Background. Rheumatoid arthritis (RA) is a chronic autoimmune disease driven by inflammatory pathways involving cytokines and complement activation. Interleukin-6 (IL-6) promotes hepatic synthesis of acute-phase proteins, including complement components C3 and C4. Tocilizumab (TCZ), a humanized monoclonal antibody targeting the IL-6 receptor, has proven effective in RA management. However, its impact on the complement system remains poorly characterized. Methods and Results. We studied 10 patients with moderate-to-severe RA treated with intravenous TCZ (8 mg/kg/month) over 48 weeks. Serum levels of C3, C4, CH50, ESR, and CRP were assessed at baseline and at 4, 12, 24, 36, and 48 weeks. Complement activation was monitored via C3 and factor B split products. A rapid and sustained reduction in C3 and C4 levels was observed starting at week 4, without changes in CH50 or detectable cleavage products. This reduction coincided with significant improvement in inflammatory markers and clinical outcomes (DAS28 and HAQ scores). Conclusions. IL-6R blockade with TCZ is associated with a rapid and sustained reduction in complement proteins C3 and C4. In a proportion of patients, complement levels reached values below the lower limit of normal during follow-up, while CH50 remained stable and complement split products were not detected. These findings are consistent with altered acute-phase/hepatic regulation of complement under IL-6 inhibition rather than overt complement consumption. The clinical significance of complement reduction and its role as a biomarker of treatment response require confirmation in larger studies.
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Dramatic Reduction of Complement System Factors in Rheumatoid Arthritis Patients Treated with Tocilizumab †
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Received: 04 Aug 2025 | Revised: 24 Dec 2025 | Accepted: 03 Mar 2026 | Published: 18 Mar 2026
Abstract
Keywords
rheumatoid arthritis | IL-6 | tocilizumab | complement | C3 | C4
References
- 1.
Chen, M.; Daha, M.R.; Kallenberg, C.G. The complement system in systemic autoimmune disease. J. Autoimmun. 2010, 34, J276–J286. https://doi.org/10.1016/j.jaut.2009.11.014.
- 2.
Okroj, M.; Heinegård, D.; Holmdahl, R.; et al. Rheumatoid arthritis and the complement system. Ann. Med. 2007, 39, 517–530. https://doi.org/10.1080/07853890701477546.
- 3.
Mihara, M.; Kasutani, K.; Okazaki, M.; et al. Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R. Int. Immunopharmacol. 2005, 5, 1731–1740. https://doi.org/10.1016/j.intimp.2005.05.010.
- 4.
Ramadori, G.; Van Damme, J.; Rieder, H.; et al. Interleukin 6 modulates hepatic protein synthesis in human and mouse. Eur. J. Immunol. 1988, 18, 1259–1264. https://doi.org/10.1002/eji.1830180817.
- 5.
Illei, G.G.; Shirota, Y.; Yarboro, C.H.; et al. Tocilizumab in systemic lupus erythematosus: Data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 2010, 62, 542–552. https://doi.org/10.1002/art.27221.
- 6.
Romano, C.; Del Mastro, A.; Sellitto, A.; et al. Tocilizumab reduces complement C3 and C4 serum levels in rheumatoid arthritis patients. Clin. Rheumatol. 2018, 37, 1695–1700. https://doi.org/10.1007/s10067-018-3992-7.
- 7.
Ferraz-Amaro, I.; Santos-Concepción, S.; Castro-Hernández, J.; et al. Tocilizumab modulates the activity of the classical and alternative complement pathways in rheumatoid arthritis patients. Front. Immunol. 2025, 16, 1486588. https://doi.org/10.3389/fimmu.2025.1486588.
- 8.
Bieber, A.; Markovits, D.; Toledano, K.; et al. Hypocomplementemia during tocilizumab treatment: Long-term follow-up results. Medicine 2022, 101, e29528. https://doi.org/10.1097/MD.0000000000029528.
- 9.
Ballanti, E.; Perricone, C.; Greco, E.; et al. Complement and autoimmunity. Immunol. Res. 2013, 56, 477–491. https://doi.org/10.1007/s12026-013-8422-y.
- 10.
Di Muzio, G.; Perricone, C.; Ballanti, E.; et al. Complement system and rheumatoid arthritis: Relationships with autoantibodies, serological, clinical features, and anti-TNF treatment. Int. J. Immunopathol. Pharmacol. 2011, 24, 357–366. https://doi.org/10.1177/039463201102400209.
- 11.
Markiewski, M.M.; Lambris J.D. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am. J. Pathol. 2007, 171, 715–727. https://doi.org/10.2353/ajpath.2007.070166.
- 12.
Tanaka, T.; Narazaki, M.; Kishimoto, T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol. 2014, 6, a016295. https://doi.org/10.1101/cshperspect.a016295.
- 13.
Genovese, M.C.; McKay, J.D.; Nasonov, E.L.; et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis. Arthritis Rheum. 2008, 58, 2968–2980. https://doi.org/10.1002/art.23940.
- 14.
Hashizume, M.; Mihara, M. Blockade of IL-6 and TNF-α inhibited the production of MMP-1 and MMP-3. Eur. J. Pharmacol. 2011, 31, 493–496. https://doi.org/10.1016/j.ejphar.2012.05.035.
- 15.
Shetty, A.; Hanson, R.; Korsten, P.; et al. Tocilizumab in the treatment of rheumatoid arthritis and beyond. Drug Des. Dev. Ther. 2014, 8, 349–364. https://doi.org/10.2147/DDDT.S41437.
- 16.
Scott, D.L.; Wolfe, F.; Huizinga, T.W. Rheumatoid arthritis. Lancet 2010, 376, 1094–1108. https://doi.org/10.1016/S0140-6736(10)60826-4.
- 17.
Smolen, J.S.; Aletaha, D.; McInnes, I.B. Rheumatoid arthritis. Lancet 2016, 388, 2023–2038. https://doi.org/10.1016/S0140-6736(16)30173-8.
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