Ir J Med Sci DOI 10.1007/s11845-014-1207-z
CASE BASED REVIEW
Novel antibody associations in immune-mediated necrotising myopathy without inflammation D. Curtin • D. Costigan • C. McCarthy • M. Jansen • M. Farrell • V. Reid • K. O’Rourke
Received: 6 April 2014 / Accepted: 27 September 2014 Ó Royal Academy of Medicine in Ireland 2014
Abstract Introduction The patient presenting with proximal muscle weakness, elevated serum creatinine kinase and myopathic electromyography and biopsy findings has a wide differential diagnosis that includes toxic, autoimmune, paraneoplastic and congenital myopathies. Autoimmune myopathies are important to identify because they may respond to immunosuppressive therapies. Methods We describe two cases of immune-mediated necrotizing myopathy each associated with a novel antibody. Results Case 1 describes a progressive myopathy in a statin user. Antibodies to 3-hydroxy-3-methyl-glutarylcoenzyme A reductase were identified and the patient responded to steroid therapy. Case 2 describes an aggressive myopathy associated with antibodies to signal recognition particle. There was no response to steroids. Clinical
D. Curtin (&) K. O’Rourke Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles St., Dublin 7, Ireland e-mail: [email protected]
improvement followed treatment with rituximab and cyclophosphamide. Conclusion The identification of myositis-specific antibodies is important because they are associated with distinct clinical phenotypes and may guide the physician in terms of treatment strategies. Keywords Immune mediated Necrotizing myopathy 3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitor Signal recognition particle Antibody
Introduction The identification of myositis-specific antibodies assists in the characterisation of subgroups with specific clinical and histopathological features [1]. We describe two cases of myopathy characterised by muscle fibre necrosis with minimal histopathological evidence of inflammation and associated with a novel antibody in each case.
Case 1 D. Costigan Department of Neurology, Mater Private Hospital, Dublin, Ireland C. McCarthy Department of Rheumatology, Mater Private Hospital, Dublin, Ireland M. Jansen M. Farrell Department of Neuropathology, Beaumont Hospital, Dublin, Ireland V. Reid Department of Clinical Neurophysiology, Mater Misericordiae University Hospital, Dublin, Ireland
A 79-year-old man developed symmetrical proximal weakness over 1 year. He needed a cane to get out of a chair and had difficulty in reaching above his head. There was no myalgia or bulbar weakness. Medications on admission included atorvastatin 40 mg daily. Investigations revealed a creatinine kinase (CK) of 6,498 i.u./L (normal 44–272), a 25-hydroxy vitamin D3 level of 15 nmol/L (normal 75–200), corrected calcium 2.08 mmol/ L (normal 2.1–2.6) and elevated liver transaminase levels. Electromyography (EMG) demonstrated normal sensory responses and compound muscle action potentials in the
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Ir J Med Sci
Fig. 1 Necrotizing myopathy with minimal lymphocytic infiltration
lower extremities. Needle EMG however showed early recruitment, chronic repetitive discharges (abundant) spontaneous activity at rest and excess small amplitude short duration units in proximal muscles examined. Paraspinal examination also demonstrated spontaneous activity. Changes were consistent with an inflammatory myopathy or myositis. A muscle biopsy was performed which revealed necrotising myopathy without lymphocytic infiltration (Fig. 1). Antibodies to 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor were detected by enzymelinked immunosorbent assay (ELISA) and confirmed by immunoprecipitation testing. Anti-SRP antibodies, antinuclear antibody, and antibodies to extractible nuclear antigen (ENA) were absent. Atorvastatin was discontinued and prednisolone was given at an initial dose of 1 mg/kg,
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with calcium and vitamin D replacement. Prednisolone was reduced by 5 mg weekly and stopped after 8 weeks. CK levels normalised more quickly than clinical improvement, but 6 months later there was minimal residual disability. A search for malignancy using computed tomography (CT) was negative.
