Consensus Treatment Plans for Induction Therapy in Juvenile Systemic Lupus Erythematosus

Arthritis Care & Research
Vol. 64, No. 3, March 2012, pp 375–383
DOI 10.1002/acr.21558
© 2012, American College of Rheumatology
ORIGINAL ARTICLE
Consensus Treatment Plans for Induction Therapy
of Newly Diagnosed Proliferative Lupus Nephritis
in Juvenile Systemic Lupus Erythematosus
RINA MINA,1 EMILY VON SCHEVEN,2 STACY P. ARDOIN,3 B. ANNE EBERHARD,4
MARILYNN PUNARO,5 NORMAN ILOWITE,6 JOYCE HSU,7 MARISA KLEIN-GITELMAN,8
L. NANDINI MOORTHY,9 EYAL MUSCAL,10 SUHAS M. RADHAKRISHNA,11
LINDA WAGNER-WEINER,12 MATTHEW ADAMS,13 PETER BLIER,14 LENORE BUCKLEY,15
ELIZABETH CHALOM,16 GAËLLE CHÉDEVILLE,17 ANDREW EICHENFIELD,18 NATALYA FISH,19
MICHAEL HENRICKSON,1 AIMEE O. HERSH,20 ROGER HOLLISTER,21 OLCAY JONES,22
LAWRENCE JUNG,23 DEBORAH LEVY,24 JORGE LOPEZ-BENITEZ,25 DEBORAH MCCURDY,26
PAIVI M. MIETTUNEN,27 ANA I. QUINTERO-DEL RIO,28 DEBORAH ROTHMAN,29 ORNELLA RULLO,26
NATASHA RUTH,30 LAURA E. SCHANBERG,31 EARL SILVERMAN,24 NORA G. SINGER,32
JENNIFER SOEP,21 REEMA SYED,33 LARRY B. VOGLER,34 ALI YALCINDAG,35
CAGRI YILDIRIM-TORUNER,18 CAROL A. WALLACE,36 AND
HERMINE I. BRUNNER,1 ON BEHALF OF THE CARRA SLE SUBCOMMITTEE
Objective. To formulate consensus treatment plans (CTPs) for induction therapy of newly diagnosed proliferative lupus
nephritis (LN) in juvenile systemic lupus erythematosus (SLE).
Methods. A structured consensus formation process was employed by the members of the Childhood Arthritis and
Rheumatology Research Alliance after considering the existing medical evidence and current treatment approaches.
Results. After an initial Delphi survey (response rate ⴝ 70%), a 2-day consensus conference, and 2 followup Delphi
surveys (response rates ⴝ 63–79%), consensus was achieved for a limited set of CTPs addressing the induction therapy
of proliferative LN. These CTPs were developed for prototypical patients defined by eligibility characteristics, and
included immunosuppressive therapy with either mycophenolic acid orally twice per day, or intravenous cyclophosphamide once per month at standardized dosages for 6 months. Additionally, the CTPs describe 3 options for standardized
use of glucocorticoids, including a primarily oral, a mixed oral/intravenous, and a primarily intravenous regimen. There
was consensus on measures of effectiveness and safety of the CTPs. The CTPs were well accepted by the pediatric
rheumatology providers treating children with LN, and up to 300 children per year in North America are expected to be
candidates for the treatment with the CTPs.
Conclusion. CTPs for induction therapy of proliferative LN in juvenile SLE based on the available scientific evidence and
pediatric rheumatology group experience have been developed. Consistent use of the CTPs may improve the prognosis of
proliferative LN, and support the conduct of comparative effectiveness studies aimed at optimizing therapeutic strategies
for proliferative LN in juvenile SLE.
Despite advances in the understanding of the disease and
research in therapeutic targets, children and adolescents
with systemic lupus erythematosus (juvenile SLE) con-
tinue to experience frequent episodes of acute disease
exacerbations and are at much higher risk than adults for
permanent organ damage due to SLE or its treatments (1,2).
This is particularly true for lupus nephritis (LN), which
affects up to 80% of children with juvenile SLE. Failure to
Supported by the NIH National Institute of Arthritis and
Musculoskeletal and Skin Diseases (grants C1AR058605-01
and R13-AR053058-04), the Childhood Arthritis and Rheumatology Research Alliance, the Arthritis Foundation, the
Wasie Foundation, and the Friends of the Childhood Arthritis and Rheumatology Research Alliance. Dr. Mina’s work
was supported by a National Institute of Arthritis and Musculoskeletal and Skin Diseases T32 training grant. Dr.
Levy’s work was supported by the National Institute of
Arthritis and Musculoskeletal and Skin Diseases (grant
K23AR053202). Dr. Schanberg’s work was supported by the
National Institute of Arthritis and Musculoskeletal and Skin
INTRODUCTION
375
376
Mina et al
achieve and maintain remission of juvenile SLE–associated LN (juvenile LN) reduces the overall 10-year survival
by an estimated 15% (3).
To determine the severity of juvenile LN, a kidney biopsy is required, and the histologic findings are graded
using the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification (4). The patho-
logic changes present on the kidney biopsy help guide
treatment decisions and may be predictive of long-term
kidney survival. Besides the presence of proliferative juvenile LN, defined as histologic findings compatible with
ISN/RPS class 3 or 4, continuously active nonremitting
juvenile LN and flares of juvenile LN are risk factors for the
development of chronic kidney disease and poor juvenile
SLE outcomes (5–9).
