- Email: [email protected]
Toxic myopathies
Joint Bone Spine 80 (2013) 231–233
Available online at
www.sciencedirect.com
Editorial
Toxic myopathies
a r t i c l e
i n f o
Keywords: Toxics Treatments Myopathies Myalgias Muscle side effects
1. Introduction Toxic myopathies are muscle diseases caused by exogenous substances. Their causative agents, pathophysiological mechanisms, histological features, and clinical presentations vary widely. Furthermore, toxic substances may either cause a primary myopathy in a patient with previously normal muscles or reveal an underlying muscle disease that is due to a genetic abnormality or to another cause. The main toxic substances responsible for myopathy are medications, recreational drugs, alcohol, venoms, and biological toxins. In a patient presenting with muscle symptoms, the first step is the collection of all current or recent medications and an evaluation of alcohol consumption, recreational drug use and dietary intakes. Some forms of toxic myopathy are extremely serious, most notably those associated with necrosis or rhabdomyolysis. Fatal cases have been reported in patients exposed to venom, statins, or toxic oils [1–6]. Medication-induced muscle disorders are common. Myalgia and muscle fatigability predominating at the proximal limbs are the main presenting symptoms. A large number of medications have been associated with muscle toxicity, including many compounds used in rheumatology. For some medications a single report of muscle toxicity is available, whereas for others myopathy has been described in a substantial proportion of exposed patients. The histopathological lesions also vary across medications and individuals.
2. Myalgia related to medications 2.1. Myalgia associated with statins and other lipid-lowering agents Statins and other lipid-lowering medications are the most commonly reported causes of toxic myopathy (Table 1). In 10% of patients the clinical symptoms include myalgia, cramps, spasms, and abnormal muscle fatigability. The creatine kinase (CK) level
Table 1 Medications most commonly incriminated in toxic myopathies. Lipid-lowering agents Statins Ezetimibe Fibrates Antiviral agents Zidovudine and similar drugs Clevudine Antimitotic agents Imatinib mesylate Vincristine Methotrexate Azathioprine Medications used in rheumatology Chloroquine/Hydroxychloroquine Colchicine Glucocorticoids Methotrexate Leflunomide Neuroleptics Typical neuroleptics: phenothiazine, haloperidol (Haldol) pimozide (Orap® ), cyamemazine (Tercian® ) Second-generation neuroleptics: clozapine (Leponex® ), olanzapine (Zyprexa® ), risperidone (Risperdal® ), quetiapine (Seroquel® ) Antidepressants Citalopram (Seropram® ) Fluoxetine (Mopral® ) Fluvoxamine (Floxyfral® ) Paroxetine (Deroxat® ) Sertraline (Zoloft® ). . . Miscellaneous Bisphosphonates Cyclosporine Tacrolimus Mycophenolate mofetil Anesthetics Cimetidine Cromolyn Danazol Gemfibrozil L-Tryptophan Sotalol Acetaminophen Amiodarone Amphetamines Antithyroid agents Cytokines (␣-interferon, interleukin) D-penicillamine Antibiotics (penicillin, minocycline, daptomycin)
1297-319X/$ – see front matter © 2012 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
232
Editorial / Joint Bone Spine 80 (2013) 231–233
is elevated in 2 to 7% of cases, but severe rhabdomyolysis is rare (0.04 to 0.2% of patients). When severe clinical symptoms develop, they usually occur early in the treatment, and it should be borne in mind that acute rhabdomyolysis often reveals a preexisting muscle disorder (e.g., mitochondrial myopathy or autoimmune myopathy). The relative risk of muscle toxicity varies across statins as follows, by decreasing order of muscle toxicity: atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin. Cerivastatin was removed from the market after several reports of fatal rhabdomyolysis. Muscle toxicity is dose-dependent and is increased (to 55% of cases) by the concomitant use of other medications such as