Toxic Myopathies

Abstract

Purpose

This article reviews the most important muscle toxins, many of which are widely prescribed medications. Particular emphasis is placed on statins, which cause muscle symptoms in a relatively large proportion of the patients who take them.

Recent Findings

As with other toxic myopathies, most cases of statin-associated myotoxicity are self-limited and subside with discontinuation of the offending agent. Importantly, about 2% of the population is homozygous for a single nucleotide polymorphism, and these individuals have a dramatically increased risk of self-limited statin myopathy. Much more rarely, statins trigger a progressive autoimmune myopathy characterized by a necrotizing muscle biopsy and autoantibodies recognizing hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the pharmacologic target of statins.

Summary

In most cases, toxic myopathies resolve after the toxic agent is stopped. Recognizing that statins can cause an autoimmune necrotizing myopathy is important because patients with this form of statin-triggered muscle disease usually require immunosuppressive therapy.

INTRODUCTION

Exposures to numerous exogenous substances have been reported to cause muscle damage. Many of these are commonly prescribed medications. Table 6-11 provides a comprehensive list of such substances, including some for which only a few case reports exist. This review will focus on the most important and well-established myotoxic substances, organizing them based on their histologic features and/or presumed pathogenic mechanisms according to a scheme adapted from Amato and Russell.2 The review will begin with a detailed discussion of statins, the most commonly prescribed class of potentially myotoxic medication, emphasizing the recent discovery that these drugs can trigger an autoimmune necrotizing myopathy.

Table 6-1.

Potentially Myotoxic Substances^a

NECROTIZING MYOPATHIES

The following section highlights several classes of medications that are associated predominantly with myofiber necrosis on muscle biopsy. Although the pathogenic mechanisms are poorly understood, it is thought that some of these medications may destabilize the lipophilic muscle membrane and thereby cause myofiber degeneration. As a consequence of myofiber necrosis, patients typically have creatine kinase (CK) elevations and features of an irritable myopathy on EMG. Fortunately, discontinuation of the offending agent usually leads to resolution of the myopathic process and restoration of muscle strength. An important exception is the case of statin-associated immune-mediated necrotizing myopathy, which requires immunosuppressive treatment to halt and reverse the disease process.

Statin-Associated Myopathy

Self-limited statin-associated myopathy. Statins decrease serum cholesterol levels and thereby reduce the risk of cardiovascular events by inhibiting hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the rate-limiting step of cholesterol biosynthesis (Figure 6-13). Although they are generally well tolerated, mild statin-associated musculoskeletal side effects, such as myalgia or cramps, occur in as many as 20% of statin users,4 which may represent a 1.5-fold to 10-fold increase compared to those not on statins.5,6,7 However, severe myotoxicity in the form of rhabdomyolysis is much more rare and only occurs at a rate of 0.44 per 10,000 patient-years.8 Nonetheless, because close to 30 million Americans are currently prescribed a statin medication, patients with significant statin myotoxicity are regularly encountered in clinical practice. Fortunately, in most cases, both mild and severe side effects are self-limiting, with discontinuation of the offending medication resulting in resolution of symptoms after an average of 2 months (range 1 week to 14 months).9

Figure 6-1.

The mevalonate pathway. HMG-CoA reductase catalyzes the rate-limiting step in the production of cholesterol, CoQ10, and isoprenylated proteins from the precursors acetyl-CoA and acetoacetyl-CoA. Inhibition of HMG-CoA by statins results in decreased levels of cholesterol and the other downstream products of this pathway. Decreased levels of cholesterol cause compensatory increased levels of HMG-CoA; this may provoke an immune response against the enzyme in immunogenetically susceptible individuals. CoA = coenzyme A; HMG-CoA = hydroxymethylglutaryl coenzyme A; PP = pyrophosphate; tRNA = transfer RNA; CoQ10 = coenzyme Q10. Reprinted with permission from Greenberg SA, Amato AA, Continuum (Minneap Minn).3 © 2006, American Academy of Neurology. journals.lww.com/continuum/Fulltext/2006/06000/Statin_Myopathies.8.aspx.

Several factors appear to increase the risk of statin-triggered myopathy. For instance, older age, hypothyroidism, obesity, and preexisting liver disease all increase the risk of side effects. Different statin medications appear to have different risks of toxicity; for example, fluvastatin and pravastatin may have significantly higher rates of myopathy compared to rosuvastatin.7 Importantly, higher statin doses also appear to increase the risk of statin myopathy. For example, 98 out of 6031 (1.6%) subjects taking simvastatin at a dose of 80 mg/d developed myopathy, compared to just 8 out of 6033 (0.1%) of subjects who were taking 20 mg/d.10

Because of the dose-dependent nature of statin toxicity, the coadministration of medications that increase serum levels of statins can increase the risk of myopathy. Since atorvastatin, lovastatin, and simvastatin are metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme, other drugs that are metabolized by this enzyme can increase the risk of statin myopathy. Many prescribed drugs belong to this category, including calcium channel blockers, antibiotics, antifungals, antiretrovirals, antidepressants, and immunosuppressants (Table 6-2). Pravastatin and rosuvastatin are not metabolized by the CYP3A4 system and therefore are not susceptible to these interactions.

