Targeting IL-6 Signaling Pathways for Musculoskeletal Disorders Treatment: Risks and Benefits
DOI:
https://doi.org/10.54133/ajms.v4i.101Keywords:
Interleukin-6, IL-6 receptors, Musculoskeletal disorders, IL-6 antagonistsAbstract
Pro-inflammatory mediators like IL-6 effectively mediated the majority of musculoskeletal disorders such rheumatoid arthritis (RA), osteoarthritis (OA), and tendinitis. Increased levels of IL-6 are found in the serum or synovial fluid of patients with these disorders, and these levels are correlated with the incidence and severity of the disease. IL-6 is crucial for the development of cartilage pathology, for example, by inducing a variety of pathways that are involved in the induction and spread of inflammation. The expression of anti-catabolic factors is similarly increased by IL-6, indicating a protective function. The differential impacts of IL-6 classic and trans-signaling may be the reason for this dual role of IL-6, which has so far remained poorly understood. In this article, the experimental and clinical data on the function of inhibiting IL-6 signaling in the development and progression of pathologies of the synovium, cartilage, and bones were thoroughly reviewed. By evaluating the IL-6 targeting approaches that are currently being considered in research and clinical practice, it may provide a glimpse into the future of these illnesses' treatment.
Downloads
References
Hirano T. IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 2021;33(3):127-148. doi: 10.1093/intimm/dxaa078. DOI: https://doi.org/10.1093/intimm/dxaa078
Niculet E, Chioncel V, Elisei AM, Miulescu M, Buzia OD, Nwabudike LC, et al. Multifactorial expression of IL 6 with update on COVID 19 and the therapeutic strategies of its blockade. Exp Ther Med. 2021;21:263. doi: 10.3892/etm.2021.9693. DOI: https://doi.org/10.3892/etm.2021.9693
Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(10):a016295. doi: 10.1101/cshperspect.a016295. DOI: https://doi.org/10.1101/cshperspect.a016295
Tanaka T, Narazaki M, Kishimoto T. Interleukin (IL-6) Immunotherapy. Cold Spring Harb Perspect Biol. 2018;10(8):a028456. doi: 10.1101/cshperspect.a028456. DOI: https://doi.org/10.1101/cshperspect.a028456
Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014;5:520. doi: 10.3389/fimmu.2014.00520. DOI: https://doi.org/10.3389/fimmu.2014.00520
Scheller J, Chalaris A, Schmidt-Arras D, S, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813:878-888. DOI: https://doi.org/10.1016/j.bbamcr.2011.01.034
Villar-Fincheira P, Sanhueza-Olivares F, Norambuena-Soto I, Cancino-Arenas N, Hernandez-Vargas F, Troncoso R, et al. Role of interleukin-6 in vascular health and disease. Front Mol Biosci. 2021;8:641734. doi: 10.3389/fmolb.2021.641734. DOI: https://doi.org/10.3389/fmolb.2021.641734
Perrone F, Piccirillo MC, Ascierto PA, Salvarani C, Parrella R, Marata AM, et al. Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial. J Transl Med. 2020;18(1):405. doi: 10.1186/s12967-020-02573-9. DOI: https://doi.org/10.1186/s12967-020-02573-9
Santa Cruz A, Mendes-Frias A, Oliveira AI, Dias L, Matos AR, Carvalho A, et al. Interleukin-6 is a biomarker for the development of fatal severe acute respiratory syndrome coronavirus 2 pneumonia. Front Immunol. 2021;12:613422. doi: 10.3389/fimmu.2021.613422. DOI: https://doi.org/10.3389/fimmu.2021.613422
Hojyo S, Uchida M, Tanaka K, Hasebe R, Tanaka Y, Murakami M, et al. How COVID-19 induces cytokine storm with high mortality. Inflamm Regen. 2020;40:37. doi: 10.1186/s41232-020-00146-3. DOI: https://doi.org/10.1186/s41232-020-00146-3
