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Endocrine, Metabolic & Immune Disorders - Drug Targets


ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Research Article

Interleukin-6 Blockers Improve Inflammation-Induced Lipid Metabolism Impairments but Induce Liver Fibrosis in Collagen-Induced Arthritis

Author(s): Tshimangadzo M. Denga, Sulè Gunter, Serena Fourie, Regina le Roux, Ashmeetha Manilall, Aletta M.E. Millen* and Lebogang Mokotedi*

Volume 23, Issue 4, 2023

Published on: 19 December, 2022

Page: [548 - 557] Pages: 10

DOI: 10.2174/1871530323666221017153157

Price: $65


Background: Interleukin-6 (IL-6) receptor blockers improve systemic inflammation, however, their inconsistent effects on lipid metabolism and drug-induced liver injuries warrant further investigation. This study aimed to determine the effects of IL-6 receptor blocker therapy on lipid metabolism and liver morphology in collagen-induced arthritis.

Methods: Sixty three Sprague Dawley rats were divided into control (n = 24), inflammation (n = 24), and IL-6 blocker (n = 15) groups. Inflammation was induced in the inflammation and IL-6- blocker groups using Bovine type-II collagen and incomplete Freund’s adjuvant. At first signs of arthritis, the IL-6 blocker group received an IL-6 blocker, tocilizumab for six weeks. Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and ATP-binding cassette transporter-A1 (ABCA1) were measured. Liver fibrosis was determined by histological stains and liver enzymes were measured using the colorimetric-chemistry analyzer.

Results: In the inflammation group, HDL-C and ABCA1 were reduced compared to control (p < 0.0001 and p = 0.04, respectively) and IL-6 blocker (p = 0.0003 and p < 0.0001, respectively) groups. LDL-C was increased in the inflammation compared to control (p = 0.02). Markers of liver fibrosis were increased in the IL-6 blocker group compared to control and inflammation groups (picrosirius red collagen area fraction: p < 0.0001 and p = 0.0008, respectively; Masson’s trichrome collagen area fraction: p = 0.0002 and p = 0.01, respectively). Alkaline phosphatase concentrations were increased in the IL-6 blocker group compared to the control (p < 0.0001) and inflammation (p = 0.002) groups.

Conclusion: IL-6 blockers ameliorated inflammation-induced lipid metabolism impairments, however they induced liver fibrosis. Although IL-6 blockers may reduce inflammation-induced metabolic impairments in chronic inflammatory disorders, routine monitoring of liver function is warranted while on treatment.

Keywords: Inflammation, lipid metabolism, liver fibrosis, IL-6 receptor blocker, collagen-induced arthritis, tocilizumab.

