Association of rheumatoid factor, anti-citrullinated protein antibodies and shared epitope with clinical response to initial treatment in patients with early rheumatoid arthritis: data from a randomised controlled trial.

Mikkel Østergaard, Jeroen Christiaans, Giulia Frazzei, Dan C Nordström, Marte Schrumpf Heiberg, Gerdur Grondal, Anna Rudin, Kristina Lend, Ronald F van Vollenhoven, Theo Rispens, Jos W R Twisk, Bjorn Gudbjornsson, Merete Lund Hetland, Espen A Haavardsholm, Kim Hørslev-Petersen, Michael T Nurmohamed, Tuulikki Sokka-Isler, Leonid Padyukov, Gertjan Wolbink, Till Uhlig, Jon Lampa

Journal: Annals of the rheumatic diseases 2024;83(12):1657-1665

PMID: 39079894

Free Full Text on Elsevier Science View on PubMed

Abstract

OBJECTIVES

To investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional treatment (ACT).

METHODS

Patients with treatment-naïve early rheumatoid arthritis were randomised in the NORD-STAR trial to ACT, certolizumab pegol, abatacept or tocilizumab, all with methotrexate. Centralised laboratory analyses for ACPA, RF and SE were performed. Clinical Disease Activity Index remission was analysed longitudinally with logistic generalised estimating equations. Differences in treatment effect across RF, ACPA and SE subgroups were assessed with interaction terms at 24 and 48 weeks, adjusted for sex, country, age, body mass index, Disease Activity Score of 28 joints based on C-reactive protein and smoking.

RESULTS

In total, 778 patients were included. At 24 weeks, abatacept treatment showed a better response than ACT in the RF and/or ACPA-positive subgroups, but this effect was not significantly different from the negative subgroups. By 48 weeks, abatacept treatment showed better response regardless of RF/ACPA status. No differences were found across RF, ACPA, SE allele, valine at amino acid position 11 or valine-arginine-alanine haplotype subgroups for any biological treatment at 48 weeks.

CONCLUSIONS

Based on this randomised controlled trial, abatacept treatment was associated with a better response than ACT in the RF and/or ACPA-positive subgroup at 24 weeks, but this was no longer seen at 48 weeks; adding SE allele-related genetic markers did not strengthen the association. Moreover, ACPA, RF and SE allele-related genotypes were not, alone or in combination, associated with clinical responses of importance sufficiently strongly to warrant implementation in clinical practice.

TRIAL REGISTRATION NUMBER

EudraCT 2011-004720-35; ClinicalTrials.gov NCT01491815.

Address: Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centers, Amsterdam, The Netherlands [email protected].; Division of Rheumatology, Department of Medicine, Karolinska Institute, Stockholm, Sweden.; Division of Rheumatology, Department of Medicine, Karolinska Institute, Stockholm, Sweden.; Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden.; Division of Rheumatology, Department of Medicine, Karolinska Institute, Stockholm, Sweden.; Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.; Department of Clinical Medicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark.; Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet Glostrup, Glostrup, Denmark.; Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway.; Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.; University of Helsinki, Helsinki, Uusimaa, Finland.; Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands.; Rheumatology, Sahlgrenska University Hospital, Gothenburg, Sweden.; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden.; Danish Hospital for Rheumatic Diseases, University Hospital of Southern Denmark, Sønderborg, Denmark.; Department of Regional Health Research, University of Southern Denmark, Odense, Syddanmark, Denmark.; Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway.; University of Oslo, Oslo, Norway.; Department of Medicine and University of Eastern Finland, Jyväskylä Central Hospital, Jyväskylä, Finland.; Centre for Rheumatology Research, Landspitali University Hospital, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.; Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands.; Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands.; Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands.; Institute for Infection and Immunity, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Department of Epidemiology and Data Science, Amsterdam University Medical Centres, Amsterdam, The Netherlands.; Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Division of Rheumatology, Department of Medicine, Karolinska Institute, Stockholm, Sweden.

DOI: 10.1136/ard-2024-226024

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MeSH Terms: Humans, Arthritis, Rheumatoid, Rheumatoid Factor, Anti-Citrullinated Protein Antibodies, Female, Male, Middle Aged, Antirheumatic Agents, Treatment Outcome, Abatacept, Epitopes, Adult, Antibodies, Monoclonal, Humanized, Certolizumab Pegol, Methotrexate, Drug Therapy, Combination, Aged, HLA-DRB1 Chains, Alleles, Severity of Illness Index