Death by Macrophage: Rethinking the Concept of Inflammation in Immune-Mediated Necrotizing Myopathy

Inflammatory myopathies are characterized as autoimmune muscle diseases. So, the concept of a subtype of inflammatory myopathy with minimal inflammation on biopsy confused many rheumatologists for some years. In fact, it was thought that necrotizing myopathies involved very little if no inflammation, which seems counter-intuitive due to the autoimmune nature of immune-mediated myopathies. However, immune-mediated necrotizing myopathy (IMNM) has been recently added as a standalone entity among dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM).

IMNM was commonly characterized in the literature by muscle fiber necrosis on biopsy with a lack of inflammatory infiltrates. There are two autoantibodies that are associated with IMNM: anti-signal recognition protein (SRP) and anti-3-hydroxy-3-methylglutaryl-CoA reductase antibody (HMGCR). Patients with these autoantibodies have a characteristic clinical phenotype, which consists of severe proximal muscle weakness, higher CK levels, and relative lack of extra-muscular involvement. Knowing more about this disease entity, including its severity and disease course, is crucial for implementing treatment, especially given the observation that most cases can be quite resistant to therapy.

With that in mind, a group from France (Allenbach et al., Abstract #282) aimed to analyze and describe the morphology of skeletal muscle alterations in patients with SRP and HMGCR autoantibody-mediated IMNM. They analyzed muscle biopsies from patients in these subgroups and compared them to patients with DM as well as Jo-1 associated inflammatory myopathy. Interestingly, they found that SRP patients had the highest proportion of necrotic muscle fibers compared to HMGCR patients. In fact, similar amounts of necrosis were seen in HMGCR and Jo-1 patient populations. However, the pattern of necrosis was different. In Jo-1 patients, the pattern was perfascicular, whereas random distribution was seen in SRP and HMGCR patients. There was a positive correlation where the more necrosis in muscle, the higher the CK values.

Where there was muscle cell death, regeneration was also seen and correlated with the amount of necrosis. While IMNM was traditionally regarded as lacking inflammation, inflammation was regularly observed in the muscle biopsy samples; macrophages were most commonly seen, but a large number of T cells was seen as well, in most cases in the same range as the myositis control patients. The number of T cells present often correlated with the proportion of necrotic muscle fibers. Moreover, humoral immunity was also observed, with the classical pathway of the complement cascade being observed in many cases.

So what does this mean? Contrary to previous opinion, SRP and HMGCR IMNM may no longer be considered as non-inflammatory myopathies, as inflammation correlates with muscle necrosis. This seems to make intuitive sense, since the severe muscle weakness and degree of CK elevation, as well as the extent of necrosis, is driven by an autoimmune phenomenon. Moreover, the presence of specific autoantibodies points to this process as well.

More reports from ACR 2016