Statin-induced Necrotizing Autoimmune Myopathy

Czech version

Authors: T. Horák ¹; S. Voháňka ¹; E. Tvrdíková ²; M. Horáková ¹; J. Bednařík ¹
Authors‘ workplace: Neurologická klinika LF MU a FN Brno ¹; Ústav patologie, LF MU a FN Brno ²
Published in: Cesk Slov Neurol N 2017; 80/113(5): 569-577
Category: Original Paper
doi: https://doi.org/10.14735/amcsnn2017569

Overview

Aim:
Statin therapy might be rarely associated with production of specific autoantibodies against 3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR), proximal muscle weakness, high creatine kinase (CK) levels and myofibril necrosis in muscle biopsy. Presence of these symptoms established the main criteria of a new clinical unit called Statin Induced Necrotizing Autoimmune Myopathy (SINAM). Assumed autoimmune etiopathogenesis justifies the use of combined immunosuppressive therapy. Clinical course, diagnostic criteria and therapeutic efficacy of immunosuppressive treatment are similar to that of Immune Mediated Necrotizing Myopathy (IMNM) without association with statin therapy.

Methods:
The group of 7 SINAM patients was classified by reassessment of the diagnostic group of 30 patients diagnosed with autoimmune myopathies based on determination of anti-HMGCR antibodies, structured quantitative revision of muscle biopsies and detailed medical history (confirming chronic statin therapy).

Results:
In total 30 subjects with the original diagnosis dermatomyositis, polymyositis or IMNM were tested for HMGCR antibodies. Twelve patients out of them were anti-HMGCR positive (IMNM 5×, 7× PM) and 7 of them had been on statin therapy before the symptoms developed. These 7 patients were reclassified as SINAM. Myofibrillar necrosis was found in their muscle biopsies in all cases and 5 patients also had inflammatory cell infiltration. All these patients had significantly elevated CK levels (> 10 fold) at early stage of the disease. Combined immunosuppression led to remission of clinical symptoms and normalization or significant CK level drop in all patients.

Key words:
myopathy – statins – autoimmunity – necrosis – autoantibodies – anti-HMGCR

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Chinese summary - 摘要

他汀类药物诱导的坏死性自身免疫性肌病

目标：

在肌肉活检中，他汀治疗可能很少与特异性自身抗体3-羟基-3-甲基戊二酰辅酶A还原酶（抗HMGCR）生成量、近端肌肉无力、高肌酸激酶（CK）水平和肌原纤维坏死有关。这些症状的存在确立了被称为他汀诱导的坏死性自身免疫性肌病的新临床单位的主要标准（SINAM）。假定自身免疫发病机理适合使用联合免疫抑制疗法。免疫抑制治疗的临床过程，诊断标准和治疗效果与免疫介导的坏死性肌病（IMNM）相似，而与他汀治疗无关。

方法：

基于抗HMGCR抗体检测、肌肉活检结构化定量修正和详细病史（确认的慢性他汀治疗），对一组30名被诊断为自身免疫性肌病的患者进行重新评估，分出了7名SINAM患者。

结果：

在30名最初被诊断为皮肌炎的被试中，测试了多发性肌炎或IMNM的HMGCR抗体。其中12例患者抗HMGCR结果呈阳性（IMNM5×，7×PM），7例在症状出现前已接受他汀类药物治疗，这7名患者被重新分为SINAM类。所有病例均发现了肌纤维坏死，并且5例患者患有炎性细胞浸润。所有这些患者在疾病早期CK水平显著升高（> 10倍）。联合免疫抑制疗法可以缓解所有患者的临床症状和CK水平显著降低。

关键词：

肌病 - 他汀类药物 - 自身免疫 - 坏死 - 自身抗体 - 抗HMGCR

Sources

1. IMS Health. Medicines Use and Spending in the U.S. – A Review of 2015 and Outlook to 2020. [accessed 12 Dec 2016]. Dostupné z URL: http://www.imshealth.com/sites/en/thought-leadership/ims-institute/reports/medicines-use-and-spending-in-the-us-a-review-of-2015-and-outlook-to-2020.

2. Visiongain. Statins: World Market Outlook 2011-2021. [accessed 12 Dec 2016]. Dostupné z URL: https://www.visiongain.com/Report/581/Statins-World-Market-Outlook-2011-2021.

