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June 2015; 2 (3) ArticleOpen Access

Clinical course and treatment of anti-HMGCR antibody–associated necrotizing autoimmune myopathy

Sudarshini Ramanathan, Daman Langguth, Todd A. Hardy, Nidhi Garg, Chris Bundell, Arada Rojana-Udomsart, Russell C. Dale, Thomas Robertson, Andrew L. Mammen, Stephen W. Reddel
First published April 2, 2015, DOI: https://doi.org/10.1212/NXI.0000000000000096
Sudarshini Ramanathan
From the Department of Neurology (S.R., T.A.H., N.G., S.W.R.), Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Neuroimmunology Group (S.R., R.C.D.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Neurology (S.R.), Westmead Hospital, Sydney, New South Wales, Australia; Sullivan Nicolaides Pathology (D.L.), Brisbane, Queensland, Australia; Concord Clinical School (T.A.H., S.W.R.), University of Sydney, New South Wales, Australia; Clinical Immunology (C.B.), PathWest, QEII Medical Center, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine (C.B.), University of Western Australia, Nedlands, Western Australia, Australia; Australian Neuro-Muscular Research Institute (ANRI) and Centre for Neuromuscular and Neurological Disorders (CNND) (A.R.-U.), University of Western Australia, QEII Medical Centre, Nedlands, Western Australia, Australia; Pathology Queensland (T.R.), Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; and National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.L.M.), National Institutes of Health, Bethesda, MD.
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Daman Langguth
From the Department of Neurology (S.R., T.A.H., N.G., S.W.R.), Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Neuroimmunology Group (S.R., R.C.D.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Neurology (S.R.), Westmead Hospital, Sydney, New South Wales, Australia; Sullivan Nicolaides Pathology (D.L.), Brisbane, Queensland, Australia; Concord Clinical School (T.A.H., S.W.R.), University of Sydney, New South Wales, Australia; Clinical Immunology (C.B.), PathWest, QEII Medical Center, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine (C.B.), University of Western Australia, Nedlands, Western Australia, Australia; Australian Neuro-Muscular Research Institute (ANRI) and Centre for Neuromuscular and Neurological Disorders (CNND) (A.R.-U.), University of Western Australia, QEII Medical Centre, Nedlands, Western Australia, Australia; Pathology Queensland (T.R.), Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; and National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.L.M.), National Institutes of Health, Bethesda, MD.
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Todd A. Hardy
From the Department of Neurology (S.R., T.A.H., N.G., S.W.R.), Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Neuroimmunology Group (S.R., R.C.D.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Neurology (S.R.), Westmead Hospital, Sydney, New South Wales, Australia; Sullivan Nicolaides Pathology (D.L.), Brisbane, Queensland, Australia; Concord Clinical School (T.A.H., S.W.R.), University of Sydney, New South Wales, Australia; Clinical Immunology (C.B.), PathWest, QEII Medical Center, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine (C.B.), University of Western Australia, Nedlands, Western Australia, Australia; Australian Neuro-Muscular Research Institute (ANRI) and Centre for Neuromuscular and Neurological Disorders (CNND) (A.R.-U.), University of Western Australia, QEII Medical Centre, Nedlands, Western Australia, Australia; Pathology Queensland (T.R.), Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; and National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.L.M.), National Institutes of Health, Bethesda, MD.
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Nidhi Garg
From the Department of Neurology (S.R., T.A.H., N.G., S.W.R.), Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Neuroimmunology Group (S.R., R.C.D.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Neurology (S.R.), Westmead Hospital, Sydney, New South Wales, Australia; Sullivan Nicolaides Pathology (D.L.), Brisbane, Queensland, Australia; Concord Clinical School (T.A.H., S.W.R.), University of Sydney, New South Wales, Australia; Clinical Immunology (C.B.), PathWest, QEII Medical Center, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine (C.B.), University of Western Australia, Nedlands, Western Australia, Australia; Australian Neuro-Muscular Research Institute (ANRI) and Centre for Neuromuscular and Neurological Disorders (CNND) (A.R.-U.), University of Western Australia, QEII Medical Centre, Nedlands, Western Australia, Australia; Pathology Queensland (T.R.), Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; and National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.L.M.), National Institutes of Health, Bethesda, MD.
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Chris Bundell
From the Department of Neurology (S.R., T.A.H., N.G., S.W.R.), Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Neuroimmunology Group (S.R., R.C.D.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Neurology (S.R.), Westmead Hospital, Sydney, New South Wales, Australia; Sullivan Nicolaides Pathology (D.L.), Brisbane, Queensland, Australia; Concord Clinical School (T.A.H., S.W.R.), University of Sydney, New South Wales, Australia; Clinical Immunology (C.B.), PathWest, QEII Medical Center, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine (C.B.), University of Western Australia, Nedlands, Western Australia, Australia; Australian Neuro-Muscular Research Institute (ANRI) and Centre for Neuromuscular and Neurological Disorders (CNND) (A.R.-U.), University of Western Australia, QEII Medical Centre, Nedlands, Western Australia, Australia; Pathology Queensland (T.R.), Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; and National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.L.M.), National Institutes of Health, Bethesda, MD.
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Arada Rojana-Udomsart
