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Arthritis Care Res (Hoboken). Author manuscript; available in PMC Mar 1, 2013.
Published in final edited form as:
PMCID: PMC3457803
NIHMSID: NIHMS343327
CONSENSUS TREATMENT PLANS FOR INDUCTION THERAPY OF NEWLY-DIAGNOSED PROLIFERATIVE LUPUS NEPHRITIS IN JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS
Rina Mina, MD, MSc,1* Emily von Scheven, MD, MAS,2* Stacy P. Ardoin, MD, MSc,3 B. Anne Eberhard, MBBS, MSc, FRACP, FRCP(C),4 Marilynn Punaro, MD,5 Norman Ilowite, MD,6 Joyce Hsu, MD,7 Marisa Klein-Gitelman, MD, MPH,8 L. Nandini Moorthy, MD, MS,9 Eyal Muscal, MD, MS,10 Suhas M. Radhakrishna, MD,11 Linda Wagner-Weiner, MD,12 Matthew Adams, MD,13 Peter Blier, MD, PhD,14 Lenore Buckley, MD, MPH,15 Elizabeth Chalom, MD,16 Gaëlle Chédeville, MD,17 Andrew Eichenfield, MD,18 Natalya Fish, MD,19 Michael Henrickson, MD, MPH,1 Aimee O. Hersh, MD, MS,20 Roger Hollister, MD,21 Olcay Jones, MD,22 Lawrence Jung, MD, PhD,23 Deborah Levy, MD, MS,24 Jorge Lopez-Benitez, MD,25 Deborah McCurdy, MD,26 Paivi M. Miettunen, MD,27 Ana I. Quintero-Del Rio, MD, MPH,28 Deborah Rothman, MD,29 Ornella Rullo, MD,26 Natasha Ruth, MD, MS,30 Laura E. Schanberg, MD,31 Earl Silverman, MD,24 Nora G. Singer, MD,32 Jennifer Soep, MD,21 Reema Syed MBBS, MD,33 Larry B. Vogler, MD,34 Ali Yalcindag, MD,35 Cagri Yildirim-Toruner, MD,18 Carol A. Wallace, MD,36 and Hermine I. Brunner, MD, MSc1, on behalf of the CARRA SLE Subcommittee
1Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
2Division of Pediatric Rheumatology, University of California at San Francisco, San Francisco, CA
3Division of Pediatric Rheumatology, Nationwide Children’s Hospital and The Ohio State University, Columbus, OH
4Division of Pediatric Rheumatology, Steven and Alexandra Cohen Children's Medical Center of New York, New York, NY
5Division of Pediatric Rheumatology, Texas Scottish Rite Hospital, Dallas, TX
6Division of Pediatric Rheumatology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY
7Division of Pediatric Rheumatology, Lucile Packard Children’s Hospital at Stanford, Palo Alto, CA
8Division of Pediatric Rheumatology, Children's Memorial Hospital, Chicago, IL
9Department of Pediatrics, University of Medicine and Dentistry of NJ-Robert Wood Johnson Medical School, New Brunswick, NJ
10Texas Children’s Hospital Pediatric Rheumatology Center, Baylor College of Medicine, Houston, TX
11Division of Pediatric Rheumatology, Children's Hospital Los Angeles, Los Angeles, CA
12Division of Pediatric Rheumatology, University of Chicago Comer Children's Hospital, Chicago, IL
13Division of Rheumatology, Children's Hospital of Michigan, Detroit, MI
14Division of Rheumatology, Baystate Children's Hospital, Springfield, MA
15Division of Rheumatology, Allergy and Immunology, VCU School of Medicine, Richmond, VA
16Department of Pediatrics, St. Barnabas Medical Center Livingston, NJ
17Division of Rheumatology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada
18Division of Pediatric Rheumatology, Morgan Stanley Children's Hospital of New York-Presbyterian Columbia University Medical Center, New York, NY
19Division of Pediatric Rheumatology Penn State Hershey Children's Hospital, Hershey, PA
20Division of Allergy, Immunology and Rheumatology, University of Utah, Salt Lake City, UT
21Division of Allergy, Immunology and Rheumatology, Children’s Hospital Colorado, Aurora, CO
22Rheumatology and Clinical Immunology Services, Walter Reed Army Medical Center, Washington, DC
23Division of Pediatric Rheumatology, Children's National Medical Center, Washington, DC
24Division of Rheumatology. Hospital for Sick Children, Toronto, ON
25Department of Pediatric Rheumatology, Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts
26Division of Pediatric Rheumatology, Mattel Children's Hospital UCLA, Los Angeles, CA
27Division of Rheumatology, University of Calgary, Calgary, Canada
28Department of Pediatrics, Universidad Central del Caribe, Bayamón, Puerto Rico
29Division of Pediatrics and Rheumatology, Shriners Hospital for Children, Springfield, MA
30Division of Pediatric Rheumatology, Medical University of South Carolina, Charleston, SC
31Division of Pediatric Rheumatology, Duke University Medical Center, Durham, NC
32Division of Rheumatology, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH
33Division of Rheumatology, St. Louis University, St. Louis, MO
34Division of Pediatric Rheumatology and Immunology, Emory-Children’s Center, Atlanta, GA
35Division of Pediatric Rheumatology, Hasbro Children's Hospital Providence, RI
36Division of Rheumatology, Seattle Children’s Hospital, University of Washington, Seattle, WA
