-DQB1*05 are
associated with the presence of ACA, and it seems likely
that the generation of ACA is influenced by the presence
of both HLA-DRB1 and HLA-DQB1 alleles [2,12,37•].
Other MHC genes have also been implicated. A group
from the United Kingdom has recently implicated tumor
necrosis factor (TNF) genes, located in the MHC class
III region, in the ACA response, specifically the TNF863A allele, the TNF-1031C allele, and with a TNF
promoter haplotype, suggesting this to be the strongest
non-HLA genetic marker so far described in SSc [37•].
Antitopoisomerase I antibodies
Antitopoisomerase I (anti-Scl-70) antibodies have classically been determined by double immunodiffusion techniques against calf or rabbit thymus extract, including
Ouchterlony and counterimmunoelectrophoresis. The
Scl-70 antigen was found to be a basic, nonhistone chromosomal protein of 70,000 molecular weight found in rat
liver, calf, or rabbit thymus, or in HEp-2 or lymphoid
cells, and was subsequently found to represent topoisomerase I [10••]. Although initial ELISAs used topoisomerase I purified from calf thymus glands, more
recent studies have used recombinant topo I fusion proteins as the substrate for the ELISAs [10••].
phenomenon can confer an increase in the future development of SSc [14,15].
As many as half of patients with SSc in whom pulmonary
fibrosis develops will have Scl-70 autoantibodies, which
in some studies have also been predicted more severe
pulmonary disease (Table 1) [10,18–20]. A higher rate of
decline in pulmonary function test results has been described in patients with anti-Scl-70, although this association is not universally seen [10••,39]. Despite a report
in one study of Japanese patients with SSc, no convincing association has been established for anti-Scl-70 and
scleroderma renal crisis [40].
Anti-Scl-70 antibodies carry an increased mortality rate,
attributed to the higher rate of ventricular failure secondary to pulmonary disease [41,42]. As with ACA, a
recent study did not show any effect of anti-Scl-70 antibodies on coronary flow reserve [24•].
As with ACA, an increased frequency of anti-Scl-70 in
SSc patients in whom cancer develops has been reported
previously [43]. However, a more recent case-control
study in a large cohort of patients with SSc mentioned
previously was unable to replicate these findings [33•].
The clinical utility of serial determinations of anti-Scl-70
antibodies is controversial. Some studies have shown patients initially seen to be Scl-70 positive and anti-Scl-70
negative remained so, whereas other studies revealed
varying antibody levels over time [10••]. In a more recent study, Hu et al. [44•] examined the correlations
between anti-Scl-70 antibody levels measured by ELISA
with the degree and extent of skin thickening in a larger
cohort of SSc patients and in SSc patients from whom
multiple serum samples had been obtained. Serum levels of anti-Scl-70 antibodies correlated positively with
disease severity in the skin (total Rodnan skin score) and
with disease activity, on both cross-sectional and longitudinal analysis.
When determined by immunodiffusion, anti-Scl-70 antibodies are found in 9 to 20% of patients with SSc and
are highly disease specific (Table 1) [10••,12,13•,22•].
Anti-Scl-70 autoantibodies (by immunodiffusion) are virtually never seen in healthy control individuals, in nonaffected relatives of patients with SSc, or in patients with
other connective tissue diseases or primary Raynaud
phenomenon and are thus very useful in the diagnosis of
SSc [10••]. The determination of anti-Scl-70 by ELISA
is somewhat less specific for SSc, as illustrated in a more
recent study where 25% of 128 patients with systemic
lupus erythematosus (SLE) were found to be positive for
anti-Scl-70 antibody by ELISA [38]. None of these SLE
patients had an SSc overlap syndrome, and no relation
was found with pulmonary fibrosis as is seen in scleroderma. Interestingly, the presence and levels of anti-Scl70 correlated with higher lupus activity scores, the presence of double-stranded DNA antibodies, and more
pulmonary hypertension and renal involvement than in
SLE patients without the antibody [38].
Antinucleolar antibodies
The classic clinical association of anti-Scl-70 antibodies
is with diffuse cutaneous involvement (Table 1)
[10••,11,12,16]. As with ACA, the presence of anti-Scl70 antibodies in a patient initially evaluated for Raynaud
Antinucleolar antibodies are defined by their characteristic appearance on indirect immunofluorescence and
have been reported in 15 to 40% of patients with SSc
[10••]. They are rarely detected in healthy control individuals [6,19,21].
The association of anti-Scl-70 antibodies and HLADRB1*1101/*1104 and DPB1*1301 is well described
[2,12,45]. In a recent study of TNF polymorphisms in
patients with SSc, anti-Scl-70 showed a positive association with the TNF-857T allele and a negative association with both TNF-1031C and TNF-863A [37•].
Anti-PM-Scl
The anti-PM-Scl autoantibody has been found in patients with myositis, scleroderma, and the polymyositisscleroderma overlap syndrome, which combines myositis, Raynaud phenomenon, arthritis, and interstitial lung
disease [4]. In general, autoantibodies against the PMScl complex are found in approximately a quarter of patients with the polymyositis-scleroderma overlap syndrome, compared with only 2% of patients with
scleroderma alone and 6% of patients with myositis
(polymyositis or dermatomyositis) alone (Table 1) [4,46].
Conversely, between 43% and 88% of patients positive
for anti-PM-Scl antibodies received diagnoses of myositis-scleroderma overlap syndrome [4,47].
The anti-PM-Scl autoantibody is directed against a
multi-subunit nucleolar and nucleolar protein complex.
The PM-Scl complex has been shown to be the equivalent of the yeast exosome, a complex consisting of at
least 10 proteins, all displaying characteristics of exoribonucleases, which have been shown to be involved in
the degradation and processing of many RNA species
[48]. PM-Scl-100 and PM-Scl-75 contain the main autoantigenic epitopes of the human exosome. Recently, an
N-terminally elongated PM-Scl-75 protein has been described [49]. Raijmakers et al. [50•] recently compared
the autoantigenicity of the recently described Nterminally elongated PM-Scl-75 protein with that of PMScl-100 and the originally defined PM-Scl-75 polypeptide, and found that anti-PM-Scl-75 is more prevalent in
patients with the polymyositis-scleroderma overlap syndrome than are anti-PM-Scl-100 autoantibodies, which
until now were considered to be present most frequently. The clinical utility needs to be confirmed.
Anti-Th/To
Anti-Th/To antibodies are directed against components
of the ribonuclease MRP and ribonuclease P complexes,
more frequently Rp25 and hPop1. The Th40 autoantigen is identical to Rpp38 protein [51]. They are present
in approximately 2 to 5% of patients with SSc and are
associated with milder skin and systemic involvement
(Table 1) [10••,42,51–54]. The marked exception is the
more severe pulmonary fibrosis that has been reported in
patients with anti-Th/To and resultant greater mortality
[53–55]. In one study, anti-Th/To antibodies were increased in patients with xerophthalmia, esophageal dysmotility, and decreased DLCO [55]. The presence of
anti-Th/To antibodies has been associated with HLADRB1*11 in some but not all studies [2,56]. Anti-Th/To
has also been reported in localized scleroderma in one
study, with its presence possibly indicating a mild form
of cutaneous involvement [57].
[7–9,58,59]. Although they tend to coexist, their infrequency limits their utility in the diagnosis of SSc. AntiRNA polymerase II (RNAP II) autoantibodies have also
been described in patients with SLE and overlap syndromes [60].
Anti-RNAP antibodies are associated with diffuse cutaneous involvement and SSc-related renal crisis, as well as
with greater mortality [8,9,10••,42,61•]. A recent study
analyzing sera from 115 Italian SSc patients found that
anti-RNAP I and III were found to be less frequent than
in Caucasian patients from the United Kingdom or the
United States [61•]. However, only 2 patients from this
series had scleroderma renal crisis, one of them having
RNAP antibodies, which may explain the lower frequency of scleroderma renal crisis in this cohort.
Previously, two reports examined HLA class II gene associations with anti-RNAP I/III antibodies in SSc patients [62,63]. Both studies failed to detect any statistically significant associations between the presence of
anti-RNAP I/III antibodies and HLA-DRB1 or DQB1
alleles. More recently, Kuwana et al. [64•] found that the
presence of anti-RNAP I/III antibodies was associated
with HLA-DRB1*0405 and DQB1*0401 in Japanese SSc
patients, and with HLA-DRB3*02 (formerly known as
HLA-DR52b) in Caucasians. However, these associations were weak and inconsistent between these two ethnic groups.
Antifibrillarin/anti-U3 RNP
Anti-U3 RNP antibodies have been described in SSc
patients as far back as 1988 [3]. More recently, it has
been shown that the mammalian U3 small nuclear RNP
is one member of a family of nucleolar small nuclear
RNPs that are immunoprecipatable by antifibrillarin antibodies (AFA) [65]. AFA are present in fewer than 10%
of patients with SSc and have also been described in
patients with SLE, UCTD, and primary Raynaud phenomenon [19,55]. AFA are highly associated with diffuse
cutaneous SSc (Table 1). AFA frequency is higher in
patients of African descent with SSc than in Caucasian
patients with SSc, and they have been associated with
myositis, pulmonary hypertension, and renal disease
[19,66,67].
Anti-U3-RNP antibodies have also been found in serum
samples from patients with localized scleroderma [68].
However, no correlation between clinical and laboratory
manifestations was found.
In one study, U3-RNP was found to be associated with
HLA-DQB1*0604 [67].
Anti-RNA polymerase I–III antibodies
Anti-Ku antibodies
Autoantibodies to RNA polymerase I and III (RNAP I
and III, respectively) are highly specific for SSc, although they occur in only 20% of patients (Table 1)
Originally, autoantibodies against the 80-kDa subunit
protein of the human autoantigen Ku (p70/p80) (anti-Ku
antibodies) were described in patients with scleroderma-
myositis overlap syndromes [69]. Subsequently, associations were established with pulmonary hypertension in
this setting [70]. It is now known that anti-Ku antibodies
can occur in a wide spectrum of rheumatic diseases and
have little utility in clinical practice [71,72].
Antiphospholipid antibodies
The frequency of antiphospholipid antibodies (aPL) in
SSc is approximately 20 to 25% (ranging widely from 0 to
63%) [72,73]. There may be an increased frequency of
pregnancy losses in SSc patients with aPL [74]. The
presence of anticardiolipin antibodies (aCL) in patients
with SSc has been associated with a history of thrombosis
and pulmonary hypertension [75,76]. Some studies have
correlated the presence of aCL with greater skin and
systemic involvement, although this is not seen in others
[73,77–79]. The role of aPL in pathogenesis and determining long-term outcomes in SSc presently is not clear
because of limited and inconsistent data. Therefore, the
clinical utility of determining aCL in patients with SSc
has not yet been established.
The frequency of anti-U1RNP antibodies in SSc is approximately 8% (ranging from 2 to 14%) [12,88,89]. High
titers of anti-U1RNP antibodies are most often found in
association with what was previously designated “mixed
connective tissue disease” with a frequency of more than
90% [88,90–93]. Clinically, anti-U-1-RNP is associated
with a benign course characterized by less cutaneous and
renal involvement with a favorable response to corticosteroids [88,91]. Other clinical manifestations associated
with U-1RNP include Raynaud phenomenon, puffy
hands, sicca, pulmonary disease, esophageal disease, and
cor pulmonale secondary to pulmonary hypertension
[88–91,94]. U1-RNP antibodies have also been reported
in serum samples from patients with localized scleroderma [95].
Anti-Ro antibodies
Anti-Ro antibodies occur at a lower frequency in SSc
(<35%) than in SLE or Sjögren syndrome [96]. Sjögren
syndrome has been described in up to 20% of all patients
with SSc, with about one third to one half of those with
anti-Ro antibodies [97,98].
Only a few studies have been performed to examine the
association between Raynaud phenomenon and aCL,
with conflicting results [80,81–84]. A more recent study
by Caccavo et al. [85] found that secondary Raynaud
phenomenon is not positively associated with the presence of aPL in patients with SLE as well as a negative
association between IgG aCL and RP.
ANCA have been reported at a low incidence in SSc
(∼3%) without any significantly associated clinical features [99]. Case reports of scleroderma with vasculitis are
rarely seen, and routine screening of ANCA in SSc is not
recommended.
Another study of 48 patients investigated whether aPL
were detected in patients with localized scleroderma
[86]. In this study, patients with localized scleroderma
exhibited aCL (46%) and (LAC) (24%), whereas B2GPI
antibodies were not detected. 70% of patients with generalized morphea had aCL and LAC, suggesting that
aCL and LAC may be the major autoantibodies in patients with generalized morphea. Despite the high
prevalence of aCL and LAC, however, thrombosis was
detected in only 1 patient with generalized morphea.
Autoantibodies against endothelial cell antigen have also
been described in patients with SSc. They have been
found to be associated with alveolocapillary involvement, pulmonary hypertension, digital ulcers and ischemia, severe Raynaud phenomenon, and capillaroscopic
abnormalities [100–102]. Anti-endothelial cell antibodies
have also been found to be correlated with pulmonary
fibrosis [103,104•]. Further studies are needed with this
antibody to determine whether it is useful in clinical
practice.
Antibodies against extractable
nuclear antigens
Autoantibodies directed against fibrillin-1 protein, an extracellular matrix microfibrillar protein can occur in both
localized scleroderma and in SSc [105]. In a prospective
study analyzing serial serum samples, antifibrillin-1 autoantibody was present in 49% of those with limited
scleroderma and 47% of those with mixed connective
tissue disease 106].
Anti-Sm and anti-U1-RNP antibodies
The presence of anti-Sm antibodies is considered to be
highly specific for SLE, although they have been described as occurring uncommonly in patients with SSc
[12,87,88]. By contrast, anti-U1-RNP antibodies are associated with a variety of connective tissue diseases, including SLE, SSc, polymyositis, and mixed connective
tissue diseases [88].
When found in patients with SSc, anti-Sm antibodies are
found most often with SLE overlap and carry a poorer
prognosis and complications such as lupus nephritis, renal crisis, and pulmonary hypertension [87].
Less extensively studied autoantibodies
A recent study showed anti-U1 RNA antibodies to be
present in patients with SSc with anti-U1 RNP antibodies, mixed connective tissue disease, and SLE, but not in
healthy control individuals [107]. These results indicate
that anti-U1 RNA antibodies may be a serologic indicator
for pulmonary fibrosis in SSc patients with anti-U1 RNP
antibodies; however, clearly more studies are needed.
Fibrosing disorders
The fibrosing disorders represent a diverse group of
chronic, frequently progressive, systemic or localized diseases characterized by an over-accumulation of extracellular matrix components that interferes with function
(Table 2). The cause of most fibrosing disorders is generally still a mystery. Despite the frequent occurrence of
these diseases, the medical management of these disorders is inadequate, and our understanding of their pathogenesis is limited. The association with most of these
fibrosing disorders and autoantibodies has for the most
part been inconclusive.
scleroderma and 100% of patients with generalized morphea [115]. Whether this is a marker for localized scleroderma remains to be determined.
Graft-versus-host disease
A variety of autoantibodies have been reported in patients with graft-versus-host disease, particularly when
sclerodermatous skin changes are present, including discrepant reports of anti-Scl-70 (21% in one study but not
in another), anti-PM-Scl, aCL, or ANCA, although their
significance and clinical utility is unclear [116–120].
Eosinophilia myalgia syndrome
Localized scleroderma
Whereas anti-topoisomerase I antibody is almost exclusively detected in SSc, autoantibodies against topoisomerase-II-␣ have been detected in idiopathic pulmonary
fibrosis, SSc, insulin-dependent diabetes mellitus, juvenile rheumatoid arthritis, and SLE [108–113]. A recent
study suggests that anti-topo-II-␣ is a major autoantibody in localized scleroderma [114]. Further studies are
needed with this autoantibody.
As described above, aPL, anti-U1, U3-RNP, and antiTh/To autoantibodies have also been described in patients with localized scleroderma.
Recently, a novel autoantibody to Cu/Zn superoxide dismutase was detected in 89% of patients with localized
Table 2. Selected fibrosing disorders
Skin and musculoskeletal system
Systemic sclerosis
Localized form of scleroderma
Scleredema
Scleromyxedema
Keloids
Dupuytren contracture
Eosinophilic fasciitis
Eosinophilia-myalgia syndrome
Graft-versus-host disease
Plantar fasciitis
Nephrogenic fibrosing dermopathy
Diabetic stiff-hand syndrome
Radiation fibrosis
Lungs
Pulmonary fibrosis
Chronic pleural reaction
Cardiovascular system
Constrictive pericarditis
Intimal proliferation
Gastrointestinal system
Primary biliary cirrhosis
Sclerosing cholangitis
Collagenous colitis
Genitourinary system
Nephrosclerosis
Peyronie disease
Nephritis
Other
Reidel struma
Retroperitoneal fibrosis
Cancer
Some past studies have suggested an association between eosinophilia myalgia syndrome and autoantibodies such as ANA and antiphospholipid antibodies
[121,122]. However, the clinical significance of these antibodies remains unclear in this increasingly rare syndrome.
Nephrogenic fibrosing dermopathy
It is well known that patients with chronic renal failure
and hemodialysis frequently have increased serum levels
of antinuclear antibodies and circulating immune complexes. It is therefore difficult to assess the diagnostic
validity of serologic autoimmune phenomena in patients
undergoing hemodialysis. This is illustrated by the problem with aCL, which have been reported in nephrogenic
fibrosing dermopathy [123]. However, elevated aCL may
occur in approximately 30% of patients with chronic hemodialysis [124]. There have also been reports of nephrogenic fibrosing dermopathy associated with anti–
double-stranded DNA antibodies [125]. Hence, there are
few data to justify determining autoantibodies in patients with nephrogenic fibrosing dermopathy at this
point.
Conclusion
Autoantibodies in SSc provide important and prognostic
information (Table 3) and are useful in defining clinical
subsets of the disease. ACA are very useful in the diagnosis of SSc, particularly in patients with limited cutaneous involvement, and rarely occur in those with pulmonary fibrosis. They are also associated with a better
prognosis, whereas anti-Scl-70 antibodies, also useful in
the diagnosis of SSc, predict diffuse skin involvement
and pulmonary fibrosis and are associated with a poorer
prognosis. SSc patients who express ANoA run the
gamut of having mild disease (anti-PM-Scl) through limited skin but severe pulmonary involvement (antiTh/To), to intermediately severe disease (anti-fibrillarin)
(anti-RNA polymerase I and III). Other autoantibodies
(anti-RNP, anti-Ro) are less specific for SSc, although
they do define clinical subsets (overlap syndromes and
sicca complex, respectively). Still other autoantibodies
have been reported whose clinical relevance is doubtful
Table 3. Autoantibodies in systemic sclerosis
Prevalence
in SSc
HLA
associations
ACA
20 to 30% (highest
frequency seen in
Caucasians)
HLA-DRB1*01, *04
HLA-DQB1*05
Anti-Scl-70
9 to 20%
HLA-DRB1*1101,
*1104
HLA-DPB1*1301
Anti-PM-Scl-70
24% of patients with
PM/SSc overlap
2% in SSc alone
Anti-Th/To
Autoantibody
Clinical and
serologic
associations
Prognosis
Other
CREST
lcSSc
Lower frequency of
pulm. fibrosis
Increased risk of
pulmonary
hypertension
dcSSc
Increased frequency
of pulm. fibrosis
Lower mortality rate
than anti-Scl-70 or
ANoA
? Relation with
cancer
No need for serial
measurements
Increased mortality
rate
? Relation with
cancer
Serial determinations
controversial
HLA-DQA1*0501
HLA-DRB1*0301
PM/SSc overlap
2 to 5%
HLA-DRB1*11
Anti-RNAP
20%
AFA
< 10%
?HLA-DRB1*0405
?HLA-DQB1*0401
?HLA-DBR3*2
?HLA-DQB1*0604
Milder skin and
systemic
involvement
More severe
pulmonary fibrosis
dcSSc
?Renal crisis
Benign and chronic
course with
favorable
response to
steroids
Worse prognosis
Anti-Ku antibodies
Infrequent
No known
association
aPL
20 to 25% (ranging
widely from 0 to
63%)
No known
association
Anti-Sm
Rare
Highly specific for
SLE
No known
association
Anti-U1RNP
8%
HLA-DR2, DR4
Anti-Ro
Infrequent
ANCA
Infrequent
Antifibrillin-1
antibody
Antiendothelial cell
antibodies
Infrequent
HLA-DRB1*0301,
DQA1*0501,
DQB1*0201
No known
association
No known
association
No known
association
Infrequent
dcSSc
Myositis, pulmonary
hypertension and
renal disease
Overlap syndrome
with scleroderma
features
? Thrombosis,
pulmonary
hypertension
? More skin
involvement
When found in
patients with SSc,
most often with
SLE overlap, lupus
nephritis, renal
crisis, pulmonary
hypertension
MCTD, RP, puffy
hands, myositis,
pulmonary
hypertension
Sicca symptoms
Increased mortality
Poorer prognosis
when found with
SSc/SLE overlap
More benign course
Rare reports of SSC
with vasculitis
SSc, MCTD
Limited scleroderma
Alveolocapillary
involvement
pulmonary htn,
severe RP,
pulmonary fibrosis,
digital ulcers
ACA, anticentromere antibodies; SSc, systemic sclerosis; lcSSc, limited cutaneous systemic sclerosis; ANoA, antinucleolar antibodies; dcSSc,
diffuse cutaneous systemic sclerosis; PM, polymyositis; RNAP, RNA-polymerase; AFA, antifibrillarin antibodies; aPL, antiphospholipid; MCTD,
mixed connective tissue disease; ANCA, anti-neutrophil cytoplasmic antibodies.
