- Email: [email protected]
Glucocorticoid-induced myopathy
Joint Bone Spine 78 (2011) 41–44
Review
Glucocorticoid-induced myopathy Rosa Maria Rodrigues Pereira ∗ , Jozélio Freire de Carvalho Rheumatology Division, Faculdade de Medicina, Universidade de São Paulo, avenue Dr. Arnaldo, 455, 3 andar, sala 3105, São Paulo, 01246-903, Brazil
a r t i c l e
i n f o
Article history: Accepted 3 February 2010 Available online 14 May 2010 Keywords: Myopathy Glucocorticoid Muscle weakness Muscle Type II fiber atrophy
a b s t r a c t Glucocorticoid-induced myopathy, characterized by muscle weakness without pain, fatigue and atrophy, is an adverse effect of glucocorticoid use and is the most common type of drug-induced myopathy. This muscle disturbance has a frequency of 60%, and it has been most often associated with fluorinated glucocorticoid preparations. Glucocorticoids have a direct catabolic effect on muscle, decreasing protein synthesis and increasing the rate of protein catabolism leading to muscle atrophy. In clinical practice, it is important to differentiate myopathy due to glucocorticoid from muscle inflammatory diseases. The treatment is based on reduction or, if possible, on discontinuation of the steroid. Fluorinated glucocorticoids such as dexamethasone should be replaced with nonfluorinated glucocorticoids such as prednisone. Other experimental treatments may be tried such as IGF-I, branched-chain amino acids, creatine, androgens such as testosterone, nandrolone and dehydroepiandrosterone (DHEA), and glutamine. © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Glucocorticoid-induced myopathy was first described in 1932 by Harvey Cushing, in Cushing’s syndrome [1]. The introduction of glucocorticoids as therapeutic agents, in 1950, made clinicians more aware of glucocorticoid-induced myopathy. Glucocorticoidinduced myopathy, characterized by muscle weakness without pain, fatigue and atrophy, is an adverse effect of glucocorticoid use and is the most common type of drug-induced myopathy. Although glucocorticoid-induced myopathy can affect any individual, cancer patients and the elderly are most at risk for this muscle disorder [2]. The reported incidence of glucocorticoid-induced myopathy is 60% [3], and it has been most often associated with fluorinated glucocorticoid preparations [4]. 2. Pathogenesis Glucocorticoids have a direct catabolic effect on muscle, decreasing protein synthesis and increasing the rate of protein catabolism, thereby leading to muscle atrophy [5,6]. The catabolic effect of glucocorticoids might result from different mechanisms: inhibition of amino acid transport within the muscle, affecting protein synthesis; inhibition of the stimulatory action of insulin, insulin-like growth factor I (IGF-I) and amino acids (leucine in particular) in the phosphorylation of two factors that play a key role in the protein synthesis machinery, eIF4E-binding protein 4E-BP1 and
∗ Corresponding author. Tel.: +55 11 3061 7490; fax: +55 11 3061 7490. E-mail address: [email protected] (R.M.R. Pereira).
ribosomal protein S6-kinase 1; inhibition of myogenesis through the downregulation of myogenin, a transcription factor involved in the differentiation of satellite cells into muscle fibers. The inhibition of protein synthesis by glucocorticoids is mainly due to the mammalian target of rapamycin, a kinase responsible for the phosphorylation of 4E-BP1 and S6-kinase 1 [6]. The catabolic effect of glucocorticoids results from the activation of the most important cellular proteolytic systems: ubiquitin-proteasome system, lysosomal system (cathepsins) and calcium-dependent system (calpains). Protein degradation by glucocorticoids primarily affects myofibrillar proteins, as evidenced by an increase in urinary 3-methyl-histidine excretion. Because proteasomes cannot degrade intact myofibrils, it is believed that actin and myosin must be dissociated from myofibrils before they are broken down by the ubiquitin-proteasome system [7]. Some in vivo studies suggest that caspase-3 might be involved in glucocorticoidinduced muscle breakdown. The signaling pathways present in this protein breakdown are the forkhead box class O transcription factor and glycogen-synthase kinase 3 beta [6]. Local factors might also be involved in the physiopathology of glucocorticoid-induced myopathy. In addition, glucocorticoids can cause muscle atrophy because they affect the production of growth factors that exert local control over muscle development. Glucocorticoids inhibit muscle production of IGF-I, a factor that stimulates muscle development by increasing protein synthesis and myogenesis, as well as decreasing apoptosis and proteolysis. On the other hand, glucocorticoids stimulate muscle production of myostatin, a factor that inhibits muscle development through the downregulation of protein synthesis, as well as of the proliferation and differentiation of satellite cells [8]. Another mechanism related to myostatin that induces muscle atrophy is reversing
1297-319X/$ – see front matter © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2010.02.025
42
R.M.R. Pereira, J. Freire de Carvalho / Joint Bone Spine 78 (2011) 41–44
the IGF-I/PI3K/Akt hypertrophy pathway. Moreover, myostatin increases the levels of active FOXO allowing increased expression of atrogenes through inhibition of Akt phosphorylation [6]. This hypothesis has been confirmed by disruption of myostatin gene expression in mice that lead to dramatic increase in skeletal muscle mass due to fiber hyperplasia and/or hypertrophy [6]. Additional mechanism to glucocorticoid induced myopathy is mitochondrial dysfunction. Previous studies demonstrated that mitochondria are enlarged or aggregated and GC also reduces mitochondrial oxidative capacity [9].
