Drugs Causing Muscle Disease




Many drugs can cause myopathies, and such myopathies may range widely from asymptomatic elevations in the serum creatine phosphokinase levels to severe myalgias, cramps, exercise intolerance, muscle weakness, and even rhabdomyolysis. In this article, some of the commonly used drugs that may induce myopathies, as well as the clinical phenotypes, diagnosis, and management of these syndromes are reviewed.


Muscle weakness and/or myalgia is a common complaint among rheumatologic patients, and rheumatologists are aware of the importance of correctly diagnosing autoimmune myositis. However, while the differential diagnosis of muscle weakness should almost always also include drug effects, such effects may be difficult to identify. Many drugs can cause myopathies, and such myopathies may range widely from asymptomatic elevations in the serum creatine phosphokinase (CK) levels to severe myalgias, cramps, exercise intolerance, muscle weakness, and even rhabdomyolysis. Reviewing the literature frequently results in confusion because individual drugs may cause varying effects in different patients and imprecise terminologies are used to describe muscle pathology. In this article, some of the commonly used drugs that may induce myopathies, and the clinical syndromes, diagnosis, and management of these drug-induced myopathies are reviewed. For the convenience of the reader, the potential offending agents are segregated according to their major clinical indications.


Drugs for cardiovascular disease


Statins and Other Lipid-Lowering Agents


The most prevalent drug-induced myopathies are those caused by lipid-lowering agents. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), fibric acid derivatives (fibrates), niacin, and ezetimibe may all cause myopathy in some patients. However, it should be noted that the high prevalence of myotoxicities associated with these agents is not because of a large risk from their use but rather because the use of such drugs is extremely common. The typical syndrome of statin myopathies includes muscle pain and tenderness and weakness, with serum CK levels elevated at least 10-fold higher than the normal upper limit. By this definition, the incidence of statin-associated myopathy is no more than 11 per 100,000 person-years, with the incidence of statin-associated rhabdomyolysis being roughly 3.5 per 100,000 person-years. Milder syndromes with lower CK levels may be more common. The combined use of fibrates and statins may increase the incidence of muscle diseases by as much as 10-fold. Statins vary vis-à-vis their ability to induce these effects; lovastatin, simvastatin, and atorvastatin (metabolized by cytochrome P450 [CYP]) carry a higher risk than pravastatin and fluvastatin.


The effects of statins are quite variable. Some patients taking statins experience muscle symptoms despite normal CK levels, whereas others experience elevated CK levels without symptoms. Caution must be exerted in interpreting isolated CK level elevations; in some studies, elevations less than 10 times the upper limit of the normal level have been documented to occur at equal rates irrespective of the patient taking a statin or a placebo. Symptoms of statin-induced myopathy include myalgias, muscle tenderness, or weakness; localized ache or cramping may be characteristic features. Tendon pain and nocturnal leg cramps may occur. Weakness can occur in any muscle group but may be common in the proximal limbs and trunk. Vigorous exercise is often poorly tolerated and can aggravate statin-induced myotoxicity.


Typically, the onset of myopathy requires about 6 months of statin use to manifest. Muscle symptoms usually, but not always, resolve after stopping the offending agent, but this may take some time. Persistent symptoms after statin discontinuation may reflect the unmasking of a preexisting but previously unrecognized neuromuscular disorder, such as hypothyroidism, metabolic myopathy, myotonic dystrophy, spinal muscular atrophy, or inflammatory myositis. In one study, 25 patients with proximal muscle weakness associated with statin use were found to have persistent weakness and elevated CK levels despite discontinuation of the offending drug. In these patients, muscle biopsy findings showed necrotizing myopathy. The lack of improvement after discontinuation of statins and the need for immunosuppressive therapy in treating these patients suggest an immune-mediated cause for this unusual statin-associated necrotizing myopathy. In severe cases of myopathy, rhabdomyolysis may result in acute renal failure, disseminated intravascular coagulation, and death.


Muscle biopsy specimens from patients with statin-associated myopathies may appear normal when viewed under light microscopy. In other cases, biopsy specimens may show evidence of mitochondrial dysfunction, including ragged red fibers, and deficiency of cytochrome C oxidase on immunohistochemical analysis. Fiber atrophy and lipid-laden vacuoles may also be observed.


