METHOTREXATE PULMONARY TOXICITY

The treatment of rheumatoid arthritis (RA) with methotrexate (MTX) has been a major advance 38,40,52,57,60,61,62,63,66 Methotrexate is now the most commonly used second-line treatment for RA. 66 Comparative studies have suggested that RA patients continue MTX longer than other second-line antirheumatic drugs. 66 Longitudinal and comparative studies have shown that MTX can be continued in RA patients with sustained benefit. 40,52,61 When MTX was initially being evaluated in RA patients, significant concern was expressed about this drug's potential toxicity. Prospective trials and retrospective studies have evaluated the adverse events associated with MTX treatment of RA. Liver biopsies have been performed to determine the impact of MTX on liver histology, frequent blood counts have been collected to survey for hematologic toxicity, and clinical monitoring for symptomatic complaints has been routinely performed. 62 Fortunately, many of the toxicities anticipated to be associated with MTX treatment of RA have not been observed in the severity or frequency that was originally envisioned. In contrast to the anticipation of significant liver pathology associated with MTX during the treatment of RA, some investigators speculated that MTX-induced pulmonary toxicity would not be reported in RA patients receiving this agent. Previous experience with MTX in the treatment of malignancies, psoriasis, and other medical conditions had suggested that MTX toxicity did not occur at doses less than 20 mg/week. 54 Because the doses of MTX used in RA were lower than this presumed threshold, the possibility of MTX-induced pulmonary reactions was not given serious consideration in the early literature deliberating the potential risks and benefits of MTX in the treatment of RA. Subsequent clinical experience has demonstrated and recognized MTX-induced pulmonary toxicity as a significant, potentially life-threatening, and rarely fatal adverse drug reaction to MTX.* *References 2,4,5,10,11,12,13,14,19,20,22,25,31,32,43,45,51,63 The clinician using MTX must be aware of the clinical presentation of this important disorder. A systematic approach must be applied when evaluating patients receiving MTX who develop pulmonary complaints. The evaluation must determine if the new lung symptoms represent a manifestation of the underlying pulmonary disease, the onset of an unrelated lung process such as infection, or the development of MTX-induced pulmonary toxicity. This article reviews the different types of MTX-induced pulmonary disease, describes the clinical features associated with this disease, reports the diagnostic criteria proposed, and suggests a management approach for these patients. The goal of this article is to provide the clinician with the information to successfully evaluate RA patients who develop new pulmonary symptoms while being treated with MTX and appropriately manage those individuals if MTX-induced pulmonary toxicity is identified.