fibrates, cyclosporine, mibefradil, macrolides, digoxin, warfarin, diltiazem, and imidazole antifungal agents; as well as by several substances of abuse. Statin-induced toxic myopathy has no specific histological features. Toxicity is greater in individuals with abnormalities in cytochromes (particularly P450) and/or in myocyte calcium channels. Other factors can exacerbate the clinical and laboratory abnormalities such as alcohol use, diabetes, and vitamin D deficiency. Several hypotheses are being investigated in an effort to identify the pathophysiological mechanism of statin-induced muscle toxicity. Mutations or polymorphisms of liver transporter genes have been implicated, including a polymorphism in the SLCO1B1 gene, mutations in genes encoding muscle enzymes such as myophosphorylase, and mutations in the LPIN1 gene involved in muscle dystrophy and/or metabolic myopathies. The symptoms typically resolve within 2 to 3 months of treatment discontinuation. However, the course may be chronic in patients with necrotizing myopathy or an underlying muscle disease. Recommendations for use of statins include a CK assay before treatment initiation. In the event of moderate CK elevation during treatment, the patient should be switched to a different statin and the CK level monitored regularly. In the event of major rhabdomyolysis (more than five times the normal value), statin therapy should be stopped [1,7–9]. Among other lipid-lowering agents, fibrates produce similar symptoms to those seen with statins. A very small number of cases have been reported with ezetimibe. Rarely, omega-3 fatty acids may generate muscle disorders responsible for pain. 2.2. Myalgia and antiviral agents The main antiviral agents responsible for muscle disorders are nucleoside analog reverse-transcriptase inhibitors such as zidovudine and other drugs used to treat HIV infection and clevudine used in Korea to treat chronic hepatitis B infection. This last drug induces genuine mitochondrial myopathies [1,2,4,10]. 2.3. Myalgia and antimitotic treatments Muscle toxicity has been reported with imatinib mesylate (Gleevec® ) in patients with chronic myeloid leukemia or gastrointestinal cancers. The second most often incriminated antimitotic agent is vincristine, which damages the microtubule system. 2.4. Myalgia and medications used in rheumatology Chloroquine and hydroxychloroquine can induce fatigability of the girdle muscles, diffuse fatigability, or pain in 12.6% of patients. Pseudo-myasthenia is among the clinical presentations. No threshold dose or treatment duration has been identified. Nevertheless, prolonged treatment is among the risk factors for muscle toxicity, together with Caucasian ethnicity, female gender, advanced age, renal failure, and concomitant exposure to other myotoxic substances. Muscle biopsies, when performed, showed lysosomal alterations in two-thirds of patients, with myotubule necrosis in the most severe cases.
Colchicine can induce proximal neuromyopathies with lysosomal dysfunction responsible for microtubule damage. In particular, colchicine interacts with cytochrome P450 3A4 (CYP3A4). Glucocorticoids can induce progressive chronic myopathies with muscle wasting predominating at the limb girdles, usually with no pain. The muscle toxicity of glucocorticoids is dose-dependent, being chiefly seen with chronic oral treatment in dosages greater than 10 mg/day or intermittent high-dose intravenous treatment. The CK level is usually normal and the muscle involvement resolves after treatment discontinuation. Life-threatening flaccid paralysis may develop during highdose intravenous glucocorticoid therapy in immunocompromised patients [4–6]. 