Myotoxicity from statins and other lipid-lowering agents occurs more frequently in the presence of higher serum drug levels. Thus, drug dose, drug-to-drug interactions, and renal and hepatic dysfunctions may all contribute to increased risk. Older age and female sex also are independent risk factors for myopathy related to these agents.


At the cellular level, molecular functions that increase intracellular statin concentrations may play a role in increased toxicity. For example, the transporter organic anion transporting polypeptide (OATP) promotes cellular uptake of statins and may promote toxicity. In one in vitro study, OATP inhibition protected skeletal myofibers against statin-induced toxicity. At the genetic level, specific polymorphisms of SLCO1B1 (the OATP gene) have been shown to affect transporter activity, with potential implications for statin myotoxic susceptibility. In another study, polymorphisms in the gene for ABCB1, an efflux transporter, were associated with altered risk for simvastatin-related myopathy.


Myotoxicity risk may be increased when more than one class of lipid-lowering agents are administered together. Gemfibrozil (but not fenofibrate) inhibits statin elimination. Use of a statin together with niacin is associated with a rare but increased risk of rhabdomyolysis. Anecdotal reports of myopathy attributed to the combination of statin and ezetimibe have been reported, but these reports are not supported by pooled data from clinical trials, including 14,471 patients.


Because most statins are metabolized by the hepatic CYP system, coadministration of such agents with another drug that is metabolized by the CYP system can result in drug-to-drug interactions. Drugs that are metabolized by the alternative liver isoenzyme CYP3A4 (cyclosporine, erythromycin, azole antifungals, diltiazem, ritonavir, and nefazodone) can also increase the risk of statin-induced myotoxicity. Metabolism of fluvastatin can be impaired by coadministration of other CYP2C9 substrates, such as diclofenac, warfarin, or tolbutamide.


The mechanisms through which lipid-lowering agents cause myotoxicity are not well established. Proposed mechanisms include alterations to membranes and/or mitochondria. HMG-CoA reductase inhibition (the major statin effect) may affect the function of transfer RNAs, glycoproteins, the electron transport chain, and proteins that depend on HMG-CoA reductase for posttranslational modification. Decreases in ubiquinone expression have been described in the muscles of some patients, but it is unknown whether this decrease may be a cause or consequence of statin use. Some patients with statin-induced myopathy have been found to have abnormalities in muscle carnitine levels. Hanai and colleagues reported that lovastatin induced the expression of atrogin-1, a key gene involved in human skeletal muscle atrophy. Induction of atrogin-1 by statins was accompanied by morphologic changes and muscle fiber damage, an effect that was similar to knocking down HMG-CoA reductase, suggesting that atrogin-1 may be a mediator of the muscle damage induced by statins. In a follow-up study, the investigators reported that lovastatin-induced atrogin-1 expression and muscle damage could be prevented in the presence of geranylgeranylation inhibitors. These findings support the concept that dysfunction of small GTP-binding proteins leads to statin-induced muscle damage.


Management of severe myopathy induced by lipid-lowering drugs is straightforward and requires drug discontinuation and, if necessary, hospital admission to manage rhabdomyolysis. Management is less clear for milder cases and may range from close monitoring to lowering or discontinuing the agent or switching to a different statin or other lipid-lowering agent; some reports suggest a possible benefit from coenzyme Q10 supplementation.


Antiarrhythmic Agents


Reports suggest that several antiarrhythmic agents may also cause muscle problems. Amiodarone may rarely cause both proximal and distal muscle weakness, as well as distal sensory loss, tremor, and ataxia. These toxicities are more common in patients with chronic kidney disease. Serum CK levels may be increased. Electromyography (EMG) results reveal positive sharp waves, fibrillation potentials, and early recruitment of motor unit action potentials in proximal muscles versus polyphasic action potentials of large amplitude and long duration in distal muscles. Autophagic vacuoles containing myeloid inclusions and debris are found on biopsy analysis. Amiodarone-induced myopathy gradually resolves after therapy is discontinued. Clinicians should keep in mind, however, that amiodarone can also induce hypothyroidism with resulting muscle sequelae that can confuse the clinical picture.