Browning L, Patel MR, Horvath EB, Tawara K, Jorcyk CL. IL-6 and ovarian cancer: inflammatory cytokines in promotion of metastasis. Cancer Manag Res. 2018;10:6685-6693. doi: 10.2147/CMAR.S179189. DOI: https://doi.org/10.2147/CMAR.S179189
Coperchini F, Chiovato L, Rotondi M. Interleukin-6, CXCL10 and infiltrating macrophages in COVID-19-related cytokine storm: Not one for all but all for one! Front Immunol. 2021;12:668507. doi: 10.3389/fimmu.2021.668507. DOI: https://doi.org/10.3389/fimmu.2021.668507
Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-10975. doi: 10.1073/pnas.2005615117. DOI: https://doi.org/10.1073/pnas.2005615117
Li Y, Zhao J, Yin Y, Li K, Zhang C, Zheng Y. The Role of IL-6 in fibrotic diseases: Molecular and cellular mechanisms. Int J Biol Sci. 2022;18(14):5405-5414. doi: 10.7150/ijbs.75876. DOI: https://doi.org/10.7150/ijbs.75876
Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 2012;8(9):1237-1247. doi: 10.7150/ijbs.4989. DOI: https://doi.org/10.7150/ijbs.4989
Bharadwaj U, Kasembeli MM, Robinson P, Tweardy DJ. Targeting Janus Kinases and signal transducer and activator of transcription 3 to treat inflammation, fibrosis, and cancer: Rationale, progress, and caution. Pharmacol Rev. 2020;72(2):486-526. doi: 10.1124/pr.119.018440. DOI: https://doi.org/10.1124/pr.119.018440
Chen JJ, Zhang LN, Hou H, Xu L, Ji K. Interleukin-6 signaling blockade treatment for cytokine release syndrome in COVID-19. Exp Ther Med. 2021;21(1):24. doi: 10.3892/etm.2020.9456. DOI: https://doi.org/10.3892/etm.2020.9456
Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med. 2020;383(23):2255-2273. doi: 10.1056/NEJMra2026131. DOI: https://doi.org/10.1056/NEJMra2026131
Kern L, Mittenbühler MJ, Vesting AJ, Ostermann AL, Wunderlich CM, Wunderlich FT. Obesity-induced TNFα and IL-6 signaling: The missing link between obesity and inflammation-driven liver and colorectal cancers. Cancers (Basel). 2018;11(1):24. doi: 10.3390/cancers11010024. DOI: https://doi.org/10.3390/cancers11010024
Majidpoor J, Mortezaee K. Angiogenesis as a hallmark of solid tumors - clinical perspectives. Cell Oncol (Dordr). 2021;44(4):715-737. doi: 10.1007/s13402-021-00602-3. DOI: https://doi.org/10.1007/s13402-021-00602-3
Majidpoor J, Mortezaee K. Interleukin-2 therapy of cancer-clinical perspectives. Int Immunopharmacol. 2021;98:107836. doi: 10.1016/j.intimp.2021.107836. DOI: https://doi.org/10.1016/j.intimp.2021.107836
Mortezaee K. Hypoxia induces core-to-edge transition of progressive tumoral cells: A critical review on differential yet corroborative roles for HIF-1α and HIF-2α. Life Sci. 2020;242:117145. doi: 10.1016/j.lfs.2019.117145. DOI: https://doi.org/10.1016/j.lfs.2019.117145
Heo TH, Wahler J, Suh N. Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer. Oncotarget. 2016;7(13):15460-15473. doi: 10.18632/oncotarget. DOI: https://doi.org/10.18632/oncotarget.7102
AlDeghaither D, Smaglo BG, Weiner LM. Beyond peptides and mAbs--current status and future perspectives for biotherapeutics with novel constructs. J Clin Pharmacol. 2015;55 (Suppl 3):S4-20. doi: 10.1002/jcph.407. DOI: https://doi.org/10.1002/jcph.407
Ridker PM, Rane M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circ Res. 2021;128(11):1728-1746. doi: 10.1161/CIRCRESAHA.121.319077. DOI: https://doi.org/10.1161/CIRCRESAHA.121.319077
Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, et al. Trial of tocilizumab in giant-cell arteritis. N Engl J Med. 2017;377(4):317-328. doi: 10.1056/NEJMoa1613849. DOI: https://doi.org/10.1056/NEJMoa1613849