The treatment of proliferative juvenile LN is commonly
divided into 2 distinct phases. The initial phase, induction
therapy, is composed of intense immunosuppression
aimed at achieving remission of juvenile LN with resolution of active inflammatory changes. Induction therapy is
followed by a longer maintenance phase, during which
less intense immunosuppressive drug regimens are used to
sustain remission of juvenile LN, while attempting to minimize side effects associated with immunosuppressive
therapy.
Head-to-head comparisons of treatments for proliferative juvenile LN in sufficiently large trials are lacking in
the literature (10). Therefore, no drug to date has received
Food and Drug Administration approval for the treatment
of juvenile LN. Instead, the treatment of children with
juvenile LN relies on the off-label use of medications that
are approved for immunosuppression following pediatric
kidney transplantation, treatment of solid organ tumors, or
drugs that have been found effective in adults with LN.
Despite clinical trials of cyclophosphamide (CYC), myco-
Diseases (grants NO1-AR-2-2265 and RC2-AR-058934). Dr.
Brunner’s work was supported by the National Institute of
Arthritis and Musculoskeletal and Skin Diseases (grants
1U01AR059509, U01AR055054, and P60 AR47784).
1
Rina Mina, MD, MSc, Michael Henrickson, MD, MPH,
Hermine I. Brunner, MD, MSc: Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; 2Emily von Scheven,
MD, MAS: University of California at San Francisco; 3Stacy
P. Ardoin, MD, MSc: Nationwide Children’s Hospital and
The Ohio State University, Columbus; 4B. Anne Eberhard,
MBBS, MSc, FRACP, FRCPC: Steven and Alexandra Cohen
Children’s Medical Center of New York, New York, New
York; 5Marilynn Punaro, MD: Texas Scottish Rite Hospital,
Dallas; 6Norman Ilowite, MD: Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New
York; 7Joyce Hsu, MD: Lucile Packard Children’s Hospital
at Stanford, Palo Alto, California; 8Marisa Klein-Gitelman,
MD, MPH: Children’s Memorial Hospital, Chicago, Illinois;
9
L. Nandini Moorthy, MD, MS: University of Medicine and
Dentistry of New Jersey-Robert Wood Johnson Medical
School, New Brunswick; 10Eyal Muscal, MD, MS: Texas
Children’s Hospital Pediatric Rheumatology Center, Baylor
College of Medicine, Houston; 11Suhas M. Radhakrishna,
MD: Children’s Hospital Los Angeles, Los Angeles, California; 12Linda Wagner-Weiner, MD: University of Chicago
Comer Children’s Hospital, Chicago, Illinois; 13Matthew Adams, MD: Children’s Hospital of Michigan, Detroit; 14Peter
Blier, MD, PhD: Baystate Children’s Hospital, Springfield,
Massachusetts; 15Lenore Buckley, MD, MPH: Virginia Commonwealth University School of Medicine, Richmond;
16
Elizabeth Chalom, MD: St. Barnabas Medical Center, Livingston, New Jersey; 17Gaëlle Chédeville, MD: Montreal
Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada; 18Andrew Eichenfield, MD, Cagri
Yildirim-Toruner, MD: Morgan Stanley Children’s Hospital
of New York-Presbyterian and Columbia University Medical Center, New York, New York; 19Natalya Fish, MD: Penn
State Hershey Children’s Hospital, Hershey, Pennsylvania;
20
Aimee O. Hersh, MD, MS: University of Utah, Salt Lake
City; 21Roger Hollister, MD, Jennifer Soep, MD: Children’s
Hospital Colorado, Aurora; 22Olcay Jones, MD: Walter Reed
Army Medical Center, Washington, DC; 23Lawrence Jung,
MD, PhD: Children’s National Medical Center, Washington,
DC; 24Deborah Levy, MD, MS, Earl Silverman, MD: Hospital
for Sick Children, Toronto, Ontario, Canada; 25Jorge LopezBenitez, MD: Floating Hospital for Children at Tufts Medical
Center, Boston, Massachusetts; 26Deborah McCurdy, MD,
Ornella Rullo, MD: Mattel Children’s Hospital, University of
California, Los Angeles; 27Paivi M. Miettunen, MD: University of Calgary, Calgary, Alberta, Canada; 28Ana I. QuinteroDel Rio, MD, MPH: Universidad Central del Caribe, Bayamón, Puerto Rico; 29Deborah Rothman, MD: Shriners
Hospital for Children, Springfield, Massachusetts; 30Natasha
Ruth, MD, MS: Medical University of South Carolina, Charleston; 31Laura E. Schanberg, MD: Duke University Medical Center, Durham, North Carolina; 32Nora G. Singer, MD: MetroHealth Medical Center, Case Western Reserve University
School of Medicine, Cleveland, Ohio; 33Reema Syed, MBBS,
MD: St. Louis University, St. Louis, Missouri; 34Larry B. Vogler, MD: Emory-Children’s Center, Atlanta, Georgia; 35Ali
Yalcindag, MD: Hasbro Children’s Hospital, Providence,
Rhode Island; 36Carol A. Wallace, MD: Seattle Children’s Hospital, University of Washington, Seattle.
Drs. Mina and von Scheven contributed equally to this
work.
Dr. Ardoin has received consultant fees, speaking fees,
and/or honoraria (less than $10,000) from Johnson & Johnson.
Address correspondence to Emily von Scheven, MD,
MAS, Pediatric Rheumatology, University of California, San
Francisco, Box 0107, 505 Parnassus Avenue, Room M-679,
San Francisco, CA 94143. E-mail: evonsche@peds.ucsf.edu.
Submitted for publication September 2, 2011; accepted in
revised form November 29, 2011.
