An increase in treg-and Th2-associated serum chemokines, MDC (CCL22) and TARC (CCL17) during tocilizumab monotherapy in patients with microscopic polyangiitis

Background: We have recently reported a case series that tocilizumab (TCZ) monotherapy without corticosteroids (CSs) may be an alternative treatment strategy in patients with microscopic polyangiitis (MPA). We found that four of six patients (66.7%) could be maintained drug-free after TCZ cessation for 6-15 months [1]; however, the mechanism remains unclear. Objectives: To elucidate the TCZ efficacy mechanism in patients with MPA, we examined multiple serum levels of cytokines and chemokines in patients with MPA at 0 (baseline), 4, and 24 weeks after initiating TCZ monotherapy and compared the outcomes with those of healthy controls (HC) and patients with rheumatoid arthritis (RA). Methods: The patients employed in this study were newly diagnosed with MPA (n=8; 71.0 ± 7.4 years) according to the Watts' classification algorithm, RA (n=6; 54.5 ± 13.0 years) according to the 2010 RA classification criteria, and HC (n=8, 65.1 ± 9.5 years). All MPA and RA patients received 8 mg/kg of intravenous TCZ monthly for 1 year without any CS or disease-modifying antirheumatic drugs, except for six out of eight patients with MPA who fortnightly received TCZ for the first 2 months, and then monthly for the next 10 months [1]. Multiple cyto- and chemokines in the serum of patients at 0, 4 and 24 weeks of the treatment of TCZ were analyzed by micro-spot-based multiplex assays using electrochemiluminescence. Complete remission (CR) was defined as the Birmingham Vasculitis Activity Score (BVAS) of 0 at two consecutive visits made at least a month apart, and partial response (PR) was defined as a 50% reduction of BVAS from the baseline. Results: CR/PR was achieved in six out of eight patients with MPA at 6 months (75%, LOCF). MPA at baseline showed elevated levels of various cyto- and chemokines compared with HC, such as IL-10, IL-12/IL-23p40, IL-15, IL-16, IL- 17A, IL-1α, IL-4, IL-5, IL-6, IL-7, TNFα, VEGF-A, IL-8 (CXCL8), IP-10 (CXCL10), MCP-1 (CCL2), MIP-1α (CCL3), MIP-1β (CCL4), MCP-4 (CCL13), and eotaxin-3 (CCL26) (p<0.05). Conversely, RA at baseline showed elevated levels of cyto- and chemokines compared with HC, such as IL-6, IL-7, IL-16, TNFα, VEGF-A, MIP-1β, eotaxin-3 (p<0.05). Moreover, serum levels of MDC (CCL22), TARC (CCL17), GM-CSF, IL-12p70 were not significantly different among these groups. Most of enhanced levels of serum cyto- and chemokines in MPA significantly decreased during the 24 weeks with TCZ monotherapy except IL-12/IL-23p40, IL-4, IL-13, and IL-1β, whereas only VEGF-A level was significantly decreased in RA under TCZ treatment. Interestingly, only the levels of MDC and TARC in MPA, the Th2 and Treg related chemokines, significantly increased after TCZ monotherapy, but not in RA (baseline vs 24 weeks: p<0.05) (Figure 1), even though other Th2 related cyto- and chemokines significantly decreased or remained unchanged. Conclusions: Our study suggest that TCZ monotherapy provides a new insight into the treatment strategy for MPA and TCZ may suppress the disease activities of MPA by increasing chemokines, such as MDC and TARC while other inflammatory cyto- and chemokines decreased.