http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(2): 366–371 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.852848
CASE REPORT
Inflammatory myopathy associated with statins: report of three cases Klara Kuncova1, Marie Sedlackova2, Jiri Vencovsky3, Herman Mann3, Michal Tomcik3, Laszlo Wenchich4, and Josef Zamecnik1 1Department of Pathology and Molecular Medicine, Second Medical Faculty and University Hospital Motol, Charles University, Prague 5, Czech Republic,
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2Department of Rheumatology and Rehabilitation, Thomayer Hospital, Videnska 800, Prague 4, Czech Republic, 3Institute of Rheumatology,
Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Na Slupi 450/4, Prague 2, Czech Republic, 4Department of Pediatrics, First Faculty of Medicine, Charles University, Ke Karlovu 2, Prague 2, Czech Republic Abstract
Keywords
Statins are well-established lipid-lowering drugs that reduce morbidity and mortality due to cardiovascular disease and cause adverse effects relatively rarely. It is still unclear whether statins are capable of inducing an immune-mediated response directed against skeletal muscle. Here, we present the cases of three patients who developed inflammatory myopathy in the course of statin treatment. Moreover, multiple mitochondrial DNA deletions were found in two of them. The ability of statins to induce an immune-mediated response and their interactions with mitochondrial metabolism pathways are discussed.
Drug-induced myopathy, Muscle biopsy, Inflammatory myopathy, Statins History Received 5 June 2012 Accepted 25 September 2012 Published online 17 October 2012
Introduction
Materials and methods
Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are first-line lipid-lowering drugs that are used extensively in medical practice, since statin therapy has been repeatedly proven to reduce morbidity and mortality due to cardiovascular diseases [1, 2]. As they are structural analogs of HMGCoA, statins lead to a decrease in the synthesis of cholesterol and other metabolic intermediates in the cholesterol synthetic pathway [3]. Although their key role in atherogenesis is well established [2], cholesterol and its metabolic intermediates are involved in many physiological functions in the human body, and statin-induced changes in these pathways could be responsible for some of the adverse effects of statin therapy [4]. The most severe are related to skeletal muscle, and range from myalgias without creatine kinase elevations or asymptomatic creatine kinase elevations to myofiber necrosis, with incidence rates of 1–5 % [4–6]. The most severe adverse effect, rhabdomyolysis, is believed to be rare, with an incidence of ⬍0.02 % [4–6]. Several observations suggesting that myositis can develop in the course of statin therapy have also been described recently [7–16]. New autoantibodies against 200/100 kDa proteins have recently been found in patients with immune-mediated necrotizing myopathy, and 63 % of these patients had been exposed to statin treatment prior to the onset of muscle weakness [17]. The target antigen of these antibodies was identified as the intracellular catalytic domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Herein, as support for the hypothesis of a possible link between statin exposure and autoimmune-mediated myopathy [18], we report the cases of three patients who developed biopsy-proven inflammatory myopathy in the course of statin treatment.
Three patients presented with proximal muscle weakness as well as creatine kinase and myoglobin elevations whilst on chronic statin therapy. These symptoms did not subside after statin therapy discontinuation, and a diagnosis of inflammatory myopathy with the features of polymyositis was established by muscle biopsy. Clinical examination The patients’ clinical histories were recorded with respect to the duration of myopathic symptoms and their association with statin therapy. After clinical examination, which objectified proximal muscle weakness, routine clinical biochemistry laboratory blood assays including C reactive protein (CRP), creatine kinase (CK), and myoglobin were performed. Thyroid gland disorders were excluded by appropriate biochemistry assays in each case. Specific autoantibodies were searched for in plasma via enzyme-linked immunosorbent assay and western blot [19]. Antibodies against aminoacyl tRNA synthetases (anti-Jo-1, anti PL-7, anti PL-12) and transcription-regulating protein Mi-2, antinuclear anti-Ku and anti-PM/Scl antibodies, anti-U3 small nuclear ribonucleoprotein (snRNP) antibody, and autoantibodies against 200/100 kDa proteins were searched for in order to subclassify the patients serologically. The results were presented in a dichotomous pattern as positive or negative. Common malignancies were ruled out by appropriate clinical tests. Electromyography was performed in each case, and it demonstrated myogenic changes. To identify the optimal localization for the muscle biopsy, the patients underwent magnetic resonance imagining (MRI) of the thighs. After the diagnosis was established, the patients’ follow-up data were recorded. Muscle biopsy
Correspondence to: Josef Zamecnik, Department of Pathology and Molecular Medicine, Second Medical Faculty and University Hospital Motol, Charles University, V Uvalu 84, 150 06, Prague 5, Czech Republic. Tel: +420-224-
435635. Fax: +420-224-435620. E-mail: [email protected]
A sample from the quadriceps muscle was obtained from each patient. Muscle tissues were snap frozen in isopentane (2-ethylbutane, Sigma–Aldrich, St. Louis, MO, USA) cooled in
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liquid nitrogen. Cryosections were examined by routine hematoxylin–eosin (H&E) staining and a conventional spectrum of histochemical reactions, including myofibrillary ATPase, nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR), succinate dehydrogenase (SDH), and cytochrome C oxidase (COX). Immunohistochemistry was employed according to standard protocols to phenotype lymphocytes using antibodies against the antigens CD20, CD3, CD8, and CD4, and to examine the expression of sarcolemmal proteins associated with myodystrophies, including dystrophin, sarcoglycans, merosin, emerin, and dysferlin (described in detail elsewhere [20]). Expression of HLA-I antigens as well as that of the membrane attack complex (MAC, C5b-9) of complement, which were shown to be helpful in the diagnosis of myositis [21], were also examined immunohistochemically. Paraformaldehyde-fixed tissue was used for electron microscopic analysis. In each case, semithin sections stained by toluidine blue were evaluated by light microscope, and the consequent ultrathin sections were examined by electron microscope. Diagnosis of polymyositis was based on Bohan and Peter’s criteria [22, 23]. HLA-I (human leukocyte antigen I/class I major histocompatibility complex) immunohistochemistry revealed strong diffuse muscle fiber sarcolemmal staining. Depositions of MAC were not detected in capillary walls but on the surfaces of the degenerating myofibers. Mitochondrial DNA analysis Molecular-genetic analysis of mitochondrial DNA (mtDNA) was performed in two of our cases where mitochondrial metabolism disorder was suspected due to the findings from enzyme histochemistry (SDH, COX). Total genomic DNA was isolated from muscle biopsies using a QIAmp DNA MiniKit (Qiagen) according to the
manufacturer’s protocol. The mitochondrial DNA point mutations 3243A⬎G, 3271T⬎C, and 8344A⬎G were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP), as described in detail elsewhere [24]. To screen for large-scale mtDNA deletions, a 16,267 bp-long fragment of mtDNA corresponding to the wild-type mtDNA (wt-mtDNA) molecule was amplified using Takara LA Taq DNA polymerase (Takara Shuzo Corp., Kyoto, Japan) and the primers F1482-1516 and R1180-1146. PCR products were separated by 1 % agarose gel electrophoresis in 1⫻ TBE buffer.