2.5. Myalgia and neuroleptic or antidepressant drugs Neuroleptic malignant syndrome manifests as hyperthermia, dehydration, and muscle hyperactivity. There are two clinical patterns, central anticholinergic syndrome and serotonin syndrome. Central anticholinergic syndrome is characterized by dopaminergic blockade with rhabdomyolysis, muscle rigidity, CK elevation, impaired consciousness, pallor, diaphoresis, tachycardia, hypotension, and hallucinations. Serotonin syndrome is induced by 5HT1A and 5HT2 receptor activation [6] and occurs chiefly with secondgeneration neuroleptics, also known as atypical antipsychotic agents or inappropriately as antipsychotics such as clozapine (Leponex® ), olanzapine (Zyprexa® ), risperidone (Risperdal® ), and quetiapine (Seroquel® ). Clinical symptoms are rare and consist of gastrointestinal disorders, agitation with behavioral abnormalities, hallucinations, muscle rigidity, myoclonus, and hyperthermia. Severe forms exist with a coma in extreme cases. Selective serotonin reuptake inhibitors (SSRIs) or serotoninergic drugs such as citalopram (Seropram® ), fluoxetine (Mopral® ), fluvoxamine (Floxyfral® ), paroxetine (Deroxat® ) and sertraline (Zoloft® ) induce similar side effects in rare cases. 2.6. Myalgia associated with other medications Many other medications can induce muscle toxicity ranging from isolated myalgia to rhabdomyolysis or necrosis. Examples include bisphosphonates, methotrexate, azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, leflunomide, anesthetics such as halothane and propofol, cimetidine, cromolyn, danazol, gemfibrozil, L-tryptophan, sotalol, amiodarone, amphetamines, acetaminophen (rarely, with diffuse myalgia and rhabdomyolysis), and nonsteroidal anti-inflammatory agents (rarely, with presumptive causality). In patients with electrolyte disorders, a number of medications may have deleterious effects, including diuretics and laxatives in the event of hypokalemic myopathy. Finally, inflammatory myopathies have been reported in patients exposed to medications used to treat hyperthyroidism (propylthiouracil and carbimazole), cytokines (␣-interferon or interleukin), cimetidine, hydroxycarbamide, azathioprine, Dpenicillamine, tiopronin, and several antibiotics (penicillin, minocycline, daptomycin) [2–6]. 3. Myalgia and toxic substances 3.1. Alcohol and recreational drugs Acute or chronic alcohol abuse is among the most common causes of rhabdomyolysis (Table 2). Episodes of acute inebriation are followed in 40 to 60% of cases by CK elevation with induction of hepatic P450 cytochromes and production of toxic
Editorial / Joint Bone Spine 80 (2013) 231–233 Table 2 Main toxic substances responsible for myopathies. Substances of abuse Alcohol Drugs (cocaine, heroin) Performance enhancers (anabolic agents) Naturally occurring toxic substances Bacterial toxins Botulinum toxin Streptococcal toxin Tetanus toxin Animal toxins (venoms) Plant toxins (herbs, roots, mushrooms) Industrial toxic substances Organophosphates Pesticides Hydrocarbons. . .
metabolites. Alcohol can impair the transport of calcium, potassium, and sodium, as well as membrane fluidity. Alcohol also exerts direct toxic effects on the cell membrane [6]. Cocaine, opioids such as heroin, and caffeine have direct toxic effects on muscles and can cause diffuse muscle symptoms including myalgia, fatigability, and rhabdomyolysis. Cases of severe myopathy have been reported in professional and amateur athletes who used performance enhancers such as anabolic androgens or creatine [1,2]. 3.2. Industrial toxic agents Substances with marked muscle toxicity include organophosphates such as pesticides and hydrocarbons such as benzene, toluene, and naphthalene (glues and bitumens). Muscle toxicity due to these substances is sometimes classified as an occupational disease, for instance among gardeners, tilers, construction workers, road markers, and carpenters. In 1981, contaminated colza oil caused severe muscle toxicity known as toxic oil syndrome [11]. 