Dalakas, Marinos C.

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Thomas Jefferson University Jefferson Digital Commons Department of Neurology Faculty Papers Department of Neurology 10-24-2019 Case 22-2019: A 65-Year-Old Woman with Myopathy. Marinos C. Dalakas Thomas Jefferson University Follow this and additional works at: https://jdc.jefferson.edu/neurologyfp  Part of the Neurology Commons Let us know how access to this document benefits you Recommended Citation Dalakas, Marinos C., "Case 22-2019: A 65-Year-Old Woman with Myopathy." (2019). Department of Neurology Faculty Papers. Paper 204. https://jdc.jefferson.edu/neurologyfp/204 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Neurology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: JeffersonDigitalCommons@jefferson.edu. Correspondencen engl j med 381;17 nejm.org October 24, 2019 16932. Pareek M, Vaduganathan M, Biering-Sørensen T, et al. Pulse pressure, cardiovascular events, and intensive blood-pressure lowering in the Systolic Blood Pressure Intervention Trial (SPRINT). Am J Med 2019; 132: 733-9.3. Vidal-Petiot E, Greenlaw N, Ford I, et al. Relationships be-tween components of blood pressure and cardiovascular events in patients with stable coronary artery disease and hyperten-sion. Hypertension 2018; 71: 168-76.4. Bhatt DL. Troponin and the J-curve of diastolic blood pres-sure: when lower is not better. J Am Coll Cardiol 2016; 68: 1723-6.5. Vidal-Petiot E, Ford I, Greenlaw N, et al. Cardiovascular event rates and mortality according to achieved systolic and diastolic blood pressure in patients with stable coronary artery disease: an international cohort study. Lancet 2016; 388: 2142-52.DOI: 10.1056/NEJMc1911059Case 22-2019: A 65-Year-Old Woman with MyopathyTo the Editor: The case reported by Freeman et al. (July 18 issue)1 contains conclusions that may perpetuate misconceptions. The patient had acute rhabdomyolysis and necrotizing autoim-mune myositis, but the connection with statins is unlikely.In this patient, myopathy started 2 weeks af-ter coryza and cough; this suggests a preceding viral infection, which is a more likely trigger of necrotizing autoimmune myositis2 than atorva-statin, which had been initiated 6 months pre-viously. Statins can rarely lead to acute myotox-icity, but the contention that they induce anti-HMGCR (3-hydroxy-3-methylglutaryl coen-zyme A reductase)–mediated autoimmunity is un-substantiated and disputed.3 HMGCR is normally expressed in regenerating rather than necrotic fibers, and there is no evidence that it induces muscle-fiber necrosis or triggers autoimmunity, especially since HMGCR is a ubiquitous cyto-plasmic antigen that is not accessible to anti-HMGCR antibodies.4 HMGCR is expressed in normal myotubes, but anti-HMGCR IgG does not induce myotubular necrosis5 and does not explain pathogenicity.4 Most important, anti-HMGCR autoantibodies are not statin-specific because they are most frequently seen in pa-tients with paraneoplastic, viral, or other forms of necrotizing autoimmune myositis who have not received statins.6In the few patients in whom necrotizing auto-immune myositis does develop after receipt of statins for years, the association is more of a chance phenomenon, considering that necrotiz-ing autoimmune myositis is now the most com-mon inflammatory myopathy2,4 and that 25% of Americans older than 40 years of age take statins. The authors’ conclusions could deprive the patient, as well as others with a similar pre-sentation, of a helpful drug.Marinos C. Dalakas, M.D.Thomas Jefferson University Philadelphia, PA marinos . dalakas@ jefferson . eduNo potential conflict of interest relevant to this letter was re-ported.1. Case Records of the Massachusetts General Hospital (Case 22-2019). N Engl J Med 2019; 381: 275-83.2. Dalakas MC. Inflammatory muscle diseases. N Engl J Med 2015; 372: 1734-47.3. Allenbach Y, Arouche-Delaperche L, Preusse C, et al. Necro-sis in anti-SRP+ and anti-HMGCR+ myopathies: role of autoanti-bodies and complement. Neurology 2018; 90(6): e507-e517.4. Dalakas MC. Myositis: are autoantibodies pathogenic in nec-rotizing myopathy? Nat Rev Rheumatol 2018; 14: 251-2.5. Arouche-Delaperche L, Allenbach Y, Amelin D, et al. Patho-genic role of anti-signal recognition protein and anti-3-hydroxy-3-methylglutaryl-CoA reductase antibodies in necrotizing  myopathies: myofiber atrophy and impairment of muscle regen-eration in necrotizing autoimmune myopathies. Ann Neurol 2017; 81: 538-48.6. Watanabe Y, Uruha A, Suzuki S, et al. Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy. J Neurol Neurosurg Psychiatry 2016; 87: 1038-44.DOI: 10.1056/NEJMc1911058To the Editor: We would like to expand on the discussion by Freeman et al. on statin-associated autoimmune myopathy with autoantibodies against HMGCR in a patient who had been pre-scribed a statin medication. First, we would note that this disease may also be associated with a dietary source of statins, such as red yeast rice or oyster mushrooms.1 Second, since at least 25% of patients with anti-HMGCR–associated autoim-mune myopathy have no known exposure to statins,2 testing for anti-HMGCR autoantibodies may be considered in other patients with myopa-thy. This includes adults and children with clini-cal presentations that are consistent with genetic muscle disease but no known genetic defect; some of these patients have anti-HMGCR–associ-ated autoimmune myopathy that responds to treatment.3 Third, reinitiation of statins is con-The New England Journal of Medicine Downloaded from nejm.org at THOMAS JEFFERSON UNIVERSITY on November 20, 2019. For personal use only. No other uses without permission.  