Absence of anti–HMG‐CoA reductase autoantibodies in severe self‐limited statin‐related myopathy

Introduction: Patients with self‐limited statin‐related myopathy improve spontaneously when statins are stopped. In contrast, patients with statin‐associated autoimmune myopathy have autoantibodies recognizing 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase (HMGCR) and usually require immunosuppressive therapy to control their disease. On initial presentation, it can sometimes be difficult to distinguish between these 2 diseases, as both present with muscle pain, weakness, and elevated serum creatine kinase (CK) levels. The goal of this study was to determine whether patients with severe self‐limited statin‐related myopathy also make anti‐HMGCR autoantibodies. Methods: We screened 101 subjects with severe self‐limited cerivastatin‐related myopathy for anti‐HMGCR autoantibodies. Results: No patient with severe self‐limited cerivastatin‐related myopathy had anti‐HMGCR autoantibodies. Conclusion: Anti‐HMGCR autoantibody testing can be used to help differentiate whether a patient has self‐limited myopathy due to cerivastatin or autoimmune statin‐associated myopathy; these findings may apply to other statins as well. Muscle Nerve 54 : 142–144, 2016     

Prognosis in AZT myopathy.

The myopathy caused by zidovudine (AZT) appears to be common but is incompletely characterized, particularly regarding prognosis. Twenty patients with HIV infection developed a necrotizing myopathy while taking AZT for 9 to 30 months. Ten presented with myalgia and 17 with proximal muscle weakness. Serum CK was elevated in all (two to 11 times normal), and EMG suggested active myopathy in all but two. There were scattered granular degenerating fibers, with scant or no inflammation, in a pattern consistent with a toxic myopathy in all 18 patients biopsied. Three patients with an HIV-related inflammatory myopathy were distinguished by histologic differences. After stopping AZT (n = 15), myalgia promptly resolved (10 of 10). Strength improved more slowly with 12 of 15 regaining normal or nearly normal strength, but three have persistent weakness. CK returned to normal in 12 of 15, and follow-up EMG (n = 11) documented reduced fibrillation density in all 11 patients. These findings underscore the need for early diagnosis of this reversible myopathy.     

Skeletal muscle cell MHC I expression: Implications for statin‐induced myopathy

Statins can induce necrotizing or inflammatory myopathies in some patients. Increased major histocompatibility complex class I (MHC I) expression has been shown in muscle biopsies of statin‐induced myopathy. Therefore, we investigated the effect of statins on the expression of MHC I in muscle cells. Using flow cytometry and polymerase chain reaction (PCR), the rhabdomyosarcoma cell line TE671 and primary cultured skeletal muscle cells (SKMC) were investigated for MHC I expression after incubation with different statins and/or interferon‐gamma (IFN‐γ). TE671 and SKMC express MHC I in the untreated condition. Statins alone reduced the expression of MHC I in SKMC and had no effect on MHC I in TE671 cells. Statins potentiated the MHC I–inducing effect of IFN‐γ in TE671, but not in SKMC, neither at the protein level nor at the mRNA level. The increased muscle MHC I expression in statin‐induced myopathy might not be induced directly by statins themselves. Muscle Nerve, 2010     

Hyaline inclusion myopathy: Unmasked by statin therapy

We report a case of a patient with history of alcohol abuse, treatment for hepatitis C and repeated strenuous physical activity who developed severe muscle pain and weakness during statin therapy. The symptoms persisted after discontinuation of the drug. The diagnosis of myopathy was made clinically and by electromyography. As his symptoms persisted a muscle biopsy was performed which showed inclusions consistent with hyaline inclusions. Hyaline inclusion myopathy is discussed in the context of this case with review of the literature. Muscle Nerve, 2009     

A case of asymptomatic cytoplasmic body myopathy revealed by sinvastatin

There are only a few reports on the effect of statins over diseased muscle and none in cytoplasmic body myopathy. This is a heterogeneous entity that can be asymptomatic until late in life and is characterized by the presence of numerous cytoplasmic bodies in muscle biopsy.A 74-years-old male received statin treatment on two separate occasions, first with sinvastatin and afterwards with rosuvastatin. In both cases, he experienced diffuse myalgia, lower limbs weakness and respiratory fatigue and improved after interruption of each treatment course. Electromyography has shown signs of muscle necrosis, serum creatine kinase (CK) concentration was increased and muscle biopsy revealed numerous cytoplasmic bodies.To our knowledge this is the first report of statin-related muscle necrosis in a patient with CBM. According to the literature neuropathological features of statin myopathy do not include the presence of cytoplasmic bodies so we assume that cytoplasmic body myopathy was asymptomatically present before statin treatment. This case supports the role of muscle biopsy in patients that develop muscular necrosis while on statin treatment.     