Table 6-2.

Inhibitors and Inducers of the CYP3A4 P450 Enzymatic Pathway

Recently, a genome-wide association study identified a polymorphism within the SLCO1B1 gene as a significant genetic risk factor for developing statin-associated myopathy.10 This gene encodes a protein responsible for the hepatic uptake of statins, and people who are homozygous for this polymorphism most likely have higher serum levels of statins, thus accounting for the increased risk. Around 2% of the general population fall into this category, and the best evidence suggests that around 15% of these patients would develop a myopathy within the first year of treatment with simvastatin at a dose of 80 mg/d. Although other genetic risk factors for developing statin myopathy have been proposed (eg, mutations in genes encoding carnitine palmitoyltransferase 2 and myoadenylate deaminase), evidence to support these associations is less robust.

Proposed mechanisms of self-limited statin-myopathy. Statins reduce cholesterol levels by inhibiting HMG-CoA reductase and thereby decreasing levels of mevalonate, a principal cholesterol precursor. While it has been proposed that decreased cholesterol levels might cause myotoxicity by disrupting the integrity of the muscle fiber membrane, a reduction in other downstream products of mevalonate could also conceivably lead to muscle damage (Figure 6-1). For example, mevalonate is required for production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which in turn are required for protein prenylation, an important posttranslational modification. The production of ubiquinone (ie, coenzyme Q10), a key component of the mitochondrial electron transport chain, also depends on protein prenylation. Other prenylated proteins include Rho and Rab, small guanosine triphosphatases (GTPases) that promote cell survival; inhibiting production of these proteins could conceivably lead to cell death. Furthermore, prenylation is required for the process of N-glycosylation, a critical posttranslational modification, the inhibition of which could be damaging to muscle cells. While some observational and experimental evidence supports each of these mechanisms in mediating self-limited statin myopathy,11 the actual mechanisms underlying muscle damage in humans taking statins remain unknown.

Statin-triggered immune-mediated necrotizing myopathy. In most subjects with statin-associated musculoskeletal side effects, discontinuing theoffending medication will halt the pathophysiologic process, and the subsequent regeneration of myofibers will restore muscle function. However, recent evidence suggests that statins can also trigger an autoimmune myopathy that progresses even after the statin is discontinued.12,13,14 After periods of statin exposure ranging from weeks to years, these patients develop proximal muscle weakness, markedly elevated CK levels (mean is approximately 10,000 IU/L), an irritable myopathy on needle EMG, and muscle MRI demonstrating edema. Muscle biopsies typically reveal a necrotizing myopathy with minimal inflammatory cell infiltrates (Figure 6-2). When present, infiltrating lymphocytes occur most typically in a perivascular distribution. Immunostaining reveals that the sarcolemmal surface of many specimens from these patients is positive for major histocompatibility complex (MHC)–I, as seen in other forms of autoimmune myopathy. Some specimens also show membrane attack complex on the surface of nonnecrotic muscle fibers.

Figure 6-2.

A muscle biopsy from a patient with statin-associated immune-mediated necrotizing myopathy shows myofiber degeneration, necrosis, myophagocytosis, and regeneration without prominent lymphocytic infiltrates (hematoxylin and eosin stain).

Many, if not all, patients with statin-triggered autoimmune myopathy develop antibodies recognizing HMG-CoA reductase, the pharmacologic target of statins.15 These antibodies appear to be specific for patients with an autoimmune process and have not been found in other statin-treated subjects, including those with mild self-limited muscle symptoms.16 Therefore, when testing for the presence of these antibodies becomes commercially available, this should help clinicians differentiate those with immune-mediated myopathy-who require treatment-from those with self-limited statin toxicity.

Patients with statin-associated autoimmune myopathy do not have an increased prevalence of the SLCO1B1 single nucleotide polymorphism that is associated with a susceptibility to self-limited statin toxicity. However, as in other systemic autoimmune diseases, immunogenetic factors can protect or predispose individuals to developing anti–HMG-CoA reductase-positive myopathy.17 For example, the class II human leukocyte antigen (HLA) alleles DQA1 and DQB6 are negatively associated with developing this form of autoimmune muscle disease. In contrast, the odds ratios for developing anti–HMG-CoA reductase myopathy are 24.5 (P=3.2 × 10⁻¹⁰) in white patients and 56.5 (P=3.1 × 10⁻⁶) in black patients who have the class II HLA allele DRB1*11:01 compared to those without this allele. It should be noted, however, that testing for the DRB1*11:01 allele is not useful in clinical practice because the vast majority of those with this allele most likely tolerate statins without developing an autoimmune myopathy.

