Journal of the Neurological Sciences 351 (2015) 13–17
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Review article
Statin induced necrotizing autoimmune myopathy Suma Babu, Yuebing Li ⁎ Neuromuscular Center, Department of Neurology, Cleveland Clinic, OH, United States
a r t i c l e
i n f o
Article history: Received 5 December 2014 Received in revised form 7 February 2015 Accepted 24 February 2015 Available online 3 March 2015 Keywords: Statin Myopathy Statin myotoxicity Necrotizing autoimmune myopathy HMGCR antibody Immunosuppression
a b s t r a c t Statin induced necrotizing autoimmune myopathy (SINAM) is a recently characterized entity belonging to the spectrum of statin myotoxicity. It is a more severe form, and is usually associated with significant proximal muscle weakness, strikingly elevated creatine kinase levels and persistent symptoms despite statin discontinuation. The characteristic pathological finding is a marked muscle fiber necrosis with minimal or no inflammation on muscle biopsy. SINAM is an autoimmune disorder associated with an antibody against 3-hydroxy-3methyglutaryl-coenzyme A reductase (HMGCR), and the antibody titer is a useful marker for assessing treatment response. However, anti-HMGCR positive myopathies are also caused by unknown etiologies other than statin exposure, especially in the younger population. SINAM should be promptly recognized as immunosuppressive therapy can improve its clinical outcome significantly. Further research is needed to elucidate its pathogenesis and provide evidence based guidelines for management. © 2015 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . Classification of statin-induced myotoxicity Clinical features of SINAM . . . . . . . Identification of specific antibody in SINAM Pathogenesis of SINAM . . . . . . . . . Diagnosis and treatment of SINAM . . . 6.1. Diagnosis . . . . . . . . . . . . 6.2. Differential diagnosis . . . . . . 6.3. Treatment . . . . . . . . . . . 7. Conclusion . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
1. Introduction Statins are a class of medications that are widely prescribed for the prevention of cerebrovascular and cardiovascular diseases. An estimated 25 million patients take statin class medications worldwide [1]. ⁎ Corresponding author at: Neuromuscular Center Desk S90, Department of Neurology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, United States. Tel.: +1 216 445 9525; fax: +1 216 445 4653. E-mail address: [email protected] (Y. Li).
http://dx.doi.org/10.1016/j.jns.2015.02.042 0022-510X/© 2015 Elsevier B.V. All rights reserved.
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
13 14 14 15 15 16 16 16 16 16 17 17
Statins are safe in majority of patients, but side effects limit their usage, resulting in discontinuation in 5 to 20% of patients [2]. Among these, muscle-related adverse events are the most common [3]. The clinical spectrum of statin-induced myotoxicity varies greatly from asymptomatic elevation of creatine kinase (CK) to muscle pain, muscle weakness, biopsy proven myositis and rhabdomyolysis. More recently, a rare but unique entity named statin induced necrotizing autoimmune myopathy (SINAM) was characterized [4–7]. This review aims at consolidating the latest development on SINAM, with a focus on its pathogenesis, clinical features and treatment strategies.
14
S. Babu, Y. Li / Journal of the Neurological Sciences 351 (2015) 13–17
2. Classification of statin-induced myotoxicity
3. Clinical features of SINAM
Based on pathogenesis, statin associated myotoxicity can be classified into toxic and autoimmune forms. Until recently, statin induced myotoxicity, if not otherwise specified, referred to the nonautoimmune and often self-limited adverse events related to muscle. In an effort to unify the terminology, the Phenotype Standardization Project recently convened an international expert workshop on statin induced myotoxicity to agree upon the definitions for a variety of statin related myotoxicity. The proposed definitions, categories and their incidences are outlined in Table 1 [8]. Among self-limited statin myopathies, asymptomatic CK elevation and myalgia without CK elevation are the most commonly occurring, while rhabdomyolysis is the least frequent but the most serious entity, characterized by significant CK elevation and often release of myoglobin into the blood stream. Most self-limited statin myotoxicity occurs within first 12 weeks of statin exposure [9]. From the Prediction of Muscular Risk in Observational Conditions (PRIMO) study, the median time to onset of muscle symptoms was 1 month after statin initiation, although 15% patients developed symptoms 6 months later [3]. Myalgias in statin myopathy were mostly localized to the thighs and calves, and generalized myalgias occurred in approximately 25% of patients [3]. Except for the rare fatal cases of acute rhabdomyolysis, statin induced muscle symptoms usually resolve upon cessation of offending medication. One study reported that myalgias took an average of 2.3 months to dissipate, with a range of 1 week to 14 months. Approximately half of patients who developed side effects on one statin tolerated a different statin without recurrence of similar symptoms [10]. The underlying mechanisms for self-limited statin myotoxicity have not been fully understood. Several mechanisms were suggested, including isoprenoid depletion, decreased sarcolemmal membrane cholesterol, inhibition of ubiquinone or coenzyme Q10 synthesis or disturbed calcium metabolism. The muscle pathological findings are non-specific, often with observations of muscle fiber necrosis, degeneration, and phagocytic infiltration. In some cases, lipid filled vacuoles and ragged red fibers were observed [11,12]. Risk factors for self-limited statin myotoxicity include age above 65 years, Asian descent, heavy exercise, low body mass index, excess alcohol consumption, vitamin D deficiency, diabetes mellitus, thyroid dysfunction, renal or liver disease, and exposure to other interacting drugs [3,13–15]. Presence of a single nucleotide polymorphism rs4363657 in the SLCO1B1 gene is strongly associated with the occurrence of statin myotoxicity [16]. Occurrence of self-limited statin myotoxicity is often related to the pharmacological properties of statins. Hydrophilic statins (rosuvastatin or pravastatin) are less likely to enter myocytes and therefore less myotoxic than lipophilic ones (lovastatin, simvastatin, fluvastatin, atorvastatin and pivastatin). The higher the dose of statin used, the more likely myotoxicity occurs. A meta-analysis of 4 large randomized trials showed an almost 10-fold increased risk of myopathy in patients on high dose statins (i.e. simvastatin or atorvastatin 80 mg/day) when compared with moderate doses [17].