From the Department of Neurology (S.R., T.A.H., N.G., S.W.R.), Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Neuroimmunology Group (S.R., R.C.D.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Neurology (S.R.), Westmead Hospital, Sydney, New South Wales, Australia; Sullivan Nicolaides Pathology (D.L.), Brisbane, Queensland, Australia; Concord Clinical School (T.A.H., S.W.R.), University of Sydney, New South Wales, Australia; Clinical Immunology (C.B.), PathWest, QEII Medical Center, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine (C.B.), University of Western Australia, Nedlands, Western Australia, Australia; Australian Neuro-Muscular Research Institute (ANRI) and Centre for Neuromuscular and Neurological Disorders (CNND) (A.R.-U.), University of Western Australia, QEII Medical Centre, Nedlands, Western Australia, Australia; Pathology Queensland (T.R.), Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; and National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.L.M.), National Institutes of Health, Bethesda, MD.
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Russell C. Dale
From the Department of Neurology (S.R., T.A.H., N.G., S.W.R.), Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Neuroimmunology Group (S.R., R.C.D.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Neurology (S.R.), Westmead Hospital, Sydney, New South Wales, Australia; Sullivan Nicolaides Pathology (D.L.), Brisbane, Queensland, Australia; Concord Clinical School (T.A.H., S.W.R.), University of Sydney, New South Wales, Australia; Clinical Immunology (C.B.), PathWest, QEII Medical Center, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine (C.B.), University of Western Australia, Nedlands, Western Australia, Australia; Australian Neuro-Muscular Research Institute (ANRI) and Centre for Neuromuscular and Neurological Disorders (CNND) (A.R.-U.), University of Western Australia, QEII Medical Centre, Nedlands, Western Australia, Australia; Pathology Queensland (T.R.), Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; and National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.L.M.), National Institutes of Health, Bethesda, MD.
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Thomas Robertson
From the Department of Neurology (S.R., T.A.H., N.G., S.W.R.), Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Neuroimmunology Group (S.R., R.C.D.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Neurology (S.R.), Westmead Hospital, Sydney, New South Wales, Australia; Sullivan Nicolaides Pathology (D.L.), Brisbane, Queensland, Australia; Concord Clinical School (T.A.H., S.W.R.), University of Sydney, New South Wales, Australia; Clinical Immunology (C.B.), PathWest, QEII Medical Center, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine (C.B.), University of Western Australia, Nedlands, Western Australia, Australia; Australian Neuro-Muscular Research Institute (ANRI) and Centre for Neuromuscular and Neurological Disorders (CNND) (A.R.-U.), University of Western Australia, QEII Medical Centre, Nedlands, Western Australia, Australia; Pathology Queensland (T.R.), Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; and National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.L.M.), National Institutes of Health, Bethesda, MD.
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Andrew L. Mammen
From the Department of Neurology (S.R., T.A.H., N.G., S.W.R.), Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Neuroimmunology Group (S.R., R.C.D.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Neurology (S.R.), Westmead Hospital, Sydney, New South Wales, Australia; Sullivan Nicolaides Pathology (D.L.), Brisbane, Queensland, Australia; Concord Clinical School (T.A.H., S.W.R.), University of Sydney, New South Wales, Australia; Clinical Immunology (C.B.), PathWest, QEII Medical Center, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine (C.B.), University of Western Australia, Nedlands, Western Australia, Australia; Australian Neuro-Muscular Research Institute (ANRI) and Centre for Neuromuscular and Neurological Disorders (CNND) (A.R.-U.), University of Western Australia, QEII Medical Centre, Nedlands, Western Australia, Australia; Pathology Queensland (T.R.), Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; and National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.L.M.), National Institutes of Health, Bethesda, MD.
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Stephen W. Reddel
From the Department of Neurology (S.R., T.A.H., N.G., S.W.R.), Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Neuroimmunology Group (S.R., R.C.D.), Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Neurology (S.R.), Westmead Hospital, Sydney, New South Wales, Australia; Sullivan Nicolaides Pathology (D.L.), Brisbane, Queensland, Australia; Concord Clinical School (T.A.H., S.W.R.), University of Sydney, New South Wales, Australia; Clinical Immunology (C.B.), PathWest, QEII Medical Center, Nedlands, Western Australia, Australia; School of Pathology and Laboratory Medicine (C.B.), University of Western Australia, Nedlands, Western Australia, Australia; Australian Neuro-Muscular Research Institute (ANRI) and Centre for Neuromuscular and Neurological Disorders (CNND) (A.R.-U.), University of Western Australia, QEII Medical Centre, Nedlands, Western Australia, Australia; Pathology Queensland (T.R.), Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; and National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.L.M.), National Institutes of Health, Bethesda, MD.
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Citation
Clinical course and treatment of anti-HMGCR antibody–associated necrotizing autoimmune myopathy
Sudarshini Ramanathan, Daman Langguth, Todd A. Hardy, Nidhi Garg, Chris Bundell, Arada Rojana-Udomsart, Russell C. Dale, Thomas Robertson, Andrew L. Mammen, Stephen W. Reddel
Neurol Neuroimmunol Neuroinflamm Jun 2015, 2 (3) e96; DOI: 10.1212/NXI.0000000000000096