Importantly, patients with statin-associated immune-mediated necrotizing myopathy often require aggressive immunosuppressive therapy. To date, optimal treatment strategies have not been validated in trials. However, based on the author’s clinicalexperience and that of others, optimal results are achieved in patients with moderate to severe weakness when they are initiated on “triple therapy” with high-dose oral prednisone, IV immunoglobulin (IVIg), and another steroid-sparing agent (eg, azathioprine, methotrexate, or mycophenolate mofetil) (Case 6-1). In treated statin-exposed anti–HMG-CoA reductase myopathy patients followed for an average of over 2 years, CK levels declined from an average of 4835 IU to 878 IU, and proximal muscle strength improved from an average of approximately 3/5 to 4+/5 on the Medical Research Council scale.18

Case 6-1

A 64-year-old man with hypercholesterolemia had been on atorvastatin for 3 years when he developed progressive bilateral quadriceps muscle pain. After 3 weeks of myalgia, he saw his primary care doctor, who found that the patient’s creatine kinase (CK) was elevated to 1047 IU/L and subsequently discontinued the statin medication. Four weeks later, the muscle pain had not diminished, and the patient noticed that he was having increasing difficulty climbing stairs. His CK was 2216 IU/L, and his physician now noted moderate hip flexor weakness on examination. No rash was present. Two weeks later, the patient underwent EMG that revealed an irritable myopathy. A muscle biopsy performed the next week showed many degenerating and regenerating myofibers with a few perivascular inflammatory cells. He was diagnosed with probable statin-associated immune-mediated necrotizing myopathy, and prednisone was initiated at 60 mg/d, at which time his CK was 5231 IU/L and he was experiencing difficulty with proximal arm weakness as well as increasing difficulty walking even on flat surfaces. After 4 weeks of high-dose oral steroids, his CK decreased to 3742 IU/L, but his weakness had not improved. Oral methotrexate was started, but 6 weeks later his CK remained markedly elevated and he was no stronger. IV immunoglobulin (IVIg) was initiated at a dose of 0.4 g/kg/d for 5 days each month. After 3 months of high-dose steroids, methotrexate, and IVIg, his CK had normalized, and he was back to near normal strength. Over the next 6 months, the steroids were tapered off and the IVIg was discontinued without relapse; however, when the methotrexate was stopped, he developed recurrent muscle pain with a CK elevation to 631 IU/L. Methotrexate was restarted, and he underwent a short course of oral prednisone therapy with resolution of the symptoms and the elevated muscle enzymes. He required continued methotrexate therapy to keep the muscle disease in remission.

Comment. Patients with statin-associated immune-mediated necrotizing myopathy develop weakness in the context of statin exposure that continues to progress despite discontinuation of the statin. These patients typically require aggressive immunosuppressive therapy, often with multiple agents, in order to control the disease. Some patients require long-term immunosuppressive therapy. In the author’s experience, reexposure to lipid-lowering medications may precipitate relapse of the myopathy.

An approach to the patient with muscle symptoms after statin exposure. In statin-treated patients who present with muscle symptoms, strength should be assessed and serum muscle enzyme levels should be measured. Those with normal muscle enzymes and strength most likely have a mild process that may or may not be related to the statin. If possible, the statin should be discontinued to see whether the muscle symptoms spontaneously resolve over weeks to months. If muscle symptoms do not resolve or become worse, then other causes of these symptoms should be considered. However, if the symptoms do resolve, then rechallenging the patient with a different statin at an initially low dose can be considered. For example, the majority of patients who experienced myalgia on another statin were able to tolerate rosuvastatin dosed at 5 mg every other day with an adequate reduction in low-density lipoprotein (LDL) cholesterol levels (Case 6-2).19

Case 6-2

A 59-year-old man with hypercholesterolemia and a strong family history of coronary artery disease was started on simvastatin at a dose of 40 mg/d. After several months, he began to experience muscle pain without weakness, and the dose of statin was reduced to 20 mg/d. He continued to have muscle pain after 2 weeks on the lower dose. His creatine kinase level was checked and found to be normal at 187 IU/L. The simvastatin was discontinued, and he was started on atorvastatin at a dose of 20 mg/d. After 4 weeks, the myalgias persisted and were particularly troublesome after exercise. On repeat testing, serum muscle enzyme levels remained within normal limits. The atorvastatin was stopped, and his muscle symptoms only resolved after 4 months without statin treatment. Given his cardiovascular risk factors, he was started on rosuvastatin at a dose of 5 mg once per week. After he tolerated this well for a month, the dose was increased to 5 mg every other day. He was able to tolerate increasing the dose to 10 mg every other day and reached his target goal for lipid reduction without adverse effects.