Report of three cases Case 1 A 72-year-old woman with hypercholesterolemia, treated by atorvastatin 40 mg per day for 30 months, presented with general malaise, photosensitivity, Raynaud’s phenomenon, proximal muscle weakness in the lower extremities, and exertional dyspnea with an obvious progression during the previous 4 months. Statin therapy was discontinued due to elevation of CK and myoglobin, but the proximal muscle weakness progressed after discontinuation of the therapy and the patient was readmitted one month later. Results of biochemistry laboratory blood assays, electromyography, and muscle biopsy are summarized in Table 1. Myopathic changes with focal muscle fiber necrosis and regeneration and lymphocytic inflammatory infiltrate in the endomysium (consisting of CD8+ T lymphocytes and macrophages) surrounding non-necrotic muscle fibers was detected in the muscle biopsy (Fig. 1). Moreover, autoaggressive invasion of lymphocytes into the non-necrotic muscle fibers was seldom found. Autoantibodies against 200/100 kDa proteins were not detected. Spirometry disclosed a slight reduction in forced lung capacity to 2.42 l (89 %); the diffusing capacity of the lung for carbon monoxide was decreased to 68 %. A diagnosis of polymyositis was established by muscle biopsy. Aside from
Table 1. Results of biochemistry laboratory blood assays, electromyography, and muscle biopsy Case number Clinical/history information Age (years) Sex Lipid lowering drug formula and dose per day (duration of treatment in months)
1
2
3
72 Female Atorvastatin 40 mg (30)
58 Male Simvastatin 20 mg (36)
73 Female Simvastatin 20 mg (36), atorvastatin 20 mg (24), fenofibrate 200 mg (12), combined atorvastatin 20 mg and fenofibrate 200 mg (1)
Proximal muscle weakness
Proximal muscle weakness
Severe proximal muscle weakness
Muscle fiber fibrillation, presence of sharp positive waves
Muscle fiber fibrillation, small motor unit potentials
Muscle fiber fibrillation, increased insertional activity
1.9 75.00 2591.00
38.17 211.00 Over 1000.00
3.77 107.00 Over 2000.00
Neurological status upon admission Electromyography
Biochemical analysis CRP (normal ⬍8 mg/l) Creatine kinase (normal 0.50–2.40 μkat/l) Myoglobin (normal 25.00–58.00 μg/l) Muscle biopsy Hematoxylin eosin stain Immunohistochemistry Enzyme histochemistry
Immunology Detected autoantibodies
Muscle fiber necrosis and regeneration, intense lymphocytic inflammatory infiltrate in the endomysium, seldomly with autoaggressive invasion into the non-necrotic muscle fibers Inflammatory infiltrate consisting predominantly of CD8-positive lymphocytes, diffuse HLA-I expression on muscle fiber surface No abnormalities in histochemical Focal subsarcolemmal Focal subsarcolemmal examination detected accumulation of SDH accumulation of SDH reaction product, up to 2 reaction product, one % COX-negative muscle COX-negative muscle fiber fibers detected detected Anti-nuclear, anti-Mi-2
Anti-Jo-1, anti-Ro52, anti-Ro60
`COX cytochrome C oxidase, CRP C-reactive protein, SDH succinate dehydrogenase
None detected
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Fig 1. Inflammatory myopathy occurring during statin therapy in case 1. Endomysial lymphocytic inflammatory infiltrate is accompanied by myopathic changes with focal muscle fiber necrosis and regeneration. Hematoxylin and eosin stain, ⫻200. Inset: CD8-positive lymphocytes surrounding nonnecrotic muscle fibers (asterisks) (immunoperoxidase method, counterstained slightly with hematoxylin, ⫻200)
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Fig 2. Inflammatory myopathy occurring during statin therapy in case 2. Endomysial lymphocytic inflammatory infiltrate is accompanied by myopathic changes with focal muscle fiber necrosis and regeneration. Hematoxylin and eosin stain, ⫻200. Inset: CD8-positive lymphocytes surrounding nonnecrotic muscle fibers (asterisk) (immunoperoxidase method, counterstained slightly with hematoxylin, ⫻200)
changes consistent with the diagnosis of polymyositis, focal subsarcolemmal accumulation of SDH reaction product was detected, as was one COX-negative muscle fiber in the sample. Subsequent mitochondrial DNA analysis revealed multiple mtDNA deletions. The patient was started on prednisone 60 mg per day and methotrexate 10 mg per week. She improved significantly during the next 3 months, both clinically and in laboratory findings, and a stepwise withdrawal of the immunosuppressive therapy was performed. At present, 7 months after the diagnosis, the patient is being treated with 20 mg prednisone per day and has not shown any clinical or laboratory signs of relapsing disease. Case 2 A 58-year-old man with hypercholesterolemia, treated with 20 mg of simvastatin per day for 3 years, was admitted with a two-month history of symmetric small joint pain associated with stiffness, low-grade fever, general malaise, exertional muscle pain, and progressive proximal muscle weakness. High-resolution computed tomography revealed interstitial lung fibrosis in the lower pulmonary lobes bilaterally. Statin therapy was discontinued and the patient was started on prednisone 60 mg per day. His joint pain improved, but the muscle weakness persisted and muscle biopsy was performed. Muscle biopsy revealed a similar histopathological pattern of changes to that described for case 1, and a diagnosis of polymyositis was established (Fig. 2). Moreover, focal subsarcolemmal accumulation of SDH reaction product and up to 2 % COX-negative muscle fibers were detected (Fig. 3). As in case 1, subsequent mitochondrial DNA analysis revealed multiple mtDNA deletions (Fig. 4). Autoantibodies against 200/100 kDa proteins were not detected. The patient continued with prednisone 50 mg per day and 100 mg azathioprine daily. Both clinical improvement and laboratory improvement were achieved after 3 months of treatment. However, because of persistent hypercholesterolemia, the patient was started on 200 mg fenofibrate per day 3 months later. After 2 months of fenofibrate administration, the patient’s muscle enzymes had again increased to levels up to five times the upper limit of normal, and his lipid-lowering therapy had to be discontinued. Although the patient continues to require immunosuppressive therapy consisting of prednisone 20 mg and azathioprine 150 mg daily 10 months after the diagnosis, his muscle strength has almost
