Treatment with methotrexate plus oral prednisolone versus triple therapy (methotrexate/sulfasalazine/hydroxychloroquine) plus intra-articular glucocorticoids in early rheumatoid arthritis: a prespecified nonrandomised subgroup analysis of clinical and radiographic data at 48 weeks from the NORD-STAR trial's conventional treatment arm

Merete Lund Hetland; Marte S Heiberg; Tuulikki Sokka-Isler; Anna Rudin; Mikkel Østergaard; Espen Haavardsholm; Jarno Rutanen; Ronald van Vollenhoven; Gerdur Grondal; Lykke Midtbøll Ørnbjerg; Pernille Bøyesen; Jon Lampa; Michael Nurmohamed; Bjorn Gudbjornsson; Till Uhlig; Aulikki Kononoff; Kristina Lend; Simon Krabbe; Inge C Olsen; Joe Sexton; Kim Hørslev-Petersen

doi:10.1016/j.ard.2025.03.002

Treatment with methotrexate plus oral prednisolone versus triple therapy (methotrexate/sulfasalazine/hydroxychloroquine) plus intra-articular glucocorticoids in early rheumatoid arthritis: a prespecified nonrandomised subgroup analysis of clinical and radiographic data at 48 weeks from the NORD-STAR trial's conventional treatment arm

Ann Rheum Dis. 2025 Apr 4:S0003-4967(25)00819-2. doi: 10.1016/j.ard.2025.03.002. Online ahead of print.

Authors

Merete Lund Hetland¹, Marte S Heiberg², Tuulikki Sokka-Isler³, Anna Rudin⁴, Mikkel Østergaard⁵, Espen Haavardsholm⁶, Jarno Rutanen⁷, Ronald van Vollenhoven⁸, Gerdur Grondal⁹, Lykke Midtbøll Ørnbjerg¹⁰, Pernille Bøyesen¹¹, Jon Lampa¹², Michael Nurmohamed¹³, Bjorn Gudbjornsson⁹, Till Uhlig⁶, Aulikki Kononoff¹⁴, Kristina Lend⁸, Simon Krabbe¹⁰, Inge C Olsen¹⁵, Joe Sexton², Kim Hørslev-Petersen¹⁶

Affiliations

¹ DANBIO and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre for Head and Orthopedics, Rigshospitalet, Glostrup, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address: merete.hetland.01@regionh.dk.
² Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway.
³ University of Eastern Finland, Kuopio, and Hospital Nova, Wellbeing services county of Central Finland, Jyväskylä, Finland.
⁴ Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁵ DANBIO and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre for Head and Orthopedics, Rigshospitalet, Glostrup, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁶ Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁷ Centre for Rheumatology, Tampere University Hospital, Tampere, Finland; Tampere University, Faculty of Social Sciences, Tampere, Finland.
⁸ Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centers, Amsterdam, The Netherlands; Division of Rheumatology, Department of Medicine Karolinska Institute, Stockholm, Sweden.
⁹ Centre for Rheumatology Research, Landspitali University Hospital, Reykjavík, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁰ DANBIO and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre for Head and Orthopedics, Rigshospitalet, Glostrup, Denmark.
¹¹ Department of Rheumatology, Dermatology and Infectious Diseases, Oslo University Hospital, Oslo, Norway.
¹² Department of Medicine, Rheumatology Unit, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
¹³ Amsterdam Rheumatology and Immunology Center, Reade, The Netherlands; Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, Amsterdam, The Netherlands.
¹⁴ Kuopio University Hospital, Kuopio, Finland.
¹⁵ Department of Research Support for Clinical Trials, Oslo University Hospital, Oslo, Norway; Oslo Centre for Biostatistics and Epidemiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
¹⁶ Danish Hospital for the Rheumatic Diseases, Sønderborg, Denmark; University of Southern Denmark, Odense, Denmark.

PMID: 40188008
DOI: 10.1016/j.ard.2025.03.002

Abstract

Objectives: In the NOrdic Rheumatic Diseases Strategy Trials And Registries (NORD-STAR) trial, the active conventional arm had 2 nonrandomised regimens: arm 1A (oral group; Sweden, Norway, Netherlands, and Iceland) and arm 1B (injection group; Denmark and Finland). We report clinical, patient-reported, safety, and radiographic outcomes after 48 weeks.

Methods: Oral group received methotrexate plus oral prednisolone (20.0 mg/d, tapered rapidly, discontinued week 36); Injection group received triple therapy (methotrexate, sulphasalazine, hydroxychloroquine) and mandatory intra-articular glucocorticoid injections. The primary end point was analysed by logistic regression with several approaches for handling missing outcomes.

Results: In total, 137 and 80 patients were included in the oral group and injection group; 78% vs. 89% completed, respectively. At 48 weeks, adjusted clinical disease activity index remission ≤2.8 rates (95% CI) were 36% (28-44) and 55% (42-68), respectively; the risk difference (primary outcome) was 19% (2-35). Similarly, key secondary clinical, patient-reported and safety outcomes showed numerically better results in the injection group vs oral group, for example, infections occurred in 53% vs 30%, respectively. Radiographic progression (Δtotal van der Heijde-modified Sharp Score) was low: oral group: adjusted mean, 0.26 (95% CI, 0.08-0.43); injection group: adjustedd mean, 0.80 (95% CI, 0.55-1.05). Cumulative dose of oral/intra-articular glucocorticoids (median) was 1905 mg prednisolone for the oral group and 165 mg for the injection group.

Conclusions: In treatment-naïve patients with early rheumatoid arthritis, triple therapy and mandatory glucocorticoid joint injections had numerically better clinical outcomes, fewer withdrawals, fewer adverse events, and lower cumulative dose of glucocorticoids, but slightly worse radiographic outcomes than treatment with methotrexate and oral prednisolone. These findings, although nonrandomised, suggest a potential for optimising treatment strategy with conventional therapies in early rheumatoid arthritis.