(as a result of either their rare occurrence or the conflicting data), such as anti-Ku, antiphospholipid antibodies,
anti-Sm, and ANCA. Newer autoantibodies systems,
such as anti-endothelial cell antibodies, antifibrillin-1 autoantibody, and anti-U1 RNA antibodies, look interesting but need more study. Data on these autoantibodies
and other fibrosing disorders have for the most part been
inconclusive.
Autoantibodies associated with SSc differ in their associated clinical manifestations, ethnic and genetic associations, pathophysiology, and frequencies. Although it remains controversial whether these autoantibodies have
an actual role in pathogenesis, these serologic markers
can be useful in the diagnosis and clinical management
of SSc when backed by careful clinical judgment.
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13
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1
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10
••
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33
•
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37
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44
•
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61
•
62
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64
•
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72
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Cellular origins of fibroblasts: possible implications for
organ fibrosis in systemic sclerosis
Arnold E. Postlethwaitea,b, Hidenobu Shigemitsub,c and Siva Kanangata,c
Purpose of review
There is an intense interest in the potential of circulating blood
cells and epithelium-related nonfibroblast cells to change into
matrix synthesizing fibroblasts and myofibroblasts. These
sources of fibroblasts may have importance in systemic
sclerosis (scleroderma).
Recent findings
Epithelial cells from different sources can transition into
fibroblasts and myofibroblasts in response to transforming
growth factor ␤ and other growth factors/cytokines. This is
called epithelial-mesenchymal transition (EMT). EMT has been
repeatedly demonstrated to occur in several models of renal
fibrosis including lupus prone mice. Quite unexpectedly, bone
morphogenic protein 7 prevents EMT and protects lupus mice
and other renal fibrosis models from developing fibrosis in the
kidneys. Human peripheral blood mononuclear cells under
different conditions of culture give rise to several different
types of fibroblast-like cells. In SSc, it has been observed that
the sera have low levels of serum amyloid protein. Serum
amyloid protein has been found to inhibit the generation of
fibrocytes from CD14+ precursors. The implications of these
potential sources of fibroblasts and myofibroblasts in systemic
sclerosis and related rheumatic diseases are discussed.
Summary
Fibroblasts and myofibroblasts in skin and internal organs of
patients with systemic sclerosis and related diseases may
possibly arise not only from the resident fibroblast population
but from epithelial cells, pericytes, monocytes, and other
progenitors from the circulating pool of hematopoietic cells
and stem cells. These alternative sources of fibroblasts would
best be treated by specifically targeting the transition or
transdifferentiation process by which cells change into
fibroblasts.
Keywords
epithelial-mesenchymal transition, transition,
transdifferentiation, monocyte, scleroderma
a
Division of Connective Tissue Diseases, University of Tennessee Health Science
Center, Memphis, Tennessee, USA; bDivision of Pulmonary Medicine, University of
Tennessee Health Science Center, Memphis, Tennessee, USA; and cDepartment
of Veterans Affairs Medical Center, Memphis, Tennessee, USA
Correspondence to Arnold E. Postlethwaite, MD, Division Connective Tissue
Diseases, University of Tennessee Health Science Center, 956 Court Avenue,
Room G326, Memphis, TN 38163, USA
Tel: 901 448 4979; fax: 901 448 7265; e-mail: apostlethwai@utmem.edu
This work was supported in part by a VA Merit Review Grant, an NIAMS
Scleroderma SCOR USPHS AR44890 grant, and a NIAMS/NIAID grant NO1
AR92242.
Abbreviations
EMT
FLCs
MOMPs
PBMCs
SSc
SLE
TGF-␤
epithelial-mesenchymal transition
fibroblast-like cells
monocyte-derived mesenchymal progenitors
peripheral blood mononuclear cells
systemic sclerosis
transforming growth factor ␤
1040–8711
Introduction
Fibroblasts are mesenchymally derived spindle-shaped
cells that synthesize the major interstitial fibrillar collagens that provide structure to organs and tissues of the
body [1]. They are critical for wound repair and maintenance of the connective tissue matrix. Fibroblasts from
different anatomic locations in human adults and fetuses
differ remarkably in the genes that they express [2–5]. It
is suggested from microarray analyses that fibroblasts
from different anatomic sites should be considered distinct differentiated cell types [2]. Remarkably, HOX
genes (a family of highly conserved transcription factors),
which function during embryogenesis to determine positional orientation of differentiating cells, were found in
adult fibroblasts to retain main characteristics of HOX
gene expression patterns used during embryogenesis,
suggesting that there is imprinting of fibroblasts [2].
Myofibroblasts develop from fibroblasts in response to
stimulation of transforming growth factor ␤ (TGF-␤) and
other growth factors and cytokines [6]. Myofibroblasts
are highly contractile and are essential for contracting
wounds. They express ␣-smooth muscle actin, which
plays a major role in effecting these contractile properties
[6]. Increased numbers of fibroblasts and myofibroblasts
with excessive matrix disposition in skin and involved
internal organs are a hallmark of the prototypic fibrosing
disease systemic sclerosis (scleroderma, SSc) and fibrotic
complications of other rheumatic diseases (e.g., pulmonary fibrosis associated with rheumatoid arthritis, systemic lupus erythematous [SLE] and polymyositis and
end-stage renal disease associated with SLE). Although
great advances have been made in characterizing the
733
plethora of growth factors, cytokines, and other inflammatory mediators that regulate fibroblast growth and
function [1], until recently, little attention has been paid
to the cellular origins of fibroblasts and myofibroblasts
that populate fibrotic tissues. It is now apparent that
fibroblasts arise not only from proliferation of resident
fibroblasts but can metamorphose from different cell
types (e.g., circulating fibrocytes, CD14+ monocytes,
pericytes, epithelial cells, and hepatic stellate cells) as
fibrosis develops. In this article, we briefly review this
topic.
TGF-␤1, TGF-␤2, basic fibroblast growth factor, platelet-derived growth factor AB-AA-BB, and epidermal
growth factor, resulting in fibrosis or scar formation [1].
Fibroblasts are quite diverse in their phenotypic,
morphologic and synthetic response to cytokines, growth
factors, and matrix molecules [10–12,13••,14,15], and,
therefore, the cytokines and growth factors mediating fibrosis may not be the same in different locations in the
skin and other organs. Could such fibroblast heterogeneity explain differences in locations of fibrosis in subtypes of SSc?
Origins of fibroblasts
The circulating pool
Tissue-specific fibroblast precursor cells
Historically, Metchnikoff [16] in 1892 reported that
blood mononuclear cells transformed into connective tissue cells during cicatrization in the tail fin of tadpoles.
Later, Maximov [17] in 1928 confirmed the findings of
Metchnikoff. There was criticism from skeptics that the
results of Metchnikoff and Maximov were the result of
contaminating fibroblasts entering the blood sample and
that, in culture, these fibroblasts would expand. This
skepticism prevailed until the issue was revisited by Labat et al. [18] and Bucala et al. [19] in the early 1990s.
The most extensively studied fibroblast precursors are
epithelial cells. This topic was recently reviewed in detail by Kalluri and Neilson [7••]. In studies using radiation bone marrow chimeras, transgenic receptor mice and
the unilateral ureter obstruction model of renal fibrosis,
it was observed that 15% of fibroblasts in the fibrotic
regions of the unilateral ureter obstruction kidney were
derived from bone marrow, and 36% were derived from
tubular epithelium by a process termed epithelialmesenchymal transition (EMT) [7••]. EMT occurs in
developing vertebrate embryos and is a mechanism by
which epithelial cells are released to migrate to various
parts of the embryo where they undergo differentiation
into other structures [8]. EMT is initiated by cytokines
(e.g., TGF-␤, fibroblast growth factor-2, epidermal
growth factor, insulinlike growth factor-II) and proteases
that degrade basement membranes beneath epithelia
[9–12]. The epithelial cells lose their polarity, tight junctions, adherence junctions, desmosomes, and cytokeratin
intermediate filaments and then acquire a phenotype
suited for migration that includes rearrangement of
F-actin stress fibers and expression of fibropodia and
lamellipodia [7••]. They then acquire fibroblast characteristics and express fibroblast-specific protein-1) [7••].
EMT in the kidney is inhibited by bone morphogenic
protein-7, and EMT likely contributes to renal fibrosis
in murine models of SLE [13••]. EMT may also play a
role in pulmonary fibrosis in circumstances in which pulmonary epithelial cells might transition into fibroblasts/myofibroblasts. An additional possible tissuespecific fibroblast progenitor includes hepatic stellate
cells, which are related to their more ubiquitous perivascular relative, the pericyte, and which are thought to
transdifferentiate into myofibroblasts and contribute to
the fibrogenesis of cirrhosis [14].
Leftovers from embryonic development
The prevailing view for decades has been that fibroblasts
populating normal tissues are derived from mesenchyme
left over when organs were formed during fetal development. During inflammation and tissue injury, these resident fibroblasts proliferate and upregulate matrix synthesis in response to cytokine and growth factors such as
Neo-fibroblasts
Labat et al. [18] reported that blood monocytes from
patients’ with osteomyelosclerosis and Engelmann disease in culture spontaneously transformed into fibroblast-like cells (FLCs) he termed neo-fibroblasts. These
neo-fibroblasts arose from HLA-DR+ monocytes cultured from the blood of patients with cystic fibrosis [20].
These neo-fibroblasts were found to be pluripotent and
secreted not only collagen type I but also uromodulin,
amyloid-␤ peptide, ␣-fetoprotein, and carcinoembryonic
antigen [21], reminiscent of the pluripotent stem cells
reported by Zhao et al. [22•] discussed below. From normal donors, neo-fibroblast generation was enhanced by
soluble factors from T cells but was short-lived, surviving
in culture only 17 days, and reverted to a macrophage
phenotype after contact with T cells [18,20].
Fibrocytes
Bucala et al. [19] have described a FLC that they call the
“fibrocyte.” Fibrocytes are present in small numbers in
human and murine peripheral blood and are optimally
isolated by culturing peripheral blood mononuclear cells
(PBMCs) in medium with a low serum concentration on
tissue culture surfaces coated with fibronectin [17]. They
express collagen type I, CD11b, CD13, CD34, CD45
RO, major histocompatibility complex class II and CD86
but are negative for ␣-smooth muscle actin [19]. Fibrocytes are negative for monocyte markers (CD14 and
CD16) as well as being negative for dendritic cell markers (CD25, CD10, CD38) and pan-B cell antigen CD19
[19]. Abe et al. [23] found that CD14+ human blood
monocytes in the presence of T cells gives rise to fibrocytes and that TGF-␤1 can induce fibrocytes to assume
Cellular origins of fibroblasts Postlethwaite et al. 735
a myofibroblast phenotype expressing ␣-smooth muscle
actin and contracting collagen gels. Studies using transwell cultures showed that T cells had to be in physical
contact with the CD14+ monocytes for fibrocytes to develop [23].
Fibrocytes have some functional differences from normal
dermal fibroblasts. For example, they chemotax to interleukin-1␤ but not to tumor necrosis factor ␣, TGF-␤1, or
platelet-derived growth factor, recognized chemoattractants for dermal fibroblasts [23–26]. The response of
fibrocytes to cytokines with regards to collagen synthesis
also differs from that of fibroblasts in that interleukin-1␤
inhibits, whereas tumor necrosis factor ␣ stimulates, collagen synthesis, opposite from dermal fibroblast responses to these cytokines [24,27].
Pluripotent stem cells
There is increasing interest in blood mononuclear nonT, non-B, and non-NK cells as progenitors of not only
fibroblasts but of different cell types. Zhao et al. [22•]
claim in a recent article that normal CD14+ enriched
human blood mononuclear cells grown in eight-well Lab
Tech chamber slides coated with collagen and stimulated repeatedly with monocyte colony-stimulating factor and leukemia inhibitory factor assume a spindleshaped morphology after 7 days in culture. These cells
stained positive for CD14, CD45, CD34, and CI and
were called pluripotent stem cells by these authors [22•].
These pluripotent stem cells were not further characterized as to the monocyte subset from which they arise or
what cellular markers or functional properties they might
share with fibroblasts and/or myofibroblasts (e.g., production of collagen type I, hyaluronic acid, prostaglandin E2,
matrix metalloproteinase-1, tissue inhibitor of metalloproteinase, proliferation or chemotaxis in response to
various cytokines/growth factors, contraction of collagen
gels). Interestingly, these pluripotent stem cells were
able to be differentiated into CD3+/CD8+ T cells after
exposure to interleukin-2 and could differentiate into
epithelial cells when cultured with epidermal growth factor, neuronal cells when cultured with nerve growth factor, endothelial cells when cultured with vascular endothelial growth factor, and hepatocytes when cultured
with hepatocyte growth factor, and, quite remarkably,
could be converted to macrophages on exposure in culture to lipopolysaccharide [22•].
Monocyte-derived mesenchymal progenitors
A related study by Kuwana et al. [28•] described a
spindle-shaped cell that was CD14+/CD45+/CD34+/CI+
and derived from CD14+ monocytes. They called these
cells monocyte-derived mesenchymal progenitors
(MOMPs). In their hands, MOMPs arose in culture only
when PBMCs were cultured on fibronectin-coated surfaces in the presence of low-glucose Dulbecco modified
Eagle medium supplemented with 10% fetal calf serum.
For generation of MOMPs, there were absolute requisites for growing PBMCs on a fibronectin-coated surface
and exposure to a soluble factor(s) from CD14− blood
cells [28•]. By electron microscopic examination,
MOMPs had structural components representing a mixture of features of phagocytes, mesenchymal, and endothelial cells [28•]. MOMPs stopped growing after five
subpassages or 4 weeks in culture [26]. MOMPs could be
made to differentiate along mesenchymal cell lineages
into osteoblasts, myocytes, chondrocytes, and adipocytes
by appropriate additives to growth medium [28•]. Analysis by flow cytometry or immunohistochemistry revealed
that MOMPs also express additional monocyte markers
(CD13, CD11b/Mac-1, CD11c, CD64), HLA class I and
HLA-DR, costimulatory molecules (CD40, CD86), adhesion molecules (CD29, CD44, and CD54), stem cell
markers (CD105/SH2), endothelial cell markers (CD31,
CD144, Flt-1, Ac-LDL), and mesenchymal cell markers
(type III collagen, fibronectin, vimentin) [28•]. MOMPs
were not further characterized as to the functions that
they might share with fibroblasts/myofibroblasts. Bone
marrow has recently been shown to be a source of fibroblasts in the bleomycin pulmonary fibrosis model in vivo
[29••].
Fibroblast progenitors: scleroderma and
related diseases
Possible participation in fibrosis associated with scleroderma and related rheumatic diseases of fibroblasts derived from sources other than those in the resident pool
has received little attention to date, but investigations
are ongoing to explore this issue. In this regard, Pilling et
al. [30••] observed that serum amyloid protein inhibits
outgrowth of fibrocytes from PBMCs and that sera from
patients with SSc have reduced levels of serum amyloid
protein [29••]. In abstracts that we have submitted for
presentation at the 2004 meeting of the American College of Rheumatology, we report that we have observed
that PBMCs from patients with SSc generate large numbers of FLCs, which are derived from CD14+ monocytes
when cultured with type I collagen compared with controls. Furthermore, there is an inverse relationship between the degree to which FLCs grow from PBMCs of
patients with diffuse SSc to the DLCO, suggesting that
increased outgrowth of FLCs from SSc PMBCs might be
a marker for pulmonary fibrosis in diffuse SSc. The
FLCs that we observe from SSc PMBCs cultured with
collagen type I appear to be different from classic fibrocytes in that they are CD14+/CD34−/CI+. A list of some
fibroblast and mesenchymal cell progenitors is given in
Table 1.
In Figure 1, we present a diagram showing events that
could lead to transdifferentiation of circulating monocytes into FLCs in SSc. If circulating monocytes are
eventually shown to play a significant role in the fibrogenesis associated with SSc, then treatment of SSc could
Table 1. Comparison of fibroblast-like cells from systemic sclerosis with other known possible sources of
circulating fibroblast and mesenchymal progenitors
Cell markers
FLC from SSc
Fibrocyte
MOMP
Type I collagen
CD14
CD45
CD11b
CD34
Culture
conditions
+
+
+
+
−
Grows in serum and
plastic-coated culture
plates; PBMC-derived
factors for growth
+
−
+
+
+
Requires serum-free
medium for optimal
growth
Survival
Months
Published data for
weeks
+
+
+
+
+
Requires culture plates
to be coated with
fibronectin and
CD14− PBMC
soluble factors
Weeks
Mesenchymal
stem cell
Monocytederived PSC
+
−
−
−
−
Grows in
plastic-coated
plates
Unknown
+
+
Unknown
+
Requires MCSF
and LIF
Months
Published data for
weeks
FLC, fibroblast-like cell; SSc, systemic scleroderma; MOMP, monocyte-derived mesenchymal progenitor; PSC, pluripotent stem cell; PBMC,
peripheral blood mononuclear cell; MCSF, monocyte colony-stimulating factor; LIF, leukemia inhibitory factor.
be directed at several potential sites in the process.
These would include (1) the endothelial cell activation
and upregulation of adhesion, which allow circulating T
cells and monocytes to attach and migrate through small
blood vessels into perivascular sites; (2) the T cell, which
has to produce cytokines for transdifferentiation of SSc
monocytes to occur; and (3) the CD14+ monocyte precursors of the FLCs.
Several of the ongoing and planned clinical trials in SSc
funded by the National Institutes of Health might intervene in the process. The oral tolerance trial of type I
bovine collagen could tolerize the T cell to type I collagen and other T-cell antigens in patients with SSc, essentially shutting down cytokine production by T cells.
The autologous stem cell transplant trial in SSc, soon to
begin, might have a similar effect on T cells but potentially
could convert endothelial cell abnormalities and monocyte
abnormalities in the disease by replacing these with naïve
endothelial cells and monocytes of a younger age.
The pannus of the rheumatoid joint might develop in
part from transdifferentiation of blood monocytes into
synovial fibroblasts. The particular cytokine milieu in
the rheumatoid arthritis synovium might favor transdifferentiation of blood monocytes into a synovial fibroblast
with marked propensity to synthesize matrix metalloproteinase that degrade cartilage ligands and tendons.