Copyright © 2019 Massachusetts Medical Society. All rights reserved. Correspondencen engl j med 381;17 nejm.org October 24, 20191694traindicated in patients with statin-associated autoimmune myopathy. However, the use of pro-protein convertase subtilisin–kexin type 9 (PCSK9) inhibitors appears to be safe in this patient pop-ulation and may be considered in patients with clinically significant cardiovascular risk factors.4Iago Pinal-Fernandez, M.D., Ph.D. Andrew L. Mammen, M.D., Ph.D.National Institutes of Health Bethesda, MD iagopf@ yahoo . esNo potential conflict of interest relevant to this letter was re-ported.1. Barbacki A, Fallavollita SA, Karamchandani J, Hudson M. Immune-mediated necrotizing myopathy and dietary sources of statins. Ann Intern Med 2018; 168: 893-904.2. Tiniakou E, Pinal-Fernandez I, Lloyd TE, et al. More severe disease and slower recovery in younger patients with anti-3- hydroxy-3-methylglutaryl-coenzyme A reductase-associated auto-immune myopathy. Rheumatology (Oxford) 2017; 56: 787-94.3. Mohassel P, Landon-Cardinal O, Foley AR, et al. Anti-HMGCR myopathy may resemble limb-girdle muscular dystro-phy. Neurol Neuroimmunol Neuroinflamm 2018; 6(1): e523.4. Tiniakou E, Rivera E, Mammen AL, Christopher-Stine L. Use of proprotein convertase subtilisin/kexin type 9 inhibitors in statin-associated immune-mediated necrotizing myopathy: a case series. Arthritis Rheumatol 2019; 71: 1723-6.DOI: 10.1056/NEJMc1911058The discussants reply: Dalakas raises an im-portant point about the relationship between statin use and necrotizing autoimmune myopa-thy. There is considerable epidemiologic evidence of an association between statin use and necro-tizing autoimmune myopathy; however, data to establish statins as causal agents of the illness are lacking. In a large series involving 1947 pa-tients with suspected myopathy who were evalu-ated at the Johns Hopkins Myositis Center, 104 (5.3%) were positive for anti-HMGCR autoanti-bodies.1 Of these 104 patients, 75% had a history of statin use. Widespread use of statins, as seen in the United States, can lead to ascertainment bias, linking a rare myopathy with a commonly used drug class. Nevertheless, in the Johns Hop-kins cohort, there was a strong association be-tween antibodies and statin use. However, 25% of the patients with anti-HMGCR autoantibodies did not have a history of statin use; thus, necro-tizing autoimmune myopathy can occur in the absence of statin exposure. As Dalakas suggests, anti-HMGCR autoantibodies may not necessarily be pathogenic, but they could be biomarkers of the immune-mediated process. Although viral illness is a potential trigger, we did not find compelling literature linking viral illness with anti-HMGCR autoantibodies. Although the dura-tion of statin use before anti-HMGCR myopathy is variable, 2 or more years of exposure is fre-quently reported. Thus, the time course in this pa-tient is consistent with a statin-associated event.2,3 We agree that Koch’s postulates for causality are not satisfied with regard to the role of statins or HMGCR autoantibodies in causing necrotizing autoimmune myopathy; until there is stronger evidence, it may be better to view the condition as statin-associated rather than statin-induced. We do not agree, however, with rechallenging pa-tients with statins; this perspective was support-ed in a recent review article stating that all five patients who were rechallenged had adverse ef-fects.4 In our opinion, rechallenging a patient with a statin would require conclusive proof that a statin was not implicated in the disorder. Given the very refractory nature of necrotizing autoim-mune myopathy, we think alternative cholesterol-lowering therapy with the use of PCSK9 antibod-ies or ezetimibe should be the recommended treatment for a patient after the development of a statin-associated anti-HMGCR myopathy.We thank Pinal-Fernandez and Mammen for their comments. These letters raise important issues in understanding this rare immune-medi-ated myopathy.Mason W. Freeman, M.D. Amanda C. Guidon, M.D. Sheila L. Arvikar, M.D.Massachusetts General Hospital Boston, MASince publication of their article, the authors report no fur-ther potential conflict of interest.1. Tiniakou E, Pinal-Fernandez I, Lloyd TE, et al. More severe disease and slower recovery in younger patients with anti-3- hydroxy-3-methylglutaryl-coenzyme A reductase-associated auto-immune myopathy. Rheumatology (Oxford) 2017; 56: 787-94.2. Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010; 62: 2757-66.3. Ramanathan S, Langguth D, Hardy TA, et al. Clinical course and treatment of anti-HMGCR antibody-associated necrotizing autoimmune myopathy. Neurol Neuroimmunol Neuroinflamm 2015; 2(3): e96.4. Nazir S, Lohani S, Tachamo N, Poudel D, Donato A. Statin-associated autoimmune myopathy: a systematic review of 100 cases. J Clin Rheumatol 2017; 23: 149-54.DOI: 10.1056/NEJMc1911058Correspondence Copyright © 2019 Massachusetts Medical Society.The New England Journal of Medicine Downloaded from nejm.org at THOMAS JEFFERSON UNIVERSITY on November 20, 2019. For personal use only. No other uses without permission.  Copyright © 2019 Massachusetts Medical Society. All rights reserved. 

Case 22-2019: A 65-Year-Old Woman with Myopathy.

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Case 22-2019: A 65-Year-Old Woman with Myopathy.

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