Significance & Innovations
●
Treatment approaches that are based on scientific
evidence and clinical experience and endorsed by
the majority of pediatric rheumatology professionals in North America are presented.
●
Induction therapy of proliferative, newly diagnosed lupus nephritis in children includes treatment with glucocorticoids and either oral mycophenolic acid or intravenous cyclophosphamide
for 6 months.
●
Consistent use of consensus treatment plans may
improve the prognosis of proliferative lupus nephritis, and support the conduct of comparative
effectiveness studies aimed at optimizing therapeutic strategies for proliferative lupus nephritis
in juvenile systemic lupus erythematosus.
Induction Therapy for Proliferative LN in Juvenile SLE
377
Figure 1. The development of the consensus treatment plans for proliferative lupus nephritis (jLN) in juvenile systemic lupus erythematosus based on consensus formation techniques. CARRA ⫽ Childhood Arthritis and Rheumatology Research Alliance.
phenolate mofetil (MMF), and azathioprine for treatment
of proliferative LN in adults with SLE, the optimal dosing,
efficacy, and safety of these immunosuppressive agents
when used in children and adolescents with juvenile LN
remain to be determined (11–14).
Based on experience in other chronic pediatric diseases,
consensus treatment plans (CTPs) represent an alternative
approach to determine the preferred treatment in settings
where clinical trial data are not available or the conduct of
large-scale trials is too difficult due to population size or
lack of funding (15,16). The reduction of clinical practice
variability through the use of a limited set of CTPs can
allow for future comparison of outcomes and standardization of therapy. CTPs are best developed by organizations
that represent the health care providers that most frequently determine the treatments prescribed. Therapeutic
decisions for juvenile SLE are generally made by pediatric
rheumatologists, and the majority of pediatric rheumatologists in North America are members of the Childhood
Arthritis and Rheumatology Research Alliance (CARRA), a
research network whose mission is “to prevent, treat, and
cure rheumatic diseases in children and adolescents
through fostering, facilitating, and conducting high quality
research.”
The current project was part of a larger CARRA initiative
aimed at the development of CTPs for various pediatric
rheumatic diseases. With respect to juvenile SLE, there
was close to unanimous support among CARRA members
to develop CTPs for proliferative juvenile LN. Therefore,
the objectives of this project were to obtain insight into
and describe the current treatment practices for juvenile
LN among pediatric rheumatologists in North America,
and to develop CTPs for induction therapy of proliferative
juvenile LN that are consistent with both current practice
and the best available evidence in the literature.
MATERIALS AND METHODS
Fundamental to this project was an in-depth review of the
medical literature addressing the current scientific evidence for the treatment of juvenile LN (see Supplementary Appendix A and Supplementary Appendix B, both
available in the online version of this article at http://
onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).
The literature search included studies of adults with SLE
because of the limited published data specifically addressing treatment of juvenile LN. Levels of evidence were
assigned based on Oxford Centre for Evidence-Based Medicine criteria (www.cebm.net) and were as follows: A (supported by randomized clinical trials [RCTs]), B (supported
by nonrandomized controlled studies or extrapolations
from RCTs), C (supported by uncontrolled studies, extrapolations from nonrandomized controlled studies, or
marked extrapolations from RCTs [e.g., inference and adaptation of results in pediatrics from a study with adult
patients]), and D (based on expert opinion).
Members of CARRA employed consensus formation
techniques with the goal of developing CTPs for proliferative juvenile LN (Figure 1) (17). The group had experience in using these techniques when developing outcome
measures of several pediatric rheumatologic diseases (18 –
20). The level of consensus for the Delphi surveys and the
consensus conference was set at 80%.
Phase I: delineation of current practices. The first
phase of the project consisted of an online Delphi survey
that was sent to the 103 members of the CARRA SLE
Disease Specific Committee. The questionnaire included
20 questions designed to delineate current clinical practice in the management of proliferative juvenile LN. We
used a clinical case of a prototypical patient with proliferative juvenile LN to guide survey responses (see Supplementary Appendix C, available in the online version
of this article at http://onlinelibrary.wiley.com/journal/
10.1002/(ISSN)2151-4658).
Phase II: consensus conference. The second phase of
the project consisted of a formal face-to-face consensus
meeting held for 2 days in April 2010. The goal of the
consensus conference was to develop a limited set of CTPs
for induction therapy of proliferative juvenile LN that was
consistent with current practice and informed by the best
available evidence (see Phase I above). Participants included 32 voting members of the CARRA SLE Disease
Specific Committee who were pediatric rheumatologists
with substantial experience in the assessment and treatment of juvenile SLE. Twelve trainees supported the con-
378
Mina et al
Figure 2. Modified nominal group process used to achieve consensus.
sensus meeting activities, but they were not involved in
the nominal group deliberations or the voting process.
We employed a modified nominal group technique using an approach similar to that previously used by CARRA
investigators (Figure 2) (18 –20). Conference participants
were assigned to 1 of 5 subgroups that were led by moderators trained in nominal group technique. Table 1 shows
the key questions addressed by these subgroups. Evidence
from the literature and summaries of current clinical practice obtained by the initial Delphi survey were referenced
during the discussions to ensure consistency of the final
agreed-upon CTPs with these practices. All subgroups
achieved consensus about the patient population to which
the CTPs were to be applied. Each subgroup focused on
discussing a specific question pertaining to treatments.
Subgroup leaders then reported back to all members of the
CARRA SLE Disease Specific Committee who were present
at the consensus conference for further discussion and final
voting. Complex issues, for which no large-group consensus
was achieved during the face-to-face meeting, were addressed in a subsequent Delphi survey (see Phase III below).
