A novel autoantibody recognizing 200‐kd and 100‐kd proteins is associated with an immune‐mediated necrotizing myopathy

Abstract

Objective. Myofiber necrosis without prominent inflammation is a nonspecific finding in patients with dystrophies and toxic or immune-mediated myopathies. However, the etiology of a necrotizing myopathy is often obscure, and the question of which patients would benefit from immunosuppression remains unanswered. The aim of this study was to identify novel autoantibodies in patients with necrotizing myopathy.Methods. Muscle biopsy specimens and serum samples were available for 225 patients with myopathy. Antibody specificities were determined by performing immunoprecipitations from 35 S-methionine-labeled HeLa cell lysates. Selected biopsy specimens were stained for membrane attack complex, class I major histocompatibility complex (MHC), and endothelial cell marker CD31.Results. Muscle biopsy specimens from 38 of 225 patients showed predominantly myofiber necrosis. Twelve of these patients had a known autoantibody association with or other etiology for their myopathy. Sixteen of the remaining 26 sera immunoprecipitated 200-kd and 100-kd proteins; this specificity was observed in only 1 of 187 patients without necrotizing myopathy. Patients with the anti-200/100 autoantibody specificity had proximal weakness (100%), high creatine kinase levels (mean maximum 10,333 IU/liter), and an irritable myopathy on electromyography (88%). Sixtythree percent of these patients had been exposed to statins prior to the onset of weakness. All patients responded to immunosuppressive therapy, and many experienced a relapse of weakness when the medication was tapered. Immunohistochemical studies showed membrane attack complex on small blood vessels in 6 of 8 patients and on the surface of non-necrotic myofibers in 4 of 8 patients. Five of 8 patients had abnormal capillary morphology, and 4 of 8 patients expressed class I MHC on the surface of non-necrotic myofibers.Conclusion. An anti-200/100-kd specificity defines a subgroup of patients with necrotizing myopathy who previously were considered to be autoantibody negative. We propose that these patients have an immune-mediated myopathy that is frequently associated with prior statin use and should be treated with immunosuppressive therapy.

Treatment and outcomes in necrotising autoimmune myopathy: An Australian perspective

“…This supports the recently published diagnostic algorithm by Mammen et al, [14] which recommends serological testing for anti-HMGCR antibodies prior to muscle biopsy. Given the specificity of positive anti-HMGCR antibodies for NAM in the context of patients over 50 years with previous stain exposure [6,18,19], perhaps future diagnoses could be based on clinical picture and serology alone, without the need for invasive muscle biopsies. All patients were screened clinically for malignancy and 40% of our cohort received formal malignancy screening including either PET or CT imaging of chest, abdomen, pelvis, although no patients were found to have malignancy.…”

An Unusual Case of Statin-Induced Myopathy: Anti-HMGCoA Necrotizing Autoimmune Myopathy

“…11 Deposition of complement membrane attack complexes on non-necrotic muscle fibers is consistent with the concept that the myofiber degeneration in anti-HMGCR NAM is a complement-mediated antibody-dependent toxicity. 12 Additionally, there is an identified association between anti-HMGCR NAM and HLA-DRB1*11. 13 The novel anti-HMGCR antibody, which was discovered in 2010, is a promising diagnostic marker for statin-associated NAM.…”

“…13 The novel anti-HMGCR antibody, which was discovered in 2010, is a promising diagnostic marker for statin-associated NAM. 12 Nearly all patients with statin-induced necrotizing . This confirms that during the early antibody-mediated phase of the disease, the membrane is relatively intact, but in later phases, the membrane integrity is compromised.…”

Paraneoplastic necrotizing myopathy in association with metastatic malignant melanoma: two case reports and a review of the literature

“…Two recent case series have suggested that anti-SRP levels do correlate with disease severity, and may serve as a marker of poor prognosis [13,14] . Additionally, a recent study identified anti-HMGCoA reductase autoantibodies in 63% of patients with necrotizing autoimmune myopathy [15] . These antibodies are more frequently found in patients with statin-associated necrotizing myopathy, and less frequently in statin-unexposed subjects [16] .…”