Procainamide can cause myalgias and proximal muscle weakness, often as part of a drug-induced lupus syndrome. Serum CK levels are increased, and EMG findings are consistent with those of inflammatory myopathy. Labetalol may sometimes induce an acute or insidious onset of proximal muscle weakness or myalgias. Other cardioactive drugs that may rarely cause myopathy after prolonged administration include aminocaproic acid, warfarin, and calcium channel antagonists such as diltiazem.




Rheumatologic drugs


Corticosteroids


Corticosteroid myopathy is relatively common, owing to both the toxicity of these agents and the frequency with which they are prescribed. In steroid myopathy, weakness (especially proximal muscle weakness) typically comes on insidiously, and CK levels are normal. Corticosteroid myopathy usually is seen in the setting of chronic use of high doses of steroids, especially multiple doses per day. However, corticosteroid myopathy may come on rapidly (days) and even when low doses are used. Some data suggest that fluorinated glucocorticoids (triamcinolone, betamethasone, and dexamethasone) may carry a lower risk. In contrast, according to the more recent literature, side effects occur more frequently and are worse after treatment with fluorinated steroids than after treatment with nonfluorinated steroids. Respiratory muscles can occasionally be involved. Necrotizing myopathy is a very rare consequence of steroid use, and high-dose intravenous corticosteroids have been reported to cause an acute quadriplegic state.


As in the case of statins, the mechanisms through which steroids act on the muscle remain uncertain. Proposed hypotheses include alterations in muscle protein synthesis and/or degradation, altered muscle metabolism, reduced sarcolemmal excitability, and corticosteroid-induced hypokalemia. EMG findings are typically normal, and muscle biopsy results either are normal or show nonspecific type 2 fiber atrophy. Whenever possible, treatment of corticosteroid-induced myopathy should include discontinuation of the offending agent. If not possible, attempts should be made to reduce the dosage to a physiologic dose. Recovery usually occurs with discontinuation of the steroid but may take an extended period, especially if usage has been long-term. Rapid withdrawal of chronically used steroids may itself result in hypoadrenalism, including weakness.


Colchicine


Colchicine can cause multiple neuromuscular complications. Generalized myopathy and painful neuromyopathy are the most common complications and may appear early after initiation or after months of therapy. Chronic kidney disease or diuretic use increases the risk. Colchicine is metabolized by the CYP3A4 system, and coadministration of any drug that is metabolized by CYP3A4 can precipitate colchicine myopathy. Concomitant cyclosporine or clarithromycin use increases the risk of colchicine-induced rhabdomyolysis.


Colchicine myopathy is believed to result from colchicine’s ability to inhibit microtubule polymerization, as well as changes in the expression of dopaminergic receptors. Patients may be symptomatic or asymptomatic, with CK level elevations from minimal to 100 times normal. EMG and nerve conduction studies may show both neuropathic and myopathic changes, including prolonged distal motor and sensory latencies. Muscle biopsy specimens show autophagic vacuoles that stain positively for acid phosphatase. Electron microscopy may show colchicine bodies (clumps of chromatin in the nuclei of hepatocytes). Nerve biopsy rarely needs to be performed, but its results may show axonal neuropathy. Treatment is discontinuation of colchicine, which generally results in complete resolution, although this may take months.


Chloroquines


Chloroquine and related agents may cause myopathy that is typically painless, slowly progressive, and typically more pronounced proximally and in the lower extremities. Severe cases may present as myasthenia-like syndrome or myotonia. Neuropathy may occur uncommonly, and cardiomyopathy has been reported. Onset typically occurs months to years after start of treatment. Serum CK levels are elevated, and EMG shows myopathic changes of increased insertional activity with positive waves, fibrillations, and other characteristic changes. Muscle biopsy specimens show vacuoles containing acid phosphatase and, on electron microscopy, concentric lamellar debris and curvilinear bodies.


The pathologic mechanism of chloroquine myopathy is thought to derive from the ability of these agents to form drug-lipid complexes in cellular membranes, resulting in the accumulation of autophagic vacuoles. This model has been confirmed in rats administered chloroquine (50 mg/kg twice daily for 8 weeks), resulting in myopathy characterized by accumulation of autophagic vacuoles. In patients, discontinuation of the chloroquine results in improvement over months. Animal studies suggest that administration of the cysteine proteinase inhibitor EST (loxistation) may hasten resolution.


