Diana Milojevic

Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis.

There is wide variation in therapeutic approaches to systemic juvenile idiopathic arthritis (JIA) among North American rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available for treatment of systemic JIA can result in better health outcomes. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans and standardized assessment schedules for use in clinical practice to facilitate such studies.

Oligoarticular and polyarticular JIA: epidemiology and pathogenesis

Juvenile idiopathic arthritis (JIA) refers to a group of chronic childhood arthropathies of unknown etiology, currently classified into subtypes primarily on the basis of clinical features. Research has focused on the hypothesis that these subtypes arise through distinct etiologic pathways. In this Review, we discuss four subtypes of JIA: persistent oligoarticular, extended oligoarticular, rheumatoid-factor-positive polyarticular and rheumatoid-factor-negative polyarticular. These subtypes differ in prevalence between ethnic groups and are associated with different HLA alleles. Non-HLA genetic risk factors have also been identified, some of which reveal further molecular differences between these subtypes, while others suggest mechanistic overlap. Investigations of immunophenotypes also provide insights into subtype differences: adaptive immunity seems to have a prominent role in both polyarticular and oligoarticular JIA, and the more-limited arthritis observed in persistent oligoarticular JIA as compared with extended oligoarticular JIA may reflect more-potent immunoregulatory T-cell activity in the former. Tumor necrosis factor seems to be a key mediator of both polyarticular and oligoarticular JIA, especially in the extended oligoarticular subtype, although elevated levels of other cytokines are also observed. Limited data on monocytes, dendritic cells, B cells, natural killer T cells and neutrophils suggest that the contributions of these cells differ across subtypes of JIA. Within each subtype, however, common pathways seem to drive joint damage.

Randomized, Double-Blind, Placebo-Controlled Trial of the Efficacy and Safety of Rilonacept in the Treatment of Systemic Juvenile Idiopathic Arthritis

To assess the efficacy and safety of rilonacept, an interleukin‐1 inhibitor, in a randomized, double‐blind, placebo‐controlled trial.

The challenges of transferring chronic illness patients to adult care: reflections from pediatric and adult rheumatology at a US academic center

BackgroundLittle is known about the transfer of care process from pediatric to adult rheumatology for patients with chronic rheumatic disease. The purpose of this study is to examine changes in disease status, treatment and health care utilization among adolescents transferring to adult care at the University of California San Francisco (UCSF).MethodsWe identified 31 eligible subjects who transferred from pediatric to adult rheumatology care at UCSF between 1995–2005. Subject demographics, disease characteristics, disease activity and health care utilization were compared between the year prior to and the year following transfer of care.ResultsThe mean age at the last pediatric rheumatology visit was 19.5 years (17.4–22.0). Subject diagnoses included systemic lupus erythematosus (52%), mixed connective tissue disease (16%), juvenile idiopathic arthritis (16%), antiphospholipid antibody syndrome (13%) and vasculitis (3%). Nearly 30% of subjects were hospitalized for disease treatment or management of flares in the year prior to transfer, and 58% had active disease at the time of transfer. In the post-transfer period, almost 30% of subjects had an increase in disease activity. One patient died in the post-transfer period. The median transfer time between the last pediatric and first adult rheumatology visit was 7.1 months (range 0.7–33.6 months). Missed appointments were common in the both the pre and post transfer period.ConclusionA significant percentage of patients who transfer from pediatric to adult rheumatology care at our center are likely to have active disease at the time of transfer, and disease flares are common during the transfer period. These findings highlight the importance of a seamless transfer of care between rheumatology providers.