Case 2 A 57-year-old man developed left shoulder pain followed by myalgia, progressive proximal weakness, and dysphagia. Three months later he was unable to walk independently, and by the 10th months he developed respiratory failure requiring non-invasive ventilation. Initial serum
Ir J Med Sci
creatine kinase (CK) level was 12,939 i.u./L (normal 44–272). Electromyography was consistent with an irritable myopathic process. An extensive myositis immunological screen detected antibodies to signal recognition particle (SRP). The remainder of the screen was negative. Muscle biopsy revealed similar appearances to case 1. There was no response to methylprednisolone (3,000 mg intravenously over 3 days followed by a maintenance dose of 60 mg prednisolone tapering to 20 mg) or to intravenous immunoglobulin (0.4 g/kg/day for 5 days). Nine months after onset of symptoms he was treated with two 1 g doses of rituximab 2 weeks apart, followed by monthly intravenous cyclophosphamide (750 mg/square metre) for 6 months. This was followed by significant improvement in bulbar function, respiratory function, and limb power, and his CK levels decreased. He was discharged to a rehabilitation facility and rehabilitated for being an independent wheelchair user. Positron-emission tomography (PET) revealed no evidence of underlying malignancy. He had never been exposed to statins. Eighteen months after presentation SRP antibodies remained detectable with a CK of 2,446 i.u./L.
Discussion Signal receptor particle is a ribronuclear protein that regulates protein translation across the endoplamic reticulum membrane during protein synthesis. Approximately 5 % of patients with presumed immune-mediated myopathy have anti-SRP antibodies [2]. Anti-SRP myopathy is aggressive and is associated with very high serum CK levels, leading to major disability within months with a poor response to corticosteroids and conventional immunosuppressant agents. The positive response to rituximab seen in our patient is consistent with previous observations [3], suggesting that B-cell depletion therapy may be effective in patients with refractory disease, even when the muscle biopsy shows minimal B-cell infiltration. In 2007, a progressive necrotizing myopathy without prominent inflammation was reported in statin users [4]. The need for immunosuppression in addition to statin discontinuation suggested an immune-driven process, leading to the identification of antibodies to 3-hydroxy-3methyl-glutaryl-coenzyme A reductase (HMGCR), the pharmacological target of statins [5]. It was subsequently shown that anti-HMGCR antibodies did not develop in the
majority patients previously exposed to statins, including those with short-lived musculoskeletal side effects [6]. Statins are known to upregulate the expression of HMGCR [7] and it is possible that this increased expression of HMGCR could trigger anti-HMGCR autoimmunity which is propagated by regenerating muscle fibres expressing high levels of this protein [5]. Vitamin D deficiency has been associated with statin-induced myalgia [8] but not previously with necrotising myopathy. In summary, we describe two novel antibodies causing myopathy and associated with a distinctive histopathological appearance. The identification of myositis-specific antibodies is important because they are associated with distinct clinical phenotypes and may guide the physician in terms of treatment strategies and prognostication. Conflict of interest
None.
References 1. Sordet C, Goetz J, Sibilia J (2006) Contribution of autoantibodies to the diagnosis and nosology of inflammatory muscle disease. Joint bone Spine 73:646–654 2. Kao A, Lacomis D, Lucas M, Fertig N, Oddis C (2004) Anti-signal recognition particle autoantibody in patients with and without idiopathic inflammatory myopathy. Arthritis Rheum 50:209–215 3. Valiyil R, Casciola-Rosen L, Hong G, Mammen A, ChristopherStine L (2010) Rituximab therapy for myopathy associated with anti-signal recognition particle antibodies: a case series. Arthritis Care Res 62:1328–1334 4. Needham M, Fabian V, Knezevic W, Panegyres P, Zilko P, Mastaglia F (2007) Progressive myopathy with up-regulation of MHC-I associated with statin therapy. Neuromuscul Disord 17:194–200 5. Mammen A, Chung T, Christopher-Stine L, Rosen P, Rosen A, Doering K, Casciola-Rosen L (2011) Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 63:713–721 6. Mammen AL, Pak K, Williams E, Brisson D, Coresh J, Selvin E, Gaudet D (2012) Rarity of anti-3-hydroxy-3-methylglutarylcoenzyme a reductase antibodies in statin users, including those with self-limited musculoskeletal side effects. Arthritis Care Res (Hoboken) 64:269–272 7. Morikawa S, Murakami T, Yamazaki H, Izumi A, Saito Y, Hamakubo T, Kodama T (2005) Analysis of the global RNA expression profiles of skeletal muscle cells treated with statins. J Atheroscler Thromb 12:121–131 8. Lee P, Greenfield J, Campbell L (2009) Vitamin D insufficiency— a novel mechanism of statin-induced myalgia? Clin Endocrinol (Oxf.) 71:154–155