Other Immunomodulatory Agents


With persistent use, cyclosporine and tacrolimus may induce myalgias, cramps, proximal muscle weakness, and, in some cases, rhabdomyolysis. EMG shows fibrillation potentials, sharp positive waves, and myotonic potentials, and atrophy and necrosis may be seen in muscle biopsy specimens. The risk of myopathy from these drugs is exacerbated by the concurrent use of a statin or colchicine. Because these drugs may occasionally be used in inflammatory myositis, their potential adverse effects on the muscle may complicate the clinical picture.


d -Penicillamine can induce polymyositis or dermatomyositis in a small percentage of patients. Azathioprine has been rarely associated with rhabdomyolysis. Myokymia (arrhythmic rippling of muscles) is a rare complication of gold therapy. In one study, infliximab was associated with clinical worsening of myositis. Cases of myositis in the setting of interferon use have been reported and improve with treatment discontinuation.




Rheumatologic drugs


Corticosteroids


Corticosteroid myopathy is relatively common, owing to both the toxicity of these agents and the frequency with which they are prescribed. In steroid myopathy, weakness (especially proximal muscle weakness) typically comes on insidiously, and CK levels are normal. Corticosteroid myopathy usually is seen in the setting of chronic use of high doses of steroids, especially multiple doses per day. However, corticosteroid myopathy may come on rapidly (days) and even when low doses are used. Some data suggest that fluorinated glucocorticoids (triamcinolone, betamethasone, and dexamethasone) may carry a lower risk. In contrast, according to the more recent literature, side effects occur more frequently and are worse after treatment with fluorinated steroids than after treatment with nonfluorinated steroids. Respiratory muscles can occasionally be involved. Necrotizing myopathy is a very rare consequence of steroid use, and high-dose intravenous corticosteroids have been reported to cause an acute quadriplegic state.


As in the case of statins, the mechanisms through which steroids act on the muscle remain uncertain. Proposed hypotheses include alterations in muscle protein synthesis and/or degradation, altered muscle metabolism, reduced sarcolemmal excitability, and corticosteroid-induced hypokalemia. EMG findings are typically normal, and muscle biopsy results either are normal or show nonspecific type 2 fiber atrophy. Whenever possible, treatment of corticosteroid-induced myopathy should include discontinuation of the offending agent. If not possible, attempts should be made to reduce the dosage to a physiologic dose. Recovery usually occurs with discontinuation of the steroid but may take an extended period, especially if usage has been long-term. Rapid withdrawal of chronically used steroids may itself result in hypoadrenalism, including weakness.


Colchicine


Colchicine can cause multiple neuromuscular complications. Generalized myopathy and painful neuromyopathy are the most common complications and may appear early after initiation or after months of therapy. Chronic kidney disease or diuretic use increases the risk. Colchicine is metabolized by the CYP3A4 system, and coadministration of any drug that is metabolized by CYP3A4 can precipitate colchicine myopathy. Concomitant cyclosporine or clarithromycin use increases the risk of colchicine-induced rhabdomyolysis.


Colchicine myopathy is believed to result from colchicine’s ability to inhibit microtubule polymerization, as well as changes in the expression of dopaminergic receptors. Patients may be symptomatic or asymptomatic, with CK level elevations from minimal to 100 times normal. EMG and nerve conduction studies may show both neuropathic and myopathic changes, including prolonged distal motor and sensory latencies. Muscle biopsy specimens show autophagic vacuoles that stain positively for acid phosphatase. Electron microscopy may show colchicine bodies (clumps of chromatin in the nuclei of hepatocytes). Nerve biopsy rarely needs to be performed, but its results may show axonal neuropathy. Treatment is discontinuation of colchicine, which generally results in complete resolution, although this may take months.


Chloroquines


Chloroquine and related agents may cause myopathy that is typically painless, slowly progressive, and typically more pronounced proximally and in the lower extremities. Severe cases may present as myasthenia-like syndrome or myotonia. Neuropathy may occur uncommonly, and cardiomyopathy has been reported. Onset typically occurs months to years after start of treatment. Serum CK levels are elevated, and EMG shows myopathic changes of increased insertional activity with positive waves, fibrillations, and other characteristic changes. Muscle biopsy specimens show vacuoles containing acid phosphatase and, on electron microscopy, concentric lamellar debris and curvilinear bodies.


