Best Practice & Research Clinical Rheumatology

Best Practice & Research Clinical Rheumatology 26 (2012) 61–72
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Best Practice & Research Clinical
Rheumatology
journal homepage: www.elsevierhealth.com/berh
5
Mixed connective tissue disease: An overview of clinical
manifestations, diagnosis and treatment
Oscar-Danilo Ortega-Hernandez a, Yehuda Shoenfeld a, b, *
a
b
The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases, Israel
Keywords:
Mixed connective tissue disease
Raynaud’s phenomenon
Erosive arthritis
Anti-RNP antibodies
Myositis
Organ involvement and treatment
The most common clinical manifestations of mixed connective
disease are Raynaud’s phenomenon, arthralgias, swollen joints,
esophageal dysfunction, muscle weakness and fingers sausage-like
appearance together with the presence of anti-ribonucleoprotein
(RNP) antibodies. However, organ involvement is more extensive
than first descriptions reported. The disease can be serious with
development of pulmonary, kidney, cardiovascular, gastrointestinal and central nervous system manifestations. The worst prognosis and high mortality are associated with the presence of
pulmonary disease. Although a different set of clinical criteria have
been proposed, there is no consensus about the most accurate.
There is no full agreement about treatment and the initial
impression of a satisfactory response to low doses of steroids is not
always the rule. Herein, we review available evidence to a better
approach to all previous topics.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights
reserved.
Mixed connective tissue disease: from the criticism to the concept
Mixed connective tissue disease (MCTD) was first described in 1972 as an entity with mixed features
of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/
DM) and rheumatoid arthritis (RA) together with the presence of high-titre anti-U1small nuclear (sn)
anti-ribonucleoprotein (anti-RNP) antibodies [1,2]. The disease has been reported in children and in
* Corresponding author. Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer 52621, Israel.
Tel.: þ972 3 530 8070; fax: þ972 3 535 2855.
E-mail address: shoenfel@post.tau.ac.il (Y. Shoenfeld).
1521-6942/$ – see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.berh.2012.01.009
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O.-D. Ortega-Hernandez, Y. Shoenfeld / Best Practice & Research Clinical Rheumatology 26 (2012) 61–72
individuals over 80 years and is more prevalent in women in the third decade of life (from 80% to 90%)
[3]. Since 1972, the concept of MCTD has been criticised because of the following aspects: (1) the
difficulty to distinguish MCTD patients from SLE, SSc or RA [4] and (2) because many patients who have
anti-U1-RNP antibodies satisfy the criteria for SLE or SSc during the clinical course, and may experience
a shift of symptoms from MCTD to the true features of SLE [4]. However, after years, other studies
supported the concept of MCTD as a different disease. In this regard, different set of diagnostic criteria
were proposed [5–8]. MCTD has also been associated with HLA class II alleles and such linkage is
distinct from that one for SLE, SSc or PM/DM. HLA-DR4, -DR1 and less frequent -DR2 are the main HLAassociated alleles [9,10]. To remark, relevant similar conditions have different HLA-DR associations; SLE
is mainly associated with HLA-DR2 and DR3 [11], whereas SSc shows an association with HLA-DR3 or
DR5 [12,13]. PM/DM shows association with HLA-DR3 [14]. A murine model also suggests some genetic
linkage, HLA-DR4 transgenic mice C57BL/6-derived mice immunised with UI-70k in combination with
complete freund’s adjuvant developed anti-70K autoantibodies and perivascular infiltrates resembling
histopathological findings in MCTD [15]. Regarding clinical manifestations, the most common at
disease onset are Raynaud’s phenomenon (RP), arthralgias, swollen hands, fingers sausage-like
appearance and muscle weakness. They appear in 90% of patients and usually develop insidiously
[16]. Asthenia and myalgias are also frequent. However, organ involvement is more extensive than first
descriptions reported [1,2], and the initial impression of a satisfactory response to low doses of steroids
and a favourable prognosis is not the rule. MCTD can be a serious disease with development of
pulmonary arterial hypertension (PAH), glomerulonephritis (GNF), vasculitis, gastrointestinal bleeding
and severe central nervous involvement, which does not always have a good prognosis.