Comment. Patients with statin intolerance may experience disabling muscle pain any time after starting statin medications without overt weakness or elevations in muscle enzymes. It may take weeks to months (in some cases as long as a year) for myalgias to resolve after the statin is discontinued. Fortunately, a majority of statin-intolerant patients can tolerate low-dose, every-other-day rosuvastatin treatment with adequate reductions in lipid levels.

Most patients with elevated muscle enzymes and muscle weakness due to statins also have a self-limited process, and a similar approach can be taken. However, if muscle strength continues to worsen (or fails to improve) or CK levels do not begin to drop within a few weeks of statin discontinuation, it may be that the patient has a statin-triggered autoimmune process. A muscle biopsy should be considered to look for other potential causes of severe myopathy. If the patient has a necrotizing muscle biopsy with no likely alternative diagnosis, immunosuppressive therapy may be instituted. If, in the future, a commercially available test for anti–HMG-CoA reductase antibodies becomes available, this may allow for the earlier recognition and treatment of statin-triggered autoimmune myopathy.

The role of dietary supplements in treating statin-related muscle symptoms. In addition to decreasing cholesterol levels, statins decrease the production and serum concentration of coenzyme Q10, an essential component of the mitochondrial respiratory chain. It has been hypothesized that self-limited statin-induced myopathy may result from coenzyme Q10 depletion and the subsequent disruption of mitochondrial function. It has also been suggested that statins may cause myopathy by disrupting selenoprotein synthesis. To determine whether coenzyme Q10 and selenium supplementation ameliorate statin-induced myopathy, 43 patients with atorvastatin-induced myopathy were randomized to receive either 400 mg coenzyme Q10 and 200 μg selenium per day or placebo for 12 weeks.20 Despite increasing serum coenzyme Q10 and selenium concentrations in those taking the supplements, no differences in muscle symptoms or measures of muscle function were found between the two groups. Similar studies investigating the effect of coenzyme Q10 supplementation have yielded mixed results.21,22,23 Therefore, specific recommendations about coenzyme Q10 and selenium supplementation in those with statin intolerance will have to wait until more definitive studies are conducted.

Some evidence exists that low vitamin D levels may be associated with statin myopathy,24 but this association has not been consistently reproduced.25 Although one unblinded trial suggested that vitamin D supplementation may improve statin-associated myalgias,26 placebo-controlled trials will be required to determine whether patients with statin-associated myopathy and normal vitamin D levels benefit from vitamin D supplementation. In the meantime, it can only be recommended that those with documented vitamin D deficiency (lower than 32 ng/mL) be provided with vitamin D supplementation.

Cholesterol-Lowering Drugs (Excluding Statins)

Fibric acid derivatives (eg, fenofibrate and gemfibrozil), niacin, and ezetimibe are also prescribed to control hyperlipidemia. Although monotherapy with each of these has been reported to cause a myopathy, the link between drug exposure and development of myopathy is best established for gemfibrozil. With each agent, the risk of myopathy appears to be highest in patients who are also taking statins. Again, this is particularly well-established for gemfibrozil, which interferes with statin metabolism, increases statin plasma concentrations, and is associated with a 15-fold increased risk of rhabdomyolysis compared to fenofibrate when coadministered with a statin.27

As with patients who take statins, those who are exposed to nonstatin lipid-lowering drugs have been reported to develop CK elevations, myalgias, or weakness within weeks of starting the medications. However, these manifestations of muscle injury more commonly develop several months after drug initiation. In some cases, patients may tolerate these cholesterol-lowering agents well for years before developing an overt myopathy. Interestingly, patients who have developed rhabdomyolysis after statin exposure may be at risk for recurrence of rhabdomyolysis following use of a different class of lipid-lowering agent as monotherapy.28

Immunophilins

Cyclosporine and tacrolimus are potent immunosuppressive medications used in many patients to prevent the rejection of transplanted organs, and used in some patients with autoimmune disease. In rare cases, these drugs have been associated with myalgias, CK elevations, or muscle weakness in the months after they are initiated. A cardiomyopathy has also been reported in some patients taking tacrolimus. In one comprehensive review including 34 patients who developed myopathy on cyclosporine, only 2 received cyclosporine monotherapy.29 In the remaining cases, cyclosporine was administered along with other potential myotoxins such as a statin or colchicine. This makes it difficult to determine whether cyclosporine alone can cause a myopathy. In addition to myofiber necrosis, muscle biopsies sometimes revealed evidence of mitochondrial damage including ragged red fibers and lipid vacuoles.

