Toxicity Of Methotrexate Treatment Research Articles

Associations between single-nucleotide polymorphisms of RFC-1, GGH, MTHFR , TYMS, and TCII genes and the efficacy and toxicity of methotrexate treatment in patients with rheumatoid arthritis.

The differences in drug efficacy and adverse reactions may be caused by genetic variations in drug metabolism between individuals. The aim of the study was to evaluate the effect of gene polymorphisms on the efficacy of therapy and side effects in patients with rheumatoid arthrit s (RA) treated with methotrexate (MTX). A total of 273 Caucasian patients with RA were treated with MTX for at least 6 months or stopped MTX because of adverse effects. Seven polymorphisms (RFC-1 c.80G>A, GGH c.-401C>T, MTHFR c.1298A>C and c.677C>T, TYMS 2R/3R, TYMS 6-bp deletion, and TCII c.593T>C) were examined for their effects on MTX efficacy and toxicity. Genomic DNA was obtained from peripheral blood leukocytes. Of all patients, 53% reported some adverse effects during at least 1 visit, which led to MTX withdrawal in 17% of the patients. Adverse effects were more frequent in patients with the MTHFR 677T allele than in those with the 677CC genotype (odds ratio [OR], 1.97; P = 0.01) and in those with the GGH 401CC genotype than in those with the GGH 401CT and TT genotypes (OR, 3.8; P = 0.05). Furthermore, the MTHFR 677T allele was associated with increased activity of aminotransferases (OR, 3.4; P = 0.02). MTX-related hepatotoxicity and alopecia were more common in patients with the RFC-1 80AA genotype (OR, 3.5, P = 0.01; OR, 2.4, P = 0.04; respectively). A more rapid positive response to MTX therapy was demonstrated in MTHFR 677CC homozygotes (OR, 3.4; P = 0.001). There were no other associations between single -nucleotide polymorphisms and the efficacy of MTX treatment. The MTHFR 677CC and GGH 401TT and CT genotypes were associated with a reduction in the number of MTX-related adverse events. Future allele and genotype analyses may help identify the subsets of RA patients with an increased risk of adverse effects.

Pharmacogenetics and Pharmacogenomics for Rheumatoid Arthritis Responsiveness to Methotrexate Treatment: The 2013 Update

Rheumatoid arthritis (RA) is a complex, systemic autoimmune disease characterized by chronic inflammation of multiple peripheral joints, which leads to serious destruction of cartilage and bone, progressive deformity and severe disability. Methotrexate (MTX) is one of the first-line drugs commonly used in RA therapy owing to its excellent long-term efficacy and cheapness. However, the efficacy and toxicity of MTX treatment have significant interpatient variability. Genetic factors contribute to this variability. In this review, we have summarized and updated the progress of RA response to MTX treatment since 2009 by focusing on the fields of pharmacogenetics and pharmacogenomics. Identification of genetic factors involved in MTX treatment response will increase the understanding of RA pathology and the development of new personalized treatments.

Toxicity of methotrexate treatment in psoriasis and psoriatic arthritis--short- and long-term toxicity in 104 patients.

Methotrexate (MTX) is an effective anti-psoriatic agent but there are major concerns about its long-term toxicity, in particular to the liver. Reported frequencies and recommendations for monitoring patients on MTX vary considerably. The aim of this study was to analyse the frequency and severity of MTX-associated adverse drug reactions (ADR) in patients with psoriasis and psoriatic arthritis. A retrospective analysis was performed of 104 psoriasis and psoriatic arthritis patients (60 male, 44 female) treated with MTX between October 1968 and October 1998. The severity of ADR was classified according to Common Toxicity Criteria (CTC). Acute ADR was defined as adverse effects within the first 90 days of MTX therapy. ADR seen later were classified as chronic. In 83 patients 165 ADR were noted within the beginning of MTX therapy. In five patients treatment was terminated because of ADR. During long-term therapy 23 patients received < or = 2000 mg MTX (group A); 81 received a cumulative dose greater than 2000 mg (group B). The total frequency of ADR in group B and the frequency of ADR CTC grade 3 or 4 in general was not significantly increased in group B (chi2 test; P = 0.468). Group B was characterised as follows: CTC grade 3 or 4 blood count changes led significantly more often to the termination of MTX (Fisher's exact test; P = 0.048), CNS side-effects (P = 0.016) and infections were more frequent (chi test; P<0.001). Liver changes and serum enzyme level increases were not significantly more frequent in group B. ADR are common in psoriasis patients on MTX therapy independent of the cumulative dose. In most cases they are temporary by nature and mild. Liver changes and serum enzyme level increases were not a major problem in our patients.