Contact Information: Emily von Scheven, MD, MAS, Professor of Clinical Pediatrics, Pediatric Rheumatology, University of California, San Francisco, Box 0107, 505 Parnassus Avenue, Room M-679, San Francisco, CA 94143, Phone: 415-502-6627, Fax: 415-502-7540, Evonsche/at/peds.ucsf.edu
*contributed equally
Objective
To formulate consensus treatment plans (CTPs) for induction therapy of newly-diagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (jSLE).
Methods
A structured consensus formation process was employed by the members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) after considering the existing medical evidence and current treatment approaches.
Results
After an initial Delphi survey (response rate 70%), a 2-day consensus conference, and two follow-up Delphi surveys (response rates 63–79%), consensus was achieved for a limited set of CTPs addressing the induction therapy of proliferative LN. These CTPs were developed for prototypic 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 doses for six months. Additionally, the CTPs describe three 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 jSLE 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 jSLE.
Key Terms: children, SLE, lupus nephritis, induction therapy, consensus
Despite advances in the understanding of the disease and research in therapeutic targets, children and adolescents with systemic lupus erythematosus (jSLE) continue 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 treatments1, 2. This is particularly true for lupus nephritis which affects up to 80% of children with jSLE. Failure to achieve and maintain remission of jSLE-associated lupus nephritis (jLN) reduces the overall 10-year survival by an estimated 15%3.
To determine the severity of jLN, a kidney biopsy is required, and the histological findings are graded using the International Society of Nephrology/Renal Pathology Society (ISN/RPS) Classification 4. The pathologic changes present on kidney biopsy help guide treatment decisions and may be predictive of long-term kidney survival. Besides the presence of proliferative jLN, defined as histological findings compatible with ISN/RPS Class 3 or 4, continuously active non-remitting jLN and flares of jLN are risk factors for the development of chronic kidney disease and poor jSLE outcomes 59.
The treatment of proliferative jLN is commonly divided into two distinct phases. The initial phase, induction therapy, is composed of intense immunosuppression aimed at achieving remission of jLN 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 jLN, while attempting to minimize side effects associated with immunosuppressive therapy.
Head-to-head comparisons of treatments for proliferative jLN in sufficiently large trials are lacking10. Hence, no drug to date has received Food and Drug Administration (FDA) approval for the treatment of jLN. Instead, the treatment of children with jLN 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), mycophenolate mofetil (MMF), and azathioprine for proliferative LN in adults with SLE, the optimal dosing, efficacy and safety of these immunosuppressive agents when used in children and adolescents with jLN remain to be determined11,1214.
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 jSLE are generally led by pediatric rheumatologists, and the vast 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 is part of a larger CARRA initiative aimed at the development of CTPs for various pediatric rheumatic diseases. With respect to jSLE, there was close to unanimous support among CARRA members to develop CTPs for proliferative jLN. Thus, the objectives of this project are: (1) to obtain insight into and describe the current treatment practices for jLN among pediatric rheumatologists in North America, and (2) to develop CTPs for induction therapy of proliferative jLN that are consistent with both current practice and the best available evidence in the literature.
Fundamental to the project was an in-depth review of the medical literature addressing the current scientific evidence for the treatment of jLN (Appendix A and B). The literature search included studies of adults with SLE because of the limited published data specifically addressing treatment of jLN. Levels of evidence were assigned based on Oxford Centre for Evidence-based Medicine (www.cebm.net) and were as follows: “A” [supported by randomized clinical trials (RCT)], “B” [supported by non-randomized controlled studies or extrapolations from RCT], “C” [supported by uncontrolled studies, extrapolations from nonrandomized controlled studies, or marked extrapolations from RCT(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 jLN (Figure 1)17. The group has experience in using these techniques when developing outcome measures of several pediatric rheumatologic diseases 1820. The level of consensus for the Delphi surveys and the consensus conference was set at 80%.