Other Agents Associated With Necrotizing Myopathy

The antihypertensive agent labetalol and the anesthetic propofol have rarely been associated with a necrotizing myopathy characterized by weakness, high CK levels, and an irritable myopathy on EMG.

Snake Venoms

Snake venom includes numerous compounds, some of which are potent myotoxins. For example, venom from the South American rattlesnake contains crotamine and other peptides that interact with sodium channels in the sarcolemma and T tubules. This results in increased sodium influx with resulting myofiber necrosis. Other snake venoms, such as that produced by the cobra, include peptides with phospholipase A₂ activity, which can cause rapid muscle-fiber necrosis within a few hours of injection. Snake-venom poisoning often involves multiple organ systems and is a medical emergency requiring consultation with experts who can be contacted at a regional poison control center.30

AMPHIPHILIC DRUG MYOPATHIES

Amphiphilic medications include both hydrophobic and hydrophilic domains, thus allowing them to interact with and disrupt cellular membranes. These drugs can be myopathic, causing high CK levels and proximal weakness. They may also cause neuropathy, with resulting distal weakness and sensory loss. In addition to features of an irritable myopathy seen on EMG, motor and sensory nerve conduction studies may reveal decreased amplitudes and slow velocities. Weakness is typically more severe in the legs than the arms.

Chloroquine and Hydroxychloroquine

These medications are used in the treatment and prevention of malaria because of their ability to accumulate in the parasite’s food vacuole, disrupt the metabolism of heme, and ultimately kill the parasite. Chloroquine and hydroxychloroquine are also used in several rheumatic diseases, where they exert immunomodulatory effects by inhibiting intracellular toll-like receptors. In one 3-year longitudinal study of patients with rheumatic diseases taking antimalarials, the prevalence of myopathy was 9.2%, and the annual incidence of myopathy was 1.2%; in all cases, the myopathy resolved with discontinuation of the antimalarial agent.31 In this and other studies, electron microscopy of muscle biopsies revealed myeloid bodies and curvilinear bodies due to lipid deposition; in some cases, light microscopy revealed a vacuolar myopathy. Of note, cardiac muscle may also be vulnerable to chloroquine-induced toxicity, resulting in a vacuolar cardiomyopathy.

Amiodarone

This antiarrhythmic medication may cause tremor or ataxia along with a neuromyopathy, especially in patients with renal insufficiency. The myotoxic effects of amiodarone may be exacerbated in those who also develop amiodarone-induced hypothyroidism. Muscle biopsies reveal a vacuolar myopathy, and nerve biopsies typically show lysosomal inclusions.32 In most cases, the neuropathy and myopathy resolve after the medication is discontinued or the dose is reduced, although this can take from 1 to 6 months. It should be noted that concurrent use of amiodarone and statin medications increases the risk of statin myopathy.

ANTIMICROTUBULAR DRUG MYOPATHIES

Medications that disrupt the assembly of microtubules, such as colchicine and vincristine, may interfere with the intracellular trafficking of lysosomes, thereby causing the accumulation of autophagic vacuoles. In addition to a proximal myopathy, these drugs can cause an axonal sensorimotor polyneuropathy resulting in distal sensory loss or weakness. Both myogenic and neurogenic motor units may be seen on EMG. Nerve conduction studies show reduced amplitudes and slightly reduced conduction velocities.

Colchicine

Colchicine is used to prevent and treat gout flares as well as in the management of familial Mediterranean fever. Patients can develop a myopathy and neuropathy leading to gradually progressive weakness, markedly elevated CK levels, and an irritable myopathy on EMG.33 As illustrated in Case 6-3, this may occur in the context of renal failure, which causes increased serum colchicine levels. Muscle biopsies reveal the accumulation of lysosomes and autophagic vacuoles (Figure 6-3). Discontinuation of colchicine usually results in resolution of weakness within 3 to 4 weeks.

Figure 6-3.

This muscle biopsy from a patient with colchicine myopathy shows autophagic vacuoles (Gomori one-step trichrome stain). Courtesy of Andrea M. Corse, MD.

