Serious problems with methotrexate?

Low dose methotrexate (5-25 mg/week) represents a major therapeutic advance in the management of RA in the last decade. Its established efficacy has led to it being used as the lead comparator drug in slow acting anti-rheumatic drug (SAARD) trials, to its increasing use in early disease, and to its inclusion in many drug combinations currently being evaluated. It seems to be the best tolerated SAARD with up to 75% remaining on it after 5 years [1]. Its therapeutic mode of action is still a matter of conjecture as low dose therapy is not anti-proliferative yet is still anti-inflammatory [2]. Its anti-inflammatory effect may be mediated by ade-nosine [3] although direct effects on cytokine and eico-sanoid production have been claimed. Methotrexate's pharmacodynamics vary, absorption and excretion differing enormously and unpredictably between individuals as well as being influenced by measurable factors such as renal function and concomitant therapies including NSAIDs and probenicid. The latter can elevate methotrexate levels by 400% [4]. This is important when assessing the relative efficacy and side effects in individual patients. Minor adverse reactions with methotrexate are relatively common but generally do not result in treatment discontinuation. This contrasts with other SAARDs e.g. myocrisin, minor reactions to which often lead to stopping therapy when temporary cessation or dosage reduction, may be more appropriate [5]. Non life-threatening methotrexate side effects such as nausea or diarrhoea may be improved by dosage adjustment, altering route of administration from oral to parenteral or using divided weekly dosage. Increased nodulosis is an unusual but well-recognized occurrence with meth-otrexate which can be troublesome. It has been reported to be helped by co-treatment with hydroxychloroquine [6]. Other less serious but troublesome adverse reactions such as minor stomatitis, alopaecia and skin rashes are self-evident and can be treated according to their severity by withdrawal of therapy, dosage adjustment or topical treatment. It has been suggested that methotrex-ate is associated with increased post-operative infections or delayed wound healing and that it should be stopped pre-operatively. Several small prospective studies have not confirmed such an effect [7, 8], yet a definitive answer requires a much larger study. The more potentially lethal adverse haematological, pulmonary and hepatic reactions seem to be associated with an older group, renal impairment and relative folate deficiency. There is some evidence that folate supplements cause no loss of efficacy and protect against toxicity [9]. Serious haematological toxicity seems to be relatively rare [10] …