Immune reaction in the lungs of patients with rheumatoid arthritis, SLE, polymyositis, and SSc might set the
Figure 1. Endothelium is damaged in various parts of the body in patients with systemic sclerosis, resulting in
upregulation of vascular adhesion molecules that bind receptors in circulating T cells and monocytes
These cells then migrate through vessel walls into the
interstitium where they come in contact with type I
collagen (CI) and other antigens triggers release of
cytokines and growth factors from the T cells and
monocytes. Monocytes respond to transdifferentiation into
fibroblasts and myofibroblasts, which synthesize new
matrix.
Cellular origins of fibroblasts Postlethwaite et al. 737
stage for trafficking of circulating fibroblast progenitors
such as CD14 monocytes and fibrocytes to the lung parenchyma where the cytokine environment would favor
transdifferentiation of the progenitor into high matrix
producing fibroblasts/myofibroblasts.
The glomerular damage in SLE might facilitate trafficking of fibroblast progenitors into the glomerular structure, and tubular epithelial cells by EMT could participate in renal fibrosis to lead to an end-stage fibrotic
kidney.
Renal failure in SSc might be owing in part to EMT of
tubular epithelial cells in response to injury and cytokine
and growth factor signals generated in the SSc kidney.
The possibility that fibroblasts might originate from circulating progenitors and from EMT in patients with SSc
and related rheumatic diseases characterized by lung and
renal fibrosis is intriguing and certainly deserves further
investigation.
A must read for the latest review on EMT with a heavy emphasis on the relationship
to developmental biology and renal fibrosis. There are extensive references.
8
Hay ED: An overview of epithelio-mesenchymal transformations. Acta Anat
1995, 154:8–20.
9
Fan JM, Ng YY, Hill PA, et al.: Transforming growth factor-beta regulates
tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int 1999,
56:1455–1467.
10
Okada H, Dannoff TM, Kalluri R, et al.: The early role of FSP1 in epithelialmesenchymal transformation. Am J Physiol 1997, 273:563–574.
11
Moralie OG, et al.: IGF-II induces rapid beta-catenin relocation to the nucleus
during epithelium to mesenchyme transition. Oncogene 2001, 20:4942–
4950.
12
Strutz F, et al.: Role of basic fibroblast growth factor-2 in epithelialmesenchymal transformation. Kidney Int 2002, 61:1714–1728.
Zeisberg M, Bottiglio C, Kumar N, et al.: Bone morphogenic protein-7 inhibits
progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol 2003, 285:F1060–F1067.
Very interesting article that shows that bone morphogenic protein-7 protects mice
with deficiency of ␣3-chain of type IV collagen and MLR/MpJlpr/lpr lupus mice from
developing chronic renal fibrosis.
13
••
14
Cassiman D, Libbrecht L, Desmet V, et al.: Hepatic stellate cell/myofibroblast
subpopulation in fibrotic human and rat livers. J Hepatol 2002, 36:200–209.
15
Goldring SR, Stephenson ML, Downie E, et al.: Heterogeneity in hormone
responses and patterns of collagen synthesis in cloned dermal fibroblasts. J
Clin Invest 1990, 85:798–803.
16
Metchnikoff E: Lecons sur la pathologie comparee de l’inflammation. (Données à I’Institut Pasteur en avril et mai 1881) In: Bibliothèque des Annales de
I’Institut Pasteur. Masson, Paris, 111, 1882
17
Maximov A: Culture of blood leucocytes. From lymphocytes and monocytes
to connective tissue. Arch Exp Zellforsch 1928, 5:12.
18
Labat ML, Bringuier AF, Séébold-Choqueux C, et al.: Monocytic origin of
fibroblasts: spontaneous transformation of blood monocytes into neofibroblastic structures in osteomyelosclerosis and Engelmann’s disease.
Biomed Pharmacother 1991, 45:289.
19
Bucala R, Spiegel LA, Chesney J, et al.: Circulating fibrocytes define a new
leukocyte subpopulation that mediates tissue repair. Mol Med 1994, 1:71.
20
Labat ML, Bringuier AF, Séébold-Choquex C, et al.: Cystic fibrosis: production of high levels of uromodulin-like protein by HLA-DR blood monocytes
differentiating towards a fibroblastic phenotype. Biomed Pharmacother
1991, 45:387.
21
Bringuier AF, Séébold-Choqueux C, Moricard Y, et al.: T-lymphocyte control
of HLA-DR blood monocyte differentiation into neo-fibroblasts. Further evidence of pluripotential secreting functions of HLA-DR monocytes, involving
not only collagen but also uromodulin, amyloid-␤ peptide, ␣-fetoprotein and
carcinoembryonic antigen. Biomed Pharmacother 1992, 46:91–108.
Conclusion
Little, if any, progress has been made to date on halting
or reversing the fibrosis characteristic of SSc and related
rheumatic diseases. Perhaps we have been focusing on
the wrong targets. The observations that circulating fibroblast and mesenchymal progenitors play roles in some
animal models of fibrosis and that epithelial cells by
EMT can assume a fibroblast/myofibroblast phenotype
are ample reason to stimulate further study into the role
of these alternative sources of fibroblasts in SSc and related diseases.
Acknowledgments
The authors thank Ginny Geer for the typing of the manuscript and constructing the
figure.
•
Of special interest
••
1
Postlethwaite AE, Kang AH: Fibroblasts and matrix proteins. In: Inflammation:
Basic Principles and Clinical Correlation. Edited by Gallin JI, Goldstein IM,
Snyderman R. New York: Raven Press; 1992:747–773.
2
Chiang HY, Chi JT, Dudoit S, et al.: Diversity, topographic differentiation and
positional memory in human fibroblasts. Proc Natl Acad Sci U S A 2002,
99:12877–12882.
3
Müller GA, Rodemann HP: Characterization of human renal fibroblasts in
health and disease. I. Immunophenotyping of cultured tubular epithelial cells
and fibroblasts derived from kidneys with histologically proven interstitial fibrosis. Am J Kidney Dis 1991, 17:680–683.
4
Garrett DM, Conrad GW: Fibroblast-like cells from embryonic chick cornea,
heat, and skin are antigenically distinct. Dev Biol 1979, 70:50–70.
5
Dugina V, Alexandrova A, Chaponnier C, et al.: Rat fibroblasts cultured from
various organs exhibit differences in alpha-smooth muscle actin expression,
cytoskeletal pattern, and adhesive structure organization. Exp Cell Res 1998,
238:481–490.
6
Serini G, Gabbiani G: Mechanisms of myofibroblast activity and phenotypic
modulation. Exp Cell Res 1999, 250:273–283.
7
••
Kalluri R, Neilson EG: Epithelial-mesenchymal transition and its implications
for fibrosis. J Clin Invest 2003, 112:1776–1784.
Zhao Y, Glesne D, Huberman E: A human peripheral blood monocytesderived subset acts as pluripotent stem cells. Proc Natl Acad Sci U S A 2003,
100:2426–2431.
This paper demonstrates the tremendous plasticity of the human CD14+ monocyte
with its ability to differentiate into a variety of mesenchyme-related cells.
22
•
23
Abe R, Donnelly SC, Peng T, et al.: Peripheral blood fibrocytes: differentiation
pathway and migration to wound sites. J Immunol 2001, 166:7556–7562.
24
Postlethwaite AE, Raghow R, Stricklin GP, et al.: Modulation of fibroblast
functions by interleukin-1: increased steady state accumulation of type I procollagen mRNAs and stimulation of other functions but not chemotaxis by
human recombinant interleukin 1␣ and ␤. J Cell Biol 1988, 106:311–318.
25
Postlethwaite AE, Keski-Oja J, Moses HL, et al.: Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor ␤. J Exp Med
1987, 165:251–256.
26
Senior RM, Huang JS, Griffin GL, et al.: Dissociation of the chemotactic and
mitogenic activities of PDGF by human neutrophil elastase. J Cell Biol 1985,
100:351–356.
27
Chesney J, Metz C, Stavitsky AB, et al.: Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J Immunol
1998, 160:419–425.
Kuwana M, Okazaki Y, Kodama H, et al.: Human circulating CD14+ monocytes as a source of progenitors that exhibit mesenchymal cell differentiation.
J Leukoc Biol 2003, 74:833–845.
This paper describes MOMPS as having features of several different mesenchymal
cell types.
28
•
29 Hashimoto N, Jin H, Liu T, et al.: Bone marrow-derived progenitor cells in
pulmonary fibrosis. J Clin Invest 2004, 113:243–252.
••
This is an interesting paper that uses GFP labeled bone marrow chimera mice to
induce pulmonary fibrosis secondary to bleomycin inhalation. They found that the
bone marrow contributes fibroblasts to the fibrotic process in lungs of the bleomycin-treated mice.
30 Pilling D, Buckley CD, Salmon M, et al.: Inhibition of fibrocyte differentiation by
serum amyloid P1. J Immunol 2003, 171:5537–5546.
••
Excellent demonstration that serum amyloid protein inhibits fibrocyte development
and that SSc sera have low levels of serum amyloid protein. These low levels are
postulated to possibly predispose SSc monocytes to transdifferentiate into fibrocytes.
Recent advances in fibroblast signaling and biology
in scleroderma
Jaspreet Pannu and Maria Trojanowska
Purpose of review
Systemic sclerosis is a complex disease manifesting itself by
fibrosis of skin and other internal organs. Fibroblasts isolated
from scleroderma lesions and cultured in vitro are
characterized by increased synthesis of collagen and other
extracellular matrix proteins, consistent with the disease
phenotype. Cultured systemic sclerosis fibroblasts therefore
serve as a principal experimental model for studying the
molecular and cellular mechanisms involved in collagen
overproduction in this disease. This review will discuss recent
findings related to intracellular signal transduction pathways
implicated in deregulated extracellular matrix deposition by
systemic sclerosis fibroblasts.
Recent findings
Recent findings suggest that constitutively elevated synthesis
of extracellular matrix by cultured systemic sclerosis fibroblasts
is, at least in part, due to the aberrant activation of the
autocrine transforming growth factor-␤ signaling. Enhanced
constitutive transforming growth factor-␤ signaling may result
from the elevated levels of transforming growth factor-␤
receptor type I and/or inappropriate activation of Smad3.
These alterations of the transforming growth factor-␤ signaling
in systemic sclerosis fibroblasts may facilitate increased
collagen production in vivo even under conditions of low
ligand availability. However, there exist many inconsistencies
among published reports regarding the detailed mechanisms
of this pathway in systemic sclerosis fibroblasts, and additional
studies in this area are needed. Other signaling molecules
implicated in fibrotic phenotype include several members of
the protein kinase C family, mammalian target of rapamycin,
mitogen-activated protein kinase, necdin, reactive oxygen
species, and sphingolipids. These signaling pathways may
work in conjunction with transforming growth factor-␤
signaling to regulate the behavior of systemic sclerosis
fibroblasts.
Summary
Alterations in multiple signaling pathways contribute to
elevated extracellular matrix synthesis by systemic sclerosis
fibroblasts. Improved understanding of the key signaling
molecules may provide a novel avenue for therapeutic
interventions.
Division of Rheumatology and Immunology, Medical University of South Carolina,
Charleston, South Carolina, USA
Correspondence to Maria Trojanowska, Medical University of South Carolina,
Division of Rheumatology and Immunology, 96 Jonathan Lucas Street, Suite 912,
Charleston, SC 29425, USA
Tel: 843 792 7921; fax: 843 792 7121; e-mail: trojanme@musc.edu
Abbreviations
ECM
MAPK
mTOR
PKC
SSc
TGF
extracellular matrix
mitogen-activated protein kinase
mammalian target of rapamycin
protein kinase C
systemic sclerosis, scleroderma
transforming growth factor
1040–8711
Introduction
Fibroblasts cultured from the skin or lungs of patients
with systemic sclerosis (scleroderma, SSc) show elevated
collagen synthesis and several other phenotypic differences when compared with healthy skin fibroblasts [1•,
2]. Earlier findings indicated that the collagen type I
gene is upregulated at the transcriptional level in SSc
fibroblasts [3,4]. These findings have been facilitated by
the cloning of the regulatory proximal regions of the collagen type I genes [5]. These fruitful studies resulted in
characterization of the transcription factors altered in SSc
fibroblasts and have been summarized in several recent
reviews [6–8]. In comparison, the signal transduction
pathways contributing to SSc in general, and collagen
synthesis in particular, until recently, have been largely
unexplored. This review will discuss our current knowledge of the signaling molecules involved in the regulation of cell behavior relevant to fibrosis with the emphasis on those pathways that are deregulated in SSc
fibroblasts (Table 1). As outlined below, significant progress has been made in characterizing SSc-specific alterations of the transforming growth factor (TGF)-␤ signaling cascade. The TGF-␤ signaling pathway is discussed
in detail elsewhere, and readers are referred to recent
reviews on this topic [9,10,11•].
Transforming growth factor-␤ signaling
Keywords
scleroderma, systemic sclerosis, fibroblasts, signaling
pathways
The TGF-␤ is the most potent fibrogenic cytokine and
is considered to play a principal role in various fibrotic
diseases, including SSc [9]. Accumulated evidence suggests that defected TGF-␤ signaling contributes to the
phenotypic alterations of SSc fibroblasts in culture. This
739
area of investigation, however, will require further clarification because different laboratories have reported inconsistent findings. The differences may reflect heterogeneity of the disease, ethnic background, or stage of the
disease.
Elevated levels of transforming growth
factor-␤ receptors contribute to phenotypic
changes in systemic sclerosis fibroblasts:
the hypothesis
Cultured SSc fibroblasts differ from healthy skin fibroblasts with regard to extracellular matrix (ECM) production and other cellular responses related to fibrosis [12].
Furthermore, many of the characteristics of SSc fibroblasts can be induced in healthy skin fibroblasts by
TGF-␤ treatment [13]. It was hypothesized that altered
phenotype of SSc fibroblast in culture is dependent on
autocrine TGF-␤ signaling. Because TGF-␤ production
has been shown to be similar in SSc and healthy skin
fibroblasts, whereas TGF-␤ receptor levels were shown
to be elevated in SSc fibroblasts, it was suggested that
the elevated levels of TGF-␤ receptors is the primary
defect leading to enhanced autocrine TGF-␤ signaling
[14,15]. Although this hypothesis has been supported by
subsequent studies, the finding of the elevated TGF-␤
receptor levels has not been universally reproduced.
Work by Ihn et al. [16], Kubo et al. [17], and Yamane et al.
[18] consistently demonstrated elevated levels of TGF-␤
receptor-I and -II in Japanese patients. However, in a
recent study by Pannu et al. [19••], only TGF-␤ receptor-I protein levels were shown to be consistently elevated in SSc fibroblasts, whereas TGF-␤ receptor-II
levels were only occasionally increased. In a majority of
SSc fibroblasts analyzed in the latter study, TGF-␤ receptor-II protein levels were modestly decreased. Interestingly, decreased TGF-␤ receptor-II levels were observed in fibroblasts obtained from Caucasian patients,
whereas in African-American patients, TGF-␤ receptorII levels were either elevated or not changed (Pannu and
Trojanowska, unpublished observations). This intriguing
preliminary observation warrants further investigation. A
study by Dong et al. [20] found no differences in TGF-␤
receptor levels. A marked heterogeneity with regard to
TGF-␤ receptor-I expression in vivo was observed in a
study by Pannu et al. [19••], which may also explain
some of the discrepancies among different reports.
The evidence for autocrine transforming
growth factor-␤ signaling in systemic
sclerosis fibroblasts
Ihn et al. have shown that blockade of endogenous
TGF-␤ signaling via neutralizing antibodies or antisense
TGF-␤ oligonucleotides prevented upregulated collagen
synthesis by SSc fibroblasts [16]. Blockade of TGF-␤
signaling also reduced the expression of Smad7, another
TGF-␤ inducible gene, upregulated in SSc fibroblasts
[21••]. Surprisingly, upregulation of collagen synthesis
by a subset of SSc fibroblasts was resistant to a blockade
of TGF-␤ signaling by a different approach, ie, the overexpression of the kinase-deficient TGF-␤ receptor-II
[19••]. Pannu et al. [19••] have shown that SSc fibroblasts with the highest levels of TGF-␤ receptor-I were
the least responsive, suggesting that upregulation of collagen synthesis by SSc fibroblasts may primarily depend
on the signaling downstream from the TGF-␤ receptor-I.
In support of this concept, it was shown that forced expression of TGF-␤ receptor-I (but not receptor-II) in
healthy fibroblasts in a range corresponding to the elevated levels of TGF-␤ receptor-I found in SSc fibroblasts results in elevated collagen synthesis. Of note,
studies from other experimental models showed that decreased signaling from TGF-␤ receptor-II correlated
with the induction of epithelial mesenchymal transition
and preservation of ECM induction with the selective
loss of growth inhibitory responses [22,23]. Furthermore,
in transgenic mice with fibroblast-specific expression of
a kinase-deficient TGF-␤ receptor-II receptor dermal
and pulmonary fibrosis developed, suggesting that perturbations of specific aspects of the TGF-␤ signaling
pathway in fibroblasts may induce fibrosis in vivo [24].
Transforming growth factor-␤ receptor
turnover is defective in systemic
sclerosis fibroblasts
What is the mechanism of upregulation of TGF-␤ receptors in SSc fibroblasts? According to the current theory of
TGF-␤ receptor trafficking, receptor internalization via
the caveolae pathway leads to receptor degradation,
whereas the clathrin-dependent internalization into
SARA-containing early endosomes promotes postreceptor signaling [25••]. Interestingly, the half-life of TGF-␤
receptor-I protein is significantly longer than the half-life
of TGF-␤ receptor-II protein, suggesting distinct degradation pathways for these two receptors [26]. Furthermore, ␤-arrestin 2 has been reported to be involved in
the co-internalization of TGF-␤ receptor-II with TGF-␤
receptor-III but not TGF-␤ receptor-I, thus strengthening the viewpoint of different internalization/degradation
pathways for these receptors [27]. Significantly, a recent
study by Asano et al. [21••] revealed that TGF-␤ receptor-I protein is stabilized in SSc fibroblasts. These authors also showed that in SSc fibroblasts, TGF-␤ receptors are localized to presently uncharacterized subcellular
structures with a punctate appearance. Because TGF-␤
signaling appears to be constitutively activated in SSc
cells, presumably these receptor-containing structures
represent early endosomes in which signaling occurs.
Paradoxically, however, Smad7 was colocalized with
TGF-␤ receptors to these subcellular structures. In addition, it was shown that in SSc fibroblasts, TGF-␤ receptor-I turnover was insensitive to the ectopically expressed Smurf1/2, whereas such treatment promoted
receptor degradation in control fibroblasts [21••]. Because the association of TGF-␤ receptors with Smad7-
Fibroblast signaling and biology in scleroderma Pannu and Trojanowska 741
Table 1. Signaling molecules implicated in scleroderma
Molecule
Functional relevance
Status in SSc fibroblasts
Study
TGF-␤ pathway:
receptor type I
Main signaling receptor in TGF␤
pathway
Elevated levels in vitro and in
vivo
Receptor type II
Binds ligand and activates
TGF␤RI
Nonsignaling high-affinity TGF␤
receptor generally associated
with endothelial cells
Downstream effectors of TGF␤
signaling pathway
Elevated or decreased levels in
vitro; elevated in vivo
Elevated levels in vitro
Kawakami et al. [15], Kubo et al.
[17], Yamane et al. [18],
Pannu et al. [19••]
Kawakami et al. [15], Yamane et
al. [18], Pannu et al. [19••]
Leask et al. [61]
Receptor type III
(endoglin/CD1 05)
Smad2/3
Smad7
Inhibits TGF␤ signaling
␣1␤1 and ␣2␤1
integrins
␣v␤5 integrin
Cell surface receptors for
collagen
Receptor for vitronectin—
stimulates human alpha2(I)
collagen promoter activity
through Sp-1 and Smad3
Receptors for endothelin-1;
promote myofibroblast
phenotype in lung fibroblasts
Endothelin receptor A
and B
Angiotensin II receptor
type I (AT1)
PDGF receptor ␣
PDGF receptor ␤
Necdin
PKC␦
PKC␧
p38 MAPK
JNK/SAPK
ERK MAPK
Cell surface receptor for
angiotensin II (Ang II).
