ABSTRACT

Myopathies are generally divided into acquired and inherited forms. Most common forms of the acquired myopathies include the idiopathic inflammatory myopathies (IIMs), myopathy associated with medications and toxins, infectious myopathies, and myopathies associated with systemic conditions. IIMs are rare but are often chronic, progressive, and disabling. The literature on incidence and prevalence rates, psycho-social and economic impact, and outcome of IIMs in the US population are limited.

Statins are one of the most commonly prescribed medications worldwide. Common clinically benign muscle problems can occur in approximately 10% to 25% of patients on statins. Due to the aging of the population, the use of statins may increase in the upcoming years. Public Health Relevance: Therefore, statin-associated adverse events can have a huge impact on a large portion of the population. Involvement of representatives from organizations such as American College of Rheumatology and Myositis Associationcan result in better understanding of the statin-associated muscle injury and reduction of its health burden.

TABLE OF CONTENTS

1.0Introduction

1.1Adult polymyositis (PM) and adult dermatomyositis (DM)

1.2Inclusion body myositis (IBM)

1.3STATIN MYOPATHY

2.0Conclusion

bibliography

1

1.0 Introduction

Skeletal muscle is a dynamic and complex tissue that is composed of many structural proteins and metabolic pathways. Myopathy refers to a disorder of the skeletal muscle. Myopathies can be divided into acquired and inherited myopathies. Most common forms of the acquired myopathies include the idiopathic inflammatory myopathies (IIMs), myopathy associated with medications and toxins, infectious myopathies, and myopathies associated with systemic disorders. The inherited forms of myopathies include metabolic myopathies, muscular dystrophies, and congenital myopathies.

IIMs are a group of heterogeneous, systemic rheumatic diseases that include adult polymyositis (PM), adult dermatomyositis (DM), myositis associated with other connective tissue disease or cancer, and inclusion body myositis (IBM), juvenile myositis (juvenile dermatomyositis and juvenile polymyositis). The literature on incidence and prevalence rates, and prognosis of myopathies in the in the US population and the resultant magnitude of their impact on the public's health are limited. In order to understand the public health importance of myopathies it is necessary to have estimates of the actual number of persons in the United States that are affected by myopathies and the prognosis.

In this review, we will update the epidemiology of IIMs, and statin myopathy which is a common form of myopathy associated with medications.

1.1Adult polymyositis (PM) and adult dermatomyositis (DM)

The estimated combined annual incidence of adult PM and DM in the general population is approximately 2 per 100,000 persons [1]. The prevalence of adult PM and DM has been estimated at5 to 22 per 100,000 according to age, sex and region [2, 3]. The reported female to male ratio is 2 to 1. The peak incidence of adult PM and DM occurs between the ages of 40 and 50, but they can affect people of any age [4, 5].

In a recent population-based study in Olmsted County, Minnesota, patients with a diagnosis of dermatomyositis were identified from the Rochester Epidemiology Project database from 1976 through 2007 [6]. The estimated overall age- and sex-adjusted annual incidence of DM in the residents of Olmstead County in Minnesota was approximately 1 per 100,000 persons (95% confidence interval [CI], 0.609-1.317) in which the estimated annual incidence of the amyopathic subset of DM was 0.2 per 100,000 persons. Average duration of follow-up from the date of disease diagnosis was 6.85 years (range: 0.07-19.56 years). At the end of the study period, 8 of the 29 patients (28%) had died. Kaplan-Meier estimates of overall 5- and 10-year survival was 0.80 (95% CI, 0.66-0.97) and 0.73 (95% CI, 0.56-0.96), respectively while the expected 5- and 10-year survival for the age- and sex-matched general Minnesota population was 0.92 and 0.85, respectively. The IIMs has been shown in other studies to be associated with an increase in mortality. In a review from Karolinska Institute in Sweden, the 5-year survival ranged from 52 to 65 percent in studies from 1971 to 1985, improving to 75 to 95 percent in studies from 2001 to 2006 [7]. The clinical features that have been associated with poor prognosis in adult PM and DM include interstitial lung disease, associated malignancy, greater proximal muscle weakness at presentation, the presence of dysphagia, respiratory muscle involvement, cardiac involvement, and delay in the initiation of treatment [8-10]. Increased age has been suggested to be associated with poor prognosis [11] but this finding has not been consistent. Interestingly, there is no convincing data to suggest predictive value ofserum creatine kinase (CK) elevation, the presence or absence of rash, sex, or race. The presence of myositis-associated auto-antibodies may predict the clinical course and prognosis [12]. The most common myositis-associated autoantibodies include anti-synthetase autoantibodies that are directed against one of the aminoacyl-transfer ribonucleic acid (tRNA) synthetase enzymes. To date, 8 anti-synthetase autoantibodies have been identified which include anti-Jo-1 and non Jo-1 antibodies. In a recent study, non-Jo-1 anti-synthetase antibody positive patients were shown to have decreased survival compared with Jo-1 patients [13]. The common causes of death in patients with adult PM and DM include respiratory failure (in the setting of ILD, rapidly progressive ILD, respiratory tract infections, or respiratory muscle weakness), malignancies, and cardiovascular disease.

