Pirjo Tynjälä

Infliximab and etanercept in the treatment of chronic uveitis associated with refractory juvenile idiopathic arthritis

Objective: To evaluate the efficacy of anti-tumour necrosis factor (anti-TNF) treatment in juvenile idiopathic arthritis (JIA)-associated uveitis. Methods: 24 patients with uveitis taking etanercept and 21 taking infliximab were studied. The endpoint ophthalmological evaluation was at 24 months or at the termination of the first biological agent. The ocular inflammatory activity was graded on the basis of the number of anterior chamber cells. Results: Of the 45 patients, uveitis improved in 14 (31%), no change was observed in 14 (31%) and the activity of uveitis increased in 17 (38%). Inflammatory activity improved more frequently (p = 0.047) in the patients taking infliximab than in those taking etanercept. The number of uveitis flares/year was higher (p = 0.015) in the patients taking etanercept (mean 1.4, range 0–3.2) than in those taking infliximab (mean 0.7, range 0–2). Uveitis developed for the first time while taking anti-TNF treatment in five patients—4 taking etanercept (2.2/100 patient-years) and 1 taking infliximab (1.1/100 patient-years). Conclusions: During anti-TNF treatment, the ophthalmological condition improved in one-third of the patients with uveitis. In chronic anterior uveitis, associated with refractory JIA, infliximab may be more effective than etanercept.

Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis

OBJECTIVE To evaluate the efficacy of adalimumab in juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS Retrospective observational study of 20 patients with JIA and chronic uveitis on adalimumab treatment. The ocular inflammation and improvement was assessed according to the Standardization of Uveitis Nomenclature criteria. RESULTS At the initiation of adalimumab, the mean age of patients was 13.4 yrs and the mean duration of uveitis 8.7 yrs. Seventeen (85%) patients had polyarticular JIA and 19 (95%) had previously been on anti-TNF treatment. The mean duration of adalimumab therapy was 18.7 months. Of the 20 patients, 7 (35%) showed improved activity, 1 (5%) worsening activity and in 12 (60%) no change was observed in the activity of uveitis. Those with improved activity were younger and had shorter disease duration. The mean number of flares/yr decreased from 1.9 to 1.4 during adalimumab treatment. Serious adverse events or side-effects were not observed. Seven patients discontinued adalimumab during the follow-up: six because of inefficacy and one because of inactive uveitis. CONCLUSION Adalimumab is a potential treatment option in JIA-associated uveitis, even in patients non-responsive to previous other anti-TNF therapy.

Aggressive Combination Drug Therapy in Very Early Polyarticular Juvenile Idiopathic Arthritis (ACUTE–JIA): a multicentre randomised open-label clinical trial

Objectives In juvenile idiopathic arthritis (JIA), the efficacy of very early disease-modifying drug therapy, synthetic or biological, is not well known. Three alternative strategies were compared for treating recent‑onset polyarticular JIA. Methods In a 54-week multicentre open-label clinical trial, 60 disease-modifying antirheumatic drug (DMARD)-naive patients aged 4–15 years were randomly assigned into three treatment arms. The efficacy of infliximab plus methotrexate (TNF) was compared to that of two synthetic therapies: methotrexate alone (MTX) and DMARD methotrexate, sulphasalazine and hydroxychloroquine in combination (COMBO). Primary endpoint was American College of Rheumatology paediatric 75% improvement (ACR Pedi 75). Secondary endpoints were inactive disease and safety. Results In 59 patients, mean (±SE) age at baseline was 9.6±0.4 years, duration of JIA 1.9±0.2 months and number of active joints 18±1. ACR Pedi 75 was achieved in 100% (19/19) of patients receiving TNF, 65% (13/20) on COMBO (95% CI 44% to 86%) and 50% (10/20) on methotrexate (95% CI 28% to 72%) p<0.0001. Thirteen patients receiving TNF (68%; 95% CI 47% to 89%) achieved inactive disease, whereas eight (40%; 95% CI 22% to 63%) on COMBO and five (25%; 95% CI 6% to 44%) on methotrexate did (p=0.002). Patients on TNF spent a mean 26 weeks (95% CI 18 to 34) with inactive disease, longer than did those receiving COMBO (13 weeks; 95% CI 6 to 20), or methotrexate (6 weeks; 95% CI 2 to 10). Serious adverse events were rare. Conclusion In early polyarticular JIA, targeting to achieve minimally active or inactive disease, infliximab plus methotrexate was superior to synthetic DMARD in combination and strikingly superior to methotrexate alone.