Signaling receptor for PDGF A,
B, and C; implicated in lung
and cardiac fibrosis
Signaling receptor for PDGF B
and D
Nuclear protein; associates with
pre-IL-1␣ and stimulates
collagen production
Member of the novel subfamily of
PKCs implicated in collagen
and fibronectin upregulation
Member of the conventional
subfamily of PKCs implicated
TN-C upregulation and
promotion of myofibroblast
phenotype
Mediator of TGF-␤ induced
collagen synthesis
Negative regulator of collagen
transcription
Implicated in CTGF and collagen
upregulation
Elevated expression and
phosphorylation levels;
constitutive nuclear
localization
Conflicting data: elevated and
decreased levels
Unchanged
Asano et al. [63••}
Elevated total ET-1 receptor;
decreased ETA and
increased ETB levels in SSc
lung fibroblasts
vivo
Abraham et al. [64], Shi-Wen et
al. [65]
Elevated in vivo
Klareskog et al. [70]
Both, necdin and pre-IL-1␣
have elevated expression
Kawaguchi et al. [71], Hu et al.
[72••]
Elevated levels in vitro;
interacts with TGF␤ pathway
in pulmonary fibrosis
Decreased levels in SSC lung
fibroblasts; constitutively
associated with ␣-SMA
Jimenez et al. [49], Gore-Hyer et
al. [50], Zhang et al. [52],
Mimura et al. [73]
Tourkina et al. [54], Tourkina et
al. [55]
No change
Sato et al. [74]
Unknown
Fisher et al. [75]
Constitutively activated in SSc
lung and dermal fibroblasts
Tourkina, unpublished
observations; Pannu and
Trojanowska, unpublished
observations
Shegogue et al. [59••]; Pannu
and Trojanowska, unpublished
observations
Yamanaka and Trojanowska,
unpublished observations
Sato et al. [76]
Positive regulator of collagen
synthesis
Sphingosine kinase
Upregulated by TGF␤; mediates
stimulation of TIMP-1
Induced by TGF-␤; cooperates
with TGF-␤ in collagen
upregulation
Implicated in stimulation of
collagen synthesis
Unknown
Reactive oxygen species
Dong et al. [20], Asano et al.
[21••], Mori et al. [30]
Herzhoff et al. [62]
vivo
mTOR
Ceramide
Mori et al. [30••], Asano et al.
[31]
Unknown
Elevated levels in SSc
fibroblasts
Kawaguchi et al. [66•]
Yamakage et al. [67], Zhuo et al.
[68], Ponten et al. [69]
Sambo et al. [77]
IL, interleukin; TGF, transforming growth factor; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin.
Smurf2 is linked to the caveolae-dependent degradation pathway, it appears that in SSc fibroblasts a receptor degradation defect occurs downstream from
Smad7/Smurf2/TGF-␤ receptor complex formation. At
present, it is difficult to reconcile the existing observations from SSc fibroblasts with the current theories re-
garding TGF-␤ receptor internalization and turnover.
Clearly, additional studies are needed to characterize
the vesicles involved in TGF-␤ signaling in SSc cells. It
may be relevant that fibroblasts from SSc lung
tissues have lower levels of caveolin-1 (Tourkina, unpublished data). If this observation extends to skin fibroblasts,
it may suggest that the balance between the caveolaedependent degradation pathway and clathrin-dependent
signaling pathway is shifted toward the clathrin-dependent pathway in SSc fibroblasts (Fig. 1).
Smad2/3 pathway is constitutively
activated in systemic sclerosis fibroblasts
R-Smads are the primary transducers of TGF-␤ signaling. Their role in fibrosis has also been confirmed in
various animal models [28•,29]. Thus, it is reasonable to
expect that constitutive activation of TGF-␤ signaling in
SSc fibroblasts will also involve R-Smad activation. Recent studies by Mori et al. [30••] support this concept.
Their study showed elevated phosphorylation levels of
Smad2 and increased nuclear localization of Smad2/3 in
SSc fibroblasts. Consistent with the study by Pannu et al.
[19••], nuclear localization of Smads in SSc fibroblasts
was insensitive to the blockade of TGF-␤ signaling via
neutralizing TGF-␤ antibody or overexpression of kinase-deficient TGF-␤ receptor-II [30••]. Other investigators reported moderately increased levels of phosphorylated Smad2 and Smad3 in SSc fibroblasts [21••,31]. A
recent study by Asano et al. [31] showed that a treatment
with the pharmacologic inhibitor of PI-3 kinase abrogated constitutive Smad3 phosphorylation in SSc fibroblasts. This finding is consistent with the previous study,
which showed that inhibitors of the PI-3 kinase pathway
markedly reduced the expression of TGF-␤ receptor-II
Figure 1. Hypothetical model of alterations in transforming
growth factor (TGF)-␤ signaling pathway occurring in systemic
sclerosis (SSc) fibroblasts
in SSc fibroblasts [32]. Therefore, although it is formally
possible that Smad2/3 phosphorylation in SSc fibroblasts
is independent of TGF-␤ signaling, existing evidence
places the activation of Smad2/3 downstream from the
TGF-␤ receptors. Clearly, more studies are needed to
explain the mechanism involved in constitutive phosphorylation and nuclear localization of Smads in SSc fibroblasts, especially in view of recent findings on Smad
regulation. It is now evident that Smads actively shuttle between the nucleus and the cytoplasm and that
the subcellular localization of Smads is subjected to a
complex regulatory mechanism that is not yet fully elucidated [33].
In contrast to consistent findings of elevated phosphorylation status of Smad3 in SSc fibroblasts, reports regarding the expression levels of Smad7 are highly inconsistent. Asano et al. [21••] reported elevated levels of
Smad7 in SSc fibroblasts, whereas no consistent changes
in expression levels of Smad7 were reported by other
studies [30••] . Finally, reduced Smad7 expression in
SSc fibroblasts was reported by Dong et al. [20].
Activation of the Smad pathway cannot, however, explain some of the principal characteristics of SSc fibroblasts. For example, elevated expression of CTGF in
SSc fibroblasts was shown to be Smad-independent [34].
A possible explanation may be provided by our recent
unpublished studies. Dermal fibroblasts with ectopically
increased levels of TGF-␤ receptor type I, as described
by Pannu et al. [19••], showed elevated mRNA expression of COL1A1, COL1A2, and CTGF. Furthermore,
elevated TGF-␤ receptor-I levels resulted in activation
of ERK mitogen-activated protein kinase (MAPK) pathway, without activation of the Smad2/3 pathway (Pannu
and Trojanowska, unpublished observations). These
preliminary observations suggest a TGF-␤–dependent,
Smad-independent upregulation of CTGF in SSc fibroblasts, which involves activation of ERKs. Regulation of
CTGF expression by an ERK-dependent pathway has
previously been reported [35,36••].
Does transforming growth factor-␤ play
a role in maintenance of fibrosis?
In SSc fibroblasts increased receptor levels (either R1 or both) lead to
constitutive activation of Smad2/3 pathway and upregulation of matrix genes.
Other factors, presently uncharacterized, may also contribute to Smad2/3
activation. The downregulation of the TGF-␤ signaling pathway is impaired in
SSc fibroblasts, possibly owing to the defects in the components of caveolae,
including caveolin and/or sphingolipids. Data from Yamane et al. [18], Pannu
et al. [19••], Varga [9], and Asano et al. [21••].
Early SSc lesions are characterized by the influx of TGF␤–positive cells. This elevated expression of TGF-␤ is
limited to the inflammatory leading edge, and TGF-␤ is
no longer detectable during subsequent stages of the
disease, which is characterized by elevated ECM deposition [37]. On the basis of these observations, it has been
suggested that TGF-␤ signaling is involved in the early
stages, whereas other signaling pathways (eg, CTGF) are
responsible for ECM deposition during chronic stages of
the disease [38]. The question, then, is whether TGF-␤
signaling is still active in fibroblasts in vivo in these later
stages and whether it contributes to the progression of
the disease. Although involvement of CTGF is critical
for the fibrogenic effects of TGF-␤, we propose that
TGF-␤ is the major player also in chronic stages of SSc
[39]. First, it cannot be excluded that the low levels of
TGF-␤ are synthesized by fibroblasts in the skin in vivo.
Furthermore, latent TGF-␤ sequestered by ECM may
serve as an additional source of the ligand. Consistent
with this possibility, it has been observed that fibrillincontaining fibrils are unstable in SSc skin in vivo, which
may lead to the release of the matrix-bound TGF-␤ [40].
Evidence from cultured SSc fibroblasts, as well as the
demonstration of elevated TGF-␤ receptor levels in vivo,
strongly suggests that specific alterations of the TGF-␤
signaling may facilitate robust ECM synthesis in vivo
even when the ligand availability is low [17,19••]. Although additional studies are needed to support this notion, it is noteworthy that those alterations were also
observed in collagen-producing cells isolated from other
fibrotic tissues [41–44]. The question remains how SSc
fibroblasts acquire these changes. Recent studies of animal models of fibrosis strongly suggest that the collagenproducing fibroblasts seen in the fibrotic lesions either
originate in the circulation or are derived from epithelial
cells via epithelial-mesenchymal transformation (EMT)
[45,46]. This possibility remains to be tested for SSc skin
and lung fibroblasts. Other possible mechanisms to explain the phenotypic differences of SSc fibroblasts include mutational changes and gene polymorphisms [47].
Protein kinase C pathway
The protein kinase C (PKC) isoforms constitute a family
of serine-threonine kinases that form three subfamilies
based on structural homology and sensitivity to activators
and have been extensively reviewed [48]. Elevated levels of PKC␦ were found in SSc skin fibroblasts [49].
Furthermore, blockade of the PKC␦ activity by a specific
inhibitor, rottlerin, significantly reduced collagen synthesis in SSc and healthy fibroblasts [49]. PKC␦ activity was
also necessary to mediate the stimulatory effect of
CTGF in cooperation with insulin/IGF-I signaling on
collagen synthesis by SSc fibroblasts [50]. Importantly,
PKC␦ has been shown to interact with the TGF-␤ signaling pathway (Fig. 2). In mesangial cells, TGF-␤ activated PKC␦ and, in turn, PKC␦, positively regulated
Smad3 transcription activity and COL1A2 transcription
[51]. Likewise, TGF-␤ activated PKC␦ in lung fibroblasts, whereas interleukin-7, an antagonist of TGF-␤
function, inhibited PKC␦ activity [52]. Another PKC isoform, PKC␧, has been reported to function aberrantly in
SSc lung fibroblasts. PKC␧ activity has been linked to
myofibroblast differentiation, upregulation of Tenascin
C expression, and increased sensitization of SSc lung
fibroblasts to proapoptotic agents [53–55].
Figure 2. Crosstalk between transforming growth factor
(TGF)-␤ and other signaling pathways in fibrosis
TGF-␤ activates PKC␦, which contributes to Smad-mediated upregulation of
collagen gene. TGF-␤–dependent interaction between ␣v␤3 integrin
(Tenascin-C or Vitronectin receptor) and T␤RII enhances the proliferative effects
of TGF-␤. ␣v␤3 also activates the mTOR pathway, which positively regulates
collagen transcription and mRNA stability. mTOR is an effector of the Akt
pathway, which was shown to be constitutively activated in SSc fibroblasts.
There is evidence that mTOR phosphorylates PKC␦. PKC␦, vitronectin receptor
(␣v␤5), and mTOR levels are upregulated in SSc fibroblasts. This crosstalk may
contribute to enhanced collagen production by SSc fibroblasts. Data from
Runyan et al. [51], Shegogue et al. [59••], Maeshima et al. [79], Jun et al. [80],
Parekh et al. [81], Jimenez et al. [49], and Asano et al. [63••].
tion [56]. Because mTOR is a key nutrient sensor as well
as a mediator of mitogen and hormone signaling through
the PI3 kinase/Akt pathway, it is postulated that it functions as an integrator of pathways regulating cell size and
cell division [57,58]. mTOR has been shown to positively regulate collagen production in dermal fibroblasts
via a P1-3-kinase–independent pathway [59••]. Interestingly, COL1A1 and COL1A2 are differentially regulated
by mTOR. COL1A1 is regulated at transcriptional and
posttranscriptional (mRNA stability) levels, whereas
COL1A2 is regulated via mRNA stability only. The relevance of this differential regulation is currently unknown. Our preliminary studies indicate that mTOR
protein levels are elevated in SSc fibroblasts (Pannu and
Trojanowska, unpublished observations). How the
mTOR pathway is integrated with other signaling pathways involved in collagen synthesis is not known; however, functional interactions between mTOR and PKC␦
have been reported (Fig. 2) [60].
Mammalian target of rapamycin pathway
Conclusion
The mammalian target of rapamycin (mTOR), a member of the PI3 kinase superfamily, plays a key role in the
regulation of cell growth, proliferation, and differentia-
The regulation of ECM synthesis occurs at many levels
and involves integration of the signals from the cytokines, various matrix molecules, and other cells. Delin-
eation of the signaling molecules involved in this process
and especially the key molecules that are deregulated in
SSc fibroblasts is an area of intense research. Many parallels between SSc fibroblasts and collagen-producing
cells from other fibrotic diseases have been found. The
signaling molecules, including components of the
TGF-␤ signaling cascade, PKC␦, or mTOR, may serve
as universal targets for designing therapies to benefit
patients with SSc and other fibrotic diseases.
•
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72
••
Animal models of systemic sclerosis: insights into
systemic sclerosis pathogenesis and potential
therapeutic approaches
Paul J. Christner and Sergio A. Jimenez
Purpose of review
Animal models have been extremely valuable in contributing
to a better understanding of the pathogenesis of systemic
sclerosis. Discussed here are recent studies that have
examined the molecular pathways and potential therapeutic
approaches for systemic sclerosis using animal models.
Recent findings
Reported evidence further indicates that the immune system
plays a role in modulating the fibrosis observed in the tight
skin-1/+ mouse model for systemic sclerosis. CD19,
interleukin-6, and interleukin-4 are involved. The injection of
spleen cells into immune-compromised mice resulted in
fibrotic, vascular, and immunologic alterations quite similar to
those of systemic sclerosis. Transforming growth factor-␤ and
its signaling pathway (JAK kinase and STAT-6, Smad2/3, and
Smad7) appear to play a central role in the development of
fibrosis as well as monocyte chemoattractant protein-1,
CCR-2, platelet-derived growth factor C, and excessive
apoptosis. Viruses were shown to be possible cofactors. The
therapeutic agents hepatocyte growth factor and halofuginone
were shown to prevent fibrosis in animal models of systemic
sclerosis.
Summary
The transforming growth factor-␤ signaling pathway is a
common mechanism of tissue fibrosis in animal models of
systemic sclerosis, although numerous additional molecules
modulate this pathway or have a direct effect on fibrosis.
Keywords
systemic sclerosis, animal models, Tsk (tight skin) mouse,
bleomycin-induced scleroderma, transforming growth factor ␤
Division of Rheumatology, Department of Medicine, Jefferson Medical College,
Thomas Jefferson University, Philadelphia, Pennsylvania, USA
IL
MAGP-2
MCP
MMP
PAI
PDGF
SSc
TGF
TIMP
Tsk
interleukin
microfibril-associated glycoprotein 2
monocyte chemoattractant protein
matrix metalloproteinase
plasminogen activator inhibitor
platelet-derived growth factor
systemic sclerosis
transforming growth factor
tissue inhibitor of metalloproteinase
tight skin
1040–8711
Introduction
Animal models of systemic sclerosis (SSc) have provided
valuable insights into the causative mechanisms and the
pathogenesis of SSc and have furnished the means to
potentially test useful therapeutic interventions [1–3].
Among the numerous animal models for SSc, the most
extensively studied are murine because of the large
number of inbred mouse strains available and the detailed genetic and molecular information available for
this species. Although the animal models described to
date do not reproduce precisely all the clinical and pathologic alterations of the human disease, several of them
show some of the typical abnormalities of this disorder,
and prudent interpretation of the results obtained from
their study has provided substantial and valuable information about the pathogenesis of SSc. Here we review
recent studies using animal models of SSc, emphasizing
their contribution to understanding the pathogenesis
of the human disease and potential approaches for its
treatment.
Insights into pathogenesis and molecular
pathways of systemic sclerosis
Numerous recent studies have examined molecular
pathways that may be of relevance to the pathogenesis
of SSc.
Supported by NIH grants AR32564 to S.A.J. and AR42666 to P.J.C.
Correspondence to Sergio A. Jimenez, Thomas Jefferson University, Division of
Rheumatology, 233 South 10th Street, Room 509 BLSB, Philadelphia,
PA 19107, USA
Tel: 215 503 5042; fax: 215 923 4649; e-mail: sergio.jimenez@jefferson.edu
Abbreviations
BALF
ECM
HGF
746
bronchoalveolar lavage fluid
extracellular matrix
hepatocyte growth factor
Studies with Tsk1 mice
Saito et al. [4] reported that the level of the cytokine
CD19 can influence skin fibrosis and autoimmunity in
the tight skin (Tsk)1/+ mouse. Tsk1/+ mice were hyperresponsive to CD19 transmembrane signals and had a
decreased expression of IgM expression, enhanced serum Ig levels, and spontaneous autoantibody production.
The reason for this aberrant immune response appeared
Animal models of systemic sclerosis Christner and Jimenez 747
to be the constitutive increase in tyrosine phosphorylation
of CD19 in B cells from the Tsk1/+ mouse. In addition,
CD19-mediated [Ca2+]i responses, Vav phosphorylation
and Lyn kinase activity were increased. Furthermore,
Tsk1/+ mice deficient in CD19 had significantly less
skin fibrosis and showed a much higher expression of
surface IgM on their B cells, did not develop the autoantibodies characteristic of Tsk1/+ animals, and had reduced interleukin (IL)-6 production. The authors concluded that chronic B cell activation resulting from
augmented CD19 signaling could lead to skin sclerosis
and autoantibody production through a mechanism of
IL-6 overproduction.
In another study, Kodera et al. [5] reported that the IL-4
gene was crucial for the expression of the Tsk1 phenotype. Tsk1/Tsk1 mice are not viable, and they die
in utero at approximately the same time that expression
of the mutated fibrillin 1 gene is initiated. These authors
reported that elimination of either one copy or both copies of the IL-4 gene allowed survival of the homozygous
Tsk1/Tsk1 mouse. Histopathology indicated that these
mice did not show any cutaneous hyperplasia but still
displayed pulmonary emphysema. In vitro experiments
indicated that IL-4 regulated the levels of transforming
growth factor (TGF)-␤, and the authors postulated that
the downregulation of TGF-␤ levels in these IL-4–
deficient Tsk mice prevented the development of cutaneous fibrosis. The important conclusion of these studies
is that IL-4 is crucial in the development of the Tsk
phenotype and is involved in the mortality of Tsk/Tsk
embryos. In a follow-up study, McGaha et al. [6] reported
that IL-4 induced a substantial increase in collagen synthesis in both Tsk1/+ and normal mouse dermal fibroblasts, but the effect was greater in Tsk1/+ cells. They
further showed that the IL-4 signaling cascade was altered in Tsk1/+ fibroblasts compared with control specimens. In Tsk1/+ cells, the phosphorylation of JAK kinases, which in turn phosphorylate the IL-4 receptor,
was constitutive, whereas in cells from normal mice, IL-4
was required for JAK phosphorylation. Another signal
transduction molecule, STAT-6, was also involved because IL-4 induced higher levels of phosphorylated
STAT-6 in Tsk1/+ cells than in control cells. Transfection studies with a portion of the ␣2(I) collagen gene
promoter showed that IL-4 and STAT-6 could upregulate its transcriptional activity and that AP-1 and Sp-1
transcription factors were involved in this effect. The
authors concluded that type I collagen gene expression is
enhanced by IL-4 either directly or through TGF-␤–
mediated mechanisms.
