Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis.

BACKGROUND: Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, is effective in the treatment of juvenile idiopathic arthritis (JIA). We tested the efficacy of adalimumab in the treatment of JIA-associated uveitis. METHODS: In this multicenter, double-blind, randomized, placebo-controlled trial, we assessed the efficacy and safety of adalimumab in children and adolescents 2 years of age or older who had active JIA-associated uveitis. Patients who were taking a stable dose of methotrexate were randomly assigned in a 2:1 ratio to receive either adalimumab (at a dose of 20 mg or 40 mg, according to body weight) or placebo, administered subcutaneously every 2 weeks. Patients continued the trial regimen until treatment failure or until 18 months had elapsed. They were followed for up to 2 years after randomization. The primary end point was the time to treatment failure, defined according to a multicomponent intraocular inflammation score that was based on the Standardization of Uveitis Nomenclature criteria. RESULTS: The prespecified stopping criteria were met after the enrollment of 90 of 114 patients. We observed 16 treatment failures in 60 patients (27%) in the adalimumab group versus 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P<0.0001 [the prespecified stopping boundary]). Adverse events were reported more frequently in patients receiving adalimumab than in those receiving placebo (10.07 events per patient-year [95% CI, 9.26 to 10.89] vs. 6.51 events per patient-year [95% CI, 5.26 to 7.77]), as were serious adverse events (0.29 events per patient-year [95% CI, 0.15 to 0.43] vs. 0.19 events per patient-year [95% CI, 0.00 to 0.40]). CONCLUSIONS: Adalimumab therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis who were taking a stable dose of methotrexate. Patients who received adalimumab had a much higher incidence of adverse events and serious adverse events than those who received placebo. (Funded by the NIHR Health Technology Assessment Programme and Arthritis Research UK; SYCAMORE EudraCT number, 2010-021141-41 .).

Cost-Effectiveness Analysis of Adalimumab for the Treatment of Uveitis Associated with Juvenile Idiopathic Arthritis.

PURPOSE: To investigate the cost effectiveness of adalimumab in combination with methotrexate, compared with methotrexate alone, for the management of uveitis associated with juvenile idiopathic arthritis (JIA). DESIGN: A cost-utility analysis based on a clinical trial and decision analytic model. PARTICIPANTS: Children and adolescents 2 to 18 years of age with persistently active uveitis associated with JIA, despite optimized methotrexate treatment for at least 12 weeks. METHODS: The SYCAMORE (Randomised controlled trial of the clinical effectiveness, SafetY and Cost effectiveness of Adalimumab in combination with MethOtRExate for the treatment of juvenile idiopathic arthritis associated uveitis) trial (identifier, ISRCTN10065623) of methotrexate (up to 25 mg weekly) with or without fortnightly administered adalimumab (20 or 40 mg, according to body weight) provided data on resource use (based on patient self-report and electronic records) and health utilities (from the Health Utilities Index questionnaire). Surgical event rates and long-term outcomes were based on data from a 10-year longitudinal cohort. A Markov model was used to extrapolate the effects of treatment based on visual impairment. MAIN OUTCOME MEASURES: Medical costs to the National Health Service in the United Kingdom, utility of defined health states, quality-adjusted life-years (QALYs), and incremental cost per QALY. RESULTS: Adalimumab in combination with methotrexate resulted in additional costs of £39 316, with a 0.30 QALY gain compared with methotrexate alone, resulting in an incremental cost-effectiveness ratio of £129 025 per QALY gained. The probability of cost effectiveness at a threshold of £30 000 per QALY was less than 1%. Based on a threshold analysis, a price reduction of 84% would be necessary for adalimumab to be cost effective. CONCLUSIONS: Adalimumab is clinically effective in uveitis associated with JIA; however, its cost effectiveness is not demonstrated compared with methotrexate alone in the United Kingdom setting.

HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 × 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.

Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. METHODS: We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. RESULTS: The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. CONCLUSIONS: The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.

Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers.

The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be 'gold standard' on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.

Eric Bywaters and Barbara Ansell: Founders of Modern Pediatric Rheumatology.

Eric Bywaters and Barbara Ansell were, without doubt, two of the giants in the field of Rheumatology. With their keen clinical observations and their visionary development of a dedicated multidisciplinary program focusing on diagnosis, treatment, and research, they are remembered as the founders of the modern specialty of Pediatric Rheumatology.

Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis.

