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Objectives ANA-associated rheumatic and musculoskeletal (MSK) diseases (RMDs) [SLE, primary SS (pSS), scleroderma, inflammatory myositis, MCTD and UCTD] make up a disease spectrum with overlapping clinical and immunological features. MSK inflammation is common and impactful across ANA-associated RMDs. The objectives of this study were to evaluate MSK inflammation (ANA-associated arthritis) prevalence in a multidisease ANA-associated RMD study, assess its clinical impact across ANA-associated RMD diagnoses, propose new basket groupings of patients, and evaluate immunological profiles in legacy and new basket contexts. Methods An observational study enrolled patients with ANA-associated RMDs. Demographic variables, comorbidities, therapies, disease activity instruments [BILAG, SLEDAI, the EULAR SS disease activity index (ESSDAI), physician visual analogue scale (VAS)], patient-reported outcomes [SF36, FACIT-Fatigue, EQ5D, ICECAP-A, Work Productivity and Activity impairment (WPAI), patient VAS] and the biomarker profile (six-gene expression scores, flow cytometry, autoantibody profile) were analysed. Reclustering utilized Gaussian mixture modelling (GMM). The clinical and immune features of new and legacy clusters were compared. Results Inflammatory MSK symptoms were prevalent across ANA-associated RMDs, in 213/294 patients. In ANA-associated arthritis patients, most variables did not differ between diagnoses, with the exception of the EQ5D-5L index and mobility domains (lower in MCTD/pSS, both P  < 0.05). FM and OA prevalence were similar across diagnoses. Therapy use differed significantly, the use of biologics being greatest in SLE (P  < 0.05). GMM yielded two multidisease clusters: High MSK disease activity (n  = 89) and low MSK disease activity (n  = 124). The high MSK disease activity cluster included all patients with active joint swelling, and they had significantly higher prednisolone usage, physician global assessment (PGA), Sm/RNP/SmRNP/chromatin positivity, Tetherin mean fluorescence intensity (MFI), and IFN Score-A activity, along with numerically lower FM and OA prevalence. Conclusion We defined ANA-associated arthritis, a more clinically and immunologically homogeneous population than existing RMD populations for trials, and a more prevalent population for therapies in the clinic. [ABSTRACT FROM AUTHOR]

Objective: Gene expression profiles are associated with the clinical heterogeneity of systemic lupus erythematosus (SLE) but are not well studied as biomarkers for therapy. We studied gene expression and response to rituximab in a multiethnic UK cohort who were refractory to standard therapy. Methods: We evaluated baseline expression levels of transcripts known to associate with clinical features of SLE using a 96‐probe TaqMan array and whole blood samples from 213 patients with active SLE who had been prospectively enrolled in the British Isles Lupus Assessment Group (BILAG) Biologics Register. We measured autoantibodies using immunoprecipitation and enzyme‐linked immunosorbent assays. We determined responses to first‐cycle rituximab at 6 months from treatment start in 110 SLE patients by assessing BILAG 2004 disease activity. Results: Interferon gene expression scores were lower in patients of European ancestry than in all other ancestry groups. The relationship between blood interferon gene expression scores and scores annotated to plasmablasts, neutrophils, myeloid lineage, inflammation, and erythropoiesis differed between patients of European and non‐European ancestries. Hierarchical clustering revealed 3 distinct non‐European ancestry patient subsets with stratified responses to rituximab that were not explained by sociodemographic and clinical variables, with responses lowest in an interferon‐low, neutrophil‐high cluster and highest in a cluster with high expression levels across all signatures (P < 0.001). Clusters in European ancestry patients did not predict response to rituximab but segregated patients by global disease activity and renal involvement. In both ancestral groups, interferon‐high clusters were associated with U1 RNP/Sm antibodies. Conclusion: Ancestry appears central to the immunologic and clinical heterogeneity in SLE. These results suggest that ancestry, disease activity, and transcriptional signatures could each assist in predicting the effectiveness of B cell depletion therapies. [ABSTRACT FROM AUTHOR]