In 2007, Needham et al. published a case series of 8 patients who developed statin associated myopathy presenting with progressive weakness and high CK levels which persisted even after statin discontinuation. On pathology, significant muscle fiber necrosis was seen in 7 of 8 patients while mostly minimal endomysial inflammatory infiltrates were present in 3 cases. Despite a relative lack of inflammation on muscle biopsy, a few findings strongly supported the immunemediated nature of this newly defined entity. A diffuse or multifocal up-regulation of MHC class I expression in non-necrotic muscle fibers was seen in all patients, and an up-regulation of MHC class II expression was also seen in 2 of 8 patients. The up-regulation of both MHC class molecules is characteristic of inflammatory myopathies including polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM) but rarely found in metabolic or inherited myopathies [18,19]. Additionally, 7 patients were treated with prednisone alone or in combination with methotrexate. All improved symptomatically and serologically within 2 months, and complete resolution of symptoms occurred within 9 months after treatment initiation [4]. Three years later, a second case series with similar clinical and pathological features of statin induced necrotizing myopathy was reported [5]. In this study, all 25 cases demonstrated symmetrical proximal weakness and elevated CK levels persisting for at least one month after statins were discontinued. In all cases, the predominant finding on muscle biopsy was myonecrosis without significant inflammation around nonnecrotic fibers, and clinical improvements were observed following immunosuppressive treatment. These two studies provided strong evidence that statin usage may lead to development of a necrotizing autoimmune myopathy with unique features (Table 2). Statin induced necrotizing autoimmune myopathy (SINAM) is usually characterized by a rapid onset of severe proximal weakness, and CK levels of typically over 6000 IU/L. Distal weakness and dysphagia may also occur [5]. SINAM can also start off by mimicking self-limited statin intolerance with myalgia and/or mild weakness, and severe symptoms may develop later [6]. From the Grable-Esposito et al. cohort, the average duration of statin exposure prior to symptomatic onset was 3 years (range of 2 months to 10 years) [5]. It is not yet clear if the severity of SINAM is related to the length or dose of statin exposure. Clinical symptoms may persist or even start after stopping the offending medication, although rare cases of spontaneous improvement following statin discontinuation were recently described [7]. The incidence of myalgia in SINAM is variable among different studies [4–6]. Extramuscular involvement including pulmonary fibrosis, skin manifestation and arthritis does not typically occur. Multiple statins including simvastatin, lovastatin, pravastatin, fluvastatin and atorvastatin were associated with SINAM suggesting that this is a class rather than a specific statin effect [4–7]. Additionally, SINAM appears to have more consistent statin exposure when compared to other inflammatory myopathies including PM, DM and IBM in age adjusted incidence comparison [4,5]. SINAM typically occurs in the absence of all other known risk factors for self-limited statin
Table 1 Statin-related myotoxicity phenotype classification [8]. Classification Phenotype SRM 0 SRM 1 SRM 2 SRM 3 SRM 4 SRM 5 SRM 6
CK elevation b 4 X ULN Myalgia, tolerable Myalgia, intolerable Myopathy Severe myopathy Rhabdomyolysis Autoimmune-mediated necrotizing myositis
Definition
Incidence
No muscle symptoms Muscle symptoms without CK elevation Muscle symptoms, CK b 4 X ULN CK 4 to 10 X ULN +/− muscle symptoms CK 10 to 50 X ULN, muscle symptoms CK N 10 X ULN with muscle symptoms and renal impairment; Or CK N 50 X ULN HMGCR antibodies, incomplete resolution upon discontinuation
1.5–26% 0.3–33% 0.1–1/1,000 5/100,000 Patient-years 0.11% 0.1–8.4/100,000 Patient –years ~2/million per year
SRM statin-related myotoxicy, CK creatine kinase, ULN upper limit of normal.
S. Babu, Y. Li / Journal of the Neurological Sciences 351 (2015) 13–17 Table 2 Clinical features for statin-associated necrotizing myopathy. Features
Needham et al. [4]
Grable-Esposito et al. [5]
No. of patients Age (years) Statin usage duration Statin used
8 62–82 7 months–9 yrs Atorvastatin, simvastatin, cerivastatin 4 1 3 958–45,000 9737 3 (ANA, Jo) 100%
25 47–89 2 months–10 yrs Atorvastatin, simvastatin, pravastatin 21 0 4 3000–17,280 8203 2 (ANA) 100%
Painless weakness Myalgia only Myalgia and weakness Maximum CK(IU/L) Mean CK (IU/L) Other markers Improve on treatment CK creatine kinase.
myotoxicity. Unlike other form of autoimmune muscle diseases, SINAM rarely occurs in the context of another systemic autoimmune disease. So far only a minority of patients had other identified autoimmune diseases such as Hashimoto thyroiditis, positive ANA, positive Jo-1 antibody or elevation of C reactive protein [4,5,7]. Table 3 summarizes different features between the non-autoimmune statin myotoxicity and SINAM. 4. Identification of specific antibody in SINAM Independently at John Hopkins Myositis Center, Christopher-Steine et al. described a group of 16 patients with similar features of proximal muscle weakness, CK elevation, muscle fiber necrosis and response to immunotherapy [6]. In all 16 patients, a novel anti-200/100 kd antibody was detected in the serum which was subsequently recognized to target the intracellular catalytic domain (C terminus) of hydroxy-3methyglutaryl-coenzyme A reductase receptor protein (HMGCR) [20]. The association of anti-HMGCR autoantibody with necrotizing autoimmune myopathies was further confirmed by a recently accomplished European study of 45 patients [7]. The anti-HMGCR positive myopathy is rare with an estimated incidence of 2 per million per year [21]. There seemed to be a female predominance of 57.8% and 73% respectively from previous studies [7,20]. Initial data from John Hopkins revealed that approximately 70% anti-HMGCR positive patients were exposed to statins therefore belonged to SINAM while the remaining 30% had no clearly identified triggers. Percentage of statin usage was even higher in older patients, reaching 92.3% in patients aged 50 years or older [20]. However, in the recent European study which included more patients of younger age including pediatric patient, only 44.4% of anti-HMGCR positive cases were exposed to statin [7]. An acute to subacute onset was seen in the majority of patients with anti-HMGCR positive myopathy. However, a slow progressive course over years was observed in rare cases [7]. The anti-HMGCR positive myopathy and SINAM are clearly overlapping entities as they share many common features as discussed above. Not all cases of anti-HMGCR positive myopathies were exposed to statins [7,20]. Similarly, it can be speculated that not all SINAM cases
15
possess anti-HMGCR antibodies in the serum. The true incidence of anti-HMGCR antibody positivity in SINAM awaits further large-scale studies. The subgroup of anti-HMGCR positive patients without statin exposure were clinically indistinguishable from those with prior statin usage except for their young age, higher percentage of African–American race, higher CK value and less responsiveness to immunosuppressive treatment [7,20]. Among a group of 15 patients in the statin non-exposed group, one patient was found to have Jo-1 antibody with interstitial lung disease, and another case had scleroderma. So in rare cases, patients with anti-HMGCR autoantibodies may have an overlap syndrome with connective tissue disorders [20]. Five cases of cancers (adenocarcinoma of breast, lung, kidney and melanoma) were described in the recent European cohort but the potential association between cancer status and anti-HMGCR positivity remains unclear [7]. In anti-HMGCR positive myopathy with prior statin exposure (i.e., SINAM), the initial anti-HMGCR antibody levels correlated with indicators of disease activity including CK elevation and muscle weakness. Following immunosuppressive treatment and clinical improvement, antibody levels decreased but often did not normalize in these patients [22]. Data from the recent European study also confirmed a similar correlation between anti-HMGCR titer, muscle strength and CK level in their group of patients who had positive or no exposure to statin [7]. The presence of such a positive correlation between anti-HMGCR titer and disease severity indicates that anti-HMGCR can be used as a marker for monitoring treatment response. Specificity of anti-HMGCR antibody in the pathogenesis of SINAM was investigated in a variety of patient subgroups. Using the immunoprecipitation method, anti-HMGCR antibodies were rarely found in 881 subjects who were never exposed to statins, 1085 patients who were on statins but without muscle symptoms, and 51 patients with self-limited statin intolerance [23]. Anti-HMGCR antibody was neither detected in 33 DM cases (5 with prior statin exposure), 31 IBM cases (11 with prior statin exposure) and 10 patients with necrotizing myopathy with positive antisynthetase or anti-signal recognition particle (SRP) antibodies [6,23]. The absence of anti-HMGCR antibody in the large number of statin-non exposed subjects, statin users with no or mild symptoms and various myopathies verified its fairly high specificity for this particular subset of necrotizing autoimmune myopathy. 5. Pathogenesis of SINAM Evidence appears to support a genetic predisposition in the development of anti-HMGCR positive myopathy including SINAM. Contrary to the self-limited statin myotoxicity, anti-HMGCR positive patients do not demonstrate an increased prevalence of rs4149056 C polymorphism [20]. However, HLA class II allele DRB1*11:01 is a strong risk factor for the development of anti-HMGCR positive myopathy [24]. It should be noted that the majority of patients with DRB1*11:01 who are on statins do not develop anti-HMGCR positive myopathy. Thus, additional genetic factors or environmental triggers must be required for the necrotizing myopathy to occur in the majority of patients.
