Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy.

Authors: Mammen, AL  Chung, T  Christopher-Stine, L  Rosen, P  Rosen, A  Doering, KR  Casciola-Rosen, LA 
Citation: Mammen AL, etal., Arthritis Rheum. 2011 Mar;63(3):713-21. doi: 10.1002/art.30156.
Pubmed: (View Article at PubMed) PMID:21360500
DOI: Full-text: DOI:10.1002/art.30156

OBJECTIVE: In addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necrotizing myopathy (IMNM), with autoantibodies that recognize approximately 200-kd and approximately 100-kd autoantigens. The purpose of this study was to identify these molecules to help clarify the disease mechanism and facilitate diagnosis. METHODS: The effect of statin treatment on autoantigen expression was addressed by immunoprecipitation using sera from patients. The identity of the approximately 100-kd autoantigen was confirmed by immunoprecipitation of in vitro-translated 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) protein. HMGCR expression in muscle was analyzed by immunofluorescence. A cohort of myopathy patients was screened for anti-HMGCR autoantibodies by enzyme-linked immunosorbent assay and genotyped for the rs4149056 C allele, a predictor of self-limited statin myopathy. RESULTS: Statin exposure induced expression of the approximately 200-kd/ approximately 100-kd autoantigens in cultured cells. HMGCR was identified as the approximately 100-kd autoantigen. Competition experiments demonstrated no distinct autoantibodies recognizing the approximately 200-kd protein. In muscle biopsy tissues from anti-HMGCR-positive patients, HMGCR expression was up-regulated in cells expressing neural cell adhesion molecule, a marker of muscle regeneration. Anti-HMGCR autoantibodies were found in 45 of 750 patients presenting to the Johns Hopkins Myositis Center (6%). Among patients ages 50 years and older, 92.3% had taken statins. The prevalence of the rs4149056 C allele was not increased in patients with anti-HMGCR. CONCLUSION: Statins up-regulate the expression of HMGCR, the major target of autoantibodies in statin-associated IMNM. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response even after statins are discontinued. These studies demonstrate a mechanistic link between an environmental trigger and the development of sustained autoimmunity. Detection of anti-HMGCR autoantibodies may facilitate diagnosis and direct therapy.

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CRRD Object Information
CRRD ID: 5508448
Created: 2011-10-18
Species: All species
Last Modified: 2011-10-18
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.