Objective
To prospectively validate the preliminary criteria for clinical inactive disease (CID) in patients with select categories of juvenile idiopathic arthritis (JIA).
Methods
We used the process ...for development of classification and response criteria recommended by the American College of Rheumatology Quality of Care Committee. Patient‐visit profiles were extracted from the phase III randomized controlled trial of infliximab in polyarticular‐course JIA (i.e., patients considered to resemble those with select categories of JIA) and sent to an international group of expert physician raters. Using the physician ratings as the gold standard, the sensitivity and specificity were calculated using the preliminary criteria. Modifications to the criteria were made, and these were sent to a larger group of pediatric rheumatologists to determine quantitative, face, and content validity.
Results
Variables weighted heaviest by physicians when making their judgment were the number of joints with active arthritis, erythrocyte sedimentation rate (ESR), physician's global assessment, and duration of morning stiffness. Three modifications were made: the definition of uveitis, the definition of abnormal ESR, and the addition of morning stiffness. These changes did not alter the accuracy of the preliminary set.
Conclusion
The modified criteria, termed the “criteria for CID in select categories of JIA,” have excellent feasibility and face, content, criterion, and discriminant validity to detect CID in select categories of JIA. The small changes made to the preliminary criteria set did not alter the area under the receiver operating characteristic curve (0.954) or accuracy (91%), but have increased face and content validity.
To develop preliminary criteria for inactive disease and clinical remission for select categories of juvenile idiopathic arthritis (JIA), and to decide what such clinical states should predict in ...terms of probability of disease recurrence.
A Delphi serial questionnaire consensus-formation approach was used initially to gather criteria in use by pediatric rheumatologists (PR) for defining clinical remission in oligoarticular (persistent and extended), rheumatoid factor (RF) positive and negative polyarticular, and systemic JIA. Results from sequential questionnaires provided an agenda for a nominal group technique (NGT) conference to reach consensus on unresolved questions.
One hundred and thirty PR from 34 countries responded to the questionnaires and 20 PR from 9 countries attended the conference. Draft criteria for inactive disease include the following: no active arthritis; no fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA; no active uveitis; normal erythrocyte sedimentation rate or C-reactive protein; and a physician's global assessment of disease activity rated at the best score possible for the instrument used. According to consensus vote, 6 continuous months of inactive disease on medication defines clinical remission on medication, while 12 months of inactive disease off all anti-arthritis (and anti-uveitis) medications defines clinical remission off medication. The finalized criteria for remission off medication ideally should predict that a patient has </= 20% probability of disease recurrence within the next 5 years.
Using consensus formation techniques, we formulated preliminary criteria for inactive disease and clinical remission on and off medication for use in select categories of JIA. Retrospective validation is in progress; prospective validation will follow. Future efforts will include other categories of JIA.
Objective
Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index ...in dcSSc (CRISS) for use in randomized controlled trials (RCTs).
Methods
We developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT.
Results
Sixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient‐level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982–0.983) and specificity was 0.931 (95% confidence interval 0.930–0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1‐year RCT (P = 0.02).
Conclusion
We have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc.
Macrophage activation syndrome (MAS) has been reported in association with many rheumatic diseases, most commonly in systemic juvenile rheumatoid arthritis (sJRA). Clinically, MAS is similar to ...hemophagocytic lymphohistiocytosis (HLH), a genetic disorder with absent or depressed natural killer (NK) function. We have previously reported that, as in HLH, patients with MAS have profoundly decreased NK activity, suggesting that this abnormality might be relevant to the pathogenesis of the syndrome. Here we examined the extent of NK dysfunction across the spectrum of diseases that comprise juvenile rheumatoid arthritis (JRA). Peripheral blood mononuclear cells (PBMC) were collected from patients with pauciarticular (n = 4), polyarticular (n = 16), and systemic (n = 20) forms of JRA. NK cytolytic activity was measured after co-incubation of PBMC with the NK-sensitive K562 cell line. NK cells (CD56+/T cell receptor TCR-alphabeta-), NK T cells (CD56+/TCR-alphabeta+), and CD8+ T cells were also assessed for perforin and granzyme B expression by flow cytometry. Overall, NK cytolytic activity was significantly lower in patients with sJRA than in other JRA patients and controls. In a subgroup of patients with predominantly sJRA, NK cell activity was profoundly decreased: in 10 of 20 patients with sJRA and in only 1 of 20 patients with other JRA, levels of NK activity were below two standard deviations of pediatric controls (P = 0.002). Some decrease in perforin expression in NK cells and cytotoxic T lymphocytes was seen in patients within each of the JRA groups with no statistically significant differences. There was a profound decrease in the proportion of circulating CD56bright NK cells in three sJRA patients, a pattern similar to that previously observed in MAS and HLH. In conclusion, a subgroup of patients with JRA who have not yet had an episode of MAS showed decreased NK function and an absence of circulating CD56bright population, similar to the abnormalities observed in patients with MAS and HLH. This phenomenon was particularly common in the systemic form of JRA, a clinical entity strongly associated with MAS.
