Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA.
We randomly assigned 112 ...children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension.
At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology ACR core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 85% vs. 9 of 37 24%, P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range.
Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).
Objective
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.
Methods
Case‐based surveys were administered to CARRA members to identify prevailing treatments for new‐onset systemic JIA. A 2‐day consensus conference in April 2010 employed modified nominal group technique to formulate preliminary treatment plans and determine important data elements for collection. Followup surveys were employed to refine the plans and assess clinical acceptability.
Results
The initial case‐based survey identified significant variability among current treatment approaches for new‐onset systemic JIA, underscoring the utility of standardized plans to evaluate comparative effectiveness. We developed 4 consensus treatment plans for the first 9 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The 4 treatment regimens included glucocorticoids only, or therapy with methotrexate, anakinra, or tocilizumab, with or without glucocorticoids. This approach was approved by >78% of the CARRA membership.
Conclusion
Four standardized treatment plans were developed for new‐onset systemic JIA. Coupled with data collection at defined intervals, use of these treatment plans will create the opportunity to evaluate comparative effectiveness in an observational setting to optimize initial management of systemic JIA.
Objective
To investigate the impact of tocilizumab treatment on growth and growth‐related laboratory parameters in patients with systemic juvenile idiopathic arthritis (JIA) enrolled in a phase III ...clinical trial.
Methods
Patients with systemic JIA ages 2–17 years (n = 112) received tocilizumab in a 12‐week, randomized, placebo‐controlled period and a long‐term open‐label extension. Height velocity and standard deviation (SD) score; levels of insulin‐like growth factor 1 (IGF‐1), osteocalcin (OC), and C‐telopeptide of type I collagen (CTX‐I); and Juvenile Arthritis Disease Activity Score in 71 joints (JADAS‐71) were measured in a post hoc analysis of 83 patients who never received growth hormone and did not reach Tanner stage 5 by the end of the first year of treatment.
Results
Patients had stunted growth at baseline (mean height SD score −2.2). During tocilizumab treatment, males (73%) and females (83%) experienced above‐normal mean height velocities of 6.6 cm/year (P < 0.0001 versus World Health Organization norms). Mean height SD score increases during year 1 (0.29) and year 2 (0.31) were significant (both P < 0.0001). The mean SD score for IGF‐1 levels increased significantly (−0.2 for year 1 and −0.1 for year 2 versus −1.0 at baseline; both P < 0.0001). Mean OC and CTX‐I levels (both P < 0.0001) and the OC:CTX‐I ratio (P = 0.014) significantly increased from baseline to year 2. In multiple regression analysis, first‐year height velocity had a significant inverse relationship to JADAS‐71 at year 1, age, mean glucocorticoid dosage during the year, and height SD score at baseline.
Conclusion
Our findings indicate that during treatment with tocilizumab, patients with systemic JIA experience significant catch‐up growth, normalization of IGF‐1 levels, and bone balance improvement favoring bone formation.
Systemic onset juvenile rheumatoid arthritis (JRA) accounts for 10-15% of all JRA. Macrophage activation syndrome (MAS), which can also be considered as secondary hemophagocytic lymphohistiocytosis, ...is a potentially life-threatening complication of systemic onset JRA. We describe a child with systemic onset JRA who developed MAS after initiation of etanercept therapy.
Specialized research networks are essential to achieve drug approvals for rare pediatric diseases. Such networks help realize the potential of global legislation enacted upon the recognition that ...most children are treated with drugs whose most beneficial dose and regimen have not been established in pediatric patients. The Pediatric Rheumatology Collaborative Study Group (PRCSG) is a North American clinical trials network that is specialized in the performance of clinical trials of new therapies for pediatric populations with rheumatic diseases. This review provides an overview of the strategies employed by this research network to achieve drug and biologic approvals for children with pediatric rheumatic diseases, particularly juvenile idiopathic arthritis.
Clinical trial conduct in rare pediatric diseases has required global recruitment. Supported or led by the PRCSG, highly responsive, validated, composite measures have been established to assess drug efficacy. For pediatric orphan diseases with high disease burdens, specialized investigative sites and study designs are needed to complete adequately powered trials at the high standard necessary to enable drug labeling by regulatory agencies. Novel trial designs have been utilized for more efficient testing of innovative drug candidates. All these have been developed or co-developed by the PRCSG research network.
Specialized research networks in pediatric rheumatology, such as the PRCSG, have changed the landscape of available therapies and improved overall disease outcomes for children with pediatric rheumatic diseases.