3.3. Biological toxic agents Finally, biological toxins such as venoms can cause muscle toxicity. These toxins may be produced by animals, bacteria and plants. The muscle symptoms vary in intensity, with fatal rhabdomyolysis in the most severe cases (3 to 25%). Antidotes exist for some biological toxins. The main bacterial toxins are the botulinum toxin, tetanus toxin, and streptotoccal toxin. Animal toxins include venoms produced by snakes (chiefly vipers), wasps, bees, spiders, and fish (stonefish and fugu). Ciguatera is caused by eating fish contaminated with ciguatoxin (e.g., in the Reunion Island and Tahiti), whose symptoms include severe muscle pain and pruritus. Plant toxins may be found in herbs, roots, or other plant parts. The most widely described are those found in kava-kava (Piper methysticum) consumed as a narcotic drink in the southern Pacific and used as an anxiolytic agent [3–6]. The ingestion of various types of wild mushrooms can cause muscle symptoms ranging from severe myalgia to rhabdomyolysis and myocardial toxicity. In 2001, Tricholoma equestre (also known as yellow knight or man on horseback) was implicated in 12 cases, some of which occurred in southern France; three patients died. In Asia and North America, fatal rhabdomyolysis has been reported after the ingestion of Russula subnigricans [1,2,12,13]. Red yeast rice is being increasingly consumed as a dietary alternative to cholesterol-lowering medications but its ingestion as capsules has been reported to cause myalgia, CK elevation, and rhabdomyolysis. This muscle toxicity is ascribable to
233
the yeast Monascus purpureus, which produces monacolins, particularly monacolin K, a compound similar to lovastatin and capable of inhibiting the enzyme HMGCR [2,14]. Toxic myopathies are among the main causes of myalgia and muscle cell damage. They constitute a highly heterogeneous group of disorders in terms of the inducing agents, muscle cell abnormalities, manifestations, and clinical severity. Establishing the diagnosis is crucial, as life-threatening rhabdomyolysis can occur in some cases. The number of substances known to induce toxic myopathies is increasing, and consequently careful attention should be given to the clinical setting, diet and dietary supplements, and symptoms suggesting an underlying muscle disease, in order to ensure the optimal management of patients with toxic myopathies. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Kushlaf HA. Emerging toxic neuropathies and myopathies. Neurol Clin 2011;29:679–87. [2] Mastaglia FL, Needham M. Update on toxic myopathies. Curr Neurol Neurosci Rep 2012;12:54–61. [3] Guis S, Krahn M, Fernandez C, Mattei JP, Levy N, Bendahan D. Pathologies des muscles striés squelettiques. EMC - Appareil Locomoteur 2010:1–19 [Article 15-143-A-10]. [4] Guis S, Mattei JP, Lioté F. Drug-induced and toxic myopathies. Best Pract Res Clin Rheumatol 2003;17:877–907. [5] Dalakas MC. Toxic and drug-induced myopathies. J Neurol Neurosurg Psychiatry 2009;80:832–8. [6] Guis S, Mattei JP, Cozzone PJ, et al. Pathophysiology and clinical presentations of rhabdomyolysis. Joint Bone Spine 2005;72:382–91. [7] Smiley IW, Khan BV, Sperling LS. Management of the statin-intolerant patient. Curr Treat Options Cardiovasc Med 2009;11:26–71. [8] Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009;150:858–68. [9] Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy: a genome wide study. N Engl J Med 2008;359:789–99. [10] Seok JI, Lee DK, Lee CH, et al. Long-term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA. Hepatology 2009;49:2080–6. [11] Kilbourne EM, Rigau-Perez JG, Heath CW, et al. Clinical epidemiology of toxic oil syndrome: manifestations of a new illness. N Engl J Med 1983;309:1408–14. [12] Bedry R, Baudrimont I, Deffieux G, et al. Wild mushroom intoxication as a cause of rhabdomyolysis. N Engl J Med 2001;345:798–802. [13] Matsuura M, Saikawa Y, Inui K, et al. Identification of the toxic trigger in mushroom poisoning. Nat Chem Biol 2009;5:465–7. [14] Prasad GV, Wong T, Meliton G, et al. Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient. Transplantation 2002;74:1200–1.
