Hypothesis: An immuno-biomechanical model of anti-cyclic citrullinated peptide antibody positive rheumatoid arthritis

• ACPA-positive RA arises from the interaction between primed immune systems and the articular connective tissue substrate. • ACPA-positive RA develops as thresholds of articular stiffness are crossed producing normal age incidence distributions. • Increases in articular stiffness at menopause account for the earlier age incidence peak in women. • Greater articular stiffness causes more severe RA in late-life may explain “difficult-to-treat” RA. • Arterial and articular stiffness correlate. This partly accounts for the excess cardiovascular disease in ACPA-positive RA. The dramatic scientific and therapeutic advances of the last century have transformed outcomes in the management of anti-CCP positive rheumatoid arthritis (ACPA + RA). However, therapeutic challenges remain. While ACPA + RA is fundamentally an immunological disease the Immuno-Biomechanical Model (IBM) adopts a novel perspective proposing that ACPA + RA is the outcome of the interaction between primed immune systems and the connective tissue substrate. The model starts with the simple premise that ACPA + RA develops as immunologically primed individuals cross biomechanical thresholds of articular stiffness and that subsequent RA severity is similarly influenced by articular stiffness. This biologically plausible model is based upon established RA epidemiology and observational studies informed by studies of connective tissue biomechanics. The hypothetical implications of the model are explored graphically revealing how changes in articular stiffness could explain the unimodal age incidence distributions, the earlier age peak in women, the paradox of increasing RA severity in the face of declining RA incidence in late-life and suggesting new potential mechanisms for delayed treatment failure and refractory RA. The model suggests that a component of the excess cardiovascular disease in ACPA + RA may have a biomechanical basis not influenced by standard immunotherapies that contributes to the persistence of excess CVD regardless of the therapeutic advances in RA therapeutics. The IBM presents a plausible hypothesis describing a landscape for further research with broad implications for the treatment of ACPA + RA.