Camptocormia as presenting manifestation of a spectrum of myopathic disorders

Introduction: Camptocormia is the involuntary flexion of the thoracolumbar spine leading to an abnormal posture. Methods: We retrospectively identified patients with myopathy who manifested with camptocormia and were seen in our neuromuscular clinic. The diagnosis of myopathy was based on myopathic electromyographic changes, often accompanied by 1 or more of the following: elevated creatine kinase (CK); myopathic histopathological findings; and genetic confirmation. Results: Fifty‐two patients were identified; 35 had symptoms limited to camptocormia, but were found to have additional weakness of facial (8 patients), neck (11 patients), and limb muscles (17 patients). CK values were normal or mildly to moderately elevated. MRI/CT of the spine showed paraspinal muscle atrophy and fat replacement. Facioscapulohumeral muscular dystrophy and sporadic inclusion body myositis were the most commonly identified myopathies in this cohort. Conclusions: Despite the difficulty in characterizing the myopathy in patients with camptocormia, a definitive diagnosis was possible in 54% of cases. The pattern of associated extra‐axial weakness may provide clues to the diagnosis. Muscle Nerve 52 : 1008–1012, 2015     

Autoimmune myopathies: autoantibodies, phenotypes and pathogenesis

The different autoimmune myopathies-for example, dermatomyositis, polymyositis, and immune-mediated necrotizing myopathies (IMNM)-have unique muscle biopsy findings, but they also share specific clinical features, such as proximal muscle weakness and elevated serum levels of muscle enzymes. Furthermore, around 60% of patients with autoimmune myopathy have been shown to have a myositis-specific autoantibody, each of which is associated with a distinct clinical phenotype. The typical clinical presentations of the autoimmune myopathies are reviewed here, and the different myositis-specific autoantibodies, including the anti-synthetase antibodies, dermatomyositis-associated antibodies, and IMNM-associated antibodies, are discussed in detail. This Review also focuses on a newly recognized form of IMNM that is associated with statin use and the production of autoantibodies that recognize 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the pharmacological target of statins. The contribution of interferon signaling to the development of dermatomyositis and the potential link between malignancies and the initiation of autoimmune myopathies are also assessed.     

Progressive myopathy with up-regulation of MHC-I associated with statin therapy

Statins can cause a necrotizing myopathy and hyperCKaemia which is reversible on cessation of the drug. What is less well known is a phenomenon whereby statins may induce a myopathy, which persists or may progress after stopping the drug. We investigated the muscle pathology in 8 such cases. All had myofibre necrosis but only 3 had an inflammatory infiltrate. In all cases there was diffuse or multifocal up-regulation of MHC-I expression even in non-necrotic fibres. Progressive improvement occurred in 7 cases after commencement of prednisolone and methotrexate, and in one case spontaneously. These observations suggest that statins may initiate an immune-mediated myopathy that persists after withdrawal of the drug and responds to immunosuppressive therapy. The mechanism of this myopathy is uncertain but may involve the induction by statins of an endoplasmic reticulum stress response with associated up-regulation of MHC-I expression and antigen presentation by muscle fibres.     

Isolated gluteal and paravertebral muscle weakness due to anti‐3‐hydroxy‐3‐methylglutaryl‐coenzyme a reductase antibody–associated necrotizing autoimmune myopathy

Introduction: A 56‐year‐old man with a distant history of statin use presented with progressive isolated very proximal lower limb and truncal weakness. Electromyogram (EMG) showed isolated gluteal and lumbar paraspinal muscle involvement. Methods: Gluteus medius muscle biopsy was performed under general anesthesia. Results: The biopsy showed a pauci‐inflammatory necrotizing myopathy. Serum antibodies to 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) were positive. He has since partially responded to corticosteroids and methotrexate. Conclusions: Anti‐HMGCR–associated necrotizing autoimmune myopathy (NAM) can present in a restricted form after cessation of a statin. Biopsy of a symptomatic but uncommonly studied muscle is worthwhile. Muscle Nerve 54 : 150–152, 2016     

Statin-associated changes in skeletal muscle function and stress response after novel or accustomed exercise