Objective: To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). Methods: Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtained in silico (dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package. Significance was defined as p<0.05 after 100,000 permutations. Results: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3000 controls. Quality control operations produced a set of 481 cases and 2924 ancestrally-matched control subjects. RVT of sJIA cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF]<0.01) of STXBP2 (p=0.020), and ultra-rare variants (MAF<0.001) of STXBP2 (p=0.007) and UNC13D (p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rare UNC13D variants (p=0.0047). Additionally, sJIA patients more often carried ≥2 HLH variants than did controls (p=0.007), driven largely by digenic combinations involving LYST. Conclusion: We identified an enrichment of rare HLH variants in sJIA patients compared with healthy controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.

Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH)-associated genes among patients with systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). METHODS: Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtained in silico (dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package. Significance was defined as p < 0.05 after 100,000 permutations. RESULTS: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3000 controls. Quality control operations produced a set of 480 cases and 2924 ancestrally-matched control subjects. RVT of cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF] < 0.01) of STXBP2 (p = 0.020), and ultra-rare variants (MAF < 0.001) of STXBP2 (p = 0.006) and UNC13D (p = 0.046). A sub-analysis of 32 cases with known MAS and 90 without revealed a significant difference in the distribution of rare UNC13D variants (p = 0.0047) between the groups. Additionally, sJIA patients more often carried ≥ 2 HLH variants than did controls (p = 0.007), driven largely by digenic combinations involving LYST. CONCLUSION: We identified an enrichment of rare HLH variants in sJIA patients compared with controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.

A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features.

OBJECTIVE: To assess dosing, preliminary safety, and efficacy of canakinumab, a fully human anti-interleukin-1ß (anti-IL-1ß) antibody, in children with systemic juvenile idiopathic arthritis (JIA) and active systemic features. METHODS: In this phase II, multicenter, open-label, dosage-escalation study, children with systemic JIA who were ≥4 years of age, had fever, and were receiving ≤0.4 mg/kg/day of corticosteroids were administered a single subcutaneous dose of canakinumab, 0.5-9 mg/kg of body weight, and were redosed upon relapse. Response to treatment was assessed according to an adaptation of the American College of Rheumatology (ACR) pediatric criteria for improvement. RESULTS: A total of 23 children ages 4-19 years with active disease were enrolled. Of these, 1 patient was excluded from analysis, and 3 of the reenrolled patients were included twice in the efficacy analysis. By day 15 of the first treatment cycle, 15 of 25 patients (60%) had achieved an adapted ACR Pediatric 50 response, with 4 of them achieving inactive disease status. Response was sustained over time, with 11 of 13 patients able to maintain their response throughout the study. In 8 of the 11 responders who had been receiving steroids at baseline, the steroid dosage was decreased from a mean of 0.38 mg/kg/day to 0.13 mg/kg/day over the first 5 months, and 4 of them were able to discontinue steroids. At a dose of 4 mg/kg of canakinumab given subcutaneously every 4 weeks, the median percentage of patients predicted to relapse within 4 weeks was estimated to be 6% (95% confidence interval 1-21). Therapy was generally well tolerated and few patients experienced injection-site reactions. CONCLUSION: Canakinumab has a promising preliminary safety and efficacy profile in this limited cohort. Based on the findings of this trial, further studies in a larger population of children with systemic JIA are warranted.

An international registry on autoinflammatory diseases: the Eurofever experience.

OBJECTIVE: To report on the demographic data from the first 18 months of enrollment to an international registry on autoinflammatory diseases in the context of the Eurofever project. METHODS: A web-based registry collecting baseline and clinical information on autoinflammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms. RESULTS: 1880 (M:F=916:964) individuals from 67 centers in 31 countries have been entered in the Eurofever registry. Most of the patients (1388; 74%), reside in western Europe, 294 (16%) in the eastern and southern Mediterranean region (Turkey, Israel, North Africa), 106 (6%) in eastern Europe, 54 in Asia, 27 in South America and 11 in Australia. In total 1049 patients with a clinical diagnosis of a monogenic autoinflammatory diseases have been enrolled; genetic analysis was performed in 993 patients (95%): 703 patients have genetically confirmed disease and 197 patients are heterozygous carriers of mutations in genes that are mutated in patients with recessively inherited autoinflammatory diseases. The median diagnosis delay was 7.3 years (range 0.3-76), with a clear reduction in patients born after the identification of the first gene associated with autoinflammatory diseases in 1997. CONCLUSIONS: A shared online registry for patients with autoinflammatory diseases is available and enrollment is ongoing. Currently, there are data available for analysis on clinical presentation, disease course, and response to treatment, and to perform large scale comparative studies between different conditions.

