Revisiting the INSPIRE trial: Antibody profiling reveals high prevalence of occult autoimmunity

Rationale : The INSPIRE trial failed to demonstrate improved survival in participants labeled as Idiopathic Pulmonary Fibrosis (IPF) after treatment with IFN-gamma-1β. This outcome became the impetus to develop more personalized approaches to the diagnosis, classification, and management of pulmonary fibrosis. Objective : The present study was designed to assess autoantibody profiles in a randomly selected group of INSPIRE trial participants in order to better define IPF on a molecular diagnostic level and define subsets with potentially different underlying disease processes. Methods : We performed conventional, gel-based protein and RNA immunoprecipitation (IP) on 483 plasma specimens derived from patients enrolled in both the treatment and placebo arms of INSPIRE. Tandem immunoprecipitation and mass spectrometry proteomics (IP-to-MS) of selected specimens was performed to confirm conventional IP interpretation and to identify unknown autoantigens. Results : Based on conventional IP approaches, approximately 30% of trial participants had evidence of autoimmune disease-specific autoantibodies and an additional ~ 10% had evidence of autoantibodies of unknown specificity. IP-to-MS revealed additional autoantigens, including Annexin 11. Conclusions : IP analyses demonstrated an unexpectedly high prevalence of autoantibodies potentially indicative of underlying connective tissue disease-associated ILD, underscoring the importance of classification schemes incorporating unbiased autoantibody profiling.Word count: 192