Tumor necrosis factor inhibitors are associated with reduced complement activation in spondylarthropathies: An observational study

Ingrid Hokstad, Gia Deyab, Morten Wang Fagerland, Torstein Lyberg, Gunnbjørg Hjeltnes, Øystein Førre, Stefan Agewall, Tom Eirik Mollnes, Ivana Hollan, Ingrid Hokstad, Gia Deyab, Morten Wang Fagerland, Torstein Lyberg, Gunnbjørg Hjeltnes, Øystein Førre, Stefan Agewall, Tom Eirik Mollnes, Ivana Hollan

Abstract

Background: The complement system is involved in pathogenesis of cardiovascular disease, and might play a role in accelerated atherogenesis in spondylarthropathies (SpA). Hence, we examined complement activation in SpA, and its relationship to antirheumatic treatment, inflammatory and cardiovascular markers.

Methods: From PSARA, a prospective observational study, we examined 51 SpA patients (31 psoriatic arthritis (PsA), and 20 ankylosing spondylitis (AS)), starting tumor necrosis factor (TNF) inhibitor alone (n = 25), combined with methotrexate (MTX) (n = 10), or MTX monotherapy (n = 16). Complement activation was determined by the soluble terminal complement complex (sC5b-9), inflammation by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and endothelial function by finger plethysmography (Endopat) at baseline, after 6 weeks and 6 months of treatment.

Results: SpA patients had sC5b-9 levels at (PsA) or above (AS) the upper limit of the estimated reference range. Median sC5b-9 levels decreased significantly from baseline to 6 weeks, with no significant difference between the AS and PsA group. Notably, a significant reduction in sC5b-9 was observed after administration of TNF inhibitor ± MTX, whereas no significant changes were observed in patients treated with MTX alone. Between 6 weeks and 6 months, sC5b-9 remained stable across all subgroups. Reduction in sC5b-9 was independently related to decreased ESR and CRP, and to increased high density cholesterol and total cholesterol. Reduction in sC5b-9 from baseline to 6 weeks was associated with improved EF in age and gender adjusted analyses.

Conclusion: TNF-inhibition, but not MTX monotherapy, led to rapid and sustained reduction of complement activation in SpA. Thus, the observed decrease in cardiovascular morbidity in patients treated with TNF-inhibitors might be partly due to its beneficial effect on complement.

Trial registration: Clinical Trials (NCT00902005), retrospectively registered on the 14th of May 2009.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Change in complement activation with…
Fig 1. Change in complement activation with treatment.
sC5b-9 levels in CAU/ml at baseline, after 6 weeks and after 6 months of treatment for the whole study group (A), and for PsA (B), AS (C), MTX (D) and TNF ± MTX (E) subgroups. Points represent median value, while error bars show 95% confidence interval. Abbreviations: PsA: psoriatic arthritis, AS: ankylosing spondylitis, MTX: methotrexate, TNF: tumor necrosis factor inhibitor, CAU: complement activation units.