Favalli EG. Understanding the role of interleukin-6 (IL-6) in the joint and beyond: A comprehensive review of IL-6 inhibition for the management of rheumatoid arthritis. Rheumatol Ther. 2020;7:473-516. doi: 10.1007/s40744-020-00219-2. DOI: https://doi.org/10.1007/s40744-020-00219-2
Maioli G, Caporali R, Favalli EG. Lessons learned from the preclinical discovery and development of sarilumab for the treatment of rheumatoid arthritis. Expert Opin Drug Discov. 2022;17(8):799-813. doi: 10.1080/17460441.2022.2093852. DOI: https://doi.org/10.1080/17460441.2022.2093852
Dougados M. Comorbidities in rheumatoid arthritis. Curr Opin Rheumatol. 2016;28:282-288. doi: 10.1097/BOR.0000000000000267. DOI: https://doi.org/10.1097/BOR.0000000000000267
Isaacs JD, Harari O, Kobold U, Lee JS, Bernasconi C. Effect of tocilizumab on haematological markers implicates interleukin-6 signaling in the anaemia of rheumatoid arthritis. Arthritis Res Ther. 2013;15:R204. doi: 10.1186/ar4397. DOI: https://doi.org/10.1186/ar4397
Genovese MC, Fleischmann R, Kivitz AJ, Rell-Bakalarska M, Martincova R, Fiore S, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: Results of a phase III study. Arthritis Rheumatol. 2015;67:1424-1437. doi: 10.1002/art.39093. DOI: https://doi.org/10.1002/art.39093
Poole JA, Mikuls TR, Thiele GM, Gaurav R, Nelson AJ, Duryee MJ, et al. Increased susceptibility to organic dust exposure-induced inflammatory lung disease with enhanced rheumatoid arthritis-associated autoantigen expression in HLA-DR4 transgenic mice. Respir Res. 2022;23(1):160. doi: 10.1186/s12931-022-02085-8. DOI: https://doi.org/10.1186/s12931-022-02085-8
Gaurav R, Mikuls TR, Thiele GM, Nelson AJ, Niu M, Guda C, et al. High-throughput analysis of lung immune cells in a combined murine model of agriculture dust-triggered airway inflammation with rheumatoid arthritis. PLoS One. 2021;16(2):e0240707. doi: 10.1371/journal.pone.0240707. DOI: https://doi.org/10.1371/journal.pone.0240707
Khanna D, Lin CJF, Furst DE, Wagner B, Zucchetto M, Raghu G, et al. Long-term safety and efficacy of tocilizumab in early systemic sclerosis-interstitial lung disease: Open-label extension of a phase 3 randomized controlled trial. Am J Respir Crit Care Med. 2022;205(6):674-684. doi: 10.1164/rccm.202103-0714OC. DOI: https://doi.org/10.1164/rccm.202103-0714OC
Choy EH, De Benedetti F, Takeuchi T, Hashizume M, John MR, Kishimoto T. Translating IL-6 biology into effective treatments. Nat Rev Rheumatol 2020;16:335-345. https://doi.org/10.1038/s41584-020-0419-z. DOI: https://doi.org/10.1038/s41584-020-0419-z
Venkiteshwaran A. Tocilizumab. MAbs. 2009;1:432-438. doi: 10.4161/mabs.1.5.9497. DOI: https://doi.org/10.4161/mabs.1.5.9497
Rubbert-Roth A, Furst DE, Nebesky JM, Jin A, Berber E. A review of recent advances using tocilizumab in the treatment of rheumatic diseases. Rheumatol Ther. 2018; 5:21-42. doi: 10.1007/s40744-018-0102-x. DOI: https://doi.org/10.1007/s40744-018-0102-x
Senolt L. Emerging therapies in rheumatoid arthritis: focus on monoclonal antibodies. F1000Res. 2019;8:F1000 Faculty Rev-1549. doi: 10.12688/f1000research.18688.1. DOI: https://doi.org/10.12688/f1000research.18688.1
Genovese MC, Fleischmann R, Furst D, Janssen N, Carter J, Dasgupta B, et al. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: Outcomes of a randomized phase IIb study. Ann Rheum Dis. 2014;73:1607-1615. doi: 10.1136/annrheumdis-2013-204760. DOI: https://doi.org/10.1136/annrheumdis-2013-204760