Phase III: finalization of the CTPs for induction therapy
of proliferative juvenile LN. Through the third Delphi
survey, we presented the CTPs formulated by the CARRA
SLE Disease Specific Committee to the entire CARRA voting membership (n ⫽ 216) to achieve CARRA-wide consensus. We also collected information about the potential
impact of applying the CTPs in actual clinical practice.
RESULTS
Assessment of current treatment practices for proliferative juvenile LN. The key findings of the initial Delphi
survey (response rate 71/103 ⫽ 70%) included that
monthly intravenous (IV) CYC (56/71 ⫽ 79%) was the
most commonly prescribed immunosuppressive medication for the induction therapy of proliferative juvenile LN,
followed by MMF (12/71 ⫽ 17%). Rituximab and azathioprine were rarely prescribed for induction therapy of juvenile LN (0 –1% of 71). Not surprisingly, the survey revealed striking variability in the dosing, route of
administration, tapering schedule, and duration of glucocorticoid therapy among pediatric rheumatology providers, despite its almost universal use for juvenile LN therapy (69/70 ⫽ 99%).
The majority of providers (62/71 ⫽ 87%) prescribed IV
CYC in accordance with the National Institutes of Health
protocol (level C) (21). The choice of the immunosuppressive medication was influenced by coexistent morbidities,
especially lupus cerebritis (55/68 ⫽ 81%), and the perceived risk of nonadherence of the patient to oral medications (58/67 ⫽ 87%). Almost all pediatric rheumatologists
described themselves as the prescribing physician who
selected the immunosuppressive therapy, although patient
care was often shared with a pediatric nephrologist (65/
66 ⫽ 98%) whose focus was typically the management of
coexisting proteinuria and/or hypertension.
We achieved consensus on adapting the criteria for flare
Table 1. Questions considered in the consensus conference to establish CTPs for induction therapy in newly diagnosed
proliferative LN in juvenile SLE*
1.
2.
3.
4.
5.
6.
7.
What would be the patient characteristics that are appropriate for use of these treatment plans?
What should be the patient characteristics that would indicate that these treatment plans would not be appropriate to use?
What should be the dose/route/frequency for use of cyclophosphamide in the treatment plans?
What should be the dose/route/frequency for use of mycophenolic acid in the treatment plans?
What should be the dose/route/frequency for use of glucocorticoids in the treatment plans?
What outcome measures should be used to define response to treatment and how often should they be measured?
How should quality of life and medication toxicity be measured?
* CTPs ⫽ consensus treatment plans; LN ⫽ lupus nephritis; SLE ⫽ systemic lupus erythematosus.
Induction Therapy for Proliferative LN in Juvenile SLE
379
Table 2. Patient characteristics for application of consensus treatment plans*
Patients should
Fulfill at least 4 of 11 criteria of the American College of Rheumatology classification for SLE or fulfill 3 of the 11 criteria,
provided 1 is histologic evidence of lupus nephritis (1)
Be ⱕ16 years of age at SLE diagnosis
Be currently ⱕ20 years of age
Have new diagnosis of class III or IV lupus nephritis, with or without class V lesions, as defined by the International Society of
Nephrology Classification System/Renal Pathology Society Classification of Lupus Nephritis (4)
Patients should not have/be
Severe infection
Pregnant or nursing
Requirement for intensive care unit support
* SLE ⫽ systemic lupus erythematosus.
(60/66 ⫽ 91%) and response to therapy (64/67 ⫽ 96%) that
were developed for LN by the American College of Rheumatology (ACR) and the European League Against Rheumatism (level D) (22,23).
Phase II: consensus conference results. We achieved
consensus on characteristics of the patients for whom the
CTPs are suitable (Table 2). As is summarized in Figure 3,
either MMF or CYC will be prescribed concomitantly with
the chosen glucocorticoid dosing regimen. This will result
in 6 potential treatment approaches.
Glucocorticoids. The dosing of the glucocorticoids reflected physician experience and was informed by regimens used in previous studies of juvenile LN (level D)
(24,25). Recent evidence suggests that high-dose IV methylprednisolone pulses, but not oral glucocorticoids, have
the potential to eliminate the interferon-␣ gene expression
signature in juvenile SLE by reducing the number of plasmacytoid dendritic cells (26). Therefore, all 3 glucocorticoid regimens allowed for the use of up to 3 high-dose
methylprednisolone pulses (30 mg/kg/dose up to 1,000
mg/dose) at the time of induction therapy initiation (level
Figure 3. Consensus treatment plans for proliferative juvenile systemic lupus erythematosus–associated lupus nephritis. IV ⫽ intravenous; q ⫽ every; PO ⫽ oral; BID ⫽ twice daily.
380
C) (27). Despite dramatic variability of glucocorticoid prescribing practices, we achieved consensus to treat juvenile
LN with 1 of the 3 glucocorticoid regimens (primarily oral,
primarily IV, and mixed oral and IV). The common goal for
these 3 glucocorticoid regimens is to achieve a daily dosage of oral glucocorticoids between 10 and 20 mg upon
completion of the induction therapy after 24 weeks (or 6
months; level D) (28).
CYC. Consensus was reached to administer a total of 6
monthly IV CYC dosages. The initial dose of CYC is 500
mg/m2 body surface area, and subsequent doses are to be
increased, but will not exceed a maximum monthly dosage
of 1,500 mg (level C) (21,29,30). The group recommended
adjusting the CYC dose for renal insufficiency and for a
low white blood cell nadir, which is anticipated 7–10 days
after the infusion of CYC (level C) (21).
