Skip to main content

Statin-associated immune-mediated necrotizing myopathy: a retrospective analysis of individual case safety reports from VigiBase

European Journal of Clinical Pharmacology volume 75, pages 409–416 (2019)Cite this article

Abstract

Purpose

Statins represent an effective treatment for hyperlipidaemia. Immune-mediated necrotising myopathy (IMNM), a form of statin myopathy, has recently been described, and is characterized by elevated creatine kinase, presence of antibodies against HMG-CoA and no improvement after drug discontinuation, even with immunosuppressive treatment. Information on IMNM is mainly from case reports and small case series. Therefore, all reported cases of IMNM in VigiBase, the WHO global database of individual case safety reports (ICSRs) including the underlying reporting patterns, were analysed to characterize more detailed this adverse drug reaction.

Methods

ICSRs of IMNM up to October 1, 2016 were extracted from VigiBase. Corresponding case narratives were requested from responsible national authorities to maximize the available data. The reports were analysed in terms of reporting criteria, co-reported terms, patient demographics, clinical data, administered medication, latency time, seriousness of the reaction and outcome.

Results

One hundred one deduplicated ICSRs of IMNM were reported from 17 countries until October 2016. Approximately two thirds of the cases were from the year 2016. Slightly more males than females were affected (52 [57%] males vs 39 [42%] females). Median reported patient age was 68 years (range 16 – 87 years). Ninety-one cases (99%) were classified as serious. Median latency time was 26 months (range 1 – 288 months). Median creatine kinase value was 6860 U/L (range 576 – 35,000 U/L). In total, eight patients (9%) had recovered from IMNM. Atorvastatin was the most frequently reported statin in 80% of cases.

Conclusions

The number of IMNM reports has increased in recent years. IMNM associated with statin treatment seems to occur worldwide. Most IMNM cases were reported with atorvastatin. No dose dependency of statin-associated IMNM pathogenesis was identified.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Ž (2016) 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 37(39):2999–3058

    Article  PubMed  Google Scholar 

  2. Zodda D, Giammona R, Schifilliti S (2018) Treatment strategy for dyslipidemia in cardiovascular disease prevention: focus on old and new drugs. Pharmacy 6(1):10. https://doi.org/10.3390/pharmacy6010010

    Article  Google Scholar 

  3. Buettner C, Davis RB, Leveille SG, Mittleman MA, Mukamal KJ (2008) Prevalence of musculoskeletal pain and statin use. J Gen Intern Med 23(8):1182–1186

    Article  PubMed  PubMed Central  Google Scholar 

  4. Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R (2004) Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 292:2585–2590

    Article  CAS  PubMed  Google Scholar 

  5. Mammen AL (2016) Statin-associated autoimmune myopathy. N Engl J Med 374(7):664–669

    Article  CAS  PubMed  Google Scholar 

  6. Mammen AL, Chung T, Christopher-Stine L, Rosen P, Rosen A, Doering KR, Casciola-Rosen LA (2011) Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme a reductase in patients with statin associated autoimmune myopathy. Arthritis Rheum 63:713–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liang WC, Uruha A, Suzuki S, Murakami N, Takeshita E, Chen WZ, Jong YJ, Endo Y, Komaki H, Fujii T, Kawano Y, Madoka MY, Oya Y, Xi J, Zhu W, Zhao C, Watanabe Y, Ikemoto K, Nishikawa A, Hamanaka K, Mitsuhashi S, Suzuki N, Nishino I (2017) Pediatric necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase antibodies. Rheumatology 56:287–293

    Article  PubMed  Google Scholar 

  8. Kipfer S, Frigerio S, Hench J, Aussy A, Boyer O (2015) Immune-mediated necrotizing myopathy linked to statin use. Lancet 386:e26

    Article  PubMed  Google Scholar 

  9. Kassardjian CD, Lennon VA, Alfugham NB, Mahler M, Milone M (2015) Clinical features and treatment outcomes of necrotizing autoimmune myopathy. JAMA Neurol 72(9):996–1003