Fig 3. Changes in mitochondrial metabolism identified in case 2 by enzyme histochemistry: COX (cytochrome C oxidase)-negative myofibers (asterisks). Magnification ⫻200
returned to normal. However, exertional dyspnea persists, with a severely limited carbon monoxide diffusing capacity and slight progression of lung interstitial fibrosis observed on the computed tomography scan. Case 3 A 73-year-old woman with hypercholesterolemia, hypertension, and hypothyroidism had been treated with lipid-lowering drugs for 6 years. Due to stepwise development of moderate muscle weakness, her lipid-lowering formula was changed repeatedly (see Table 1). Additional medication included levothyroxine 50 μg per day, acidum acetylsalicylicum 100 mg per day, furosemide 40 mg per day, spironolactone 25 mg per day, metoprolol tartrate 100 mg, and citalopram 10 mg per day. After myocardial infarction, combined atorvastatin 20 mg and fenofibrate 200 mg per day therapy was started. After one month of this therapy, the patient was admitted due to severe proximal muscle weakness. A diagnosis of polymyositis was established by muscle biopsy (Fig. 5). Autoantibodies
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32.5 mg per day and 20 mg methotrexate weekly, with a continuous but slow improvement in muscle strength.
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Discussion
Fig. 4 Ethidium bromide-stained gel of the products amplified by longrange PCR of the mtDNA region m.3485–m.14786 in skeletal muscle DNA. The 11335 bp long PCR product corresponds to wt-mtDNA. The smaller bands represent PCR products that were amplified from mtDNA molecules with a certain deletion length. In the DNA sample from patient 2, the PCR product of wt-mtDNA was very faint, and several shorter PCR products proved that there were multiple deletions in the mtDNA. M DNA molecular-weight standard; kb kilobase; C-negative negative control containing only wild-type mtDNA; C-positive positive control containing both deleted and wild-type mtDNA
against 200/100 kDa proteins were not detected. The patient was started on prednisone 60 mg per day and methotrexate 20 mg per week. The elevated muscle enzymes normalized after 2 months of therapy, whereas clinical improvement was languid—her muscle strength improved slightly and the patient began to be able to walk after 3 months of therapy. At the last follow-up control (5 months after the diagnosis), she was still on prednisone
Fig 5. Inflammatory myopathy occurring during statin therapy in case 3. Endomysial lymphocytic inflammatory infiltrate is accompanied by myopathic changes with focal muscle fiber necrosis and regeneration. Hematoxylin eosin stain, ⫻400. Inset: CD8-positive lymphocytes surrounding non-necrotic muscle fibers (asterisk) (immunoperoxidase method, counterstained slightly with hematoxylin, ⫻400)
Establishing a diagnosis of drug-induced myopathy remains difficult, especially in patients with comorbidities receiving multiple medications. Drug-induced myopathy has been recently defined by Dalakas as a subacute manifestation of myopathic symptoms that occur in patients without muscle disease when exposed to therapeutic doses of certain drugs [25]. The improvement of myopathic symptoms after drug discontinuation may aid diagnosis [26]. On the other hand, myopathic symptoms may continue even after therapy cessation [25], as seen in our cases. Although a causative link between statin therapy and the development of polymyositis cannot be proven directly, we suppose that statins played at least a contributory role in disease development in our cases. This hypothesis is based on the temporal sequences and interrelationships among the patients’ pharmacological histories, the development of inflammatory myopathy and the regression in myopathic symptoms after immunosuppressive therapy. The proposed link between inflammatory myopathy and statin therapy is most obvious in the third patient, who (in contrast to the first two patients) had no myositis-specific autoantibodies. Moreover, the recurrence of myopathy after the reinsertion of lipid-lowering therapy in that case is strongly suggestive of possible drug-induced myopathy. Indeed, the temporal sequence and clinical course is not typical of the development of idiopathic polymyositis, even in the other two cases, again providing a certain degree of evidence for the hypothesized interrelationship: the myopathic symptoms of the second patient worsened stepwise during the lipid-lowering therapy, which lasted 6 years, and aggravated markedly during the final 3 weeks of the combined atorvastatin–fenofibrate treatment. Autoimmune-mediated inflammatory myopathies have been associated with therapies involving cimetidine, penicillamine, L-tryptophan, interferon-α, and proton pump inhibitor administration [26–28]. Apart from dermatomyositis and polymyositis, cases of lupus-like syndrome [29], pneumonitis, polymyalgia rheumatica [30], segmental necrotizing glomerulonephritis and Churg–Strauss disease [31] have been reported in association with statin therapy. Five cases of dermatomyositis associated with statin therapy (three males and two females, age range 44–76 years) were described previously [9, 11, 13, 14, 16]; the symptoms appeared from 2 months to 2 years after introducing statins, and two of the patients required immunosuppressive therapy. Seven cases of polymyositis associated with statin therapy (four males and three females aged from 42 to 78) were also reported [7, 8, 10, 