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

Bas Dijkshoorn¹, Ting Wang², Gerdur Maria Grondal³, Daisy Vedder⁴, Anna Rudin⁵, Dan Nordstrom⁶, Bjorn Gudbjornsson⁷, Kristina Lend⁸, Till Uhlig⁹, Espen Haavardsholm⁹, Merete L Hetland¹⁰, Marte Schrumpf Heiberg¹¹, Mikkel Østergaard¹², Kim Horslev-Petersen¹³, John Lampa¹⁴, Ronald van Vollenhoven¹⁵, Christian Lood² and Michael Nurmohamed¹⁶, ¹Amsterdam Rheumatology and Immunology Center, Location Reade, Amsterdam, Netherlands, ²University of Washington, Seattle, WA, ³Department for Rheumatology, Landspitali University Hospital, Reykjavik, Iceland, ⁴Reade, Amsterdam, Netherlands, ⁵Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, ⁶Helsinki University Hospital, Helsinki, Finland, ⁷Centre for Rheumatology Research, University Hospital, Reykjavik, Iceland, ⁸Amsterdam UMC, Karolinska Institute, Stockholm, Sweden, ⁹Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway, ¹⁰Copenhagen Center for Arthritis Research, Rigshospitalet, Copenhagen, Denmark, ¹¹Diakonhjemmet Hospital, Oslo, Norway, ¹²Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre for Head and Orthopaedics, Rigshospitalet; University of Copenhagen, Copenhagen, Denmark, ¹³Danish Hospital for Rheumatic Diseases, Sønderborg, Denmark, ¹⁴Stockholm County, Hãsselby, Sweden, ¹⁵Amsterdam University Medical Centers, Amsterdam, Netherlands, ¹⁶Amsterdam University Medical Centers, Kortenhoef, Netherlands

Meeting: ACR Convergence 2023

Keywords: Biologicals, Cell Death, rheumatoid arthritis

Session Information

Date: Sunday, November 12, 2023

Title: (0380–0422) RA – Diagnosis, Manifestations, and Outcomes Poster I

Session Type: Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: 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. The objective of the study is 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) tocilizumab¹. 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 study². 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

Disclosures: B. Dijkshoorn: Galapagos, 2, Novartis, 2; T. Wang: None; G. Grondal: None; D. Vedder: None; A. Rudin: AstraZeneca, 12, financial support; D. Nordstrom: AbbVie/Abbott, 2, BMS, 2, Lilly, 2, MSD, 2, Novartis, 2, Pfizer, 2, UCB, 2; B. Gudbjornsson: Nordic-Pharma, 6, Novartis, 2, 6; K. Lend: None; T. Uhlig: Galapagos, 2, 6, Lilly, 2, 6, Novartis, 2, 6, Pfizer, 2, 6, UCB, 2, 6; E. Haavardsholm: AbbVie/Abbott, 2, Boehringer-Ingelheim, 2, Eli Lilly, 2, Gilead, 2, Pfizer, 6, UCB, 6; M. Hetland: AbbVie/Abbott, 1, 5, Bristol-Myers Squibb(BMS), 5, Danbio, 12, MLH has chaired the steering committee of the Danish Rheumatology Quality Registry (DANBIO, DRQ), which receives public funding from the hospital owne, Eli Lilly, 5, MEDAC, 6, Novartis, 5, Pfizer, 5, 6, Sandoz, 5, 6; M. Schrumpf Heiberg: Roche, 6; M. Østergaard: AbbVie, 2, 5, 6, Amgen, 5, Boehringer-Ingelheim, 2, 6, Bristol-Myers Squibb(BMS), 2, 5, 6, Celgene, 2, 5, 6, Eli Lilly, 2, 6, Galapagos, 2, 6, Gilead, 2, 6, Hospira, 2, 6, Janssen, 2, 6, MEDAC, 6, Merck, 2, 5, 6, Novartis, 2, 5, 6, Novo Nordisk, 2, 6, Orion, 2, 6, Pfizer, 2, 6, Regeneron, 2, 6, Roche, 2, 6, Sandoz, 2, 6, Sanofi, 2, 6, UCB, 2, 6; K. Horslev-Petersen: None; J. Lampa: None; R. van Vollenhoven: AbbVie, 2, 6, AstraZeneca, 2, 5, 6, Biogen, 6, Bristol-Myers Squibb(BMS), 2, 5, 6, Galapagos, 2, 5, 6, GlaxoSmithKline, 6, Janssen, 2, 6, MSD/Merck Sharp and Dohme, 5, Novartis, 5, Pfizer, 2, 5, 6, RemeGen, 2, Roche, 5, Sanofi, 5, UCB, 2, 5, 6; C. Lood: Amytryx, 5, Boehringer-Ingelheim, 5, Bristol-Myers Squibb(BMS), 5, Citryll, 2, Eli Lilly, 5, Gilead, 5, Horizon Therapeutics, 5, Pfizer, 5, Redd Pharma, 5, 11; M. Nurmohamed: AbbVie/Abbott, 2, 5, 6, Bristol-Myers Squibb(BMS), 2, 5, 6, Celgene, 2, 5, 6, Galapagos, 2, 5, Janssen, 2, 5, 6, Menarini, 2, 5, 6, Merck/MSD, 2, 5, 6, Mundipharma, 2, 5, 6, Pfizer, 2, 5, 6, Roche, 2, 5, 6, Sanofi, 2, 5, 6, UCB, 2, 5, 6.

To cite this abstract in AMA style:

Dijkshoorn B, Wang T, Grondal G, Vedder D, Rudin A, Nordstrom D, Gudbjornsson B, Lend K, Uhlig T, Haavardsholm E, Hetland M, Schrumpf Heiberg M, Østergaard M, Horslev-Petersen K, Lampa J, van Vollenhoven R, Lood C, Nurmohamed M. Targeting NET Formation in Early RA Patients; A Spin-off Study from the NORD-STAR [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/targeting-net-formation-in-early-ra-patients-a-spin-off-study-from-the-nord-star/. Accessed .

« Back to ACR Convergence 2023

ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-net-formation-in-early-ra-patients-a-spin-off-study-from-the-nord-star/