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      Medically Significant Infections Are Increased in Patients With Juvenile Idiopathic Arthritis Treated With Etanercept: Results From the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study

      research-article
      1 , 2 , 1 , 1 , 3 , , on behalf of the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study
      Arthritis & Rheumatology (Hoboken, N.j.)
      John Wiley and Sons Inc.

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          Abstract

          Objective

          The association between anti–tumor necrosis factor therapy and increased rates of infection is widely documented in adults with rheumatoid arthritis. Findings in children with juvenile idiopathic arthritis (JIA) have been less well documented. The aims of this analysis were to compare the rates of medically significant infections (MSIs) in children with JIA treated with etanercept (ETN) versus methotrexate (MTX) and to compare the rates between combination therapy with ETN plus MTX and monotherapy with ETN.

          Methods

          A total of 852 ETN‐treated children and 260 MTX‐treated children had been recruited to the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study (BSPAR‐ETN). MSIs included infections that resulted in death or hospitalization or were deemed medically significant by the clinician. This on‐drug analysis followed the patients until the first MSI, treatment discontinuation, the last followup, or death. Cox proportional hazards models, which were adjusted using propensity deciles, were used to compare rates of MSI between cohorts. Sensitivity analyses were conducted specifically with regard to serious infections (SIs), which were defined as those requiring hospitalization or treatment with intravenous antibiotics/antivirals.

          Results

          The ETN‐treated cohort was older and had a longer disease duration, but the disease activity was similar between the cohorts. A total of 133 first MSIs were reported (109 with ETN and 24 with MTX). Patients receiving ETN had higher rates of MSI than did the controls (propensity decile adjusted hazard ratio 2.13 [95% confidence interval 1.22–3.74]). The risk of MSI was higher whether patients were receiving combination or monotherapy. Sensitivity analysis showed no between‐group difference in the rate of SIs, which were much less common.

          Conclusion

          ETN therapy is associated with an increased risk of MSI; however, this increased risk disappears when considering only SIs, which suggests that either there were differences in the severity of infections and/or there was a possible reporting bias.

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          Most cited references16

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          Juvenile idiopathic arthritis.

          Juvenile idiopathic arthritis is a broad term that describes a clinically heterogeneous group of arthritides of unknown cause, which begin before 16 years of age. This term encompasses several disease categories, each of which has distinct methods of presentation, clinical signs, and symptoms, and, in some cases, genetic background. The cause of disease is still poorly understood but seems to be related to both genetic and environmental factors, which result in the heterogeneity of the illness. Although none of the available drugs has a curative potential, prognosis has greatly improved as a result of substantial progresses in disease management. The most important new development has been the introduction of drugs such as anticytokine agents, which constitute a valuable treatment option for patients who are resistant to conventional antirheumatic agents. Further insights into the disease pathogenesis and treatment will be provided by the continuous advances in understanding of the mechanisms connected to the immune response and inflammatory process, and by the development of new drugs that are able to inhibit selectively single molecules or pathways.
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            Measurement of health status in children with juvenile rheumatoid arthritis.

            To develop and validate a self- or parent-administered instrument for measuring functional status in children with juvenile rheumatoid arthritis (JRA). We adapted the Stanford Health Assessment Questionnaire (HAQ) for use in children ages 1-19 years, by adding several new questions, such that for each functional area, there was at least 1 question relevant to children of all ages. The face validity of the instrument was evaluated by a group of 20 health professionals and parents of 22 healthy children. The questionnaire was then administered to parents of 72 JRA patients (mean age 9.1 years, onset type systemic in 16, polyarticular in 21, pauciarticular in 35). The instrument showed excellent internal reliability (Cronbach's alpha = 0.94), with a mean inter-item correlation of 0.6. The convergent validity was demonstrated by strong correlations of the Disability Index (average of scores on all functional areas) with Steinbrocker functional class (Kendall's tau b = 0.77, P 8 years) was 0.84 (n = 29; P 0.9 by paired t-test; Spearman's correlation coefficient = 0.8, P < 0.002). The Childhood HAQ, which takes less than 10 minutes to complete, is a valid, reliable, and sensitive instrument for measuring functional status in children with JRA.
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              Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient?

              Objective To examine the risk of serious infection conveyed by tumour necrosis factor α (TNFα) inhibitors in the treatment of rheumatoid arthritis (RA). Methods Data from patients with RA enrolled in the German biologics register RABBIT were used for analysis. Baseline patient characteristics, time-varying risk factors (treatment changes, functional capacity) and selection processes caused by dropout, death or switching to non-anti-TNF treatment were taken into account to estimate the adjusted incidence rate ratios (IRRadj) of serious infection during treatment with TNF inhibitors compared with non-biological disease-modifying antirheumatic drug treatment. Results Data were available on 5044 patients, in whom 392 serious infections occurred. The crude rates of serious infections in patients treated with TNF inhibitors declined over the first 3 years of observation (from 4.8 to 2.2/100 patient-years). This decline was driven by (1) treatment termination or loss to follow-up in patients at increased risk and (2) a risk reduction through decreasing glucocorticoid doses and improvement in function. Adjusted for selection processes and time-varying risk factors, the following parameters assessed at baseline (age, chronic diseases) or at follow-up prior to the infection were significantly associated with an increased risk: age >60 years, chronic lung or renal disease, low functional capacity, history of serious infections, treatment with glucocorticoids (7.5–14 mg/day, IRRadj 2.1 (95% CI 1.4 to 3.2); ≥15 mg/day, IRRadj 4.7 (95% CI 2.4 to 9.4)) and treatment with TNFα inhibitors (IRRadj 1.8 (95% CI 1.2 to 2.7)). Conclusion Reasons for the decline in infection rates observed at the group level were identified. The results enable expected infection rates to be calculated in individual patients based on their risk profiles.
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                Author and article information

                Journal
                Arthritis Rheumatol
                10.1002/(ISSN)2326-5205
                ART
                Arthritis & Rheumatology (Hoboken, N.j.)
                John Wiley and Sons Inc. (Hoboken )
                2326-5191
                2326-5205
                September 2015
                26 August 2015
                : 67
                : 9 ( doiID: 10.1002/art.v67.9 )
                : 2487-2494
                Affiliations
                [ 1 ]University of Manchester and Manchester Academic Health Science Centre ManchesterUK
                [ 2 ]University of Birmingham and Birmingham Children's Hospital BirminghamUK
                [ 3 ]University of Manchester, Manchester Academic Health Science Centre, and Central Manchester University Hospitals NHS Foundation Trust ManchesterUK
                Author notes
                [*] [* ]Address correspondence to Kimme L. Hyrich, MD, PhD, FRCPC, Arthritis Research UK Centre for Epidemiology, Room 2.800, Stopford Building, University of Manchester, Manchester Academic Health Sciences Centre, Oxford Road, Manchester M13 9PT, UK. E‐mail: kimme.hyrich@ 123456manchester.ac.uk .
                [†]

                Dr. Hyrich has received honoraria from AbbVie and Pfizer (less than $10,000 each).

                Article
                ART39197
                10.1002/art.39197
                5049649
                25989609
                78edc582-131f-4191-acf5-38fa30c6546f
                © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 10 December 2014
                : 12 May 2015
                Page count
                Pages: 8
                Categories
                Pediatric Rheumatology
                Pediatric Rheumatology
                Custom metadata
                2.0
                art39197
                September 2015
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:04.10.2016

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