Case 6-3

A 73-year-old woman with hypertension, diabetes mellitus, and gout developed worsening renal function over the course of a year. She then began to experience painless proximal muscle weakness, with increasing difficulty walking up stairs and brushing her hair. On examination, her physician noted proximal muscle weakness and a creatine kinase (CK) level of 2532 IU/L. EMG showed an irritable myopathy. She was started on prednisone 40 mg/d for a presumptive diagnosis of polymyositis. Her diabetes mellitus and hypertension worsened, and her weakness failed to improve after 2 months of prednisone treatment. She also began to experience paresthesia in her feet and some mild but persistent nausea. A muscle biopsy was performed, which showed variation in fiber size, disrupted internal architecture on NADH staining, and prominent nonrimmed vacuoles on Gomori one-step trichrome stain; no accumulations of lymphocytes were evident, and no perifascicular atrophy was noted. Review of the patient’s medication list revealed that she had been taking colchicine to control her gout for many years. The prednisone and colchicine were both discontinued, and her muscle strength and CK levels returned to normal within a month. She also experienced resolution of her sensory and gastrointestinal symptoms.

Comment. Colchicine binds to tubulin, prevents the formation of microtubules, and disrupts the intracellular movement of vesicles and lysosomes. With high serum concentrations, colchicine can be myotoxic, with muscle biopsy revealing a distinctive vacuolar myopathy. Since clearance of colchicine depends on adequate renal function, those who have tolerated the medication previously can develop toxicity in the context of a declining glomerular filtration rate. Of note, colchicine toxicity may also result in an axonal neuropathy, cardiac toxicity, and gastrointestinal symptoms such as nausea, vomiting, and abdominal pain. This case also highlights the importance of obtaining a muscle biopsy to rule out other causes of myopathy when a diagnosis of polymyositis is suspected. Ideally, when polymyositis is suspected, muscle biopsy should be performed before initiating immunosuppressive treatment.

Vincristine

This chemotherapeutic agent predominantly causes a dose-limiting polyneuropathy but has also rarely been associated with proximal muscle weakness in the absence of elevated serum muscle enzymes. Muscle biopsies have demonstrated necrotic muscle fibers with disarray of the normal myofibrillar architecture, but not autophagic vacuoles.34

DRUGS TOXIC TO MITOCHONDRIA

Nucleoside Reverse-Transcriptase Inhibitors

Nucleoside reverse-transcriptase inhibitors (NRTIs) were the first class of antiretroviral drugs to be developed; they interfere with replication of the HIV virus through their inhibition of the viral reverse transcriptase. However, these medications also inhibit mitochondrial DNA polymerase, resulting in mitochondrial dysfunction. It has been hypothesized that mitochondrial dysfunction underlies the muscle weakness seen in patients using NRTIs.

Azidothymidine (AZT), an analog of thymidine, is the NRTI most tightly linked to development of a myopathy.35 Patients with AZT myopathy typically present with myalgias, slowly progressive weakness, modestly elevated CK levels, and an irritable myopathy on EMG. These features may not distinguish AZT myopathy from other HIV-related myopathies such as polymyositis and inclusion body myositis; however, muscle biopsies in patients with AZT myopathy are unique because of the presence of ragged red fibers on modified Gomori one-step trichrome stain, reflecting the subsarcolemmal accumulation of abnormal mitochondria. In contrast to those with HIV-associated polymyositis or inclusion body myositis, inflammatory cells are not found in muscle biopsies of patients with AZT myopathy. Thus, muscle biopsy may be helpful in differentiating AZT myopathy from other HIV-associated myopathies, which may require immunosuppressive therapy. In those with AZT myopathy, discontinuation of the drug results in clinical improvement and resolution of the mitochondrial abnormalities seen on muscle biopsy.

Other NRTIs (eg, lamivudine, zalcitabine, stavudine, and didanosine) may also damage mitochondria. However, the risk of myopathy with these appears to be less compared to that seen in patients exposed to AZT.

INFLAMMATORY DRUG-INDUCED MYOPATHIES

A number of medications, including cimetidine, levodopa, and imatinib mesylate, have been reported to cause an inflammatory myopathy. However, the apparent associations are based on very few cases (in some instances, only a single patient), and so the relationship between drug exposure and the development of myopathy is unclear. If these medications do cause myopathy, this is most likely a very rare event.

The evidence is stronger that interferon-α exposure may trigger autoimmune muscle disease in a small minority of patients who take this medication for viral hepatitis or to treat some cancers. Similarly, a dermatomyositislike illness has been reported in patients taking adalimumab, a tumor necrosis factor inhibitor, for rheumatoid arthritis.36 However, this reaction has not been reported in patients taking adalimumab for other conditions, such as Crohn disease, so it is unclear whether development of the inflammatory myopathy is related to the medication or the underlying rheumatoid arthritis.

The occurrence of inflammatory myopathy in patients with rheumatoid arthritis treated with D-penicillamine has been well documented.37 Similarly, procainamide can be associated with myalgias, weakness, CK elevations, and an inflammatory muscle biopsy. In both cases, withdrawal of the medication should lead to resolution of the myopathy.