Th1 and Th17 cell subpopulations are enriched in the peripheral blood of patients with systemic juvenile idiopathic arthritis.

OBJECTIVE: The role of the adaptive immune system has not been explored in detail compared with the innate immune system in systemic JIA (sJIA) pathogenesis. The aim of this study was to examine the phenotype of circulating peripheral blood CD4(+) T-cell subpopulations in a cross-sectional study of sJIA patients during disease remission on medication and during acute flare of the disease. METHODS: Flow cytometry was used to examine the phenotype and cytokine production of IFNγ-, IL-4- and IL-17-producing CD4(+) T cells in the peripheral blood of 10 sJIA patients with active disease, 9 sJIA with inactive disease, 14 JIA patients with oligoarticular onset, 10 adult control subjects and 10 age-matched control subjects. In parallel, we examined the proportion of FoxP3(+) Tregs. RESULTS: IFNγ- and IL-17-producing CD4(+) T cells and IL-17-producing CD3(+)CD4(-) T cells were present at higher proportions in the peripheral blood of sJIA patients, irrespective of their disease status. Our data also confirm the known increase of the proportions of IFNγ-producing Th1 cells with increasing age and suggest an increase with age in the IL-17-producing CD4(+) T-cell population. CONCLUSION: This study is the first to describe significantly higher proportions of Th1 and Th17 T helper cell subsets in the peripheral blood of sJIA patients. These proinflammatory cells may play a pathogenic role in sJIA. Our data also emphasize the importance of using paediatric age-matched control subjects when evaluating the T-cell cytokine profile in JIA.

INSAID Variant Classification and Eurofever Criteria Guide Optimal Treatment Strategy in Patients with TRAPS: Data from the Eurofever Registry.

BACKGROUND: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNF super family receptor 1A (TNFRSF1A) gene. Data regarding long-term treatment outcomes are lacking. OBJECTIVE: To assess correlations of genotype-phenotypes in patients with TRAPS, as defined by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification and Eurofever criteria, with treatment responses. METHODS: Data from 226 patients with variants of the TNFRSF1A gene and enrolled in the Eurofever registry were classified according to the INSAID classification in groups A (pathogenic or likely pathogenic variants), B (variants of uncertain significance or not classified variants), and C (benign or likely benign variants) and screened for Eurofever criteria. RESULTS: In group A (127 of 226 patients, 56%), all fulfilled Eurofever criteria and 20 of 127 patients (16%) developed AA amyloidosis. In group B (78 of 226 patients, 35%), 40 of 78 patients (51%) did not fulfill Eurofever criteria, displaying a lower incidence of abdominal pain (P < .02) and higher efficacy rate of on-demand nonsteroidal anti-inflammatory drugs (P < .02) and colchicine (P < .001). Group C (21 of 226 patients, 9%) presented a milder disease (P < .02) and none fulfilled Eurofever criteria. Anti-IL-1 drugs were the most frequently used in patients fulfilling Eurofever criteria, with the highest efficacy rate (>85% complete response). No patients on anti-IL-1 treatments developed AA amyloidosis, and 7 women with a history of failure to conceive had successful pregnancies. CONCLUSION: Anti-IL-1 drugs are the best maintenance treatment in patients with TRAPS. The diagnosis of TRAPS should be considered very carefully in patients of group B not fulfilling Eurofever criteria and group C, and colchicine may be preferable as the first maintenance treatment.

Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open-label treatment extension.

OBJECTIVE: To assess the long-term efficacy and safety of infliximab plus methotrexate in juvenile rheumatoid arthritis (JRA). METHODS: Patients eligible for the open-label extension (OLE, weeks 52-204) received infliximab 3-6 mg/kg every 8 weeks plus methotrexate. RESULTS: 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. CONCLUSIONS: 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.

Biologic therapy in refractory chronic non-bacterial osteomyelitis of childhood.

OBJECTIVE: To date there is no uniformly effective treatment for either chronic recurrent multifocal osteomyelitis (CRMO) or synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome. We report on our clinical experience of using biologic therapy to treat children with these conditions. METHODS: Retrospective descriptive case series of four children with refractory disease treated with biologics. Disease activity was assessed at predetermined time points (T = 0, T = 6 weeks and T = 12 months after the start of biologic therapy, and at latest follow-up) using a combination of clinical examination and radiological findings: a 10 cm pain and physician visual analogue scale; the Childhood Health Assessment Questionnaire as an assessment of disability; and changes in markers of systemic inflammation. RESULTS: There was an initial improvement in all parameters assessed for all three children treated with TNF-alpha blockade, although the third case had to discontinue the therapy due to a suspected (but unconfirmed) fungal skin infection. Anakinra treatment alleviated the symptoms in the fourth patient at 6 weeks, but there was no sustained response to treatment at 1-year follow-up. CONCLUSION: We present our preliminary experience of using biological therapies to treat children with CRMO and SAPHO in conjunction with other immunosuppression. Further studies are needed to establish the role of these therapies in refractory CRMO and SAPHO.