References

    1. Ramonda R, Lo NA, Modesti V, Nalotto L, Musacchio E, Iaccarino L, et al. Atherosclerosis in psoriatic arthritis. AutoimmunRev [Internet]. 2011;10(12):773–8. Available from:
    1. Peters MJ, Symmons DP, McCarey D, Dijkmans BA, Nicola P, Kvien TK, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis [Internet]. 2010;69(2):325–31. Available from: 10.1136/ard.2009.113696
    1. Peters MJ, IE VDH-B, Dijkmans BA, Nurmohamed MT. Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis. Semin Rheum [Internet]. 2004;34(3):585–92. Available from:
    1. Heeneman S, Daemen MJ. Cardiovascular risks in spondyloarthritides. CurrOpinRheumatol [Internet]. 2007;19(4):358–62. Available from:
    1. Libby P. Inflammation in atherosclerosis. Nature [Internet]. 2002. December 19 [cited 2017 Oct 13];420(6917):868–74. Available from: 10.1038/nature01323
    1. Smith JA. Update on ankylosing spondylitis: current concepts in pathogenesis. Curr Allergy Asthma Rep [Internet]. 2015. January [cited 2015 Nov 14];15(1):489 Available from: 10.1007/s11882-014-0489-6
    1. Hertle E, Stehouwer CD, van Greevenbroek MM. The complement system in human cardiometabolic disease. Mol Immunol [Internet]. 2014/07/16. 2014;61(2):135–48. Available from: 10.1016/j.molimm.2014.06.031
    1. Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol [Internet]. 2013;190(8):3831–8. Available from: 10.4049/jimmunol.1203487
    1. Sturfelt G, Truedsson L. Complement in the immunopathogenesis of rheumatic disease. Nat Rev Rheumatol [Internet]. 2012;8(8):458–68. Available from: 10.1038/nrrheum.2012.75
    1. Melis JPM, Strumane K, Ruuls SR, Beurskens FJ, Schuurman J, Parren PWHI. Complement in therapy and disease. Mol Immunol [Internet]. 2015;1–14. Available from:
    1. Triantafilou M, Hughes TR, Morgan BP, Triantafilou K. Complementing the inflammasome. Immunology [Internet]. 2016. February [cited 2016 Jan 22];147(2):152–64. Available from: 10.1111/imm.12556
    1. Chen M, Daha MR, Kallenberg CGM. The complement system in systemic autoimmune disease. J Autoimmun. 2010;34(3).
    1. Carter AM, M. A. Complement activation: an emerging player in the pathogenesis of cardiovascular disease. Scientifica (Cairo) [Internet]. Hindawi Publishing Corporation; 2012. [cited 2017 May 22];2012:402783 Available from:
    1. Lindberg S, Pedersen SH, Mogelvang R, Galatius S, Flyvbjerg A, Jensen JS, et al. Soluble form of membrane attack complex independently predicts mortality and cardiovascular events in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Am Heart J [Internet]. 2012. November [cited 2017 Oct 9];164(5):786–92. Available from: 10.1016/j.ahj.2012.08.018
    1. Lewis RD, Jackson CL, Morgan BP, Hughes TR. The membrane attack complex of complement drives the progression of atherosclerosis in apolipoprotein E knockout mice. Mol Immunol. 2010;47(5):1098–105. 10.1016/j.molimm.2009.10.035
    1. Nurmohamed MT, Heslinga M, Kitas GD. Cardiovascular comorbidity in rheumatic diseases. Nat Rev Rheumatol [Internet]. 2015. December [cited 2016 Oct 15];11(12):693–704. Available from: 10.1038/nrrheum.2015.112
    1. Deyab G, Hokstad I, Whist JE, Småstuen MC, Agewall S, Lyberg T, et al. Anti-rheumatic treatment is not associated with reduction of pentraxin 3 in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Kuwana M, editor. PLoS One [Internet]. 2017. February 22 [cited 2017 Mar 6];12(2):e0169830 Available from: 10.1371/journal.pone.0169830
    1. Bergseth G, Ludviksen JK, Kirschfink M, Giclas PC, Nilsson B, Mollnes TE. An international serum standard for application in assays to detect human complement activation products. Mol Immunol [Internet]. 2013/06/22. 2013;56(3):232–9. Available from: 10.1016/j.molimm.2013.05.221
    1. Bonetti PO, Pumper GM, Higano ST, Holmes DR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol [Internet]. 2004. December 7 [cited 2016 Dec 23];44(11):2137–41. Available from: 10.1016/j.jacc.2004.08.062
    1. Oleesky DA, Daniels RH, Williams BD, Amos N, Morgan BP. Terminal complement complexes and C1/C1 inhibitor complexes in rheumatoid arthritis and other arthritic conditions. Clin Exp Immunol [Internet]. 1991. May [cited 2015 Oct 6];84(2):250–5. Available from:
    1. Triolo G, Accardo-Palumbo A, Sallì L, Ciccia F, Ferrante A, Tedesco L, et al. Impaired expression of erythrocyte glycosyl-phosphatidylinositol-anchored membrane CD59 in patients with psoriatic arthritis. Relation to terminal complement pathway activation. Clin Exp Rheumatol [Internet]. January [cited 2015 Oct 6];21(2):225–8. Available from:
    1. Neumann E, Barnum SR, Tarner IH, Echols J, Fleck M, Judex M, et al. Local production of complement proteins in rheumatoid arthritis synovium. Arthritis Rheum [Internet]. 2002. April [cited 2017 Feb 28];46(4):934–45. Available from:
    1. Brodeur JP, Ruddy S, Schwartz LB, Moxley G. Synovial fluid levels of complement SC5b-9 and fragment Bb are elevated in patients with rheumatoid arthritis. Arthritis Rheum [Internet]. 1991. December [cited 2017 Feb 28];34(12):1531–7. Available from:
    1. Zimmermann-Nielsen E, Agnholt J, Thorlacius-Ussing O, Dahlerup JF, Baatrup G. Complement activation in plasma before and after infliximab treatment in Crohn disease. Scand J Gastroenterol [Internet]. 2003. October [cited 2016 May 13];38(10):1050–4. Available from: 10.1080/00365520310005767