The pathologic mechanism of chloroquine myopathy is thought to derive from the ability of these agents to form drug-lipid complexes in cellular membranes, resulting in the accumulation of autophagic vacuoles. This model has been confirmed in rats administered chloroquine (50 mg/kg twice daily for 8 weeks), resulting in myopathy characterized by accumulation of autophagic vacuoles. In patients, discontinuation of the chloroquine results in improvement over months. Animal studies suggest that administration of the cysteine proteinase inhibitor EST (loxistation) may hasten resolution.


Other Immunomodulatory Agents


With persistent use, cyclosporine and tacrolimus may induce myalgias, cramps, proximal muscle weakness, and, in some cases, rhabdomyolysis. EMG shows fibrillation potentials, sharp positive waves, and myotonic potentials, and atrophy and necrosis may be seen in muscle biopsy specimens. The risk of myopathy from these drugs is exacerbated by the concurrent use of a statin or colchicine. Because these drugs may occasionally be used in inflammatory myositis, their potential adverse effects on the muscle may complicate the clinical picture.


d -Penicillamine can induce polymyositis or dermatomyositis in a small percentage of patients. Azathioprine has been rarely associated with rhabdomyolysis. Myokymia (arrhythmic rippling of muscles) is a rare complication of gold therapy. In one study, infliximab was associated with clinical worsening of myositis. Cases of myositis in the setting of interferon use have been reported and improve with treatment discontinuation.




Infectious disease drugs


Antiviral Agents


Many antiviral agents can cause myopathy. The most common offending agent is zidovudine, which causes myalgias and proximal muscle weakness. Other nucleoside analogue reverse transcriptase inhibitors (didanosine, lamivudine, and zalcitabine) can have similar effects. Serum CK levels are typically normal or slightly elevated. EMG changes, seen in proximal muscles, may include insertional activity with sharp waves and fibrillation potentials, early recruitment of polyphasic action potentials, and complex repetitive discharges. However, these findings must be differentiated from primary human immunodeficiency virus–associated myopathy. Histologic examination of reverse transcriptase–associated myopathy shows signs of mitochondrial involvement, including ragged red fibers. Necrosis, microvacuoles, cytoplasmic bodies, and nemaline rods may all be seen. Proposed mechanisms of antiretroviral myopathy include the effects of oxidative stress, inhibition of mitochondrial energetics, l -carnitine depletion, and apoptosis. Tenofovir and ritonavir have been reported to cause rhabdomyolysis, particularly in patients taking another myopathy-inducing drug.


Antifungal and Antibacterial Agents


Ketoconazole and itraconazole have been reported to cause myopathy or rhabdomyolysis in conjunction with simultaneous statin use. Rifampin use had been associated with a proximal myopathy with normal EMG findings and CK levels. Myalgias and malignant hyperthermia have been associated with quinolone derivatives, as also described earlier.




Oncology drugs


Vincristine, an agent that disrupts microtubule polymerization, may cause proximal muscle weakness and myalgias, with denervation and necrosis observed on biopsy findings. Imatinib mesylate causes myalgias in up to 50% of patients, with a single case report of imatinib-associated polymyositis. Cardiotoxicity and dermatomyositis-like disease have also been reported. An inflammatory myopathy has been reported in association with the use of leuprolide acetate. Cases of rhabdomyolysis have been reported in patients taking 5-azacytidine, cytarabine, and the combination of cyclophosphamide and mitoxantrone.


All-trans retinoic acid is used to treat patients with acute promyelocytic leukemia. Cases of new-onset myopathy after receiving this agent have been reported. The condition can manifest as myalgia, stiffness, and, in rare cases, rhabdomyolysis. CK levels have been found to be elevated, occasionally by up to 100 times the normal value, particularly in patients performing physical exercise. Inflammatory myositis has been described as well. This adverse reaction is noticeable for fever, myalgia, arthralgia, and Sweet syndrome, accompanied by distinct magnetic resonance imaging findings involving the lower extremity musculature. Treatment consists of discontinuation of the offending drug and, often, high-dose steroids.

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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Drugs Causing Muscle Disease
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