Table 3 A comparison of toxic statin myopathy with SINAM.
Incidence Proximal weakness Maximum CK (IU/L) Genetic risk factor Timing relationship to statin Anti-HMGCR antibody Electromyography MRI Biopsy Treatment
Toxic statin myopathy Frequent Infrequent Normal or mildly elevated, N100,000 in rhabdomyolysis SNP in SLCO1B1 Following initiation, resolve after discontinuation Absent Non-specific or normal Non-specific or normal Non-specific Statin withdrawal or dose reduction
SINAM Rare Common 1000–50,000 HLA-DRB1*11:01 May present after years of usage; may appear or persist after statin discontinuation Present Irritable myopathy Myoedema Prominent muscle necrosis with minimal or no inflammation Statin withdrawal and immunosuppressive therapy
CK creatine kinase, SINAM statin induced necrotizing autoimmune myopathy, SNP single nucleotide polymorphism.
16
S. Babu, Y. Li / Journal of the Neurological Sciences 351 (2015) 13–17
As the pharmacological target of statin, HMGCR is constitutively expressed at low level by mature muscle cells; however, its expression can be induced by statin exposure, and is markedly up-regulated in regenerating muscle fibers in anti-HMGCR positive patients [20,25]. Upregulated HMGCR protein acts as an autoantigen to induce antibody production and anti-HMGCR antibody may trigger necrosis and regeneration of muscle fibers, resulting in severe muscle damage even after statins are discontinued. It remains to be determined whether antiHMGCR antibody plays a direct pathogenic role in SINAM. Passive transfer of HMGCR antibodies or direct immunization using HMGCR protein to animal models can be pursued to characterize their effects on muscle fibers and possible provide more direct evidence. It was consistently noted in all studies on SINAM that almost all patients tolerated statins for at least a few months to years before onset of muscle weakness. It remains unexplained why some patients tolerated statin exposure for a long duration before SINAM developed. It may suggest that additional environmental factors (e.g., viral infection) are required to initiate the autoimmune process which could be further promoted by statin usage. Similarly, anti-HMGCR seropositivity in the statin non-exposed patients substantiates the hypothesis that additional factors other than statin exposure play a significant role in causing a necrotizing myopathy resembling SINAM.
deficiency) [31]. The possibilities of these rare disorders may merit some consideration in evaluating patients for SINAM. It is also important to recognize that statin exposure is not the only etiology in causing a necrotizing autoimmune myopathy. Other immune-mediated necrotizing myopathies include those associated with the presence of anti-SRP antibody and paraneoplastic necrotizing myositis. The range of cancers in association with paraneoplastic necrotizing autoimmune myositis includes gastrointestinal, pancreatic and gallbladder adenocarcinoma, small cell and non-small cell lung, breast, prostate and transitional cell cancers and myeloma [32,33]. Another remaining question is whether statin usage leads to the development of PM or DM. It was suggested that PM may be an overdiagnosed entity and many PM cases often turn into other diagnoses [34]. Using the Bohan and Peter criteria, the vast majority of SINAM patients would be classified as having probable or definite PM [35]. Whether this can be classified within the range of PM is largely a matter of which criteria is used. In the literature, 14 cases of statin associated DM were reported [36]. Among them, only 2 of whom resolved spontaneous after statin discontinuation without immunosuppressive treatment, suggesting a causal relationship [37,38]. The widespread use of statins makes it difficult to exclude a chance association between statins and PM in the remaining cases.
6. Diagnosis and treatment of SINAM
6.3. Treatment
6.1. Diagnosis
The treatment of SINAM is promising but cumbersome. In addition to stopping the offending drug, immunosuppressive therapy is the mainstay of treatment. Prednisone with or without methotrexate is usually the first-line, but other agents (azathioprine, cyclosporine, cyclophosphamide, intravenous immunoglobulin, mycophenolate, rituximab) are often used in varying combinations. In the GrableEsposito et al. cohort, all 25 patients improved with immunosuppressive therapy, with a drop of the mean CK levels from 6490 to 1052 IU/L [5]. However, the majority of patients in this study had residual weakness despite aggressive treatment. A total of 15 patients initially improved but relapsed as immunosuppressive therapy was tapered. Only 2 of 25 cases were treated with prednisone alone and 10 of 25 required multiple immunosuppressive agents. Eventually only 3 patients were stable off immunosuppressive treatment at the end of study [5]. Intravenous immunoglobulin treatment seems to be particularly beneficial for SINAM [39]. Long-term management of hyperlipidemia remains a challenge in SINAM patients. It is unclear whether a different class of statin can be given, even at lower dosage or reduced frequency. Needham et al. reported a re-challenge of statin in two patients (one with same, one with different statin); symptoms recurred with CK elevation in both cases [4]. Several strategies can be considered for lipid lowering: One option is to avoid statin treatment completely and consider alternative use of non-statin lipid lowering agents, such as ezetimibe or cholestyramine. Alternative strategies, such as lifestyle modification including smoking cessation, weight reduction and dietary modification should be undertaken.