Sandrine Guis ∗ Jean-Pierre Mattei David Bendahan Aix-Marseille University, Centre de Résonance Magnétique Biologique et Médicale (CRMBM) CNRS, CRMBM UMR CNRS 7339, Faculté de Médecine de Marseille, 27, Boulevard Jean-Moulin, 13005 Marseille, France ∗ Corresponding
author. Tel.: +33 4 91 32 48 07; fax: +33 4 91 25 65 39. E-mail address: [email protected] (S. Guis) Accepted 1st October 2012 Available online10 December 2012
Available online at
www.sciencedirect.com
Editorial
Toxic myopathies
a r t i c l e
i n f o
Keywords: Toxics Treatments Myopathies Myalgias Muscle side effects
1. Introduction Toxic myopathies are muscle diseases caused by exogenous substances. Their causative agents, pathophysiological mechanisms, histological features, and clinical presentations vary widely. Furthermore, toxic substances may either cause a primary myopathy in a patient with previously normal muscles or reveal an underlying muscle disease that is due to a genetic abnormality or to another cause. The main toxic substances responsible for myopathy are medications, recreational drugs, alcohol, venoms, and biological toxins. In a patient presenting with muscle symptoms, the first step is the collection of all current or recent medications and an evaluation of alcohol consumption, recreational drug use and dietary intakes. Some forms of toxic myopathy are extremely serious, most notably those associated with necrosis or rhabdomyolysis. Fatal cases have been reported in patients exposed to venom, statins, or toxic oils [1–6]. Medication-induced muscle disorders are common. Myalgia and muscle fatigability predominating at the proximal limbs are the main presenting symptoms. A large number of medications have been associated with muscle toxicity, including many compounds used in rheumatology. For some medications a single report of muscle toxicity is available, whereas for others myopathy has been described in a substantial proportion of exposed patients. The histopathological lesions also vary across medications and individuals.
2. Myalgia related to medications 2.1. Myalgia associated with statins and other lipid-lowering agents Statins and other lipid-lowering medications are the most commonly reported causes of toxic myopathy (Table 1). In 10% of patients the clinical symptoms include myalgia, cramps, spasms, and abnormal muscle fatigability. The creatine kinase (CK) level
Table 1 Medications most commonly incriminated in toxic myopathies. Lipid-lowering agents Statins Ezetimibe Fibrates Antiviral agents Zidovudine and similar drugs Clevudine Antimitotic agents Imatinib mesylate Vincristine Methotrexate Azathioprine Medications used in rheumatology Chloroquine/Hydroxychloroquine Colchicine Glucocorticoids Methotrexate Leflunomide Neuroleptics Typical neuroleptics: phenothiazine, haloperidol (Haldol) pimozide (Orap® ), cyamemazine (Tercian® ) Second-generation neuroleptics: clozapine (Leponex® ), olanzapine (Zyprexa® ), risperidone (Risperdal® ), quetiapine (Seroquel® ) Antidepressants Citalopram (Seropram® ) Fluoxetine (Mopral® ) Fluvoxamine (Floxyfral® ) Paroxetine (Deroxat® ) Sertraline (Zoloft® ). . . Miscellaneous Bisphosphonates Cyclosporine Tacrolimus Mycophenolate mofetil Anesthetics Cimetidine Cromolyn Danazol Gemfibrozil L-Tryptophan Sotalol Acetaminophen Amiodarone Amphetamines Antithyroid agents Cytokines (␣-interferon, interleukin) D-penicillamine Antibiotics (penicillin, minocycline, daptomycin)
1297-319X/$ – see front matter © 2012 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
232
Editorial / Joint Bone Spine 80 (2013) 231–233
