TARGETING COMPLEMENT AND PROTEASOME PATHWAYS IN RHEUMATOID ARTHRITIS: EMERGING THERAPEUTIC STRATEGIES
Main Article Content
Keywords
Rheumatoid arthritis, Complement pathway, Proteasome pathway, NF-κB, Synovial inflammation, Immunoproteasome, Cytokines, Targeted therapy, Biologics, Combination therapy
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovial inflammation, cartilage destruction, and bone erosion, leading to disability and reduced quality of life. Although conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) have improved outcomes, many patients remain refractory or develop adverse effects, necessitating exploration of novel therapeutic strategies. The complement and proteasome pathways play pivotal roles in RA pathogenesis by sustaining immune activation, cytokine amplification, and NF-κB–mediated inflammatory signaling. Pharmacological interventions targeting these pathways, including complement inhibitors (C3, C5, C5aR antagonists) and proteasome inhibitors (Bortezomib, Carfilzomib, Immunoproteasome-selective agents), have demonstrated promising efficacy in preclinical and early clinical studies. Furthermore, combination regimens and dual-targeting approaches provide synergistic effects by simultaneously disrupting extracellular and intracellular inflammatory mechanisms. Advances in immunoproteasome-selective molecules, oral small-molecule inhibitors, nanoparticle-based delivery, and biomarker-driven patient selection are expected to enhance both safety and therapeutic outcomes. Collectively, targeting the complement and proteasome pathways represents an innovative and promising frontier in RA management, particularly for difficult-to-treat and refractory cases.
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2. Q. Guo, Y. Wang, D. Xu, J. Nossent, N. Pavlos, J. Xu, Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies, Bone Research, 2018. https://doi.org/10.1038/s41413-018-0016-9
3. A. Romanycheva, M. Korsakov, M. Dorogov, V. Fedorov, A. Shetnev, A. Arshinov, Prospects for Innovative Drugs for the Treatment of Rheumatoid Arthritis, Problems of Biological Medical and Pharmaceutical Chemistry, 2023. https://doi.org/10.29296/25877313-2023-12-07
4. S. Shams et al., The Therapeutic Landscape of Rheumatoid Arthritis: Current State and Future Directions, Frontiers in Pharmacology, 2021. https://doi.org/10.3389/fphar.2021.680043
5. V. N. Fedorov et al., Potential role of PAR2 inhibitors for treating rheumatoid arthritis, 2025. https://doi.org/10.37489/2588-0519-2024-4-4-14
6. Romi, D. Sharma, A. Sharma, P. Gupta, A New Era of Therapeutics: Innovation in the Treatment of Rheumatoid Arthritis, Recent Advances in Anti-Infective Drug Discovery, 2025. https://doi.org/10.2174/0127724344382299250818070846
7. J. Polyakova et al., The Role of New Cytokines in the Pathogenesis Rheumatoid Arthritis, 2019. https://doi.org/10.1136/annrheumdis-2019-eular.1437
8. Q. Fang, C. Zhou, K. S. Nandakumar, Molecular and Cellular Pathways Contributing to Joint Damage in Rheumatoid Arthritis, Hindawi Publishing Corporation, 2020. https://doi.org/10.1155/2020/3830212
9. S. Nalbant, M. Brlk, Cytokines in Rheumatoid Arthritis (RA), 2017. https://doi.org/10.5772/65893
10. Q. Meng, K. Wei, Y. Shan, E3 ubiquitin ligase gene BIRC3 modulates TNF-induced cell death pathways and promotes aberrant proliferation in rheumatoid arthritis fibroblast-like synoviocytes, Frontiers in Immunology, 2024. https://doi.org/10.3389/fimmu.2024.1433898
11. S. Srirangan, E. Choy, The role of Interleukin 6 in the pathophysiology of rheumatoid arthritis, SAGE Publishing, 2010. https://doi.org/10.1177/1759720x10378372
12. W. H. Faour, A. Mancini, Q. He, J. A. D. Battista, T-cell-derived Interleukin-17 Regulates the Level and Stability of Cyclooxygenase-2 (COX-2) mRNA through Restricted Activation of the p38 Mitogen-activated Protein Kinase Cascade, Elsevier BV, 2003. https://doi.org/10.1074/jbc.m212790200
13. M. Ostrowska, W. Maslinski, M. Prochorec-Sobieszek, M. Nieciecki, I. Sudo-Szopiska, "Cartilage and bone damage in rheumatoid arthritis, Rheumatology, 2018. https://doi.org/10.5114/reum.2018.75523
14. A. Mueller et al., Recent Advances in Understanding the Pathogenesis of Rheumatoid Arthritis: New Treatment Strategies, Cells, 2021. https://doi.org/10.3390/cells10113017
15. O. Alekseeva, T. Saykovskaya, A. Smirnov, A. Volkov, E. Nasonov, Relationship of biomarkers, ultrasound (US) signs of joint damage and radiographic progression in patients with rheumatoid arthritis(RA), 2018. https://doi.org/10.1136/annrheumdis-2018-eular.6448