SINAM tends to have an aggressive phenotype, with significant weakness on exam, high CK levels on lab testing, irritable pattern on EMG and notable myonecrosis on biopsy. Detection of anti-HMGCR seropositivity in such patients remains most valuable in confirming diagnosis. Anti-HMGCR antibody testing is now commercially available through the RDL reference laboratories. Other diagnostic tests that provide supportive evidence for diagnosis of SINAM include electrophysiological and imaging studies. On EMG, the most frequent abnormal findings are abnormal spontaneous activity in the form of fibrillation potentials, positive sharp waves, and myotonic or pseudomyotonic discharges [5]. MRI examination of the muscles can also be helpful in detecting muscle edema and necrosis. In patients who underwent bilateral thigh MRI, 100% had evidence of edema, 75% muscle atrophy, and 67% fatty replacement [20]. The most prominent finding on pathology in SINAM is muscle fiber necrosis. There is generally an absence of CD8+ T cells invading muscle fibers, although their presence does not exclude a diagnosis of SINAM [26]. In addition to the lack of lymphocyte infiltration, abundant myophagocytosis is often present [27]. There is typically no significant denervation or amyloid deposition. MHC class I and class II staining helps to differentiate SINAM from metabolic or genetic muscle disorders [4,19]. Sarcolemmal MHC class I staining appears particularly specific to SINAM, in sharp contrast to other inflammatory myopathies [27]. 6.2. Differential diagnosis Given the high prevalence of statin usage in the general population and the relative rarity of SINAM, an exposure history alone is not adequate to make a diagnosis of SINAM, and the exclusion of more common myopathies should be undertaken. It is important to recognize that slightly raised CK levels are common in general population [28]. CK levels are higher in black than in white, and in men than women. One common cause of high CK levels is moderate to strenuous exercise especially in untrained individuals [29]. Latent or subclinical hypothyroidism is another cause of high CK and it has been reported that 3% of hyperlipidemia patients referred with asymptomatic high CK have high thyroid-stimulating hormone [30]. Statin usage may rarely reveal latent mitochondrial or metabolic diseases (McArdle, carnitine palmitoyltransferase II deficiency, or myoadenylate deaminase
7. Conclusion Statin induced necrotizing myopathy is a severe form of muscle toxicity associated with statin usage. Albeit rare, awareness and knowledge of SINAM are very useful for a practicing clinician. It is important to recognize that the anti-HMGCR antibody is specific for diagnosing SINAM. Once the diagnosis is made, early immunosuppressive therapy should be initiated to improve patient outcome significantly. There are several gaps in this field with potentials for future research. With an increasing recognition of this entity and commercial available testing, we may be able to better understand its epidemiological characteristics including its true incidence and clinical course. The role of antiHMGCR antibody and the molecular mechanism underlying SINAM
S. Babu, Y. Li / Journal of the Neurological Sciences 351 (2015) 13–17
await further clarification. In addition to statin exposure, additional risk factors for anti-HMGCR positive necrotizing myopathy should be actively sought. Evidence-based therapeutic options to guide SINAM treatment are needed. Finally, it would be valuable to know if every SINAM patient needs to permanently avoid all statins or a statin class/dose change is permissible in the context of effective immunosuppressive therapy. Disclosures None. References [1] Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285: 2486–97. [2] Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding statin use in america and gaps in patient education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol 2012;6:208–15. [3] Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther 2005;19:403–14. [4] Needham M, Fabian V, Knezevic W, Panegyres P, Zilko P, Mastaglia FL. Progressive myopathy with up-regulation of MHC-I associated with statin therapy. Neuromuscul Disord 2007;17:194–200. [5] Grable-Esposito P, Katzberg HD, Greenberg SA, Srinivasan J, Katz J, Amato AA. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve 2010;41:185–90. [6] Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010;62:2757–66. [7] Allenbach Y, Drouot L, Rigolet A, Charuel JL, Jouen F, Romero NB, et al. Anti-HMGCR autoantibodies in european patients with autoimmune necrotizing myopathies: inconstant exposure to statin. Med (Baltimore) 2014;93:150–7. [8] Alfirevic A, Neely D, Armitage J, Chinoy H, Cooper RG, Laaksonen R, et al. Phenotype standardization for statin-induced myotoxicity. Clin Pharmacol Ther 2014;96: 470–6. [9] Molokhia M, McKeigue P, Curcin V, Majeed A. Statin induced myopathy and myalgia: time trend analysis and comparison of risk associated with statin class from 1991-2006. PLoS One 2008;3:e2522. [10] Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med 2005;165:2671–6. [11] Radcliffe KA, Campbell WW. Statin myopathy. Curr Neurol Neurosci Rep 2008;8: 66–72. [12] Vaklavas C, Chatzizisis YS, Ziakas A, Zamboulis C, Giannoglou GD. Molecular basis of statin-associated myopathy. Atherosclerosis 2009;202:18–28. [13] Pasternak RC, Smith Jr SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Stroke 2002;33: 2337–41. [14] Vladutiu GD. Genetic predisposition to statin myopathy. Curr Opin Rheumatol 2008; 20:648–55. [15] Gupta A, Thompson PD. The relationship of vitamin D deficiency to statin myopathy. Atherosclerosis 2011;215:23–9. [16] SEARCH Collaborative GroupLink E, Parish S, Armitage J, Bowman L, Heath S, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 2008;359:789–99. [17] Silva M, Matthews ML, Jarvis C, Nolan NM, Belliveau P, Malloy M, et al. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther 2007;29:253–60.
17
[18] van der Pas J, Hengstman GJ, ter Laak HJ, Borm GF, van Engelen BG. Diagnostic value of MHC class I staining in idiopathic inflammatory myopathies. J Neurol Neurosurg Psychiatry 2004;75:136–9. [19] Rodriguez Cruz PM, Luo YB, Miller J, Junckerstorff RC, Mastaglia FL, Fabian V. An analysis of the sensitivity and specificity of MHC-I and MHC-II immunohistochemical staining in muscle biopsies for the diagnosis of inflammatory myopathies. Neuromuscul Disord 2014;24:1025–35. [20] Mammen AL, Chung T, Christopher-Stine L, Rosen P, Rosen A, Doering KR, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011;63: 713–21. [21] Mohassel P, Mammen AL. Statin-associated autoimmune myopathy and antiHMGCR autoantibodies: a review. Muscle Nerve 2013;48:477–83. [22] Werner JL, Christopher-Stine L, Ghazarian SR, Pak KS, Kus JE, Daya NR, et al. Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Rheum 2012;64:4087–93. [23] Mammen AL, Pak K, Williams EK, Brisson D, Coresh J, Selvin E, et al. Rarity of anti-3hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects. Arthritis Care Res 2012;64: 269–72 (Hoboken). [24] Mammen AL, Gaudet D, Brisson D, Christopher-Stine L, Lloyd TE, Leffell MS, et al. Increased frequency of DRB1*11:01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Care Res 2012;64:1233–7 (Hoboken). [25] Morikawa S, Murakami T, Yamazaki H, Izumi A, Saito Y, Hamakubo T, et al. Analysis of the global RNA expression profiles of skeletal muscle cells treated with statins. J Atheroscler Thromb 2005;12:121–31. [26] Casciola-Rosen L, Mammen AL. Myositis autoantibodies. Curr Opin Rheumatol 2012; 24:602–8. [27] Stenzel W, Goebel HH, Aronica E. Review: immune-mediated necrotizing myopathies–a heterogeneous group of diseases with specific myopathological features. Neuropathol Appl Neurobiol 2012;38:632–46. [28] Brewster LM, Mairuhu G, Sturk A, van Montfrans GA. Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J 2007;154: 655–61. [29] Brancaccio P, Maffulli N, Limongelli FM. Creatine kinase monitoring in sport medicine. Br Med Bull 2007;81–82:209–30. [30] Glueck CJ, Rawal B, Khan NA, Yeramaneni S, Goldenberg N, Wang P. Should high creatine kinase discourage the initiation or continuance of statins for the treatment of hypercholesterolemia? Metabolism 2009;58:233–8. [31] Vladutiu GD, Simmons Z, Isackson PJ, Tarnopolsky M, Peltier WL, Barboi AC, et al. Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle Nerve 2006;34:153–62. [32] Kao AH, Lacomis D, Lucas M, Fertig N, Oddis CV. Anti-signal recognition particle autoantibody in patients with and patients without idiopathic inflammatory myopathy. Arthritis Rheum 2004;50:209–15. [33] Wegener S, Bremer J, Komminoth P, Jung HH, Weller M. Paraneoplastic necrotizing myopathy with a mild inflammatory component: a case report and review of the literature. Case Rep Oncol 2010;3:88–92. [34] van der Meulen MF, Bronner IM, Hoogendijk JE, Burger H, van Venrooij WJ, Voskuyl AE, et al. Polymyositis: an overdiagnosed entity. Neurology 2003;61:316–21. [35] Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344–7. [36] Padala S, Thompson PD. Statins as a possible cause of inflammatory and necrotizing myopathies. Atherosclerosis 2012;222:15–21. [37] Noel B, Cerottini JP, Panizzon RG. Atorvastatin-induced dermatomyositis. Am J Med 2001;110:670–1. [38] Thual N, Penven K, Chevallier JM, Dompmartin A, Leroy D. Fluvastatin-induced dermatomyositis. Ann Dermatol Venereol 2005;132:996–9. [39] Albayda J, Mammen AL. Is statin-induced myositis part of the polymyositis disease spectrum? Curr Rheumatol Rep 2014;16:433.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Review article
Statin induced necrotizing autoimmune myopathy Suma Babu, Yuebing Li ⁎ Neuromuscular Center, Department of Neurology, Cleveland Clinic, OH, United States
a r t i c l e
i n f o
Article history: Received 5 December 2014 Received in revised form 7 February 2015 Accepted 24 February 2015 Available online 3 March 2015 Keywords: Statin Myopathy Statin myotoxicity Necrotizing autoimmune myopathy HMGCR antibody Immunosuppression
a b s t r a c t Statin induced necrotizing autoimmune myopathy (SINAM) is a recently characterized entity belonging to the spectrum of statin myotoxicity. It is a more severe form, and is usually associated with significant proximal muscle weakness, strikingly elevated creatine kinase levels and persistent symptoms despite statin discontinuation. The characteristic pathological finding is a marked muscle fiber necrosis with minimal or no inflammation on muscle biopsy. SINAM is an autoimmune disorder associated with an antibody against 3-hydroxy-3methyglutaryl-coenzyme A reductase (HMGCR), and the antibody titer is a useful marker for assessing treatment response. However, anti-HMGCR positive myopathies are also caused by unknown etiologies other than statin exposure, especially in the younger population. SINAM should be promptly recognized as immunosuppressive therapy can improve its clinical outcome significantly. Further research is needed to elucidate its pathogenesis and provide evidence based guidelines for management. © 2015 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . Classification of statin-induced myotoxicity Clinical features of SINAM . . . . . . . Identification of specific antibody in SINAM Pathogenesis of SINAM . . . . . . . . . Diagnosis and treatment of SINAM . . . 6.1. Diagnosis . . . . . . . . . . . . 6.2. Differential diagnosis . . . . . . 6.3. Treatment . . . . . . . . . . . 7. Conclusion . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
1. Introduction Statins are a class of medications that are widely prescribed for the prevention of cerebrovascular and cardiovascular diseases. An estimated 25 million patients take statin class medications worldwide [1]. ⁎ Corresponding author at: Neuromuscular Center Desk S90, Department of Neurology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, United States. Tel.: +1 216 445 9525; fax: +1 216 445 4653. E-mail address: [email protected] (Y. Li).