Overview of clinical manifestations
MCTD may begin with any clinical manifestations of SLE, SSc, PM or RA, at disease onset or during
clinical course. The most common clinical features are polyarthritis, RP, sclerodactyly, swollen hands,
muscle disorders and oesophageal dysmotility. Alopecia, malar rash, lymphadenopathy or kidney
damage are less common but can be present [17]. Unspecific constitutional symptoms such as fever,
fatigue, arthralgias or myalgias are also common. In general, a broad spectrum of signs and symptoms
can be present some of which, we intent to abridge herein.
Joint and forearm manifestations
Joint involvement varies from minimal arthralgias, arthritis in small or large joints and erosions
typical of RA to arthritis mutilans [16]. Although rheumatoid factor can be positive in up to 70% of
patients with erosive arthritis [18], no specific findings are found. In general, polyarthralgia is an early
and common symptom in MCTD, occurs in approximately 60% of patients and may be accompanied by
joint deformities with changes in radiographs [19,20]. In addition, small peritendinous nodules in
forearms have also been reported in some patients [21].
Muscle disease
Between 80% and 90% of patients develop some muscle involvement. Proximal muscles are the
more frequently affected with elevation of creatine kinase. However, it does not present any peculiar
pattern different from other connective tissue diseases (CTDs) with muscle involvement. Electromyography is typical of inflammatory myopathy, although, focal myositis may also occur. Histological
findings reveal myositis which is reminiscent of patients with PM or SLE [19,22]. In most patients,
myositis presents acutely in the setting of general disease activity and may be associated with fever.
Nevertheless, patients may also present with a more insidious onset, and persistent myopathy [23,24].
Skin manifestations
RP is one of the most consistent features. RP appears in approximately 75–90% of patients and may
precede other clinical manifestations in months or years and correlates with vascular disease in
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63
middle-sized vessels as well [1]. Almost 70% of patients develop swollen hands and sausage-like
appearance of the digits. The histological appearance of the skin of the hands is remindful greatly to
findings in SSc [1]. Nailfold capillaroscopy of fingers demonstrates changes that are more evocative of
SSc than SLE, but bushy formations seem to be characteristic of MCTD [17]. Dermatomyositis-like rash,
orogential ulceration and sicca complex syndrome have also been reported [19,25]. Although
uncommon, hypocomplementemic urticarial vasculitis was informed in some patients with MCTD [26].
In general, clinical manifestations such as SLE-like skin rash, oral ulcerations and photosensitivity may
also be present [24,27].
Lung manifestations
Pulmonary abnormalities are found in up to 85% of patients. Although various abnormalities
have been described such as fibrosis, interstitial disease and pulmonary arterial hypertension
(PAH), most of them have an asymptomatic course. In prospective studies, it has been found that
PAH and congestive heart failures as well as infections are the most common causes of death in
those patients. However, the clinical picture is less severe than in other conditions [17,24,28]. In
a recent study named the ‘registry to evaluate early and long-term pulmonary arterial hypertension
disease management (REVEAL)’, it was found that patients with MCTD with PAH had better haemodynamic and favourable right ventricular echocardiographic findings but a higher prevalence of
pericardial effusions. Additional findings were higher levels of B-type natriuretic peptide and lower
diffusing capacity of carbon monoxide. One-year survival and discharge from hospitalisation were
lower in patients with MCTD and PAH when compared to patients with SLE, SSc and RA with PAH
[29]. Other common clinical pulmonary manifestations include dyspnea and pleuritic chest pain.
Radiographic findings include interstitial changes, pleural effusions, pneumonic infiltrates and
pleural thickening [30,31]. Patients can also develop interstitial lung disease, which is usually mild
or even asymptomatic. Cases of acute interstitial pneumonia and pulmonary haemorrhage have
been reported as well [3,32,33].
