Skip to main content

Advertisement

SpringerLink
Log in

Immune-Mediated Necrotizing Myopathy

  • Inflammatory Muscle Disease (I Lundberg, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Immune-mediated necrotizing myopathy (IMNM) is a type of autoimmune myopathy characterized by relatively severe proximal weakness, myofiber necrosis with minimal inflammatory cell infiltrate on muscle biopsy, and infrequent extra-muscular involvement. Here, we will review the characteristics of patients with IMNM.

Recent Findings

Anti-signal recognition particle (SRP) and anti-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies are closely associated with IMNM and define unique subtypes of patients. Importantly, the new European Neuromuscular Centre criteria recognize anti-SRP myopathy, anti-HMGCR myopathy, and autoantibody-negative IMNM as three distinct subtypes of IMNM. Anti-SRP myopathy patients have more severe muscle involvement, have more common extra-muscular features, and may respond best to immunosuppressive regimens that include rituximab. In contrast, anti-HMGCR myopathy is often associated with statin exposure and intravenous immunoglobulin treatment may be an effective treatment, even as monotherapy. Both anti-SRP and anti-HMGCR myopathy tend to be most severe in younger patients. Furthermore, children with these forms of IMNM may present with dystrophy-like features which are potentially reversible with immunosuppressant treatment. IMNM patients with either autoantibody may experience fatty replacement of muscle soon after disease onset, suggesting that intense and early immunosuppressant therapy may provide the best chance to avoid long-term disability.

Summary

IMNM is composed of anti-SRP myopathy, anti-HMGCR myopathy, and autoantibody-negative IMNM. Both anti-SRP and anti-HMGCR myopathy can cause severe weakness, especially in younger patients. Anti-SRP myopathy patients tend to have the most severe weakness and most prevalent extra-muscular features. Autoantibody-negative IMNM remains poorly described.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

Recently published papers of particular interest have been highlighted as: • Of importance •• Of major importance

  1. Dalakas MC. Inflammatory muscle diseases. N Engl J Med. 2015;373(4):393–4.

    Article  CAS  PubMed  Google Scholar 

  2. Hoogendijk JE, Amato AA, Lecky BR, Choy EH, Lundberg IE, Rose MR, et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands. Neuromuscul Disord. 2004;14(5):337–45.

    Article  PubMed  Google Scholar 

  3. •• Allenbach Y, Mammen AL, Stenzel W, Benveniste O, Immune-mediated necrotizing myopathies working G. 224th ENMC International Workshop:: Clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14–16 October 2016. Neuromuscul Disord 2017. Most recent classification criteria in IMNM. It includes consensus treatment recommendations for the different IMNM subsets.

  4. Senecal JL, Raynauld JP, Troyanov Y. Editorial: a new classification of adult autoimmune myositis. Arthritis Rheumatol. 2017;69(5):878–84.

    Article  PubMed  Google Scholar 

  5. Nakao Y, Mukai R, Kabashima T, Ohshima Y, Hamaguchi H, Kashiwagi H, et al. A novel antibody which precipitates 7.5S RNA is isolated from a patient with autoimmune disease. Biochem Biophys Res Commun. 1982;109(4):1332–8.

    Article  CAS  PubMed  Google Scholar 

  6. Okada N, Mimori T, Mukai R, Kashiwagi H, Hardin JA. Characterization of human autoantibodies that selectively precipitate the 7SL RNA component of the signal recognition particle. J Immunol. 1987;138(10):3219–23.

    CAS  PubMed  Google Scholar 

  7. Reeves WH, Nigam SK, Blobel G. Human autoantibodies reactive with the signal-recognition particle. Proc Natl Acad Sci U S A. 1986;83(24):9507–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum. 2010;62(9):2757–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mammen AL, Chung T, Christopher-Stine L, Rosen P, Rosen A, Doering KR, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum. 2011;63(3):713–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pinal-Fernandez I, Casciola-Rosen LA, Christopher-Stine L, Corse AM, Mammen AL. The prevalence of individual histopathologic features varies according to autoantibody status in muscle biopsies from patients with dermatomyositis. J Rheumatol. 2015;42(8):1448–54.

    Article  CAS  PubMed  Google Scholar 

  11. Paik JJ, Wigley FM, Lloyd TE, Corse AM, Casciola-Rosen L, Shah AA, et al. Spectrum of muscle histopathologic findings in forty-two scleroderma patients with weakness. Arthritis Care Res (Hoboken). 2015;67(10):1416–25.

    Article  Google Scholar 

  12. Schneider I, Stoltenburg G, Deschauer M, Winterholler M, Hanisch F. Limb girdle muscular dystrophy type 2L presenting as necrotizing myopathy. Acta Myol. 2014;33(1):19–21.