Introduction: The most common side effect of statins, myopathy, is more likely in exercisers. We investigated the interaction of statin treatment with novel vs. accustomed exercise on muscle function, heat shock protein (Hsp) expression, and caspase activation. Methods: Mice received daily cerivastatin or saline for 2 weeks, with/without wheel running (RW) (novel/sedentary). Accustomed groups completed 2 weeks of RW before statins. At 4 weeks, plantarflexor isometric force, Hsp25, αB‐crystallin, caspase‐3 and ‐9, and plasma creatine kinase (CK) were quantified. Results: Statins reduced force in sedentary and novel groups, compared with saline, by 15% and 27%, respectively. Muscle fatigability increased 21% and 30% with statins compared with saline in sedentary and novel groups, respectively. Accustomed exercise prevented statin‐associated force loss and increased fatigability. CK did not correlate with functional outcomes. RW increased Hsp protein in all groups. Conclusion: Our results suggest that exercise prior to statin treatment can protect against decrements in muscle function. Muscle Nerve 2011     

Statin myopathy

Many different classes of medications can cause toxic myopathy. One of the most frequently implicated classes is the statins. Statin myotoxicity ranges from asymptomatic creatine kinase elevations or myalgias to muscle necrosis and fatal rhabdomyolysis. Statins may also cause an autoimmune myopathy requiring immunosuppressive treatment. The mechanisms of statin myotoxicity are unclear. If unrecognized in its early manifestations, complications from continued statin therapy may lead to rhabdomyolysis and death. Risk factors for myotoxicity include concomitant medication use and medical conditions, and the patient’s underlying genetic constitution. We review these considerations along with the recommended evaluation and treatment for patients presenting with statin myotoxicity.     

Anti-Signal Recognition Particle Myopathy in the First Decade of Life

Autoantibodies to signal recognition particle have been associated with juvenile and adult-onset necrotizing myopathy. However, only a few teenage patients with anti-signal recognition particle myopathy have been reported, and to date, to our knowledge, no patient younger than 10 years has been documented. We describe 2 Japanese girls with anti-signal recognition particle myopathy who developed symptoms from the ages of 5 and 9 years, respectively. Both patients had progressive muscle weakness and atrophy without myalgia. Facioscapulohumeral muscular dystrophy was initially suspected because of asymmetric shoulder girdle muscle involvement in one patient, and limb girdle muscular dystrophy due to proximal limb muscle weakness in the other. There were no extramuscular manifestations, including fever or arthritis. Serum creatine kinase levels were elevated to 2,467-4,629 IU/L. Results of muscle biopsy revealed necrotizing myopathy with minimal to mild endomysial fibrosis but without inflammatory infiltrates. Immunosuppressive agents were not effective for muscle weakness, resulting in marked disability. Anti-signal recognition particle myopathy can occur in the first decade of life and should be included in the differential diagnosis for children with progressive limb girdle muscle weakness and high creatine kinase levels.     

Distal inflammatory myopathy: unusual presentation of polymyositis or new entity?

New classification of idiopathic inflammatory myopathy (IIM) defined three major entities, polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body myositis (s-IBM). We report the clinical, electrophysiological and pathological characteristics of three patients with a rare form of IIM not fulfilling the diagnostic criteria for any of these three major entities. The three patients presented with a subacute, distal asymmetrical weakness in upper limbs. Muscle biopsy showed an active myositis, with necrosis and regeneration, T cell infiltrates with invasion of non-necrotic fibers, without rimmed vacuoles, and diffuse major histocompatibility complex-I (MHC-I) immunostaining in muscle fibers. All patients responded to immunosuppressive agents. Seven others cases were identified in the literature. It is important to recognize this atypical presentation as it seems to respond to immunosuppressive agents.     

Statins may aggravate myasthenia gravis

Statin-induced myopathy is well-known, but the effect of cholesterol-lowering agents on myasthenia gravis (MG) has not been studied in detail. We investigated statin use and its effects on MG among patients with this disease. Statin information was systemically obtained from 170 patients being treated at the Neuromuscular Disease Clinic at the University of Alabama at Birmingham. When a new myalgic syndrome or worsening of MG developed within 4 months after statin treatment, no other likely cause was found, and clinical improvement occurred either with or without discontinuation of the statin, we considered these symptoms to be statin-induced. Fifty-four patients (31%) were on statins. The statin group had proportionally more males, and older patients compared with the non-statin group. A myalgic syndrome was noted in 7 (13%) patients, but it resolved without any sequelae after withdrawal of the statin. MG worsening occurred in 6 (11%) patients without regard to type of MG or brand of statin. MG worsening occurred independently of myalgic syndrome and involved predominantly oculobulbar symptoms within 1-16 weeks of statin treatment. In 4 patients, additional treatment was needed to reverse MG worsening. Statins are safe in the majority of MG patients, but their use must be accompanied by close observation for possible MG worsening.     

