Anti-HMGCR Myopathy

Abstract

Anti-HMGCR myopathy was first recognized and characterized in patients with a history of statin exposure and immune-mediated necrotizing myopathy. After the discovery of anti-HMGCR autoantibodies, several international groups identified and characterized more patients, expanding the phenotypic spectrum of this disease to include pediatric patients and young adults without statin exposure and those with a chronic myopathy resembling limb-girdle muscular dystrophy. We provide a summary of clinical findings, pathologic features, muscle imaging, and immunogenetic risk factors of the disease. We also discuss the current treatment strategies and approaches to monitoring the therapeutic response. Lastly, we briefly summarize the current understanding of the pathophysiology of the disease and postulate a model for autoimmunity initiation and propagation in this disease.

Keywords: Anti-HMGCR myopathy; autoimmunity; limb-girdle muscular dystrophy; myositis; necrotizing myopathy.

Fig.1

Typical Clinicopathologic features of anti-HMGCR Myopathy. (A) Summary of clinical findings on exam and ancillary testing. (B) muscle MRI of the lower extremities. Note selective involvement of paraspinal, gluteals in the hip and posterior and medial compartments of the thigh. Short tau inversion recovery (STIR) signal increase can be patchy and asymmetric. (C) A typical hematoxylin and eosin stain of a patient with anti-HMGCR myopathy showing myofiber atrophy, degeneration, and regeneration without prominent lymphocytic inflammation.

Fig.2

Schematic of postulated pathomechanisms of anti-HMGCR myopathy. (A) Statin exposure results in overexpression of HMGCR in multiple tissues and cell types. (B) Processing of HMGCR by antigen-presenting cells under different scenarios. Variants in HMGCR or cryptic epitopes unmasked by drugs (e.g. statins) and/or polymorphisms in the HLA molecule may increase T-cell receptor activation and initiate autoimmunity. (C) Immune-mediated injury to the muscle is directed against HMGCR or other antigens recognized by anti-HMGCR antibody. Attempts at myofiber repair results in increased HMGCR (or its mimic) expression and sustained autoimmunity with ultimate atrophy and degeneration of myofibers.