32]. The symptoms first appeared from 2 weeks to 2 years after beginning the therapy and, in agreement with our cases, all of the patients required immunosuppressive treatment. Anti-Jo-1 antibody—also observed in one of our cases—was detected in three of them [10, 15]. Several studies have been published on statins as immunomodulators [32–36]. In these studies, statins were proven to act as immunosuppressive agents. In contrast, there are few recent publications that describe statins as agents capable of inducing autoimmune disorder. Grable-Esposito et al. [37] presented 25 patients who developed autoimmune necrotizing myopathy during statin therapy. In nine of the patients, who discontinued statin therapy due to asymptomatic creatine kinase elevation, the onset of muscle weakness occurred 0.5–20 months after statin therapy cessation. Although inflammatory infiltrate was not detected in muscle biopsies, all of the patients required immunosuppressive therapy. Christopher-Stine et al. [17] described 26 cases of patients with predominant necrotizing myopathy. A novel autoantibody recognizing 200 and 100 kDa proteins was detected in 16 of them, and 63 % of these patients had been exposed to statin therapy before
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the diagnosis. In the muscle biopsies, they observed diffuse HLA-I overexpression on the surfaces of muscle fibers in four of eight patients. This diffuse HLA-I overexpression was detected in the muscle biopsies for all of our patients as well, but an autoantibody recognizing 200 and 100 kDa proteins was not detected in our cases. As in the study of Grable-Esposito et al. [37], the majority of the patients responded insufficiently to immunosuppressive treatment, thus requiring combination immunosuppressive therapy, and they experienced a relapse of weakness upon tapering the immunosuppressive medications. Mammen et al. [18] recently identified the 100 kd protein as 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGCR), and described 45 anti-HMGCR-positive patients, 30 of whom had prior statin exposure. 95.6 % of these patients suffered from proximal muscle weakness. Forty of them underwent muscle biopsy, which highlighted prominent degenerating and regenerating muscle fibers in all cases, with significant inflammatory infiltrate being found in eight of them. Moreover, Mammen et al. [18] found that HMGCR was upregulated in the regenerating muscle fibers. This may offer an explanation for the persistent necrotizing myopathy even after statin discontinuation in patients with antiHMGCR antibody. Needham et al. [32] described eight cases of statin-treated patients with myopathy that did not resolve after statin therapy cessation, thus requiring immunosuppressive treatment in seven of them. Necrotic and regenerating muscle fibers were found in all of the muscle biopsies performed, whereas endomysial inflammatory infiltrate was found in only three of them. However, HLA-I overexpression on the surfaces of muscle fibers was described in all cases. Needham et al. [32] suggested that HLA-I overexpression is affected by statin therapy through the induction of the endoplasmic reticulum stress response. This is in agreement with the findings of Nagaraju et al. [38], who supposed that muscle fiber death in myositis could be induced by not only immune attack (caused by cytotoxic T lymphocytes or autoantibodies) but also the endoplasmic reticulum stress response, which leads to intracellular homeostasis disturbance. The endoplasmic reticulum stress response leads to cell death via apoptosis and autophagy, with the latter becoming even more important recently [39]. Aside from the inflammatory changes, significant alteration to mitochondrial metabolism was observed in two of our patients. Mitochondrial mutations that accumulate with age are known to cause alterations in mitochondrial energy metabolism in aging persons [40], which may offer an explanation for one of our observations: that the first patient affected was 72 years old at the time of diagnosis. However, the second patient with evidence of mitochondrial metabolism alteration was 58 years old. In our opinion, a combination of inflammatory myopathy in a patient on a chronic statin therapy and signs of mitochondrial metabolism disorder in a muscle biopsy from that patient should lead to consideration that the statin therapy has contributed to disease development [25, 41, 42]. Evidence of mitochondrial dysfunction in muscle biopsies of patients on statin therapy was described previously for six patients [43, 44]. The age distribution in that report was similar to the age distribution for our cases (range 62–76, median 64.5). Concerning the possible pathogenesis of the impact of MHG-CoA reductase inhibitors on mitochondrial metabolism, mevalonate (one of the metabolic intermediates in the cholesterol synthetic pathway) is a precursor in the synthesis of ubiquinone (coenzyme Q10); a lack of mevalonate may therefore interfere with oxidative phosphorylation pathways. Moreover, plasma coenzyme Q10 is transported with lipoproteins, so coenzyme Q10 levels may be reduced by reducing low-density lipoprotein levels too. Cytochrome Q10 supplementation therapy in patients with statininduced myopathies has been tested with encouraging results [41, 42]. In conclusion, adverse effects of statin therapy are relatively rare, and the majority of them subside after statin therapy discon-
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tinuation. On the other hand, very occasionally, a patient may suffer from autoimmune myopathy during statin treatment, requiring prompt immunosuppressive therapy based on correct diagnosis, which can be established by a muscle biopsy.
Acknowledgments Supported by the Ministry of Health of the Czech Republic project for the conceptual development of research organization 00064203 (University Hospital Motol, Prague, Czech Republic).
