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Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases.

ABSTRACT: Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1 × 10(-5)): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.

SUBMITTER: Cobb J

PROVIDER: S-EPMC4091986 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases.

Cobb J J Cule E E Moncrieffe H H Hinks A A Ursu S S Patrick F F Kassoumeri L L Flynn E E Bulatović M M Wulffraat N N van Zelst B B de Jonge R R Bohm M M Dolezalova P P Hirani S S Newman S S Whitworth P P Southwood T R TR De Iorio M M Wedderburn L R LR Thomson W W

The pharmacogenomics journal 20140408 4

Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association w ...[more]

PMID: 24709693

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Project description:BackgroundMethotrexate (MTX) is an effective and safe drug in the treatment of juvenile idiopathic arthritis (JIA). Despite its safety, MTX-related gastrointestinal adverse effects before and after MTX administration, termed MTX intolerance, occur frequently, leading to non-compliance and potentially premature MTX termination. The aim of this study was to construct a risk model to predict MTX intolerance.MethodsIn a prospective JIA cohort, clinical variables and single nucleotide polymorphisms were determined at MTX start. The Methotrexate Intolerance Severity Score was employed to measure MTX intolerance in the first year of treatment. MTX intolerance was most prevalent at 6 or 12 months after MTX start, which was defined as the outcome for the prediction model. The model was developed in 152 patients using multivariable logistic regression analysis and subsequently internally validated using bootstrapping.ResultsThe prediction model included the following predictors: JIA category, antinuclear antibody, parent/patient assessment of pain, Juvenile Arthritis Disease Activity Score-27, thrombocytes, alanine aminotransferase and creatinine. The model classified 77.5% of patients correctly, and 66.7% of patients after internal validation by bootstrapping. The lowest predicted risk of MTX intolerance was 18.9% and the highest predicted risk was 85.9%. The prediction model was transformed into a risk score (range 0-17). At a cut-off of ≥6, sensitivity was 82.0%, specificity 56.1%, positive predictive value was 58.7% and negative predictive value 80.4%.ConclusionsThis clinical prediction model showed moderate predictive power to detect MTX intolerance. To develop into a clinically usable tool, it should be validated in an independent cohort and updated with new predictors. Such an easy-to-use tool could then assist clinicians in identifying patients at risk to develop MTX intolerance, and in turn to monitor them closely and intervene timely in order to prevent the development of MTX intolerance.Trial registrationISRCTN register, www.isrctn.com, ISRCTN13524271.

Project description:ObjectiveTo analyze the prognostic value of demographic, clinical, and therapeutic factors and laboratory biomarkers and to assess their role in predicting uveitis occurrence in patients with juvenile idiopathic arthritis (JIA).MethodsPatients with JIA were enrolled within the first year after JIA diagnosis. Demographic and clinical parameters were documented. Serum samples were collected at study enrollment, at 3-month follow-up visits within the first year, and then every 6 months. A multivariable Cox regression analysis was performed to evaluate the impact of demographic, clinical, laboratory, and therapeutic parameters on uveitis onset.ResultsWe included 954 JIA patients (67.2% female, 54.2% antinuclear antibody [ANA] positive, mean ± SD age at onset 7.1 ± 4.6 years). Uveitis occurred in 133 patients (observation period 44.5 months). Young age at JIA onset and ANA positivity were significantly associated with the onset of uveitis (both P < 0.001). Treatment of arthritis with methotrexate alone (hazard ratio [HR] 0.18 [95% confidence interval (95% CI) 0.12-0.29], P < 0.001) or combined with etanercept (HR 0.10 [95% CI 0.04-0.23], P < 0.001) or adalimumab (HR 0.09 [95% CI 0.01-0.61], P = 0.014) reduced the risk of uveitis onset and the occurrence of uveitis-related complications. Predictors of uveitis onset included elevated erythrocyte sedimentation rate at baseline (HR 2.36 [95% CI 1.38-4.02], P = 0.002) and continuing moderate or high disease activity during follow-up as measured by the 10-joint clinical Juvenile Arthritis Disease Activity Score (HR 4.30 [95% CI 2.51-7.37], P < 0.001). Additionally, S100A12 levels ≥250 ng/ml at baseline were significantly associated with the risk of uveitis (HR 2.10 [95% CI 1.15-3.85], P = 0.016).ConclusionApart from demographic risk factors and treatment modalities, JIA disease activity scores and laboratory biomarkers could be used to better define the group of JIA patients at high risk of uveitis onset.

Dataset Information

Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases.

Publications

Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases.

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