Cardiovascular disease
Cardiac involvement varies between 11% and 85%, depending on the method used to detect
abnormalities and the definition of cardiac involvement [34,35]. The most frequent manifestation is
pericarditis (10–29%), which is usually mild [36]. Myocarditis, conduction disturbances (heart block)
and abnormal left ventricular diastolic filling failure besides mitral valve prolapsed (26%) have also
been detected by echocardiography in several patients [34,35]. Vasculopathy in MCTD is usually similar
to SSc, and is characterised by a bland intimal proliferation and medial hypertrophy that affects small
and medium-sized vessels. Other cardiovascular events, such as stroke, are rarely reported in patients
with MCTD [37]. Low levels of vitamin D have been found in patients with MCTD. Among the clinical
symptoms, the cardiovascular involvement has showed an inverse correlation with vitamin D status
[38].
Gastrointestinal disease
Gastrointestinal involvement is common (66–74%) and often represents a major feature of overlap
with SSc [39]. Oesophageal dysfunction is the most prevalent gastrointestinal manifestation. It is
initially subclinical, and when it is symptomatic, dysphagia the most common symptom [40].
Oesophageal dysmotility and reflux disease occur more frequently in patients who have clinical
manifestations mostly related to SSc rather than to SLE. However, manometric abnormalities are not
related to skin disorders and are less severe than in SSc [41]. Such abnormalities consist of decreased
oesophageal sphincter pressure, reduced amplitude of peristalsis in distal oesophagus and, less
common, reduced upper sphincter pressure [42]. Other gastrointestinal manifestations that have
been described are mesenteric vasculitis, colonic perforation, protein-losing enteropathy, acute
pancreatitis, haemoperitoneum, haemobilia, diarrhea and chronic active hepatitis [43–46].
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Gastrointestinal abnormalities appear to correlate with the time of disease course but not with its
clinical expression [39].
Renal complications
Renal involvement is one of the major complications of MCTD. It has been observed in some studies
in approximately 25% of patients and it is often asymptomatic [47]. Severe renal disease is rare and the
presence of anti-U1-RNP antibodies may be protective against the development of diffuse proliferative
glomerulonephritis (GNF) [48]. Although focal or diffuse proliferative GNF can be present, membranous and mesangial GNF are the most common presentation. Immune complex-mediated nephritis has
also been reported [49,50]. Interstitial nephropathy or renal vascular disease which is characteristic of
SSc is less frequent in MCTD patients [3,24]. By contrast, juvenile MCTD is associated with a higher risk
of nephritis than in adults with renal involvement. Hypocomplementemia observed in those patients
suggests higher frequency of GNF, including membranous lesions. A more aggressive indication of renal
biopsy should be considered in children with MCTD because of the high incidence of non-clinical
nephritis [51]. Other patients with MCTD may also develop accelerated hypertension, acute renal
insufficiency and microangiopathic haemolytic anaemia with similar histopathologyfindings to those
of scleroderma renal crisis [52].
Haematological manifestations
Conceiving haematological manifestations; leucopenia, anaemia of chronic disease, broad-based
hypergammaglobulinemia and positive Coomb’s test without haemolysis are the most frequent reported haematological features [3]. Other less common haematological features include thrombocytopenia, thrombotic thrombocytopenic purpura (TTP) and red cell aplasia [53,54]. Although they are
not specific of MCTD, anaemia and leucopenia tend to correlate with disease activity and usually
improve with therapies employed to treat other organ manifestations [3,17].
Neurological disease
Although the nervous system involvement is less frequent than other organ manifestations, there
are an increased number of studies suggesting that prevalence may be greater than reported before
[55,56]. The studies show that the most common manifestation of the peripheral nervous system is the
trigeminal neuropathy, which may be an early manifestation of an undiagnosed MCTD [55,57].