Extensive discussion during the consensus conference
focused on concomitant therapies to address and avoid
CYC side effects, including the use of 2-mercaptoethane
sulfonate sodium for the prevention of hemorrhagic cystitis (level C) (31), antiemetics for nausea, gonadotropin
antagonist for ovarian protection (level C) (32), and prophylaxis for Pneumocystis jiroveci infections (level D)
(33). There was consensus that concomitant therapies will
not be included in the CTPs and that use of these concomitant therapies should be left to the discretion of the treating provider.
Mycophenolic acid. MMF will be administered at 600
mg/m2/dose twice daily with a maximum dosage of 1,500
mg taken 2 times per day. A lower dose of MMF could be
used at initiation of treatment, but the dose should be
escalated to the target dose within 4 weeks of starting
therapy, thereby allowing for dose titration according to
side effects and tolerability (level C) (12,34,35).
Mycophenolate sodium (MPA) may be used as an alternative to MMF for the treatment of juvenile LN with a
target dosage of 400 mg/m2/dose twice daily and a maximum dosage of 1,080 mg twice daily. Monitoring of complete blood count, liver function tests, and serum creatinine every 2 weeks during the first month after the
initiation of MMF/MPA followed by monthly testing during the induction therapy for juvenile LN were considered
sufficient for the surveillance of MMF/MPA side effects
(level C) (12,26,27). MMF/MPA should be held or discontinued for serum creatinine levels that increase more than
30% above baseline or for leukopenia of ⬍1.3 ⫻ 109/liter
(level C) (12). Rechallenge, dose adjustments, and interruption of MMF/MPA intake for suspected drug toxicity
are to be left to the judgment of the treating physician. No
consensus was reached on whether therapeutic drug monitoring of MMF/MPA should be utilized (level C) (36,37),
or if random mycophenolate levels should be obtained to
screen for patient adherence (level C).
Measures of effectiveness and safety. Table 3 summarizes definitions of response to induction therapy and flare
of juvenile LN as adapted from adult LN (22,23). There was
agreement to assess effectiveness of treatment at 1 month,
3 months, and 6 months after initiation of induction therapy (level C) (12). No consensus was reached about the
timing of or indication for repeat renal biopsy for routine
monitoring or assessment of flare (level C) (38).
Mina et al
Recommendations were made (based on consensus) to
also monitor extrarenal disease activity, using the Systemic Lupus Erythematosus Disease Activity Index, physician global assessment of disease activity, parent/patient
global assessment of well-being, and disease damage using
the Systemic Lupus International Collaborating Clinics/
ACR Damage Index (level D) (39). For patient-reported
outcome measures, the Pediatric Quality of Life Inventory
Generic Core Scale version 4.0 (40) will be completed by
patients at least every 6 months (level C) (41).
The National Cancer Institute’s Common Terminology
Criteria for Adverse Events version 3.0 (http://ctep.cancer.
gov) was selected as the taxonomy of choice for monitoring
treatment side effects. Moderate to severe (grade 3 or
higher) adverse events (level D) will be recorded.
A second Delphi survey was sent to 103 CARRA SLE
Disease Specific Committee members shortly after the consensus conference to address unresolved issues related to
steroid dosing, measurement of health-related quality of
life, and assessment of adherence (response rate ⫽ 79%).
Phase III: assessment of the feasibility and potential
impact of the consensus treatment plans. The third Delphi survey was sent to all voting members of CARRA at 92
pediatric rheumatology centers in the US and Canada (response rate 137/216 ⫽ 63%). Based on Delphi questionnaire responses, there was consensus among all CARRA
voting members regarding the usefulness, compatibility
with daily clinical practice, and scientific soundness of the
CTPs for the induction therapy for proliferative juvenile
LN that had been developed by the CARRA SLE Disease
Specific Committee.
Approximately 90% of the respondents stated that they
would prescribe CYC (rather than MMF) as per the CTPs to
their patients with proliferative juvenile LN. There was
also consensus that they would utilize 1 of the 3 glucocorticoid regimens when treating patients with proliferative
juvenile LN, with 39% of the survey respondents indicating a preference for the primarily oral regimen, 15% for the
primarily IV regimen, and 46% for the mixed IV/oral regimen.
An additional focus of the third Delphi survey was the
assessment of the impact of implementing the CTPs developed by the CARRA SLE Disease Specific Committee at
pediatric rheumatology centers in North America. Estimates provided by the survey respondents suggest that
there are at least 300 patients with juvenile SLE with
proliferative juvenile LN receiving treatment at CARRA
sites who could be candidates for these CTPs over a 12month period.
