By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Rubin reports no financial relationships relevant to this field of study.

SYNOPSIS: Immune-mediated necrotizing myopathy is a distinct syndrome that can be differentiated from polymyositis and dermatomyositis, and is commonly associated with underlying malignancy.

SOURCE: Allenbach Y, Keraen J, Bouvier AM, et al. High risk of cancer in autoimmune necrotizing myopathies: Usefulness of myositis specific antibody. Brain 2016;139:2131-2135.

Immune-mediated necrotizing myopathy (IMNM) is classified as one the inflammatory myopathies, which include polymyositis, dermatomyositis, and inclusion body myositis. Although immunosuppressive medication may be beneficial for IMNM, supporting an immune-mediated mechanism, inflammatory infiltrates generally are not found and little is known regarding its precise underlying pathogenesis. In 15-20% of patients, dermatomyositis in adults may be associated with malignancy, particularly lung, ovarian, stomach, pancreatic, and colorectal cancer, but polymyositis and inclusion body myositis are not. Is IMNM associated with cancer?

To answer this question, a long-term, French, observational multicenter study was undertaken looking at three groups of IMNM patients diagnosed between 2000-2014: those positive for either of the two myositis-specific antibodies (MSA) strongly associated with IMNM, anti-signal recognition particle (SRP) antibodies or anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, and those negative for any MSA, including anti-Jo1, anti-PL7, anti-PL12, anti-MI2, anti-melanoma differentiation-associated gene 5, anti-nuclear matrix protein 2, and anti-transcriptional intermediary factor 1γ. Diagnosis of IMNM was based on criteria developed by the 2003 European Neuromuscular Center international workshop held in Naarden, The Netherlands,1 and was considered cancer-associated if cancer was diagnosed within three years, before or after, the diagnosis of IMNM. Statistical analysis included Mann-Whitney, Kruskal-Wallis, and Fisher’s exact tests, with a P value < 0.5 considered statistically significant.

Among 115 IMNM patients analyzed, comprising 52 with HMGCR antibodies, 49 with SRP antibodies, and 14 with no MSA antibodies, malignancy was present in 17.3%, 8.1%, and 28.6%, respectively. Mean age of cancer diagnosis was 67, 68, and 73 years, respectively, with no particular form of cancer predominant. Only one patient was diagnosed with cancer before age 50. Mean time between myopathy diagnosis and cancer was 4.2, 6.7, and 1.2 years, respectively. Compared to an age- and sex-matched general population, the incidence of cancer was significantly higher in MSA-negative and HMGCR-positive patients, with survival significantly lower in MSA-negative IMNM. SRP-positive patients demonstrated no increased risk of malignancy. Cancer screening is warranted in MSA-negative and HMGCR-positive IMNM but not in SRP-positive myositis.

COMMENTARY

IMNM is more common than polymyositis, occurs in all ages but predominantly in adults, and reaches its zenith within days to weeks, although it may progress subacutely in a progressive decline, resulting in severe weakness with high creatine kinase levels, and occasionally interstitial pneumonitis. Autoimmune and antibody mediated, it also may occur following viral infections or with malignancy. Necrotic myofibers, phagocytosed by macrophages, and regenerating myofibers characterize its pathology and, unlike other idiopathic inflammatory myopathies, there is only mild, if any, myofiber re-expression of major histocompatibility complex class I.

No randomized, controlled trial of immunotherapy has yet been performed for IMNM. Thus, treatment is based on case reports and case series. Patients with prior statin exposure appear more responsive to therapy than statin-naïve patients, but limited experience indicates that overall IMNM patients appear more resistant to corticosteroid monotherapy, and additional intravenous immunoglobulin (IVIG) often is required. Although most respond to a combination of prednisone and a steroid-sparing immunosuppressant, relapse often occurs as the dose is tapered. Triple therapy at initiation of treatment has been recommended, including corticosteroids, immunosuppressants, and IVIG.2 Other agents, including intravenous cyclophosphamide, azathioprine, cyclosporine, methotrexate, and rituximab, have been used in individual cases with varied success.

REFERENCES

  1. Hoogendijk JE, Amato AA, Lecky BR, 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;14:337-345.
  2. Kassardjian CD, Lennon VA, Alfugham NB, et al. Clinical features and treatment outcomes of necrotizing autoimmune myopathy. JAMA Neurol 2015;72:996-1003.