http://dx.doi.org/10.1016/j.jns.2015.02.042 0022-510X/© 2015 Elsevier B.V. All rights reserved.
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
13 14 14 15 15 16 16 16 16 16 17 17
Statins are safe in majority of patients, but side effects limit their usage, resulting in discontinuation in 5 to 20% of patients [2]. Among these, muscle-related adverse events are the most common [3]. The clinical spectrum of statin-induced myotoxicity varies greatly from asymptomatic elevation of creatine kinase (CK) to muscle pain, muscle weakness, biopsy proven myositis and rhabdomyolysis. More recently, a rare but unique entity named statin induced necrotizing autoimmune myopathy (SINAM) was characterized [4–7]. This review aims at consolidating the latest development on SINAM, with a focus on its pathogenesis, clinical features and treatment strategies.
14
S. Babu, Y. Li / Journal of the Neurological Sciences 351 (2015) 13–17
2. Classification of statin-induced myotoxicity
3. Clinical features of SINAM
Based on pathogenesis, statin associated myotoxicity can be classified into toxic and autoimmune forms. Until recently, statin induced myotoxicity, if not otherwise specified, referred to the nonautoimmune and often self-limited adverse events related to muscle. In an effort to unify the terminology, the Phenotype Standardization Project recently convened an international expert workshop on statin induced myotoxicity to agree upon the definitions for a variety of statin related myotoxicity. The proposed definitions, categories and their incidences are outlined in Table 1 [8]. Among self-limited statin myopathies, asymptomatic CK elevation and myalgia without CK elevation are the most commonly occurring, while rhabdomyolysis is the least frequent but the most serious entity, characterized by significant CK elevation and often release of myoglobin into the blood stream. Most self-limited statin myotoxicity occurs within first 12 weeks of statin exposure [9]. From the Prediction of Muscular Risk in Observational Conditions (PRIMO) study, the median time to onset of muscle symptoms was 1 month after statin initiation, although 15% patients developed symptoms 6 months later [3]. Myalgias in statin myopathy were mostly localized to the thighs and calves, and generalized myalgias occurred in approximately 25% of patients [3]. Except for the rare fatal cases of acute rhabdomyolysis, statin induced muscle symptoms usually resolve upon cessation of offending medication. One study reported that myalgias took an average of 2.3 months to dissipate, with a range of 1 week to 14 months. Approximately half of patients who developed side effects on one statin tolerated a different statin without recurrence of similar symptoms [10]. The underlying mechanisms for self-limited statin myotoxicity have not been fully understood. Several mechanisms were suggested, including isoprenoid depletion, decreased sarcolemmal membrane cholesterol, inhibition of ubiquinone or coenzyme Q10 synthesis or disturbed calcium metabolism. The muscle pathological findings are non-specific, often with observations of muscle fiber necrosis, degeneration, and phagocytic infiltration. In some cases, lipid filled vacuoles and ragged red fibers were observed [11,12]. Risk factors for self-limited statin myotoxicity include age above 65 years, Asian descent, heavy exercise, low body mass index, excess alcohol consumption, vitamin D deficiency, diabetes mellitus, thyroid dysfunction, renal or liver disease, and exposure to other interacting drugs [3,13–15]. Presence of a single nucleotide polymorphism rs4363657 in the SLCO1B1 gene is strongly associated with the occurrence of statin myotoxicity [16]. Occurrence of self-limited statin myotoxicity is often related to the pharmacological properties of statins. Hydrophilic statins (rosuvastatin or pravastatin) are less likely to enter myocytes and therefore less myotoxic than lipophilic ones (lovastatin, simvastatin, fluvastatin, atorvastatin and pivastatin). The higher the dose of statin used, the more likely myotoxicity occurs. A meta-analysis of 4 large randomized trials showed an almost 10-fold increased risk of myopathy in patients on high dose statins (i.e. simvastatin or atorvastatin 80 mg/day) when compared with moderate doses [17].