Another study characterized the tissue expression of
elastic fiber–related proteins in Tsk1/+ mouse skin. Lemaire et al. [7] showed that Tsk mutant fibrillin 1 increases extracellular matrix (ECM) incorporation of microfibril-associated glycoprotein 2 (MAGP-2) and type I
collagen. The authors analyzed the effect of the Fbn1
mutation present in the Tsk1/+ mouse on the structure
and composition of the ECM by transfecting the mutated Fbn1 gene under the control of a tetracyclinedependent promoter into a mouse embryonic cell line. It
was found that when the mutated Fbn1 was expressed in
the mouse embryonic cell line, the sharply defined fibrillin network became smudged and blurred when examined by immunofluorescence. The fibrillin fibers produced in the presence of the mutated Fbn1 were also
broader and less intensely stained. However, in contrast
with previous studies, Col1a1 mRNA was equally expressed in the presence or absence of expression of the
mutated Fbn1. This was true even when TGF-␤1 was
added to the cultures. However, expression of the mutated Fbn1 had a significant effect on the deposition and
incorporation of type I collagen molecules into the ECM.
There was also an increase in the MAGP-2 fibrillar structures within the ECM caused by the expression of the
mutated Fbn1. The authors also reported an increase in
MAGP-2 deposits in lesional SSc skin and concluded
that alterations in the microfibril structure or deposition
may contribute to cutaneous fibrosis in SSc.
Studies with the bleomycin-induced
model of cutaneous fibrosis
Murota et al. [8] examined the effects of disruption of the
TNF-␣ receptor p55 on collagen turnover in skin fibroblasts from mice injected with bleomycin subcutaneously. The treatment caused mild sclerosis after 14 days
in normal mice, whereas it resulted in severe sclerosis
after only 3 days in TNF-␣ receptor p55−/− mutants. The
mutant mice showed thickened and homogeneous collagen bundles and dermal inflammatory infiltrates, whereas at the same time-points the control mice had severe
inflammatory infiltrates but no cutaneous sclerosis or fibrosis. After 3 days of bleomycin injections, the skin in
the mutant mice was significantly thicker than that in the
control mice, and the collagen content at the site of injection was almost threefold higher. At sites distant from
the injection site, there was no increase in dermal thickness, and the expression levels of IL-4 and plateletderived growth factor (PDGF) were also not different.
By contrast, TGF-␤ mRNA was reduced and TNF-␣
mRNA was induced in a time-dependent and dosedependent manner in the mutant and control mice as a
result of the bleomycin injections. Most interestingly,
the expression level of Col1a1 mRNA was not altered in
the mutant mice compared with control mice. However,
bleomycin induced an increased expression of matrix
metalloproteinase (MMP)-1 mRNA in the control mice,
whereas MMP-1 expression was significantly less in the
mutants. MMP-2, MMP-9, and gelatinase were equal in
both sets of mice. These same results were confirmed
when mouse embryonic fibroblasts were treated with
bleomycin in vitro. The authors concluded that TNF-␣
receptor p55 is an essential component of the signaling
pathway for MMP-1 expression leading to the degradation of collagen.
In another study, Takagawa et al. [9] examined the effects of repeated injections of bleomycin into the skin
of mice, which induced inflammation and fibrosis by 1
week. They further characterized the role of cellular
Smad3 expression in the skin using specific antibodies.
Mice injected with bleomycin had abundant Smad3
throughout the dermis, epidermis, hair follicles, and sebaceous glands. This effect was absent in control mice
injected with phosphate-buffered saline. At 3 days and
1 week, Smad3 was detected mainly in infiltrating macrophages; the inflammation began to resolve in 2 to 3
weeks, and Smad3 expression was confined mainly to
the nuclei of fibroblasts. The authors also examined
Smad 2 and Smad3 phosphorylation as an indicator of the
activation level of the TGF-␤/Smad pathway. They
showed that 70% of the lesional fibroblasts in mice injected with bleomycin were positive for phospho-Smad2/3
and that it was detectable even after 3 weeks of bleomycin injection, primarily in fibroblast nuclei. By contrast,
phospho-Smad2/3 was undetectable in control mice. The
authors concluded that activation of the Smad signaling
pathway is ongoing in resident lesional fibroblasts even
after the inflammation has resolved. In experiments with
dermal fibroblasts, it was shown that bleomycin has no
direct effect on the phosphorylation of Smad2/3 but that
its effect is mediated by TGF-␤. To understand the
mechanism by which the resident lesional fibroblasts
continued to produce phospho-Smad2/3 in the absence
of inflammation, the authors postulated that there might
be a defect in Smad7 that downregulates TGF-␤ activation of the Smad signaling pathway. In vivo expression of
Smad7 in the dermis of TGF-␤–injected mice was demonstrated after 24 hours. By contrast, in the bleomycininjected mice Smad7 was induced in the infiltrating
mononuclear cells but not in the fibroblasts. These results indicated that the ratio of phospho-Smad2/3 to
Smad7-positive fibroblasts was significantly altered in
bleomycin-injected mouse dermis and that this alteration
was responsible for the cutaneous fibrosis that develops
in these mice.
In a related study, Yamamoto and Nishioka [10] examined the role of monocyte chemoattractant protein-1
(MCP-1) and its receptor, CCR-2, in the pathogenesis of
bleomycin-induced scleroderma. The authors first examined the expression of MCP-1 and CCR-2 in the lesional
skin of mice injected subcutaneously with bleomycin.
They found that MCP-1 was weakly detectable on scattered mononuclear cells in control mice. In contrast,
MCP-1 and CCR-2 were detectable on infiltrating mononuclear cells in the dermis of bleomycin-injected mice,
and the number of positive cells peaked between 2 and
3 weeks during treatment. Positive fibroblasts were also
detected in the sclerotic dermis at later stages. The au-
thors concluded that there was concurrent upregulation
of MCP-1 and CCR-2 in mononuclear cells at early inflammatory stages and in fibroblasts at a later sclerotic
stage in the skin of bleomycin-injected mice. The authors next investigated the effect of antibodies against
MCP-1 on the course of dermal fibrosis. Administration
of the antibody every other day decreased the bleomycin-induced dermal fibrosis and reduced the number of
infiltrating mononuclear cells compared with control animals injected with bleomycin but receiving no antibody.
The link between MCP-1 and increased expression of
Col1a1 mRNA was examined in cultured fibroblasts.
The addition of MCP-1 to the fibroblast cultures increased collagen mRNA levels by more than fourfold. In
addition, decorin mRNA levels were also increased.
These mRNA increases were MCP-1 dose dependent.
However, the levels of fibronectin and biglycan mRNA
were not significantly altered. The authors concluded
that MCP-1 may induce fibrosis by directly upregulating
Col1a1 mRNA in fibroblasts as well as by exerting an
indirect effect through cytokines released from immunocytes recruited into lesional skin.
Another study by Yamamoto and Nishioka [11] examined the possible role of apoptosis in the pathogenesis of
bleomycin-induced scleroderma. These authors showed
that murine skin treated with bleomycin showed strong
apoptotic signals indicative of cell death in the infiltrating mononuclear cells, hair follicles, and sebaceous
glands in the dermis. The signals were present as early as
1 week and increased markedly after 3 weeks of bleomycin treatment. The molecular mechanism of the induced apoptosis involved Fas and FasL. Fas was detected in the cell membrane of some mononuclear cells
after 1 week of bleomycin treatment and increased to a
maximum after 2 weeks of treatment. Fas was also expressed constitutively in fibroblasts from 1 to 4 weeks of
bleomycin treatment. FasL was detectable after 1 week
of treatment in inflammatory cells and in fibroblastic
cells at 3 to 4 weeks. Reverse transcription polymerase
chain reaction showed that Fas mRNA was clearly detectable throughout all layers of skin during 1 to 4 weeks
of bleomycin treatment, whereas FasL mRNA expression was upregulated and peaked at 7.5 times the control
values at 3 weeks after the beginning of bleomycin treatment. The authors next investigated the role of caspase3, a downstream regulator of Fas/FasL. Immunohistochemistry showed that caspase-3 expression was
detected in epidermis, hair follicles, and sebaceous
glands but not in cellular infiltrates in control mice. In
bleomycin-treated skin, caspase-3 was detected in both
the nucleus and the cytoplasm of infiltrating mononuclear cells and a small portion of the fibroblasts. Reverse transcription polymerase chain reaction showed
that both caspase-1 and caspase-3 mRNA expression was
upregulated in lesional skin and peaked at 3 weeks of
bleomycin treatment. The upregulation of caspase-3 fol-
lowed the same time course as FasL upregulation. An
anti-FasL antibody partially prevented the development
of dermal fibrosis after bleomycin treatment, and collagen content was reduced 50% compared with skin from
controls treated with bleomycin and normal IgG. The
number of apoptotic mononuclear cells in the sclerotic
skin was also decreased. The authors conclude that there
is a relation between the Fas/FasL system and caspase-3
activation that mediates apoptosis and that the continuous and extensive expression of FasL may participate in
the development of cutaneous fibrosis/sclerosis by inducing excessive apoptosis or by modulating inflammatory
mediators.
Zhuo et al. [12] examined the modulation of PDGF-C
and PDGF-D in bleomycin-induced pulmonary fibrosis
in mice. PDGFs induce fibroblast proliferation and chemotaxis through cell surface receptor signaling. The authors reported that during bleomycin-induced lung fibrosis in mice, the levels of PDGF-C mRNA increased
significantly, whereas the level of PDGF-D mRNA decreased. The increased levels of PDGF-C mRNA were
localized by in situ hybridization to areas of lung fibrosis
and were not observed in the lungs of bleomycin-resistant BALB/c mice. The authors suggested that PDGF-C
is involved in the development of bleomycin-induced
pulmonary fibrosis through binding to its receptor.
Systemic sclerosis model induced by spleen cell
injections in immunodeficient mice
Ruzek et al. [13] described a modified model of induced
SSc that demonstrates all major aspects of the human
disease. The authors transferred donor B10.D2 spleen
cells into RAG-2 knockout mice to induce a graft-versushost response. RAG-2 knockout mice are genetically deficient in mature T and B cells and therefore cannot
generate an antigen-specific immune response. The results were similar to a graft-versus-host model using irradiated mice. In the treated mice, dermal thickening
developed, primarily of the extremities, with less pronounced dermal thickening in dorsal or abdominal skin.
The dermal thickening peaked at 3 to 5 weeks and began to decline by 6 weeks but did not completely disappear even by 22 weeks. Fibrosis of internal organs
including the kidneys, the intestinal tract, and the liver
was also observed, and, in contrast to the dermis, the
visceral fibrosis continued to increase over time. Overexpression of both type VII and type III collagens in the
skin and type III collagen in the kidneys was also observed. The authors also reported a significant decrease
in the luminal ratio of blood vessels in both skin and
kidney, indicating vasoconstriction and occlusion, which
was progressive over the course of the disease. In addition, the expression of the potent vasoconstrictor ET-1
was increased. The smooth muscle marker ␣SMA
showed that the cells surrounding vessels bearing this
marker had morphologic changes that likely contributed
to occlusion of the vessel lumen. The mice also showed
a prominent early immune response up to 3 weeks,
which resolved by 6 weeks. CD4+, CD8+ T cells and
macrophages were shown to participate: they increased
tenfold, sixfold, and eightfold, respectively, in the ear
dermis. CD4+ and CD8+ cells also increased in the kidney. Of remarkable importance was the observation that
ANAs with a speckled pattern developed in the mice and
that Scl-70 antibodies were present in more than 90% of
these mice. The authors concluded that this modified
model of graft-versus-host—induced SSc shows all the
major components of the human disease and can be used
to test effective therapeutic agents.
Models of pulmonary fibrosis
Kuroki et al. [14] investigated the role of TNF-␣ in pulmonary inflammation and fibrosis induced by intratracheal injection of bleomycin. They used TNF-␣ knockout (TNF-␣−/−) mice in this study. They demonstrated
that the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) peaked at 7 days in TNF␣+/+ mice and then decreased. By contrast, in TNF-␣−/−
mice the number of inflammatory cells in BALF was
persistently increased to 35 days after the instillation of
bleomycin. The predominant cells present in the BALF
of TNF-␣+/+ mice were macrophages, whereas in TNF␣−/− mice they were lymphocytes. When cells from lung
tissue were taken 21 days after bleomycin instillation,
the total cell and lymphocyte numbers were higher in
the TNF-␣−/− mice than in the TNF-␣+/+ mice. Histologic examination of TNF-␣+/+ and TNF-␣−/− mouse
lungs revealed lymphocytic and neutrophilic infiltration,
thickening of the alveolar septa, and proliferation of fibroblasts in both mouse strains 14 days after bleomycin
instillation. At day 21 no difference in hydroxyproline
content of the lungs between either strain was observed.
However, in the TNF-␣+/+ mice the inflammatory response gradually subsided, whereas in the TNF-␣−/−
mice massive infiltration of lymphocytes persisted, and a
fibrotic and honeycomb tissue morphology was observed
75 days after bleomycin instillation. TNF-␣ production
was measured in the TNF-␣+/+ mice in response to
bleomycin instillation and was shown to be biphasic
reaching an initial peak after 12 hours, declining until
7 days and then rising again and remaining persistently
elevated up to 50 days after instillation. Flow cytometry
revealed that markers for the TNF␣ receptor were upregulated on inflammatory cells in BALF from TNF␣+/+ and TNF-␣−/− mice 14 days after bleomycin instillation. Further flow cytometric analysis revealed that
significant numbers of the inflammatory cells in BALF
from the TNF-␣+/+ mice were apoptotic, whereas fewer
apoptotic cells were observed in the BALF from TNF␣−/− mice. When TNF-␣−/− mice were treated with murine rTNF-␣, the levels of apoptotic inflammatory cells
increased, and two weekly treatments with the protein
effectively diminished the pulmonary inflammatory response. The authors concluded that TNF-␣ is essential
for repressing pulmonary inflammation and fibrosis in
bleomycin-induced pneumopathy and that this effect is
mediated through induction of apoptosis of inflammatory
cells.
Potential therapeutic approaches
A very interesting study examined the role of viruses as
a cofactor in the development of pulmonary fibrosis in
bleomycin-resistant mice. Lok et al. [15] studied the development of fibrosis in BALB/c mice injected intraperitoneally with bleomycin. This mouse strain is normally
resistant to bleomycin-induced fibrosis. The mice received, in addition to the intraperitoneal injections of
bleomycin, transnasal dosing with murine gammaherpes
virus 68. Control mice received no virus and only phosphate-buffered saline injections. In mice that received
both the virus and bleomycin, significantly more severe
lung inflammation developed than in mice that received
virus alone, bleomycin alone, or saline. In addition, the
collagen content of the lung followed a similar pattern.
The authors concluded that the virus does not cause
pulmonary fibrosis by itself but can act as a cofactor in
the development of lung fibrosis or in its progression.
McGaha et al. [17] examined the effects of halofuginone,
a drug with antifibrotic properties, in preventing the appearance of dermal fibrosis in the Tsk1/+ mouse. They
reported that 1 µg of halofuginone injected intraperitoneally every other day for 60 days prevented the development of dermal fibrosis in both neonates and adult
Tsk1/+ mice, as demonstrated by histologic analysis.
The thickness of the skin of Tsk1/+ mice that had been
treated with halofuginone was less than 70% of the untreated animal skin thickness. Dermal fibroblasts derived from these mice were also sensitive to the drug,
which caused reduced type I collagen synthesis. The
drug appeared to cause this effect by affecting the promoter activity of type I collagen genes. The site of action
of halofuginone on the Col1a2 promoter was localized to
a region between −3200 and +54 bp. The mechanism by
which halofuginone exerted this inhibitory effect on collagen synthesis appeared to be through the TGF-␤ signaling pathways by blocking the phosphorylation of
Smad3.
Studies in transgenic mice
In a very interesting study, Denton et al. [16] examined
TGF-␤ signaling pathways involved in tissue fibrosis,
using transgenic mice. The authors reported the development of transgenic mice that express a kinase-deficient human type II TGF-␤ receptor (T␤RII⌬k) in fibroblasts. In previous work, T␤RII⌬k was shown to act
as a dominant negative inhibitor of TGF-␤ signaling.
However, in the present study, the authors demonstrated
that in adult mice that expressed this receptor, pulmonary and dermal fibrosis developed. Neonatal dermal fibroblasts cultured from the transgenic mice proliferated
more rapidly than control cells and produced more ECM.
Several markers of TGF-␤ signaling were upregulated,
including plasmogen activator inhibitor-1, CTGF, and
Smads 3, 4, and 7. Microarray experiments showed that
the transgenic fibroblasts had a similar gene expression
profile to that of littermate control fibroblasts that had
been treated with TGF-␤1. TGF-␤ was not able to further stimulate the transgenic fibroblasts. However, overexpression of type II TGF-␤ receptors partially restored
the responsiveness of these transgenic fibroblasts to
TGF-␤ stimulation. Additional studies of the mitogenactivated protein kinase pathways (another TGF-␤
signaling pathway separate from the Smad signaling
pathway) showed that they were less perturbed by recombinant TGF-␤, and the authors concluded that this
pathway is less affected in the transgenic mice than the
Smad pathways. Therefore, this mouse appears to be a
model for the study of TGF-␤ overexpression and signaling and the molecular pathways leading to tissue fibrosis.
Animal models have also been used in numerous studies
to examine putative therapeutic interventions that may
be effective to modulate or improve the pathologic alterations typically present in patients with SSc.
In a parallel paper, McGaha et al. [18] examined the
effect of halofuginone on the development of the Tsk1/+
phenotype. The authors administered halofuginone intraperitoneally to newborn (1-day-old) and 1-month-old
Tsk1/+ mice every other day for 60 days. They confirmed their earlier work, which showed that this drug
significantly reduces collagenous material in Sirus-red
stained skin sections. The collagen content of skin was
decreased by 20 to 25% when drug treatment was begun
in 1-month-old mice and by almost 50% when neonates
were treated. In situ hybridization studies indicated that
halofuginone-treated neonate mice had a significantly
lower number of cells expressing type I collagen mRNA
and that this number was indistinguishable from the
number detected in C57BL/6 pa/pa normal control mice.
The authors concluded that the decreased collagen content observed in halofuginone-treated Tsk1/+ mice is
due to decreased numbers of cells expressing collagen in
the dermis. The authors also presented data showing
that halofuginone had no effect on the emphysema that
develops in Tsk1/+ mice. An interesting observation was
that when adult Tsk1/+ mice were treated with the drug,
the level of anti–topoisomerase-1 and anti–fibrillin-1 antibodies typically present in these animals decreased to
control levels in adult Tsk1/+ mice but not in neonates.
A third study by McGaha et al. [19] examined the mechanisms of the inhibitory effects of halofuginone on fibrosis. They showed that the inhibition of collagen gene
promoter activity caused by the drug is mediated
through transcription factors that regulate type I collagen
gene expression. Using mouse-cultured fibroblasts, the
authors found that TGF-␤1, PDGF, and PMA induced
rapid phosphorylation of c-Jun, a component of a dimeric
transcription factor that binds with highest affinity to the
AP-1 regulatory element. In the presence of halofuginone, the induced phosphorylation of c-Jun was higher
than in its absence, indicating that the mechanism that
suppresses collagen synthesis may involve c-Jun. Further
experiments showed that TGF-␤1–induced AP-1 binding activity was greatly increased in intensity, and the
time over which the increase occurred was lengthened in
the presence of halofuginone. Transfection assays also
showed that there was a synergistic effect of TGF-␤1
and halofuginone on the activation of AP-1 activity and
that this AP-1 complex induced by TGF-␤1 in the presence of halofuginone is a potential antagonist of type I
collagen gene activity. Halofuginone abrogated the
TGF-␤1–induced upregulation of the Col1a2 promoter
and the reduction of Col1a2 mRNA levels through a
c-Jun dependent mechanism. In additional tests on
Tsk1/+ mice, the authors showed that the topical application of halofuginone led to increased amounts of phospho-c-Jun in the stratum and granular basal layer of the
epidermis.
