Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis

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Abstract
OBJECTIVE To study the influence of sulphasalazine (SSZ), methotrexate (MTX), and the combination (COMBI) of both on plasma homocysteine and to study the relation between plasma homocysteine and their clinical effects. METHODS 105 patients with early rheumatoid arthritis (RA) were randomised between SSZ (2–3 g/day), MTX (7.5–15 mg/week), and the COMBI (same dose range) and evaluated double blindly during 52 weeks. Plasma homocysteine, serum folate concentrations, and vitamin B12 were measured. The influence of the C677T mutation of the enzyme methylenetetrahydrofolatereductase (MTHFR) gene was analysed. RESULTS A slight trend towards increased efficacy and an increased occurrence of minor gastrointestinal toxicity was present in the COMBI group, no differences existed clinically between SSZ and MTX. Only a slight and temporary increase in plasma homocysteine was found in the SSZ group, in contrast with the persistent rise in the MTX group and the even greater increase in the COMBI patients. Patients homozygous for the mutation in the MTHFR gene had significantly higher baseline homocysteine, heterozygous MTHFR genotype induced a significantly higher plasma homocysteine at week 52 compared with no mutation. No correlation was found between clinical efficacy variables and homocysteine. Patients with gastrointestinal toxicity had a significantly greater increase in homocysteine. CONCLUSION A persistent increase in plasma homocysteine concentrations was observed in patients treated with MTX alone and more pronounced in combination with SSZ, in contrast with SSZ alone. An increase in plasma homocysteine is related to the C677T mutation in MTHFR. A relation in the change in homocysteine concentrations with (gastrointestinal) toxicity was found, no relation with clinical efficacy existed.