Larger population-based studies are needed to have a better estimate of the incidence and prevalence rates of adult PM and DM.

1.2Inclusion body myositis (IBM)

Epidemiologic data on IBM are scarce, and possibly biased, because some prior to the time when IBM was distinguished from PM and DM some patients who had a diagnosis of PM might have had IBM. The prevalence of IBM has been estimated at 5 to 9 cases per million persons [13-17], but the true prevalence may be higher as mentioned above. In a recent study, charts of patients with a diagnosis of myositis in Olmsted County, Minnesota, from 1981 to 2000 were reviewed [17]. The age- and sex-adjusted prevalence rate for IBM was 7.06 per 100,000 persons(95% CI 0.87-13.24) and the age- and sex-adjusted incidence rate was 0.79 per 100,000 (95% CI 0.24-1.35), both rates higher than previously reported.

Unfortunately, IBM is generally refractory to the currently available systemic immunosuppressive and immunemodulatory therapies. Increased age at onset is thought to be associated with poor prognosis. In general, the clinical course is very gradual and by 10-15 years, patients require assistance with activities of daily living (ADLs). The causes of death in patients with IBM are respiratory failure or respiratory tract infections.

1.3STATIN MYOPATHY

Statins are one of the most commonly prescribed medications worldwide that are used for the management of elevated cholesterol. Clinical studies and observational studies suggest that muscle side effects are relatively common with statin use. The spectrum of statin myopathy ranges from myalgia to rhabdomyolysis. Common clinically benign muscle problems can occur in approximately 10% to 25% of patients whereas rhabdomyolysis is very rare [19, 20]. However, in a recent meta-analysis of 42 randomized clinical trials of statin therapy, the percentage of muscle problems tended to be only slightly higher with statin treatment (12.7%) than with placebo group (12.4%, P = .06) [21]. The noted difference may be related to specific inclusion and exclusion criteria in randomized clinical trials that limit the ability to generalize their results.

The frequency and severity of muscle problems appear to vary among the different statins. The risk of muscle injury appears to be lowest with pravastatin and fluvastatin [22]. In a prospective analysis, pravastatin therapy (40mg per day)was found to be with no laboratory and clinical evidence for myositis during more than 112,000 patient-years of experience in three large controlled trials,The West of Scotland Coronary Prevention Study (WOSCOPS), the Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies [23]. With more than 243 000 blood sample analyses, the incidence of abnormal liver function test was similar for pravastatin and placebo groups. Also, the safety of rosuvastatin (20 mg daily) was confirmed in a trial of 17,802 apparently healthy men and women (with low-density lipoprotein [LDL] cholesterol levels of less than 130 mg per deciliter) in which rates of muscle toxicity were similar in rosuvastatin and placebo groups [24]. Pravastatin,fluvastatin, rosuvastatin, and pitavastatinare not extensively metabolized by CYP3A4 and therefore are less likely to be associated with drug interactions.

Genetic predisposition appears to play a major role in the susceptibility to statin myopathy [25]. In a genomewide association study using approximately 300,000 markers in 85 patients on simvastatin with definite or incipient myopathy and 90 healthy controls showed a single strong association of myopathy with rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 which encodes the organic anion transporting polypeptide 1B1 (OATP1B1) that mediates hepatic uptake of most statins [26]. Subsequently in the STRENGTH (Statin Response Examined by Genetic Haplotype Markers), 509 subjects were randomized to atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg followed by 80 mg, 80 mg, and 40 mg, respectively. A composite adverse event was defined as myalgia, CK more than 3 times upper limit of normal, or discontinuation for any side effect during follow-up. A specific SLCO1B1 variant (SLCO1B1*5) was associated with increased risk of adverse events [27]. In an in vitro study, uptake transporter OATP2B1 and the efflux transporters, multidrug resistance-associated protein (MRP)1, MRP4, and MRP5 which are expressed on the sarcolemmal membrane of human skeletal muscle fibers, were shown to increases intracellular accumulation and toxicity of statins [28].