Conflict of interest None.
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CASE REPORT
Inflammatory myopathy associated with statins: report of three cases Klara Kuncova1, Marie Sedlackova2, Jiri Vencovsky3, Herman Mann3, Michal Tomcik3, Laszlo Wenchich4, and Josef Zamecnik1 1Department of Pathology and Molecular Medicine, Second Medical Faculty and University Hospital Motol, Charles University, Prague 5, Czech Republic,
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2Department of Rheumatology and Rehabilitation, Thomayer Hospital, Videnska 800, Prague 4, Czech Republic, 3Institute of Rheumatology,
Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Na Slupi 450/4, Prague 2, Czech Republic, 4Department of Pediatrics, First Faculty of Medicine, Charles University, Ke Karlovu 2, Prague 2, Czech Republic Abstract
Keywords
Statins are well-established lipid-lowering drugs that reduce morbidity and mortality due to cardiovascular disease and cause adverse effects relatively rarely. It is still unclear whether statins are capable of inducing an immune-mediated response directed against skeletal muscle. Here, we present the cases of three patients who developed inflammatory myopathy in the course of statin treatment. Moreover, multiple mitochondrial DNA deletions were found in two of them. The ability of statins to induce an immune-mediated response and their interactions with mitochondrial metabolism pathways are discussed.
Drug-induced myopathy, Muscle biopsy, Inflammatory myopathy, Statins History Received 5 June 2012 Accepted 25 September 2012 Published online 17 October 2012
Introduction
Materials and methods
Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are first-line lipid-lowering drugs that are used extensively in medical practice, since statin therapy has been repeatedly proven to reduce morbidity and mortality due to cardiovascular diseases [1, 2]. As they are structural analogs of HMGCoA, statins lead to a decrease in the synthesis of cholesterol and other metabolic intermediates in the cholesterol synthetic pathway [3]. Although their key role in atherogenesis is well established [2], cholesterol and its metabolic intermediates are involved in many physiological functions in the human body, and statin-induced changes in these pathways could be responsible for some of the adverse effects of statin therapy [4]. The most severe are related to skeletal muscle, and range from myalgias without creatine kinase elevations or asymptomatic creatine kinase elevations to myofiber necrosis, with incidence rates of 1–5 % [4–6]. The most severe adverse effect, rhabdomyolysis, is believed to be rare, with an incidence of ⬍0.02 % [4–6]. Several observations suggesting that myositis can develop in the course of statin therapy have also been described recently [7–16]. New autoantibodies against 200/100 kDa proteins have recently been found in patients with immune-mediated necrotizing myopathy, and 63 % of these patients had been exposed to statin treatment prior to the onset of muscle weakness [17]. The target antigen of these antibodies was identified as the intracellular catalytic domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Herein, as support for the hypothesis of a possible link between statin exposure and autoimmune-mediated myopathy [18], we report the cases of three patients who developed biopsy-proven inflammatory myopathy in the course of statin treatment.
Three patients presented with proximal muscle weakness as well as creatine kinase and myoglobin elevations whilst on chronic statin therapy. These symptoms did not subside after statin therapy discontinuation, and a diagnosis of inflammatory myopathy with the features of polymyositis was established by muscle biopsy. Clinical examination The patients’ clinical histories were recorded with respect to the duration of myopathic symptoms and their association with statin therapy. After clinical examination, which objectified proximal muscle weakness, routine clinical biochemistry laboratory blood assays including C reactive protein (CRP), creatine kinase (CK), and myoglobin were performed. Thyroid gland disorders were excluded by appropriate biochemistry assays in each case. Specific autoantibodies were searched for in plasma via enzyme-linked immunosorbent assay and western blot [19]. Antibodies against aminoacyl tRNA synthetases (anti-Jo-1, anti PL-7, anti PL-12) and transcription-regulating protein Mi-2, antinuclear anti-Ku and anti-PM/Scl antibodies, anti-U3 small nuclear ribonucleoprotein (snRNP) antibody, and autoantibodies against 200/100 kDa proteins were searched for in order to subclassify the patients serologically. The results were presented in a dichotomous pattern as positive or negative. Common malignancies were ruled out by appropriate clinical tests. Electromyography was performed in each case, and it demonstrated myogenic changes. To identify the optimal localization for the muscle biopsy, the patients underwent magnetic resonance imagining (MRI) of the thighs. After the diagnosis was established, the patients’ follow-up data were recorded. Muscle biopsy
Correspondence to: Josef Zamecnik, Department of Pathology and Molecular Medicine, Second Medical Faculty and University Hospital Motol, Charles University, V Uvalu 84, 150 06, Prague 5, Czech Republic. Tel: +420-224-
435635. Fax: +420-224-435620. E-mail: [email protected]
A sample from the quadriceps muscle was obtained from each patient. Muscle tissues were snap frozen in isopentane (2-ethylbutane, Sigma–Aldrich, St. Louis, MO, USA) cooled in
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liquid nitrogen. Cryosections were examined by routine hematoxylin–eosin (H&E) staining and a conventional spectrum of histochemical reactions, including myofibrillary ATPase, nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR), succinate dehydrogenase (SDH), and cytochrome C oxidase (COX). Immunohistochemistry was employed according to standard protocols to phenotype lymphocytes using antibodies against the antigens CD20, CD3, CD8, and CD4, and to examine the expression of sarcolemmal proteins associated with myodystrophies, including dystrophin, sarcoglycans, merosin, emerin, and dysferlin (described in detail elsewhere [20]). Expression of HLA-I antigens as well as that of the membrane attack complex (MAC, C5b-9) of complement, which were shown to be helpful in the diagnosis of myositis [21], were also examined immunohistochemically. Paraformaldehyde-fixed tissue was used for electron microscopic analysis. In each case, semithin sections stained by toluidine blue were evaluated by light microscope, and the consequent ultrathin sections were examined by electron microscope. Diagnosis of polymyositis was based on Bohan and Peter’s criteria [22, 23]. HLA-I (human leukocyte antigen I/class I major histocompatibility complex) immunohistochemistry revealed strong diffuse muscle fiber sarcolemmal staining. Depositions of MAC were not detected in capillary walls but on the surfaces of the degenerating myofibers. Mitochondrial DNA analysis Molecular-genetic analysis of mitochondrial DNA (mtDNA) was performed in two of our cases where mitochondrial metabolism disorder was suspected due to the findings from enzyme histochemistry (SDH, COX). Total genomic DNA was isolated from muscle biopsies using a QIAmp DNA MiniKit (Qiagen) according to the
manufacturer’s protocol. The mitochondrial DNA point mutations 3243A⬎G, 3271T⬎C, and 8344A⬎G were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP), as described in detail elsewhere [24]. To screen for large-scale mtDNA deletions, a 16,267 bp-long fragment of mtDNA corresponding to the wild-type mtDNA (wt-mtDNA) molecule was amplified using Takara LA Taq DNA polymerase (Takara Shuzo Corp., Kyoto, Japan) and the primers F1482-1516 and R1180-1146. PCR products were separated by 1 % agarose gel electrophoresis in 1⫻ TBE buffer.
