Relapsing Polychondritis in the Genomic Era: From Classical Autoimmune Chondritis to VEXAS Syndrome and Therapeutics Advances

Background: Relapsing polychondritis (RP) is a rare systemic inflammatory disorder characterised by recurrent inflammation and progressive structural damage of cartilaginous and proteoglycan-rich tissues, particularly auricular, nasal and laryngotracheobronchial cartilage. Ocular, audiovestibular, cardiovascular, cutaneous, neurological and musculoskeletal manifestations illustrate its systemic nature. Traditionally regarded as an autoimmune chondropathy, RP is increasingly recognised as a heterogeneous clinical syndrome. The discovery of somatic mutations in UBA1 causing VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has substantially changed this conceptual framework.Objective: To provide an updated translational review of the pathophysiology, clinical phenotypes, diagnostic approach and treatment of RP, with particular emphasis on the distinction between classical immune-mediated RP and UBA1-mutated VEXAS-associated chondritis, and on the transition from empirical immunosuppression towards precision therapeutics.Methods: A narrative review of the literature was undertaken, focusing predominantly on publications between January 2000 and August 2026 while retaining seminal earlier studies defining RP and its diagnostic criteria. PubMed/MEDLINE and the reference lists of major reviews, multicentre cohorts and consensus documents were examined. Because randomised therapeutic evidence remains exceptionally limited in RP, treatment data were interpreted according to study design, number of treated patients, consistency of response and potential sources of bias.Results: Classical RP appears to involve loss of immune tolerance towards cartilage-associated extracellular matrix components, followed by interaction between adaptive and innate immune pathways. By contrast, VEXAS syndrome originates from acquired somatic UBA1 mutations in haematopoietic progenitor cells, resulting in altered ubiquitination, proteotoxic stress, clonal haematopoiesis and profound innate autoinflammation. Macrocytic anaemia, cytopenias, neutrophilic dermatosis, venous thromboembolism, persistent systemic inflammation and myelodysplastic features should prompt UBA1 testing in an appropriate RP phenotype. Airway involvement remains a major determinant of irreversible morbidity and mortality. Treatment of classical RP remains largely evidence-informed rather than evidence-based, whereas VEXAS requires a distinct strategy integrating anti-inflammatory and clone-directed therapy.Conclusions: RP should no longer be regarded exclusively as a uniform autoimmune chondropathy. The VEXAS paradigm demonstrates that a clinically similar phenotype may arise from fundamentally different pathogenic mechanisms. Contemporary management should combine clinical phenotyping, advanced imaging, haematological assessment and selective molecular testing, with therapy chosen according to organ threat, inflammatory activity, accumulated damage and underlying biology.