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Association between statin use and incidence of relapse in anti-neutrophil cytoplasmic antibody-associated vasculitis: a single-center retrospective cohort study

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Abstract

Several studies have shown the efficacy of statins for some autoimmune disorders caused by anti-inflammatory and immunomodulatory reactions. However, little information is available about the impact of statins on relapse in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). We performed the first investigation examining whether statin use has an effect on suppressing the first relapse of AAV in Japanese patients with AAV. This single-center retrospective cohort study included 98 consecutive patients with newly diagnosed AAV from Aichi Medical University Hospital, Japan between March 2009 and December 2017. Time to first relapse from the first remission was compared between 36 patients in the statin group and 62 patients in the non-statin group using multivariate Cox proportional hazard models, which were adjusted for clinically relevant factors. During the follow-up period (median, 24 months; interquartile range, 9–50 months), 35 (97.2%) patients in the statin group achieved remission, whereas 56 (90.3%) patients achieved remission in the non-statin group (P = 0.201). After achieving the first remission, 9 (25.7%) patients in the statin group and 29 (51.8%) patients in the non-statin group had at least one relapse. Multivariate Cox proportional hazard models revealed that statin use was significantly associated with a lower incidence of relapse compared with non-statin use (multivariate-adjusted hazard ratio = 0.41, 95% confidence interval: 0.18–0.92; P = 0.031). Patients with statin use were associated with a lower incidence of relapse in AAV. Our results should be assessed in well-designed randomized controlled trials.

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References

  1. Hogan SL, Falk RJ, Chin H, Cai J, Jennette CE, Jennette JC, Nachman PH (2005) Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med 143:621–631. https://doi.org/10.7326/0003-4819-143-9-200511010-00005

    Article  PubMed  Google Scholar 

  2. Nachman PH, Hogan SL, Jennette JC, Falk RJ (1996) Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol 7:33–39

    CAS  PubMed  Google Scholar 

  3. Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group (2005) Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 352:351–361. https://doi.org/10.1056/NEJMoa041884

    Article  Google Scholar 

  4. Savage CO, Winearls CG, Evans DJ, Rees AJ, Lockwood CM (1985) Microscopic polyarteritis: presentation, pathology and prognosis. Q J Med 56:467–483

    CAS  PubMed  Google Scholar 

  5. Reinhold-Keller E, Fink CO, Herlyn K, Gross WL, De Groot K (2002) High rate of renal relapse in 71 patients with Wegener's granulomatosis under maintenance of remission with low-dose methotrexate. Arthritis Rheum 47:326–332. https://doi.org/10.1002/art.10459

    Article  CAS  PubMed  Google Scholar 

  6. Chen M, Yu F, Zhao MH (2008) Relapses in patients with antineutrophil cytoplasmic autoantibody-associated vasculitis: likely to begin with the same organ as initial onset. J Rheumatol 35:448–450

    CAS  PubMed  Google Scholar 

  7. Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343:425–430

    Article  CAS  Google Scholar 

  8. Yamaguchi M, Ando M, Kato S et al (2015) Increase of antimyeloperoxidase antineutrophil cytoplasmic antibody (ANCA) in patients with renal ANCA-associated vasculitis: association with risk to relapse. J Rheumatol 42:1853–1860. https://doi.org/10.3899/jrheum.141622

    Article  CAS  PubMed  Google Scholar 

  9. Forero-Peña DA, Gutierrez FR (2013) Statins as modulators of regulatory T-cell biology. Mediators Inflamm 2013:167086. https://doi.org/10.1155/2013/167086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Khattri S, Zandman-Goddard G (2013) Statins and autoimmunity. Immunol Res 56:348–357. https://doi.org/10.1097/BOR.0000000000000438

    Article  CAS  PubMed  Google Scholar 

  11. Chen LW, Lin CS, Tsai MC, Shih SF, Lim ZW, Chen SJ, Tsui PF, Ho LJ, Lai JH, Liou JT (2019) Pitavastatin exerts potent anti-inflammatory and immunomodulatory effects via the suppression of AP-1 signal transduction in human T cells. Int J Mol Sci 20(14):E3534. https://doi.org/10.3390/ijms20143534