There may be ethnic variations in the susceptibility to statin myopathy, at least with simvastatin. In a large randomized trial (HPS2-THRIVE), in which patients were treated with simvastatin 40 mg daily and combination extended release (ER) niacin/laropiprant or placebo, any myopathy (definite or incipient) was more common among Chinese patients (138 [0.66%/year] vs. 27 [0.13%/year]) than among those in Europe (17 [0.07%/year] vs. 11 [0.04%/year]) [29].

Concurrent therapy with a variety of medications can have myopathic interactions with statins. Drugs that inhibit cytochrome P450 3A4 (CYP3A4) can increase the susceptibility to statin myopathy due tolovastatin,simvastatin, and to a lesser extentatorvastatin since they are metabolized by CYP3A4 [30]. These medications include macrolide antibiotics (such as erythromycin), systemic-azole antifungals (such as ketoconazole), HIV/HCVprotease inhibitors (such as ritonavir), and cyclosporine [30-32]. Statins that arenot highly dependent upon CYP3A4 for metabolism such as pravastatinor low-doseatorvastatinare appropriate choices for patients receiving the aforementioned medications who require statin treatment. Medications that are competitive CYP3A4 substrates may also increase the risk of statin myopathy have myopathic interactions with statins, as has been reported with colchicine and calcium channel blockers (such as amlodipine and verapamil) [33].

Grapefruit juice inhibits intestinal CYP3A4. However, customary exposure to grapefruit juice does not increase the risk of an adverse effect or muscle injury. In an investigation, patients on extended treatment with atorvastatin (10, 20 or 40 mg day) at a stable dose received 300 ml day of 100% grapefruit juice for a period of 90 days. Theaddition of daily grapefruit juice was associated with slight elevation of serum atorvastatin concentrations, but no detectable liver or muscle adverse effects [34].

Underlying neuromuscular disorders may increase the risk of statin myopathy. Amyotrophic lateral sclerosis (ALS) may interact with statin therapy. In a prospective cohort of one hundred and sixty-four consecutive patients with laboratory supported probable, clinically probable, or clinically definite ALS, demonstrated a strong association between statin therapy and an increased rate of functional decline and muscle cramp frequency and severity [35]. There have been reports of statin-associated exacerbation of myasthenia gravis [36].

The National Lipid Association's Muscle Safety Expert Panel recently issued a paradigm to enhance accurate definition of statin-associated muscle adverse events, and possible use of validated tools and neuromuscular studies to accurately diagnose statin muscle injury [37]. The panel recommended a graduated training program for metabolic adaptation and prevention of exercise-induced muscle injury in those who plan to have regular physical exertion while taking statins. Even with such adaptation, statins use may potentiate muscle injury with prolonged vigorous exercise but the injury is typically mild and often subclinical [38]. It appears that susceptibility to exercise-induced muscle injury with statins increases with age [38].

2.0 Conclusion

The literature on incidence and prevalence rates, and outcome of idiopathic inflammatory myopathies and statin myopathy in the in the US population are limited. Idiopathic inflammatory myopathies are rare conditions that affect a small portion of the population but are often chronic, progressive, and disabling. Psycho-social and economic impact of inflammatory myopathies have yet to be determined. Larger population-based studies are needed to have a better estimate of the major epidemiologic features. There is also a need for more local or national registries and research focusing on etiologic factors. The detection and treatment of inflammatory myopathies in early stages can lead to less muscle damage and disability. Better quality care measures will help focus intervention efforts.

Statins are one of the most commonly used drugs worldwide. Due to the aging of the population, the use of statins may further increase in the upcoming years. Therefore, statin-associated muscle injury can have a huge impact on a large portion of the population. Several organizations and groups are collaborating to address statin myopathy in the United States including The National Lipid Association's Muscle Safety Task Force. The most recent panel was composed of clinical cardiologists, clinical lipidologists, an exercise physiologist, and a neuromuscular specialist. Involvement of representatives from other organizations such as American College of Rheumatology and Myositis Association can result in better understanding of the statin-associated muscle adverse events and reduction of health burden

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