Headaches and peripheral neuropathies have also been reported but most likely related to a vascular
origin [56,58]. Regarding central nervous system manifestations, some patients can develop aseptic
meningitis with increased concentrations of interferon (IFN)-gamma, interleukin (IL)-6 and higher
titres of anti-U1-RNP antibodies in cerebrospinal fluid (CSF) than in serum. Titres of anti-U1-RNP
antibodies in CSF correlate well with disease activity [59]. Sato T, et al. [60] recently tested the presence of anti-U1-RNP antibodies in both CSF and sera of 24 patients with SLE and four patients with
MCTD with neuropsychiatric symptoms. It was found that titres of anti-U1-RNP antibodies in the CSF
were useful indicators of central neuropsychiatric manifestations in patients with anti-U1-RNP antibodies [60]. Intrathecal production was predominant in patients with neuropsychiatric symptoms.
Otherwise, isolated cases of intracraneal haemorrhage, transverse myelitis, cauda equine syndrome,
optic neuropathy and retinal vasculitis have been reported as well [61–65].
Autoantibodies in MCTD
The anti-U1-RNP antibodies are the hallmark of the disease. Patients with high titres without any
criteria of MCTD or other defined CTD, usually evolve into MCTD over 2 years. A pathogenic role of antiU1-RNP has not been proven, but clinical associations that have been observed in SLE and SSc patients
may suggest so [66,67]. Anti-RNP antibodies are directed against the U1-snRNP (one of the major
components of the spliceosome), which is associated with three proteins, U1-A, U1-C and U1-70K; all
of these autoantigens may be targeted by anti-U1-RNP specific antibodies [1,17]. Vlachoyiannopoulos
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et al. [68] described that anti-U1-RNP IgG isotype may be characteristic of MCTD, whereas IgM isotype
are more commonly found in SLE patients, although two types can be detected in both diseases. In any
case, antigen recognition by anti-U1-RNP antibodies seems to be different between SLE and MCTD. In
an epitope mapping study, 94% of the patients who had MCTD, but only 20% of SLE patients, recognised
the 35–58 peptide of the U1-A-protein [69]. The targeted region is different and limited to the second
of the two RNA-binding domains in SLE patients while antibodies of patients who have MCTD
recognise a larger epitope that contains sequences of both RNA-binding domains [4,70]. In most
instances, any patient with new onset of MCTD with positive anti-U1-RNP antibodies will present with
new-onset RP; polyarticular joint pain with or without frank sinovitis, and swollen, together with puffy
hands rater with the typical sclerodactyly and muscle weakness [5,71]. Otherwise, anti-U1-RNP
antibodies are not the only antibodies found in the sera of patients with MCTD. Anti-Ro/SS-A, antisingle-stranded DNA (ssDNA) [50], anti-Sm and anti-double-stranded DNA (dsDNA) antibodies [72]
have also been detected, nevertheless, they are not specific of MCTD. Antiphospholipid antibodies
have been reported in patients with MCTD. Anticardiolipin antibodies (aCL) are present in approximately 15% of patients; however, they are less prevalent than in patients with SLE [73,74]. aCL have
been associated with PAH in patients with MCTD but not with thrombotic events or other manifestations of the antiphospholipid syndrome (APS). It might be explained by low titres of IgG antibodies
with higher prevalence of IgM isotype when compared to APS patients [73,74]. Additional autoantibodies may be associated with specific clinical manifestations in patients with MCTD. Recently,
autoantibodies to angiotensin-converting enzyme 2 (ACE2) were associated with constrictive vasculopathy, PAH and persistent digital ischaemia in patients with MCTD, SLE and SSc [75]. Consistent with
this, immunosuppressive therapy given to one SLE patient with digital necrosis markedly decreased
the anti-ACE2 antibody titre and restored serum ACE2 activity, together with a substantial improvement in clinical symptoms [75]. In another study, anti-endothelial cell antibodies (AECA) were more
frequently seen in patients with MCTD than in patients with SSc [76]. Although the pathogenic role of
AECA in MCTD remains uncertain, serum AECA may constitute a useful marker of endothelial activation
and disease activity.
How to approach the diagnosis of MCTD?