Report of three cases Case 1 A 72-year-old woman with hypercholesterolemia, treated by atorvastatin 40 mg per day for 30 months, presented with general malaise, photosensitivity, Raynaud’s phenomenon, proximal muscle weakness in the lower extremities, and exertional dyspnea with an obvious progression during the previous 4 months. Statin therapy was discontinued due to elevation of CK and myoglobin, but the proximal muscle weakness progressed after discontinuation of the therapy and the patient was readmitted one month later. Results of biochemistry laboratory blood assays, electromyography, and muscle biopsy are summarized in Table 1. Myopathic changes with focal muscle fiber necrosis and regeneration and lymphocytic inflammatory infiltrate in the endomysium (consisting of CD8+ T lymphocytes and macrophages) surrounding non-necrotic muscle fibers was detected in the muscle biopsy (Fig. 1). Moreover, autoaggressive invasion of lymphocytes into the non-necrotic muscle fibers was seldom found. Autoantibodies against 200/100 kDa proteins were not detected. Spirometry disclosed a slight reduction in forced lung capacity to 2.42 l (89 %); the diffusing capacity of the lung for carbon monoxide was decreased to 68 %. A diagnosis of polymyositis was established by muscle biopsy. Aside from
Table 1. Results of biochemistry laboratory blood assays, electromyography, and muscle biopsy Case number Clinical/history information Age (years) Sex Lipid lowering drug formula and dose per day (duration of treatment in months)
1
2
3
72 Female Atorvastatin 40 mg (30)
58 Male Simvastatin 20 mg (36)
73 Female Simvastatin 20 mg (36), atorvastatin 20 mg (24), fenofibrate 200 mg (12), combined atorvastatin 20 mg and fenofibrate 200 mg (1)
Proximal muscle weakness
Proximal muscle weakness
Severe proximal muscle weakness
Muscle fiber fibrillation, presence of sharp positive waves
Muscle fiber fibrillation, small motor unit potentials
Muscle fiber fibrillation, increased insertional activity
1.9 75.00 2591.00
38.17 211.00 Over 1000.00
3.77 107.00 Over 2000.00
Neurological status upon admission Electromyography
Biochemical analysis CRP (normal ⬍8 mg/l) Creatine kinase (normal 0.50–2.40 μkat/l) Myoglobin (normal 25.00–58.00 μg/l) Muscle biopsy Hematoxylin eosin stain Immunohistochemistry Enzyme histochemistry
Immunology Detected autoantibodies
Muscle fiber necrosis and regeneration, intense lymphocytic inflammatory infiltrate in the endomysium, seldomly with autoaggressive invasion into the non-necrotic muscle fibers Inflammatory infiltrate consisting predominantly of CD8-positive lymphocytes, diffuse HLA-I expression on muscle fiber surface No abnormalities in histochemical Focal subsarcolemmal Focal subsarcolemmal examination detected accumulation of SDH accumulation of SDH reaction product, up to 2 reaction product, one % COX-negative muscle COX-negative muscle fiber fibers detected detected Anti-nuclear, anti-Mi-2
Anti-Jo-1, anti-Ro52, anti-Ro60
`COX cytochrome C oxidase, CRP C-reactive protein, SDH succinate dehydrogenase
None detected
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Fig 1. Inflammatory myopathy occurring during statin therapy in case 1. Endomysial lymphocytic inflammatory infiltrate is accompanied by myopathic changes with focal muscle fiber necrosis and regeneration. Hematoxylin and eosin stain, ⫻200. Inset: CD8-positive lymphocytes surrounding nonnecrotic muscle fibers (asterisks) (immunoperoxidase method, counterstained slightly with hematoxylin, ⫻200)
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Fig 2. Inflammatory myopathy occurring during statin therapy in case 2. Endomysial lymphocytic inflammatory infiltrate is accompanied by myopathic changes with focal muscle fiber necrosis and regeneration. Hematoxylin and eosin stain, ⫻200. Inset: CD8-positive lymphocytes surrounding nonnecrotic muscle fibers (asterisk) (immunoperoxidase method, counterstained slightly with hematoxylin, ⫻200)
changes consistent with the diagnosis of polymyositis, focal subsarcolemmal accumulation of SDH reaction product was detected, as was one COX-negative muscle fiber in the sample. Subsequent mitochondrial DNA analysis revealed multiple mtDNA deletions. The patient was started on prednisone 60 mg per day and methotrexate 10 mg per week. She improved significantly during the next 3 months, both clinically and in laboratory findings, and a stepwise withdrawal of the immunosuppressive therapy was performed. At present, 7 months after the diagnosis, the patient is being treated with 20 mg prednisone per day and has not shown any clinical or laboratory signs of relapsing disease. Case 2 A 58-year-old man with hypercholesterolemia, treated with 20 mg of simvastatin per day for 3 years, was admitted with a two-month history of symmetric small joint pain associated with stiffness, low-grade fever, general malaise, exertional muscle pain, and progressive proximal muscle weakness. High-resolution computed tomography revealed interstitial lung fibrosis in the lower pulmonary lobes bilaterally. Statin therapy was discontinued and the patient was started on prednisone 60 mg per day. His joint pain improved, but the muscle weakness persisted and muscle biopsy was performed. Muscle biopsy revealed a similar histopathological pattern of changes to that described for case 1, and a diagnosis of polymyositis was established (Fig. 2). Moreover, focal subsarcolemmal accumulation of SDH reaction product and up to 2 % COX-negative muscle fibers were detected (Fig. 3). As in case 1, subsequent mitochondrial DNA analysis revealed multiple mtDNA deletions (Fig. 4). Autoantibodies against 200/100 kDa proteins were not detected. The patient continued with prednisone 50 mg per day and 100 mg azathioprine daily. Both clinical improvement and laboratory improvement were achieved after 3 months of treatment. However, because of persistent hypercholesterolemia, the patient was started on 200 mg fenofibrate per day 3 months later. After 2 months of fenofibrate administration, the patient’s muscle enzymes had again increased to levels up to five times the upper limit of normal, and his lipid-lowering therapy had to be discontinued. Although the patient continues to require immunosuppressive therapy consisting of prednisone 20 mg and azathioprine 150 mg daily 10 months after the diagnosis, his muscle strength has almost
