Anti-gingipain antibodies and ACE1 activity in rheumatoid arthritis: associations with disease activity and cardiovascular comorbidity in a cross-sectional study

Abstract

We assessed cross-sectional relationships of rheumatoid arthritis (RA) disease activity and cardio-metabolic comorbidities with serum peptidylarginine deiminase 4 (PAD4)-potentiating activity, domain-resolved angiotensin I converting enzyme (ACE1) enzymatic activity, and Porphyromonas gingivalis-specific antibodies. 177 RA patients and 147 healthy controls (HC) were included in the study. Clinical profiling included DAS28, CRP/ESR, treatments, and comorbidities. PAD4-potentiating activity, ACE1 activities, and anti-gingipain antibodies were measured using standardized in-house assays. Associations with RA status, treatments, and outcomes were analysed using covariate-adjusted models; discrimination for selected comorbidities was explored with ROC analyses. PAD4-potentiating activity, anti-Kgp/anti-RgpB and ACE1 activities did not differ between RA and controls. In RA, anti-Kgp showed a weak correlation with DAS28 (Rs=0.17, p=0.033) and was lower with biologic disease-modifying antirheumatic drugs (DMARDs); ACE1 activity was lower among synthetic-DMARDs users across all three substrates (all p≈0.01–0.04). None of the biomarkers showed independent associations with DAS28 in adjusted models. Overall discrimination for cardio-metabolic outcomes was limited; small, predefined strata showed exploratory signals, but low event counts and multiple comparisons constrain inference. In this cohort, between-group differences were limited overall. However, two exploratory within-RA signals emerged: anti-Kgp levels were weakly associated with disease activity and therapy, and lower ACE1 activity was associated with synthetic DMARDs use. Together, anti-Kgp and ACE1 (N-domain) may reflect mucosal-immune and vascular-remodeling axes that could relate to comorbidity patterns and warrant prospective, pre-specified validation.