ANA-Arthritis: Clinical and Biomarker Characterization of a Population for Basket Trials

Background: ANA-associated RMDs (ANA-RMDs - SLE, pSS, scleroderma, inflammatory myositis, mixed connective tissue disease (MCTD) and undifferentiated connective tissue disease) are a group of diseases with overlapping clinical and immunological features. Musculoskeletal inflammation is one of the commonest and most impactful features across this spectrum. Our objective was to evaluate musculoskeletal inflammation (ANA-arthritis) prevalence in a multi-disease ANA-RMD study, determine whether it has a similar clinical impact across ANA-RMD diagnoses, propose new basket groupings of patients and evaluate immunological profiles in legacy and new basket contexts. Methods: An observational study enrolled ANA-RMD patients . Demographic variables, comorbidities, therapies, disease activity instruments (BILAG, SLEDAI, ESSDAI, physician-VAS), patient-reported outcomes (SF36, FACIT-Fatigue, EQ5D, ICECAP-A, WPAI, visual analog scales) and biomarker profile (6 gene expression scores, flow cytometry, autoantibody profile) were analysed. Reclustering was performed with Gaussian Mixture Modelling (GMM). Clinical and immune features of new and legacy clusters were compared. Findings: Inflammatory MSK symptoms were prevalent across ANA-RMDs, in 213/294 patients. In ANA-arthritis patients, most variables did not differ between RMD diagnoses, except for EQ5D-5L index and mobility domains (lower in MCTD and pSS, both p=0.03). Fibromyalgia and osteoarthritic feature prevalence did not differ significantly between diagnoses. However, therapeutic use differed significantly, biologic use being greatest in SLE (p=0.04). GMM yielded two multi-disease clusters; High-MSK disease activity (n=89) and Low-MSK disease activity (n=124). The High-MSK disease cluster contained all patients with active joint swelling and had significantly higher prednisolone usage, PGA and Sm/RNP/SmRNP/Chromatin positivity. Tetherin-MFI and Interferon Score-A activity were significantly greater in this group, fibromyalgia and osteoarthritis prevalence were numerically lower. Interpretation: We define ANA-Arthritis, a new clinically and immunologically homogenous population than existing RMDs for trials, and a more prevalent population for therapies in the clinic. Funding: This research was supported by a grant from LupusUK and AstraZeneca.Declaration of Interest: M.Y.M.Y. has received speaker fees from Roche and Novartis and consultancy fees from Aurinia Pharmaceuticals and UCB. E.M.V. has received honoraria from Novartis, AstraZeneca, Otsuka, Roche, UCB, Aurinia, Lilly, Alumis, BMS, GSK, Pfizer and research grants paid to his employer from AstraZeneca and Sandoz. All other authors declare no competing interest related to the work described in this manuscript.Ethical Approval: All individuals provided informed written consent and this research was carried out in compliance with the Declaration of Helsinki. This study was approved by the National Health Service Health Research Authority (REC Ref: 17/YH/0166). Healthy control participants’ peripheral blood was collected under the study number 04/Q1206/107. All experiments were performed in accordance with relevant guidelines and regulations. University of Leeds was contracted with administrative sponsorship.