    PubMed  PubMed Central  Google Scholar 

  13. •• Suzuki S, Nishikawa A, Kuwana M, et al. Inflammatory myopathy with anti-signal recognition particle antibodies: case series of 100 patients. Orphanet J Rare Dis. 2015;10:61. Large study on the clinical features of anti-SRP patients.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dobloug C, Garen T, Bitter H, Stjärne J, Stenseth G, Grøvle L, et al. Prevalence and clinical characteristics of adult polymyositis and dermatomyositis; data from a large and unselected Norwegian cohort. Ann Rheum Dis. 2015;74(8):1551–6.

    Article  PubMed  Google Scholar 

  15. Svensson J, Arkema EV, Lundberg IE, Holmqvist M. Incidence and prevalence of idiopathic inflammatory myopathies in Sweden: a nationwide population-based study. Rheumatology (Oxford). 2017;56(5):802–10.

    Article  Google Scholar 

  16. •• Pinal-Fernandez I, Parks C, Werner JL, et al. Longitudinal course of disease in a large cohort of myositis patients with autoantibodies recognizing the signal recognition particle. Arthritis care res (Hoboken). 2017;69(2):263–70. Longitudinal cohort study of anti-SRP patients.

    Article  CAS  Google Scholar 

  17. •• Kishi T, Rider LG, Pak K, et al. Association of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies with DRB1*07:01 and severe myositis in juvenile myositis patients. Arthritis Care Res (Hoboken). 2017;69(7):1088–94. Report of juvenile anti-HMGCR cases from the USA.

    Article  CAS  Google Scholar 

  18. •• Tansley SL, Betteridge ZE, Simou S, et al. Anti-HMGCR autoantibodies in juvenile idiopathic inflammatory myopathies identify a rare but clinically important subset of patients. J Rheumatol. 2017;44(4):488–92. Report of juvenile anti-HMGCR cases from the UK.

    Article  PubMed  Google Scholar 

  19. • Binns EL, Moraitis E, Maillard S, et al. Effective induction therapy for anti-SRP associated myositis in childhood: a small case series and review of the literature. Pediatr Rheumatol Online J. 2017;15(1):77. Report of juvenile anti-SRP patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Suzuki S, Ohta M, Shimizu Y, Hayashi YK, Nishino I. Anti-signal recognition particle myopathy in the first decade of life. Pediatr Neurol. 2011;45(2):114–6.

    Article  PubMed  Google Scholar 

  21. •• Tiniakou E, Pinal-Fernandez I, Lloyd TE, et al. More severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Rheumatology (Oxford). 2017;56(5):787–94. Comprehensive longitudinal cohort study of patients with anti-HMGCR myositis.

    Google Scholar 

  22. Ge Y, Lu X, Peng Q, Shu X, Wang G. Clinical characteristics of anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies in Chinese patients with idiopathic inflammatory myopathies. PLoS One. 2015;10(10):e0141616.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Allenbach Y, Drouot L, Rigolet A, Charuel JL, Jouen F, Romero NB, et al. Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin. Medicine (Baltimore). 2014;93(3):150–7.

    Article  CAS  Google Scholar 

  24. Pinal-Fernandez I, Casal-Dominguez M, Huapaya JA, Albayda J, Paik JJ, Johnson C, et al. A longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies. Rheumatology (Oxford). 2017;56(6):999–1007.

    Article  Google Scholar 

  25. Targoff IN, Johnson AE, Miller FW. Antibody to signal recognition particle in polymyositis. Arthritis Rheum. 1990;33(9):1361–70.

    Article  CAS  PubMed  Google Scholar 

  26. Kao AH, Lacomis D, Lucas M, Fertig N, Oddis CV. Anti-signal recognition particle autoantibody in patients with and patients without idiopathic inflammatory myopathy. Arthritis Rheum. 2004;50(1):209–15.

    Article  CAS  PubMed  Google Scholar 

  27. Hengstman GJ, Brouwer R, Egberts WT, et al. Clinical and serological characteristics of 125 Dutch myositis patients. Myositis specific autoantibodies aid in the differential diagnosis of the idiopathic inflammatory myopathies. J Neurol. 2002;249(1):69–75.

    Article  CAS  PubMed  Google Scholar 

  28. Mohassel P, Foley AR, Donkervoort S, Fequiere PR, Pak K, Bönnemann CG, et al. Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase necrotizing myopathy masquerading as a muscular dystrophy in a child. Muscle Nerve. 2017;56(6):1177–81.