ObjectivesJuvenile idiopathic arthritis (JIA) is a common chronic childhood disease and chronic pain is a debilitating feature. A strong link has been shown between poor sleep and pain in JIA. ...However, the causal direction is unknown. This study’s aim was to determine if, in adolescents with JIA, a recommended healthful sleep duration leads to reductions in pain when compared with the restricted sleep (RS) duration that is commonly seen.MethodsPatients with JIA (12–18 years old; pain score of ≥1 on a visual analogue scale) participated in a randomised, crossover sleep manipulation protocol. The 3-week protocol comprised a baseline week (BL), a week with healthy sleep duration (HSD; 9.5 hours in bed/night) and a RS week (RS; 6.5 hours in bed/night). After BL, participants were randomly assigned to either HSD or RS, and then crossed over to the other condition. Pain was self-assessed using the iCanCope with Pain app. We used Bayesian hierarchical models to estimate the effect of sleep duration on pain.ResultsParticipants (n=31; mean age=15.0±1.8 years) averaged 1.4 (95% credible interval (CrI) 1.2–1.6) more hours of sleep per night during HSD relative to RS. Compared with RS, HSD resulted in a favourable effect on pain scores (OR 0.61, 95% CrI 0.39–0.95).ConclusionIt is possible to have adolescents with childhood arthritis get a healthier sleep duration, and this longer sleep results in reduced pain. These findings complement prior correlational studies and confirm a causal relationship between reduced sleep duration and increased pain.Trial registration numberNCT04133662.
Kawasaki disease (KD) and systemic juvenile idiopathic arthritis (sJIA) are two distinct systemic inflammatory diseases of childhood. Each diagnosis is based on criteria, but numerous clinical ...features are overlapping. As no specific diagnostic tests are available, differentiation between both disease entities can be challenging. Here, we describe the disease course of patients with co-diagnosis of both KD and sJIA (KD/sJIA). All our KD (
= 1765) and sJIA (
= 112) cases were critically reviewed for co-diagnosis of KD/sJIA. Eight KD/sJIA cases were identified and their clinical presentation, treatment regimens, coronary artery outcome and complications are herein described. Each KD/sJIA patient fulfilled diagnostic criteria for KD and for sJIA. Ongoing fever, rash and arthritis were present in each patient. The KD/sJIA patients had recalcitrant KD requiring multiple doses of intravenous immunoglobulin and steroids. Five patients had coronary artery dilatation at KD diagnosis, which resolved in all by 6 weeks. Pericardial effusion was present in 5 patients. One KD/sJIA patient developed macrophage activation syndrome. In conclusion, a small proportion (0.5%) of our KD patients evolved into sJIA, and 7% of our sJIA population presented initially as KD. KD/sJIA patients were characterized by a recalcitrant KD course and a high prevalence of coronary artery dilatation. Patients with co-diagnoses may provide a clue to potentially shared immunopathology in KD and sJIA, leading us to posit that both entities may be part of the same clinical spectrum.
We describe 3 patients who presented with features of macrophage activation syndrome (MAS) at the time of presentation of systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis, ...and Kawasaki disease. Immunohistochemical studies in the patient with SLE demonstrated extensive expression of CD163 on hemophagocytic macrophages, suggesting a possible role as a marker of MAS.
We describe a Childhood Arthritis and Rheumatology Research Alliance (CARRA) survey of North American pediatric rheumatologists that assesses physician attitudes on withdrawal of medications in ...systemic juvenile idiopathic arthritis (SJIA).
A REDCap anonymous electronic survey was distributed to 100 random CARRA JIA workgroup physician-voting members. The survey had three broad sections including: A) demographic information; B) physicians' opinions on clinical inactive disease (CID) in SJIA and C) existing practices for withdrawing medications in SJIA.
The survey had an 86% response rate. 88 and 93% of participants agreed with the current criteria for CID and clinical remission on medications (CRM) respectively. 78% thought it necessary to meet CRM before tapering medications except steroids. 76% use CARRA SJIA consensus treatment plans always or the majority of the time. All participants weaned steroids first in SJIA patients on combination therapy, 47% waited > 6 months before tapering additional medications. 35% each tapered methotrexate over > 6 months and 2-6 months; however, 39% preferred tapering anakinra, canakinumab and tocilizumab more quickly over 2-6 months and favored spacing the dosing interval for canakinumab and tocilizumab. When patients are on combination therapy with methotrexate and biologics, 58% preferred tapering methotrexate first while others considered patient/family preference and adverse effects to guide their choice.
Most CARRA members surveyed use published consensus treatment plans for SJIA and agree with validated definitions of CID and CRM. There was agreement with tapering steroids first in SJIA. There was considerable variability with tapering decisions of all other medications.
High-dose intravenous pulse methylprednisolone is an important therapeutic modality for many autoimmune conditions in both children and adults. Adverse effects of this therapy include hypertension, ...hyperglycemia, and, in children, behavioral changes. Cardiac rhythm disturbances, both tachyarrhythmias and bradyarrhythmias, have been reported in adults but much less commonly in children. Here we report our experience over a 6-month period with 5 children with rheumatic diseases who developed sinus bradycardia during consecutive daily therapy with intravenous pulse methylprednisolone. Reductions in resting heart rate of between 35% and 50% of baseline were observed in each case. All patients were asymptomatic, and all recovered spontaneously over a variable period of time after cessation of pulse therapy. Sinus bradycardia after repeated administration of high-dose pulse methylprednisolone in children may be more common than previously appreciated.
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