Figure 1
Figure 1
The development of the Consensus Treatment Plans for proliferative lupus nephritis (jLN) in juvenile SLE based on consensus-formation techniques
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 jLN. We used a clinical case of a prototypic patient with proliferative jLN to guide survey responses (Appendix C).
Phase II - Consensus Conference
The second phase of the project consisted of a formal face-to-face consensus meeting held over 2 days in April, 2010. The goal of the consensus conference was to develop a limited set of CTPs for induction therapy of proliferative jLN that were consistent with current practice and informed by the best available evidence (see Phase I). Participants included 32 voting members of the CARRA SLE Disease Specific Committee who are pediatric rheumatologists with substantial experience in the assessment and treatment of jSLE. Twelve trainees supported the consensus meeting activities but 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)1820. Conference participants were assigned to one of five subgroups which were led by moderators trained in nominal group technique (HBr, EvS, LP, SA, and AE). Table 1 presents 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).
Figure 2
Figure 2
Modified nominal group process used to achieve consensus
Table 1
Table 1
Questions considered in the consensus conference to establish Consensus Treatment Plans for induction therapy in newly diagnosed proliferative lupus nephritis in juvenile systemic lupus Erythematosus (jSLE)
Phase III – Finalization of the CTPs for Induction Therapy of proliferative jLN
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.
Phase I: Assessment of current treatment practices for proliferative jLN
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 jLN, followed by MMF (12/71=17%). Rituximab and azathioprine were rarely prescribed for induction therapy of jLN (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 jLN therapy (69/70=99%).
The majority of providers (62/71=87%) prescribed IV CYC in accordance with the National Institutes of Health (NIH) protocol (level C) 21. The choice of the immunosuppressive medication was influenced by co-existent morbidities, especially lupus cerebritis (55/68=81%), and the perceived risk of non-adherence 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 (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 (EULAR) (level D)22, 23.
Phase II: Consensus Conference
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 (Figure 3). This will result in six potential treatment approaches.
Table 2
Table 2
Patient characteristics for application of Consensus Treatment Plans
Figure 3
Figure 3
Consensus Treatment Plans for proliferative jLN
Glucocorticoids
The dosing of the glucocorticoids reflected physician experience and was informed by regimens used in previous studies of jLN (level D)24, 25. Recent evidence suggests that high-dose intravenous methylprednisolone pulses but not oral glucocorticoids, have the potential to eliminate the interferon alpha gene expression signature in jSLE by reducing the number of plasmacytoid dendritic cells26. Therefore, all three glucocorticoid regimens allowed for the use of up to three high dose methylprednisolone pulses (30 mg/kg/dose up to 1,000 mg/dose) at the time of induction therapy initiation (level C)27. Despite dramatic variability of glucocorticoid prescribing practices, we achieved consensus to treat jLN with one of three glucocorticoid regimens (primarily oral, primarily IV, and mixed oral and IV). The common goal for these three glucocorticoid regimens is to achieve a daily dose of oral glucocorticoids between 10 and 20 mg upon completion of the induction therapy after 24 weeks (or 6 months) (level D)28.
Cyclophosphamide
Consensus was reached to administer a total of six monthly IV CYC doses. 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 dose of 1,500 mg (level C) 21, 29, 30. The group recommends adjusting the CYC dose for renal insufficiency and for a low WBC nadir which is anticipated 7–10 days after the infusion of CYC (level C)21.
Extensive discussion during the Consensus Conference focused upon concomitant therapies to address and avoid CYC side effects, including the use of 2-mercaptoethane sulfonate sodium (MESNA®) for the prevention of hemorrhagic cystitis (level C)31, anti-emetics 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 dosed at 600 mg/m2/dose twice daily with a maximum dose of 1,500 mg taken two 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 four weeks of starting therapy, thereby allowing for dose titration according to side effects and tolerability (level C)12, 34, 35.