    Article  CAS  PubMed  Google Scholar 

  29. • Zhao Y, Liu X, Zhang W, Yuan Y. Childhood autoimmune necrotizing myopathy with anti-signal recognition particle antibodies. Muscle Nerve. 2017;56(6):1181–7. Report of juvenile cases of anti-SRP myositis.

    Article  CAS  PubMed  Google Scholar 

  30. •• Allenbach Y, Keraen J, Bouvier AM, et al. High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody. Brain. 2016;139(Pt 8):2131–5. Study of cancer risk in the different IMNM subsets.

    Article  PubMed  Google Scholar 

  31. • Kadoya M, Hida A, Hashimoto Maeda M, et al. Cancer association as a risk factor for anti-HMGCR antibody-positive myopathy. Neurol Neuroimmunol Neuroinflamm. 2016;3(6):e290. Cancer association in Japanese anti-HMGCR myositis.

    Article  PubMed  PubMed Central  Google Scholar 

  32. • 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(2):196–203. Report of the clinical features of anti-HMGCR patients from Australia.

    Article  CAS  PubMed  Google Scholar 

  33. •• Watanabe Y, Uruha A, Suzuki S, et al. Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy. J Neurol Neurosurg Psychiatry. 2016;87(10):1038–44. Comparison of anti-HMGCR and anti-SRP myositis in Japanese patients.

    Article  PubMed  Google Scholar 

  34. • Alshehri A, Choksi R, Bucelli R, Pestronk A. Myopathy with anti-HMGCR antibodies: perimysium and myofiber pathology. Neurol Neuroimmunol Neuroinflamm. 2015;2(4):e124. Clinical and pathologic features of anti-HMGCR patients.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mammen AL, Pak K, Williams EK, Brisson D, Coresh J, Selvin E, 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 (Hoboken). 2012;64(2):269–72.

    Article  CAS  Google Scholar 

  36. •• Mammen AL. Statin-associated autoimmune myopathy. N Engl J Med. 2016;374(7):664–9. In-depth review about anti-HMGCR myositis.

    Article  CAS  PubMed  Google Scholar 

  37. • Alvarado-Cardenas M, Marin-Sanchez A, Martinez MA, et al. Statin-associated autoimmune myopathy: a distinct new IFL pattern can increase the rate of HMGCR antibody detection by clinical laboratories. Autoimmun Rev. 2016;15(12):1161–6. New IFL pattern in anti-HMGCR myositis.

    Article  CAS  PubMed  Google Scholar 

  38. Rider LG, Werth VP, Huber AM, et al. Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI). Arthritis Care Res (Hoboken) 2011;63 Suppl 11:S118–57.

  39. Compston A. Aids to the investigation of peripheral nerve injuries. Medical Research Council: nerve injuries research committee. His Majesty’s stationery office: 1942; pp. 48 (iii) and 74 figures and 7 diagrams; with aids to the examination of the peripheral nervous system. By Michael O'Brien for the Guarantors of Brain. Saunders Elsevier: 2010; pp. [8] 64 and 94 figures. Brain 2010;133(10):2838–44.

  40. •• Pinal-Fernandez I, Casal-Dominguez M, Carrino JA, et al. Thigh muscle MRI in immune-mediated necrotising myopathy: extensive oedema, early muscle damage and role of anti-SRP autoantibodies as a marker of severity. Ann Rheum Dis. 2017;76(4):681–7. Comprehensive MRI study in patients with immune-mediated necrotizing myositis compared to other myositis subtypes.

    Article  PubMed  Google Scholar 

  41. Van De Vlekkert J, Maas M, Hoogendijk JE, De Visser M, Van Schaik IN. Combining MRI and muscle biopsy improves diagnostic accuracy in subacute-onset idiopathic inflammatory myopathy. Muscle Nerve. 2015;51(2):253–8.

    Article  Google Scholar 

  42. Zheng Y, Liu L, Wang L, Xiao J, Wang Z, Lv H, et al. Magnetic resonance imaging changes of thigh muscles in myopathy with antibodies to signal recognition particle. Rheumatology (Oxford). 2015;54(6):1017–24.

    Article  CAS  Google Scholar 

  43. • Chung T, Christopher-Stine L, Paik JJ, Corse A, Mammen AL. The composition of cellular infiltrates in anti-HMG-CoA reductase-associated myopathy. Muscle Nerve. 2015;52(2):189–95. Pathologic features of anti-HMGCR patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Selva-O'Callaghan A, Grau JM, Gamez-Cenzano C, et al. Conventional cancer screening versus PET/CT in dermatomyositis/polymyositis. Am J Med. 2010;123(6):558–62.

    Article  PubMed  Google Scholar 

  45. Valiyil R, Casciola-Rosen L, Hong G, Mammen A, Christopher-Stine L. Rituximab therapy for myopathy associated with anti-signal recognition particle antibodies: a case series. Arthritis Care Res (Hoboken). 2010;62(9):1328–34.

