Objective. To design and validate a new questionnaire for identifying patients with methotrexate (MTX) intolerance, and to determine the prevalence of MTX intolerance in patients with juvenile idiopathic arthritis (JIA) using this questionnaire.Methods. The MTX Intolerance Severity Score (MISS) questionnaire was constructed, consisting of 5 domains: stomach ache, nausea, vomiting, sore mouth, and behavioral symptoms. The domains each consisted of 3 questions pertaining to the presence of a symptom upon, prior to (anticipatory), and when thinking of (associative) MTX intake. The MISS questionnaire was validated in 86 patients by determining its discriminative power between patients with and those without MTX intolerance, identified as such by a gold standard (physician's opinion). Using the MISS questionnaire, the prevalence of MTX intolerance was determined in 297 JIA patients.Results. The MISS questionnaire discriminated well between MTX-intolerant and MTX-tolerant patients. A cutoff score of 6 yielded the best sensitivity (88%) and specificity (80%). MTX intolerance was found in 150 (50.5%) of 297 patients. Of 220 patients receiving oral MTX, 98 (44.5%) experienced MTX intolerance, whereas 67.5% of 77 patients receiving parenteral MTX experienced intolerance to the drug (P ‫؍‬ 0.001).Conclusion. Our findings indicate that the MISS questionnaire is a highly sensitive and specific tool for the diagnosis of MTX intolerance, and that there is a high prevalence of MTX intolerance among JIA patients. The prevalence of intolerance in patients receiving parenteral MTX exceeds that in patients receiving oral MTX. The frequent occurrence of anticipatory and associative symptoms suggests that classic conditioning plays an important role in MTX intolerance.

ABCB1 rs1045642, ABCC3 rs4793665, and SLC19A1 rs1051266 polymorphisms were associated with response to MTX in 287 patients with JIA studied longitudinally. Upon validation of our results in other JIA cohorts, these genetic determinants may help to individualize treatment strategies by predicting clinical response to MTX.

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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 targeted treatment. We genotyped 759 JIA cases from the UK, Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of treatment. In Phase I analysis samples were analysed for 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 reach our goal of predicting response to MTX in JIA.

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In this evidence-based case report, we studied the clinical question: Is a positive family history of acute otitis media (AOM) predictive for recurrent acute otitis media (rAOM) in children between zero and two years of age? The search yielded 3178 articles, of which only two were relevant and had a high validity regarding our clinical question. Neither of these two studies provided the final answer to our clinical question because they did not report stratified absolute risks for a positive family history. Fortunately, we were able to study the absolute risks in one of the two studies. The absolute risk of rAOM without distinguishing family history was 33 percent; the risk was 27 percent for children without a family history and 45 percent for children with a positive family history. Family history increases the absolute risk, but not in a way that it will help to predict rAOM accurately.

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