Graphical Abstract
Provan, S.A.; Lillegraven, S.; Sexton, J.; Angel, K.; Austad, C.; Haavardsholm, E.A.; Kvien, T.K.; Uhlig, T. Trends in all-cause and cardiovascular mortality in patients with incident rheumatoid arthritis: A 20-year follow-up matched case-cohort study. Rheumatology, 2020, 59(3), 505-512.
[PMID: 31504942]
Avina-Zubieta, J.A.; Thomas, J.; Sadatsafavi, M.; Lehman, A.J.; Lacaille, D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: A meta-analysis of observational studies. Ann. Rheum. Dis., 2012, 71(9), 1524-1529.
[] [PMID: 22425941]
Semb, A.G.; Ikdahl, E.; Wibetoe, G.; Crowson, C.; Rollefstad, S. Atherosclerotic cardiovascular disease prevention in rheumatoid arthritis. Nat. Rev. Rheumatol., 2020, 16(7), 361-379.
[] [PMID: 32494054]
Moriya, J. Critical roles of inflammation in atherosclerosis. J. Cardiol., 2019, 73(1), 22-27.
[] [PMID: 29907363]
Feingold, K.R.; Grunfeld, C. The effect of inflammation and infection on lipids and lipoproteins. Endotext, 2022.
Behl, T.; Kaur, I.; Sehgal, A.; Zengin, G.; Brisc, C.; Brisc, M.C.; Munteanu, M.A.; Nistor-Cseppento, D.C.; Bungau, S. The lipid paradox as a metabolic checkpoint and its therapeutic significance in ameliorating the associated cardiovascular risks in rheumatoid arthritis patients. Int. J. Mol. Sci., 2020, 21(24), 9505.
[] [PMID: 33327502]
Robertson, J.; Peters, M.J.; McInnes, I.B.; Sattar, N. Changes in lipid levels with inflammation and therapy in RA: A maturing paradigm. Nat. Rev. Rheumatol., 2013, 9(9), 513-523.
[] [PMID: 23774906]
Venetsanopoulou, A.I.; Pelechas, E.; Voulgari, P.V.; Drosos, A.A. The lipid paradox in rheumatoid arthritis: The dark horse of the augmented cardiovascular risk. Rheumatol. Int., 2020, 40(8), 1181-1191.
[] [PMID: 32524301]
Zhang, J.; Chen, L.; Delzell, E.; Muntner, P.; Hillegass, W.B.; Safford, M.M.; Millan, I.Y.N.; Crowson, C.S.; Curtis, J.R. The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis. Ann. Rheum. Dis., 2014, 73(7), 1301-1308.
[] [PMID: 24796336]
Pope, J.E.; Choy, E.H. C-reactive protein and implications in rheumatoid arthritis and associated comorbidities. Semin. Arthritis Rheum., 2021, 51(1), 219-229.
[] [PMID: 33385862]
Ogata, A.; Kato, Y.; Higa, S.; Yoshizaki, K. IL-6 inhibitor for the treatment of rheumatoid arthritis: A comprehensive review. Mod. Rheumatol., 2019, 29(2), 258-267.
[] [PMID: 30427250]
Yip, R.M.L.; Yim, C.W. Role of interleukin 6 inhibitors in the management of rheumatoid arthritis. J. Clin. Rheumatol., 2021, 27(8), e516-e524.
[] [PMID: 31876844]
Hoffman, E.; Rahat, M.A.; Feld, J.; Elias, M.; Rosner, I.; Kaly, L.; Lavie, I.; Gazitt, T.; Zisman, D. Effects of tocilizumab, an anti-interleukin-6 receptor antibody, on serum lipid and adipokine levels in patients with rheumatoid arthritis. Int. J. Mol. Sci., 2019, 20, 4633.
Tournadre, A.; Pereira, B.; Dutheil, F.; Giraud, C.; Courteix, D.; Sapin, V.; Frayssac, T.; Mathieu, S.; Malochet-Guinamand, S.; Soubrier, M. Changes in body composition and metabolic profile during interleukin 6 inhibition in rheumatoid arthritis. J. Cachexia Sarcopenia Muscle, 2017, 8(4), 639-646.
[] [PMID: 28316139]
Cacciapaglia, F.; Perniola, S.; Venerito, V.; Anelli, M.G.; Härdfeldt, J.; Fornaro, M.; Moschetta, A.; Iannone, F. The impact of biologic drugs on high-density lipoprotein cholesterol efflux capacity in rheumatoid arthritis patients. J. Clin. Rheumatol., 2022, 28(1), e145-e149.
[] [PMID: 33394831]
Cacciapaglia, F.; Anelli, M.G.; Rinaldi, A.; Fornaro, M.; Lopalco, G.; Scioscia, C.; Lapadula, G.; Iannone, F. Lipids and atherogenic indices fluctuation in rheumatoid arthritis patients on long-term tocilizumab treatment. Mediators Inflamm., 2018, 2018, 1-7.