is elevated in 2 to 7% of cases, but severe rhabdomyolysis is rare (0.04 to 0.2% of patients). When severe clinical symptoms develop, they usually occur early in the treatment, and it should be borne in mind that acute rhabdomyolysis often reveals a preexisting muscle disorder (e.g., mitochondrial myopathy or autoimmune myopathy). The relative risk of muscle toxicity varies across statins as follows, by decreasing order of muscle toxicity: atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin. Cerivastatin was removed from the market after several reports of fatal rhabdomyolysis. Muscle toxicity is dose-dependent and is increased (to 55% of cases) by the concomitant use of other medications such as fibrates, cyclosporine, mibefradil, macrolides, digoxin, warfarin, diltiazem, and imidazole antifungal agents; as well as by several substances of abuse. Statin-induced toxic myopathy has no specific histological features. Toxicity is greater in individuals with abnormalities in cytochromes (particularly P450) and/or in myocyte calcium channels. Other factors can exacerbate the clinical and laboratory abnormalities such as alcohol use, diabetes, and vitamin D deficiency. Several hypotheses are being investigated in an effort to identify the pathophysiological mechanism of statin-induced muscle toxicity. Mutations or polymorphisms of liver transporter genes have been implicated, including a polymorphism in the SLCO1B1 gene, mutations in genes encoding muscle enzymes such as myophosphorylase, and mutations in the LPIN1 gene involved in muscle dystrophy and/or metabolic myopathies. The symptoms typically resolve within 2 to 3 months of treatment discontinuation. However, the course may be chronic in patients with necrotizing myopathy or an underlying muscle disease. Recommendations for use of statins include a CK assay before treatment initiation. In the event of moderate CK elevation during treatment, the patient should be switched to a different statin and the CK level monitored regularly. In the event of major rhabdomyolysis (more than five times the normal value), statin therapy should be stopped [1,7–9]. Among other lipid-lowering agents, fibrates produce similar symptoms to those seen with statins. A very small number of cases have been reported with ezetimibe. Rarely, omega-3 fatty acids may generate muscle disorders responsible for pain. 2.2. Myalgia and antiviral agents The main antiviral agents responsible for muscle disorders are nucleoside analog reverse-transcriptase inhibitors such as zidovudine and other drugs used to treat HIV infection and clevudine used in Korea to treat chronic hepatitis B infection. This last drug induces genuine mitochondrial myopathies [1,2,4,10]. 2.3. Myalgia and antimitotic treatments Muscle toxicity has been reported with imatinib mesylate (Gleevec® ) in patients with chronic myeloid leukemia or gastrointestinal cancers. The second most often incriminated antimitotic agent is vincristine, which damages the microtubule system. 2.4. Myalgia and medications used in rheumatology Chloroquine and hydroxychloroquine can induce fatigability of the girdle muscles, diffuse fatigability, or pain in 12.6% of patients. Pseudo-myasthenia is among the clinical presentations. No threshold dose or treatment duration has been identified. Nevertheless, prolonged treatment is among the risk factors for muscle toxicity, together with Caucasian ethnicity, female gender, advanced age, renal failure, and concomitant exposure to other myotoxic substances. Muscle biopsies, when performed, showed lysosomal alterations in two-thirds of patients, with myotubule necrosis in the most severe cases.
Colchicine can induce proximal neuromyopathies with lysosomal dysfunction responsible for microtubule damage. In particular, colchicine interacts with cytochrome P450 3A4 (CYP3A4). Glucocorticoids can induce progressive chronic myopathies with muscle wasting predominating at the limb girdles, usually with no pain. The muscle toxicity of glucocorticoids is dose-dependent, being chiefly seen with chronic oral treatment in dosages greater than 10 mg/day or intermittent high-dose intravenous treatment. The CK level is usually normal and the muscle involvement resolves after treatment discontinuation. Life-threatening flaccid paralysis may develop during highdose intravenous glucocorticoid therapy in immunocompromised patients [4–6]. 