Liu X, Li L, Wang Q, Jiang F, Zhang P, Guo F, et al. A Novel Humanized anti-interleukin-6 antibody HZ0408b with anti-rheumatoid arthritis therapeutic potential. Front Immunol. 2022;12:816646. doi: 10.3389/fimmu.2021.816646. DOI: https://doi.org/10.3389/fimmu.2021.816646
Kutsuna T, Hino K, Hasegawa H, Watamori K, Kidani T, Imai H, et al. Psoriatic arthritis successfully treated with second-line anti-interleukin-6 treatment: a case report and review of the literature. J Med Case Rep. 2022;16(1):402. doi: 10.1186/s13256-022-03624-z. DOI: https://doi.org/10.1186/s13256-022-03624-z
Ravipati A, Nolan S, Alphonse M, Dikeman D, Youn C, Wang Y, et al. IL-6R/signal transducer and activator of transcription 3 signaling in keratinocytes rather than in T cells induces psoriasis-like dermatitis in Mice. J Invest Dermatol. 2022;142(4):1126-1135.e4. doi: 10.1016/j.jid.2021.09.012. DOI: https://doi.org/10.1016/j.jid.2021.09.012
Valli A, Kuuliala K, Virtanen A, Kuuliala A, Palmroth M, Peltomaa R, et al. Tofacitinib treatment modulates the levels of several inflammation-related plasma proteins in rheumatoid arthritis and baseline levels of soluble biomarkers associate with the treatment response. Clin Exp Immunol. 2022;210(2):141-150. doi: 10.1093/cei/uxac085. DOI: https://doi.org/10.1093/cei/uxac085
Padula AS, Pappas DA, Fiore S, Blachley TS, Ford K, Emeanuru K, et al. The effect of targeted rheumatoid arthritis therapeutics on systemic inflammation and anemia: analysis of data from the CorEvitas RA registry. Arthritis Res Ther. 2022;24(1):276. doi: 10.1186/s13075-022-02955-y. DOI: https://doi.org/10.1186/s13075-022-02955-y
De La Fuente F, Belkhir R, Henry J, Nguyen CD, Pham T, Germain V, et al. Use of a bDMARD or tsDMARD for the management of inflammatory arthritis under checkpoint inhibitors: an observational study. RMD Open. 2022;8(2):e002612. doi: 10.1136/rmdopen-2022-002612. DOI: https://doi.org/10.1136/rmdopen-2022-002612
Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7(1):33-42. doi: 10.1038/nrrheum.2010.196. DOI: https://doi.org/10.1038/nrrheum.2010.196
Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage. 2013;21(1):16-21. doi: 10.1016/j.joca.2012.11.012. DOI: https://doi.org/10.1016/j.joca.2012.11.012
Kloppenburg M, Peterfy C, Haugen IK, Kroon F, Chen S, Wang L, et al. Phase IIa, placebo-controlled, randomized study of lutikizumab, an anti-interleukin-1α and anti-interleukin-1β dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis. Ann Rheum Dis. 2019;78(3):413-420. doi: 10.1136/annrheumdis-2018-213336. DOI: https://doi.org/10.1136/annrheumdis-2018-213336
Fleischmann RM, Bliddal H, Blanco FJ, Schnitzer TJ, Peterfy C, Chen S, et al. A phase II trial of lutikizumab, an anti-interleukin-1α/β dual variable domain immunoglobulin, in knee osteoarthritis patients with synovitis. Arthritis Rheumatol. 2019;71(7):1056-1069. doi: 10.1002/art.40840. DOI: https://doi.org/10.1002/art.40840
Latourte A, Cherifi C, Maillet J, Ea HK, Bouaziz W, Funck-Brentano T, et al. Systemic inhibition of IL-6/Stat3 signaling protects against experimental osteoarthritis. Ann Rheum Dis. 2017;76(4):748-755. doi: 10.1136/annrheumdis-2016-209757. DOI: https://doi.org/10.1136/annrheumdis-2016-209757
Richards PJ, Nowell MA, Horiuchi S, McLoughlin RM, Fielding CA, Grau S, et al. Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis. Arthritis Rheum. 2006;54(5):1662-1672. doi: 10.1002/art.21818. DOI: https://doi.org/10.1002/art.21818