Fig 3. Changes in mitochondrial metabolism identified in case 2 by enzyme histochemistry: COX (cytochrome C oxidase)-negative myofibers (asterisks). Magnification ⫻200
returned to normal. However, exertional dyspnea persists, with a severely limited carbon monoxide diffusing capacity and slight progression of lung interstitial fibrosis observed on the computed tomography scan. Case 3 A 73-year-old woman with hypercholesterolemia, hypertension, and hypothyroidism had been treated with lipid-lowering drugs for 6 years. Due to stepwise development of moderate muscle weakness, her lipid-lowering formula was changed repeatedly (see Table 1). Additional medication included levothyroxine 50 μg per day, acidum acetylsalicylicum 100 mg per day, furosemide 40 mg per day, spironolactone 25 mg per day, metoprolol tartrate 100 mg, and citalopram 10 mg per day. After myocardial infarction, combined atorvastatin 20 mg and fenofibrate 200 mg per day therapy was started. After one month of this therapy, the patient was admitted due to severe proximal muscle weakness. A diagnosis of polymyositis was established by muscle biopsy (Fig. 5). Autoantibodies
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32.5 mg per day and 20 mg methotrexate weekly, with a continuous but slow improvement in muscle strength.
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Discussion
Fig. 4 Ethidium bromide-stained gel of the products amplified by longrange PCR of the mtDNA region m.3485–m.14786 in skeletal muscle DNA. The 11335 bp long PCR product corresponds to wt-mtDNA. The smaller bands represent PCR products that were amplified from mtDNA molecules with a certain deletion length. In the DNA sample from patient 2, the PCR product of wt-mtDNA was very faint, and several shorter PCR products proved that there were multiple deletions in the mtDNA. M DNA molecular-weight standard; kb kilobase; C-negative negative control containing only wild-type mtDNA; C-positive positive control containing both deleted and wild-type mtDNA
against 200/100 kDa proteins were not detected. The patient was started on prednisone 60 mg per day and methotrexate 20 mg per week. The elevated muscle enzymes normalized after 2 months of therapy, whereas clinical improvement was languid—her muscle strength improved slightly and the patient began to be able to walk after 3 months of therapy. At the last follow-up control (5 months after the diagnosis), she was still on prednisone
Fig 5. Inflammatory myopathy occurring during statin therapy in case 3. Endomysial lymphocytic inflammatory infiltrate is accompanied by myopathic changes with focal muscle fiber necrosis and regeneration. Hematoxylin eosin stain, ⫻400. Inset: CD8-positive lymphocytes surrounding non-necrotic muscle fibers (asterisk) (immunoperoxidase method, counterstained slightly with hematoxylin, ⫻400)
Establishing a diagnosis of drug-induced myopathy remains difficult, especially in patients with comorbidities receiving multiple medications. Drug-induced myopathy has been recently defined by Dalakas as a subacute manifestation of myopathic symptoms that occur in patients without muscle disease when exposed to therapeutic doses of certain drugs [25]. The improvement of myopathic symptoms after drug discontinuation may aid diagnosis [26]. On the other hand, myopathic symptoms may continue even after therapy cessation [25], as seen in our cases. Although a causative link between statin therapy and the development of polymyositis cannot be proven directly, we suppose that statins played at least a contributory role in disease development in our cases. This hypothesis is based on the temporal sequences and interrelationships among the patients’ pharmacological histories, the development of inflammatory myopathy and the regression in myopathic symptoms after immunosuppressive therapy. The proposed link between inflammatory myopathy and statin therapy is most obvious in the third patient, who (in contrast to the first two patients) had no myositis-specific autoantibodies. Moreover, the recurrence of myopathy after the reinsertion of lipid-lowering therapy in that case is strongly suggestive of possible drug-induced myopathy. Indeed, the temporal sequence and clinical course is not typical of the development of idiopathic polymyositis, even in the other two cases, again providing a certain degree of evidence for the hypothesized interrelationship: the myopathic symptoms of the second patient worsened stepwise during the lipid-lowering therapy, which lasted 6 years, and aggravated markedly during the final 3 weeks of the combined atorvastatin–fenofibrate treatment. Autoimmune-mediated inflammatory myopathies have been associated with therapies involving cimetidine, penicillamine, L-tryptophan, interferon-α, and proton pump inhibitor administration [26–28]. Apart from dermatomyositis and polymyositis, cases of lupus-like syndrome [29], pneumonitis, polymyalgia rheumatica [30], segmental necrotizing glomerulonephritis and Churg–Strauss disease [31] have been reported in association with statin therapy. Five cases of dermatomyositis associated with statin therapy (three males and two females, age range 44–76 years) were described previously [9, 11, 13, 14, 16]; the symptoms appeared from 2 months to 2 years after introducing statins, and two of the patients required immunosuppressive therapy. Seven cases of polymyositis associated with statin therapy (four males and three females aged from 42 to 78) were also reported [7, 8, 10, 32]. The symptoms first appeared from 2 weeks to 2 