Theoretical and practical basis for early aggressive therapy in paediatric autoimmune disorders.

PURPOSE OF REVIEW: The clinical practice of introducing anti-inflammatory therapies in paediatric autoimmune disorders has changed substantially in the last two decades. This is partly due to the fact that we are able to put disease into remission with potent drugs, and so the issue of when to introduce these drugs is important. This review will seek to highlight the consequences of chronic inflammation and the change to outcomes if adequate or 'aggressive' treatment is given early to induce remission. RECENT FINDINGS: The review not only highlights publications on this topic over the past 12-18 months but also refers to key publications before when appropriate. The disorders reviewed are juvenile idiopathic arthritis, systemic lupus erythematosis, Wegener's granulomatosis, juvenile dermatomyositis, juvenile scleroderma and autoinflammatory syndromes. SUMMARY: Outcomes can be influenced by potent anti-inflammatory therapies. Their use early in the evolution of the disorder in question can limit damage and allow the possibility of normal life and function in the child.

Validation of a protocol for the assessment of skin temperature and blood flow in childhood localised scleroderma.

BACKGROUND/PURPOSE: Localised scleroderma (LS) is the most common form of scleroderma seen in children, and usually presents unilaterally. Infrared thermography (IRT) and laser Doppler (LD) have both been reported to be useful in assessing the active, inflammatory stage of LS. We developed and validated a protocol using these techniques for the assessment of unilateral LS activity in children. METHOD: We investigated the spatial variability and repeatability of LD measurements from adult control forearm skin, and the inter- and intra-operator reproducibility of both LD blood flow trace analysis and IRT skin temperature analysis. Software was developed to produce overlay images of thermograms onto digital photographs of skin sites. In a group of seven adult control subjects, we established the normal range for skin temperature and LD blood flow at six standardised sites (forehead, cheek, abdomen, back, arm and leg), and measured contralateral differences in readings. In a group of 34 children with LS, we investigated the skin temperature and LD blood flow in unaffected skin at the same six sites. RESULTS: In adults, physiological variability in LD blood flow and skin temperature between the two sides of the body was found to be greater than the uncertainty introduced into the measurements by (inter alia) limited intra- or inter-operator reproducibility. The cheek displayed the highest mean asymmetry in both skin temperature (0.5 degrees C) and LD blood flow (40%). CONCLUSION: Our protocol combines IRT, LD and photography for LS assessment in children, and establishes a normal range of readings in line with other authors.

Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT.

