Associations of ultrasound-based inflammation patterns with peripheral innate lymphoid cell populations, serum cytokine/chemokines, and treatment response to methotrexate in rheumatoid arthritis and spondyloarthritis

Abstract Background: We aimed to clarify the associations of musculoskeletal inflammation patterns with peripheral blood innate lymphoid cell (ILC) populations, serum cytokine/chemokines, and treatment response to methotrexate in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA).Methods: We enrolled patients with either RA or SpA who had peripheral symptoms and performed comprehensive ultrasound to evaluate power Doppler signals for synovitis (52 joint regions), tenosynovitis (20 tendons), and enthesitis (44 sites). We performed clustering analysis using unsupervised random forest based on the multi-axis ultrasound information and classified the patients into groups. We identified and counted ILC1-3 populations in the peripheral blood by flow cytometry and also measured the serum levels of 20 cytokine/chemokines. We also determined the American College of Rheumatology 20% improvement (ACR20) response at 3 months in 38 patients who initiated treatment with methotrexate after baseline assessment. Results: We enrolled a total of 100 patients with RA (n=66) or SpA (n=34). Synovitis was more prevalent and severer in RA than in SpA, whereas tenosynovitis and enthesitis were comparable between RA and SpA. Patients were classified into two groups which represented synovitis-dominant and synovitis-nondominant inflammation patterns, respectively. While peripheral ILC counts were not significantly different between RA and SpA, they were significantly higher in the synovitis-nondominant group than in the synovitis-dominant group (ILC1-3 p=0.0007, p=0.0061, p=0.0002, respectively). On the other hand, clustering of patients based on serum cytokine/chemokines did not clearly correspond either to clinical diagnoses or to synovitis-dominant/nondominant patterns. The synovitis-nondominant pattern was the factor that predicted no clinical response to methotrexate most significantly (p=0.0065).Conclusions: Ultrasound-detected musculoskeletal inflammation is clustered into synovitis-dominant and nondominant patterns. These patterns are associated with peripheral ILC counts and could predict treatment response to methotrexate. These data suggest that ultrasound-based inflammation patterns can be utilized to establish more individualized treatment for both RA and SpA. Trial registration: The study has been registered in UMIN Clinical Trial Registry (UMIN ID: 000033797, date of registration: 18th of August, 2018).