Another potential therapeutic agent was studied by
Gong et al. [20]. The authors showed that the recently
described hepatocyte growth factor (HGF) modulates
matrix metalloproteinases and plasminogen activator/plasmin proteolytic pathways in progressive renal interstitial
fibrosis. HGF increased collagen catabolism in human
proximal tubular epithelial cells (HKC) treated with
TGF-␤1 associated with increased MMP activity and
plasminogen activator/plasmin proteolytic pathway enhancement. HGF also induced the production of MMP-9
and prevented TGF-␤1–induced production of tissue inhibitor of metalloproteinase (TIMP)-2 and plasminogen
activator inhibitor (PAI)-1. Continuous infusion of HGF
in the rat remnant kidney model ameliorated renal fibrosis and tubulo-interstitial collagen deposition. In this
model the authors also reported increased tubular expression of MMP-9, enhanced in situ gelatinolytic activity, restoration of plasmin activity, and decreased expression of TIMP-2 and PAI-1. There was an overall increase
in TIMP-3 expression. Anti-HGF antibodies caused increased renal fibrosis and exaggerated accumulation of
interstitial collagen deposition. Accompanying these
changes were decreased tubular expression of MMP-9
and elevated TIMP-2 and PAI-1 expression. The authors concluded that HGF ameliorates renal fibrosis by
enhancing ECM catabolism through the MMP and
PA/plasmin proteolytic pathways.
An additional study examined the possibility that HGF
may have antifibrotic effects. Wu et al. [21] showed that
HGF both prevents and ameliorates bleomycin-induced
dermal sclerosis. These authors transfected a construct
encoding human HGF into mouse skeletal muscle and
showed that expression of HGF had a marked effect
on preventing dermal sclerosis in mice injected with
bleomycin. The HGF was effective even when injected
4 weeks after bleomycin treatment. Levels of HGF
mRNA and protein were higher in skin, lung, muscle,
and serum after two transfections. It appears that the
effect of HGF in this model involves TGF-␤, because
levels of TGF-␤ were reduced. Transfections of HGF
also ameliorated lung fibrosis. The authors suggest that
gene therapy with HGF may be useful to prevent even
established tissue fibrosis.
Conclusion
Most of the work published over the past 2 years indicates that the TGF-␤ signaling pathway is a common
mechanism by which fibrosis occurs. However, there are
numerous other molecules that can either modulate this
pathway or have a direct effect on fibrosis. Two compounds, HGF and halofuginone, have been shown to be
effective in preventing or ameliorating fibrosis, and it
appears that perturbation of TGF-␤ pathways was involved in the mechanism of action of these drugs.
•
Of special interest
••
1
Zhang JC, Gilliam AC: Animal models for scleroderma: an update. Curr Rheumatol Rep 2002, 4:150–162.
2
Jimenez SA, Christner PJ: Murine animal models of systemic sclerosis. Curr
Opin Rheumatol 2002, 14:671–680.
3
Christner PJ, Jimenez SA: Spontaneous mouse models of systemic sclerosis.
In Animal Models of Human Inflammatory Skin Diseases. Edited by Chan LS.
Boca Raton, FL: CRC Press; 2004:495–515.
4
Saito E, Fujimoto M, Hasegawa M, et al.: CD19-dependent B lymphocyte
signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin
mouse. J Clin Invest 2002, 109:1453–1462.
5
Kodera T, McGaha TL, Phelps R, et al.: Disrupting the IL-4 gene rescues mice
homozygous for the tight-skin mutation from embryonic death and diminishes
TGF␤ production by fibroblasts. Proc Natl Acad Sci USA 2002, 99:3800–
3805.
6
McGaha TL, Le M, Kodera T, et al.: Molecular mechanisms of interleukin-4induced up-regulation of type I collagen gene expression in murine fibroblasts. Arthritis Rheum 2003, 48:2275–2284.
7
Lemaire R, Farina G, Kissin E, et al.: Mutant fibrillin 1 from tight skin mice
increases extracellular matrix incorporation of microfibril-associated glycoprotein 2 and type I collagen. Arthritis Rheum 2004, 50:915–926.
8
Murota H, Hamasaki Y, Nakashima T, et al.: Disruption of tumor necrosis
factor receptor p55 impairs collagen turnover in experimentally induced
sclerodermic skin fibroblasts. Arthritis Rheum 2003, 48:1117–1125.
9
Takagawa S, Lakos G, Mori Y, et al.: Sustained activation of fibroblast transforming growth factor-␤/Smad signaling in a murine model of scleroderma.
J Invest Dermatol 2003, 12:41–50.
10
Yamamoto T, Nishioka K: Role of monocyte chemoattractant protein-1 and its
receptor, CCR-2, in the pathogenesis of bleomycin-induced scleroderma.
11
Yamamoto T, Nishioka K: Possible role of apoptosis in the pathogenesis of
bleomycin-induced scleroderma. J Invest Dermatol 2004, 122:44–50.
12
Zhuo Y, Zhang J, Laboy M, et al.: Modulation of PDGF-C and PDGF-D expression during bleomycin-induced lung fibrosis. Am J Physiol Lung Cell Mol
Physiol 2004, 286:L182–L188.
13
Ruzek MC, Jha S, Ledbetter S, et al.: A modified model of graft-versus-hostinduced systemic sclerosis (scleroderma) exhibits all major aspects of the
human disease. Arthritis Rheum 2004, 50:1319–1331.
14
Kuroki M, Noguchi Y, Shimono M, et al.: Repression of bleomycin-induced
pneumopathy by TNF. J Immunol 2003, 170:567–574.
15
Lok SS, Haider Y, Howell D, et al.: Murine gammaherpes virus as a cofactor
in the development of pulmonary fibrosis in bleomycin resistant mice. Eur
Respir J 2002, 20:1228–1232.
16
Denton CP, Zheng B, Evans LA, et al.: Fibroblast-specific expression of a
kinase-deficient type II transforming growth factor ␤ (TGF␤) receptor leads to
paradoxical activation of TGF␤ signaling pathways with fibrosis in transgenic
mice. J Biol Chem 2003, 278:25109–25119.
17
McGaha TL, Phelps RG, Spiera H, et al.: Halofuginone, an inhibitor of type-I
collagen synthesis and skin sclerosis, blocks transforming-growth-factor-␤mediated Smad3 activation in fibroblasts. J Invest Dermatol 2002, 118:461–
470.
18
McGaha T, Kodera T, Phelps R, et al.: Effect of halofuginone on the development of tight skin (TSK) syndrome. Autoimmunity 2002, 35:277–282.
19
McGaha TL, Kodera T, Spiera H, et al.: Halofuginone inhibition of COL1A2
promoter activity via a c-Jun-dependent mechanism. Arthritis Rheum 2002,
46:2748–2761.
20
Gong R, Rifai A, Tolbert EM, et al.: Hepatocyte growth factor modulates matrix metalloproteinases and plasminogen activator/plasmin proteolytic pathways in progressive renal interstitial fibrosis. J Am Soc Nephrol 2003, 14:
3047–3060.
21
Wu M-H, Yokozeki H, Takagawa S, et al.: Hepatocyte growth factor both
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Erratum
In the September 2004 issue of Current Opinion in Rheumatology, a figure printed incorrectly. Figure 1 in “Apoptosis
and estrogen deficiency in primary Sjögren syndrome” (Hayashi Y, Arakaki R, and Ishimaru N, Curr Opin Rheumatol
16:522–526) is reprinted below. The author apologizes for this error.
Figure 1. An organ-specific autoantigen may play an important role on down-modulation of AICD
A cleavage product of 120-kD ␣-fodrin in the target cells
could be induced by estrogen deficiency during apoptosis
through caspase activation, in particular caspase 1.
Activation-induced cell death (AICD) results from the
interaction between Fas and FasL, and activated T cells
expressing both Fas and FasL are usually killed either by
themselves or by interacting with each other. FasL
undergo matrix metalloproteinase (MMP)-mediated
proteolytic processing in their extracellular domains,
resulting in the release of soluble FasL (sFasL).
FasL-mediated AICD is down-regulated by autoantigen
stimulation, indicating that the increased generation of
soluble FasL inhibits the normal AICD process, leading to
the proliferation of autoreactive CD4+ T cell. A defect in
AICD may result in the development of autoimmune
diseases.
AICD, activation-induced cell death; MMP, matrix
metalloproteinase; sFasL, soluble FasL.
753
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This bibliography is compiled by clinicians
from the journals listed at the end of this
publication. It is based on literature entered
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•
Papers considered by the reviewers to
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•• Papers considered by the reviewers to
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The number in square brackets following a
selected paper, for example [7], refers to its
number in the annotated references of the
corresponding review.
Current Opinion in Rheumatology
2004, 16:754–778
ISSN 1040–8711
Myositis and myopathies
Clinical assessment in adults
Review (pp 668–672)
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754
Vol 16 No 6 November 2004
768
Autoantibodies: pathogenetic
significance, clinical utility
769
Myofibroblasts, EMT, cellular
plasticity in tissue repair, fibrosis:
potential implications for
scleroderma
754
Clinical assessment in adults
754
Clinical assessment in children
755
The use of imaging to assess
patients with muscle disease
769
Recent advances in fibroblast
signaling and biology in scleroderma
755
Is it really myositis? A consideration
of the differential diagnosis
770
Animal models: insights into
pathogenesis, genetic risk factors,
potential therapeutic approaches
756
Myositis and autoantibodies
770
756
An update on pathogenesis
757
The immunogenetics of myositis
Recent advances in the
pathophysiology, diagnosis, staging,
and management of pulmonary
hypertension in scleroderma/SSc
757
New ideas about treatment
770
Anti-TGF-beta therapy in fibrosis and
scleroderma
757
Miscellaneous
770
Treatment
Raynaud phenomenon, scleroderma,
overlap syndromes, and other fibrosing
syndromes
771
Renal fibrosis
771
Hepatic fibrosis
767
771
SLE
771
Miscellaneous
Raynaud and vascular
manifestations: pathophysiology,
diagnosis, and management
Isenberg DA, Allen E, Farewell V, et al.: International
consensus on outcome measures for patients
with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult
onset disease. Rheumatology 2003, 42:1–7.
consensus outcome measures for patients
onset disease. Rheumatology 2004, 43:49–54.
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Yanaba K, Hasegawa M, Hamaguchi Y, et al.: Longitudinal analysis of serum KL-6 levels in patients with systemic sclerosis: association with
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List of journals scanned
The Index Medicus abbreviation is given in parentheses.
Acta Orthopaedica Scandinavica (Acta Orthop Scand)
Advances in Immunology (Adv Immunol)
American Journal of Human Genetics (Am J Hum Genet)
American Journal of Medicine (Am J Med)
American Journal of Nephrology (Am J Nephrol)
American Journal of Neuroradiology (AJNR Am J Neuroradiol)
American Journal of Pathology (Am J Pathol)
American Journal of Physical Medicine and Rehabilitation (Am J Phys Med
American Journal of Sports Medicine (Am J Sports Med)
Amsterdam: Elsevier (Amsterdam: Elsevier)
Annals of Internal Medicine (Ann Intern Med)
Annals of the New York Academy of Sciences (Ann N Y Acad Sci)
Annals of the Rheumatic Diseases (Ann Rheum Dis)
Annual Review of Immunology (Annu Rev Immunol)
Archives of Disease in Childhood (Arch Dis Child)
Archives of Internal Medicine (Arch Intern Med)
Archives of Physical Medicine and Rehabilitation (Arch Phys Med Rehabil)
Arthritis and Rheumatism (Arthritis Rheum)
Arthritis Care and Research (Arthritis Care Res)
Arthritis Research (Arthritis Res)
Autoimmunity (Autoimmunity)
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Journal
Baillieres Clinical Rheumatology (Baillieres Clin Rheumatol)
Best Practice and Research in Clinical Rheumatology (Best Pract Res Clin
Blood (Blood)
Bone (Bone)
Brain (Brain)
British Medical Journal (BMJ)
Bulletin on the Rheumatic Diseases (Bull Rheum Dis)
Lancet (Lancet)
Lupus (Lupus)
Calcified Tissue International (Calcif Tissue Int)
Clinical and Experimental Immunology (Clin Exp Immunol)
Clinical and Experimental Rheumatology (Clin Exp Rheumatol)
Clinical Immunology (Clin Immunol)
Clinical Infectious Diseases (Clin Infect Dis)
Clinical Orthopaedics and Related Research (Clin Orthop)
Clinical Rheumatology (Clin Rheumatol)
Clinics in Sports Medicine (Clin Sports Med)
Curr Rheumatol Rep (Curr Rheumatol Rep)
Current Opinion in Immunology (Curr Opin Immunol)
Current Opinion in Orthopedics (Curr Opin Orthop)
Current Opinion in Rheumatology (Curr Opin Rheumatol)
Digestive Diseases and Sciences (Dig Dis Sci)
Eur])
European Journal of Immunology (Eur J Immunol)
Human Immunology (Hum Immunol)
Human Molecular Genetics (Hum Mol Genet)
Immunology (Immunology)
JAMA Journal of the American Medical Association (JAMA)
JCR - Journal of Clinical Rheumatology (JCR - J Clin Rheumatol)
Jmri - Journal of Magnetic Resonance Imaging (J Magn Reson Imaging)
Journal of Arthroplasty (J Arthroplasty)
Journal of Autoimmunity (J Autoimmun)
Journal of Biological Chemistry (J Biol Chem)
Journal of Bone and Joint Surgery American Volume (J Bone Joint Surg (Am))
Journal of Bone and Joint Surgery British Volume (J Bone Joint Surg (Br))
ISSN 1040–8711
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
Bone and Mineral Research (J Bone Miner Res)
Cell Biology (J Cell Biol)
Clinical Endocrinology and Metabolism (J Clin Endocrinol Metab)
Clinical Immunology (J Clin Immunol)
Clinical Investigation (J Clin Invest)
Experimental Medicine (J Exp Med)
Hand Surgery American Volume (J Hand Surg [Am])
Hand Surgery British and European Volume (J Hand Surg [Br and
Immunology (J Immunol)
Infectious Diseases (J Infect Dis)
Investigative Dermatology (J Invest Dermatol)
Medical Genetics (J Med Genet)
Neuropathology and Experimental Neurology (J Neuropathol Exp
Orthopaedic Rheumatology (J Orthop Rheumatol)
Pediatric Orthopedics (J Pediatr Orthop)
Pediatrics (J Pediatr)
Rheumatology (J Rheumatol)
the American Society of Nephrology (J Am Soc Nephrol)
the Royal Society of Medicine (J R Soc Med)
Kidney International (Kidney Int)
Medical Care (Med Care)
Medicine (Medicine)
Micros Res Tech (Micros Res Tech)
Nature (Nature)
Nature Medicine (Nat Med)
Nephrology, Dialysis, and Transplantation (Nephrol Dial Transplant)
Neurol)
Neurology (Neurology)
Neuroscience Letters (Neurosci Lett)
New England Journal of Medicine (N Engl J Med)
Occupational Medicine (Occup Med)
Osteoarthritis and Cartilage (Osteoarth Cartilage)
Osteoarthritis Cartilage (Osteoarthritis Cartilage)
Osteoporosis International (Osteoporosis Int)
Pain (Pain)
Pediatrics (Pediatrics)
Proceedings of the Association of American Physicians (Proc Assoc Am Phys)
Proceedings of the National Academy of Sciences of the United States of
America (Proc Natl Acad Sci USA)
Radiology (Radiology)
Rehabil)
Rheumatic Disease Clinics of North America (Rheum Dis Clin North Am)
Rheumatol)
Rheumatology (Rheumatology)
Rheumatology International (Rheumatol Int)
Scandinavian Journal of Rheumatology (Scand J Rheumatol)
Science (Science)
Seminars in Arthritis and Rheumatism (Semin Arthritis Rheum)
Seminars in Neurology (Semin Neurol)
Spine (Spine)
Zeitschrift für Rheumatologie (Z Rheumatol)
Index to authors
Volume 16 2004
Abramson SB, 199
Abril A, 51
Anandarajah AP, 338
Anolik J, 180, 505
Arakaki R, 522
Arce E, 577
Askling J, 254
Atzeni F, 287
Backman CL, 148
Baecklund E, 254
Baldock PA, 450
Bardin T, 76
Benseler S, 43
Berenbaum F, 616
Bhatt DL, 18
Brune K, 628
Buckwalter JA, 634
Burmester GR, 246
Buxbaum JN, 67
Calabrese LH, 18
Callan MFC, 399
Cepeda EJ, 723
Chamian F, 331
Chinoy H, 707
Christner PJ, 746
Christopher-Stine L, 700
Cohen MD, 51
Conaghan PG, 435
Conn DL, 192
Cooper RG, 707
Cortinovis D, 357
Costello JC, 268
Crow MK, 541
Dechant SA, 177
deHueck A, 138
Delmas PD, 428
Dörner T, 246
Duffy CM, 102
Egerer K, 246
Eisman JA, 450
Ekbom A, 254
Emery P, 435
Fahmi H, 623
Feist E, 246
Firestein GS, 231
Fitzgerald GK, 143
Garnero P, 428
Gaston JSH, 371
Gay RE, 238
Gay S, 238, 411
Gershwin ME, 406
Ginzler EM, 499
Gladman DD, 329
Gohr C, 263
Goronzy JJ, 212
Gowans SE, 138
Gravallese EM, 419
Häkkinen A, 132
Hamilton CD, 393
Hamuryudan V, 38
Hanna MG, 684
Harley JB, 534
Hashkes PJ, 560
Hayashi Y, 522
Heeringa P, 4
Helliwell PS, 344
Hengstman GJD, 692
Hinz B, 628
Hirsch R, 553
Holton JL, 684
Hootman JM, 119
Horowitz MC, 464
Hungerford DS, 443
Huugen D, 4
Imperato AK, 199
Isenberg D, 665
Ishimaru N, 522
Jarrett S, 435
Jimenez SA, 746
Jones LC, 443
Jordan JM, 62
Kahaleh MB, 718
Kanangat S, 733
Kato T, 604
Kelley JT, III, 192
Kent PD, 56
Kietz D, 555
Kingsley GH, 678
Kirou KA, 541
Kirwan JR, 125
Kissin EY, 31
Klareskog L, 254
Köhler L, 380
Krueger JG, 331
Kuipers J, 380
Kyburz D, 411
Kyttaris VC, 548
Lane NE, 457
Langford CA, 1
Lauener RP, 411
Leveille SG, 114
Linn ML, 374
Liu Y, 357
Looney RJ, 180
Lorenzo JA, 464
Luthra HS, 56
Luyten FP, 599
Maksimowicz-McKinnon K, 18
Martel-Pelletier J, 595
Martin JA, 634
Martini A, 566
Masuda I, 279
Matteson EL, 177, 206
McCarthy GM, 273
Mease PJ, 366
Merkel PA, 31
Michet CJ, Jr, 56
Minor MA, 130
Miossec P, 218
Moldovan I, 499
Müller–Ladner U, 238
Nakamura H, 604
Neumann E, 238
Nirmalananthan N, 684
Nishioka K, 604
Nordborg C, 25
Nordborg E, 25
O’Shea FD, 273
Oatis C, 143
Ollier WER, 707
Østergaard M, 223
Pannu J, 739
Pascual E, 282
Pascual V, 577
Pedraz T, 282
Pelletier J-P, 595
Pilkington C, 673
Plotz PH, 700
Postlethwaite AE, 733
Prahalad S, 588
Rao JK, 119
Reboul P, 595
Reveille JD, 723
Ritchlin CT, 338
Rosandich PA, 192
Rosenquist R, 254
Rosenthal AK, 262
Ruperto N, 566
Ryan LM, 268
Sanz I, 180, 505
Sarzi-Puttini P, 287
Sawalha AH, 534
Scalzi LV, 571
Schmitt WH, 9
Schneider R, 43
Scott DL, 678
Seibl R, 411
Selmi C, 406
Shigemitsu H, 733