[] [PMID: 30405318]
Provan, S.A.; Berg, I.J.; Hammer, H.B.; Mathiessen, A.; Kvien, T.K.; Semb, A.G. The impact of newer biological disease modifying anti-rheumatic drugs on cardiovascular risk factors: A 12-month longitudinal study in rheumatoid arthritis patients treated with rituximab, abatacept and tociliziumab. PLoS One, 2015, 10(6), e0130709.
[] [PMID: 26114946]
McInnes, I.B.; Thompson, L.; Giles, J.T.; Bathon, J.M.; Salmon, J.E.; Beaulieu, A.D.; Codding, C.E.; Carlson, T.H.; Delles, C.; Lee, J.S.; Sattar, N. Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: Measure, a randomised, placebo-controlled study. Ann. Rheum. Dis., 2015, 74(4), 694-702.
[] [PMID: 24368514]
Farah, Z.; Ali, S.; Price-Kuehne, F.; Mackworth-Young, C.G. Tocilizumab in refractory rheumatoid arthritis: Long-term efficacy, safety, and tolerability beyond 2 years. Biologics, 2016, 10, 59-66.
[PMID: 27069354]
Genovese, M.C.; Kremer, J.M.; van Vollenhoven, R.F.; Alten, R.; Scali, J.J.; Kelman, A.; Dimonaco, S.; Brockwell, L. Transaminase levels and hepatic events during tocilizumab treatment: Pooled analysis of long-term clinical trial safety data in rheumatoid arthritis. Arthritis Rheumatol., 2017, 69(9), 1751-1761.
[] [PMID: 28597609]
Aoki, C.; Inaba, Y.; Choe, H.; Kaneko, U.; Hara, R.; Miyamae, T.; Imagawa, T.; Mori, M.; Oba, M.S.; Yokota, S.; Saito, T. Discrepancy between clinical and radiological responses to tocilizumab treatment in patients with systemic-onset juvenile idiopathic arthritis. J. Rheumatol., 2014, 41(6), 1171-1177.
[] [PMID: 24786929]
Avdeeva, A.S.; Aleksandrova, E.N.; Novikov, A.A.; Cherkasova, M.V.; Panasyuk, E.Y.; Nasonov, E.L. Relationship of the clinical efficiency of tocilizumab therapy to the serum level of matrix metalloproteinase-3 in patients with rheumatoid arthritis. Ter. Arkh., 2013, 85(5), 24-29.
[PMID: 23819335]
Hiura, M.; Abe, S.; Tabaru, A.; Shimajiri, S.; Hanami, K.; Saito, K.; Tanaka, Y.; Harada, M. Case of severe liver damage after the induction of tocilizumab therapy for rheumatoid vasculitis. Hepatol. Res., 2011, 41(5), 492-496.
[] [PMID: 21435128]
Muhović, D.; Bojović, J.; Bulatović, A.; Vukčević, B.; Ratković, M.; Lazović, R.; Smolović, B. First case of drug‐induced liver injury associated with the use of tocilizumab in a patient with COVID‐19. Liver Int., 2020, 40(8), 1901-1905.
[] [PMID: 32478465]
Le Roux, R.; Mokotedi, L.; Fourie, S.; Manilall, A.; Gunter, S.; Millen, A.M.E. TNF-α inhibitors reduce inflammation-induced concentric remodelling, but not diastolic dysfunction in collagen-induced arthritis. Clin. Exp. Rheumatol., 2021, 40(1), 24-32.
[PMID: 33427610]
Mokotedi, L.; Millen, A.M.E.; Mogane, C.; Gomes, M.; Woodiwiss, A.J.; Norton, G.R.; Michel, F.S. Associations of inflammatory markers and vascular cell adhesion molecule-1 with endothelial dysfunction in collagen-induced arthritis. Eur. J. Pharmacol., 2019, 865, 172786.
[] [PMID: 31712060]
Alli, A. Effect of aqueous extract of bitter leaf (Vernonia amygdalina Del) on Carbon tetrachloride (CCl4) induced liver damage in albino wistar rats. Eur. J. Sci. Res., 2009, 26, 122-130.
El-ouady, F.; Bachir, F.; Eddouks, M. Flavonoids extracted from Asteriscus graveolens improve glucose metabolism and lipid profile in diabetic rats. Endocr. Metab. Immune Disord. Drug Targets, 2021, 21(5), 895-904.
[] [PMID: 32811421]
Biesterfeld, S.; Knapp, J.; Bittinger, F.; Götte, H.; Schramm, M.; Otto, G. Frozen section diagnosis in donor liver biopsies: Observer variation of semiquantitative and quantitative steatosis assessment. Virchows Arch., 2012, 461(2), 177-183.
