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To the Editor:

Since publication of our report we have followed an additional 46 patients with rheumatoid arthritis (RA) treated with infliximab that was added to existing methotrexate (MTX) therapy at our center, and no new cases of MTX pneumonitis have been observed. However, in addition to the patient reported in the letter by Courtney et al, we are personally aware of 2 more cases similar to those that we originally reported: a 70-year-old woman who developed biopsy documented MTX pneumonitis; and a 68-year-old woman (the sister of case 2 from our report) who developed life-threatening interstitial pneumonitis that was responsive to antibiotics and high-dose corticosteroid therapy, in whom lung biopsy was not performed. As was observed in the 3 cases in our original report, and the case cited Courtney et al in his letter, the onset of pneumonitis occurred shortly after the third dose of infliximab added to a stable dose of MTX. The occurrence of the same syndrome in 2 siblings raises the possibility of an immunogenetic predisposition.

Although the incidence of MTX pneumonitis may not be increased with the addition of infliximab, the temporal pattern observed in these 6 cases suggests a potential drug-drug interaction. We urge others treating patients with RA to report any similar cases, thereby allowing a more accurate estimate of the incidence of MTX pneumonitis in patients treated with infliximab.

A plausible mechanism by which anti-tumor necrosis factor (TNF) therapy might play a permissive or synergistic role in the expression of MTX pneumonitis was recently reported by Kuroki et al (Kuroki M, Noguchi Y, Shimono M, Tomono K, Tashiro T, Obata Y, et al. Repression of bleomycin-induced pneumopathy by TNF. J Immunol 2003;170:567–74). In a murine model of bleomycin-induced pneumonitis, TNF −/− mice, in comparison with TNF +/+, had an accelerated form of bleomycin-induced pneumonitis and pulmonary fibrosis associated with deficient apoptosis of infiltrating inflammatory cells. Intratracheal instillation of TNF reversed the apoptotic defect and prevented the development of interstitial fibrosis.

Neil Kramer MD*, Yelena Chuzhin MD*, Lee Kaufman MD*, Jill Ritter MD*, Elliot D. Rosenstein MD*, * Arthritis and Rheumatic Disease Center at St. Barnabas, Livingston, NJ.