Clinically Inactive Disease in a Cohort of Children with New-onset Polyarticular Juvenile Idiopathic Arthritis Treated with Early Aggressive Therapy: Time to Achievement, Total Duration, and Predictors

Objective. To determine the elapsed time while receiving aggressive therapy to the first observation of clinically inactive disease (CID), total duration of CID and potential predictors of this response in a cohort of children with recent onset of polyarticular juvenile idiopathic arthritis (poly-JIA). Methods. Eighty-five children were randomized blindly to methotrexate (MTX), etanercept, and rapidly tapered prednisolone (MEP) or MTX monotherapy and assessed for CID over 1 year of treatment. Patients who failed to achieve intermediary endpoints were switched to open-label MEP treatment. Results. Fifty-eight (68.2%) of the 85 patients achieved CID at 1 or more visits including 18 who received blinded MEP, 11 while receiving MTX monotherapy, and 29 while receiving open-label MEP. Patients starting on MEP achieved CID earlier and had more study days in CID compared to those starting MTX, but the differences were not significantly different. Patients given MEP (more aggressive therapy) earlier in the disease course were statistically more likely to have a higher proportion of followup visits in CID than those with longer disease course at baseline. Those who achieved American College of Rheumatology Pediatric 70 response at 4 months had a significantly greater proportion of followup visits in CID, compared to those who failed to achieve this improvement (p < 0.0001). Of the 32 patients who met criteria for CID and then lost CID status, only 3 fulfilled the definition of disease flare. Conclusion. Shorter disease duration prior to treatment, a robust response at 4 months, and more aggressive therapy result in a higher likelihood and longer duration of CID in patients with poly-JIA. The original trial from which data for this analysis were obtained is registered on www.clinicaltrials.gov NCT 00443430.

Urine Peptidomic and Targeted Plasma Protein Analyses in the Diagnosis and Monitoring of Systemic Juvenile Idiopathic Arthritis

PurposeSystemic juvenile idiopathic arthritis is a chronic pediatric disease. The initial clinical presentation can mimic other pediatric inflammatory conditions, which often leads to significant delays in diagnosis and appropriate therapy. SJIA biomarker development is an unmet diagnostic/prognostic need to prevent disease complications.Experimental DesignWe profiled the urine peptidome to analyze a set of 102 urine samples, from patients with SJIA, Kawasaki disease (KD), febrile illnesses (FI), and healthy controls. A set of 91 plasma samples, from SJIA flare and quiescent patients, were profiled using a customized antibody array against 43 proteins known to be involved in inflammatory and protein catabolic processes.ResultsWe identified a 17-urine-peptide biomarker panel that could effectively discriminate SJIA patients at active, quiescent, and remission disease states, and patients with active SJIA from confounding conditions including KD and FI. Targeted sequencing of these peptides revealed that they fall into several tight clusters from seven different proteins, suggesting disease-specific proteolytic activities. The antibody array plasma profiling identified an SJIA plasma flare signature consisting of tissue inhibitor of metalloproteinase-1 (TIMP1), interleukin (IL)-18, regulated upon activation, normal T cell expressed and secreted (RANTES), P-Selectin, MMP9, and L-Selectin.Conclusions and Clinical RelevanceThe urine peptidomic and plasma protein analyses have the potential to improve SJIA care and suggest that SJIA urine peptide biomarkers may be an outcome of inflammation-driven effects on catabolic pathways operating at multiple sites.

Plasma profiles in active systemic juvenile idiopathic arthritis: Biomarkers and biological implications.

Systemic juvenile idiopathic arthritis (SJIA) is a chronic arthritis of children characterized by a combination of arthritis and systemic inflammation. There is usually non‐specific laboratory evidence of inflammation at diagnosis but no diagnostic test. Normalized volumes from 89/889 2‐D protein spots representing 26 proteins revealed a plasma pattern that distinguishes SJIA flare from quiescence. Highly discriminating spots derived from 15 proteins constitute a robust SJIA flare signature and show specificity for SJIA flare in comparison to active polyarticular juvenile idiopathic arthritis or acute febrile illness. We used 7 available ELISA assays, including one to the complex of S100A8/S100A9, to measure levels of 8 of the15 proteins. Validating our DIGE results, this ELISA panel correctly classified independent SJIA flare samples, and distinguished them from acute febrile illness. Notably, data using the panel suggest its ability to improve on erythrocyte sedimentation rate or C‐reactive protein or S100A8/S100A9, either alone or in combination in SJIA F/Q discriminations. Our results also support the panels potential clinical utility as a predictor of incipient flare (within 9 wk) in SJIA subjects with clinically inactive disease. Pathway analyses of the 15 proteins in the SJIA flare versus quiescence signature corroborate growing evidence for a key role for IL‐1 at disease flare.