16. S. J. Perper et al., TWEAK Is a Novel Arthritogenic Mediator, American Association of Immunologists, 2006. https://doi.org/10.4049/jimmunol.177.4.2610
17. P. Stenvinkel, R. PecoitsFilho, B. Lindholm, Coronary Artery Disease in End-Stage Renal Disease, American Society of Nephrology, 2003. https://doi.org/10.1097/01.asn.0000069165.79509.42
18. J. Huang, Z. Chen, S. Yang, F. Hong, Nitric Oxide Synthases in Rheumatoid Arthritis," Multidisciplinary Digital Publishing Institute, 2023. https://doi.org/10.3390/molecules28114414
19. A. D. Christensen, C. Haase, A. D. Cook, J. A. Hamilton, K/BxN Serum-Transfer Arthritis as a Model for Human Inflammatory Arthritis, Frontiers Media, 2016. https://doi.org/10.3389/fimmu.2016.00213
20. M. Carlo et al., Active synovitis of metacarpophalangeal joints a neuropathic condition in rheumatoid arthritis patients? Results from a ultrasound study at level of the palmar digital nerves, 2021. https://doi.org/10.1136/ANNRHEUMDIS-2021-EULAR.3116
21. X. Wu et al., CD5L aggravates rheumatoid arthritis progression via promoting synovial fibroblasts proliferation and activity, Clinical and Experimental Immunology, 2023. https://doi.org/10.1093/cei/uxad054
22. V. R. Arruda, P. Favaro, J. D. Finn, Strategies to Modulate Immune Responses: A New Frontier for Gene Therapy,Elsevier BV, 2009. https://doi.org/10.1038/mt.2009.150
23. J. R. Kalden, Emerging Therapies for Rheumatoid Arthritis, Adis, Springer Healthcare, 2016. https://doi.org/10.1007/s40744-016-0032-4
24. T. A. Thibaudeau, D. M. Smith, A Practical Review of Proteasome Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 2019. https://doi.org/10.1124/pr.117.015370
25. V. J. Palombella et al., Role of the proteasome and NF-B in streptococcal cell wall-induced polyarthritis, National Academy of Sciences, 1998. https://doi.org/10.1073/pnas.95.26.15671
26. A. Connor, N. Mahomed, R. Gandhi, E. Keystone, S. A. Berger, TNF modulates protein degradation pathways in rheumatoid arthritis synovial fibroblasts, BioMed Central, 2012. https://doi.org/10.1186/ar3778
27. W. Wu, Z. Cheng, Y. Nan, G. Pan, Y. Wang, L-selectin Promotes Migration, Invasion and Inflammatory Response of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via NF-kB Signaling Pathway, Inflammation, 2025. https://doi.org/10.1007/s10753-025-02242-3
28. J. Ma, T. Yan, Y. Mou, J. Jing, Y. Mo, L. Dai, Peroxisome proliferator-activated receptor-gamma coactivator-1 facilitates migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis via activation of canonical and non-canonical nf-b signalling pathway, 2018. https://doi.org/10.1136/annrheumdis-2018-eular.5103
29. A. Singh et al.,Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast, Frontiers in Immunology, 2021. https://doi.org/10.3389/fimmu.2021.746503
30. A. Miagkov et al., NF-B activation provides the potential link between inflammation and hyperplasia in the arthritic joint, National Academy of Sciences, 1998. https://doi.org/10.1073/pnas.95.23.13859
31. E. Malmhll-Bah, K. Andersson, M. Erlandsson, S. Silfverswrd, R. Pullerits, M. Bokarewa, Metabolic signature and proteasome activity controls synovial migration of CDC42hi CD14+ cells in rheumatoid arthritis, medRxiv, 2023. https://doi.org/10.3389/fimmu.2023.1187093
32. V. D. O. N. Teixeira, L. I. Filippin, R. M. Xavier, Mecanismos de perda muscular da sarcopenia, Elsevier BV, 2012. https://doi.org/10.1590/s0482-50042012000200009
33. T. A. Grigoreva, V. G. Tribulovich, G. Melino, N. A. Barlev, The 26S proteasome is a multifaceted target for anti-cancer therapies, Impact Journals LLC, 2015. https://doi.org/10.18632/oncotarget.4619
34. J. Fielitz, Cancer cachexiawhen proteasomal inhibition is not enough, Springer Science+Business Media, 2016. https://doi.org/10.1002/jcsm.12124
35. Patriquin CJ. The past, present, and future of complement therapeutics. Semin Hematol. 2019;56(3):143–153.
36. Nguyen THP, et al. Antirheumatic therapy is associated with reduced terminal complement complex in rheumatoid arthritis: a PLOS ONE study. PLoS One. 2022;17(8):e0264628.
37. Horiuchi T. Complement-targeted therapy: development of C5 and C5a inhibitors. Inflamm Regen. 2016;36:17.
38. Tornero-Molina J, et al. Experts document on methotrexate use in combined therapy with biologics/targeted synthetics in RA. Reumatol Clin. 2022;18(1):33–41
39. Jayne DRW, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, Burst V, Grundmann F, Jadoul M, Szombati I, Tesař V, Segelmark M, Potarca A, Schall TJ, Bekker P; clear Study Group. Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis. J Am Soc Nephrol. 2017 Sep;28(9):2756-2767.