2.5. Myalgia and neuroleptic or antidepressant drugs Neuroleptic malignant syndrome manifests as hyperthermia, dehydration, and muscle hyperactivity. There are two clinical patterns, central anticholinergic syndrome and serotonin syndrome. Central anticholinergic syndrome is characterized by dopaminergic blockade with rhabdomyolysis, muscle rigidity, CK elevation, impaired consciousness, pallor, diaphoresis, tachycardia, hypotension, and hallucinations. Serotonin syndrome is induced by 5HT1A and 5HT2 receptor activation [6] and occurs chiefly with secondgeneration neuroleptics, also known as atypical antipsychotic agents or inappropriately as antipsychotics such as clozapine (Leponex® ), olanzapine (Zyprexa® ), risperidone (Risperdal® ), and quetiapine (Seroquel® ). Clinical symptoms are rare and consist of gastrointestinal disorders, agitation with behavioral abnormalities, hallucinations, muscle rigidity, myoclonus, and hyperthermia. Severe forms exist with a coma in extreme cases. Selective serotonin reuptake inhibitors (SSRIs) or serotoninergic drugs such as citalopram (Seropram® ), fluoxetine (Mopral® ), fluvoxamine (Floxyfral® ), paroxetine (Deroxat® ) and sertraline (Zoloft® ) induce similar side effects in rare cases. 2.6. Myalgia associated with other medications Many other medications can induce muscle toxicity ranging from isolated myalgia to rhabdomyolysis or necrosis. Examples include bisphosphonates, methotrexate, azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, leflunomide, anesthetics such as halothane and propofol, cimetidine, cromolyn, danazol, gemfibrozil, L-tryptophan, sotalol, amiodarone, amphetamines, acetaminophen (rarely, with diffuse myalgia and rhabdomyolysis), and nonsteroidal anti-inflammatory agents (rarely, with presumptive causality). In patients with electrolyte disorders, a number of medications may have deleterious effects, including diuretics and laxatives in the event of hypokalemic myopathy. Finally, inflammatory myopathies have been reported in patients exposed to medications used to treat hyperthyroidism (propylthiouracil and carbimazole), cytokines (␣-interferon or interleukin), cimetidine, hydroxycarbamide, azathioprine, Dpenicillamine, tiopronin, and several antibiotics (penicillin, minocycline, daptomycin) [2–6]. 3. Myalgia and toxic substances 3.1. Alcohol and recreational drugs Acute or chronic alcohol abuse is among the most common causes of rhabdomyolysis (Table 2). Episodes of acute inebriation are followed in 40 to 60% of cases by CK elevation with induction of hepatic P450 cytochromes and production of toxic
Editorial / Joint Bone Spine 80 (2013) 231–233 Table 2 Main toxic substances responsible for myopathies. Substances of abuse Alcohol Drugs (cocaine, heroin) Performance enhancers (anabolic agents) Naturally occurring toxic substances Bacterial toxins Botulinum toxin Streptococcal toxin Tetanus toxin Animal toxins (venoms) Plant toxins (herbs, roots, mushrooms) Industrial toxic substances Organophosphates Pesticides Hydrocarbons. . .
metabolites. Alcohol can impair the transport of calcium, potassium, and sodium, as well as membrane fluidity. Alcohol also exerts direct toxic effects on the cell membrane [6]. Cocaine, opioids such as heroin, and caffeine have direct toxic effects on muscles and can cause diffuse muscle symptoms including myalgia, fatigability, and rhabdomyolysis. Cases of severe myopathy have been reported in professional and amateur athletes who used performance enhancers such as anabolic androgens or creatine [1,2]. 3.2. Industrial toxic agents Substances with marked muscle toxicity include organophosphates such as pesticides and hydrocarbons such as benzene, toluene, and naphthalene (glues and bitumens). Muscle toxicity due to these substances is sometimes classified as an occupational disease, for instance among gardeners, tilers, construction workers, road markers, and carpenters. In 1981, contaminated colza oil caused severe muscle toxicity known as toxic oil syndrome [11]. 