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 ; 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 . 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.
Sakai R, et al. Mod Rheumatol. 2016 (in press).
Disclosure of Interest R. Sakai: None declared, K. Yoshimoto: None declared, T. Kondo: None declared, T. Kurasawa: None declared, A. Shibata: None declared, J. Kikuchi: None declared, K. Chino: None declared, A. Okuyama: None declared, H. Takei: None declared, K. Suzuki Grant/research support from: Eisai Co., Ltd., and Bristol-Myers Squibb, T. Takeuchi Grant/research support from: Astellas Pharma Inc.; Bristol-Myers K.K.; Chugai Pharmaceutical Co., Ltd.; Daiichi Sankyo Co., Ltd.; Eisai Co., Ltd.; Mitsubishi Tanabe Pharma Co.; Pfizer Japan Inc.; Santen Pharmaceutical Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Teijin Pharma Ltd.; AbbVie GK.; Asahikasei Pharma Corp.; Taisho Toyama Pharmaceutical Co., Ltd.; and SymBio Pharmaceuticals Ltd.; Consultant for: Astra Zeneca K.K.; Eli Lilly Japan K.K.; Novartis Pharma K.K.; Mitsubishi Tanabe Pharma Co.; and Asahi Kasei Medical K.K.; AbbVie GK.; Daiichi Sankyo Co., Ltd.; Bristol-Myers K.K.; and Nipponkayaku Co., Ltd., Speakers bureau: AbbVie GK.; Bristol-Myers K.K.; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Janssen Pharmaceutical K.K.; Mitsubishi Tanabe Pharma Co.; Pfizer Japan Inc.; Takeda Pharmaceutical Co., Ltd.; Astellas Pharma; Diaichi Sankyo Co., Ltd.; Celtrion; and Nipponkayaku Co., Ltd., K. Amano Grant/research support from: Chugai Pharmaceutical Co., Ltd., Speakers bureau: AbbVie GK.; Astellas Pharma Inc.; Bristol-Myers K.K.; Chugai Pharmaceutical Co., Ltd.; Mitsubishi Tanabe Pharmaceutical Co.; and Pfizer Japan Inc.