CRITICAL ILLNESS MYOPATHY

Patients exposed to high-dose IV steroids and nondepolarizing neuromuscular blocking agents in the intensive care unit (ICU) setting are at increased risk for developing critical illness myopathy, critical illness neuropathy, or prolonged neuromuscular blockade. One large case series suggests that among those with weakness in the ICU setting, critical illness myopathy is approximately 3 times more common than critical illness neuropathy, and that prolonged neuromuscular blockade is a relatively rare phenomenon.38 The rate of critical illness myopathy in the ICU is unknown but may be less than in previous years because of physicians’ heightened awareness of the risk factors, which has led them to limit the use of high-dose steroids and long-term neuromuscular blockade in critically ill patients.

A patient’s inability to be weaned from the ventilator is commonly the first noticed manifestation of critical illness myopathy. On examination, these patients have weakness of the trunk and proximal limbs. CK levels may be normal or moderately elevated. In those without neuropathy, sensory nerve action potential (SNAP) amplitudes are normal, whereas compound muscle action potential (CMAP) amplitudes are dramatically reduced. EMG may reveal an irritable or nonirritable myopathy. However, in severe cases, patients may not be able to recruit any motor units. Muscle biopsies reveal type 1 fiber atrophy, necrotic muscle fibers, and/or loss of myosin thick filaments as visualized on the adenosine triphosphatase (ATPase) stain (Figure 6-4). To date, the mechanism of muscle injury is poorly understood. Although mortality is as high as 30% due to sepsis and organ failure in these critically ill patients, muscle weakness can be expected to improve over months in those who are discharged from the ICU.

Figure 6-4.

An area of central clearing resulting from the loss of myosin thick filaments in a muscle biopsy from a patient with critical illness myopathy (adenosine triphosphatase [ATPase] stain). Courtesy of Andrea M. Corse, MD.

STEROID MYOPATHY

Chronic exposure to high-dose oral steroids (30 mg of prednisone per day or the equivalent) confers the greatest risk of developing steroid myopathy.2 However, steroid myopathy may occur after just a few weeks of treatment. Triamcinolone, betamethasone, dexamethasone, and other fluorinated steroids are more likely to cause steroid myopathy than prednisone or hydrocortisone, which are nonfluorinated. For unclear reasons, women are more likely to develop steroid myopathy then men.

Patients with steroid myopathy typically present with progressive proximal muscle weakness in the context of normal CK levels. EMG may either be normal or reveal a nonirritable myopathy. Although not routinely performed when steroid myopathy is suspected, muscle biopsies reveal type 2 fiber atrophy and lipid accumulation in type 1 fibers (Figure 6-5). The mechanism or mechanisms whereby steroids disrupt muscle function are not clearly understood.

Figure 6-5.

Profound atrophy of type 2 fibers (stained dark) in muscle biopsy from a patient with steroid myopathy (adenosine triphosphatase [ATPase] stain at pH 9.4). Courtesy of Andrea M. Corse, MD.

Because steroids are frequently used to treat weakness associated with autoimmune neuromuscular disorders, it may be difficult to distinguish steroid myopathy from an exacerbation of the underlying disease. In myositis patients treated with steroids, a normal CK level and nonirritable myopathy may be suggestive of steroid myopathy rather than flaring of the autoimmune disease. When the role of steroids in causing weakness is unclear, a trial of steroid tapering may be considered. In patients with steroid myopathy, this should result in improved strength. In contrast, clinical worsening with steroid tapering suggests that more aggressive immunosuppressive therapy may be required to treat the underlying disease.

MALIGNANT HYPERTHERMIA

Depolarizing muscle relaxants (eg, succinylcholine) and inhalational anesthetic agents (eg, halothane, sevoflurane, and desflurane) may cause a potentially fatal malignant hyperthermia to develop during or shortly after surgery in genetically susceptible individuals. Patients present with muscle rigidity, fever, and cardiac arrhythmias. Laboratory studies may reveal high CK levels, hyperkalemia, and acidosis. Numerous susceptibility loci have been identified and are associated with mutations of the ryanodine receptor, sodium channels, calcium channels, and other proteins (Table 6-3). In addition to genetic testing, the halothane contracture test or caffeine contracture test can be used to screen for susceptibility to malignant hyperthermia. However, these tests are often only available at specialized centers. Depolarizing muscle relaxants and inhalational anesthetic agents should be avoided in subjects with known susceptibility factors. In those who develop malignant hyperthermia, the anesthetic agent must be stopped and aggressive cooling measures must be instituted. In addition to providing other measures of supportive care, dantrolene may be delivered by rapid IV injection at a dose of 2 mg/kg to 3 mg/kg every 5 minutes for a total cumulative dose of 10 mg/kg.