Currently, there is no proven alternative therapy for patients with familial Mediterranean fever (FMF) that is resistant to or intolerant of colchicine. Interleukin-1 is a key proinflammatory ...cytokine in FMF.
To assess the efficacy and safety of rilonacept, an interleukin-1 decoy receptor, in treating patients with colchicine-resistant or -intolerant FMF.
Randomized, double-blind, single-participant alternating treatment study. (ClinicalTrials.gov number: NCT00582907).
6 U.S. sites.
Patients with FMF aged 4 years or older with 1 or more attacks per month.
One of 4 treatment sequences that each included two 3-month courses of rilonacept, 2.2 mg/kg (maximum, 160 mg) by weekly subcutaneous injection, and two 3-month courses of placebo.
Differences in the frequency of FMF attacks and adverse events between rilonacept and placebo.
8 males and 6 females with a mean age of 24.4 years (SD, 11.8) were randomly assigned. Among 12 participants who completed 2 or more treatment courses, the rilonacept-placebo attack risk ratio was 0.59 (SD, 0.12) (equal-tail 95% credible interval, 0.39 to 0.85). The median number of attacks per month was 0.77 (0.18 and 1.20 attacks in the first and third quartiles, respectively) with rilonacept versus 2.00 (0.90 and 2.40, respectively) with placebo (median difference, -1.74 95% CI, -3.4 to -0.1; P = 0.027). There were more treatment courses of rilonacept without attacks (29% vs. 0%; P = 0.004) and with a decrease in attacks of greater than 50% compared with the baseline rate during screening (75% vs. 35%; P = 0.006) than with placebo. However, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days -0.5 and 2.4 days in the first and third quartiles, respectively; P = 0.32). Injection site reactions were more frequent with rilonacept (median difference, 0 events per patient treatment month medians of -4 and 0 in the first and third quartiles, respectively; P = 0.047), but no differences were seen in other adverse events.
Small sample size, heterogeneity of FMF mutations, age, and participant indication (colchicine resistance or intolerance) were study limitations.
Rilonacept reduces the frequency of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF.
U.S. Food and Drug Administration, Office of Orphan Products Development.
Objective
To validate manual muscle testing (MMT) for strength assessment in juvenile and adult dermatomyositis (DM) and polymyositis (PM).
Methods
Patients with PM/DM (73 children and 45 adults) ...were assessed at baseline and reevaluated 6–9 months later. We compared Total MMT (a group of 24 proximal, distal, and axial muscles) and Proximal MMT (7 proximal muscle groups) tested bilaterally on a 0–10 scale with 144 subsets of 6 and 96 subsets of 8 muscle groups tested unilaterally. Expert consensus was used to rank the best abbreviated MMT subsets for face validity and ease of assessment.
Results
The Total, Proximal, and best MMT subsets had excellent internal reliability (Total MMT rs = 0.91–0.98), and consistency (Cronbach's α = 0.78–0.97). Inter‐ and intrarater reliability were acceptable (Kendall's W 0.68–0.76, rs = 0.84–0.95). MMT subset scores correlated highly with Total and Proximal MMT scores and with the Childhood Myositis Assessment Scale, and correlated moderately with physician global activity, functional disability, magnetic resonance imaging, and axial and distal MMT scores, and, in adults, with creatine kinase level. The standardized response mean for Total MMT was 0.56 in juveniles and 0.75 in adults. Consensus was reached to use a subset of 8 muscles (neck flexors, deltoids, biceps, wrist extensors, gluteus maximus and medius, quadriceps, and ankle dorsiflexors) that performed as well as the Total and Proximal MMT, and had good face validity and ease of assessment.
Conclusion
These findings aid in standardizing the use of MMT for assessing strength as an outcome measure for myositis.
In this randomized, placebo-controlled trial of 133 children with polyarticular juvenile rheumatoid arthritis who had a response to a 16-week course of treatment with adalimumab, a monoclonal ...antibody to tumor necrosis factor, disease flares were less common when adalimumab was continued than when it was withdrawn. Fourteen patients had serious adverse events, including seven patients with serious infections.
In children with polyarticular juvenile rheumatoid arthritis who had a response to a 16-week course of treatment with adalimumab, a monoclonal antibody to tumor necrosis factor, disease flares were less common when adalimumab was continued than when it was withdrawn.
Juvenile rheumatoid arthritis is the most common rheumatic disease of childhood and is an important cause of disability among children.
1
Weekly methotrexate (oral or parenteral), at dosages of up to 15 mg per square meter of body-surface area per week for parenteral administration, has been established as an effective therapy in polyarticular juvenile rheumatoid arthritis.