Due to the wide spectrum of clinical findings in MCTD, the diagnosis is not often easy [77]. Different
forms of CTD such as transitory conditions and early phases of defined CTDs, which will become fully
defined within a few months or years should be considered in the differential diagnosis [78]. There are
also uncompleted forms of defined CTDs, where a diagnosis is possible based on clinical and serological
manifestations, but classification criteria are not met [79]. Many years ago, a different set of criteria
were proposed [5–8] (Table 1). Nowadays, the most common approach for diagnosis in clinical practice
requires the serological criteria plus at least three clinical criteria. However, when only hand edema, RP
or sausage-like appearance of the digits are present, four clinical criteria should be considered [5]. In
this regard, different studies have tested the accuracy of the available clinical criteria to identify
patients with MCTD rightly. In one study, Alarcon-Segovia and Cardiel [80] compared three different
set of criteria in a series of 593 patients, including 80 cases of MCTD. Results revealed that criteria by
Alarcón-Segovia had 100% sensitivity and with the presence of anti-RNP antibodies, the specificity
raises to 99.6%. Similar findings were found for Kasukawa criteria, the sensitivity was 96.2% and
specificity was 99.8%. The specificity for Sharp criteria was 87.7% [80]. This is important to remark that
testing of criteria was made internally, so results may be different in a multicentre study. In another
study, it was found that the criteria that best identified patients with MCTD were those proposed by
Alarcón-Segovia, with 62.5% sensitivity and 86.2% specificity, comparable to Kahn’s criteria. The
overlap with other CTDs was found in 16% of patients [71]. In a recent study performed by Capelli S.
et al. [81], three different classification criteria for MCTD (Kasukawa, Alarcón-Segovia and Sharp) were
compared together with define predictors (clinical features and autoantibodies) of potential evolution
towards other CTD. It was found that after a mean of 7.9 years of disease follow-up, 57.9% of patients
remained meeting the MCTD-classification criteria of Kasukawa; 17.3% evolved into SSc, 9.1% into SLE,
2.5% into RA, 11.5% was reclassified as affected by UCTD and 1.7% as suffering from overlap syndrome.
Kasukawa’s criteria were more sensitive (75%) in comparison to those of Alarcón-Segovia (73%) and
Table 1
Criteria proposed to diagnose mixed connective tissue disease.
Sharp (1987)
Major criteria
1. Myositis
2. Pulmonary
involvement:
a. Diffuse capacity
<70% of normal
values
b. Pulmonary
hypertension
c. Proliferative vascular
lesions on lung biopsy
3. Raynud’s
phenomenon
or esophageal
hypomotility
4. Swollen hands
5. Anti-ENA >
1:10.000 amd
anti-U1 RNP positive
and anti-Sm negative.
Alarcón-Segovia Serological
(1987)
Anti-RNP
titer > 1:1.600
Kasukawa
(1987)
Minor criteria
1. Alopecia
2. Leuckoepnia
3. Anemia
4. Pleuritis
5. Pericarditis
6. Arthritis
7. Trigeminal
neuropathy
8. Malar rash
9. Thrombocytopenia
10. Mild myositis
11. History of
swollen hands.
Requirements for diagnosis Sensitivity
At least four major criteria S:42%
plus anti-U1-RNP titer of
[81]
at least 1:4000. Exclusion
criteria: positivity for
anti-Sm antibody.
Two major criteria from
among criteria 1, 2 and
3 plus 2 minor criteria
plus anti-U1-RNP titer
of at least 1:1000.
Specificity Ref.
87.7%
[1,5]
[80]
Clinical
Requirements for diagnosis
Sensitivity
Specificity Ref.
Edema in hands,
synovitis, myositis,
raynaud’s
phenomenon,
acrosclerosis.
Mixed Symptoms
Serological criteria plus
at least three clinical
criteria, included either
synovitis or myositis.
62.5%
[71]
86.2%
[71]
Requirements for diagnosis
At least 1 of 2 common
symptoms plus positive
for anti-RNP plus 1 more
of the mixed symptoms
in at least 2 of the 3
disease categories.
