Rhupus syndrome: current knowledge and future perspectives

Rhupus syndrome refers to the coexistence of clinical, serological, and imaging features characteristic of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Although recognized for decades, its natural history, immunopathogenesis, and optimal management remain incompletely defined.

This narrative review (PICo framework) outlines the historical evolution and current understanding (from inception to 2025) of rhupus, emphasizing its hybrid phenotype: dual autoantibody profiles including rheumatoid factor, anti-citrullinated and anticarbamylated protein antibodies, and antinuclear and extractable nuclear antigen antibodies; RA-like erosive arthropathy demonstrable by radiography, ultrasound, and magnetic resonance imaging; and a variable, frequently milder spectrum of SLE involvement. Genetic studies implicate shared autoimmune susceptibility loci, most notably HLA-DRB1 shared-epitope alleles and PTPN22, while immunophenotyping reveals enrichment of T-helper 1 (Th1)-polarized and CD4⁺ CD28^null T-cell expansion alongside B-cell hyperactivity. Evidence guiding treatment is largely observational; nonetheless, conventional disease-modifying antirheumatic drugs, B-cell depletion, abatacept, and selective use of targeted synthetic agents have demonstrated benefit in subsets of patients.

Progress in rhupus requires standardized classification criteria, prospective international registries, and longitudinal multi-omic and single-cell analyses integrated with advanced imaging. A coordinated research agenda is essential to transition rhupus from a poorly defined clinical overlap to a precision-managed autoimmune entity.