Struglics A, Larsson S, Kumahashi N, Frobell R, Lohmander LS. Changes in cytokines and aggrecan ARGS neoepitope in synovial fluid and serum and in C-terminal crosslinking telopeptide of type II collagen and N-terminal crosslinking telopeptide of type I collagen in urine over five years after anterior cruciate ligament rupture: An exploratory analysis in the knee anterior cruciate ligament, nonsurgical versus surgical treatment trial. Arthritis Rheumatol. 2015;67(7):1816-1825. doi: 10.1002/art.39146. DOI: https://doi.org/10.1002/art.39146
Watt FE, Paterson E, Freidin A, Kenny M, Judge A, Saklatvala J, et al. Acute molecular changes in synovial fluid following human knee injury: Association with early clinical outcomes. Arthritis Rheumatol. 2016;68(9):2129-2140. doi: 10.1002/art.39677. DOI: https://doi.org/10.1002/art.39677
Wiegertjes R, van de Loo FAJ, Blaney Davidson EN. A roadmap to target interleukin-6 in osteoarthritis. Rheumatology (Oxford). 2020;59(10):2681-2694. doi: 10.1093/rheumatology/keaa248. DOI: https://doi.org/10.1093/rheumatology/keaa248
Ko KR, Han SH, Choi S, An HJ, Kwak EB, Jeong Y, et al. Substance P inhibitor promotes tendon healing in a collagenase-induced rat model of tendinopathy. Am J Sports Med. 2022;50(13):3681-3689. doi: 10.1177/03635465221126175. DOI: https://doi.org/10.1177/03635465221126175
Dougados M, Kissel K, Sheeran T, Tak PP, Conaghan PG, Mola EM, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013;72(1):43-50. doi: 10.1136/annrheumdis-2011-201282. DOI: https://doi.org/10.1136/annrheumdis-2011-201282
Gabay C, Emery P, van Vollenhoven R, Dikranian A, Alten R, Pavelka K, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381(9877):1541-1550. doi: 10.1016/S0140-6736(13)60250-0. DOI: https://doi.org/10.1016/S0140-6736(13)60250-0
Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, Rubbert-Roth A, Kelman A, et al. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis. 2016;75(6):1081-1091. doi: 10.1136/annrheumdis-2015-207628. DOI: https://doi.org/10.1136/annrheumdis-2015-207628
Kaneko Y, Kato M, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, et al. Tocilizumab discontinuation after attaining remission in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate: results from a prospective randomized controlled study. Ann Rheum Dis. 2018;77(9):1268-1275. doi: 10.1136/annrheumdis-2018-213416. DOI: https://doi.org/10.1136/annrheumdis-2018-213416
Kastrati K, Aletaha D, Burmester GR, Chwala E, Dejaco C, Dougados M, et al. A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases. RMD Open 2022;8:e002359. doi:10.1136/rmdopen-2022-002359. DOI: https://doi.org/10.1136/rmdopen-2022-002359
Boyce EG, Rogan EL, Vyas D, Prasad N, Mai Y. Sarilumab: Review of a Second IL-6 receptor antagonist indicated for the treatment of rheumatoid arthritis. Ann Pharmacother. 2018;52(8):780-791. doi: 10.1177/1060028018761599. DOI: https://doi.org/10.1177/1060028018761599
Nasonov E, Fatenejad S, Feist E, Ivanova M, Korneva E, Krechikova DG, et al. Olokizumab, a monoclonal antibody against interleukin 6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by methotrexate: efficacy and safety results of a randomized controlled phase III study. Ann Rheum Dis. 2022;81(4):469-479. doi: 10.1136/annrheumdis-2021-219876. DOI: https://doi.org/10.1136/annrheumdis-2021-219876
Worcester S. FDA committee rejects sirukumab approval on safety concerns. Rheumatology News 2017. https://www.mdedge.com/rheumatology/article/143848/rheumatoid-arthritis/fda-committee-rejects-sirukumab-approval-safety (Accessed in January 2023).