Table 6-3.

Malignant Hyperthermia

ALCOHOL

Patients who engage in binge drinking may develop myalgias, muscle cramping, and weakness.39 These symptoms are associated with high CK levels, an irritable myopathy on EMG, and, in severe cases, acute renal failure. CK levels and muscle symptoms resolve over several weeks but may recur with repeated exposure to alcohol in those who are susceptible to this form of toxic myopathy.

CONCLUSION

Many exogenous substances have the potential to cause myotoxicity, including commonly prescribed medications (eg, statins and steroids), snake venom, and alcohol. Fortunately, muscle cells have the capacity to regenerate so that damage can usually be reversed by recognizing and discontinuing the offending agent. An important exception includes patients who develop an immune-mediated necrotizing myopathy in the context of statin exposure. Recognizing this entity is essential because, unlike patients with self-limited statin myopathy, those with statin-associated autoimmune myopathy require immunosuppressive therapy to control the disease process. When testing for these becomes commercially available, the presence of anti–HMG-CoA reductase antibodies should help physicians identify this rare but important population of patients.

KEY POINTS

• As many as 20% of statin users experience myalgias or cramps.

• Statin-associated rhabdomyolysis is rare, occurring at a rate of 0.44 per 10,000 patient-years.

• Self-limited statin myopathy typically resolves 1 week to 14 months after stopping the drug.

• Higher statin doses are associated with an increased risk of toxicity.

• Atorvastatin, lovastatin, and simvastatin are metabolized by the CYP3A4 P450 system. Coadministration of other drugs metabolized by this enzyme can increase the risk of statin myopathy.

• About 2% of the population are homozygous for a single nucleotide polymorphism within the SLCO1B1 gene and consequently have an increased risk of developing self-limited statin myopathy.

• The mechanisms of statin toxicity are unknown but are probably related to decreased production of mevalonate and its downstream products, including cholesterol and isoprenylated proteins such as ubiquinone and small guanosine triphosphatases.

• In some instances, statins can trigger an autoimmune myopathy characterized by proximal muscle weakness, very high creatine kinase levels, a necrotizing muscle biopsy, and autoantibodies recognizing hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase.

• Anti–HMG-CoA reductase autoantibodies appear to be specific for those with an autoimmune myopathy and have not been found in patients with self-limited statin myopathy.

• Patients with statin-associated autoimmune myopathy often require aggressive immunosuppressive therapy to reverse the disease process.

• Many patients with self-limited statin myopathy tolerate low-dose rosuvastatin therapy with adequate reduction in cholesterol levels.

• It is unclear whether coenzyme Q10 supplementation has a role in preventing or treating statin myopathy.

• Vitamin D deficiency may predispose patients to statin myopathy and should be repleted in those with a documented deficiency.

• When coadministered with a statin, gemfibrozil dramatically increases the probability of developing a myopathy.

• Cyclosporine, especially when taken in combination with a statin or colchicine, may cause a necrotizing myopathy.

• Antimalarial medications are used to treat patients with rheumatic diseases and can cause myopathy at an annual rate of 1.2%.

• Amiodarone and colchicine can cause neuropathy as well as a vacuolar myopathy.

• Azidothymidine (AZT) myopathy can be distinguished from HIV-associated myositis on muscle biopsy by the absence of inflammation and the presence of mitochondrial abnormalities such as ragged red fibers.

• Interferon-α, tumor necrosis factor inhibitors, and D-penicillamine have been reported to precipitate an inflammatory myopathy.

• Critical illness myopathy is probably a more common cause of weakness in the intensive care unit than critical illness neuropathy or prolonged neuromuscular blockade.

• Loss of myosin thick filaments is a distinguishing muscle biopsy feature in critical illness myopathy.

• Fluorinated steroids (eg, dexamethasone) are more likely to cause steroid myopathy than nonfluorinated steroids (eg, prednisone).

• Type 2 muscle fiber atrophy is characteristic of steroid myopathy but can be seen in other contexts, such as disuse atrophy.

• Steroid myopathy does not cause an elevation in serum muscle enzyme levels and should not result in an irritable myopathy on EMG.

• Malignant hyperthermia can occur in patients with susceptibility mutations in the ryanodine receptor, sodium channels, and calcium channels.

• Dantrolene at a dose of 2 mg/kg to 3 mg/kg every 5 minutes for a total cumulative dose of 10 mg/kg may be helpful in treating patients with malignant hyperthermia.

• Binge alcohol drinking can cause a myopathy.