SALIVARY AND SERUM CYSTATINS (S/SN/C) AS SENTINELS OF THE PROTEASE–ANTIPROTEASE IMBALANCE LINKING PERIODONTITIS TO RHEUMATOID ARTHRITIS: A PERSPECTIVE FROM PILOT Q-TOF PEPTIDOMIC SCREENING

Abstract

Periodontitis and rheumatoid arthritis (RA) are both, at core, diseases of unchecked proteolysis: cysteine cathepsins degrade collagen, cartilage, and connective tissue in the periodontium and the synovium alike, held in check physiologically by an endogenous cystatin superfamily. We revisit the cystatin–cathepsin balance as a candidate convergent marker of the RA–periodontitis axis using a pilot untargeted Q-TOF peptidomic screen of serum and saliva across Control, RA-without-periodontitis, and RA-with-periodontitis groups. Among sixteen candidate protein/peptide families screened for association with clinical group, the cystatin superfamily (cystatin S, SN, and C) was the single strongest discriminator in serum, with complete separation between groups (Fisher's exact p = 2.13 × 10⁻⁷, Cramér's V = 1.00): detection rose from 0% in Control to 100% in RA-without-periodontitis (odds ratio 323, 95% CI 5.75–18,131.4), then fell back to 0% in RA-with-periodontitis. We situate this striking but small-sample pattern against an established, and sometimes contradictory, literature on salivary cystatins in periodontitis and on cystatin C as a marker of RA-associated cardiovascular and renal risk. Rather than asserting a validated biomarker, we use the pilot data to argue that the cystatin superfamily deserves systematic, isoform resolved, quantitatively calibrated study across both compartments of the RA–periodontitis axis — and we are explicit about why a nine-sample pilot group cannot settle that question on its own.