In 2007, Needham et al. published a case series of 8 patients who developed statin associated myopathy presenting with progressive weakness and high CK levels which persisted even after statin discontinuation. On pathology, significant muscle fiber necrosis was seen in 7 of 8 patients while mostly minimal endomysial inflammatory infiltrates were present in 3 cases. Despite a relative lack of inflammation on muscle biopsy, a few findings strongly supported the immunemediated nature of this newly defined entity. A diffuse or multifocal up-regulation of MHC class I expression in non-necrotic muscle fibers was seen in all patients, and an up-regulation of MHC class II expression was also seen in 2 of 8 patients. The up-regulation of both MHC class molecules is characteristic of inflammatory myopathies including polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM) but rarely found in metabolic or inherited myopathies [18,19]. Additionally, 7 patients were treated with prednisone alone or in combination with methotrexate. All improved symptomatically and serologically within 2 months, and complete resolution of symptoms occurred within 9 months after treatment initiation [4]. Three years later, a second case series with similar clinical and pathological features of statin induced necrotizing myopathy was reported [5]. In this study, all 25 cases demonstrated symmetrical proximal weakness and elevated CK levels persisting for at least one month after statins were discontinued. In all cases, the predominant finding on muscle biopsy was myonecrosis without significant inflammation around nonnecrotic fibers, and clinical improvements were observed following immunosuppressive treatment. These two studies provided strong evidence that statin usage may lead to development of a necrotizing autoimmune myopathy with unique features (Table 2). Statin induced necrotizing autoimmune myopathy (SINAM) is usually characterized by a rapid onset of severe proximal weakness, and CK levels of typically over 6000 IU/L. Distal weakness and dysphagia may also occur [5]. SINAM can also start off by mimicking self-limited statin intolerance with myalgia and/or mild weakness, and severe symptoms may develop later [6]. From the Grable-Esposito et al. cohort, the average duration of statin exposure prior to symptomatic onset was 3 years (range of 2 months to 10 years) [5]. It is not yet clear if the severity of SINAM is related to the length or dose of statin exposure. Clinical symptoms may persist or even start after stopping the offending medication, although rare cases of spontaneous improvement following statin discontinuation were recently described [7]. The incidence of myalgia in SINAM is variable among different studies [4–6]. Extramuscular involvement including pulmonary fibrosis, skin manifestation and arthritis does not typically occur. Multiple statins including simvastatin, lovastatin, pravastatin, fluvastatin and atorvastatin were associated with SINAM suggesting that this is a class rather than a specific statin effect [4–7]. Additionally, SINAM appears to have more consistent statin exposure when compared to other inflammatory myopathies including PM, DM and IBM in age adjusted incidence comparison [4,5]. SINAM typically occurs in the absence of all other known risk factors for self-limited statin
Table 1 Statin-related myotoxicity phenotype classification [8]. Classification Phenotype SRM 0 SRM 1 SRM 2 SRM 3 SRM 4 SRM 5 SRM 6
CK elevation b 4 X ULN Myalgia, tolerable Myalgia, intolerable Myopathy Severe myopathy Rhabdomyolysis Autoimmune-mediated necrotizing myositis
Definition
Incidence
No muscle symptoms Muscle symptoms without CK elevation Muscle symptoms, CK b 4 X ULN CK 4 to 10 X ULN +/− muscle symptoms CK 10 to 50 X ULN, muscle symptoms CK N 10 X ULN with muscle symptoms and renal impairment; Or CK N 50 X ULN HMGCR antibodies, incomplete resolution upon discontinuation
1.5–26% 0.3–33% 0.1–1/1,000 5/100,000 Patient-years 0.11% 0.1–8.4/100,000 Patient –years ~2/million per year
SRM statin-related myotoxicy, CK creatine kinase, ULN upper limit of normal.
S. Babu, Y. Li / Journal of the Neurological Sciences 351 (2015) 13–17 Table 2 Clinical features for statin-associated necrotizing myopathy. Features
Needham et al. [4]
Grable-Esposito et al. [5]
No. of patients Age (years) Statin usage duration Statin used
8 62–82 7 months–9 yrs Atorvastatin, simvastatin, cerivastatin 4 1 3 958–45,000 9737 3 (ANA, Jo) 100%
25 47–89 2 months–10 yrs Atorvastatin, simvastatin, pravastatin 21 0 4 3000–17,280 8203 2 (ANA) 100%
Painless weakness Myalgia only Myalgia and weakness Maximum CK(IU/L) Mean CK (IU/L) Other markers Improve on treatment CK creatine kinase.
myotoxicity. Unlike other form of autoimmune muscle diseases, SINAM rarely occurs in the context of another systemic autoimmune disease. So far only a minority of patients had other identified autoimmune diseases such as Hashimoto thyroiditis, positive ANA, positive Jo-1 antibody or elevation of C reactive protein [4,5,7]. Table 3 summarizes different features between the non-autoimmune statin myotoxicity and SINAM. 4. Identification of specific antibody in SINAM Independently at John Hopkins Myositis Center, Christopher-Steine et al. described a group of 16 patients with similar features of proximal muscle weakness, CK elevation, muscle fiber necrosis and response to immunotherapy [6]. In all 16 patients, a novel anti-200/100 kd antibody was detected in the serum which was subsequently recognized to target the intracellular catalytic domain (C terminus) of hydroxy-3methyglutaryl-coenzyme A reductase receptor protein (HMGCR) [20]. The association of anti-HMGCR autoantibody with necrotizing autoimmune myopathies was further confirmed by a recently accomplished European study of 45 patients [7]. The anti-HMGCR positive myopathy is rare with an estimated incidence of 2 per million per year [21]. There seemed to be a female predominance of 57.8% and 73% respectively from previous studies [7,20]. Initial data from John Hopkins revealed that approximately 70% anti-HMGCR positive patients were exposed to statins therefore belonged to SINAM while the remaining 30% had no clearly identified triggers. Percentage of statin usage was even higher in older patients, reaching 92.3% in patients aged 50 years or older [20]. However, in the recent European study which included more patients of younger age including pediatric patient, only 44.4% of anti-HMGCR positive cases were exposed to statin [7]. An acute to subacute onset was seen in the majority of patients with anti-HMGCR positive myopathy. However, a slow progressive course over years was observed in rare cases [7]. The anti-HMGCR positive myopathy and SINAM are clearly overlapping entities as they share many common features as discussed above. Not all cases of anti-HMGCR positive myopathies were exposed to statins [7,20]. Similarly, it can be speculated that not all SINAM cases
15
possess anti-HMGCR antibodies in the serum. The true incidence of anti-HMGCR antibody positivity in SINAM awaits further large-scale studies. The subgroup of anti-HMGCR positive patients without statin exposure were clinically indistinguishable from those with prior statin usage except for their young age, higher percentage of African–American race, higher CK value and less responsiveness to immunosuppressive treatment [7,20]. Among a group of 15 patients in the statin non-exposed group, one patient was found to have Jo-1 antibody with interstitial lung disease, and another case had scleroderma. So in rare cases, patients with anti-HMGCR autoantibodies may have an overlap syndrome with connective tissue disorders [20]. Five cases of cancers (adenocarcinoma of breast, lung, kidney and melanoma) were described in the recent European cohort but the potential association between cancer status and anti-HMGCR positivity remains unclear [7]. In anti-HMGCR positive myopathy with prior statin exposure (i.e., SINAM), the initial anti-HMGCR antibody levels correlated with indicators of disease activity including CK elevation and muscle weakness. Following immunosuppressive treatment and clinical improvement, antibody levels decreased but often did not normalize in these patients [22]. Data from the recent European study also confirmed a similar correlation between anti-HMGCR titer, muscle strength and CK level in their group of patients who had positive or no exposure to statin [7]. The presence of such a positive correlation between anti-HMGCR titer and disease severity indicates that anti-HMGCR can be used as a marker for monitoring treatment response. Specificity of anti-HMGCR antibody in the pathogenesis of SINAM was investigated in a variety of patient subgroups. Using the immunoprecipitation method, anti-HMGCR antibodies were rarely found in 881 subjects who were never exposed to statins, 1085 patients who were on statins but without muscle symptoms, and 51 patients with self-limited statin intolerance [23]. Anti-HMGCR antibody was neither detected in 33 DM cases (5 with prior statin exposure), 31 IBM cases (11 with prior statin exposure) and 10 patients with necrotizing myopathy with positive antisynthetase or anti-signal recognition particle (SRP) antibodies [6,23]. The absence of anti-HMGCR antibody in the large number of statin-non exposed subjects, statin users with no or mild symptoms and various myopathies verified its fairly high specificity for this particular subset of necrotizing autoimmune myopathy. 5. Pathogenesis of SINAM Evidence appears to support a genetic predisposition in the development of anti-HMGCR positive myopathy including SINAM. Contrary to the self-limited statin myotoxicity, anti-HMGCR positive patients do not demonstrate an increased prevalence of rs4149056 C polymorphism [20]. However, HLA class II allele DRB1*11:01 is a strong risk factor for the development of anti-HMGCR positive myopathy [24]. It should be noted that the majority of patients with DRB1*11:01 who are on statins do not develop anti-HMGCR positive myopathy. Thus, additional genetic factors or environmental triggers must be required for the necrotizing myopathy to occur in the majority of patients.