Singer NG, 571
Smiles S, 199
Staud R, 157
© 2004 Lippincott Williams & Wilkins ISSN 0268–4705
Stichweh D, 577
Stone MA, 357
Suarez-Almazor ME, 91
Suhrbier A, 374
Sultan SM, 668
Sweeney SE, 231
Tarkowski A, 527
Taylor WJ, 350
Tervaert JWC, 4
Thomas CF, 186
Ting TV, 560
Trojanowska M, 739
Trysberg E, 527
Tsao BP, 513
Tsokos G, 497
Tsokos GC, 548
Turesson C, 206
van der Woude FJ, 9
van Engelen BGM, 692
van Venrooij WJ, 692
Varga J, 714
Vassallo R, 186
Vlieland TPHV, 153
Wakefield RJ, 435
Walsh DA, 609
Walsh NC, 419
Ward MM, 89, 96
Wasko MCM, 109
Weyand CM, 212
Wiell C, 223
Xiang Y, 604
Yazici H, 38
Yurdakul S, 38
Zeidler H, 380
Cumulative Index to Subjects
Volume 16 2004
AIMS. See Arthritis Impact Measurement Scales
Alphaviruses, 374–379
chikungunya virus, 374
macrophage, 374
Ross River virus, 374
Sindbis virus, 374
viral arthritis, 374
Amyloidoses, 67–75
Amyloid A, 68, 70
Apolipoprotein A1 amyloidosis, 72
Apolipoprotein A2 amyloidosis, 71
immunoglobulin light chain, 69
serum amyloid A, 68, 70
tissue damage, 69
transthyretin amyloid, 70
b2 microglobulin amyloid, 71
treatment, 72
ANCA. See Antineutrophil cytoplasmic antibodies
Angiogenesis, 609–615
back pain, 609
hypoxia, 612
innervation, 610
neovascularization, 609
osteoarthritis, 610
spondylosis, 611
Ankylosing Spondylitis Quality of Life
Health-related quality of life, 96
Antineutrophil cytoplasmic antibodies, 4–8
animal models, 4–8
mice, 5
rats, 5
antineutrophil cytoplasmic antibody associated vasculitides,
12, 13
B cells, 181, 182
clinical applications, 9–17
assays, 10
enzyme-linked immunoabsorbent assay, 10, 11, 15
target antigens, 10
diagnostic significance, 12
microscopic polyangiitis, 9
pathophysiology, 4–8
relapse rate, 14
specificity, 14
transfer studies, 6
Wegener granulomatosis, 9
Antineutrophil cytoplasmic antibody associated vasculitides
antineutrophil cytoplasmic antibodies, 12, 13
AR. See Androgen receptor
© 2004 Lippincott Williams & Wilkins ISSN 1040–8711
Arthritis
Chlamydia-induced, 380–392
Chlamydia-host cell interaction, 386
Chlamydia molecular diagnostics, 384
HLA-B27, 381
hemochromatosis, 62–66
iron storage disease, 62–66
arthropathy, 62
genetics, 62
HFE genes, 63
pattern recognition receptors, 411–418
caspase recruitment domains, 411, 413
toll-like receptors, 411
triggering receptors expressed by myeloid cells, 411, 414
Arthritis Impact Measurement Scales
health-related quality of life, 96
ASQoL. See Ankylosing Spondylitis Quality of Life
Azathioprine
relapsing polychondritis, 59
sarcoidosis, 54
B cells
therapeutic targets, 180–185
antineutrophil cytoplasmic antibodies, 181–183
ANCA-associated vasculitis, 182
cryoglobulinemia, 182
dermatomyositis, 182
rheumatoid arthritis, 181
systemic lupus erythematous, 181
costimulatory molecules, 183
cytokine inhibition, 183
Sjögren syndrome, 180
systemic lupus erythematous, 180
systemic sclerosis, 180
differential diagnosis, 686, 687
Behcet syndrome
antibodies, 39
coagulation abnormalities, 40
infections, 40
autoantibodies, 39
central nervous system, 39
geographical differences, 38
pathogenesis, 39
prognosis, 39
renal involvement, 39
target organ associations, 38
treatment
␣-enolase, 38
anti-TNF, 40, 41
dapsone, 41
IFN-␣, 40
rebamipide, 41
Biologic agents
infectious complications, 393–398
tumor necrosis factor, 393
aspergillus species, 395
cryptococcosis, 396
histoplasmosis, 395
listeria monocytogenes, 396
tuberculosis, 394
BMD. See Becker muscular dystrophy
Bone biomarkers, 428–434
ankylosing spondylarthritis, 428
biochemical markers, 429
cartilage, 428
inflammatory arthritis, 429
Bone mass
genetic determinants, 450–456
BS. See Behcet syndrome
Calcium crystal deposition diseases, 279–281
calcium pyrophosphate dihydrate, 279
enzymes, 280
hypertrophic chondrocytes, 279
pericellular matrix, 280
transglutaminase, 280
Calcium crystal formation
articular cartilage, 263
calcium pyrophosphate dihydrate, 263
crystal models, 264
in vitro models, 263–267
CAM. See Cellular adhesion molecules
Cellular adhesion molecules
vascular inflammation, 18
Central nervous system
vasculitis
pediatric, 43–50
angiography, 45
brain biopsy, 46
causes, 44
cerebrospinal fluid, 44
clinical features, 44
epidemiology, 43
imaging, 44, 46
lab tests, 44
post-varicella-zoster virus central nervous system
vasculitis, 47
therapy, 46
Cerebrospinal fluid
CHAQ. See Childhood Health Assessment Questionnaire
Childhood Health Assessment Questionnaire
juvenile idiopathic inflammatory myopathies, 674, 675
pediatrics, 102
Childhood Myositis Assessment Scale
juvenile idiopathic inflammatory myopathies, 675
CMAS. See Childhood Myositis Assessment Scale
CNS. See Central nervous system
Computed tomography
diffuse idiopathic skeletal hyperostosis, 291
muscle disease, 678, 679
Takayasu arteritis, 34, 35
C-reactive protein
CRP. See C-reactive protein
Crystal arthropathies (overview), 262
CSF. See Cerebrospinal fluid
CT. See Computed tomography
Dermatomyositis
B cells, 182
differential diagnosis, 684
idiopathic inflammatory myopathy, 707
Diffuse idiopathic skeletal hyperostosis, 287–292
computed tomography, 291
etiopathogenesis, 288
magnetic resonance imaging, 291
ossification of ligamentum flavum, 287
ossification of posterior longitudinal ligament, 287
peripheral joint, 288
Disease-modifying antirheumatic drugs
rheumatoid arthritis, 193, 207
leflunomide, 194
methotrexate, 193
DM. See Dermatomyositis
DMARDs. See Disease-modifying antirheumatic drugs
DMD. See Duchenne muscular dystrophy
EBV. See Epstein-Barr virus
ELISA. See Enzyme-linked immunoabsorbent assay
EMS. See Extraskeletal myxoid chondrosarcoma
Enzyme-linked immunoabsorbent assay
antineutrophil cytoplasmic antibodies, 10, 11, 15
Epstein-Barr virus, 399–405
Hodgkin, 401, 403
immunosuppression, 404
lymphoma, 400
nasopharyngeal carcinoma, 231
non-Hodgkin, 401, 403
Evidence-based rheumatology rehabilitation, 130, 131
Fibroblasts
functional genomics, 238–245
adhesion, 240
angiogenesis, 240
apoptosis, 242
inflammation, 238
intracellular signaling, 241
matrix degradation, 240
synovial fibroblasts, 238
scleroderma, 733
systemic sclerosis
organ fibrosis, 733–738
fibroblast progenitors, 735
TGF-B, 733
tissue-specific fibroblast precursor cells, 734
transdifferentiation, 733
transition, 733
Fibromyalgia. See also Fibromyalgia syndrome
exercise, 138–142
fatigue/sleep, 139
intensity, 140
long-term benefits, 141
mood, 139
pain, 139
self-efficacy, 139
setting, 140
types
aerobic, 139
anaerobic, 140
flexibility, 140
pain
cytokines, 160
fibromyalgia syndrome, 157–159
Hepatitis C virus, 161
HIV infection, 161
infections, 161
neuroendocrine abnormalities, 160
polymyalgia rheumatica, 160
regional musculoskeletal pain, 159. See also myofascial
pain
Fibromyalgia syndrome
genetics, 158
nociception, 158
posttraumatic stress disorder, 158
stressors, 158
triggering events, 158
whiplash, 159
Fibrosing syndromes, 723–732
fibrosing disorders, 728
eosinophilia myalgia syndrome, 728
graft versus host disease, 728
localized scleroderma, 728
nephrogenic fibrosing dermopathy, 728
FMS. See Fibromyalgia syndrome
GCA. See Giant cell arteritis
Giant cell arteritis, 25–30
clinical manifestations
audiovestibular, 25
lower extremity, 26
imaging
duplex ultrasonography, 26
FDG-PET, 26
osteoporosis, 28
steroid-sparing agents, 28
corticosteroids, 28
methotrexate, 28
steroid therapy, 28
temporal arteritis, 25, 26
treatment strategies, 26
vasculitis, 2
GJD. See Greutzfeldt-Jakob disease
Gout, 282–286
epidemiology, 283
macrophage maturation, 283
treatment, 284
Greutzfeldt-Jakob disease
inclusion body myositis, 704
HAQ. See Health Assessment Questionnaire
Health Assessment Questionnaire
Health-related quality of life, 96–101
Ankylosing Spondylitis Quality of Life, 96
Arthritis Impact Measurement Scales, 96
Health Assessment Questionnaire, 96
health status, 96–101
ankylosing spondylitis, 97, 98
osteoarthritis, 96, 98
rheumatoid arthritis, 97, 98
Western Ontario and McMaster Universities Osteoarthritis
Index, 96
HLA. See Human leukocyte antigen
Host-infectious agent interactions, 371–373
HRQOL. See Health-related quality of life
Human leukocyte antigen
IBM. See Inclusion body myositis
ICAM-1. See Intracellular adhesion molecule-1
Idiopathic inflammatory myopathy
animal models, 711
assessing
IMACS, 670, 671
visual analogue scale, 670
autoantibodies, 708
cytokine genes, 708
disease mechanisms, 707–713
HLA-DRB1 studies, 707–713
dermatomyositis, 707
HLA-related differences, 708
polymyositis, 707
inclusion body myositis, 710
manual muscle strength testing, 668
microchimerism, 709
muscle biopsy, 669
muscle enzymes, 669
serum creatine kinase, 669
muscle imaging
magnetic resonance imaging, 669
magnetic resonance spectroscopy, 669
nonclassical HLA, 708
T cell receptors, 711
IIM. See Idiopathic inflammatory myopathy
ILD. See Interstitial lung disease
autoimmunity, 703
distal myopathy with rimmed vacuoles, 704
endoplasmic reticulum, 704
GNE mutation, 704
Greutzfeldt-Jakob disease, 704
protein folding, 704
unfolded protein response, 704
Inflammatory arthritis, 435–442
bone loss, 419–427
inflammation, 420
IL-1, 422
TNF-␣, 420
osteoclasts, 419
RANKL/RANK/OPG pathway, 422
skeletal changes
computed tomography, 438
conventional radiography, 435
digital radiogrametry, 441
dual x-ray absorptiometry, 439
ultrasound, 436
Inflammatory biomarkers, 18–24
Interleukin
rheumatic, 186–191
connective tissue disease, 189
nonspecific interstitial pneumonia, 186
pulmonary hypertension, 188
scleroderma, 189
usual interstitial pneumonia, 186
Intracellular adhesion molecule-1
JDM. See Juvenile dermatomyositis
JIA. See Juvenile idiopathic arthritis
JRA. See Juvenile rheumatoid arthritis
JSLE. See Juvenile systemic lupus erythematosus
Juvenile dermatomyositis
pediatrics, 105
Juvenile idiopathic arthritis
cardiovascular disease, 110
genetics, 588–594
pediatrics, 102
Juvenile idiopathic inflammatory myopathies
Childhood Health Assessment Questionnaire, 674, 675
Childhood Myositis Assessment Scale, 675
Disease Activity Score, 675
juvenile dermatomyositis, 673
incidence, 674
pediatric assessment tools, 674
pulmonary, 674
magnetic resonance imaging scan, 674
Juvenile rheumatoid arthritis
Childhood Health Assessment Questionnaire, 102
disability, 104
osteopenia, 105
pediatrics, 103
remission, 103
Juvenile systemic lupus erythematosus, 106
Knee osteoarthritis
physical therapy, 143–147
manual therapy, 143
transcutaneous electrical nerve stimulation, 144
LGMD. See Limb-girdle muscular dystrophy
Lipid metabolism, 76–79
musculoskeletal features, 76–79
fenofibrate, 77
primary hyperlipidemia, 77
Magnetic resonance imaging
diffuse idiopathic skeletal hyperostosis, 291
muscle disease, 678, 679
Takayasu arteritis, 31–33
Magnetic resonance spectroscopy
muscle disease, 678–680
Malignant lymphomas, 254–261
anti-TNF, 258
DMARDs, 257–259
TNF-blocking therapy, 254
MCP. See Monocyte chemoattractant protein-1
MCH. See Multicentric reticulohistiocytosis
Methotrexate
giant cell arteritis, 28
sarcoidosis, 54
Microscopic polyangiitis
antineutrophil cytoplasmic antibodies, 9
Modes of practice
case mix, 125
patient-centered care, 125
primary care, 125
Monocyte chemoattractant protein-1
MPA. See Microscopic polyangiitis
mPGES-1, 623–627
prostaglandin E2, 623
MRI. See Magnetic resonance imaging
MSA. See Myositis specific autoantibodies
MTX. See Methotrexate
Multicentric reticulohistiocytosis, 76–79
musculoskeletal features, 76–79
fenofibrate, 77
primary hyperlipidemia, 77
Muscle disease
idiopathic inflammatory myopathies, 679
imaging, 678, 679
computed tomography, 678,679
magnetic resonance imaging, 678, 679
magnetic resonance spectroscopy, 678–680
scintigraphy, 679
ultrasound, 679
x-rays, 679
calcinosis, 679
myositis ossificans, 769
muscle infarction, 680
myositis, 680
polymyositis, 679
range
muscle infarction, 678
myositis ossificans, 678
Musculoskeletal aging, 114–118
osteoarthritis, 114
osteoporosis, 115
hip fracture, 115
treatment, 115
sarcopenia, 116
self-management, 117
Myositis
cellular immune mechanisms, 701
clinical features, 685
co-stimulatory molecules, 702
differential diagnosis, 684–691
Becker muscular dystrophy, 686, 687
dermatomyositis, 684, 700
Duchenne muscular dystrophy, 686
dystrophinopathy, 687
endocrine myopathies, 689
inclusion body myositis, 684, 689, 700
Limb-girdle muscular dystrophy, 686, 687
lipid storage disorders, 689
metabolic myopathies, 688
mitochondrial myopathies, 689
muscle glycogenoses, 688
disease assessment, 665
electromyography, 685
European League against Rheumatism, 666
International Myositis Assessment and Clinical Studies, 665
interstitial lung disease, 701
muscle biopsy, 686
myosin heavy chain, 686, 702
myositis damage index, 666
myositis damage score, 666
necrotizing myopathy, 701
polymyositis, 684, 700
transglutaminase 2, 703
Myositis specific autoantibodies, 692–699
anti-signal recognition particle, 696
diagnosis criteria, 692
immunopathogenesis, 696
Jo-1, 694–696
myositis associated autoantibodies, 692
Nonsteroidal antiinflammatory drug
sarcoidosis, 54
NSAID. See Nonsteroidal antiinflammatory drug
Osteoarthritis. Also see specific locations
calcium phosphate deposition, 273–278
basic calcium phosphate crystals, 273
intracellular calcium signaling, 275
matrix metalloproteinase, 273, 275, 277
mitogenesis, 274
phosphocitrate, 276
tissue inhibitors of metalloproteinases, 275
cartilage, 604–608
neoantigens, 604
galactin-3, 595–598
mesenchymal stem cells, 599–603
musculoskeletal aging, 114
pain, 628–633
acetaminophen, 631
cyclooxygenase-2, 629
lipoxygenase, 632
NSAIDs, 630
signaling transduction, 616–622
sports, 634–637
articular cartilage, 634
posttraumatic osteoarthritis, 634
Osteoclasts, 464–468
B cell, 465
lineage development, 464
transcriptional regulation, 465
Osteonecrosis, 443–449
avascular necrosis, 443
diseases of the hip, 443
Osteoporosis
musculoskeletal aging, 115
Parathyroid hormone, 457–463
hormone replacement therapy, 460
osteoanabolic agent, 457
osteoporosis, 459
Patient-centered care, 89, 90
Patient-physician communication, 91–95
health services research, 91
medical eduction, 91
rheumatic disease, 91
PCNSL. See Primary central nervous system lymphoma
Pediatric rheumatology
Health Assessment Questionnaire, 102
juvenile dermatomyositis, 105
juvenile idiopathic arthritis, 102
juvenile rheumatoid arthritis, 103
juvenile systemic lupus erythematosus, 106
psychosocial aspects, 555–559
remittive agents, 571–576
DMARDs, 571
methotrexate, 571
mycophenolate mofetil, 572
Pediatric Rheumatology International Trials Organisation,
565–570, 676
Childhood Health Assessment Questionnaire, 674, 675
Childhood Myositis Assessment Scale, 675
PET. See Positron emission tomography
PH. See Pulmonary hypertension
PKC. See Protein kinase C
PM. See Polymyositis
PMR. See Polymyalgia rheumatica
Polymyalgia rheumatica
fibromyalgia pain, 160
Polymyositis
Positron emission tomography
Takayasu arteritis, 36
Primary biliary cirrhosis, 406–410
autoimmunity, 407
Guillain-Barre syndrome, 407
HLA-B27, 407
Spondyloarthropathies, 407
bacteria, 408
Escherichia coli, 408
Helicobacter species, 409
Sphingomonas species, 408
Primary central nervous system lymphoma, 453, 601–606
delayed neurotoxicity, 603
epidemiology, 601
pathogenesis, 601
prognostic factors, 602
rituximab, 601, 604
treatment, 602
elderly, 603
Primary hyperparathyroidism, 1–7
etiology, 1
genetics, 2
histopathology, 2
parathyroid gland, 1
surgery, 3
Protein kinase C
glucocorticoid-induced apoptosis, 556
scleroderma, 743
Psoriasis vulgaris
dendritic cells, 331
genomics, 333
inflammatory cytokines, 331
leukocytes, 331
natural killer T cells, 334
susceptibility genes, 335
T lymphocytes, 331
Psoriatic arthritis, 338–343
abnormal bone remodeling, 341
acquired immune response, 340
angiogenesis, 341
genetic factors, 338
human leukocyte antigen, 338, 339
innate immune response, 340
leflunomide, 362
methotrexate, 361
outcome assessment, 350–356
core domains, 351
measurement instrument, 351
OMERACT, 350
quality of life, 354
responder criteria, 355
pathogenesis, 338
spondyloarthropathies, 344–349
sulphasalazine, 362
TNF blockers, 362
Pulmonary hypertension
rheumatic interstitial lung disease, 188
RA. See Rheumatoid arthritis
Radiation Therapy and Oncology Group
head and neck squamous cell carcinoma, 217
metastatic lesions, 309
prostate cancer, 243
Raynaud phenomenon
fibrosing disorders, 723
scleroderma, 718–722
Relapsing polychondritis, 56–61
clinical features
cardiovascular, 58
dermatologic, 57
musculoskeletal, 57
neurologic, 58
otorhinolaryngeal, 57
pulmonary, 57
renal, 57
disease associations, 58
epidemiology, 58
management
azathioprine, 59
biologic, 59
methotrexate, 59
NSAID, 59
pathogenesis
HLA-DR4, 58
Rheumatic diseases
comorbid conditions, 109–112
cardiovascular disease, 110
juvenile idiopathic arthritis, 110
infection, 109
malignancy, 112
prevention, 119–124
behavioral, 120
cognitive, 120
exercise, 121
obesity, 121
occupational injury, 122
Rheumatoid arthritis
biologic response modifiers, 192–198
IL-1 receptor antagonist, 196
medications
DMARDs, 193
glucocorticoids, 193
NSAIDs, 193
TNF-␣, 194
comorbidity, 177
managing, 177–179
NSAIDs, 177
cytokine network, 218–222
employment, 148–152
extra-articular disease manifestations
cardiac, 206
hematologic, 207
nonpharmacologic treatments, 209
pulmonary, 206
TNF inhibitors, 208
vasculitis, 208
long-term risks, 199–205
demyelination, 203
heart failure, 203
infections, 199
bacterial, 202
myobacterium tuberculosis, 201
opportunistic, 202
lymphoma, 202
systemic lupus erythematosus-like syndromes, 203
TNF-␣ antagonists
adalimumab, 199
etanercept, 199
infliximab, 199
multidisciplinary team care, 153–156