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CASE BASED REVIEW
Novel antibody associations in immune-mediated necrotising myopathy without inflammation D. Curtin • D. Costigan • C. McCarthy • M. Jansen • M. Farrell • V. Reid • K. O’Rourke
Received: 6 April 2014 / Accepted: 27 September 2014 Ó Royal Academy of Medicine in Ireland 2014
Abstract Introduction The patient presenting with proximal muscle weakness, elevated serum creatinine kinase and myopathic electromyography and biopsy findings has a wide differential diagnosis that includes toxic, autoimmune, paraneoplastic and congenital myopathies. Autoimmune myopathies are important to identify because they may respond to immunosuppressive therapies. Methods We describe two cases of immune-mediated necrotizing myopathy each associated with a novel antibody. Results Case 1 describes a progressive myopathy in a statin user. Antibodies to 3-hydroxy-3-methyl-glutarylcoenzyme A reductase were identified and the patient responded to steroid therapy. Case 2 describes an aggressive myopathy associated with antibodies to signal recognition particle. There was no response to steroids. Clinical
D. Curtin (&) K. O’Rourke Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles St., Dublin 7, Ireland e-mail: [email protected]
improvement followed treatment with rituximab and cyclophosphamide. Conclusion The identification of myositis-specific antibodies is important because they are associated with distinct clinical phenotypes and may guide the physician in terms of treatment strategies. Keywords Immune mediated Necrotizing myopathy 3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitor Signal recognition particle Antibody
Introduction The identification of myositis-specific antibodies assists in the characterisation of subgroups with specific clinical and histopathological features [1]. We describe two cases of myopathy characterised by muscle fibre necrosis with minimal histopathological evidence of inflammation and associated with a novel antibody in each case.
Case 1 D. Costigan Department of Neurology, Mater Private Hospital, Dublin, Ireland C. McCarthy Department of Rheumatology, Mater Private Hospital, Dublin, Ireland M. Jansen M. Farrell Department of Neuropathology, Beaumont Hospital, Dublin, Ireland V. Reid Department of Clinical Neurophysiology, Mater Misericordiae University Hospital, Dublin, Ireland
A 79-year-old man developed symmetrical proximal weakness over 1 year. He needed a cane to get out of a chair and had difficulty in reaching above his head. There was no myalgia or bulbar weakness. Medications on admission included atorvastatin 40 mg daily. Investigations revealed a creatinine kinase (CK) of 6,498 i.u./L (normal 44–272), a 25-hydroxy vitamin D3 level of 15 nmol/L (normal 75–200), corrected calcium 2.08 mmol/ L (normal 2.1–2.6) and elevated liver transaminase levels. Electromyography (EMG) demonstrated normal sensory responses and compound muscle action potentials in the
123
Ir J Med Sci
Fig. 1 Necrotizing myopathy with minimal lymphocytic infiltration
lower extremities. Needle EMG however showed early recruitment, chronic repetitive discharges (abundant) spontaneous activity at rest and excess small amplitude short duration units in proximal muscles examined. Paraspinal examination also demonstrated spontaneous activity. Changes were consistent with an inflammatory myopathy or myositis. A muscle biopsy was performed which revealed necrotising myopathy without lymphocytic infiltration (Fig. 1). Antibodies to 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor were detected by enzymelinked immunosorbent assay (ELISA) and confirmed by immunoprecipitation testing. Anti-SRP antibodies, antinuclear antibody, and antibodies to extractible nuclear antigen (ENA) were absent. Atorvastatin was discontinued and prednisolone was given at an initial dose of 1 mg/kg,
123
with calcium and vitamin D replacement. Prednisolone was reduced by 5 mg weekly and stopped after 8 weeks. CK levels normalised more quickly than clinical improvement, but 6 months later there was minimal residual disability. A search for malignancy using computed tomography (CT) was negative.