Table 3 A comparison of toxic statin myopathy with SINAM.
Incidence Proximal weakness Maximum CK (IU/L) Genetic risk factor Timing relationship to statin Anti-HMGCR antibody Electromyography MRI Biopsy Treatment
Toxic statin myopathy Frequent Infrequent Normal or mildly elevated, N100,000 in rhabdomyolysis SNP in SLCO1B1 Following initiation, resolve after discontinuation Absent Non-specific or normal Non-specific or normal Non-specific Statin withdrawal or dose reduction
SINAM Rare Common 1000–50,000 HLA-DRB1*11:01 May present after years of usage; may appear or persist after statin discontinuation Present Irritable myopathy Myoedema Prominent muscle necrosis with minimal or no inflammation Statin withdrawal and immunosuppressive therapy
CK creatine kinase, SINAM statin induced necrotizing autoimmune myopathy, SNP single nucleotide polymorphism.
16
S. Babu, Y. Li / Journal of the Neurological Sciences 351 (2015) 13–17
As the pharmacological target of statin, HMGCR is constitutively expressed at low level by mature muscle cells; however, its expression can be induced by statin exposure, and is markedly up-regulated in regenerating muscle fibers in anti-HMGCR positive patients [20,25]. Upregulated HMGCR protein acts as an autoantigen to induce antibody production and anti-HMGCR antibody may trigger necrosis and regeneration of muscle fibers, resulting in severe muscle damage even after statins are discontinued. It remains to be determined whether antiHMGCR antibody plays a direct pathogenic role in SINAM. Passive transfer of HMGCR antibodies or direct immunization using HMGCR protein to animal models can be pursued to characterize their effects on muscle fibers and possible provide more direct evidence. It was consistently noted in all studies on SINAM that almost all patients tolerated statins for at least a few months to years before onset of muscle weakness. It remains unexplained why some patients tolerated statin exposure for a long duration before SINAM developed. It may suggest that additional environmental factors (e.g., viral infection) are required to initiate the autoimmune process which could be further promoted by statin usage. Similarly, anti-HMGCR seropositivity in the statin non-exposed patients substantiates the hypothesis that additional factors other than statin exposure play a significant role in causing a necrotizing myopathy resembling SINAM.
deficiency) [31]. The possibilities of these rare disorders may merit some consideration in evaluating patients for SINAM. It is also important to recognize that statin exposure is not the only etiology in causing a necrotizing autoimmune myopathy. Other immune-mediated necrotizing myopathies include those associated with the presence of anti-SRP antibody and paraneoplastic necrotizing myositis. The range of cancers in association with paraneoplastic necrotizing autoimmune myositis includes gastrointestinal, pancreatic and gallbladder adenocarcinoma, small cell and non-small cell lung, breast, prostate and transitional cell cancers and myeloma [32,33]. Another remaining question is whether statin usage leads to the development of PM or DM. It was suggested that PM may be an overdiagnosed entity and many PM cases often turn into other diagnoses [34]. Using the Bohan and Peter criteria, the vast majority of SINAM patients would be classified as having probable or definite PM [35]. Whether this can be classified within the range of PM is largely a matter of which criteria is used. In the literature, 14 cases of statin associated DM were reported [36]. Among them, only 2 of whom resolved spontaneous after statin discontinuation without immunosuppressive treatment, suggesting a causal relationship [37,38]. The widespread use of statins makes it difficult to exclude a chance association between statins and PM in the remaining cases.
6. Diagnosis and treatment of SINAM
6.3. Treatment
6.1. Diagnosis
The treatment of SINAM is promising but cumbersome. In addition to stopping the offending drug, immunosuppressive therapy is the mainstay of treatment. Prednisone with or without methotrexate is usually the first-line, but other agents (azathioprine, cyclosporine, cyclophosphamide, intravenous immunoglobulin, mycophenolate, rituximab) are often used in varying combinations. In the GrableEsposito et al. cohort, all 25 patients improved with immunosuppressive therapy, with a drop of the mean CK levels from 6490 to 1052 IU/L [5]. However, the majority of patients in this study had residual weakness despite aggressive treatment. A total of 15 patients initially improved but relapsed as immunosuppressive therapy was tapered. Only 2 of 25 cases were treated with prednisone alone and 10 of 25 required multiple immunosuppressive agents. Eventually only 3 patients were stable off immunosuppressive treatment at the end of study [5]. Intravenous immunoglobulin treatment seems to be particularly beneficial for SINAM [39]. Long-term management of hyperlipidemia remains a challenge in SINAM patients. It is unclear whether a different class of statin can be given, even at lower dosage or reduced frequency. Needham et al. reported a re-challenge of statin in two patients (one with same, one with different statin); symptoms recurred with CK elevation in both cases [4]. Several strategies can be considered for lipid lowering: One option is to avoid statin treatment completely and consider alternative use of non-statin lipid lowering agents, such as ezetimibe or cholestyramine. Alternative strategies, such as lifestyle modification including smoking cessation, weight reduction and dietary modification should be undertaken.