Impact of anti-TNF treatment on growth in severe juvenile idiopathic arthritis.

Objectives: To evaluate the impact of anti-tumour necrosis factor (TNF) treatment on growth and to identify the predictors for the change in growth in severe juvenile idiopathic arthritis (JIA). Methods: Data from 71 JIA patients (43 on etanercept, 28 on infliximab) were reviewed two years before and two years on the anti-TNF treatment. The patients had polyarticular disease course (48 polyarthritis, 19 extended oligoarthritis, two systemic arthritis, and two enthesitis related arthritis). At the initiation of the anti-TNF treatment, their mean age was 9.6 years and the mean duration of JIA, 5.7 years. Results: In the patients with delayed growth before anti-TNF treatment (n = 53), the growth velocity, measured as the change in height standard deviation score, accelerated +0.45 (95% confidence interval, 0.33 to 0.56) (p<0.001) during the anti-TNF treatment. In the patients with normal or accelerated growth before anti-TNF treatment (n = 18), the change in growth velocity was +0.05 (0.07 to 0.16) (p = 0.39). At two years on anti-TNF treatment, the growth velocity between these two groups was similar. No difference was found between the patients treated with etanercept or infliximab. A decelerating growth rate before the anti-TNF treatment was the strongest predictor for the observed increase in the growth velocity. The change in the inflammatory activity remained a significant predictor of the growth velocity even after the decrease in glucocorticoid dose was taken into account. Conclusions: In the treatment of polyarticular JIA, the anti-TNF treatment not only suppresses inflammation but also restores growth velocity.

Drug survival of the first and second course of anti-tumour necrosis factor agents in juvenile idiopathic arthritis

Objectives: To evaluate drug survival (continuation rates on drug) of anti-tumour necrosis factor (TNF) agents in juvenile idiopathic arthritis (JIA) and predictors for treatment discontinuation. Methods: A retrospective observational study on JIA patients taking etanercept (n  =  105) or infliximab (n  =  104) with at least one year follow-up. Kaplan–Meier curves and log-rank statistics were used to compare treatments and a proportional hazards model to assess risk factors for discontinuation. Results: Etanercept versus infliximab treatment survival at 12 months was 83% versus 80%, at 24 months 68% versus 68%, at 36 months 64% versus 53%, at 48 months 61% versus 48% (p = 0.194), respectively. Reasons for discontinuing the first biological treatment were inefficacy (etanercept 28% vs infliximab 20%, p = 0.445), adverse events (7% vs 22%, p = 0.002) or inactive disease (10% vs 16%, p = 0.068). Women (hazard ratio (HR) 2.8, 95% CI 1.3 to 5.8), patients with systemic JIA (HR 7.8, 95% CI 1.7 to 34.9) or those taking infliximab (HR 2.0, 95% CI 1.2 to 3.3) were at higher risk of treatment discontinuation. One-third of the patients were switched to the second anti-TNF therapy, which was discontinued less frequently than the first. At 12 months treatment survival of etanercept was 60%, infliximab 58% and adalimumab 66% as the second-line anti-TNF therapy. Conclusions: Although infliximab was discontinued more often than etanercept because of adverse events, during a 48-month follow-up the overall treatment survival of etanercept and infliximab as the first biological agent in JIA was comparable. A switch from one anti-TNF agent to another appears a reasonable therapeutic option.