3. Státní ústav pro kontrolu léčiv. Hodnocení vývoje distribuce vybrané skupiny léčivých přípravků – 2. čtvrtletí 2013 – léčivé přípravky pro léčbu poruch tukového metabolismu – dodávky v letech 2002– 2012 (fibráty, ezetimib, statiny). Dostupné z URL: http://www.sukl.cz/lecive-pripravky-pro-lecbu-poruch-tukoveho-metabolismu.

4. Bednařík J, Vlčková E, Horák T. Statinová myopatie. Neurol Praxi 2017;18(1):15– 19.

5. Echaniz-Laguna A, Mohr M, Tranchant C. Neuromuscular symptoms and elevated creatine kinase after statin withdrawal. N Engl J Med 2010;362:564– 5. doi: 10.1056/ NEJMc0908215.

6. Basharat P, Christopher-Stine L. Immune-MediatedNecrotizing Myopathy: Update on Diagnosis and Man-agement. Curr Rheumatol Rep 2015;17:72. doi: 10.1007/ s11926-015-0548-6.

7. Babu S, Li Y. Statin induced necrotizing autoimmune myopathy. J Neurol Sci 2015;351:13– 7. doi: 10.1016/ j.jns.2015.02.042.

8. Needham M, Fabian V, Knezevic W, et al. Progressive myopathy with up-regulation of MHC-I associated with statin therapy. Neuromuscul Disord NMD 2007;17:194– 200. doi: 10.1016/ j.nmd.2006.10.007.

9. Grable-Esposito P, Katzberg HD, Greenberg SA, et al. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve 2010;41:185– 90. doi: 10.1002/ mus.21486.

10. Allenbach Y, Drouot L, Rigolet A, et al. Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin. Medicine (Baltimore) 2014;93:150– 7. doi: 10.1097/ MD.0000000000000028.

11. Klein M, Mann H, Pleštilová L, et al. Increasing incidence of immune-mediated necrotizing myopathy: single-centre experience. Rheumatol Oxf Engl 2015;54:2010– 4. doi: 10.1093/ rheumatology/ kev229.

12. Patel S, Rohatgi A, Gupta P. Statin-triggered immune-mediated necrotizing myopathy. Neurol India 2016;64:562– 4. doi: 10.4103/ 0028-3886.181571.

13. McGrath NM, Turner CP. Isolated gluteal and paravertebral muscle weakness due to anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase antibody-associated necrotizing autoimmune myopathy. Muscle Nerve 2016;54:150– 2. doi: 10.1002/ mus.25130.

14. Christopher-Stine L, Casciola-Rosen LA, Hong G, et al. A novel autoantibody recognizing 200-kd and 100-kdproteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010;62:2757– 66. doi: 10.1002/ art.27572.

15. Alshehri A, Choksi R, Bucelli R, et al. Myopathy with anti-HMGCR antibodies: Perimysium and myofiber pathology. Neurol Neuroimmunol Neuroinflammation 2015;2:e124. doi: 10.1212/ NXI.0000000000000124.

16. Mammen AL. Statin-Associated Autoimmune Myopathy. N Engl J Med 2016;374:664– 9. doi: 10.1056/ NEJMra1515161.

17. Zeitlinger M, Müller M. [Clinico-pharmacologic explanation models of cerivastatin associated rhabdomyolysis]. Wien Med Wochenschr 2003;153:250– 4.

18. Limaye V, Bundell C, Hollingsworth P, et al. Clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase in patients with immune-mediated myositis and necrotizing myopathy. Muscle Nerve 2015;52:196– 203. doi: 10.1002/ mus.24541.

19. Mammen AL, Gaudet D, Brisson D, et al. Increased frequency of DRB1*11:01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Care Res 2012;64:1233– 7. doi: 10.1002/ acr.21671.

20. Morikawa S, Murakami T, Yamazaki H, et al. Analysis of the global RNA expression profiles of skeletal muscle cells treated with statins. J Atheroscler Thromb 2005;12:121– 31.

21. Watanabe Y, Suzuki S, Nishimura H, et al. Statins and myotoxic effects associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies: an observational study in Japan. Medicine (Baltimore) 2015;94:e416. doi: 10.1097/ MD.0000000000000416.

22. Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011;63:713– 21. doi: 10.1002/ art.30156.