40. Harding J. Results of a phase 2B study of the humanized anti-C5 antibody eculizumab in patients with rheumatoid arthritis. Ann Rheum Dis. 2004;63 Suppl 1:301.
41. The Pharma Letter. Alexion's eculizumab shows mixed results for RA but promise for PNH. 2004.
42. Nguyen THP, Hokstad I, Fagerland MW, Mollnes TE, Hollan I, Feinberg MW, et al. (2022) Antirheumatic therapy is associated with reduced complement activation in rheumatoid arthritis. PLoS ONE 17(2): e0264628.
43. Wijnsma KL, Ter Heine R, Moes DJAR, Langemeijer S, Schols SEM, Volokhina EB, van den Heuvel LP, Wetzels JFM, van de Kar NCAJ, Brüggemann RJ. Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab. Clin Pharmacokinet. 2019 Jul;58(7):859-874.
44. Christopher J Patriquin, Kevin H.M. Kuo,Eculizumab and Beyond: The Past, Present, and Future of Complement Therapeutics, Transfusion Medicine Reviews, Volume 33, Issue 4, 2019, ISSN 0887-7963.
45. Lee SW, Kim JH, Park YB, Lee SK. Bortezomib attenuates murine collagen-induced arthritis. Ann Rheum Dis. 2009 Nov;68(11):1761-7.
46. Yannaki, E., Papadopoulou, A., Athanasiou, E., Kaloyannidis, P., Paraskeva, A., Bougiouklis, D., Palladas, P., Yiangou, M. and Anagnostopoulos, A. (2010), The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in adjuvant-induced arthritis in rats. Arthritis & Rheumatism, 62: 3277-3288.
47. Basler M, et al. The immunoproteasome as a novel drug target for autoimmune diseases: ONX-0914 preclinical arthritis data. Clin Exp Rheumatol. 2015
48. MedChemExpress / ONX-0914 product and activity summary; ONX-0914 blocks cytokine production and attenuates experimental arthritis. (preclinical summaries).
49. Zilberberg Jenny, Matos Jennifer, Dziopa Eugenia, Dziopa Leah,Yang Zheng,Kirk Christopher J., Assefnia Shahin ,Korngold Robert, Inhibition of the Immunoproteasome Subunit LMP7 with Ameliorates Graft-versus-Host Disease in an Histocompatibility Antigen 2013;Disparate Murine Model, 2015.
50. Muchamuel T, Fan RA, Anderl JL, Bomba DJ, Johnson HWB, Lowe E, Tuch BB, McMinn DL, Millare B, Kirk CJ. Zetomipzomib (KZR-616) attenuates lupus in mice via modulation of innate and adaptive immune responses. Front Immunol. 2023 Mar 10;14:1043680.
51. Mohamad Mohty, Eolia Brissot, Bipin N. Savani, Beatrice Gaugler, Effects of Bortezomib on the Immune System: A Focus on Immune Regulation, Biology of Blood and Marrow Transplantation, Volume 19, Issue 10, 2013, 1416-1420,1083-8791.
52. Lee SW, Kim JH, Park YB, Lee SK. Bortezomib attenuates murine collagen-induced arthritis. Ann Rheum Dis. 2009 Nov;68(11):1761-7.
53. M. Kolev, C. Kemper, Keeping It All GoingComplement Meets Metabolism, Frontiers Media, 2017. https://doi.org/10.3389/fimmu.2017.00001
54. T. A. Thomas, D. M. Smith, Proteasome activator 28 (PA28) allosterically activates trypsin-like proteolysis by binding to the -ring of the 20S proteasome,Elsevier BV, 2022. https://doi.org/10.1016/j.jbc.2022.102140
55. H. Huang et al.,Two clinical drugs deubiquitinase inhibitor auranofin and aldehyde dehydrogenase inhibitor disulfiram trigger synergistic anti-tumor effects in vitro and in vivo, Impact Journals LLC, 2015. https://doi.org/10.18632/oncotarget.6425
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Published
Sep 30, 2025
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How to Cite
Vrunda Mochi, Dr. Nishkruti R. Mehta, Mr. Khinya Ram, & Dr. Pragnesh Patani. (2025). TARGETING COMPLEMENT AND PROTEASOME PATHWAYS IN RHEUMATOID ARTHRITIS: EMERGING THERAPEUTIC STRATEGIES. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1166-1177. https://doi.org/10.53555/gbc8y445
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Author Biographies
Vrunda Mochi
Student, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Nishkruti R. Mehta
Professor & Head, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Mr. Khinya Ram
Assitant Professor, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Pragnesh Patani
Principal, Khyati College of Pharmacy, Palodiya, Ahmedabad
How to Cite
Vrunda Mochi, Dr. Nishkruti R. Mehta, Mr. Khinya Ram, & Dr. Pragnesh Patani. (2025). TARGETING COMPLEMENT AND PROTEASOME PATHWAYS IN RHEUMATOID ARTHRITIS: EMERGING THERAPEUTIC STRATEGIES. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1166-1177. https://doi.org/10.53555/gbc8y445