    Article  CAS  PubMed  Google Scholar 

  12. Albert MA, Danielson E, Rifai N, Ridker PM, Investigators PRINCE (2001) Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 286:64–70. https://doi.org/10.1001/jama.286.1.64

    Article  CAS  PubMed  Google Scholar 

  13. Nayak A, Hayen A, Zhu L, McGeechan K, Glasziou P, Irwig L, Doust J, Gregory G, Bell K (2018) Legacy effects of statins on cardiovascular and all-cause mortality: a meta-analysis. BMJ Open 8:e020584. https://doi.org/10.1136/bmjopen-2017-020584

    Article  PubMed  PubMed Central  Google Scholar 

  14. Shalev V, Chodick G, Silber H, Kokia E, Jan J, Heymann AD (2009) Continuation of statin treatment and all-cause mortality: a population-based cohort study. Arch Intern Med 169:260–268. https://doi.org/10.1001/archinternmed.2008.552

    Article  PubMed  Google Scholar 

  15. Nissen SE, Tuzcu EM, Schoenhagen P et al (2005) Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 352:29–38. https://doi.org/10.1056/NEJMoa042000

    Article  CAS  PubMed  Google Scholar 

  16. Watts R, Lane S, Hanslik T, Hauser T, Hellmich B, Koldingsnes W, Mahr A, Segelmark M, Cohen-Tervaert JW, Scott D (2007) Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis 66:222–227. https://doi.org/10.1136/ard.2006.054593

    Article  PubMed  Google Scholar 

  17. Matsuo S, Imai E, Horio M et al (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982–992. https://doi.org/10.1053/j.ajkd.2008.12.034

    Article  CAS  PubMed  Google Scholar 

  18. Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, Savage C, Adu D (1994) Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM 87:671–678

    CAS  PubMed  Google Scholar 

  19. Tremoulet AH (2015) The role of statins in inflammatory vasculitides. Autoimmunity 48:177–180. https://doi.org/10.3109/08916934.2015.1027818

    Article  CAS  PubMed  Google Scholar 

  20. Karmaus PW, Shi M, Perl S, Biancotto A, Candia J, Cheung F, Kotliarov Y, Young N, Fessler MB, CHI Consortium (2019) Effects of rosuvastatin on the immune system in healthy volunteers with normal serum cholesterol. JCI Insight 4(21):131530. https://doi.org/10.1172/jci.insight.131530

    Article  PubMed  Google Scholar 

  21. Gupta A, Mackay J, Whitehouse A, Godec T, Collier T, Pocock S, Poulter N, Sever P (2018) Long-term mortality after blood pressure-lowering and lipid-lowering treatment in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy study: 16-year follow-up results of a randomised factorial trial. Lancet 392:1127–1137. https://doi.org/10.1016/S0140-6736(18)31776-8

    Article  PubMed  Google Scholar 

  22. McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N (2004) Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 363:2015–2021. https://doi.org/10.1016/S0140-6736(04)16449-0

    Article  CAS  PubMed  Google Scholar 

  23. Tang TT, Song Y, Ding YJ et al (2011) Atorvastatin upregulates regulatory T cells and reduces clinical disease activity in patients with rheumatoid arthritis. J Lipid Res 52:1023–1032. https://doi.org/10.1194/jlr.M010876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chalubinski M, Broncel M (2010) Influence of statins on effector and regulatory immune mechanisms and their potential clinical relevance in treating autoimmune disorders. Med Sci Monit 16:RA245–RA251

    CAS  PubMed  Google Scholar 

  25. Lv S, Liu Y, Zou Z, Li F, Zhao S, Shi R, Bian R, Tian H (2015) The impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol 33:69–76

    PubMed  Google Scholar 

  26. López-Pedrera C, Ruiz-Limón P, Aguirre MÁ et al (2011) Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome. Ann Rheum Dis 70:675–682. https://doi.org/10.1136/ard.2010.135525