    1. Familian A, Voskuyl AE, van Mierlo GJ, Heijst HA, Twisk JWR, Dijkmans BAC, et al. Infliximab treatment reduces complement activation in patients with rheumatoid arthritis. Ann Rheum Dis [Internet]. 2005. July 1 [cited 2017 Mar 1];64(7):1003–8. Available from: 10.1136/ard.2004.029124
    1. Chimenti MS, Perricone C, Graceffa D, Di Muzio G, Ballanti E, Guarino MD, et al. Complement system in psoriatic arthritis: a useful marker in response prediction and monitoring of anti-TNF treatment. Clin Exp Rheumatol [Internet]. January [cited 2015 Oct 6];30(1):23–30. Available from:
    1. Eng GP, Bouchelouche P, Bartels EM, Bliddal H, Bendtzen K, Stoltenberg M. Anti-Drug Antibodies, Drug Levels, Interleukin-6 and Soluble TNF Receptors in Rheumatoid Arthritis Patients during the First 6 Months of Treatment with Adalimumab or Infliximab: A Descriptive Cohort Study. Kuwana M, editor. PLoS One [Internet]. 2016. September 8 [cited 2017 Jul 7];11(9):e0162316 Available from: 10.1371/journal.pone.0162316
    1. Ridker PM. C-Reactive Protein: Eighty Years from Discovery to Emergence as a Major Risk Marker for Cardiovascular Disease. Clin Chem [Internet]. 2008. October 2 [cited 2017 Jul 7];55(2):209–15. Available from: 10.1373/clinchem.2008.119214
    1. Perlmutter DH, Dinarello CA, Punsal PI, Colten HR. Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. J Clin Invest [Internet]. 1986. November 1 [cited 2017 Mar 1];78(5):1349–54. Available from: 10.1172/JCI112721
    1. Cutolo M, Seriolo B, Pizzorni C, Craviotto C, Sulli A. Methotrexate in psoriatic arthritis. Clin Exp Rheumatol [Internet]. [cited 2017 Nov 16];20(6 Suppl 28):S76–80. Available from:
    1. Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, et al. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events—CIRT. N Engl J Med [Internet]. Massachusetts Medical Society; 2018. November 10 [cited 2018 Nov 30];NEJMoa1809798. Available from:
    1. Hertle. Complement activation products C5a and sC5b-9 are associated with low-grade inflammation and endothelial dysfunction, but not with atherosclerosis …—PubMed—NCBI. Int J Cardiol [Internet]. 2014; Available from:
    1. Higashi Y. Assessment of endothelial function. History, methodological aspects, and clinical perspectives. Int Heart J [Internet]. 2015. January [cited 2015 Dec 6];56(2):125–34. Available from: 10.1536/ihj.14-385
    1. Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, et al. The assessment of endothelial function: from research into clinical practice. Circulation [Internet]. 2012. August 7 [cited 2015 Dec 10];126(6):753–67. Available from: 10.1161/CIRCULATIONAHA.112.093245
    1. Bonetti PO, Pumper GM, Higano ST, Holmes DR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol [Internet]. 2004. December 7 [cited 2017 Mar 6];44(11):2137–41. Available from: 10.1016/j.jacc.2004.08.062
    1. Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, et al. Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens [Internet]. 2005. January [cited 2017 Nov 14];23(1):7–17. Available from:
    1. Yin W, Ghebrehiwet B, Weksler B, Peerschke EIB. Regulated complement deposition on the surface of human endothelial cells: Effect of tobacco smoke and shear stress. Thromb Res [Internet]. 2008. January [cited 2019 Jun 9];122(2):221–8. Available from: 10.1016/j.thromres.2007.11.005
    1. Robbins RA, Nelson KJ, Gossman GL, Koyama S, Rennard SI. Complement activation by cigarette smoke. Am J Physiol Cell Mol Physiol [Internet]. 1991. April [cited 2019 Jun 9];260(4):L254–9. Available from:
    1. Kew RR, Ghebrehiwet B, Janoff A. Cigarette smoke can activate the alternative pathway of complement in vitro by modifying the third component of complement. J Clin Invest [Internet]. 1985. March 1 [cited 2019 Jun 9];75(3):1000–7. Available from: 10.1172/JCI111760
    1. Pasqui AL, Puccetti L, Bova G, Di Renzo M, Bruni F, Pastorelli M, et al. Relationship between serum complement and different lipid disorders. Clin Exp Med [Internet]. 2002. May [cited 2017 Sep 19];2(1):33–8. Available from:
    1. Montecucco F, Favari E, Norata GD, Ronda N, Nofer JR, Vuilleumier N. Impact of systemic inflammation and autoimmune diseases on apoA-I and HDL plasma levels and functions. Handb Exp Pharmacol [Internet]. 2014/12/20. 2015;224:455–82. Available from: 10.1007/978-3-319-09665-0_14
    1. Van Eijk IC, De Vries MK, Levels JHM, Peters MJL, Huizer EE, Dijkmans BAC, et al. Improvement of lipid profile is accompanied by atheroprotective alterations in high-density lipoprotein composition upon tumor necrosis factor blockade: A prospective cohort study in ankylosing spondylitis. Arthritis Rheum. 2009;60(5):1324–30. 10.1002/art.24492
    1. Hamilton KK, Zhao J, Sims PJ. Interaction between apolipoproteins A-I and A-II and the membrane attack complex of complement. Affinity of the apoproteins for polymeric C9. J Biol Chem. 1993;268(5):3632–8.
    1. Gordon SM, Remaley AT. High density lipoproteins are modulators of protease activity: Implications in inflammation, complement activation, and atherothrombosis. Atherosclerosis [Internet]. 2017. April [cited 2017 Jul 12];259:104–13. Available from: 10.1016/j.atherosclerosis.2016.11.015
    1. Concato J. Observational versus experimental studies: what’s the evidence for a hierarchy? NeuroRx [Internet]. Am. Soc. for Experimental NeuroTherapeutics; 2004. July [cited 2017 Jun 29];1(3):341–7. Available from:

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する