Acute myopathy of intensive care: Clinical,electromyographic, and pathological aspects

An acute myopathy of intensive care occurs in critically ill patients treated with intravenous corticosteroids and neuromuscular junction-blocking agents. The full clinicopathological spectrum is uncertain. We evaluated the clinical, electrodiagnostic, and histopathological features of 14 patients who developed acute myopathy of intensive care after organ transplantation or during treatment of severe pulmonary disorders and sepsis. Patients received high-dose intravenous corticosteroids, usually in conjunction with relatively low to moderate doses of neuromuscular junction-blocking agents. After discontinuation of the latter drugs, most had diffuse, flaccid weakness with failure to wean frommechanical ventilation. Electrodiagnostic findings were consistent with a necrotizing myopathy. Muscle histopathology revealed myopathy with loss of thick filaments in 79%, mild myopathic changes in 14%, and atrophy of type 1 and type 2 fibers in 7%. Loss of thick filaments was identified in muscle biopsy specimens obtained 30 ± 11 days (mean ± standard deviation) after intravenous corticosteroid treatment but not in those obtained earlier (12 ± 2 days). Critically ill patients, including those receiving organ transplants, may develop acute myopathy of intensive care after exposure to intravenous corticosteroids and neuromuscular junction-blocking agents, although the exposure to the latter drugs may be minimal. Selective loss of thick filaments is common in acute myopathy of intensive care, especially if the muscle biopsy specimen is obtained 2 weeks or more after intravenous corticosteroid exposure.     

Clinical correlates of granulomas in muscle

We evaluated the clinical and myopathological features of all patients with granulomas in muscle biopsy specimens identified over a 5-year period (1992–1996) at the Washington University Medical Center. Ten patients were found to have granulomas in their muscle biopsy specimens. Of these, eight patients had myopathic changes. Seven had dysphagia as a major functional difficulty during the course of their disease. None had elevated levels of serum creatine kinase (CK). Four of the patients with myopathy had systemic sarcoidosis and relatively severe proximal weakness with functional disability. Treatment with corticosteroids was followed by marked improvement in strength and functional disability. The four other patients with myopathy had no systemic signs of sarcoidosis. Weakness was especially prominent distally in three of these patients. The two patients in this group treated with corticosteroids did not improve. The final two patients, who had granulomas in muscle but no myopathic changes, had clinical syndromes of mononeuritis multiplex and eosinophilic fasciitis (Shulman syndrome). We conclude that granulomatous myopathy, in the presence or absence of systemic sarcoidosis, is commonly associated with dysphagia (87%) and a normal serum CK. Clinical features in patients with sarcoidosis included severe proximal weakness with functional disability that often responded to corticosteroid treatment. Granulomatous myopathy without systemic sarcoidosis was associated with milder, but more predominantly distal weakness. Received: 10 August 1997 Received in revised form: 13 January 1998 Accepted: 27 January 1998     

Dermatomyositis-like syndrome and HMG-CoA reductase inhibitor (statin) intake

A patient developed an adult-onset dermatomyositis-like syndrome characterized by skin rash and progressive proximal muscle weakness concurrent with the intake of simvastatin. Despite discontinuation of the statin, symptoms progressed and required conventional steroid therapy for remission. The association between statins and the development of a musculocutaneous syndrome closely resembling dermatomyositis in susceptible subjects is poorly understood and has been reported rarely. The purpose of this report is to provide additional support for this pathological association. Since the population receiving statins is large and rapidly growing, caregivers are urged to be alert regarding the early recognition and proper care of the spectrum of neuromuscular complications linked to statin intake.     

Evaluation of skeletal muscle during calf exercise by 31-phosphorus magnetic resonance spectroscopy in patients on statin medications

Muscle pain is a common side effect of statin medications, but the cause is poorly understood. We characterized phosphocreatine (PCr) exercise recovery kinetics in 10 patients with hypercholesterolemia before and after a 4-week regimen of statin therapy using 31-phosphorus magnetic resonance spectroscopy ((31) P-MRS). (31) P spectra were obtained before, during, and after exercise on a calf flexion pedal ergometer. Creatine kinase (CK) serum levels were drawn before and after statin therapy. The mean metabolic recovery time constant in subjects increased from 28.1 s (SE = 6.5 s) to 55.4 s (SE = 7.4 s) after statin therapy. The unweighted mean of the pre/post-recovery time difference was -27.3 s (SE = 12.4 s; P = 0.02). Pre- and post-therapy CK levels were not significantly different (P = 0.50). Metabolic recovery time in the calf is prolonged in patients after statin use. This suggests that statins impair mitochondrial oxidative function, and (31) P MRS is a potential study model for statin-associated myopathy.