Verhoeven MMA, Tekstra J, Jacobs JWG, Bijlsma JWJ, van Laar JM, Pethö-Schramm A, et al. Efficacy of tocilizumab monotherapy versus tocilizumab and methotrexate combination therapy in the prevention of radiographic progression in rheumatoid arthritis: An analysis using individual patient data from multiple clinical trials. Arthritis Care Res (Hoboken). 2022;74(6):889-895. doi: 10.1002/acr.24524. DOI: https://doi.org/10.1002/acr.24524
Shekhawat J, Gauba K, Gupta S, Purohit P, Mitra P, Garg M, et al. Interleukin-6 perpetrator of the COVID-19 cytokine storm. Indian J Clin Biochem. 2021;36(4):440-450. doi: 10.1007/s12291-021-00989-8. DOI: https://doi.org/10.1007/s12291-021-00989-8
Peng L, Zhong J, Xiao Y, Wang B, Li S, Deng Y, et al. Therapeutic effects of an anti-IL-6 antibody in fungal keratitis: Macrophage inhibition and T cell subset regulation. Int Immunopharmacol. 2020;85:106649. doi: 10.1016/j.intimp.2020.106649. DOI: https://doi.org/10.1016/j.intimp.2020.106649
Ferreros P, Trapero I. Interleukin inhibitors in cytokine release syndrome and neurotoxicity secondary to CAR-T therapy. Diseases. 2022;10:41. doi: 10.3390/diseases10030041. DOI: https://doi.org/10.3390/diseases10030041
Copaescu A, Smibert O, Gibson A, Phillips EJ, Trubiano JA. The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection. J Allergy Clin Immunol. 2020;146(3):518-534.e1. doi: 10.1016/j.jaci.2020.07.001. DOI: https://doi.org/10.1016/j.jaci.2020.07.001
Kang S, Kishimoto T. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms. Exp Mol Med. 2021;53(7):1116-1123. doi: 10.1038/s12276-021-00649-0. DOI: https://doi.org/10.1038/s12276-021-00649-0
Brábek J, Jakubek M, Vellieux F, Novotný J, Kolář M, Lacina L, et al. Interleukin-6: molecule in the intersection of cancer, ageing and COVID-19. Int J Mol Sci. 2020;21(21):7937. doi: 10.3390/ijms21217937. DOI: https://doi.org/10.3390/ijms21217937
McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis - shaping the immunological landscape. Nat Rev Rheumatol. 2016;12(1):63-68. doi: 10.1038/nrrheum.2015.171. DOI: https://doi.org/10.1038/nrrheum.2015.171
Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10(12):720-727. doi: 10.1038/nrrheum.2014.127. DOI: https://doi.org/10.1038/nrrheum.2014.127
McInnes IB, Thompson L, Giles JT, Bathon JM, Salmon JE, Beaulieu AD, et al. Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomized, placebo-controlled study. Ann Rheum Dis. 2015;74(4):694-702. doi: 10.1136/annrheumdis-2013-204345. DOI: https://doi.org/10.1136/annrheumdis-2013-204345
Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121(9):3375-3383. doi: 10.1172/JCI57158. DOI: https://doi.org/10.1172/JCI57158
Drucker C, Gewiese J, Malchow S, Scheller J, Rose-John S. Impact of interleukin-6 classic- and trans-signaling on liver damage and regeneration. J Autoimmun. 2010;34(1):29-37. doi: 10.1016/j.jaut.2009.08.003. DOI: https://doi.org/10.1016/j.jaut.2009.08.003
Uciechowski P, Dempke WCM. Interleukin-6: A master player in the cytokine network. Oncology. 2020;98(3):131-137. doi: 10.1159/000505099. DOI: https://doi.org/10.1159/000505099
Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting interleukin-6 signaling in clinic. Immunity. 2019;50(4):1007-1023. doi: 10.1016/j.immuni.2019.03.026. DOI: https://doi.org/10.1016/j.immuni.2019.03.026
Wallace DJ, Strand V, Merrill JT, Popa S, Spindler AJ, Eimon A, et al. Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomized controlled trial. Ann Rheum Dis. 2017;76(3):534-542. doi: 10.1136/annrheumdis-2016-209668. DOI: https://doi.org/10.1136/annrheumdis-2016-209668
