Prediction of methotrexate efficacy and adverse events in patients with juvenile idiopathic arthritis: a systematic literature review

Abstract

BackgroundMethotrexate (MTX) is the cornerstone disease-modifying anti-rheumatic drug in juvenile idiopathic arthritis (JIA). In JIA, it is important to start effective treatment early to avoid long-term sequelae, such as joint damage. To accomplish this goal, it is crucial to know beforehand who is going to respond well to MTX. In addition, MTX adverse effects such as MTX intolerance occur frequently, potentially hindering its efficacy. To avoid inefficacy of an otherwise effective drug, the physician should be timely aware of these adverse events. Consequently, to optimise treatment of JIA patients with MTX, predictors for efficacy and adverse events should be used in daily clinical practice. The aim of this study was to summarise the existing knowledge about such predictors.MethodsA systematic literature search was performed in PubMed, Embase and The Cochrane Library, and 1,331 articles were identified. These were selected based on their relevance to the topic and critically appraised according to pre-defined criteria. Predictors for MTX efficacy and adverse events were extracted from the literature and tabulated.ResultsTwenty articles were selected. The overall quality of the studies was good. For MTX efficacy, candidate predictors were antinuclear antibody positivity, the childhood health assessment questionnaire score, the myeloid-related protein 8/14 level, long-chain MTX polyglutamates, bilateral wrist involvement and some single nucleotide polymorphisms (SNPs) in the adenosine triphosphate binding cassette and solute carrier transporter gene families. For MTX adverse events, potential predictors were alanine aminotransferase and thrombocyte level and two SNPs in the γ-glutamyl hydrolase and methylenetetrahydrofolate reductase genes. However, validation of most predictors in independent cohorts was still lacking.ConclusionsInteresting candidate predictors were found, especially for MTX efficacy. However, most of these were not validated. This should be the goal of future efforts. A clinically relevant way to validate the predictors is by means of creating a clinical prediction model.Electronic supplementary materialThe online version of this article (doi:10.1186/1546-0096-12-51) contains supplementary material, which is available to authorized users.

Efficacy of High-Dose Methotrexate in Pediatric Non-Infectious Uveitis

“…A faster remission reached by a predefined quick dose escalation scheme is probably more rewarding and motivating for a patient than a slow escalation scheme based on dose adjustments because of persisting disease activity. Also, the frequently reported MTX intolerance after longer use of MTX, might be prevented if remission on medication is sooner reached.- 24,25 Finally, MTX failure will be apparent after a shorter time interval when a faster dose escalation scheme is used, thus enabling an earlier switch in therapy. Our high-dose group is comparable to the intermediate MTX dose group of Ruperto et al 12 who evaluated the effectiveness and side effects of MTX in JIA.…”

Prediction of Methotrexate Intolerance in Juvenile Idiopathic Arthritis: a prospective, observational cohort study

“…Single nucleotide polymorphisms (SNPs) involved in the MTX metabolic pathways, and clinical predictors have been associated with MTX-related gastrointestinal adverse effects in rheumatoid arthritis (RA) [ 19 - 28 ] and JIA, the latter of which were reviewed recently [ 29 ]. However, to date no model has been constructed to predict MTX intolerance in JIA.…”

Early Prognostic Factors for Remission Achievement at Etanercept Therapy in Patients with Juvenile Idiopatic Arthritis Without Systematic Manifestations: Prospective Cohort Study

“…В 1980-х годах прошлого века, до начала использования болезньмодифицирующих антиревматических препаратов, в первую очередь метотрексата, ЮИА считался практически неизлечимым и инвалидизирующим заболеванием. В свою очередь, болезньмодифицирующие антиревматические препараты оказывались неэффективными у 30% пациентов [3]. С конца 1990-х для лечения ЮИА стали использовать генно-инженерные биологические препараты (ГИБП).…”