Although adverse events may occur at any time, they tend to develop in the early months of treatment with methotrexate. Events are common but most are minor and usually can be managed without stopping therapy. Gastrointestinal adverse effects are the most common. These include anorexia, nausea, vomiting and diarrhoea. They often resolve or improve with dose reduction or a switch to parenteral administration. Stomatitis, including erythema, painful ulcers and erosions are also frequent.
Prophylactic folic acid supplementation can reduce the rate of gastrointestinal and oral side effects. The optimal dosage of folic acid is uncertain, although 5mg weekly appears adequate and has no more than a modest impact on efficacy. Alopecia is fairly frequent and causes particular concern to female patients. Other skin reactions include urticaria, and cutaneous vasculitis. Occasionally, methotrexate causes accelerated nodulosis, usually involving small nodules on the fingers or elbows. These nodules are indistinguishable from rheumatoid nodules except for their rapid onset and the fact that they can develop in patients negative for rheumatoid factor. Controversy surrounds their management; ie, whether to stop methotrexate treatment or add an antirheumatic drug such as hydroxychloroquine which has been shown to reduce nodules in this circumstance. Other adverse events related to methotrexate therapy include fever, fatigue or myalgia. Infections sometimes occur, including opportunistic infections with organisms like Pneumocystis carinii, fungal infections and localized or disseminated herpes zoster.
Serious side effects include cytopenias (seen only rarely) or, most commonly, mild-to-moderate leucopenia, which responds to withdrawal of the drug. More severe bone marrow suppression may be treated with leukovorin or recombinant colony-stimulating factors. Mild transaminase elevations are common during treatment with methotrexate, but serious hepatotoxicity that can lead to fibrosis or frank cirrhosis is rare.
A feared but rare complication of methotrexate therapy is acute pneumoni-tis (acute pulmonary interstitial disease) which usually occurs early in the course of therapy (within 32 weeks in 50% of instances). In a recent study of over 600 methotrexate-treated patients, 551 of whom had RA, six cases of pneumonitis were identified one of which resulted in death. Suggested risk factors include older age, rheumatoid pleuropulmonary involvement, previous DMARD use and diabetes mellitus; however, prediction is very imperfect and the most important measure is to ensure that all patients and clinicians are aware of this potential problem. Methotrexate can also be linked to other more chronic forms of respiratory involvement although it is often difficult to assess whether such problems arise from the underlying disease or from treatment.
Patients should be monitored prior to and during treatment with methotrex-ate. Conventionally, full blood count (FBC) and liver function tests are undertaken monthly. A chest X-ray is taken at the beginning of treatment, providing a baseline against which any subsequent lung problems can be evaluated. To avoid methotrexate-induced liver damage, it is also standard practice to advise patients to drink either no or very little alcohol. The true value of these monitoring policies, in terms of evidence-based medicine, is open to question as considerable resources are used to detect relatively few significant events. However, in the current risk-averse climate, it seems unlikely that guidance from pharmaceutical companies, national health agencies or national rheumatology societies will change.
Teratogenicity is a potential risk of methotrexate when used to treat RA. The foetal aminopterin-methotrexate syndrome is well documented in children of women taking high-dose methotrexate for malignancies. This syndrome includes skeletal abnormalities, microcephaly and hydrocephalus. With low-dose methotrexate, the risk is less clear though many reported pregnancies have resulted in births of full-term healthy infants. Nevertheless, pregnancy is a contraindication for methotrexate treatment. Women taking methotrexate who are at risk of pregnancy should use reliable methods of birth control. After methotrexate treatment is stopped, women should wait at least three months before trying to conceive; many national teratology agencies and companies recommend a longer period of withdrawal of up to six months because of the tendency for methotrexate to be retained in tissues. Methotrexate has no effect on fertility in women, and if the drug is stopped at least 30 days prior to attempting conception, it will not affect the foetus. Breast-feeding is not recommended while taking methotrexate, because the drug may enter the mother's milk.
Methotrexate may lower sperm count, although the count should normalize once the drug is discontinued. There is limited information regarding the risk of birth defects from a father taking methotrexate at the time of conception. However, it is recommended that males discontinue methotrexate three months prior to attempting conception.
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