    Article  CAS  PubMed  Google Scholar 

  27. Ferreira GA, Navarro TP, Telles RW, Andrade LE, Sato EI (2007) Atorvastatin therapy improves endothelial-dependent vasodilation in patients with systemic lupus erythematosus: an 8 weeks controlled trial. Rheumatology (Oxford) 46(1560):1565. https://doi.org/10.1093/rheumatology/kem186

    Article  CAS  Google Scholar 

  28. Norby GE, Holme I, Fellström B, Jardine A, Cole E, Abedini S, Holdaas H, Assessment of Lescol in Renal Transplantation Study Group (2009) Effect of fluvastatin on cardiac outcomes in kidney transplant patients with systemic lupus erythematosus: a randomized placebo-controlled study. Arthritis Rheum 60(1060):1064. https://doi.org/10.1002/art.24379

    Article  CAS  Google Scholar 

  29. van Denderen JC, Peters MJ, van Halm VP, van der Horst-Bruinsma IE, Dijkmans BA, Nurmohamed MT (2006) Statin therapy might be beneficial for patients with ankylosing spondylitis. Ann Rheum Dis 65:695–696. https://doi.org/10.1136/ard.2005.044503

    Article  PubMed  Google Scholar 

  30. Inanc MT, Kalay N, Heyit T et al (2010) Effects of atorvastatin and lisinopril on endothelial dysfunction in patients with Behçet's disease. Echocardiography 27:997–1003. https://doi.org/10.1111/j.1540-8175.2010.01180.x

    Article  PubMed  Google Scholar 

  31. Hamaoka A, Hamaoka K, Yahata T, Fujii M, Ozawa S, Toiyama K, Nishida M, Itoi T (2010) Effects of HMG-CoA reductase inhibitors on continuous post-inflammatory vascular remodeling late after Kawasaki disease. J Cardiol 56:245–253. https://doi.org/10.1016/j.jjcc.2010.06.006

    Article  PubMed  Google Scholar 

  32. Abou-Raya A, Abou-Raya S, Helmii M (2008) Statins: potentially useful in therapy of systemic sclerosis-related Raynaud's phenomenon and digital ulcers. J Rheumatol 35:1801–1808

    CAS  PubMed  Google Scholar 

  33. Furukawa S, Yasuda S, Amengual O, Horita T, Atsumi T, Koike T (2006) Protective effect of pravastatin on vascular endothelium in patients with systemic sclerosis: a pilot study. Ann Rheum Dis 65:1118–1120. https://doi.org/10.1136/ard.2005.046870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kwon OC, Oh JS, Park MC, Hong S, Lee CK, Yoo B, Kim YG (2019) Statins reduce relapse rate in Takayasu arteritis. Int J Cardiol 287:111–115. https://doi.org/10.1016/j.ijcard.2019.02.046

    Article  PubMed  Google Scholar 

  35. Schmidt J, Kermani TA, Muratore F, Crowson CS, Matteson EL, Warrington KJ (2013) Statin use in giant cell arteritis: a retrospective study. J Rheumatol 40:910–915. https://doi.org/10.3899/jrheum.121150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. García-Martínez A, Hernández-Rodríguez J, Grau JM, Cid MC (2004) Treatment with statins does not exhibit a clinically relevant corticosteroid-sparing effect in patients with giant cell arteritis. Arthritis Rheum 51:674–678. https://doi.org/10.1002/art.20541

    Article  CAS  PubMed  Google Scholar 

  37. Narváez J, Bernad B, Nolla JM, Semin VJ (2007) Statin therapy does not seem to benefit giant cell arteritis. Arthritis Rheum 36:322–327. https://doi.org/10.1016/j.semarthrit.2006.10.001

    Article  CAS  Google Scholar 

  38. Weyand CM, Goronzy JJ (2003) Medium- and large-vessel vasculitis. N Engl J Med 349:160–169. https://doi.org/10.1056/NEJMra022694

    Article  CAS  PubMed  Google Scholar 

  39. Sen D, Rosenstein ED, Kramer N (2010) ANCA-positive vasculitis associated with simvastatin/ezetimibe: expanding the spectrum of statin-induced autoimmunity? Int J Rheum Dis 13:e29–e31. https://doi.org/10.1111/j.1756-185X.2010.01481.x