Occurrence of adverse events in patients with JIA receiving biologic agents: long-term follow-up in a real-life setting

OBJECTIVE The aim of this study was to carry out a safety evaluation of biologic agents in patients with JIA and associated uveitis. METHODS In three tertiary centres in Finland, all adverse events (AEs) in 348 consecutive patients were collected. AEs were classified according to the Common Terminology Criteria for AEs. RESULTS A total of 1516 patient-years (py) were included: 710 on etanercept, 591 on infliximab, 188 on adalimumab, 8 on rituximab, 5 on anakinra, 6 on tocilizumab, 6 on abatacept and 1 on golimumab. The median follow-up of an individual patient was 51 months (range 1-155). The most common of the 2902 AEs (191/100 py) observed were mild infections, infusion or injection site reactions and alanine aminotransferase elevations. At least one AE occurred in 319 (92%) patients and 121 (35%) had at least one serious AE (SAE). The rate of SAEs was 11.4/100 py on etanercept, 11.8 on infliximab, 10.1 on adalimumab, 15.7 on abatacept, 31.2 on tocilizumab and 87.5 on rituximab, higher than with most anti-TNF agents (P = 0.005). No cases of malignant neoplasms or tuberculosis were detected. New-onset uveitis occurred in 9 patients, psoriasis or psoriasiform lesions in 13 and IBD in 6. CONCLUSION Mild and moderate AEs in patients with JIA treated with biologics were more frequent than previously reported. SAEs were observed in one-third of the patients, but SAEs seldom led to drug discontinuation.

Finding specific 10-joint Juvenile Arthritis Disease Activity Score (JADAS10) and clinical JADAS10 cut-off values for disease activity levels in non-systemic juvenile idiopathic arthritis: a Finnish multicentre study

OBJECTIVES To establish the cut-off values for inactive disease, as well as low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA) in non-systemic JIA based on the Juvenile Arthritis Disease Activity Score (JADAS) and assessed with the 10-joint JADAS (JADAS10) and clinical JADAS10 (cJADAS10). METHODS In a multicentre cross-sectional study consisting of ∼20% of all patients with JIA in Finland (n = 509), we obtained data on their most recent registered visits between January 2013 and January 2014. We calculated the JADAS10 and cJADAS10 and established the cut-off values of both of these scores using two different receiver operating characteristics-based statistical methods. RESULTS Of the 509 patients studied, 65.8% were females and 53.8% had polyarticular disease. The most suitable method for determining cut-off values was the Youden index. In oligoarticular patients, a JADAS10 score of 0-0.5 represented inactive disease, 0.6-2.7 LDA and ≥2.8 MDA. In polyarticular disease, a JADAS10 score of 0-0.7 represented inactive disease, 0.8-3.9 LDA and ≥4.0 MDA. The cut-off values for HDA were not possible to establish because only two visits fulfilled HDA criteria. CONCLUSION We established cut-off values for LDA and MDA. A reliable definition for HDA will require more patients. In the clinical setting, both the cJADAS10 and JADAS10 serve equally well both for research and quality control purposes. In the future, uniform clinical disease activity levels should be established. We also suggest revising and validating the criteria for HDA. Valid and robust cut-off values for disease activity levels can guide both clinicians and researchers and equip them for quality control.

Defining new clinical derived criteria for high disease activity in non-systemic juvenile idiopathic arthritis: a Finnish multicentre study

Abstract Objectives To redefine criteria for high disease activity (HDA) in JIA, to establish HDA cut-off values for the 10-joint Juvenile Arthritis Disease Activity Score (JADAS10) and clinical JADAS10 (cJADAS10) and to describe the distribution of patients’ disease activity levels based on the JADAS cut-off values in the literature. Methods Data on 305 treatment-naïve JIA patients were collected from nine paediatric units treating JIA. The median parameters of the JADAS were proposed to be the clinical criteria for HDA. The cut-off values were assessed by using two receiver operating characteristics curve–based methods. The patients were divided into disease activity levels based on currently used JADAS cut-off values. Results We proposed new criteria for HDA. At least three of the following criteria must be satisfied in both disease courses: in oligoarthritis, two or more active joints, ESR above normal, physician global assessment (PGA) of disease activity ≥2 and parent/patient global assessment (PtGA) of well-being ≥2; in polyarthritis, six or more active joints, ESR above normal, PGA of overall disease activity ≥4 and PtGA of well-being ≥2. The HDA cut-off values for JADAS10 (cJADAS) were ≥6.7 (6.7) for oligoarticular and ≥15.3 (14.1) for polyarticular disease. The distribution of the disease activity levels based on the JADAS cut-off values in the literature varied markedly based on which cut-offs were used. Conclusion New clinically derived criteria for HDA in JIA and both JADAS and cJADAS cut-off values for HDA were proposed.

