Systemic neutrophil activation and N‐formyl methionine‐formyl peptide receptor‐1 signaling define inflammatory endotypes in rheumatoid arthritis‐associated lung involvement

Abstract Background Neutrophil activation plays a crucial role in the pathogenesis of rheumatoid arthritis (RA), but its involvement in RA‐associated interstitial lung disease (RA‐ILD) remains unclear. This study investigated the involvement of N ‐formyl methionine (fMET) and its receptor formyl peptide receptor‐1 (FPR1) in neutrophil‐mediated inflammation in RA‐ILD. Methods Plasma and sputum levels of fMET and neutrophil activation markers were measured by ELISA in two cohorts ( n = 269 and 314) spanning multiple disease subgroups. Neutrophil activation was assessed by flow cytometry following plasma stimulation, with or without FPR1 inhibitors. Results Calprotectin levels were significantly elevated in both plasma and sputum of RA‐ILD patients compared to controls and RA‐noILD patients ( p < 0.05 for all analyses) and were negatively correlated with pulmonary function in RA (forced vital capacity [FVC], r = −0.39, p = 0.0002; diffusing capacity for carbon monoxide [DLCO], r = −0.39, p = 0.001). Plasma fMET levels were higher in RA‐ILD patients compared to healthy controls ( p < 0.0001) as well as compared to RA‐noILD patients ( p < 0.01), with a significant inverse correlation to pulmonary function in RA patients (FVC, r = −0.42, p < 0.0001; DLCO, r = −0.31, p = 0.01). Plasma from RA‐ILD patients induced neutrophil activation through FPR1‐dependent mechanisms ( p < 0.0001). Hierarchical clustering identified reproducible subgroups defined by fMET and calprotectin, with the high‐fMET cluster enriched for RA‐ILD and associated with lower DLCO ( p < 0.05). Conclusions The fMET–FPR1 axis is associated with neutrophil activation in RA‐ILD and defines inflammatory endotypes associated with lung impairment. Neutrophil‐based biomarkers may enable early risk stratification and provide rationale for targeting the fMET–FPR1 axis in RA‐ILD.