Serological
1. SLE-like symptoms:
a. Polyarthritis
b. Lymphadenopathy
c. Facial erythema
d. Pericarditis
or Pleuritis
e. Leukothrombocytopenia.
2. SSc-like findings:
a. Sclerodactyly
b. Pulmonary
fibrosis, restrictive
changes of lung,
or reduced
diffusion capacity
c. Hypomotility
or dilatation
of esophagus.
3. PM-like findings:
a. Muscle weakness
b. Eleveated serum
levels of muscle
enzymes (CPK)
c. Myogenic pattern
on EMG
Clinical criteria
Sensitivity/ Specificity Ref.
specificity
99.8%
[6]
S:75%
[81]
[80]
Presence of
high titer anti-RNP
corresponding
to speckled
ANA at titer 1:2000
a. Raynauds
phenomenon
b. synovitis
c. myositis
d. swollen fingers
Common symptoms
1.Raynaud’s
phenomenon
2.Swollen fingers
or hands
Anti-RNP antibody
positive
Kahn (1991)
Requirements
for diagnosis
Serological criteria
plus Raynaud’s
phenomenon and
at least two of the
three following signs
(synovitis, myositis
and swollen fingers).
[5]
Sensitivity
Specificity Ref.
63% [71]
86. % [71] [7]
ENA: extractable nuclear antigen, SnRNP: small nuclear RNP, SLE: systemic lupus erythematosus, SSc: systemic sclerosis, PM:
polymyositis, CPK: creatine phosphokinase, EMG: electromyogram.
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Sharp criteria (42%) (Table 1) [81]. In summary, the concordance between serologic features and
clinical findings together with close clinical follow-up is still being the elementary strategy to approach
the diagnosis of MCTD.
Overview of treatment
Patients diagnosed of MCTD were initially described as having a good prognosis [1,2], being
extremely responsive to corticosteroid therapy. However, subsequent long-term studies have revealed
that not all patients have a benign clinical course and that not all clinical manifestations are responsive
to steroids [3,23,24,27,82]. Some patients may have mild self-limited disease, whereas others may
develop severe major organ involvement with life-threatening manifestations [24]. Unfortunately, no
controlled clinical trials have been performed, so treatment clues must rely largely upon the
conventional therapies that are used to treat similar clinical manifestations in other rheumatic diseases
such as SLE, SSc and PM. [28,83]. In any case, therapy should be individualised for each patient to
address the specific organs involved and the severity of underlying disease activity. Inflammatory
manifestations such as fever, serositis, myositis, arthritis and skin rash usually respond to steroid
treatment, whereas clinical sclerodermatous manifestations such as sclerodactyly, moderate oesophagueal disease, RP, sclerodermatous bowel disease and pulmonary interstitial disease more often
require cytotoxic immunosuppressive treatment [28]. In general, corticosteroids (prednisone and
methylprednisolone) and cytotoxic agents, most often cyclophosphamide, are the most frequently
employed immunosuppressants. Antimalarials (hydroxychloroquine), methotrexate and different
types of vasodilators have also been used with varying degrees of success [27]. Approach for specific
organ involvement is described below.
Constitutional symptoms
Fever, fatigue, unspecific arthralgias or myalgias usually respond to non-steroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine or low-dose of prednisone, it depends on the severity. The
possibility of fibromyalgia or reactive depression should always be considered and treated optimally
[16,23]. However, when a patient debuts with fever, careful search of occult infection or neoplasm
should also be included.
Joint involvement
Continuous evaluation of joint symptoms should be performed. All patients who have arthritis
should have baseline radiographs to determine if erosive changes are present. Most of the mild joint
involvement has been treated with NSAIDs, hydroxychloroquine and/or oral prednisone with good
response [16,17,27]. For more severe forms, methotrexate has been reported to be indicated [84]. If
methotrexate is contraindicated, other disease-modifying agents used in RA, such as leflunomide or
azathioprine, may be considered. Anti-tumour necrosis factor (TNF) inhibitors are not recommended
and if needed, patients must be followed carefully for the development of SLE-like syndrome [85].
