Treatment prescribing patterns in patients with juvenile idiopathic arthritis (JIA): Analysis from the UK Childhood Arthritis Prospective Study (CAPS).

OBJECTIVE: Initial treatment of juvenile idiopathic arthritis (JIA) is largely based on the extent of joint involvement, disease severity and ILAR category. The licensing of biologic therapies for JIA has expanded treatment options. The aims of the study are (1) to describe treatment prescribing patterns in JIA over the first 3 years following first presentation to paediatric rheumatology and (2) to determine whether patterns of treatment have changed as biologics have become more widely available. METHODS: Children with at least 3 years of follow-up within the Childhood Arthritis Prospective Study (CAPS) were included. For analysis, children were placed into one of five groups according to their initial presentation to paediatric rheumatology: oligoarthritis (oJIA), polyarthritis (pJIA), systemic (sJIA), enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). Treatment patterns over 3 years were described. RESULTS: Of 1051 children, 58% received synthetic disease-modifying anti-rheumatic drugs (sDMARD) and 20% received biologics over the 3 years. Use of sDMARDs and biologics was higher in more severe disease presentations (sJIA and pJIA); however, 35% and 10% who presented with oJIA were also treated with sDMARDs and biologics, respectively. The number of children receiving sDMARD after 2006 was higher (p = 0.02); however, there was no difference in biologic prescribing before and after 2006 (p = 0.4). CONCLUSIONS: A high proportion of children presenting with JIA received sDMARDs plus/minus biologics during 3 years of follow-up. This was most common for patients with severe JIA but was also prescribed for patients with oligoarticular disease, despite the lack of evidence for effectiveness in this category.

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies: 10 years' experience; the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies.

OBJECTIVES: The paediatric idiopathic inflammatory myopathies (IIMs) are a group of rare chronic inflammatory disorders of childhood, affecting muscle, skin and other organs. There is a severe lack of evidence base for current treatment protocols in juvenile myositis. The rarity of these conditions means that multicentre collaboration is vital to facilitate studies of pathogenesis, treatment and disease outcomes. We have established a national registry and repository for childhood IIM, which aims to improve knowledge, facilitate research and clinical trials, and ultimately to improve outcomes for these patients. METHODS: A UK-wide network of centres and research group was established to contribute to the study. Standardized patient assessment, data collection forms and sample protocols were agreed. The Biobank includes collection of peripheral blood mononuclear cells, serum, genomic DNA and biopsy material. An independent steering committee was established to oversee the use of data/samples. Centre training was provided for patient assessment, data collection and entry. RESULTS: Ten years after inception, the study has recruited 285 children, of which 258 have JDM or juvenile PM; 86% of the cases have contributed the biological samples. Serial sampling linked directly to the clinical database makes this a highly valuable resource. The study has been a platform for 20 sub-studies and attracted considerable funding support. Assessment of children with myositis in contributing centres has changed through participation in this study. CONCLUSIONS: This establishment of a multicentre registry and Biobank has facilitated research and contributed to progress in the management of a complex group of rare muscloskeletal conditions.

Duration of etanercept treatment and reasons for discontinuation in a cohort of juvenile idiopathic arthritis patients.

OBJECTIVE: Since 2004, juvenile idiopathic arthritis (JIA) patients treated with etanercept and/or MTX have been monitored in the British Society for Paediatric and Adolescent Rheumatology Biologics and New Drug Register. Here, we report the duration of etanercept use for the first 5 years of the register and reasons for discontinuation. METHODS: Disease subtype and activity, comorbidity, treatment efficacy and safety data were recorded. Etanercept discontinuation was defined as stopping the drug because of disease remission or treatment failure. Time to discontinuation was explored using Kaplan-Meier survival analysis with remaining patients censored at 5-year follow-up. RESULTS: A total of 483 etanercept-treated JIA patients were enrolled from 30 UK centres, representing 941 patient-years of follow-up. A total of 100 (20.7%) patients discontinued etanercept; 9 due to disease control, 88 because of treatment failure, 2 for unknown reasons and 1 because of a change in diagnosis. Of the 53 patients in whom etanercept was perceived to be ineffective at controlling the inflammation, 48 were prescribed other biologic drugs [26/48 (54%) infliximab]. In 21 patients with intolerance, infections, CNS events and a few isolated events were associated with discontinuation. Using Kaplan-Meier analysis, at 5 years 69% (95% CI 61, 77%) had not experienced treatment failure. Discontinuation of etanercept for inefficacy was associated with systemic arthritis subtype [odds ratio (OR) 2.55, 95% CI 1.27, 5.14], chronic anterior uveitis (OR 2.39, 95% CI 1.06, 5.35) and inefficacy of MTX before starting etanercept (OR 8.3, 95% CI 1.14, 60.58). CONCLUSIONS: In a cohort of JIA patients treated with etanercept and followed for a median of 2 years (maximum 5 years), the majority (69%) remain on the drug.

Tufting enteropathy and skeletal dysplasia: is there a link?

INTRODUCTION: Tufting enteropathy (intestinal epithelial dysplasia), a rare congenital enteropathy, presents in the first few months of life with chronic watery diarrhoea and impaired growth. The molecular basis for this condition is not known. We report our experience with a case of tufting enteropathy that developed an unusual skeletal dysplasia with an abnormal blood picture. After extensive investigations including repeated gastrointestinal endoscopies and biopsies, the diagnosis of tufting enteropathy was made. During the third year of her life, the patient's height was static. A full skeletal survey was performed and demonstrated features of generalised skeletal dysplasia, some of them consistent with those of parastremmatic dwarfism. At the age of five years, she developed Coomb's positive haemolytic anaemia and thrombocytopenia with a negative auto-antibody screen including anti-enterocyte antibodies. CONCLUSION: There might be generalised matrix (including cartilage matrix protein), basement membrane abnormalities or both. A secondary protein leak might occur in the intestine with autosensitisation and development of autoimmune phenomena. More molecular research is needed to identify a possible link.