Hepatic and pulmonary side effects after the long-term administration of low-dose methotrexate

Summary and recommendation

MTX-induced acute or chronic lung disease and pleural effusion, can occur acutely at any stage of the treatment and have been reported even at doses as low as 7.5 mg per week. These conditions were not always fully reversible, and fatal cases have been reported. In the event of typical symptoms, such as a dry, irritating cough, immediate discontinuation of treatment and careful investigation should be considered [1].

An MTX-associated chronic hepatotoxicity usually occurs after prolonged administration (≥ two years) and a cumulative total dose ≥ 1.5 g. The risk is influenced by factors such as excessive alcohol consumption, obesity, diabetes mellitus, long-term treatment, age (> 60 years), renal insufficiency and pre-existing liver disease [1]. Since histological changes, fibrosis and more rarely liver cirrhosis may not be preceded by abnormal liver function tests, non-invasive diagnostic methods should also be considered for monitoring purposes [1]. US guidelines recommend non-invasive fibrosis testing at the start of treatment and then annually for patients with risk factors [2].

The administration of folic or folinic acid (at the earliest 24 hours after MTX administration) can significantly reduce the incidence of toxic methotrexate-induced gastrointestinal, haematological and hepatic side effects in patients with autoimmune diseases [3, 4]. However, folic acid administration has no effect on the pulmonary side effects [5].