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Cathechol-O-methyltransferase Val158Met polymorphism is associated with nocebo effects, but not with methotrexate intolerance in patients with juvenile idiopathic arthritis

Methotrexate (MTX) is the drug used most frequently in the therapy of juvenile idiopathic arthritis (JIA), with few and usually transient adverse effects such as elevated liver function tests and bone marrow depression (1, 2). However, long-term treatment in children frequently leads to intolerance, with symptoms including anticipatory nausea, marked revulsion, and refusal of treatment (3). As these symptoms frequently occur before the medication is taken or applied, this is considered a psychological side effect, similar to anticipatory nausea experienced in relation to cancer treatment. Anticipatory nausea has been conceptualized as the result of classical conditioning principles, which are similar to commonly observed nocebo effects (4). The term nocebo was created in analogy to the term placebo, and describes the development of negative effects attributed to medication, usually in the placebo group of a clinical trial (5). Catechol-O-methyltransferase (COMT) is an important enzyme in dopamine catabolism; alterations in activity can lead to elevated levels of dopamine in the prefrontal cortex, which can affect processes associated with the placebo effect such as reward, pain, memory, and learning (6). Mutations in the COMT gene, especially the Val158Met mutation, are a possible biomarker of the placebo response and have been associated with an increased rate of nocebo effects in cyclosporin A (7). The aim of this study was to investigate the relation between Val158Met mutations in the COMT gene and the occurrence of MTX intolerance in paediatric patients with JIA treated with MTX. Clinical data and samples were collected from patients in the prospective JASMIn cohort, at inclusion (8). Consecutive patients from October 2012 to April 2014 were included in this study. Inclusion criteria were a diagnosis of JIA and treatment with MTX for at least 3 months before inclusion. Exclusion criteria were other diseases leading to nausea and/or abdominal complaints, and concomitant medications possibly inducing nausea (excepting biologics and non-steroidal antiinflammatory drugs). Intolerance to MTX was determined using the validated Methotrexate Intolerance Severity Score (MISS) questionnaire (3); MTX intolerance was assumed for MISS values of ≥ 6. Genotyping for the Val158Met polymorphism in the COMT gene was performed using a polymerase chain reaction assay, as described previously (9). Results were analysed using descriptive statistics, chi-square testing, and Student’s t-test. The study was approved by the ethics committee of the Bavarian State Chamber of Physicians (Bayerische Landesärztekammer). In total, 160 patients were included (73% female, average age at diagnosis 5.3 years, average disease duration 4.8 years) (Table 1). Of these, 72 (45%) showed MTX intolerance. Of the 160 patients, 42 were Val/Val homozygous carriers for the Val158Met polymorphism of the COMT gene. MTX intolerance was not found significantly more frequently in Val/Val homozygous carriers compared to heterozygous or Met/Met homozygous carriers (21/21 vs 51/67, p = 0.474). Val/Val homozygous carriers had similar MISS scores to heterozygous and Met/Met homozygous carriers (mean 6.62 vs 6.33, p = 0.805). MTX intolerance affects up to half of children with JIA treated with this medication (3). It is related to anticipatory nausea, frequently observed in chemotherapy settings; the higher frequency of anticipatory symptoms in rheumatic disease may be related to the longer treatment time with regular, repeated weekly dosing. Patients and their parents in the paediatric rheumatology setting frequently share experiences and advice, and expectations may shape medication side effects in MTX treatment. It is therefore reasonable to expect more MTX intolerance in patient groups with a