    Article  PubMed  Google Scholar 

  10. Swissmedic, Swiss Agency for Therapeutic Products (2015) Healthcare Professional Communication: https://www.swissmedic.ch/swissmedic/en/home/humanarzneimittel/market-surveillance/health-professional-communication%2D%2Dhpc-/archive/hpc%2D%2D-statin-assoziierte-immunvermittelte-nekrotisierende-myopat.html. Accessed: April 19, 2018

  11. Uppsala Monitoring Center VigiBase. https://www.who-umc.org/vigibase/vigibase/. Accessed: April 19, 2018

  12. Lindquist M (2008) Vigibase, the WHO global ICSR database system: basic facts. Drug Inf J 42:408–419

    Article  Google Scholar 

  13. Chen L, Zeng WM, Cai YD, Feng KY, Chou KC (2012) Predicting anatomical therapeutic chemical (ATC) classification of drugs by integrating chemical-chemical interactions and similarities. PLoS One 7(4):e35254. https://doi.org/10.1371/journal.pone.0035254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bergvall T, Norén GN, Lindquist M (2014) vigiGrade: a tool to identify well-documented individual case reports and highlight systematic data quality issues. Drug Saf 37(1):65–67

    Article  PubMed  Google Scholar 

  15. Mittman DE, Cawley JF, Fenn WH (2002) Physician assistants in the United States. BMJ 325(7362):485–487

    Article  PubMed  PubMed Central  Google Scholar 

  16. Salk A, Ehrenpreis E (2016) Attitudes and usage of the Food and Drug Administration adverse event reporting system among gastroenterology nurse Practioners and physician assistants. Gastroenterol Nurs 39(1):25–31

    Article  PubMed  Google Scholar 

  17. Mammen AL, Mohasel P (2013) Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle Nerve 48:477–483

    Article  CAS  PubMed  Google Scholar 

  18. Needham M, Fabian V, Knezevic W, Panegyres P, Zilko P, Mastaglia FL (2007) Progressive myopathy with up-regulation of MHC-I associated with statin therapy. Neuromuscul Disord 17:194–200

    Article  PubMed  Google Scholar 

  19. Grable-Esposito P, Katzberg HD, Greenberg SA, Srinivasan J, Katz J, Amato AA (2010) Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve 41:185–190

    CAS  PubMed  Google Scholar 

  20. Garcia MJ, Reinoso RF, Sanchez Navarro A, Prous JR (2003) Clinical pharmacokinetics of statins. Methods Find Exp Clin Pharmacol 25(6):457–481

    Article  CAS  PubMed  Google Scholar 

  21. Rosenson RS Statins: actions, side effects, and administration. In: Freeman MW (ed) UpToDate. UpToDate Inc, Waltham http://www.uptodate.com. Accessed on June 06, 2018

  22. Troyanov Y, Landon-Cardinal O, Fritzler MJ, Ferreira J, Targoff IN, Rich E, Goulet M, Goulet JR, Bourré-Tessier J, Robitaille Y, Drouin J (2017) Atorvastatin-induced necrotizing autoimmune myositis. Medicine 96(3):e5694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kit BK, Gu Q, Paulose-Ram R, Burt VL (2014) Prescription cholesterol-lowering medication use in adults aged 40 and over: United States, 2003–2012. Natl Center Health Stat 177:1–8

    Google Scholar 

  24. Woolley M, Stebbings S, Highton J (2017) Statin-associated immune-mediated necrotising myopathy: a new Zealand case series showing possible overrepresentation in Pacific islanders. Intern Med J 48(1):32–36

    Article  CAS  Google Scholar 

  25. Manoi K, Jain N, Madhu SV (2017) Myopathy in patients taking atorvastatin: a pilot study. Indian J Endocrinol Metab 21(4):504–509

    Article  Google Scholar 

  26. Nichols L, Pfeifer K, Mammen AL, Shahnoor N, Konersman CG (2015) An unusual case of statin-induced myopathy: anti-HMGCoA necrotizing autoimmune myopathy. J Gen Intern Med 30(12):1879–1883