2
,
3
During the past decade, the use of tumor necrosis factor (TNF) antagonists in adult rheumatoid arthritis has shifted the paradigm of care.
4
–
6
More recently, TNF blockade has been shown to be an efficacious treatment option for polyarticular juvenile rheumatoid arthritis.
7
Adalimumab (Humira, Abbott . . .
Summary Background Some children with juvenile idiopathic arthritis either do not respond, or are intolerant to, treatment with disease-modifying antirheumatic drugs, including anti-tumour necrosis ...factor (TNF) drugs. We aimed to assess the safety and efficacy of abatacept, a selective T-cell costimulation modulator, in children with juvenile idiopathic arthritis who had failed previous treatments. Methods We did a double-blind, randomised controlled withdrawal trial between February, 2004, and June, 2006. We enrolled 190 patients aged 6–17 years, from 45 centres, who had a history of active juvenile idiopathic arthritis; at least five active joints; and an inadequate response to, or intolerance to, at least one disease-modifying antirheumatic drug. All 190 patients were given 10 mg/kg of abatacept intravenously in the open-label period of 4 months. Of the 170 patients who completed this lead-in course, 47 did not respond to the treatment according to predefined American College of Rheumatology (ACR) paediatric criteria and were excluded. Of the patients who did respond to abatacept, 60 were randomly assigned to receive 10 mg/kg of abatacept at 28-day intervals for 6 months, or until a flare of the arthritis, and 62 were randomly assigned to receive placebo at the same dose and timing. The primary endpoint was time to flare of arthritis. Flare was defined as worsening of 30% or more in at least three of six core variables, with at least 30% improvement in no more than one variable. We analysed all patients who were treated as per protocol. This trial is registered, number NCT00095173. Findings Flares of arthritis occurred in 33 of 62 (53%) patients who were given placebo and 12 of 60 (20%) abatacept patients during the double-blind treatment (p=0·0003). Median time to flare of arthritis was 6 months for patients given placebo (insufficient events to calculate IQR); insufficient events had occurred in the abatacept group for median time to flare to be assessed (p=0·0002). The risk of flare in patients who continued abatacept was less than a third of that for controls during that double-blind period (hazard ratio 0·31, 95% CI 0·16–0·95). During the double-blind period, the frequency of adverse events did not differ in the two treatment groups. Adverse events were recorded in 37 abatacept recipients (62%) and 34 (55%) placebo recipients (p=0·47); only two serious adverse events were reported, both in controls (p=0·50). Interpretation Selective modulation of T-cell costimulation with abatacept is a rational alternative treatment for children with juvenile idiopathic arthritis. Funding Bristol-Myers Squibb.
To assess the long-term efficacy and safety of infliximab plus methotrexate in juvenile rheumatoid arthritis (JRA).
Patients eligible for the open-label extension (OLE, weeks 52-204) received ...infliximab 3-6 mg/kg every 8 weeks plus methotrexate.
Of the 78/122 (64%) children entering the OLE, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (eight patients) or patient/physician/sponsor requirement (eight patients). Infliximab (mean dose 4.4 mg/kg per infusion) was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At week 204, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24% and 13%, respectively.
In the limited population of JRA patients remaining in the study at 4 years, infliximab was safe and effective but associated with a high patient discontinuation rate.
Objective
To measure agreement among raters when scoring the physician/provider global assessment (PGA) of disease activity in patients with juvenile idiopathic arthritis (JIA) with no apparent ...disease activity, and to identify clinical and laboratory parameters that most strongly influence provider scoring of the PGA.
Methods
Profiles of clinical and laboratory findings from 20 patients with JIA with no apparent disease activity were given to 51 providers, who were asked to score the PGA using a 21‐circle visual analog scale (range 0–10). Following initial scoring, providers discussed each profile and reasons for assigning the score given, and then were asked to rescore each profile. Providers were asked to list variables that influenced their scoring most strongly. Using a mixed‐model approach, the intraclass correlation coefficient (ICC) of the final scores served as the measure of concordance.
Results
A total of 504 PGA scores were obtained. The overall ICC of the initial scores was 0.18. Thus, 18% of nonconcordance of the scores was attributable to patient differences, while 82% was due to provider variation. Variables that influenced scoring most strongly were (in order of frequency) presence of pain, questionable temporomandibular joint involvement, loss of joint motion, presence of any morning stiffness, psoriasis, and past history of uveitis.
Conclusion
The low ICC suggests poor agreement among providers scoring the PGA in JIA patients with low or no disease activity. Given the ubiquitous use of the PGA in classification and response criteria for JIA and other pediatric rheumatic diseases, substantive efforts are needed to bring about greater uniformity in scoring of global disease activity by providers.
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