Extension study of participants from the trial of early aggressive therapy in juvenile idiopathic arthritis

Objective. To follow children with juvenile idiopathic arthritis (JIA) who had completed at least 6 months of the TRial of Early Aggressive Therapy (TREAT) clinical study for an additional 2 years, describing safety of early aggressive treatment, disease activity, function, and duration of clinical inactive disease (CID) during followup. Methods. Children were treated as per provider’s discretion. Physician, patient/parent, and laboratory measures of disease status as well as safety information were collected at clinic visits every 3 months for up to 2 years. Results. Forty-eight children were followed for a mean of 28 months (range 12–42) beyond the end of the TREAT study. Half of patients were in CID for > 50% of their followup time. Overall, 88% of patients achieved CID at > 1 study visit and 54% achieved clinical remission while taking medication. Six patients were in CID for the duration of the study, and, of those, 2 achieved a full year of clinical remission while not taking medication. Active disease was mild: mean physician’s global assessment 2.4, active joint count 3.5, parent global evaluation 2.4, Childhood Health Assessment Questionnaire 0.32, erythrocyte sedimentation rate 19 mm/h, and morning stiffness 23 min. There were no serious adverse events or adverse events reported at grade 3 or higher of Common Terminology Criteria for Adverse Events. Conclusion. Early aggressive therapy in this cohort of patients with polyarticular JIA who had high initial disease activity was associated with prolonged periods of CID in the majority of patients during followup. Those not in CID had low levels of disease activity.

Algorithm development for corticosteroid management in systemic juvenile idiopathic arthritis trial using consensus methodology

BackgroundThe management of background corticosteroid therapy in rheumatology clinical trials poses a major challenge. We describe the consensus methodology used to design an algorithm to standardize changes in corticosteroid dosing during the Randomized Placebo Phase Study of Rilonacept in Systemic Juvenile Idiopathic Arthritis Trial (RAPPORT).MethodsThe 20 RAPPORT site principal investigators (PIs) and 4 topic specialists constituted an expert panel that participated in the consensus process. The panel used a modified Delphi Method consisting of an on-line questionnaire, followed by a one day face-to-face consensus conference. Consensus was defined as ≥ 75% agreement. For items deemed essential but when consensus on critical values was not achieved, simple majority vote drove the final decision.ResultsThe panel identified criteria for initiating or increasing corticosteroids. These included the presence or development of anemia, myocarditis, pericarditis, pleuritis, peritonitis, and either complete or incomplete macrophage activation syndrome (MAS). The panel also identified criteria for tapering corticosteroids which included absence of fever for ≥ 3 days in the previous week, absence of poor physical functioning, and seven laboratory criteria. A tapering schedule was also defined.ConclusionThe expert panel established consensus regarding corticosteroid management and an algorithm for steroid dosing that was well accepted and used by RAPPORT investigators. Developed specifically for the RAPPORT trial, further study of the algorithm is needed before recommendation for more general clinical use.

Regulatory T cells and their role in rheumatic diseases: a potential target for novel therapeutic development

Regulatory T cells have an important role in limiting immune reactions and are essential regulators of self-tolerance. Among them, CD4+CD25high regulatory T cells are the best-described subset. In this article, we summarize current knowledge on the phenotype, function, and development of CD4+CD25high regulatory T cells. We also review the literature on the role of these T cells in rheumatic diseases and discuss the potential for their use in immunotherapy.