BackgroundSpondyloarthropathies (SpA) comprise an inflammatory spectrum that can involve peripheral and axial joints, enthesial sites and extra-articular tissues. We hypothesized that oxidation of fibrocartilage matrix proteins collagen type II (CII) at enthesial sites might generate oxidative posttranslational modification (oxPTM)-associated neoepitopes that provoke humoral autoimmunity.Our objectives were to test for the presence and clinical significance of antibodies to oxPTM-CII in patients with SpA. MethodsLevels of antibodies specific to native CII and oxPTM-CII were assessed by enzyme-linked immunosorbent assays (ELISA). Reactivity in serum samples obtained from patients with axial SpA (axSpA, n=242) was compared to reactivity in samples from patients with predominantly peripheral arthritis such as psoriatic arthritis (PsA, n=69), undifferentiated arthritis (UA, n=48) and early rheumatoid arthritis (RA, n=60). Controls included psoriasis without musculoskeletal symptoms (Ps, n=35), fibromyalgia (FM, n=19) and healthy subjects (HC, n=178). 97 th percentile of the healthy individuals cut-off point absorbance units obtained for healthy control samples was used to construct a contingency table of positive binders to oxPTM-CII and tested it by Fishers Exact Test. ResultsIgG binding to oxPTM-CII was observed in serum samples from axSpA (52%) compared to RA (83%), PsA (28%), UA (35%), and FM (15%). Importantly, while strong IgA anti-oxPTM-CII was detected in axSpA and PsA patients, with 47% and 84% respective binders, no IgA anti-oxPTM-CII was detected in RA patients. IgA anti-oxPTM-CII reactivity in axSpA patients treated with biologics was higher and more frequent with 85% binders compared to 9% binders in patients treated with synthetic DMARDs. Sensitivity values for both IgG and IgA anti-oxPTM-CII for RA samples were 3 91% and 32%, respectively. IgG and IgA anti-oxPTM-CII for axSpA were 64% and 80%, respectively. Similartly, sensitivity for IgA anti-oxPTM-CII in PsA was doubled to 87%. Conclusions:Our data implies that axSpA is associated with the presence of antibodies specific for oxPTM-CII, suggesting that there may be a humoral component to disease-associated inflammation that may stratify patients with SpA from RA.