2756GG genotype of methionine synthase reductase gene is more prevalent in rheumatoid arthritis patients treated with methotrexate and is associated with methotrexate-induced nodulosis.

OBJECTIVE: To investigate the distribution of the A2756G polymorphism of the methionine synthase reductase (MTR) gene in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) compared with a healthy control group; and to examine the relationships among the A2756G polymorphism, plasma total homocysteine (tHcy), serum folate and vitamin B12 levels, disease activity, and MTX toxicity in patients with RA. METHODS: A cross-sectional study was performed on 86 MTX-treated RA patients, consisting of a clinical interview and physical examination to determine disease activity and MTX-related adverse reactions. Genotype analysis of the MTR gene was performed. Fasting plasma tHcy, serum folate, and vitamin B12 levels were measured. Allele and genotype distributions were compared to a healthy control group. RESULTS: The frequency of the 2756GG genotype (16.3%) in the RA study group was higher than that expected in the general population (3.6%; p < 0.000001). This genotype was associated with MTX-induced accelerated rheumatoid nodulosis (MIARN). No association of disease activity variables or plasma homocysteine with MTR A2756G polymorphisms was observed. The MTR 2756GG genotype, low plasma vitamin B12 levels, and the presence of rheumatoid nodules predicted MIARN. No association of nodulosis with any other indicator of disease activity or medical treatment was found. CONCLUSION: In our population of MTX-treated RA patients the 2756GG genotype of the MTR gene was more common than expected and was associated with MIARN.

A review of methotrexate-induced accelerated nodulosis.

OBJECTIVE: To review the English-language literature on methotrexate-induced accelerated nodulosis, compile case reports of its occurrences, and make recommendations on the clinical management of patients. METHODS: A comprehensive search of MEDLINE, TOXLINE, and EMBASE databases was performed, along with a bibliographic search of key articles. Case reports were compiled separately. The Naranjo adverse drug reaction probability scale was used to assess causality. RESULTS: Twenty-seven case reports of patients with methotrexate-induced accelerated nodulosis were identified along with one series of 10 patients and one series of 21 patients. Probability assessment for most of the case reports was weak and left room for doubt regarding causality. Most patients were older than 50 years, were positive for rheumatoid factor, and had nodules on their fingers but did not have concurrent vasculitis. Some unusual sites of nodulosis were the larynx, lungs, Achilles tendon, and heart. Of 19 patients given hydroxychloroquine, colchicine, sulfasalazine, azathioprine, or D-penicillamine, all except two showed regression of the nodules; the response was unknown for one patient. CONCLUSION: Controversy surrounds the management of patients who develop accelerated nodulosis while receiving methotrexate therapy for rheumatoid arthritis. Our review of these data does not allow definitive conclusions because the available case reports and clinical trials are fragmented and incomplete.

Rheumatoid nodules of the larynx.

A 67-year-old woman with rheumatoid arthritis was hospitalized because of dysphagia and severe nodulosis. Over a two-year period the patient had been treated with methotrexate. A computed tomography (CT) scan of the neck showed a 2 x 2 cm large tumour behind the top left lateral thyroid cartilage. A biopsy taken during direct laryngoscopy showed it was a rheumatic nodule. Treatment with colchicine reduced the patient's dysphagia. As methotrexate is used increasingly in the treatment of rheumatoid arthritis and as this particular drug causes rheumatic nodules in five to 10 per cent of the patients, it must be foreseen that the incidence of nodules in the upper airways will increase.

Accelerated nodulosis in a patient with psoriasis and arthritis during treatment with methotrexate.

A 66-year-old woman with longstanding psoriasis involving the skin presented with asymmetrical polyarthritis. Methotrexate (MTX) was given initially intramuscularly and orally. Intramuscular MTX was discontinued, and a few months after she had been taking only oral MTX she developed nodules, first in surgical incisions, and subsequently in her buttocks, thighs, legs, and arms. Reduction of the dose of oral MTX was followed by gradual diminution in size of the nodules and then total disappearance.