    Article  PubMed  PubMed Central  Google Scholar 

  27. Schröder J, Goltz L, Knoth H (2016) Medication management: simvastatin and amlodipin – a clinically relevant drug interaction? Dtsch Med Wochenschr 141(21):1575–1577

    Article  PubMed  Google Scholar 

  28. Mammen AL (2016) Autoimmune myopathies. Continuum 22(6):1852–1870

    PubMed  Google Scholar 

  29. Nazir S, Lohani S, Tachamo N, Poudel D, Donato A (2017) Statin-associated autoimmune myopathy. A systematic review of 100 cases. J Clin Rheumatol 23(3):149–154

    Article  PubMed  Google Scholar 

  30. Christopher Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL (2010) A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 62:2757–2766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Salort-Campana E, De AP, Figarella-Branger D, Pouget J (2014) Necrotizing myopathies: from genetic to acquired forms. Rev Med Interne 35:430–436

    Article  CAS  PubMed  Google Scholar 

  32. Tiniakou E, Christopher-Stine L (2017) Immune-mediated necrotizing myopathy associated with statins:history and recent developments. Curr Opin Rheumatol 29(6):604–611

    CAS  PubMed  Google Scholar 

  33. Pinal-Fernandez I, Casal-Dominguez M, Mammen AL (2018) Immune-mediated necrotizing myopathy. Curr Rheumatol Rep 20(4):21

    Article  PubMed  PubMed Central  Google Scholar 

  34. Werner JL, Christopher-Stine L, Ghazarian SR, Pak KS, Kus JE, Daya NR, Lloyd TE, Mammen AL (2012) Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase-associated autoimmune myopathy. Arthritis Rheum 64:4087–4093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank the following authorities for their assistance in providing anonymised case narratives of adverse drug reaction reports: Health Canada—Canada Vigilance Program; The staff of the US Food and Drug Administration; Australian Pharmacovigilance and Special Access Branch, Therapeutic Goods Administration; Italian Medicine Agency—AIFA Post-Marketing Surveillance Department; Czech State Institute for Drug Control; Hungarian National Institute of Pharmacy and Nutrition; German Federal Institute for Drugs and Medical Devices—Pharmacovigilance Department; Norwegian Medicines Agency—Department of Safe Use; and French Regional Pharmacovigilance Network and the Surveillance Division from the ANSM. The source of the information is the WHO database “VigiBase”. The information comes from a variety of sources and the likelihood that the suspected adverse reaction is drug-related is not the same in all cases. This information does not represent the opinion of the World Health Organization.

Author information

Affiliations

  1. Swissmedic, Swiss Agency for Therapeutic Products, Bern, Switzerland

    Dirk Essers & Martina Schäublin

  2. Department of Clinical Pharmacology and Toxicology and Regional Pharmacovigilance Centre, University Hospital Zurich, University of Zurich, Zurich, Switzerland

    Dirk Essers, Gerd A. Kullak-Ublick & Stefan Weiler

  3. National Poisons Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Zurich, Switzerland

    Stefan Weiler

Authors
  1. Dirk Essers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martina Schäublin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gerd A. Kullak-Ublick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefan Weiler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan Weiler.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest. SW is elected Pharmacovigilance Risk Assessment Committee (PRAC) member of the European Medicines Agency. The opinions expressed are those of the writers, and may not be understood or quoted as being made on behalf of the PRAC or reflecting the position of the PRAC.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Essers, D., Schäublin, M., Kullak-Ublick, G.A. et al. Statin-associated immune-mediated necrotizing myopathy: a retrospective analysis of individual case safety reports from VigiBase. Eur J Clin Pharmacol 75, 409–416 (2019). https://doi.org/10.1007/s00228-018-2589-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-018-2589-z

Keywords

  • HMG-CoA-reductase inhibitors
  • Rosuvastatin
  • Atorvastatin
  • Pravastatin
  • Simvastatin
  • Muscle pain
  • Immunosuppression
  • CK elevation
  • Creatinine-kinase
  • HMG-CoA antibody