BACKGROUND: Children with juvenile idiopathic arthritis (JIA) are at risk of uveitis. The role of adalimumab (Humira®; AbbVie Inc., Ludwigshafen, Germany) in the management of uveitis in children needs to be determined. OBJECTIVE: To compare the efficacy, safety and cost-effectiveness of adalimumab in combination with methotrexate (MTX) versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with JIA. DESIGN: This was a randomised (applying a ratio of 2 : 1 in favour of adalimumab), double-blind, placebo-controlled, multicentre parallel-group trial with an integrated economic evaluation. A central web-based system used computer-generated tables to allocate treatments. A cost-utility analysis based on visual acuity was conducted and a 10-year extrapolation by Markov modelling was also carried out. SETTING: The setting was tertiary care centres throughout the UK. PARTICIPANTS: Patients aged 2-18 years inclusive, with persistently active JIA-associated uveitis (despite optimised MTX treatment for at least 12 weeks). INTERVENTIONS: All participants received a stable dose of MTX and either adalimumab (20 mg/0.8 ml for patients weighing < 30 kg or 40 mg/0.8 ml for patients weighing ≥ 30 kg by subcutaneous injection every 2 weeks based on body weight) or a placebo (0.8 ml as appropriate according to body weight by subcutaneous injection every 2 weeks) for up to 18 months. A follow-up appointment was arranged at 6 months. MAIN OUTCOME MEASURES: Primary outcome - time to treatment failure [multicomponent score as defined by set criteria based on the Standardisation of Uveitis Nomenclature (SUN) criteria]. Economic outcome - incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the NHS in England and Personal Social Services providers. Full details of secondary outcomes are provided in the study protocol. RESULTS: A total of 90 participants were randomised (adalimumab, n = 60; placebo, n = 30). There were 14 (23%) treatment failures in the adalimumab group and 17 (57%) in the placebo group. The analysis of the data from the double-blind phase of the trial showed that the hazard risk (HR) of treatment failure was significantly reduced, by 75%, for participants in the adalimumab group (HR 0.25, 95% confidence interval 0.12 to 0.51; p < 0.0001 from log-rank test). The cost-effectiveness of adalimumab plus MTX was £129,025 per QALY gained. Adalimumab-treated participants had a much higher incidence of adverse and serious adverse events. CONCLUSIONS: Adalimumab in combination with MTX is safe and effective in the management of JIA-associated uveitis. However, the likelihood of cost-effectiveness is < 1% at the £30,000-per-QALY threshold. FUTURE WORK: A clinical trial is required to define the most effective time to stop therapy. Prognostic biomarkers of early and complete response should also be identified. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10065623 and European Clinical Trials Database number 2010-021141-41. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 15. See the NIHR Journals Library website for further project information. This trial was also funded by Arthritis Research UK (grant reference number 19612). Two strengths of adalimumab (20 mg/0.8 ml and 40 mg/0.8 ml) and a matching placebo were manufactured by AbbVie Inc. (the Marketing Authorisation holder) and supplied in bulk to the contracted distributor (Sharp Clinical Services, Crickhowell, UK) for distribution to trial centres.

Juvenile idiopathic arthritis (JIA) is one of the most common rheumatic diseases in children and young people, who are at risk of developing inflammation in an area of the eye called the uvea (called uveitis). The purpose of the study was to look at how effective the use of adalimumab in combination with methotrexate (MTX) is compared with using MTX alone to treat JIA-associated uveitis. A total of 90 children (aged 2­18 years) taking MTX with JIA-associated uveitis took part in the study. If the inflammation in a patient's eye or eyes was not getting better during the 18 months, the patient was told to stop taking the study drug. It was found that those patients who were taking placebo and MTX in the trial stopped taking the study drug sooner than those who were taking adalimumab and MTX. This means that adalimumab and MTX was better at treating uveitis than MTX alone. It was found that more patients taking adalimumab and MTX together either reduced or stopped taking topical steroids than the patients taking placebo and MTX. It was found that patients taking adalimumab and MTX together experienced more side effects than those taking placebo with MTX. However, these were expected based on what was already known about adalimumab's side effects. An economic evaluation was conducted to estimate whether or not adalimumab would represent value for money for the NHS for this condition. This included long-term effects based on information about patients' clarity of vision. The analysis showed that adalimumab may not be cost-effective, as the additional costs of treatment may not be justified by the benefits. The final results show that although adalimumab used in combination with MTX does help to treat patients with JIA and uveitis, it may not represent good value for the NHS.

Free Interleukin (IL)-18 levels, and the impact of IL18 and IL18BP genetic variation, in CHD patients and healthy men.

OBJECTIVE: To investigate free interleukin-18 (fIL-18) levels, and variation within the IL-18 system genes, in heart surgery patients, and healthy men. METHODS AND RESULTS: fIL-18 was calculated from IL-18 and IL-18 binding protein (BP) levels, in 421 healthy men and 196 post-coronary artery bypass graft (CABG) patients. After surgery, fIL-18 peaked at 6 hours (from 117 to 331 pg/mL) but fell to below presurgery levels at 24 hours (99 pg/mL), because of changes in total IL-18 and IL-18BP. fIL-18 24 hours postsurgery was significantly higher in those who suffered a major complication after surgery (125 versus 80 pg/mL, P<0.01). Baseline total IL-18 was also higher in healthy men who went on to suffer an MI over 17 years of prospective study (276 versus 240 pg/mL, P=0.01). Tagging SNPs for IL18 (n=5) and IL18BP (n=3) were determined, in both studies the IL18 HapIII haplotype (frequency 30%) was associated with 36% lower baseline fIL-18 levels before surgery (P<0.01), and 7% lower in healthy men (P=0.04). The frequency of HapIII was lower in CABG patients than in healthy men (20.7 versus 29.8%, P<0.01). CONCLUSIONS: IL-18 levels, which are determined in part by variation in IL18, play a role in CHD development and postsurgery outcome.

IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date. METHODS: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10-4 ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]). CONCLUSION: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.