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

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://clinicaltrials.gov/ct2/show/NCT01491815.

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

“…IFN-α associated with raised ESR in our cohort and in other autoimmune conditions12 but is also relevant prior to onset of inflammation as an IGS predicts progression to RA in ‘at risk’ cohorts 19–21. Furthermore, autoantibodies predate clinical presentation, and we demonstrate a clear association between IFN-α and RF titres in eRA consistent with previous observations in autoimmunity 12 17. In contrast, there was no association between IFN-α and ACPA.…”

“… 16 Furthermore, both IGS and serum IFN-α levels fall in parallel with clinical response over 6 months, additionally supporting the role of IFN-α driving the IGS in eRA. Like others, 17 and in contrast to the IGS, we could not demonstrate an association of baseline IFN-α with longitudinal clinical outcomes. A potential explanation is that the IRG integrates activity over time of IFN-α, which itself has a short half-life.…”

Role and Therapeutic Potential for Targeting Fibroblast Growth Factor 10/FGFR1 in Relapsed Rheumatoid Arthritis

“…Recently, type I interferon (IFN-I) and interferon gene signatures (IGSs) have drawn considerable attention in RA. 36,56,57 Emerging evidence has shown that circulating IFN-α is primarily responsible for IGSs in the peripheral blood of drug-naive patients with eRA, and baseline IGS is associated with 6-month DAS-28 and ESR. However, circulating IGSs were not associated with disease activity in established RA.…”

Serum level of IFNβ distinguishes early from late relapses after biologics withdrawal in rheumatoid arthritis

“…IFNα is another major type I IFN, but it was not selected in the present study 22 . Whether there are differences in the pathophysiological action of these two cytokines in RA or a switch-on role of early relapse in RA needs to be elucidated; patients with a high baseline IFNβ/α ratio showed poorer response to TNF inhibitors in RA 23 .…”