3.3. Biological toxic agents Finally, biological toxins such as venoms can cause muscle toxicity. These toxins may be produced by animals, bacteria and plants. The muscle symptoms vary in intensity, with fatal rhabdomyolysis in the most severe cases (3 to 25%). Antidotes exist for some biological toxins. The main bacterial toxins are the botulinum toxin, tetanus toxin, and streptotoccal toxin. Animal toxins include venoms produced by snakes (chiefly vipers), wasps, bees, spiders, and fish (stonefish and fugu). Ciguatera is caused by eating fish contaminated with ciguatoxin (e.g., in the Reunion Island and Tahiti), whose symptoms include severe muscle pain and pruritus. Plant toxins may be found in herbs, roots, or other plant parts. The most widely described are those found in kava-kava (Piper methysticum) consumed as a narcotic drink in the southern Pacific and used as an anxiolytic agent [3–6]. The ingestion of various types of wild mushrooms can cause muscle symptoms ranging from severe myalgia to rhabdomyolysis and myocardial toxicity. In 2001, Tricholoma equestre (also known as yellow knight or man on horseback) was implicated in 12 cases, some of which occurred in southern France; three patients died. In Asia and North America, fatal rhabdomyolysis has been reported after the ingestion of Russula subnigricans [1,2,12,13]. Red yeast rice is being increasingly consumed as a dietary alternative to cholesterol-lowering medications but its ingestion as capsules has been reported to cause myalgia, CK elevation, and rhabdomyolysis. This muscle toxicity is ascribable to
233
the yeast Monascus purpureus, which produces monacolins, particularly monacolin K, a compound similar to lovastatin and capable of inhibiting the enzyme HMGCR [2,14]. Toxic myopathies are among the main causes of myalgia and muscle cell damage. They constitute a highly heterogeneous group of disorders in terms of the inducing agents, muscle cell abnormalities, manifestations, and clinical severity. Establishing the diagnosis is crucial, as life-threatening rhabdomyolysis can occur in some cases. The number of substances known to induce toxic myopathies is increasing, and consequently careful attention should be given to the clinical setting, diet and dietary supplements, and symptoms suggesting an underlying muscle disease, in order to ensure the optimal management of patients with toxic myopathies. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Kushlaf HA. Emerging toxic neuropathies and myopathies. Neurol Clin 2011;29:679–87. [2] Mastaglia FL, Needham M. Update on toxic myopathies. Curr Neurol Neurosci Rep 2012;12:54–61. [3] Guis S, Krahn M, Fernandez C, Mattei JP, Levy N, Bendahan D. Pathologies des muscles striés squelettiques. EMC - Appareil Locomoteur 2010:1–19 [Article 15-143-A-10]. [4] Guis S, Mattei JP, Lioté F. Drug-induced and toxic myopathies. Best Pract Res Clin Rheumatol 2003;17:877–907. [5] Dalakas MC. Toxic and drug-induced myopathies. J Neurol Neurosurg Psychiatry 2009;80:832–8. [6] Guis S, Mattei JP, Cozzone PJ, et al. Pathophysiology and clinical presentations of rhabdomyolysis. Joint Bone Spine 2005;72:382–91. [7] Smiley IW, Khan BV, Sperling LS. Management of the statin-intolerant patient. Curr Treat Options Cardiovasc Med 2009;11:26–71. [8] Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009;150:858–68. [9] Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy: a genome wide study. N Engl J Med 2008;359:789–99. [10] Seok JI, Lee DK, Lee CH, et al. Long-term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA. Hepatology 2009;49:2080–6. [11] Kilbourne EM, Rigau-Perez JG, Heath CW, et al. Clinical epidemiology of toxic oil syndrome: manifestations of a new illness. N Engl J Med 1983;309:1408–14. [12] Bedry R, Baudrimont I, Deffieux G, et al. Wild mushroom intoxication as a cause of rhabdomyolysis. N Engl J Med 2001;345:798–802. [13] Matsuura M, Saikawa Y, Inui K, et al. Identification of the toxic trigger in mushroom poisoning. Nat Chem Biol 2009;5:465–7. [14] Prasad GV, Wong T, Meliton G, et al. Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient. Transplantation 2002;74:1200–1.
Sandrine Guis ∗ Jean-Pierre Mattei David Bendahan Aix-Marseille University, Centre de Résonance Magnétique Biologique et Médicale (CRMBM) CNRS, CRMBM UMR CNRS 7339, Faculté de Médecine de Marseille, 27, Boulevard Jean-Moulin, 13005 Marseille, France ∗ Corresponding
author. Tel.: +33 4 91 32 48 07; fax: +33 4 91 25 65 39. E-mail address: [email protected] (S. Guis) Accepted 1st October 2012 Available online10 December 2012