Dynamics of the Type I Interferon Response During Immunosuppressive Therapy in Rheumatoid Arthritis

Abstract

Objective: The type I interferon (IFN) response in rheumatoid arthritis (RA) has been extensively studied in relation to therapy with biological DMARDs (bDMARDs). However, the effect of conventional synthetic (cs)DMARDs and glucocorticoids (GCs) on IFN response gene (IRG) expression remains largely unknown, even though csDMARDS are used throughout all disease phases, including simultaneously with biologic therapy. This study was aimed to determine the dynamics of IFN response upon immunosuppressive treatment. Methods: Whole blood was collected in PAXgene tubes from 35 RA patients who received either COBRA therapy (combination of prednisone, initially 60 mg, methotrexate and sulfasalazine) ( n = 14) or COBRA-light therapy (prednisone, initially 30 mg, and methotrexate) ( n = 21). Expression of 10 IRGs was determined by real-time PCR at baseline (T0), after 4 weeks (T4), and 13 weeks (T13) of treatment. IRG selection was based on the differential presence of transcription factor binding sites (TFBS), in order to study the therapy effect on different pathway components involved in IFN signaling. Results: Seven of the 10 IRGs displayed significant changes during treatment ( p ≤ 0.016). These 7 IRGs all displayed a particularly pronounced decrease between T0 and T4 (≥1.6-fold, p ≤ 0.0059). The differences between IRG sensitivity to the treatment appeared related to the presence of TFBS for STAT1 and IRF proteins within the genes. The extent of the decreases between T0 and T4 was similar for the COBRA- and COBRA-light-treated group, despite the differences in drug combination and doses in those groups. Between T4 and T13, however, IRG expression in the COBRA-light-treated group displayed a significant increase, whereas it remained stable or decreased even further in most COBRA-treated patients (comparison of mean fold changes, p = 0.011). A significant association between IRG dynamics and clinical response to therapy was not detected. Conclusions: Immunosuppressive treatment with csDMARDs, in this case a combination of prednisolone, methotrexate and sulfasalazine, substantially downregulates the IFN response in RA patients. The dynamics of this downregulation were partly dependent on the presence of TFBS within the IRGs and the combination and dosages of agents, but they were irrespective of the clinical response to therapy.

Gout, Rheumatoid Arthritis, and the Risk of Death Related to Coronavirus Disease 2019: An Analysis of the UK Biobank

“…We identified RA as a risk factor for death related to COVID‐19 in a multivariable‐adjusted analysis of the UK Biobank cohort. Of clinical relevance, given implication of the type 1 interferon response in biologic therapy in RA (25), is involvement of a type 1 interferon–mediated immune response in people who die of COVID‐19 (26), including in people with mutations in regulatory genes (27). It is important that the findings presented here are replicated in larger administrative data sets (eg, the US‐based National COVID Cohort Collaborative [http://www.ncats.nih.gov/n3c] and the UK OpenSAFELY cohort) (2).…”

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

“…Elevated baseline IRG expression associated with increased DAS28 6 months after treatment initiation with MTX and glucocorticoid [ 5 ] as well as MTX, intramuscular glucocorticoid, and/or hydroxychloroquine [ 11 ]. However, another study found no association to disease activity 6 months after treatment initiation with MTX, prednisolone, and/or sulfasalazine [ 38 ]. In the present study, IFNα protein positivity was not related to disease activity or remission 6 months after initiation of conventional or biologic treatment.…”

Gout, rheumatoid arthritis and the risk of death from COVID-19: an analysis of the UK Biobank

“…A parallel can be drawn with the increased risk of death from COVID-19 we observed in immunodeficiencies, in that suppression of the immune system in RA using immunosuppressive disease-modifying anti-rheumatic drugs may affect the same pathway(s) contributing to death from COVID-19. Of relevance is the implication of a type 1 interferon-mediated immune response in people who die from COVID-19 (18), including in people with mutations in regulatory genes (19) given mplication of the type 1 interferon response in therapy of RA with biologics (20).…”