Felten R, Devauchelle-Pensec V, Seror R, Duffau P, Saadoun D, Hachulla E, et al. Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial. Ann Rheum Dis. 2021;80(3):329-338. doi: 10.1136/annrheumdis-2020-218467. DOI: https://doi.org/10.1136/annrheumdis-2021-220220
Baek HJ, Lim MJ, Park W, Park SH, Shim SC, Yoo DH, et al. Efficacy and safety of tocilizumab in Korean patients with active rheumatoid arthritis. Korean J Intern Med. 2019;34(4):917-931. doi: 10.3904/kjim.2017.159. DOI: https://doi.org/10.3904/kjim.2017.159
Edwards CJ, Östör AJK, Naisbett-Groet B, Kiely P. Tapering versus steady-state methotrexate in combination with tocilizumab for rheumatoid arthritis: a randomized, double-blind trial. Rheumatology (Oxford). 2018;57(1):84-91. doi: 10.1093/rheumatology/kex358. DOI: https://doi.org/10.1093/rheumatology/kex358
Kremer JM, Rigby W, Singer NG, Birchwood C, Gill D, Reiss W, et al. Sustained response following discontinuation of methotrexate in patients with rheumatoid arthritis treated with subcutaneous tocilizumab: Results from a randomized, controlled trial. Arthritis Rheumatol. 2018;70(8):1200-1208. doi: 10.1002/art.40493. DOI: https://doi.org/10.1002/art.40493
Pablos JL, Navarro F, Blanco FJ, Román-Ivorra JA, Alonso A, Martín Mola E, et al. Efficacy of tocilizumab monotherapy after response to combined tocilizumab and methotrexate in patients with rheumatoid arthritis: the randomized JUST-ACT study. Clin Exp Rheumatol. 2019;37(3):437-444.
Huizinga TW, Conaghan PG, Martin-Mola E, Schett G, Amital H, Xavier RM, et al. Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study. Ann Rheum Dis. 2015;74(1):35-43. doi: 10.1136/annrheumdis-2014-205752. DOI: https://doi.org/10.1136/annrheumdis-2014-205752
Schoels MM, van der Heijde D, Breedveld FC, Burmester GR, Dougados M, Emery P, et al. Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement. Ann Rheum Dis. 2013;72(4):583-589. doi: 10.1136/annrheumdis-2012-202470. DOI: https://doi.org/10.1136/annrheumdis-2012-202470
Lally L, Forbess L, Hatzis C, Spiera R. Brief Report: A prospective open-label phase IIa trial of tocilizumab in the treatment of polymyalgia rheumatica. Arthritis Rheumatol. 2016;68(10):2550-2554. doi: 10.1002/art.39740. DOI: https://doi.org/10.1002/art.39740
Devauchelle-Pensec V, Berthelot JM, Cornec D, Renaudineau Y, Marhadour T, Jousse-Joulin S, et al. Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study. Ann Rheum Dis. 2016;75(8):1506-1510. doi: 10.1136/annrheumdis-2015-208742. DOI: https://doi.org/10.1136/annrheumdis-2015-208742
Zhang C, Zhang M, Qiu W, Ma H, Zhang X, Zhu Z, et al. Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicenter, randomized, phase 2 trial. Lancet Neurol. 2020;19(5):391-401. doi: 10.1016/S1474-4422(20)30070-3. DOI: https://doi.org/10.1016/S1474-4422(20)30070-3
Yang S, Zhang C, Zhang TX, Feng B, Jia D, Han S, et al. A real-world study of interleukin-6 receptor blockade in patients with neuromyelitis optica spectrum disorder. J Neurol. 2023;270(1):348-356. doi: 10.1007/s00415-022-11364-9. DOI: https://doi.org/10.1007/s00415-022-11364-9
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Al-Rafidain Journal of Medical Sciences ( ISSN: 2789-3219 )
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Published by Al-Rafidain University College. This is an open access journal issued under the CC BY-NC-SA 4.0 license (https://creativecommons.org/licenses/by-nc-sa/4.0/).