[] [PMID: 22772768]
Brown, G.T.; Kleiner, D.E. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metabolism, 2016, 65(8), 1080-1086.
[] [PMID: 26775559]
Abdel El-Gaphar, O.A.M.; Abo-Youssef, A.M.; Abo-Saif, A.A. Effect of losartan in complete freund’s adjuvant induced arthritis in rats. Iran. J. Pharm. Res., 2018, 17(4), 1420-1430.
[PMID: 30568700]
Soubrier, M.; Pei, J.; Durand, F.; Gullestad, L.; John, A. Concomitant use of statins in tocilizumab-treated patients with rheumatoid arthritis: A post hoc analysis. Rheumatol. Ther., 2017, 4(1), 133-149.
[] [PMID: 27900570]
Wendt, M.M.N.; de Oliveira, M.C.; Franco-Salla, G.B.; Castro, L.S.; Parizotto, Â.V.; Souza Silva, F.M.; Natali, M.R.M.; Bersani-Amado, C.A.; Bracht, A.; Comar, J.F. Fatty acids uptake and oxidation are increased in the liver of rats with adjuvant-induced arthritis. Biochim. Biophys. Acta Mol. Basis Dis., 2019, 1865(3), 696-707.
[] [PMID: 30593897]
Fernández-Ortiz, A.M.; Ortiz, A.M.; Pérez, S.; Toledano, E.; Abásolo, L.; González-Gay, M.A.; Castañeda, S.; González-Álvaro, I. Effects of disease activity on lipoprotein levels in patients with early arthritis: Can oxidized LDL cholesterol explain the lipid paradox theory? Arthritis Res. Ther., 2020, 22(1), 213.
[] [PMID: 32917272]
Kim, J.Y.; Lee, E.Y.; Park, J.K.; Song, Y.W.; Kim, J.R.; Cho, K.H. Patients with rheumatoid arthritis show altered lipoprotein profiles with dysfunctional high-density lipoproteins that can exacerbate inflammatory and atherogenic process. PLoS One, 2016, 11(10), e0164564.
[] [PMID: 27736980]
Chen, D.Y.; Chen, Y.M.; Hsieh, T.Y.; Hsieh, C.W.; Lin, C.C.; Lan, J.L. Significant effects of biologic therapy on lipid profiles and insulin resistance in patients with rheumatoid arthritis. Arthritis Res. Ther., 2015, 17(1), 52.
[] [PMID: 25889426]
Xie, B.; University, J.; He, J.; Liu, Y.; Liu, T.; Liu, C. HDL cholesterol efflux capacity and concentration in patients with rheumatoid arthritis: A systematic review and meta-analysis. Research Square, 2020.
Qian, H.; Zhao, X.; Cao, P.; Lei, J.; Yan, N.; Gong, X. Structure of the human lipid exporter ABCA1. Cell, 2017, 169(7), 1228-1239.e10.
[] [PMID: 28602350]
Segrest, J.P.; Tang, C.; Song, H.D.; Jones, M.K.; Davidson, W.S.; Aller, S.G.; Heinecke, J.W. ABCA1 is an extracellular phospholipid translocase. Nat. Commun., 2022, 13(1), 4812.
[] [PMID: 35974019]
Okuda, L.S.; Castilho, G.; Rocco, D.D.F.M.; Nakandakare, E.R.; Catanozi, S.; Passarelli, M. Advanced glycated albumin impairs HDL anti-inflammatory activity and primes macrophages for inflammatory response that reduces reverse cholesterol transport. Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 2012, 1821(12), 1485-1492.
[] [PMID: 22940078]
Sato, S.; Imachi, H.; Lyu, J.; Miyai, Y.; Fukunaga, K.; Dong, T.; Ibata, T.; Kobayashi, T.; Yoshimoto, T.; Kikuchi, F.; Yonezaki, K.; Yamaji, N.; Iwama, H.; Murao, K. Effect of TNF-α on the expression of ABCA1 in pancreatic β-cells. J. Mol. Endocrinol., 2018, 61(4), 185-193.
[] [PMID: 30131353]
Frisdal, E.; Lesnik, P.; Olivier, M.; Robillard, P.; Chapman, M.J.; Huby, T.; Guerin, M.; Le Goff, W. Interleukin-6 protects human macrophages from cellular cholesterol accumulation and attenuates the proinflammatory response. J. Biol. Chem., 2011, 286(35), 30926-30936.
[] [PMID: 21757719]
Mao, M.; Lei, H.; Liu, Q.; Chen, Y.; Zhao, L.; Li, Q.; Luo, S.; Zuo, Z.; He, Q.; Huang, W.; Zhang, N.; Zhou, C.; Ruan, X.Z. Effects of miR-33a-5P on ABCA1/G1-mediated cholesterol efflux under inflammatory stress in THP-1 macrophages. PLoS One, 2014, 9(10), e109722.
[] [PMID: 25329888]
