Background Cytokines, including chemokines are key mediators of the pathogenesis of rheumatoid arthritis (RA). Because tocilizumab, a humanized monoclonal antibody that is specific for the IL-6 receptor, induces rapid clinical improvement in RA patients, it is important to investigate whether tocilizumab administration has any effect(s) on serum cytokine profiles and whether such changes correlated with the clinical improvement of RA disease activity.
Objectives To examine the relationship between serum cytokine levels and clinical responsiveness to tocilizumab in patients with RA and to investigate the impact of tocilizumab administration on serum cytokine levels.
Methods The disease status of 26 RA patients was assessed at baseline and after 12 weeks of tocilizumab administration (8 mg/kg) using the clinical disease activity index (CDAI) and the disease activity score 28 (DAS28). The minor and major responses to tocilizumab were defined as an improvement of as an improvement of ≥6.7 and 14, respectively, from the baseline CDAI1. Serum levels of the following cytokines at baseline and after 12 weeks were quantified using double ligand enzyme-linked immunosorbent assays: TNF alpha, IL-6, CCL2, CCL3, CXCL8, CXCL10, CX3CL1 and macrophage migration inhibitory factor (MIF).
Results After 12 weeks of tocilizumab administration, 19 patients achieved minor and major responses (referred to as the responder group), but there were no significant responses in the other 7 patients (the non-responder group). Although no significant differences at baseline were found for disease activity (CDAI and DAS28), clinical parameters, and baseline serum cytokine levels measured between the groups, only serum MIF levels at baseline were higher in the responder group (2501.5±2325.8 pg/ml, p<0.05) than in the non-responder group (905.9±873.3 pg/ml). Furthermore, MIF levels in the responder group, but not in the non-responder group, were significantly decreased after tocilizumab administration. When RA patients were divided into two groups based on their basal MIF levels, a comparison of patients with lower (<1347 pg/ml; median of MIF levels) and higher basal MIF levels revealed no significant differences in clinical parameters. However, the rate of clinical responses to tocilizumab appeared to be significantly higher (p<0.05) in the higher MIF group (responder, 12 cases vs. non-responder, 1 case) than the lower MIF group (responder, 7 cases vs. non-responder, 6 cases). Finally, in response to tocilizumab, serum MIF levels significantly decreased in patients with higher basal MIF levels (3470.6±2270.9 to 1252.3±1117.7, p<0.01) but not in those with lower basal levels.
Conclusions We demonstrated that the MIF levels declined in patients who showed a clinical response to tocilizumab therapy, whereas the serum levels of other cytokines which were affected by TNF antagonists2 were not significantly affected by tocilizumab treatment. Further, our results suggest that the MIF regulation in patients with active RA may be sensitive to anti-IL-6 therapy.
Saevarsdottir S, et al. Ann Rheum Dis 2011;70:469.
Kasama T, et al. J Clin Rheumatol Musculoskel Med 2010;1:19.
Disclosure of Interest None Declared