DISCUSSION
Consensus has been achieved by the majority of pediatric
rheumatologists in North America for a limited set of treatment regimens for the induction therapy of newly diagnosed proliferative juvenile LN. These CTPs, which are
consistent with the best available scientific evidence, specify the use of either MMF or IV CYC in combination with
1 of 3 standard glucocorticoid regimens. The CTPs reflect
Induction Therapy for Proliferative LN in Juvenile SLE
381
Table 3. Renal response definitions and other outcomes to measure safety and effectiveness of the consensus treatment plans*
Outcome measures
Core renal parameters†
Renal response definitions†
Substantial response (complete remission)
Moderate response
Mild response
No response
Renal flare definitions†
Proteinuric/nephrotic renal flare
Nonproteinuric/nephritic renal flare
Other measures of safety, effectiveness, and
extrarenal SLE
Physician rating of disease activity†
Patient well-being†
Physician estimated adherence †
Disease activity†
Disease damage§
Safety†
Quality of life§
Kidney biopsy
Definition
Proteinuria (spot urine protein/creatinine ratio)
Renal function (creatinine clearance or serum creatinine)‡
Urine sediment (urine WBCs, RBCs, and casts)
Normalization of renal function, inactive urine sediment (⬍5 WBCs/hpf,
⬍5 RBCs/hpf, and no casts), plus spot protein/creatinine ratio ⬍0.2 or
age appropriate
At least 50% improvement in 2 core renal parameters (with maximum spot
protein/creatinine ratio ⱕ1.0) without clinically relevant worsening of
the remaining renal core parameter
30–50% improvement in 2 core renal parameters without clinically
relevant worsening of the remaining renal core parameter
Patient does not qualify for any improvement as above
A persistent increase in proteinuria to values ⬎0.5 after achieving
complete response, or a doubling of proteinuria with values ⬎1.0, after
achieving a partial response
Increase or recurrence of active urinary sediment (increased hematuria
with or without reappearance of cellular casts), with or without a
concomitant increase in proteinuria
Physician global assessment of disease activity as measured on a 10-cm
visual analog scale (0 ⫽ inactive, 10 ⫽ very active)
Parent/patient global assessment of well-being as measured on a 10-cm
visual analog scale (0 ⫽ very poor, 10 ⫽ very well)
10-cm visual analog scale of adherence (0 ⫽ nonadherent, 10 ⫽ complete
adherence)
Systemic Lupus Erythematosus Disease Activity Index (44)
Systemic Lupus International Collaborating Clinics/American College of
Rheumatology Damage Index (45)
Moderate or serious adverse events at grade ⱖ3 according to the National
Cancer Institute Common Terminology Criteria for Adverse Events
Pediatric Quality of Life Inventory Generic Core Scale 4.0 (38)
Results of initial and any subsequent renal biopsy pathology reports
* WBCs ⫽ white blood cells; RBCs ⫽ red blood cells; hpf ⫽ high-power field; SLE ⫽ systemic lupus erythematosus.
† Minimal frequency of assessment is at baseline, 1 month, 3 months, and 6 months post-initiation of therapy and at the time of clinical deterioration,
and change in immunosuppressive therapy unless otherwise indicated.
‡ Calculated by Schwartz formula.
§ Minimal frequency of assessment is at baseline and 6 months post-initiation of therapy.
common current treatment practices employed by the pediatric rheumatology community and provide agreement
regarding definitions of response to therapy, dosing of
medications, and patient monitoring.
The results of RCTs are often used as the foundation of
treatment standards in medicine in an effort to improve
disease prognosis. Unfortunately, as shown in our review
of the literature, there is limited high-quality evidence
from clinical trials to guide therapeutic decisions in juvenile LN because of challenges inherent to the design and
conduct of clinical trials for relatively rare and highly
complex pediatric diseases, like juvenile SLE. As an alternative approach, in an effort to improve the outcome of
juvenile LN, members of CARRA developed CTPs that
allow for the standardization of juvenile LN therapy. The
experience from other adult and pediatric diseases suggests that standardization of care using CTPs has the potential to improve disease outcomes (42– 44). This is because CTPs promote the provision of therapies using the
best available scientific knowledge, and allow for the conduct of comparative effectiveness analyses that can further
elucidate the most effective treatment approach.
It is important to emphasize that these CTPs are not
meant to serve as treatment guidelines since sufficient
evidence regarding the best treatment for juvenile LN is
not available. In contrast to treatment guidelines, these
CTPs do not address all treatment and management issues
for patients with juvenile LN. Further, these CTPs focus on
the treatment of prototypical patients with newly diagnosed proliferative juvenile LN and not those with longstanding proliferative juvenile LN. Therefore, these CTPs
do not address treatment strategies for patients with intractable extrarenal or multisystemic disease. Nevertheless, we believe that these CTPs are highly relevant because they are applicable to a large proportion of patients
with juvenile LN. These CTPs might also be used by other
providers, such as adult rheumatologists or pediatric
nephrologists, who care for patients with juvenile LN in
382
Mina et al
areas where there is limited access to pediatric rheumatology.
Although we are optimistic about the current applicability of these CTPs for the induction therapy of proliferative juvenile LN, we are cognizant that the formulation of
CTPs is a dynamic process. New drugs and biomarkers for
juvenile SLE are in development, and the CTPs will need
to be modified and updated to incorporate such new medical evidence. Additionally, there is interest in developing
consensus around the use of alternate-day steroid dosing
and the use of low-dose CYC regimens similar to those
tested in the Euro-Lupus Nephritis Trial for adults with LN
(13).
The development of CTPs for the induction therapy of
proliferative juvenile LN represents a major cornerstone
for the systematic evidence-based evaluation of current
treatment strategies of children with juvenile SLE. Once
widely utilized, these CTPs will allow for the accumulation of data that, when analyzed for comparative effectiveness, will have the potential to pave the way for the identification of therapies that have a high potential for
achieving remission of juvenile LN. Complete treatment of
these patients requires ongoing maintenance therapy following induction, and therefore the development of CTPs
addressing maintenance therapy of proliferative juvenile
LN is currently in process.
4.
5.
6.
7.
8.
9.
10.
11.
ACKNOWLEDGMENTS
The authors acknowledge Lena Das, Ofra Goldzweig, Michael Blakley, Amanda Brown, Ioannis Kalampokis, Arzu
Soybilgic, Geraldina Lionetti, Annette Lopez-Martinez,
Anjalii Patwardhan, Caitlin Sgarlat, Karen Peterson, Anna
Huttenlocher, and Jenny Palter.
