Tu115 - Autoantibodies to PAD4 Associate with the Presence of Rheumatoid Arthritis, STAT3 Mutations, and Neutropenia in Patients with T-Large Granular Lymphocytic Leukemia

Abstract Text: T-large granular lymphocytic leukemia (T-LGLL) is a lymphoproliferative disorder characterized by clonally expanded CD8+ T cells enriched in somatic STAT3-activating mutations, neutropenia, and a strikingly high prevalence of rheumatoid arthritis (RA) compared to the general population. The peptidylarginine deiminase IV (PAD4) enzyme is strongly implicated in the pathogenesis of RA, and functions both as a generator of citrullinated autoantigens and as a direct target of autoantibodies in a subset of patients. Despite growing evidence for a central role of PAD4 in RA, the relationship between PAD4 and T-LGLL has not been explored. Here, we measured anti-PAD4 autoantibodies in well-characterized cohorts of patients with T-LGLL alone (n=95), T-LGLL with RA (T-LGLL/RA; n=94), and RA alone (n=380), and defined associations with neutropenia and STAT3 mutations. We found that patients with T-LGLL/RA were significantly more likely to have anti-PAD4 autoantibodies (60%) than patients with T-LGLL alone (2%; p< 0.0001), or RA alone (27%; p< 0.0001). Among anti-PAD4+ patients, T-LGLL/RA patients had a higher median level of anti-PAD4 antibodies compared to RA patients (0.84 [IQR 0.70-1.01] vs. 0.59 [IQR 0.29-0.87] units; p< 0.0001). A larger proportion of anti-PAD4+ T-LGLL/RA patients harbored activating STAT3 mutations in their peripheral blood mononuclear cells than anti-PAD4- patients (90% vs. 74%; p=0.047), especially the D661Y mutation (71% vs. 39%; p=0.005). Also, in T-LGLL/RA, anti-PAD4 levels were inversely correlated with absolute neutrophil count (Spearman’s rho=-0.236; p=0.022). These data suggest a mechanistic link between humoral immunity to PAD4 and the presence of RA in the T-LGLL population.