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.
Highlights
Treatment of rheumatoid arthritis (RA) has proven effective in decreasing disease activity and limiting joint damage [1, 2]
With regard to biologic therapy, we have previously demonstrated that the predictive performance of the type I interferon (IFN) response gene set for non-response to rituximab was impaired when patients were using prednisolone at the moment of blood collection [7]
COBRA therapy consists of initially high-dose prednisolone (60 mg/day) combined with sulfasalazine (SSZ) and low-dose methotrexate (MTX) (7.5 mg/week), COBRAlight consists of a lower initial prednisolone dose (30 mg/day) but a higher starting dose of MTX (10 mg/week) and no SSZ
Summary
Treatment of rheumatoid arthritis (RA) has proven effective in decreasing disease activity and limiting joint damage [1, 2]. One treatment strategy which has shown effectiveness in early RA is COBRA (Dutch acronym for COmbinatietherapy Bij Reumatoïde Arthritis), which is a step-down strategy consisting of initial high dose prednisolone (60 mg per day), methotrexate (MTX) and sulfasalazine (SSZ). The use of glucocorticoids (GCs) such as prednisolone and conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) such as MTX and SSZ is not restricted to early disease. These therapies are used throughout all phases of the disease, either as monotherapy or in combination, including simultaneously with biologic therapy [6]
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