Muscle disease
Most of patients with acute onset of severe myositis, often accompanied by fever, respond to high
doses of corticosteroids [24,27]. Some reports have suggested a more favourable prognosis for muscle
disease in MCTD with less steroid requirements [23,24]. Myalgias in the absence of myositis can be
treated with NSAIDs, hydroxycloroquine and/or low-dose prednisone. Otherwise, SLE-like skin rash,
oral ulcerations and photosensitivity have been treated effectively with topical steroids, prednisone
and/or hydroxycloroquine [16,17,27]. Immunosupressants such as cyclophosphamide or cyclosporine
might be considered for more severe cases. Intravenous immunoglobulin (IVIG) may constitute another
option for refractory symptoms. The effects of IVIG are beneficial, but do not last very long. Repeat
infusions every 6–8 weeks are often enough if it is necessary.
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Sclerodermatous involvement
Sclerodermatous-like skin manifestations are often responsive to steroid therapy. RP in MCTD
usually responds to conventional vasodilator therapies such as calcium channel blockers together with
preventive measures like avoidance of cold temperatures and other triggering factors such as smoking,
and sympathomimetic agents. The use of warm and protection techniques of fingers are also beneficial.
In recent years, therapy with prostaglandin-analogues was considered to treat severe ischaemic digital
lesions [86]. However, current strategies include Bosentan (a dual endothelin receptor antagonist) as
the recommended treatment of RP as well as for the prevention of new digital ulcers especially in
patients who have SSc [87]. Prazocin, losartan or pentoxifylline may cause modest improvement of
vascular symptoms in some patients. There is a report of successful treatment of severe, refractory RP
with rituximab (anti-CD20) (in combination with methylprednisolone, cyclophosphamide and iloprost, a prostacyclin analogue), in a patient with MCTD [88].
Lung involvement
Regarding treatment of patients with PAH, recent advances have expanded the therapeutic options.
First, an early detection is mandatory, all patients with MCTD must undergo screening echocardiography
and high-resolution computed tomography at the time of diagnosis [89]. Mild cases must be followed
with serial testing monitoring for any signs of progression. Traditional regimen of calcium channel
blockers, angiotensin-converting enzyme (ACE) inhibitors, immunosuppression and conventional heart
failure therapies should be considered [90,91]. Currently, prostacyclin analogues (Treprostinil) represent
a useful tool for its treatment. Treatment with Treprostinil has demonstrated to improved exercise
capacity, symptoms of PAH and haemodynamics in patients with moderate to severe PAH. In patients
requiring combination therapy, the addition of oral Bosentan to Treprostinil-based therapy is well
tolerated, and associated with further clinical improvements [90–93]. Conceiving other pulmonary
manifestations, mild cases with pleurisy usually respond to NSAIDs and if symptoms persist, varying
doses of corticosteroids are often useful. In some other patients, pleurisy is self-limited and resolve
without treatment. Immunosuppressive agents are rarely indicated to treat them [30,31]. In any case, the
possibility of infection and thromboembolic events must always be excluded.
Cardiovascular disease
Concerning cardiovascular involvement, pericarditis usually responds to NSAIDs and/or varying doses
of corticosteroids depending on the severity. Massive pericardial effusion with cardiac tamponade rarely
occurs and it may need surgical drainage. It depends of the severity. Moderate to severe myocarditis should
be treated with high-dose steroid therapy together with common therapy employed to treat congestive
heart failure if it is present. Patients with myocarditis often require additional therapies with azathioprine,
cyclophosphamide or IVIG with variable rates of response [36,94]. Although uncommon, hypocomplementemic urticarial vasculitis has also been reported in some patients, and usually responds to
hydroxychloroquine after a period of corticosteroid dependence [26]. The official European League against
Rheumatism (EULAR) recommendations on the assessment and management of cardiovascular disease in
CTDs are to be developed soon [95].