23. Martini C, Trapani L, Narciso L, et al. 3-hydroxy 3-methylglutaryl coenzyme A reductase increase is essential for rat muscle differentiation. J Cell Physiol 2009;220:524– 30. doi: 10.1002/ jcp.21810.

24. Trapani L, Segatto M, La Rosa P, et al. 3-hydroxy 3-meth-ylglutaryl coenzyme A reductase inhibition impairs muscle regeneration. J Cell Biochem 2012;113:2057– 63. doi: 10.1002/ jcb.24077.

25. Vanderlugt CL, Miller SD. Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat Rev Immunol 2002;2:85– 95. doi: 10.1038/ nri724.

26. Wattjes MP, Fischer D. Neuromuscular imaging. New York: Springer-Verlag 2013.

27. Mammen AL, Pak K, Williams EK, et al. Rarity of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects. Arthritis Care Res 2012;64:269– 72. doi: 10.1002/ acr.20662.

28. Werner JL, Christopher-Stine L, Ghazarian SR, et al. Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Rheum 2012;64:4087– 93. doi: 10.1002/ art.34673.

29. Allenbach Y, Keraen J, Bouvier A-M, et al. High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody. Brain J Neurol 2016;139:2131– 5. doi: 10.1093/ brain/ aww054.

30. Joseph CG, Darrah E, Shah AA, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 2014;343:152– 7. doi: 10.1126/ science.1246886.

31. Liang C, Needham M. Necrotizing autoimmune myopathy. Curr Opin Rheumatol 2011;23:612– 9. doi: 10.1097/ BOR.0b013e32834b324b.

32. Chung T, Christopher-Stine L, Paik JJ, et al. The composition of cellular infiltrates in anti-HMG-CoA reductase-associated myopathy. Muscle Nerve 2015;52:189– 95. doi: 10.1002/ mus.24642.

33. Tidball JG. Mechanisms of muscle injury, repair, and regeneration. Compr Physiol 2011;1:2029– 62. doi: 10.1002/ cphy.c100092.

34. Needham M, Mastaglia FL. Immunotherapies for Immune-Mediated Myopathies: A Current Perspective. Neurother J Am Soc Exp Neurother 2016;13:132– 46. doi: 10.1007/ s13311-015-0394-2.

35. Ramanathan S, Langguth D, Hardy TA, et al. Clinical course and treatment of anti-HMGCR antibody-associated necrotizing autoimmune myopathy. Neurol Neuroimmunol Neuroinflammation 2015;2:e96. doi: 10.1212/ NXI.0000000000000096.

36. Watad A, Soriano A, Vaknine H, et al. Immune Mediated Myopathy following Long-Term Statin Therapy. Isr Med Assoc J IMAJ 2015;17:128– 9.

37. Mammen AL, Tiniakou E. Intravenous Immune Glo-bulin for Statin-Triggered Autoimmune Myopathy. N Engl J Med 2015;373:1680– 2. doi: 10.1056/ NEJMc1506163.

38. Dalakas MC. Controlled studies with high-dose intravenous immunoglobulin in the treatment of dermatomyositis, inclusion body myositis, and polymyositis. Neurology 1998;51:S37– 45.

39. Mosca M, Strigini F, Carmignani A, et al. Pregnant patient with dermatomyositis successfully treated with intravenous immunoglobulin therapy. Arthritis Rheum 2005;53:119– 21. doi: 10.1002/ art.20913.

40. Kadoya M, Hida A, Hashimoto Maeda M, et al. Cancer association as a risk factor for anti-HMGCR antibody-positive myopathy. Neurol Neuroimmunol Neuroinflammation 2016;3:e290. doi: 10.1212/ NXI.0000000000000290.

41. Allenbach Y, Benveniste O. Acquired necrotizing myopathies. Curr Opin Neurol 2013;26:554– 60. doi: 10.1097/ WCO.0b013e328364e9d9.

42. Dalakas MC. Necrotising autoimmune myopathy (NAM): antibodies seem to be specific markers in aiding diagnosis. J Neurol Neurosurg Psychiatry 2016;87:1037. doi: 10.1136/ jnnp-2016-313418.

43. Basharat P, Lahouti AH, Mammen AL, et al. Diabetes and Atorvastatin Are Potential Risk Factors for Statin-associated Myopathy with Autoantibodies Against 3-hydroxy-3-methylglutaryl-coenzyme a Reductase. Arthritis Rheumatol 2014;66:S554.