12.
AUTHOR CONTRIBUTIONS
14.
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved the final version to be published. Dr. von Scheven had full
access to all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data analysis.
Study conception and design. Von Scheven, Wallace, Brunner.
Acquisition of data. Mina, von Scheven, Ardoin, Eberhard, Punaro, Ilowite, Hsu, Klein-Gitelman, Moorthy, Muscal, Radhakrishna,
Wagner-Weiner, Adams, Blier, Buckley, Chalom, Chédeville,
Eichenfield, Fish, Henrickson, Hersh, Hollister, Jones, Jung, Levy,
Lopez-Benitez, McCurdy, Miettunen, Quintero-Del Rio, Rothman,
Rullo, Ruth, Schanberg, Silverman, Singer, Soep, Syed, Vogler,
Yalcindag Yildirim-Toruner, Wallace, Brunner.
Analysis and interpretation of data. Von Scheven, Ardoin, Eberhard, Punaro, Klein-Gitelman, Muscal, Wallace, Brunner.
REFERENCES
1. Hochberg MC, for the Diagnostic and Therapeutic Criteria
Committee of the American College of Rheumatology. Updating the American College of Rheumatology revised criteria for
the classification of systemic lupus erythematosus [letter].
Arthritis Rheum 1997;40:1725.
2. Mina R, Brunner HI. Pediatric lupus: are there differences in
presentation, genetics, response to therapy, and damage accrual compared with adult lupus? Rheum Dis Clin North Am
2010;36:53– 80, vii–viii.
3. Marks SD, Sebire NJ, Pilkington C, Tullus K. Clinicopatholog-
13.
15.
16.
17.
18.
19.
20.
21.
ical correlations of paediatric lupus nephritis. Pediatr Nephrol 2007;22:77– 83.
Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE,
Appel GB, et al. The classification of glomerulonephritis in
systemic lupus erythematosus revisited. J Am Soc Nephrol
2004;15:241–50.
Gruppo Italiano per lo Studio della Nefrite Lupica (GISNEL).
Lupus nephritis: prognostic factors and probability of maintaining life-supporting renal function 10 years after the diagnosis. Am J Kidney Dis 1992;19:473–9.
Lee BS, Cho HY, Kim EJ, Kang HG, Ha IS, Cheong HI, et al.
Clinical outcomes of childhood lupus nephritis: a single center’s experience. Pediatr Nephrol 2007;22:222–31.
Moroni G, Quaglini S, Gallelli B, Banfi G, Messa P, Ponticelli
C. The long-term outcome of 93 patients with proliferative
lupus nephritis. Nephrol Dial Transplant 2007;22:2531–9.
Hiramatsu N, Kuroiwa T, Ikeuchi H, Maeshima A, Kaneko Y,
Hiromura K, et al. Revised classification of lupus nephritis is
valuable in predicting renal outcome with an indication of the
proportion of glomeruli affected by chronic lesions. Rheumatology (Oxford) 2008;47:702–7.
Nezhad ST, Sepaskhah R. Correlation of clinical and pathological findings in patients with lupus nephritis: a five-year
experience in Iran. Saudi J Kidney Dis Transpl 2008;19:32–
40.
Tanaka H, Tsugawa K, Oki E, Suzuki K, Ito E. Mizoribine
intermittent pulse protocol for induction therapy for systemic
lupus erythematosus in children: an open-label pilot study
with five newly diagnosed patients. Clin Rheumatol 2008;27:
85–9.
Grootscholten C, Ligtenberg G, Hagen EC, van den Wall Bake
AW, de Glas-Vos JW, Bijl M, et al. Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus
nephritis: a randomized controlled trial. Kidney Int 2006;70:
732– 42.
Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill
JT, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005;353:2219 –28.
Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, Garrido E, Danieli MG, et al. Immunosuppressive therapy in
lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002;46:2121–31.
Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D,
Jayne D, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc
Nephrol 2009;20:1103–12.
Esquenazi A, Novak I, Sheean G, Singer BJ, Ward AB. International consensus statement for the use of botulinum toxin
treatment in adults and children with neurological
impairments: introduction. Eur J Neurol 2010;17 Suppl 2:1– 8.
Buie T, Campbell DB, Fuchs GJ III, Furuta GT, Levy J, Vandewater J, et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus
report. Pediatrics 2010;125 Suppl 1:S1–18.
Delbecq AL, Van de Ven AH, Gustafson DH. Group techniques for program planning: a guide to nominal group and
Delphi processes. Glenview (IL): Scott, Foresman; 1975.
Brunner HI, Mina R, Pilkington C, Beresford MW, Reiff A,
Levy DM, et al. Preliminary criteria for global flares in childhood-onset systemic lupus erythematosus. Arthritis Care Res
(Hoboken) 2011;63:1213–23.
Lovell DJ, Passo MH, Beukelman T, Bowyer SL, Gottlieb BS,
Henrickson M, et al. Measuring process of arthritis care: a
proposed set of quality measures for the process of care in
juvenile idiopathic arthritis. Arthritis Care Res (Hoboken)
2011;63:10 – 6.
Wallace CA, Ruperto N, Giannini E. Preliminary criteria for
clinical remission for select categories of juvenile idiopathic
arthritis. J Rheumatol 2004;31:2290 – 4.
Gourley MF, Austin HA III, Scott D, Yarboro CH, Vaughan
EM, Muir J, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus
Induction Therapy for Proliferative LN in Juvenile SLE
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
nephritis: a randomized, controlled trial. Ann Intern Med
1996;125:549 –57.