    Article  CAS  Google Scholar 

  46. •• Mammen AL, Tiniakou E. Intravenous immune globulin for statin-triggered autoimmune myopathy. N Engl J Med. 2015;373(17):1680–2. Case series suggesting that IVIG in monotherapy is effective in anti-HMGCR myopathy.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Mammen AL, Gaudet D, Brisson D, Christopher-Stine L, Lloyd TE, Leffell MS, et al. Increased frequency of DRB1*11:01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Care Res (Hoboken). 2012;64(8):1233–7.

    CAS  Google Scholar 

  48. • Ohnuki Y, Suzuki S, Shiina T, et al. HLA-DRB1 alleles in immune-mediated necrotizing myopathy. Neurology. 2016;87(18):1954–5. HLA in anti-SRP and anti-HMGCR myositis.

    Article  PubMed  Google Scholar 

  49. Watanabe Y, Suzuki S, Nishimura H, Murata KY, Kurashige T, Ikawa M, 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(4):e416.

    Article  CAS  Google Scholar 

  50. Lo YC, Lin SY, Ulziijargal E, Chen SY, Chien RC, Tzou YJ, et al. Comparative study of contents of several bioactive components in fruiting bodies and mycelia of culinary-medicinal mushrooms. Int J Med Mushrooms. 2012;14(4):357–63.

    Article  CAS  PubMed  Google Scholar 

  51. Klimek M, Wang S, Ogunkanmi A. Safety and efficacy of red yeast rice (Monascus purpureus) as an alternative therapy for hyperlipidemia. P T. 2009;34(6):313–27.

    PubMed  PubMed Central  Google Scholar 

  52. Jeng KC, Chen CS, Fang YP, Hou RC, Chen YS. Effect of microbial fermentation on content of statin, GABA, and polyphenols in pu-erh tea. J Agric Food Chem. 2007;55(21):8787–92.

    Article  CAS  PubMed  Google Scholar 

  53. Morikawa S, Murakami T, Yamazaki H, Izumi A, Saito Y, Hamakubo T, et al. Analysis of the global RNA expression profiles of skeletal muscle cells treated with statins. J Atheroscler Thromb. 2005;12(3):121–31.

    Article  CAS  PubMed  Google Scholar 

  54. Pinal-Fernandez I, Ferrer-Fabregas B, Trallero-Araguas E, et al. Tumour TIF1 mutations and loss of heterozygosity related to cancer-associated myositis. Rheumatology (Oxford) 2017.

  55. Trallero-Araguas E, Rodrigo-Pendas JA, Selva-O'Callaghan A, et al. Usefulness of anti-p155 autoantibody for diagnosing cancer-associated dermatomyositis: a systematic review and meta-analysis. Arthritis Rheum. 2012;64(2):523–32.

    Article  CAS  PubMed  Google Scholar 

  56. Leff RL, Burgess SH, Miller FW, Love LA, Targoff IN, Dalakas MC, et al. Distinct seasonal patterns in the onset of adult idiopathic inflammatory myopathy in patients with anti-Jo-1 and anti-signal recognition particle autoantibodies. Arthritis Rheum. 1991;34(11):1391–6.

    Article  CAS  PubMed  Google Scholar 

  57. •• Arouche-Delaperche L, Allenbach Y, Amelin D, et al. Pathogenic role of anti-signal recognition protein and anti-3-hydroxy-3-methylglutaryl-CoA reductase antibodies in necrotizing myopathies: Myofiber atrophy and impairment of muscle regeneration in necrotizing autoimmune myopathies. Ann Neurol. 2017;81(4):538–48. Manuscript suggesting that in vitro, anti-SRP, and anti-HMGCCR autoantibodies are pathogenic.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Expression, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 50 South Drive, Room 1146, Building 50, MSC 8024, Bethesda, MD, 20892, USA

    Iago Pinal-Fernandez, Maria Casal-Dominguez & Andrew L. Mammen

  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Iago Pinal-Fernandez, Maria Casal-Dominguez & Andrew L. Mammen

  3. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Andrew L. Mammen

Authors
  1. Iago Pinal-Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Casal-Dominguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew L. Mammen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Iago Pinal-Fernandez or Andrew L. Mammen.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Inflammatory Muscle Disease

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pinal-Fernandez, I., Casal-Dominguez, M. & Mammen, A.L. Immune-Mediated Necrotizing Myopathy. Curr Rheumatol Rep 20, 21 (2018). https://doi.org/10.1007/s11926-018-0732-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11926-018-0732-6

Keywords

Search

Navigation