Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases

Objectives: To analyze the clinical characteristics, outcomes, and patterns of association with the different biologic agents used in all reported cases of adult patients developing interstitial lung disease (ILD) after biologic therapy.

Methods: In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project. One objective was to collect data on autoimmune diseases secondary to the use of biologic agents by quarterly Medline search surveillance of reported cases. For this study, the baseline included articles published between January 1990 and March 2010, including the MeSH term "lung diseases, interstitial" as the key research term. In addition, we report an unpublished case of ILD secondary to biologic therapy.

Results: There are 122 reported cases of new-onset or exacerbation of ILD secondary to administration of biologic therapies. Biologic agents associated with ILD were overwhelmingly anti-tumor necrosis factor agents (etanercept in 58 cases and infliximab in 56) and were administered for rheumatoid arthritis in 108 (89%) patients. ILD appeared a mean of 26 weeks after initiation of biologic agents. ILD was confirmed by pulmonary biopsy in 26 cases, although a specific histopathologic description was detailed in only 20: 7 patients were classified as usual interstitial pneumonia, 6 as nonspecific interstitial pneumonia, 5 as organizing pneumonia, 1 as diffuse alveolar damage, and 1 as lymphoid interstitial pneumonia. Treatment of ILD included withdrawal of biologic agents in all cases but 1. The outcome of ILD was detailed in 52 cases. Complete resolution was reported in 21 (40%) cases, improvement or partial resolution in 13 (25%), and no resolution in 18 (35%). Fifteen (29%) patients died during the follow-up, the majority (70%) during the first 5 weeks after initiating biologic therapy. In comparison with survivors, patients who died were aged >65 years (67% vs 33%, P = 0.036), with later onset of ILD (46 weeks vs 15 weeks, P = 0.006), received immunosuppressive drugs more frequently (33% vs 8%, P = 0.036), and more often had a previous diagnosis of ILD (67% vs 29%, P = 0.025).

Conclusions: We found that 97% of cases of ILD associated with biologic agents were associated with agents blocking tumor necrosis factor-α, a cytokine that has been implicated in the pathophysiology of pulmonary fibrosis. Strikingly, drug-induced ILD had a poor prognosis, with an overall mortality rate of around one third, rising to two thirds in patients with preexisting ILD.