Renal Disease Subcommittee of the American College of
Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Response Criteria. The American College of Rheumatology response criteria for proliferative and membranous
renal disease in systemic lupus erythematosus clinical trials.
Arthritis Rheum 2006;54:421–32.
Gordon C, Jayne D, Pusey C, Adu D, Amoura Z, Aringer M, et
al. European consensus statement on the terminology used in
the management of lupus glomerulonephritis. Lupus 2009;18:
257– 63.
Vu TV, Escalante A. A comparison of the quality of life of
patients with systemic lupus erythematosus with and without
endstage renal disease. J Rheumatol 1999;26:2595– 601.
Walsh M, Jayne D, Moist L, Tonelli M, Pannu N, Manns B.
Practice pattern variation in oral glucocorticoid therapy after
the induction of response in proliferative lupus nephritis.
Lupus 2010;19:628 –33.
Guiducci C, Gong M, Xu Z, Gill M, Chaussabel D, Meeker T,
et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 2010;465:937– 41.
Barron KS, Person DA, Brewer EJ Jr, Beale MG, Robson AM.
Pulse methylprednisolone therapy in diffuse proliferative lupus nephritis. J Pediatr 1982;101:137– 41.
Ad Hoc Working Group on Steroid-Sparing Criteria in Lupus.
Criteria for steroid-sparing ability of interventions in systemic
lupus erythematosus: report of a consensus meeting. Arthritis
Rheum 2004;50:3427–31.
Hagelberg S, Lee Y, Bargman J, Mah G, Schneider R, Laskin C,
et al. Longterm followup of childhood lupus nephritis.
J Rheumatol 2002;29:2635– 42.
Lau KK, Ault BH, Jones DP, Butani L. Induction therapy for
pediatric focal proliferative lupus nephritis: cyclophosphamide versus mycophenolate mofetil. J Pediatr Health Care
2008;22:282– 8.
Chiu SJ, Ou LS, Tsai TL, Hung IJ, Huang JL. Sequential evaluation of clinical and laboratory changes amongst children
suffering from lupus nephritis during intermittent intravenous cyclophosphamide therapy. Clin Rheumatol 2006;25:
515–9.
Manger K, Wildt L, Kalden JR, Manger B. Prevention of gonadal toxicity and preservation of gonadal function and fertility in young women with systemic lupus erythematosus
treated by cyclophosphamide: the PREGO-Study. Autoimmun Rev 2006;5:269 –72.
Gupta D, Zachariah A, Roppelt H, Patel AM, Gruber BL.
Prophylactic antibiotic usage for Pneumocystis jirovecii
pneumonia in patients with systemic lupus erythematosus on
383
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
cyclophosphamide: a survey of US rheumatologists and the
review of literature. J Clin Rheumatol 2008;14:267–72.
Buratti S, Szer IS, Spencer CH, Bartosh S, Reiff A. Mycophenolate mofetil treatment of severe renal disease in pediatric
onset systemic lupus erythematosus. J Rheumatol 2001;28:
2103– 8.
Kazyra I, Pilkington C, Marks SD, Tullus K. Mycophenolate
mofetil treatment in children and adolescents with lupus.
Arch Dis Child 2010;95:1059 – 61.
Sagcal-Gironella AC, Fukuda T, Wiers K, Cox S, Nelson S,
Dina B, et al. Pharmacokinetics and pharmacodynamics of
mycophenolic acid and their relation to response to therapy
of childhood-onset systemic lupus erythematosus. Semin Arthritis Rheum 2011;40:307–13.
Filler G, Hansen M, LeBlanc C, Lepage N, Franke D, Mai I, et
al. Pharmacokinetics of mycophenolate mofetil for autoimmune disease in children. Pediatr Nephrol 2003;18:445–9.
Askenazi D, Myones B, Kamdar A, Warren R, Perez M, De
Guzman M, et al. Outcomes of children with proliferative
lupus nephritis: the role of protocol renal biopsy. Pediatr
Nephrol 2007;22:981– 6.
Brunner HI, Silverman ED, To T, Bombardier C, Feldman BM.
Risk factors for damage in childhood-onset systemic lupus
erythematosus: cumulative disease activity and medication
use predict disease damage. Arthritis Rheum 2002;46:436 –
44.
Varni JW, Seid M, Rode CA. The PedsQL: measurement
model for the pediatric quality of life inventory. Med Care
1999;37:126 –39.
Brunner HI, Higgins GC, Wiers K, Lapidus SK, Olson JC, Onel
K, et al. Health-related quality of life and its relationship to
patient disease course in childhood-onset systemic lupus erythematosus. J Rheumatol 2009;36:1536 – 45.
Poe SS, Nolan MT, Dang D, Schauble J, Oechsle DG, Kress L,
et al. Ensuring safety of patients receiving sedation for
procedures: evaluation of clinical practice guidelines. Jt
Comm J Qual Improv 2001;27:28 – 41.
David BA, Rodriguez A, Marks SW. Risk reduction and systematic error management: standardization of the pediatric
chemotherapy process. In: Henriksen K, Battles JB, Keyes MA,
Grady ML, editors. Advances in patient safety: new directions
and alternative approaches (vol. 2: culture and redesign).
Rockville (MD): Agency for Healthcare Research and Quality;
2008.
Little RR, Rohlfing CL, Wiedmeyer HM, Myers GL, Sacks DB,
Goldstein DE. The national glycohemoglobin standardization
program: a five-year progress report. Clin Chem 2001;47:
1985–92.