Babashamsi, M.M.; Koukhaloo, S.Z.; Halalkhor, S.; Salimi, A.; Babashamsi, M. ABCA1 and metabolic syndrome; a review of the ABCA1 role in HDL-VLDL production, insulin-glucose homeostasis, inflammation and obesity. Diabetes Metab. Syndr., 2019, 13(2), 1529-1534.
[] [PMID: 31336517]
Summers, G.D.; Metsios, G.S.; Stavropoulos-Kalinoglou, A.; Kitas, G.D. Rheumatoid cachexia and cardiovascular disease. Nat. Rev. Rheumatol., 2010, 6(8), 445-451.
[] [PMID: 20647995]
Frayn, K.N.; Arner, P.; Yki-Järvinen, H. Fatty acid metabolism in adipose tissue, muscle and liver in health and disease. Essays Biochem., 2006, 42, 89-103.
[] [PMID: 17144882]
Sethi, J.K.; Hotamisligil, G.S. Metabolic messengers: tumour necrosis factor. Nat. Metab., 2021, 3(10), 1302-1312.
[] [PMID: 34650277]
Robertson, J.; Porter, D.; Sattar, N.; Packard, C.J.; Caslake, M.; McInnes, I.; McCarey, D. Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: A cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis. Ann. Rheum. Dis., 2017, 76(11), 1949-1952.
[] [PMID: 28916714]
Ferreira, H.B.; Melo, T.; Paiva, A.; Domingues, M.R. Insights in the role of lipids, oxidative stress and inflammation in rheumatoid arthritis unveiled by new trends in lipidomic investigations. Antioxidants, 2021, 10(1), 45.
[] [PMID: 33401700]
Tang, K.T.; Dufour, J.F.; Chen, P.H.; Hernaez, R.; Hutfless, S. Antitumour necrosis factor-α agents and development of new-onset cirrhosis or non-alcoholic fatty liver disease: a retrospective cohort. BMJ Open Gastroenterol., 2020, 7(1), e000349.
[] [PMID: 32377366]
Akhlaghi, S.; Sahebari, M.; Mahmoodi, M.; Yaseri, M.; Mansournia, M.A.; Rafatpanah, H.; Zeraati, H. Additional effect of etanercept or infliximab on the liver function tests of patients with rheumatoid arthritis: a cohort study. Ther. Clin. Risk Manag., 2018, 14, 1943-1950.
[] [PMID: 30349273]
Dehestani, V.; Shariati-Sarabi, Z.; Mohiti, S. Liver toxicity in rheumatoid arthritis patients treated with methotrexate. Asia Pac. J. Med. Toxicol., 2015, 4, 102-105.
Schmidt-Arras, D.; Rose-John, S. IL-6 pathway in the liver: From physiopathology to therapy. J. Hepatol., 2016, 64(6), 1403-1415.
[] [PMID: 26867490]
Lala, V.; Goyal, A.; Bansal, P.; Minter, D.A. Liver Function Tests; StatPearls Publishing: Florida, 2020.
Hu, J.; Zhang, X.; Gu, J.; Yang, M.; Zhang, X.; Zhao, H.; Li, L. Serum alkaline phosphatase levels as a simple and useful test in screening for significant fibrosis in treatment-naive patients with hepatitis B e-antigen negative chronic hepatitis B. Eur. J. Gastroenterol. Hepatol., 2019, 31(7), 817-823.
[] [PMID: 30543572]
Mahmud, M.; Safadi, R.; Mader, R. Hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: Management decisions. Clin. Pharmacol., 2011, 3, 39-43.
[] [PMID: 22287855]
Zhang, C.Y.; Yuan, W.G.; He, P.; Lei, J.H.; Wang, C.X. Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets. World J. Gastroenterol., 2016, 22(48), 10512-10522.
Abdel-Maged, A.E.S.; Gad, A.M.; Abdel-Aziz, A.K.; Aboulwafa, M.M.; Azab, S.S. Comparative study of anti-VEGF ranibizumab and interleukin-6 receptor antagonist tocilizumab in adjuvant-induced arthritis. Toxicol. Appl. Pharmacol., 2018, 356, 65-75.
[] [PMID: 30025850]
Drepper, M.; Rubbia-Brandt, L.; Spahr, L. Tocilizumab-induced acute liver injury in adult onset Still’s disease. Case Reports Hepatol., 2013, 2013, 1-3.
[] [PMID: 25374723]
Serviddio, G.; Villani, R.; Stallone, G.; Scioscia, G.; Foschino-Barbaro, M.P.; Lacedonia, D. Tocilizumab and liver injury in patients with COVID-19. Therap. Adv. Gastroenterol., 2020, 13, 1756284820959183.
[] [PMID: 33101458]

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