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Abstract

Objective: We examined a cohort of Australian patients with statin exposure who developed a necrotizing autoimmune myopathy (NAM) associated with a novel autoantibody against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and describe the clinical and therapeutic challenges of managing these patients and an optimal therapeutic strategy.

Methods: Clinical, laboratory, EMG, and histopathologic results and response to immunomodulation are reported in 6 Australian patients with previous statin exposure and antibodies targeting HMGCR.

Results: All patients presented with painless proximal weakness following statin therapy, which persisted after statin cessation. Serum creatine kinase (CK) levels ranged from 2,700 to 16,200 IU/L. EMG was consistent with a myopathic picture. Muscle biopsies revealed a pauci-immune necrotizing myopathy. Detailed graphical representation of the clinical course of these patients showed a close association with rising CK and an increase in clinical weakness signifying relapses, particularly upon weaning or ceasing steroids. All 6 patients were responsive to initial steroid therapy, with 5 relapsing upon attempts to wean steroids. Both CK and clinical strength improved with the reinstitution of immunotherapy, in particular steroids and IV immunoglobulin (IVIg). All patients required treatment with varying multiagent immunosuppressive regimens to achieve clinical remission, including prednisone (n = 6), IVIg (n = 5), plasmapheresis (n = 2), and additional therapy including methotrexate (n = 6), cyclophosphamide (n = 2), rituximab (n = 2), azathioprine (n = 1), and cyclosporine (n = 1).

Conclusions: Recognition of HMGCR antibody–associated NAM is important because these patients are responsive to immunosuppression, and early multiagent therapy and a slow and cautious approach to withdrawing steroids may improve outcomes.

GLOSSARY

CK=
creatine kinase;
DM=
dermatomyositis;
HMGCR=
3-hydroxy-3-methylglutaryl-coenzyme A reductase;
IVIg=
IV immunoglobulin;
MHC=
major histocompatibility complex;
NAM=
necrotizing autoimmune myopathy;
PM=
polymyositis

Footnotes

  • Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by the authors.

  • Supplemental data at Neurology.org/nn

  • Received August 24, 2014.
  • Accepted in final form January 20, 2015.
  • © 2015 American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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