clinical nurse specialist, 154
inpatient vs. day patient, 153
interdisciplinary communication, 155
outcome assessment, 155
signal transduction, 231–237
mitogen-activated protein kinase, 231
c-Jun-N-terminal kinase, 232
extracellular signal-related kinases, 232
p38, 231
NF-␬␤, 232
Janus kinase, 233
signal transducer activator of transcription, 233
toll-like receptors, 234
strength training, 132–137
muscle function, 132
principles, 132
safety, 136
scientific evidence, 135
T-cell regulation, 212–217
regulatory T cells, 213
autoantibodies, 214
CD-28 mediated costimulation, 213
novel costimulatory pathways, 214
senescent CD4 T cells, 214
thymic function, 212
ultrasonography, 223–230
work disability, 148–152
assessing, 149
Work Instability Scale, 149
Work Limitations Questionnaire, 149, 150
prevalence, 148
return-to-work, 150
risk factors, 149
work retention, 150
Rheumatoids factor, 246–253
autoimmunity, 246
germinal centers, 246
B cell, 250
SAA. See Serum amyloid A, 68, 70
Sarcoidosis
rheumatologic manifestations, 51–55
general clinical features
diagnosis, 52
granulomas, 51
rheumatology, 52
acute arthritis, 53
bone, 53
chronic arthritis, 53
myopathy, 53
treatment
antimalarials, 54
azathioprine, 54
cyclosporine, 54
methotrexate, 54
NSAIDs, 54
TNF, 54
Scleroderma
connective tissue disease, 718
endothelial-dependent relaxation, 719
genetic factors, 719
fibroblasts, 733
signaling, 739–745
fibrosis, 742
protein kinase C pathway, 743
rapamycin pathway, 743
Smad 2/3 pathway, 742
TGF-B signaling, 739
fibrinolysis, 719
angiogenesis, 720
atherosclerosis, 719
circulating endothelial cells, 720
endothelial apoptosis, 720
gene expression profile, 720
hyperlipidemia, 719
vasculogenesis, 720
immune involvement
cytokines, 720
lymphocyte transendothelial migration, 720
Raynaud phenomenon, 718–722
vascular disease, 718–722
Serum amyloid A
amyloidoses, 68, 70
Spondyloarthropathy
autoimmunity, 407
treatment, 357–365
ankylosing spondylitis, 357
DMARD, 358
exercise, 358
NSAIDs, 358
pamidronate, 358
thalidomide, 359
TNF blockers, 359
psoriatic arthritis
leflunomide, 362
methotrexate, 361
sulphasalazine, 362
TNF blockers, 362
STAT. See Signal transducer activator of transcription
Signal transducer activator of transcription
Sjögren syndrome
apoptosis, 522–526
B cells, 180
estrogen deficiency, 522, 523
T-cell apoptosis, 523
rheumatic interstitial lung disease, 187, 189
systemic lupus erythematosus, 497, 498
SLE. See Systemic lupus erythematosus
Spondyloarthropathies (overview), 329, 330
STAT. See Signal transducer activator of transcription
Systemic lupus erythematosus
antibodies, 181
antinuclear antibodies, 534–540
B cells, 180
human, 505
murine, 505
cerebral inflammation, 527–533
biochemistry, 528
cytokines, 528
metalloproteinases, 527
neuroimaging, 530
genetics, 513–521
association, 513
gene variants, 515–519
linkage, 513
Interferon-␣, 541–547
overview, 497, 498
pediatric, 577–587
T lymphocytes, 548–552
chemokine receptors, 549
co-stimulatory molecules, 459
intracellular signaling, 550
T-cell receptor, 548
trials
biologics, 501
immunoablation, 502
immunosuppressive therapy, 500
nonpharmacologic, 503
SELENA, 499
Systemic sclerosis, 723–732
animal models, 746–752
bleomycin-induced scleroderma, 746
pathogenesis, 746
Tsk mice, 746
pulmonary fibrosis, 749
TGF-B, 746
transgenic mice, 750
autoantibodies
antibodies against extractable nuclear antigens, 727
anticentromere antibodies, 724
antinuclear antibodies, 725
antiphospholipid antibodies, 727
antitopoisomerase 1 antibodies, 725
TAK. See Takayasu arteritis
Takayasu arteritis
diagnostic imaging, 31–37
computed tomography scan, 34
diagnosis, 34
disease activity, 35
limitations, 35
Doppler ultrasound, 33
diagnosis, 33
limitations, 34
magnetic resonance imaging/angiography, 31
diagnosis, 31
limitations, 34
positron emission tomography
diagnosis, 36
limitations, 36
TLR. See Toll-like receptors
Toll-like receptors
Transcranial Doppler ultrasound
Transthyretin amyloid
amyloidoses, 70
TSC. See Tuberous sclerosis complex
TTR. See Transthyretin amyloid
Tuberous sclerosis complex
renal cell carcinoma, 247
Varicella-Zoster virus
Vascular cellular adhesion molecule-1
Vascular inflammation, 18–24
accessory signaling molecules
acute phase proteins, 21
C-reactive protein, 21
cellular adhesion molecules, 18
chemokines, 19
monocyte chemoattractant protein-1, 19
cytokines, 19
Interleukins, 20
TNF-␣, 19
intercellular adhesion molecule-1, 18
interleukin, 20
IL-1, 20
IL-6, 20
IL-10, 20
IL-18, 20
proteases
matrix metalloproteinases, 21
vascular cellular adhesion molecule-1, 18
Vasculitides
childhood, 560–565
Behcet disease, 563
Central nervous system vasculitis, 563
Henoch-Schönlein purpura, 560
Secondary vasculitis, 563
Wegener granulomatosis, 562
Vasculitis, 1
anti-neutrophil cytoplasmic antibodies, 1
Behcet syndrome, 2
giant cell arteritis, 2
inflammatory biomarkers, 3
C-reactive protein, 3
VCAM-1. See Vascular cellular adhesion molecule-1
VZV. See Varicella-Zoster virus
Wegener granulomatosis
antineutrophil cytoplasmic antibodies, 9
WG. See Wegener granulomatosis
Western Ontario and McMaster Universities Osteoarthritis
Index
Current Opinion in
RHEUMATOLOGY
Reviews of all advances ⴢ Evaluations of key references
Comprehensive listing of papers
Volume 16 ⴢ 2004
Lippincott Williams & Wilkins
Copyright © 2004 Lippincott Williams & Wilkins ISSN 1040–8711
Current Opinion in
RHEUMATOLOGY
Volume 16
Number 1 January 2004
The systemic amyloidoses
Joel N Buxbaum
67
Vasculitis syndromes
Musculoskeletal features of disorders of lipid
metabolism and multicentric
reticulohistiocytosis
Thomas Bardin
76
Edited by Carol A Langford
Editorial overview: vasculitis: from
pathophysiology to clinical applications
Carol A Langford
1
Antineutrophil cytoplasmic autoantibodies and
pathophysiology: new insights from
animal models
Dennis Huugen, Jan Willem Cohen Tervaert and
Peter Heeringa
4
Clinical applications of antineutrophil
cytoplasmic antibody testing
Wilhelm H Schmitt and Fokko J van der Woude
9
Current world literature
Vasculitis syndromes
80
Systemic disorders with rheumatic manifestations
84
Recent advances in vascular inflammation:
C-reactive protein and other inflammatory
biomarkers
Kathleen Maksimowicz-McKinnon, Deepak L Bhatt and
Leonard H Calabrese
18
Giant cell arteritis: strategies in diagnosis
and treatment
Elisabeth Nordborg and Claes Nordborg
25
Diagnostic imaging in Takayasu arteritis
Eugene Y Kissin and Peter A Merkel
Number 2 March 2004
Epidemiology and health-related services
Edited by Michael Ward
Patient-centered care and health outcomes
Michael M Ward
89
Patient-physician communication
Maria E Suarez-Almazor
91
96
31
Outcome measurement: health status and quality
of life
Michael M Ward
Behçet syndrome
Sebahattin Yurdakul, Vedat Hamuryudan and
Hasan Yazici
38
Health outcomes in pediatric rheumatic diseases
Ciaran M Duffy
102
109
Central nervous system vasculitis in children
Susanne Benseler and Rayfel Schneider
43
Comorbid conditions in patients with rheumatic
diseases: an update
Mary Chester M Wasko
Musculoskeletal aging
Suzanne G Leveille
114
Prevention research and rheumatic disease
Jaya K Rao and Jennifer M Hootman
119
125
Systemic disorders with rheumatic
manifestations
Edited by Doyt Ladean Conn
Rheumatologic manifestations of sarcoidosis
Andy Abril and Marc D Cohen
51
New modes of practice
John R Kirwan
Relapsing polychondritis
Peter D Kent, Clement J Michet, Jr and Harvinder S Luthra
56
Rehabilitation medicine in rheumatic diseases
Arthritis in hemochromatosis or iron
storage disease
Joanne M Jordan
62
Edited by Marian A Minor
Editorial overview: meeting the challenges of
evidence-based rheumatology rehabilitation
Marian A Minor
130
Effectiveness and safety of strength training in
rheumatoid arthritis
Arja Häkkinen
132
Effectiveness of exercise in management
of fibromyalgia
Susan E Gowans and Amy deHueck
138
Role of physical therapy in management of
knee osteoarthritis
G Kelley Fitzgerald and Carol Oatis
143
Employment and work disability in
Catherine L Backman
Edited by Gerd R Burmester
T-cell regulation in rheumatoid arthritis
Jörg J Goronzy and Cornelia M Weyand
212
An update on the cytokine network in
Pierre Miossec
218
223
148
Ultrasonography in rheumatoid arthritis: a very
promising method still needing
more validation
Mikkel Østergaard and Charlotte Wiell
153
Signal transduction in rheumatoid arthritis
Susan E Sweeney and Gary S Firestein
231
Multidisciplinary team care and outcomes in
Thea PM Vliet Vlieland
238
Fibromyalgia pain: do we know the source?
Roland Staud
157
Functional genomics of fibroblasts
Elena Neumann, Renate E Gay, Steffen Gay and
Ulf Müller–Ladner
Rheumatoid factor revisited
Thomas Dörner, Karl Egerer, Eugen Feist and
Gerd R Burmester
246
Rheumatoid arthritis and malignant lymphomas
Eva Baecklund, Johan Askling, Richard Rosenquist,
Anders Ekbom and Lars Klareskog
254
Epidemiology and health-related services
164
Rehabilitation medicine in rheumatic diseases
171
Crystal deposition diseases
Edited by Ann K Rosenthal
Number 3 May 2004
Clinical therapeutics
Editorial overview: crystal arthropathies and
other unpopular rheumatic diseases
Ann K Rosenthal
262
In vitro models of calcium crystal formation
Claudia Gohr
263
268
Editorial overview: managing comorbidity risks
in rheumatoid arthritis
Sonja A Dechant and Eric L Matteson
177
Modulation of chondrocyte production of
extracellular inorganic pyrophosphate
Jill C Costello and Lawrence M Ryan
273
B cells as therapeutic targets for
rheumatic diseases
R John Looney, Jennifer Anolik and Inãki Sanz
180
Basic calcium phosphate deposition in the joint:
a potential therapeutic target in osteoarthritis
Finbar D O’Shea and Geraldine M McCarthy
279
Advances in the treatment of rheumatic
interstitial lung disease
Robert Vassallo and Charles F Thomas
186
Calcium crystal deposition diseases: lessons
from histochemistry
Ikuko Masuda
Gout
Eliseo Pascual and Teresa Pedraz
282
Perioperative management of patients with
rheumatoid arthritis in the era of biologic
response modifiers
Peter A Rosandich, Joe T Kelley, III and Doyt L Conn
192
New developments in our understanding of
DISH (diffuse idiopathic skeletal hyperostosis)
Piercarlo Sarzi-Puttini and Fabiola Atzeni
287
Long-term risks associated with biologic response
modifiers used in rheumatic diseases
Anna K Imperato, Stephen Smiles and
Steven B Abramson
199
Management of extra-articular disease
manifestations in rheumatoid arthritis
Carl Turesson and Eric L Matteson
206
Edited by Eric L Matteson
Clinical therapeutics
293
305
Crystal deposition diseases
324
Metabolic bone disease
Number 4 July 2004
Edited by Steven Goldring
Spondyloarthropathies
Edited by Dafna D Gladman
Editorial overview: spondyloarthropathies
Dafna D Gladman
329
Psoriasis vulgaris: an interplay of T lymphocytes,
dendritic cells, and inflammatory cytokines
in pathogenesis
Francesca Chamian and James G Krueger
331
Pathogenesis of psoriatic arthritis
Allen P Anandarajah and Christopher T Ritchlin
338
Relationship of psoriatic arthritis with the
other spondyloarthropathies
Philip S Helliwell
344
Assessment of outcome in psoriatic arthritis
William J Taylor
350
Recent advances in the treatment of
the spondyloarthropathies
Yan Liu, Daniela Cortinovis and Millicent A Stone
357
Recent advances in the management of
psoriatic arthritis
Philip J Mease
366
Bone loss in inflammatory arthritis: mechanisms
and treatment strategies
Nicole C Walsh and Ellen M Gravallese
419
Noninvasive techniques for assessing skeletal
changes in inflammatory arthritis:
bone biomarkers
Patrick Garnero and Pierre D Delmas
428
Noninvasive techniques for assessing skeletal
changes in inflammatory arthritis:
imaging technique
Richard J Wakefield, Philip G Conaghan, Steve Jarrett and
Paul Emery
435
Osteonecrosis: etiology, diagnosis, and treatment
Lynne C Jones and David S Hungerford
443
Genetic determinants of bone mass
PA Baldock and John A Eisman
450
Parathyroid hormone: evolving therapeutic
concepts
Nancy E Lane
457
The origins of osteoclasts
Mark C Horowitz and Joseph A Lorenzo
464
Spondyloarthropathies
469
Infectious arthritis and immune dysfunction
Infectious arthritis and immune dysfunction
475
Edited by JS Hill Gaston
Metabolic bone disease
482
Editorial overview: host–infectious agent
interactions in the pathogenesis of
rheumatic disease
JS Hill Gaston
371
Clinical and pathologic aspects of arthritis due to
Ross River virus and other alphaviruses
Andreas Suhrbier and May La Linn
374
Chlamydia-induced arthritis
Henning Zeidler, Jens Kuipers and Lars Köhler
380
Infectious complications of treatment with
biologic agents
Carol Dukes Hamilton
393
Epstein-Barr virus, arthritis, and the development
of lymphoma in arthritis patients
Margaret FC Callan
Number 5 September 2004
Systemic lupus erythematosus and Sjögren
syndrome
Edited by George Tsokos
Editorial overview: SLE and Sjögren syndrome in
2004
George Tsokos
497
499
399
Systemic lupus erythematosus trials: successes
and issues
Ellen M Ginzler and Ioana Moldovan
505
Bacteria and human autoimmunity: the case of
primary biliary cirrhosis
Carlo Selmi and M Eric Gershwin
406
B cells in human and murine systemic
lupus erythematosus
Jennifer Anolik and Iñaki Sanz
513
Pattern recognition receptors and their
involvement in the pathogenesis of arthritis
Reinhart Seibl, Diego Kyburz, Roger P Lauener and
Steffen Gay
411
Update on human systemic lupus
erythematosus genetics
Betty P Tsao
Apoptosis and estrogen deficiency in primary
Sjögren syndrome
Yoshio Hayashi, Rieko Arakaki and Naozumi Ishimaru
522
mPGES-628s a novel target for arthritis
Hassan Fahmi
623
Pain and osteoarthritis: new drugs
and mechanisms
Burkhard Hinz and Kay Brune
628
Sports and osteoarthritis
Joseph A Buckwalter and James A Martin
634
541
548
Cerebral inflammation and degeneration in
Estelle Trysberg and Andrej Tarkowski
527
Antinuclear autoantibodies in systemic
lupus erythematosus
Amr H Sawalha and John B Harley
534
Interferon-␣ in systemic lupus erythematosus
Mary K Crow and Kyriakos A Kirou
T lymphocytes in systemic lupus erythematosus:
an update
Vasileios C Kyttaris and George C Tsokos
Systemic lupus erythematosus and Sjögren
syndrome
640
Pediatric and heritable disorders
Pediatric and heritable disorders
649
Edited by Raphael Hirsch
Osteoarthritis
652
Editorial overview: pediatric rheumatology
workforce: a status update
Raphael Hirsch
553
Psychosocial aspects in pediatric rheumatology
Daniel Kietz
555
Number 6 November 2004
Update on childhood vasculitides
Tracy V Ting and Philip J Hashkes
560
International research networks in pediatric
rheumatology: the PRINTO perspective
Nicolino Ruperto and Alberto Martini
566
Remittive agents in pediatric rheumatology
Nora G Singer and Lisabeth V Scalzi
571
Update on pediatric systemic lupus
erythematosus
Dorothee Stichweh, Edsel Arce and Virginia Pascual
577
Genetics of juvenile idiopathic arthritis:
an update
Sampath Prahalad
588
Edited by David Isenberg
Osteoarthritis
Edited by Johanne Martel-Pelletier and Jean-Pierre
Pelletier
Editorial overview: making sure the treatment of
myositis does not get “lost in translation”
David Isenberg
665
Clinical assessment in adult onset idiopathic
inflammatory myopathy
SM Sultan
668
Clinical assessment in juvenile idiopathic
inflammatory myopathies and the
development of disease activity and
damage tools
Clarissa Pilkington
673
Use of imaging to assess patients with muscle
disease
David L Scott and Gabrielle H Kingsley
678
684
Editorial overview: galectin-3 in osteoarthritis:
when the fountain of youth doesn’t deliver
its promises
Pascal Reboul, Johanne Martel-Pelletier and
Jean-Pierre Pelletier
595
Is it really myositis? A consideration of the
Niranjanan Nirmalananthan, Janice L Holton and
Michael G Hanna
692
Mesenchymal stem cells in osteoarthritis
Frank P Luyten
599
Myositis specific autoantibodies: changing
insights in pathophysiology and
clinical associations
Gerald JD Hengstman, Baziel GM van Engelen and
Walther J van Venrooij
Neoantigens in osteoarthritic cartilage
Tomohiro Kato, Y Xiang, H Nakamura and K Nishioka
604
Myositis: an update on pathogenesis
Lisa Christopher-Stine and Paul H Plotz
700
Angiogenesis in osteoarthritis and spondylosis:
successful repair with undesirable outcomes
David A Walsh
609
707
Signaling transduction: target in osteoarthritis
Francis Berenbaum
616
Have recent immunogenetic investigations
increased our understanding of disease
mechanisms in the idiopathic
inflammatory myopathies?
Hector Chinoy, William ER Ollier and Robert G Cooper
Raynaud phenomenon, scleroderma, overlap
syndromes, and other
fibrosing syndromes
Edited by John Varga
Editorial overview: illness and art: the legacy of
Paul Klee
John Varga
714
Raynaud phenomenon and the vascular disease
in scleroderma
M Bashar Kahaleh
718
Autoantibodies in systemic sclerosis and
fibrosing syndromes: clinical indications
and relevance
Eduardo J Cepeda and John D Reveille
723
Cellular origins of fibroblasts: possible
implications for organ fibrosis in
systemic sclerosis
733
Arnold E Postlethwaite, Hidenobu Shigemitsu and
Siva Kanangat
Recent advances in fibroblast signaling and
biology in scleroderma
Jaspreet Pannu and Maria Trojanowska
739
Animal models of systemic sclerosis: insights into
systemic sclerosis pathogenesis and potential
therapeutic approaches
Paul J Christner and Sergio A Jimenez
746
Erratum
753
754
Raynaud phenomenon, scleroderma, overlap
syndromes, and other fibrosing syndromes
767
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