    Article  PubMed  Google Scholar 

  40. Kwak B, Mulhaupt F, Myit S, Mach F (2000) Statins as a newly recognized type of immunomodulator. Nat Med 6:1399–1402. https://doi.org/10.1038/82219

    Article  CAS  PubMed  Google Scholar 

  41. Arnaud C, Mach F (2006) Potential antiinflammatory and immunomodulatory effects of statins in rheumatologic therapy. Arthritis Rheum 54:390–392. https://doi.org/10.1002/art.21757

    Article  CAS  PubMed  Google Scholar 

  42. Youssef S, Stüve O, Patarroyo JC et al (2002) The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420:78–84. https://doi.org/10.1038/nature01158

    Article  CAS  PubMed  Google Scholar 

  43. Zhang X, Jin J, Peng X, Ramgolam VS, Markovic-Plese S (2008) Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol 180:6988–6996. https://doi.org/10.4049/jimmunol.180.10.6988

    Article  CAS  PubMed  Google Scholar 

  44. Wagner AH, Gebauer M, Güldenzoph B, Hecker M (2002) 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells. Arterioscler Thromb Vasc Biol 22:1784–1789. https://doi.org/10.1161/01.atv.0000037098.20829.31

    Article  CAS  PubMed  Google Scholar 

  45. von Borstel A, Sanders JS, Rutgers A, Stegeman CA, Heeringa P, Abdulahad WH (2018) Cellular immune regulation in the pathogenesis of ANCA-associated vasculitides. Autoimmun Rev 17:413–421. https://doi.org/10.1016/j.autrev.2017.12.002

    Article  CAS  Google Scholar 

  46. Kemna MJ, Damoiseaux J, Austen J, Winkens B, Peters J, van Paassen P, Cohen TJW (2015) ANCA as a predictor of relapse: useful in patients with renal involvement but not in patients with nonrenal disease. J Am Soc Nephrol 26:537–542. https://doi.org/10.1681/ASN.2013111233

    Article  CAS  PubMed  Google Scholar 

  47. Fauci AS, Haynes BF, Katz P, Wolff SM (1983) Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 98:76–85. https://doi.org/10.7326/0003-4819-98-1-76

    Article  CAS  PubMed  Google Scholar 

  48. Harigai M, Nagasaka K, Amano K et al (2019) 2017 Clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis. Mod Rheumatol 29:20–30. https://doi.org/10.1080/14397595.2018.1500437

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, 480-1195, Japan

    Makoto Yamaguchi, Takayuki Katsuno, Shiho Iwagaitsu, Hironobu Nobata, Hiroshi Kinashi, Shogo Banno & Yasuhiko Ito

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  1. Makoto Yamaguchi
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  2. Takayuki Katsuno
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  3. Shiho Iwagaitsu
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  7. Yasuhiko Ito
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Contributions

MY and TK contributed to the study design. MY, SI, HK, SB, and YI contributed to the implementation and supervision of the study. MY, NH, and YI analyzed the data and took responsibility for the accuracy of the data analysis. All authors participated in the writing of the report and took full responsibility for all aspects of the study and the final manuscript.

Corresponding author

Correspondence to Yasuhiko Ito.

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Conflict of interest

We have no relationships with pharmaceutical agencies promoting statins. The authors declare that they have no conflicts of interest. There was no congress abstract publication.

Ethical approval

The study protocol was approved by the Ethics Committees of Aichi Medical University (approval number 2018-H350, date November 3, 2019). Because of the retrospective nature of the present study, patients’ informed consent was not obtained.

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Yamaguchi, M., Katsuno, T., Iwagaitsu, S. et al. Association between statin use and incidence of relapse in anti-neutrophil cytoplasmic antibody-associated vasculitis: a single-center retrospective cohort study. Rheumatol Int 40, 1291–1299 (2020). https://doi.org/10.1007/s00296-020-04562-z

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