Mycophenolate sodium (MPA; Myfortic®) may be used as an alternative to MMF for the treatment of jLN with a target dose of 400 mg/m2/dose twice daily and maximum dose of 1,080 mg twice daily. Monitoring of complete blood count, liver function tests, and serum creatinine every two weeks during the first month after the initiation of MMF/MPA followed by monthly testing during the induction therapy for jLN was 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 increased more than 30% above baseline or for leukopenia of < 1.3 ×109/L (level C)12. Re-challenge, dose adjustments, and interruption of MMF/MPA intake for suspected drug toxicity was 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 jLN as adapted from adult LN22, 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.
Table 3
Table 3
Renal response definitions and other outcomes to measure safety and effectiveness of the Consensus Treatment Plans
Recommendations were made (based on consensus) to also monitor extra-renal 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 Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (level D)39. For patient reported outcome measure, the Pediatric Quality of Life Inventory Generic Core Scale version 4.040 will be completed by patients at least every 6 months (level C)41.
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) 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 shortly after the Consensus Conference to address unresolved issues related to steroid dosing, measurement of HRQOL, and assessment of adherence (response rate: 79%).
Phase III: Assessment of the feasibility & 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 USA 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 jLN that had been developed by the Disease Specific SLE Subcommittee.
Approximately 90% of the respondents stated that they would prescribe CYC (rather than MMF) as per the CTPs to their patients with proliferative jLN. There was also consensus that they would utilize one of the three glucocorticoid regimens when treating patients with proliferative jLN, with 39% of the survey respondents indicating a preference for the primarily oral regimen, 15% for primarily IV, 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 jSLE patients with proliferative jLN receiving treatment at CARRA sites who could be candidates for these CTPs over a 12 month period.
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 jLN. These CTPs, which are consistent with the best available scientific evidence, specify the use of either MMF or IV CYC in combination with one of three standard glucocorticoid regimens. The CTPs reflect 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 randomized clinical trials 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 literature, there is limited high-quality evidence from clinical trials to guide therapeutic decisions in jLN because of challenges inherent to the design and conduct of clinical trials for relatively rare and highly complex pediatric diseases, like jSLE. As an alternative approach, in an effort to improve the outcome of jLN, members of CARRA developed CTPs which allow for the standardization of jLN therapy. The experience from other adult and pediatric diseases suggests that standardization of care using CTPs has the potential to improve disease outcomes4244. 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 as sufficient evidence regarding the best treatment for jLN is not available. In contrast to treatment guidelines, these CTPs do not address all treatment and management issues for patients with jLN. Further, these CTPs focus on the treatment of prototypic patients with newly diagnosed proliferative jLN and not those with long-standing proliferative jLN. Thus, these CTPs do not address treatment strategies for patients with intractable extra-renal or multi-systemic disease. Nevertheless, we believe that these CTPs are highly relevant as they are applicable to a large proportion of patients with jLN. These CTPs might also be used by other providers, such as adult rheumatologists or pediatric nephrologists, who care for patients with jLN in 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 jLN, we are cognizant that the formulation of CTPs is a dynamic process. New drugs and biomarkers for jSLE 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 Trial for adults with LN13.
The development of CTPs for the induction therapy of proliferative jLN represents a major cornerstone for the systematic evidence-based evaluation of current treatment strategies of children with jSLE. 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 jLN. Complete treatment of these patients requires ongoing maintenance therapy following induction, and thus the development of CTPs addressing maintenance therapy of proliferative jLN is currently in process.
Knowledge Gained – Innovation
  • Treatment approaches based on scientific evidence and clinical experience that are endorsed by the majority of pediatric rheumatology professionals in North America are presented.
  • Induction therapy of proliferative, newly diagnosed lupus nephritis in children includes glucocorticoids and either oral mycophenolic acid or intravenous cyclophosphamide for 6 months.
Supplementary Material
Supp App S1-S3
Acknowledgment
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.
Grant Support:
This work was completed with support from the National Institute of Arthritis and Musculoskeletal and Skin Disease at the National Institutes of Health (NIH (C1AR058605-01 and R13-AR053058-04), the Children’s Arthritis and Rheumatology Research Alliance (CARRA), the Arthritis Foundation, the Wasie Foundation, and the Friends of CARRA. Dr. Mina is supported by a NIAMS T32 training grant, Dr. Schanberg by NIAMS grants: NO1-AR-2-2265 and RC2-AR-058934, Dr. Levy by NIAMS K23AR053202 grant, and Dr. Brunner by NIAMS grants: 1U01AR059509, U01AR055054 and P60 AR47784.
Footnotes
There is no other existing or perceived conflict of interest of any of the authors.
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