The treatment of rheumatoid arthritis (RA) with methotrexate (MTX) has been a major advance <sup>38 Kremer J.M., Alarcón G.S., Alexander R.W. , e al. Methotrexate (MTX) lung toxicity: Clinical features of thirty-seven cases from seven rheumatology practices Arthritis Rheum 1997 ; in press.

Cliccare qui per andare alla sezione Riferimenti, 40 Kremer J.M., Phelps C.T. Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months Arthritis Rheum 1992 ;  35 : 138-145  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 52 Scully C.J., Anderson C.J., Cannon G.W. Long-term methotrexate therapy for rheumatoid arthritis Semin Arthritis Rheum 1991 ;  20 : 317-331  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 57 Tishler M., Caspi D., Yaron M. Long-term experience with low dose methotrexate in rheumatoid arthritis Rheumatol Int 1993 ;  13 : 103-106  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 60 Weinblatt M.E., Kaplan H., Germain B.F. , e al. Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study Arthritis Rheum 1994 ;  37 : 1492-1498  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 61 Weinblatt M.E., Weissman B.N., Holdsworth D.E. , e al. Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis: 84-month update Arthritis Rheum 1992 ;  35 : 129-137  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 62 Weinstein A., Marlowe S., Korn J. , e al. Low-dose methotrexate treatment of rheumatoid arthritis, long-term observations Am J Med 1985 ;  79 : 331-337  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 63 Whitcomb M.E., Schwarz M.I., Tormey D.C. Methotrexate pneumonitis: Case report and review of the literature Thorax 1972 ;  27 : 636-639  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 66 Wolfe F., Hawley D.J., Cathey M.A. Termination of slow acting antirheumatic therapy in rheumatoid arthritis: A 14-year prospective evaluation of 1017 consecutive starts J Rheumatol 1990 ;  17 : 994-1002

Cliccare qui per andare alla sezione Riferimenti</sup> Methotrexate is now the most commonly used second-line treatment for RA.<sup>66 Wolfe F., Hawley D.J., Cathey M.A. Termination of slow acting antirheumatic therapy in rheumatoid arthritis: A 14-year prospective evaluation of 1017 consecutive starts J Rheumatol 1990 ;  17 : 994-1002

Cliccare qui per andare alla sezione Riferimenti</sup> Comparative studies have suggested that RA patients continue MTX longer than other second-line antirheumatic drugs.<sup>66 Wolfe F., Hawley D.J., Cathey M.A. Termination of slow acting antirheumatic therapy in rheumatoid arthritis: A 14-year prospective evaluation of 1017 consecutive starts J Rheumatol 1990 ;  17 : 994-1002

Cliccare qui per andare alla sezione Riferimenti</sup> Longitudinal and comparative studies have shown that MTX can be continued in RA patients with sustained benefit.<sup>40 Kremer J.M., Phelps C.T. Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months Arthritis Rheum 1992 ;  35 : 138-145  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 52 Scully C.J., Anderson C.J., Cannon G.W. Long-term methotrexate therapy for rheumatoid arthritis Semin Arthritis Rheum 1991 ;  20 : 317-331  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 61 Weinblatt M.E., Weissman B.N., Holdsworth D.E. , e al. Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis: 84-month update Arthritis Rheum 1992 ;  35 : 129-137  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup>

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.<sup>62 Weinstein A., Marlowe S., Korn J. , e al. Low-dose methotrexate treatment of rheumatoid arthritis, long-term observations Am J Med 1985 ;  79 : 331-337  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> 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.<sup>54 Sostman H.D., Matthay R.A., Putman C.E. , e al. Methotrexate-induced pneumonitis Medicine 1976 ;  55 : 371-388  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> 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.