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Immune-mediated necrotizing myopathy: clinical features and pathogenesis

Nature Reviews Rheumatology volume 16, pages 689–701 (2020)Cite this article

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Abstract

Immune-mediated necrotizing myopathy (IMNM) is a group of inflammatory myopathies that was distinguished from polymyositis in 2004. Most IMNMs are associated with anti-signal recognition particle (anti-SRP) or anti-3-hydroxy-3-methylglutaryl-coA reductase (anti-HMGCR) myositis-specific autoantibodies, although ~20% of patients with IMNM remain seronegative. These associations have led to three subclasses of IMNM: anti-SRP-positive IMNM, anti-HMGCR-positive IMNM and seronegative IMNM. IMNMs are frequently rapidly progressive and severe, displaying high serum creatine kinase levels, and failure to treat IMNMs effectively may lead to severe muscle impairment. In patients with seronegative IMNM, disease can be concomitant with cancer. Research into IMNM pathogenesis has shown that anti-SRP and anti-HMGCR autoantibodies cause weakness and myofibre necrosis in mice, suggesting that, as well as being diagnostic biomarkers of IMNM, they may play a key role in disease pathogenesis. Therapeutically, treatments such as rituximab or intravenous immunoglobulins can now be discussed for IMNM, and targeted therapies, such as anticomplement therapeutics, may be a future option for patients with refractory disease.

Key points

  • Anti-3-hydroxy-3-methylglutaryl-coA reductase (anti-HMGCR) and anti-signal recognition particle (anti-SRP) myositis-specific autoantibodies are crucial for defining immune-mediated necrotizing myopathy (IMNM) when muscle biopsy is absent but required for diagnosis.

  • IMNM can be considered a muscle-specific autoimmune disease; patients with anti-SRP-positive IMNM are at an increased risk of myocarditis and patients with seronegative IMNM are at a major risk of associated malignancy.

  • Among treatable idiopathic inflammatory myopathies, IMNM is the most severe in terms of muscle-related morbidities such as muscle atrophy, muscle fat replacement and/or disability, and is of long duration.

  • Anti-HMGCR and anti-SRP myositis-specific autoantibodies seem to play a key role in the pathophysiology of IMNM; autoantibody-induced muscle damage is complement dependent.

  • A combination of corticosteroids, immunosuppressants and intravenous immunoglobulins is frequently required to control disease activity.

  • No specific randomized clinical trial is available to define the best treatment strategy for keeping patients with IMNM in remission.

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Fig. 1: Proposed mechanisms of seropositive IMNM pathogenesis.
Fig. 2: Treatment recommendations for IMNM.

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Acknowledgements

The authors thank the Association Française contre les Myopathies (AFM) for its support. The authors are grateful to N. Sabourin-Gibbs, Rouen University Hospital, for her help in editing the manuscript.

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Author notes

  1. These authors contributed equally: Yves Allenbach, Olivier Benveniste.

  2. These authors contributed equally: Werner Stenzel, Olivier Boyer.

Authors and Affiliations

  1. Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Inserm U974, Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière University Hospital, Paris, France

    Yves Allenbach & Olivier Benveniste

  2. Department of Neuropathology, Charité -Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

    Werner Stenzel

  3. Normandie University, UNIROUEN, Inserm U1234, Department of Immunology and Biotherapy, Rouen University Hospital, Rouen, France

    Olivier Boyer

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Glossary

Sarcolemma

The thin membrane enclosing a striated muscle fibre.

Exocrine pancreatic insufficiency

A condition characterized by deficiency of the exocrine pancreatic enzymes, resulting in the inability to digest food properly or maldigestion.

Scapular winging

Occurs when a shoulder blade sticks out rather than resting flat against the back of the chest wall.

Muscle fascicles

A bundle of muscle fibres surrounded by perimysium (connective tissue demarcating a fascicle of skeletal muscle fibres).

Endomysium

The sheath of delicate reticular fibrils that surrounds each muscle fibre.

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Allenbach, Y., Benveniste, O., Stenzel, W. et al. Immune-mediated necrotizing myopathy: clinical features and pathogenesis. Nat Rev Rheumatol 16, 689–701 (2020). https://doi.org/10.1038/s41584-020-00515-9

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