Plasma interferon-alpha is associated with double-positivity for autoantibodies but is not a predictor of remission in early rheumatoid arthritis-a spin-off study of the NORD-STAR randomized clinical trial

Marit Stockfelt, Anna-Carin Lundell, Merete Lund Hetland, Mikkel Østergaard, Till Uhlig, Marte Schrumpf Heiberg, Espen A Haavardsholm, Michael T Nurmohamed, Jon Lampa, Dan Nordström, Kim Hørslev Petersen, Bjorn Gudbjornsson, Gerdur Gröndal, Jonathan Aldridge, Kerstin Andersson, Kaj Blennow, Henrik Zetterberg, Ronald van Vollenhoven, Anna Rudin, Marit Stockfelt, Anna-Carin Lundell, Merete Lund Hetland, Mikkel Østergaard, Till Uhlig, Marte Schrumpf Heiberg, Espen A Haavardsholm, Michael T Nurmohamed, Jon Lampa, Dan Nordström, Kim Hørslev Petersen, Bjorn Gudbjornsson, Gerdur Gröndal, Jonathan Aldridge, Kerstin Andersson, Kaj Blennow, Henrik Zetterberg, Ronald van Vollenhoven, Anna Rudin

Abstract

Background: The type I interferon (IFN) gene signature is present in a subgroup of patients with early rheumatoid arthritis (RA). Protein levels of IFNα have not been measured in RA and it is unknown whether they associate with clinical characteristics or treatment effect.

Methods: Patients with early untreated RA (n = 347) were randomized to methotrexate combined with prednisone, certolizumab-pegol, abatacept, or tocilizumab. Plasma IFNα protein levels were determined by single molecular array (Simoa) before and 24 weeks after treatment initiation and were related to demographic and clinical factors including clinical disease activity index, disease activity score in 28 joints, swollen and tender joint counts, and patient global assessment.

Results: IFNα protein positivity was found in 26% of the patients, and of these, 92% were double-positive for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). IFNα protein levels were reduced 24 weeks after treatment initiation, and the absolute change was similar irrespective of treatment. IFNα protein positivity was associated neither with disease activity nor with achievement of CDAI remission 24 weeks after randomization.

Conclusion: IFNα protein positivity is present in a subgroup of patients with early RA and associates with double-positivity for autoantibodies but not with disease activity. Pre-treatment IFNα positivity did not predict remission in any of the treatment arms, suggesting that the IFNα system is distinct from the pathways of TNF, IL-6, and T-cell activation in early RA. A spin-off study of the NORD-STAR randomized clinical trial, NCT01491815 (ClinicalTrials), registered 12/08/2011, https://ichgcp.net/clinical-trials-registry/NCT01491815 .

Conflict of interest statement

MS, ACL, TU, MTN, JL, KHP, GG, JA, KA, and AR have no competing interests to declare. MLH has received research grants from Abbvie, Biogen, BMS, Celltrion, Eli-Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Bioepis, Sandoz, and Novartis; chairs the steering committee of the Danish Rheumatology Quality Registry (DANBIO), which receives public funding from the hospital owners and funding from pharmaceutical companies; and co-chairs EuroSpA, which generates real-world evidence of treatment of psoriatic arthritis and axial spondyloarthritis based on secondary data and is partly funded by Novartis. MØ has received research grants from Abbvie, BMS, Merck, Celgene, and Novartis, and speaker and/or consulting fees from Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB. MSH has received speaker’s honoraria from Lilly and Roche over the last 4 years outside the submitted work. EAH has received grants from the Norwegian Regional Health Authorities and The South-Eastern Norway Regional Health Authority during the conduct of the NORD-STAR study, and speaker and/or consulting fees from Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli-Lilly, and UCB outside the submitted work. DN has received consulting fees from AbbVie, BMS, MSD, Novartis, Pfizer, Roche, and UCB. BG has received speaking fees from Amgen and Novartis. KB has served as a consultant, at advisory boards or at data monitoring committees for Abcam, Axon, Biogen and JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside the submitted work). HZ has served at scientific advisory boards for Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, and CogRx; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). RV has received research and educational support (grants) from BMS, GSK, Lilly, Pfizer, Roche, and UCB and consultancy and/or speaking fees from AbbVie, AstraZeneca, Biogen, Biotest, BMS, Galapagos, Gilead, GSK, Janssen, Pfizer, Sanofi, Servier, UCB, and Vielabio.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Elevated IFNα protein levels at baseline in early RA. IFNα protein levels in plasma from patients with early RA before treatment initiation in four treatment arms, methotrexate + prednisone, methotrexate + TNFi, methotrexate + CTLA-4Ig, and methotrexate + IL-6Ri. The dotted line denotes the cut-off for IFNα positivity (136 fg/mL). MTX (methotrexate), TNFi (certolizumab-pegol), CTLA-4Ig (abatacept), and IL-6Ri (tocilizumab). Kruskal-Wallis test followed by Dunn’s multiple comparison test
Fig. 2
Fig. 2
IFNα protein levels are reduced after treatment initiation with conventional and biologic treatment strategies. IFNα protein levels in plasma from patients with early RA before (d1) and 24 weeks after treatment initiation (w24) with A methotrexate + prednisone (n = 85), B methotrexate + TNFi (n = 87), C methotrexate + CTLA-4Ig (n = 91), and D methotrexate + IL-6Ri (n = 82). Wilcoxon matched-pairs signed rank test. E Absolute difference in IFNα plasma protein levels between week 24 and day 1 in four treatment arms. MTX (methotrexate), TNFi (certolizumab-pegol), CTLA-4Ig (abatacept), and IL-6Ri (tocilizumab). Kruskal-Wallis test followed by Dunn’s multiple comparison test
Fig. 3
Fig. 3
Baseline IFNα protein levels do not predict remission after treatment. Baseline IFNα protein levels in plasma from patients with early RA, stratified according to CDAI 24 weeks after treatment initiation; in remission (CDAI 0–2.8), low disease activity (CDAI 2.9–10.0), and moderate/high disease activity (CDAI 10.1–76.0) with A all treatments, B methotrexate + prednisone, C methotrexate + TNFi, D methotrexate + CTLA-4Ig, and E methotrexate + IL-6Ri. MTX (methotrexate), TNFi (certolizumab-pegol), CTLA-4Ig (abatacept), IL-6Ri (tocilizumab). Kruskal-Wallis test followed by Dunn’s multiple comparison test

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