THU0516 Health-Related Quality of Life in Patients with Newly Diagnosed JIA with Different Treatment Strategies (Acute-JIA Study): Table 1.

Background Health-related quality of life (HrQoL) is impaired in patients with juvenile idiopathic arthritis (JIA). Objectives To study HrQoL in patients with newly diagnosed JIA on three treatment strategies. Methods In ACUTE-JIA Study (1), 60 patients were randomized into three treatment arms: infliximab with methotrexate (TNF); a combination of methorexate, hydroxychloroquine, and sulphasalazine (COMBO), or methotrexate monotherapy (MTX). During the first year, at seven study visits, efficacy was measured with ACRped criteriae and HrQoL with Child Health Questionnaire (CHQ). Results All 20 patients continued intended therapy until week 54 in the TNF, 16 in COMBO, and 11 in MTX group. The last CHQ scores before discontinuation of the therapy were carried forward. Physical summary scores (PhS) and Psychosocial summary scores (PsS) improved from week 0 to 54 (Table 1) in all treatment groups with no differences between the groups. In all groups, significant improvements in PhS occurred over time until week 24 of the study, but not after that. In univariate analyses, CHAQ at weeks 0 (β=20.07; p<0.001) and 12 (β=-14.75; p=0.04), and cumulative use of steroids (β=-3.89; p=0.006) correlated with absolute change in PhS from week 0 to 54 (R2=0.381). Table 1. Psychosocial Summary scores (PsS) and Physical Summary scores (PhS) (median [range]) at onset (0) and at week 54 All Anti-TNF COMBO MTX p PsS0 52.63 [27.11-65.84]* 54.47 [27.11-58.53] 47.64 [37.08-62.64] 53.02 [40.23-65.84] 0.28 PsS54 54.62 [40.60-64.61] 55.13 [45.38-65.61] 55.58 [40.60-62.79] 53.84 [44.20-63.77] 0.98 PhS0 27.30 [-19.29-59.17]* 25.65 [10.52-51.82] 31.17 [-19.29-59.17] 19.49 [-6.41-51.11] 0.61 PhS54 51.69 [-2.21-65.81] 54.31 [13.34-62.81] 52.68 [0-62.87] 47.14 [6.35-65.18] 0.37* PsS0 vs PsS54 p<0.001; PhS0 vs PhS54 p<0.001 Wilcoxon signed rank test. Conclusions During the first year of treatment of JIA, HrQoL improved in all treatment categories. Patients and parents seem to acknowledge a significant change in PhS during the first half-year, but not thereafter. References Tynjälä P, Vähäsalo P, Tarkiainen M, et al. Aggressive Combination Drug Therapy in Very Early Polyarticular Juvenile Idiopathic Arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial. Ann Rheum Dis. 2011 Sep;70(9):1605-12. Disclosure of Interest None declared

Finding specific cut-off values of JADAS-10 and JADAS3-10 for disease activity levels in juvenile idiopathic arthritis: a finnish multicenter study

It’s crucial to observe the changes in disease activity in JIA in order to investigate reliably the effects of the new treatments and to optimize their use. Several tools for outcome measurements have been developed. Juvenile Arthritis Disease Activity Score (JADAS) is an independent measure of the treatment response and enables the comparison between cohorts. However, the use of ESR restricts the feasibility of JADAS. That’s why a JADAS index excluding ESR has been tested (JADAS3). In order to simplify the interpretation of the JADAS score, efforts have been made to define cut-off values of JADAS for low and high diease activity. Cut-off values of JADAS for disease activity levels, as defined by ACR, have not been developed. Neither have any cut-off values for JADAS3 been defined.