Case 2 A 57-year-old man developed left shoulder pain followed by myalgia, progressive proximal weakness, and dysphagia. Three months later he was unable to walk independently, and by the 10th months he developed respiratory failure requiring non-invasive ventilation. Initial serum
Ir J Med Sci
creatine kinase (CK) level was 12,939 i.u./L (normal 44–272). Electromyography was consistent with an irritable myopathic process. An extensive myositis immunological screen detected antibodies to signal recognition particle (SRP). The remainder of the screen was negative. Muscle biopsy revealed similar appearances to case 1. There was no response to methylprednisolone (3,000 mg intravenously over 3 days followed by a maintenance dose of 60 mg prednisolone tapering to 20 mg) or to intravenous immunoglobulin (0.4 g/kg/day for 5 days). Nine months after onset of symptoms he was treated with two 1 g doses of rituximab 2 weeks apart, followed by monthly intravenous cyclophosphamide (750 mg/square metre) for 6 months. This was followed by significant improvement in bulbar function, respiratory function, and limb power, and his CK levels decreased. He was discharged to a rehabilitation facility and rehabilitated for being an independent wheelchair user. Positron-emission tomography (PET) revealed no evidence of underlying malignancy. He had never been exposed to statins. Eighteen months after presentation SRP antibodies remained detectable with a CK of 2,446 i.u./L.
Discussion Signal receptor particle is a ribronuclear protein that regulates protein translation across the endoplamic reticulum membrane during protein synthesis. Approximately 5 % of patients with presumed immune-mediated myopathy have anti-SRP antibodies [2]. Anti-SRP myopathy is aggressive and is associated with very high serum CK levels, leading to major disability within months with a poor response to corticosteroids and conventional immunosuppressant agents. The positive response to rituximab seen in our patient is consistent with previous observations [3], suggesting that B-cell depletion therapy may be effective in patients with refractory disease, even when the muscle biopsy shows minimal B-cell infiltration. In 2007, a progressive necrotizing myopathy without prominent inflammation was reported in statin users [4]. The need for immunosuppression in addition to statin discontinuation suggested an immune-driven process, leading to the identification of antibodies to 3-hydroxy-3methyl-glutaryl-coenzyme A reductase (HMGCR), the pharmacological target of statins [5]. It was subsequently shown that anti-HMGCR antibodies did not develop in the
majority patients previously exposed to statins, including those with short-lived musculoskeletal side effects [6]. Statins are known to upregulate the expression of HMGCR [7] and it is possible that this increased expression of HMGCR could trigger anti-HMGCR autoimmunity which is propagated by regenerating muscle fibres expressing high levels of this protein [5]. Vitamin D deficiency has been associated with statin-induced myalgia [8] but not previously with necrotising myopathy. In summary, we describe two novel antibodies causing myopathy and associated with a distinctive histopathological appearance. The identification of myositis-specific antibodies is important because they are associated with distinct clinical phenotypes and may guide the physician in terms of treatment strategies and prognostication. Conflict of interest
None.
References 1. Sordet C, Goetz J, Sibilia J (2006) Contribution of autoantibodies to the diagnosis and nosology of inflammatory muscle disease. Joint bone Spine 73:646–654 2. Kao A, Lacomis D, Lucas M, Fertig N, Oddis C (2004) Anti-signal recognition particle autoantibody in patients with and without idiopathic inflammatory myopathy. Arthritis Rheum 50:209–215 3. Valiyil R, Casciola-Rosen L, Hong G, Mammen A, ChristopherStine L (2010) Rituximab therapy for myopathy associated with anti-signal recognition particle antibodies: a case series. Arthritis Care Res 62:1328–1334 4. Needham M, Fabian V, Knezevic W, Panegyres P, Zilko P, Mastaglia F (2007) Progressive myopathy with up-regulation of MHC-I associated with statin therapy. Neuromuscul Disord 17:194–200 5. Mammen A, Chung T, Christopher-Stine L, Rosen P, Rosen A, Doering K, Casciola-Rosen L (2011) Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 63:713–721 6. Mammen AL, Pak K, Williams E, Brisson D, Coresh J, Selvin E, Gaudet D (2012) Rarity of anti-3-hydroxy-3-methylglutarylcoenzyme a reductase antibodies in statin users, including those with self-limited musculoskeletal side effects. Arthritis Care Res (Hoboken) 64:269–272 7. Morikawa S, Murakami T, Yamazaki H, Izumi A, Saito Y, Hamakubo T, Kodama T (2005) Analysis of the global RNA expression profiles of skeletal muscle cells treated with statins. J Atheroscler Thromb 12:121–131 8. Lee P, Greenfield J, Campbell L (2009) Vitamin D insufficiency— a novel mechanism of statin-induced myalgia? Clin Endocrinol (Oxf.) 71:154–155
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