Methotrexate in rheumatoid arthritis: toxicity issues.

IT has been lOyr since the initial randomized placebo-controlled trials were published which established the short-term efficacy of low-dose weekly methotrexate in rheumatoid arthritis [1,2]. For the past 10 yr there has been an extensive clinical research programme including comparative studies of methotrexate versus auranofin [3], azathioprine [4], i.m. gold [5] and cyclosporin A [6], and long-term prospective studies [7-9]. There is now little debate about the efficacy of methotrexate in rheumatoid arthritis. Methotrexate is now the most popular second-line therapy utilized in the USA for the treatment of rheumatoid arthritis. The enthusiasm and interest in this compound have expanded, and include our colleagues worldwide. It is timely to re-emphasize the toxicity profile of methotrexate. Toxicity is the major reason for methotrexate discontinuation [9, 10]. The most common side-effects of low-dose methotrexate are gastrointestinal toxicities, including anorexia, nausea, stomatitis and diarrhoea. Central nervous system toxicity, including headaches, dizziness, fatigue and mood alterations, may also occur. Many of these side-effects can be reduced by supplemental folk acid, 1 mg/day. Folic acid at this dose decreases many side-effects without interfering with the efficacy of the drug [11, 12]. When folic acid is not successful in improving side-effects, a trial of folinic acid administered 8-12 h after methotrexate may be effective [13]. Haematological toxicity with methotrexate is uncommon. Leucopenia, thrombocytopenia, megaloblastic anaemia and pancytopenia may occur. In almost all cases of haematological toxicity, an identifiable risk factor can be found. These risk factors include untreated folate deficiency, renal insufficiency, the use of methotrexate during a superimposed infection and the concomitant use of selected drugs such as trimethoprim/sulphamethoxazole or probenecid. Methotrexate is teratogenic; women of child-bearing potential should not become pregnant while taking it. Several decades ago, methotrexate was used as an abortifacient and it has again been proposed as such an agent [14]. Women of child-bearing potential must discontinue methotrexate for at least one menstrual cycle prior to attempting conception. Until recently, no carcinogenic effect of low-dose methotrexate had been demonstrated in either patients with psoriasis or rheumatoid arthritis. Recently, non-Hodgkin's (B-cell) lymphoma which reversed with methotrexate discontinuation has been reported in patients with rheumatoid arthritis [15-17]. EpsteinBarr virus was expressed in the tumour cells. The regression of the tumour without chemotherapy is a rare event in the course of non-Hodgkin's lymphoma. This suggests a relationship between this lymphoma and the drug. This spontaneous resolution of the lymphoma with drug discontinuation has been observed with other immunosuppressive therapies, including azathioprine and cyclosporin A when used in organ transplantation. Opportunistic infections are rare with methotrexate, but include localized and disseminated zoster, fungal infections and Pneumocystis carinii infection. Pulmonary toxicity remains a concern. This month's issue of the British Journal of Rheumatology contains two papers on the lung and methotrexate. One is from France describing the experience at Cochin Hospital with pulmonary complications in rheumatoid arthritis patients receiving methotrexate [18]. Their experience is similar to that previously observed. In the second paper, investigators from Switzerland prospectively studied pulmonary function in rheumatoid patients treated with methotrexate [19]. They reported that there was no significant change in pulmonary function in patients receiving low-dose weekly methotrexate for rheumatoid arthritis. Routine pulmonary testing did not identify patients who subsequently developed pulmonary disease. In fact, this study confirms that routine pulmonary function testing is not indicated in patients receiving low-dose methotrexate for rheumatoid arthritis. Identification of risk factors for the development of methotrexate pneumonitis has been an area of intense study. Several small studies suggested a relationship between pre-existing lung disease and the development of methotrexate pneumonitis [20-22]. At last year's American College of Rheumatology meeting, investigators reported a multicentre case-control study in which risk factors for methotrexate lung disease were identified, and included age, diabetes and the presence of pleuropulmonary disease prior to methotrexate administration [23]. As with other studies, disease duration, methotrexate duration, and weekly and cumulative doses were not risk factors for this side-effect. Whether rheumatoid arthritis patients are at greater risk for developing this side-effect as compared to patients receiving methotrexate for other diseases is unknown. There is little debate that methotrexate is hepatotoxic. Risk factors associated with liver toxicity in psoriatic patients receiving methotrexate include insulin-dependent diabetes, morbid obesity, renal insufficiency, alcohol consumption, daily or several methotrexate doses per week and cumulative dose of methotrexate [24]. Based on the association of hepatotoxicity with cumulative dose, the dermatology community has recommended routine liver biopsies