Rheumatology 2003; 42: 803-804
© 2003 British Society for Rheumatology
Letters to the Editor |
Reply
Department of Rheumatology, St Helens Hospital, Marshalls Cross Road, St Helens, Merseyside, UK
We thank Dr Provenzano for his interest in our recent article, and are encouraged by his supportive findings. We are concerned about the interchangeable use of the terms ‘methotrexate pulmonary toxicity’, ‘methotrexate pneumonitis' and ‘chronic pulmonary fibrosis caused by methotrexate’. We wish to clarify that the described complications of low-dose methotrexate are acute hypersensitivity pneumonitis, drug-induced asthma, pulmonary fibrosis, accelerated pulmonary nodulosis and infection with Pneumocystis carinii, cytomegalovirus, para-influenza virus, Cryptococcus neoformans, Aspergillus fumigatus, Histoplasma capsulatum and Candida albicans.
Pulmonary fibrosis and nodulosis may be manifestations of RA, and it is difficult to confidently ascribe this complication to methotrexate. Several reports, particularly early ones, describing acute hypersensitivity pneumonitis have used the term ‘pulmonary fibrosis’, which seems to have increased the belief that methotrexate causes a chronic pulmonary fibrosis. Pulmonary fibrosis has been reported in just three patients with psoriasis [1–3]; with this condition there is no associated lung disease and so the case for methotrexate being the causative agent seems stronger. However, one patient had features compatible with sarcoidosis [3]. Seven published studies incorporating pulmonary function testing have not demonstrated the development of pulmonary fibrosis in patients on methotrexate [4–10] and two of these also included high-resolution computed tomography of the chest in assessment of the patients [5, 8]. Certainly, if methotrexate causes chronic pulmonary fibrosis it is incredibly rare and risk factors for its development have definitely not been studied. There is no evidence that methotrexate accelerates pre-existing lung disease [6, 8].
The prevalence rate of methotrexate pneumonitis (MTX-P) in prospective series is between 0.7 and 7.7%. In most cases the condition occurs early in the treatment course. Case reports have suggested that pulmonary fibrosis (PF) in patients with rheumatoid arthritis (RA) predisposes them to MTX-P [11]. It should be remembered that the diagnosis of MTX-P is difficult because there are no pathognomonic findings and this condition mimics PF and pulmonary infection. Although infection is rigidly excluded, RA-associated PF fulfils many of the criteria. Even on histological examination by experts in the field of hypersensitivity pneumonitis, exclusion of acute rheumatoid lung disease is sometimes difficult [12].
The published studies aiming to identify risk factors for MTX-P in patients with RA have rarely stated how carefully they have excluded PF related to RA and often have not included RA control cases that are not receiving methotrexate. The best-defined study so far is a multicentre case-controlled study in which the basis for the diagnosis of methotrexate pneumonitis included a histological diagnosis agreed to by two expert pathologists [12]. The strongest predictors of methotrexate pneumonitis, after adjustment for other variables, were older age [odds ratio (OR) 5.1, 95% confidence interval (CI) 1.2–21.1]; diabetes (OR 35.6, 95% CI 1.3 to infinity), rheumatoid pleuropulmonary involvement (OR 7.1, 95% CI 1.1–45.4), previous use of disease-modifying anti-rheumatic drugs (OR 5.6, 95% CI 1.2–27.0), and hypoalbuminaemia (OR 19.5, 95% CI 3.5–109.7). Unfortunately the precision with which the authors diagnosed MTX-P was not extended to the definition of pre-existing lung disease. Only 26 of the 111 patients in the study had a chest radiograph and no further detail is given as regards the breakdown of pleuropulmonary involvement. It is, unfortunately, a common theme through the case–control studies that rather non-specific categories, such as pre-existing lung disease, interstitial shadowing on chest radiograph and pleuropulmonary involvement, are the risk factors for MTX-P, and so whether PF specifically is a significant risk factor remains unknown.
From our study and the brief outline of the literature on PF and methotrexate, we hope that we can encourage rheumatologists not to withhold methotrexate from patients with stable PF associated with RA. We also feel it is important for physicians with a research interest in this area to be as accurate as possible with their terminology, to prevent further inaccuracies and perpetuation of myths.
Notes
Correspondence to: J. K. Dawson. E-mail: twodocs{at}doctors.org.uk 
References
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