Gastrointestinal involvement
Gastrointestinal disease in MCTD can be treated following common recommendations to treat
similar disorders such as SSc. In any case, the first-line therapy is the conventional treatment with
proton-pump inhibitors, H2-receptor antagonists and lifestyle modifications, together with oesophageal PH monitoring in patients with persistent reflux symptoms. However, there is one remarkable
difference when treating oesophageal dysfunction in patients with MCTD [39]. In contrast to SSc, it
usually improves with corticosteroid therapy showing a significant change in lower oesophageal
pressure and a trend to ameliorate peristaltic pressures in the oesophagus body [39,40]. Screening for
Barrett’s oesophagus is also recommended [39].
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Renal impairment
As previously mentioned, renal involvement can be asymptomatic and although, nephrotic
syndrome can develop, this may respond to high-dose of corticosteroid therapy. Approximately, 70% of
nephropathy episodes resolved or improve significantly [47], with a few percentage of progression to
renal failure [47,96]. If a patient presents SSc-like renal crisis, treatment with ACE inhibitors as well as
intravenous prostacyclin (Epoprostenol) are indicated. They are believed to improve microvascular
lesions without precipitating hypotension, and should be administered at the onset of hypertensive
renal crisis. The combined therapy may be a more effective treatment for this complication. Short-term
haemodialysis can be started if necessary, and continuous peritoneal dialysis often works well if longterm renal replacement is needed [52].
Neurological disease
Although nervous system involvement can be serious and sometimes fatal, it is potentially treatable. Unfortunately, there is a lack of randomised clinical trials in MCTD, so clinical trials performed for
SLE patients and isolated observations provide the main evidence [97,98]. In general, to treat nervous
system involvement, corticosteroids are used in low-dose oral, high-dose oral or high-dose intravenous
regimens according to the severity of potential damage. Therapeutic efforts to treat major intracranial
manifestations in MCTD largely fall into three categories: stroke prevention, immunosuppression and
symptomatic treatment if it is necessary [62]. Trigeminal neuropathy (the most common neurological
symptom) and peripheral neuropathies are less responsive to treatment; however, attempts with
intensive traditional symptomatic treatment are recommended [55,57]. We are aware of only a single
randomised trial assessing steroids and/or immunosuppression in neurolupus, and this included only
32 patients [97,98]. Results suggest that for serious (non-stroke) neurological complications including
neuropsychiatric manifestations, optic neuritis, neuropathy, coma, brainstem disease or transverse
myelitis, steroids alone were inferior to steroids plus cyclophosphamide. A common recommendation
is therefore to start with high dose intravenous methylprednisolone followed by oral prednisone,
decreasing doses at weekly intervals accompanied by oral or intravenous cyclophosphamide [97,98].
Careful monitoring of the blood count for bone marrow suppression should be performed. Cyclophosphamide is associated with haemorrhagic cystitis which can be reduced by adequate hydration.
Cyclophosphamide is also associated with high increase in bladder cancer. Other malignancies,
infertility, cardiotoxicity and pulmonary fibrosis have been described as well. Additional clinical
syndromes such as aseptic meningitis are usually treated with high doses of steroids with good
response [59].
Conclusions
MCTD is a well-defined entity with a wide spectrum of clinical manifestations. Long-term studies
reveal that some patients may have mild self-limited disease, whereas others may develop severe
major organ involvement. Although there is a different set of clinical criteria, the most common
approach for the diagnosis requires the serological criteria plus at least three clinical criteria. The worst
prognosis and high mortality is associated with the presence of pulmonary arterial hypertension. There
is no consensus about the treatment of MCTD. Specific clinical manifestations should be addressed
according to recommendations to treat the same manifestations in other diseases such as SLE, SSc and
RA. In all cases, therapy should be individualised for each patient to address the specific organs
involved. Life-threatening manifestations require aggressive treatment. Further prospective clinical
trials are needed to evaluate clinical course, long-term prognosis and response to therapy.
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