Changes in serum levels of cytokines with methotrexate monotherapy in active rheumatoid arthritis: results from a multicentre, randomized controlled trial on methotrexate escalation in rheumatoid arthritis

Abstract Background/Aims Identification of novel biomarkers of disease activity and prediction of treatment response in rheumatoid arthritis (RA) is an area of active research. Reliable biomarkers of methotrexate (MTX) response in RA are yet to be identified. We sought to study the change in serum levels of IL-6, MMP-3, and TNF-α with MTX monotherapy in patients with active RA. Methods Patients with active RA (SJC≥2 and TJC≥4) not on DMARDs (except HCQ and low-dose prednisolone) who had been enrolled in the multicentre, parallel-group RCT comparing two different MTX escalation strategies in RA (MEIRA) were included. All these patients received MTX monotherapy started at 15 mg/week and escalated to 25 mg/week by 4-8 weeks. Serum levels of IL-6, MMP-3, and TNF-α were measured by ELISA before starting MTX and after 16 weeks of MTX therapy. Responders were defined as patients who achieved a EULAR good or moderate response (based on DAS28ESR-3v) at 16 weeks. Analyses were intention-to-treat. Results 16 weeks of MTX therapy led to a decline in serum levels of both MMP-3 (p = 0.03, n = 129) and IL-6 (p = 0.048, n = 151). The decline in IL-6 levels was seen only in MTX responders (p = 0.003), but not in non-responders, while the decline in MMP-3 levels was seen in both MTX non-responders (p = 0.015) and responders (p = 0.44) (Table 1). Baseline (pre-treatment) serum levels of both IL-6 and MMP-3 were similar between MTX responders and non-responders. Correlations of serum levels of IL-6 (but not MMP-3) with measures of disease activity (DAS28, tender joint count) were weak but significant at 16 weeks. Serum TNF-α levels (n = 137) were undetectable in a majority of patients (93%). Serum IL-6 was not detectable in 67 (44%) patients at baseline. Conclusion Although serum levels of both MMP-3 and IL-6 reduced significantly with MTX therapy, the decline of IL-6 was seen only in MTX responders but not in non-responders. Pre-treatment serum levels did not predict future MTX response or non-response. IL-6 levels also correlated weakly but significantly with disease activity. Serial measurement of serum IL-6 merits further exploration in larger studies as a potential biomarker of MTX response in RA. Disclosure S. Jain: None. V. Dhir: None. A. Aggarwal: None. R. Gupta: None. S. Maurya: None. B. Leishangthem: None. A. Khullar: None. S. Naidu: None. S.K. Sharma: None. A. Sharma: None. S. Jain: None.