Targeting NET Formation in Early RA Patients; A Spin-off Study from the NORD-STAR

Background The formation of neutrophil extracellular traps (NETs) with extrusion of nuclear, granular and cytosolic components from a dying neutrophil, has been described extensively in patients with rheumatoid arthritis (RA), and linked to generation of autoantigens (e.g. citrullinated proteins), inflammation and organ damage. Thus far there have been very few studies describing the effect of treatment in patients with RA on NET formation, and no studies comparing the effects of treatment strategies in (very) early RA. Objectives To assess the effects of different initial treatments on NET formation in patients with early RA. Methods NORD-STAR is an international, multicenter, open-label, assessor-blinded, phase 4 study where patients with newly diagnosed RA started methotrexate (MTX) and were randomized 1:1:1:1 to a) conventional treatment (either prednisolone tapered to 5mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), b) certolizumab pegol, c) abatacept, or d) tocilizumab [1]. This study is a spin-off from the main NORD-STAR study measuring neutrophil biomarkers MPO-DNA (Myeloperoxidase-DNA; NETs) and calprotectin in 24 consecutive Dutch participants and 94 Swedish patients at baseline, 12 weeks and 24 weeks after the start of the treatment. Statistical analysis was done using the Wilcoxon Signed Rank test for paired samples and independent samples median test to compare patients to healthy controls in SPSS version 28. Results At baseline patients had elevated levels of NETs and neutrophil activation compared to healthy controls as indicated by calprotectin (median 1080ng/ml vs 133ng/ml, p<0.001) and elevated MPO-DNA (median 7185pM vs 3976pM, p<0.001). Both of the biomarkers decreased significantly at 12 and 24 weeks after treatment in the total group demonstrating reduced neutrophil activity and NET formation. After 24 weeks of treatment, calprotectin was significantly reduced in all groups by up to 93% (Table 1). MPO-DNA showed a more modest reduction of up to 13%, and was relatively similar in all groups, although the reduction in MPO-DNA did not reach statistical significance in the tocilizumab group. Conclusion These results indicate highly elevated neutrophil activation and NET formation in recently diagnosed RA patients. All four treatments studied here reduced these detrimental processes within 3 months. The calprotectin reduction seen in this study is in line with an earlier spin-off study [2]. The rapid decline in these markers may have contributed to the minimal radiological progression that was seen in the NORD-STAR trial. References [1]Hetland M et al. BMJ. 2020 [2]Stevens D et al. Ann Rheum Dis. 2022 Acknowledgements: NIL. Disclosure of Interests Bas Dijkshoorn: None declared, Ting Wang: None declared, Daisy Vedder: None declared, Anna Rudin: None declared, Dan Nordström Speakers bureau: Novartis, UCB, Consultant of: Abbvie, BMS, Lilly, Novartis, Pfizer, Roche, UCB, Björn Gudbjornsson Speakers bureau: Amgen and Novartis - not related to this work, Consultant of: Novartis - not related to this work, Kristina Lend: None declared, Till Uhlig Speakers bureau: Grünenthal, Novartis, Consultant of: Grünenthal, Novartis, Grant/research support from: NORDFORSK, Espen A Haavardsholm Consultant of: Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli-Lilly, UCB, Grant/research support from: NORDFORSK, Norwegian Regional Health Authorities, South-Eastern Norway Regional Health Authority, Merete Lund Hetland Consultant of: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Grant/research support from: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Marte Heiberg: None declared, Mikkel Østergaard Speakers bureau: Abbvie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Orion, Pfizer, Roche and UCB, Consultant of: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB, Grant/research support from: Abbvie, Amgen, BMS, Merck, Celgene and Novartis, Kim Hørslev-Petersen: None declared, Jon Lampa Speakers bureau: Pfizer, Janssen, Novartis, Ronald van Vollenhoven Speakers bureau: AbbVie, Galapagos, GSK, Janssen, Pfizer, R-Pharma, UCB, Consultant of: AbbVie, AstraZeneca, Biogen, BMS, Galapagos, Janssen, Miltenyi, Pfizer, UCB, Grant/research support from: BMS, GSK, UCB, Tuulikki Sokka-Isler Speakers bureau: Abbvie, BMS, Celgene, Medac, Merck, Novartis, Orion Pharma, Pfizer, Roche, Sandoz, UCB, Bohringer Ingelheim, Amgen, Grant/research support from: Amgen, Christian Lood Consultant of: Redd Pharma, Grant/research support from: Eli Lilly, Gilead Sciences, Boehringer Ingelheim, Redd Pharma, Amytryx, Horizon Pharma, Pfizer, and Bristol Meyers Squibb, Michael Nurmohamed Speakers bureau: Abbvie, Janssen, Celgene, Consultant of: Abbvie, Grant/research support from: Abbvie, Amgen, Pfizer, Galapagos, BMS.