years after beginning the therapy and, in agreement with our cases, all of the patients required immunosuppressive treatment. Anti-Jo-1 antibody—also observed in one of our cases—was detected in three of them [10, 15]. Several studies have been published on statins as immunomodulators [32–36]. In these studies, statins were proven to act as immunosuppressive agents. In contrast, there are few recent publications that describe statins as agents capable of inducing autoimmune disorder. Grable-Esposito et al. [37] presented 25 patients who developed autoimmune necrotizing myopathy during statin therapy. In nine of the patients, who discontinued statin therapy due to asymptomatic creatine kinase elevation, the onset of muscle weakness occurred 0.5–20 months after statin therapy cessation. Although inflammatory infiltrate was not detected in muscle biopsies, all of the patients required immunosuppressive therapy. Christopher-Stine et al. [17] described 26 cases of patients with predominant necrotizing myopathy. A novel autoantibody recognizing 200 and 100 kDa proteins was detected in 16 of them, and 63 % of these patients had been exposed to statin therapy before
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the diagnosis. In the muscle biopsies, they observed diffuse HLA-I overexpression on the surfaces of muscle fibers in four of eight patients. This diffuse HLA-I overexpression was detected in the muscle biopsies for all of our patients as well, but an autoantibody recognizing 200 and 100 kDa proteins was not detected in our cases. As in the study of Grable-Esposito et al. [37], the majority of the patients responded insufficiently to immunosuppressive treatment, thus requiring combination immunosuppressive therapy, and they experienced a relapse of weakness upon tapering the immunosuppressive medications. Mammen et al. [18] recently identified the 100 kd protein as 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGCR), and described 45 anti-HMGCR-positive patients, 30 of whom had prior statin exposure. 95.6 % of these patients suffered from proximal muscle weakness. Forty of them underwent muscle biopsy, which highlighted prominent degenerating and regenerating muscle fibers in all cases, with significant inflammatory infiltrate being found in eight of them. Moreover, Mammen et al. [18] found that HMGCR was upregulated in the regenerating muscle fibers. This may offer an explanation for the persistent necrotizing myopathy even after statin discontinuation in patients with antiHMGCR antibody. Needham et al. [32] described eight cases of statin-treated patients with myopathy that did not resolve after statin therapy cessation, thus requiring immunosuppressive treatment in seven of them. Necrotic and regenerating muscle fibers were found in all of the muscle biopsies performed, whereas endomysial inflammatory infiltrate was found in only three of them. However, HLA-I overexpression on the surfaces of muscle fibers was described in all cases. Needham et al. [32] suggested that HLA-I overexpression is affected by statin therapy through the induction of the endoplasmic reticulum stress response. This is in agreement with the findings of Nagaraju et al. [38], who supposed that muscle fiber death in myositis could be induced by not only immune attack (caused by cytotoxic T lymphocytes or autoantibodies) but also the endoplasmic reticulum stress response, which leads to intracellular homeostasis disturbance. The endoplasmic reticulum stress response leads to cell death via apoptosis and autophagy, with the latter becoming even more important recently [39]. Aside from the inflammatory changes, significant alteration to mitochondrial metabolism was observed in two of our patients. Mitochondrial mutations that accumulate with age are known to cause alterations in mitochondrial energy metabolism in aging persons [40], which may offer an explanation for one of our observations: that the first patient affected was 72 years old at the time of diagnosis. However, the second patient with evidence of mitochondrial metabolism alteration was 58 years old. In our opinion, a combination of inflammatory myopathy in a patient on a chronic statin therapy and signs of mitochondrial metabolism disorder in a muscle biopsy from that patient should lead to consideration that the statin therapy has contributed to disease development [25, 41, 42]. Evidence of mitochondrial dysfunction in muscle biopsies of patients on statin therapy was described previously for six patients [43, 44]. The age distribution in that report was similar to the age distribution for our cases (range 62–76, median 64.5). Concerning the possible pathogenesis of the impact of MHG-CoA reductase inhibitors on mitochondrial metabolism, mevalonate (one of the metabolic intermediates in the cholesterol synthetic pathway) is a precursor in the synthesis of ubiquinone (coenzyme Q10); a lack of mevalonate may therefore interfere with oxidative phosphorylation pathways. Moreover, plasma coenzyme Q10 is transported with lipoproteins, so coenzyme Q10 levels may be reduced by reducing low-density lipoprotein levels too. Cytochrome Q10 supplementation therapy in patients with statininduced myopathies has been tested with encouraging results [41, 42]. In conclusion, adverse effects of statin therapy are relatively rare, and the majority of them subside after statin therapy discon-
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tinuation. On the other hand, very occasionally, a patient may suffer from autoimmune myopathy during statin treatment, requiring prompt immunosuppressive therapy based on correct diagnosis, which can be established by a muscle biopsy.
Acknowledgments Supported by the Ministry of Health of the Czech Republic project for the conceptual development of research organization 00064203 (University Hospital Motol, Prague, Czech Republic).
Conflict of interest None.
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