SINAM tends to have an aggressive phenotype, with significant weakness on exam, high CK levels on lab testing, irritable pattern on EMG and notable myonecrosis on biopsy. Detection of anti-HMGCR seropositivity in such patients remains most valuable in confirming diagnosis. Anti-HMGCR antibody testing is now commercially available through the RDL reference laboratories. Other diagnostic tests that provide supportive evidence for diagnosis of SINAM include electrophysiological and imaging studies. On EMG, the most frequent abnormal findings are abnormal spontaneous activity in the form of fibrillation potentials, positive sharp waves, and myotonic or pseudomyotonic discharges [5]. MRI examination of the muscles can also be helpful in detecting muscle edema and necrosis. In patients who underwent bilateral thigh MRI, 100% had evidence of edema, 75% muscle atrophy, and 67% fatty replacement [20]. The most prominent finding on pathology in SINAM is muscle fiber necrosis. There is generally an absence of CD8+ T cells invading muscle fibers, although their presence does not exclude a diagnosis of SINAM [26]. In addition to the lack of lymphocyte infiltration, abundant myophagocytosis is often present [27]. There is typically no significant denervation or amyloid deposition. MHC class I and class II staining helps to differentiate SINAM from metabolic or genetic muscle disorders [4,19]. Sarcolemmal MHC class I staining appears particularly specific to SINAM, in sharp contrast to other inflammatory myopathies [27]. 6.2. Differential diagnosis Given the high prevalence of statin usage in the general population and the relative rarity of SINAM, an exposure history alone is not adequate to make a diagnosis of SINAM, and the exclusion of more common myopathies should be undertaken. It is important to recognize that slightly raised CK levels are common in general population [28]. CK levels are higher in black than in white, and in men than women. One common cause of high CK levels is moderate to strenuous exercise especially in untrained individuals [29]. Latent or subclinical hypothyroidism is another cause of high CK and it has been reported that 3% of hyperlipidemia patients referred with asymptomatic high CK have high thyroid-stimulating hormone [30]. Statin usage may rarely reveal latent mitochondrial or metabolic diseases (McArdle, carnitine palmitoyltransferase II deficiency, or myoadenylate deaminase
7. Conclusion Statin induced necrotizing myopathy is a severe form of muscle toxicity associated with statin usage. Albeit rare, awareness and knowledge of SINAM are very useful for a practicing clinician. It is important to recognize that the anti-HMGCR antibody is specific for diagnosing SINAM. Once the diagnosis is made, early immunosuppressive therapy should be initiated to improve patient outcome significantly. There are several gaps in this field with potentials for future research. With an increasing recognition of this entity and commercial available testing, we may be able to better understand its epidemiological characteristics including its true incidence and clinical course. The role of antiHMGCR antibody and the molecular mechanism underlying SINAM
S. Babu, Y. Li / Journal of the Neurological Sciences 351 (2015) 13–17
await further clarification. In addition to statin exposure, additional risk factors for anti-HMGCR positive necrotizing myopathy should be actively sought. Evidence-based therapeutic options to guide SINAM treatment are needed. Finally, it would be valuable to know if every SINAM patient needs to permanently avoid all statins or a statin class/dose change is permissible in the context of effective immunosuppressive therapy. Disclosures None. References [1] Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285: 2486–97. [2] Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding statin use in america and gaps in patient education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol 2012;6:208–15. [3] Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther 2005;19:403–14. [4] Needham M, Fabian V, Knezevic W, Panegyres P, Zilko P, Mastaglia FL. Progressive myopathy with up-regulation of MHC-I associated with statin therapy. Neuromuscul Disord 2007;17:194–200. [5] Grable-Esposito P, Katzberg HD, Greenberg SA, Srinivasan J, Katz J, Amato AA. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve 2010;41:185–90. [6] Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010;62:2757–66. [7] Allenbach Y, Drouot L, Rigolet A, Charuel JL, Jouen F, Romero NB, et al. Anti-HMGCR autoantibodies in european patients with autoimmune necrotizing myopathies: inconstant exposure to statin. Med (Baltimore) 2014;93:150–7. [8] Alfirevic A, Neely D, Armitage J, Chinoy H, Cooper RG, Laaksonen R, et al. Phenotype standardization for statin-induced myotoxicity. Clin Pharmacol Ther 2014;96: 470–6. [9] Molokhia M, McKeigue P, Curcin V, Majeed A. Statin induced myopathy and myalgia: time trend analysis and comparison of risk associated with statin class from 1991-2006. PLoS One 2008;3:e2522. [10] Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med 2005;165:2671–6. [11] Radcliffe KA, Campbell WW. Statin myopathy. Curr Neurol Neurosci Rep 2008;8: 66–72. [12] Vaklavas C, Chatzizisis YS, Ziakas A, Zamboulis C, Giannoglou GD. Molecular basis of statin-associated myopathy. Atherosclerosis 2009;202:18–28. [13] Pasternak RC, Smith Jr SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Stroke 2002;33: 2337–41. [14] Vladutiu GD. Genetic predisposition to statin myopathy. Curr Opin Rheumatol 2008; 20:648–55. [15] Gupta A, Thompson PD. The relationship of vitamin D deficiency to statin myopathy. Atherosclerosis 2011;215:23–9. [16] SEARCH Collaborative GroupLink E, Parish S, Armitage J, Bowman L, Heath S, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 2008;359:789–99. [17] Silva M, Matthews ML, Jarvis C, Nolan NM, Belliveau P, Malloy M, et al. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther 2007;29:253–60.
17
[18] van der Pas J, Hengstman GJ, ter Laak HJ, Borm GF, van Engelen BG. Diagnostic value of MHC class I staining in idiopathic inflammatory myopathies. J Neurol Neurosurg Psychiatry 2004;75:136–9. [19] Rodriguez Cruz PM, Luo YB, Miller J, Junckerstorff RC, Mastaglia FL, Fabian V. An analysis of the sensitivity and specificity of MHC-I and MHC-II immunohistochemical staining in muscle biopsies for the diagnosis of inflammatory myopathies. Neuromuscul Disord 2014;24:1025–35. [20] Mammen AL, Chung T, Christopher-Stine L, Rosen P, Rosen A, Doering KR, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011;63: 713–21. [21] Mohassel P, Mammen AL. Statin-associated autoimmune myopathy and antiHMGCR autoantibodies: a review. Muscle Nerve 2013;48:477–83. [22] Werner JL, Christopher-Stine L, Ghazarian SR, Pak KS, Kus JE, Daya NR, et al. Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Rheum 2012;64:4087–93. [23] Mammen AL, Pak K, Williams EK, Brisson D, Coresh J, Selvin E, et al. Rarity of anti-3hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects. Arthritis Care Res 2012;64: 269–72 (Hoboken). [24] Mammen AL, Gaudet D, Brisson D, Christopher-Stine L, Lloyd TE, Leffell MS, et al. Increased frequency of DRB1*11:01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Care Res 2012;64:1233–7 (Hoboken). [25] Morikawa S, Murakami T, Yamazaki H, Izumi A, Saito Y, Hamakubo T, et al. Analysis of the global RNA expression profiles of skeletal muscle cells treated with statins. J Atheroscler Thromb 2005;12:121–31. [26] Casciola-Rosen L, Mammen AL. Myositis autoantibodies. Curr Opin Rheumatol 2012; 24:602–8. [27] Stenzel W, Goebel HH, Aronica E. Review: immune-mediated necrotizing myopathies–a heterogeneous group of diseases with specific myopathological features. Neuropathol Appl Neurobiol 2012;38:632–46. [28] Brewster LM, Mairuhu G, Sturk A, van Montfrans GA. Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J 2007;154: 655–61. [29] Brancaccio P, Maffulli N, Limongelli FM. Creatine kinase monitoring in sport medicine. Br Med Bull 2007;81–82:209–30. [30] Glueck CJ, Rawal B, Khan NA, Yeramaneni S, Goldenberg N, Wang P. Should high creatine kinase discourage the initiation or continuance of statins for the treatment of hypercholesterolemia? Metabolism 2009;58:233–8. [31] Vladutiu GD, Simmons Z, Isackson PJ, Tarnopolsky M, Peltier WL, Barboi AC, et al. Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle Nerve 2006;34:153–62. [32] Kao AH, Lacomis D, Lucas M, Fertig N, Oddis CV. Anti-signal recognition particle autoantibody in patients with and patients without idiopathic inflammatory myopathy. Arthritis Rheum 2004;50:209–15. [33] Wegener S, Bremer J, Komminoth P, Jung HH, Weller M. Paraneoplastic necrotizing myopathy with a mild inflammatory component: a case report and review of the literature. Case Rep Oncol 2010;3:88–92. [34] van der Meulen MF, Bronner IM, Hoogendijk JE, Burger H, van Venrooij WJ, Voskuyl AE, et al. Polymyositis: an overdiagnosed entity. Neurology 2003;61:316–21. [35] Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344–7. [36] Padala S, Thompson PD. Statins as a possible cause of inflammatory and necrotizing myopathies. Atherosclerosis 2012;222:15–21. [37] Noel B, Cerottini JP, Panizzon RG. Atorvastatin-induced dermatomyositis. Am J Med 2001;110:670–1. [38] Thual N, Penven K, Chevallier JM, Dompmartin A, Leroy D. Fluvastatin-induced dermatomyositis. Ann Dermatol Venereol 2005;132:996–9. [39] Albayda J, Mammen AL. Is statin-induced myositis part of the polymyositis disease spectrum? Curr Rheumatol Rep 2014;16:433.
