Joint disease in systemic lupus erythematosus: clinical manifestations, immunopathology, and treatment

Abstract

Joint involvement affects the majority of patients with systemic lupus erythematosus and is consistently ranked among the manifestations with the largest impact on daily function, yet lupus synovium remains one of the least interrogated major target tissues in this disease. The primary literature on lupus synovial tissue rests mainly on two datasets, neither generated by single-cell transcriptomic or mass cytometric methods, and what they describe is a relatively pauci-immune and myeloid-dominated compartment carrying an interferon-inducible transcriptional signature in situ , without the ectopic germinal centers and expanded pathogenic fibroblast populations that characterize rheumatoid synovitis. The cell populations now central to systemic lupus biology, among them T peripheral helper cells and double-negative 2 B cells, have never been examined in lupus synovial tissue, so that every cellular account of this compartment remains an extrapolation from rheumatoid arthritis. Recent large-cohort data nevertheless indicate that lupus arthropathy is not a single entity, since non-deforming arthritis and Jaccoud’s arthropathy are both associated with a high type I interferon signature whereas arthritis with clinically irreducible deformity is interferon-low, although whether these represent distinct biological trajectories or successive stages of a single process remains to be established. This heterogeneity is invisible to the instruments used in practice, because the composite indices that grade disease activity and determine eligibility for advanced therapy depend on the detection of joint swelling at the bedside, while musculoskeletal ultrasound and contrast-enhanced magnetic resonance imaging independently demonstrate inflammation in approximately half of patients whose joints appear clinically unremarkable, together with erosive change in patients who lack anti-citrullinated protein antibodies. Misclassification of articular disease is therefore systematic and bidirectional, and the same failure has propagated into drug development, where no recent registrational program has used imaging to define articular response, even though the proportion of patients failing on articular endpoints lies between roughly a third and a half. This review synthesizes the immunopathological, biomarker, imaging and therapeutic literatures, and argues that single-cell interrogation of the lupus synovium, a lupus-specific imaging scoring system and a validated imaging-anchored articular outcome measure are the necessary next steps if this manifestation is to be treated with the precision now applied to lupus nephritis.