3. Clinical manifestations Glucocorticoid-induced myopathy can occur in an acute form or a chronic form, either at the initiation of or during the maintenance phase of glucocorticoid treatment, the dose being increased in the latter phase due to exacerbation of the underlying disease. The acute form of glucocorticoid-induced myopathy most often occurs in the intensive care unit setting. It is clinically characterized by rapidly progressive weakening of the proximal and distal muscle groups. The respiratory muscles can also be affected, and recovery can take months [8]. Intensive care unit patients, who can present nutritional deficiencies concomitantly with sepsis, as well as potentially being on mechanical ventilation and receiving neuromuscular non depolarizing agents, are generally treated with high doses of glucocorticoids [10]. Chronic myopathy caused by the use of steroids is characterized by muscle weakness that is painless or only mildly painful and progresses slowly, affecting the proximal muscles, particularly the pelvic girdle muscles, and, more rarely, the distal muscles [11]. Chronic myopathy can lead to muscle atrophy that regresses only after a matter of weeks or months [12,13]. Clinical manifestations of Cushing’s syndrome, such as moon face, diabetes mellitus, mood disorders, fragile skin and osteoporosis, are common but not always present [14]. Regarding to osteoporosis/fractures, Natsui et al. showed that high-dose glucocorticoid treatment induces rapid loss of trabecular bone mineral density and lean body mass and suggested that decreased lean mass may be also responsible for the increased risk of fracture [15]. The population at risk for glucocorticoid-induced myopathy is composed of the elderly, cancer patients, patients with diseases that affect the respiratory muscles, patients with negative nitrogen balance before the initiation of glucocorticoid treatment and patients who are physically inactive [2].
4. Myopathy: glucocorticoid presentation and dose Glucocorticoid-induced myopathy is more frequently associated with the use of fluorinated glucocorticoid preparations, such as dexamethasone, betamethasone and triamcinolone, than with the use of nonfluorinated preparations, such as prednisone and prednisolone. The glucocorticoid dose that can induce glucocorticoid-induced myopathy varies greatly among patients. Some might present with muscle weakness after a low dose of steroids, whereas others might not suffer from such weakness even if they are treated with high doses of steroids for months or years. However, the following are typically observed: the use of prednisone or equivalent drugs in doses of lower than 10 mg/day are rarely associated with glucocorticoid-induced myopathy; higher glucocorticoid doses result in more rapid onset of clinically significant muscle weakness, which can be observed within 2 weeks after the initiation of corticosteroid therapy; the use of prednisone or equivalent drugs in doses of 40–60 mg/day for at least 1 month results in some degree of muscle weakness [2].
Treatment with non fluorinated glucocorticoids, especially methylprednisolone, has been shown to cause acute muscle weakness in situations of stress, such as acute spinal cord injury or acute respiratory distress syndrome [16,17]. It is noteworthy that, when the glucocorticoid dexamethasone is used in combination with the anticonvulsant phenytoin, the risk of developing glucocorticoidinduced myopathy is significantly lower. It is argued that phenytoin can induce hepatic corticosteroid metabolism [18]. Inhaled corticosteroids are rarely associated with myopathy; if such myopathy occurs, it can be quickly reversed by interrupting the steroid treatment [19].Glucocorticoid-induced myopathy following epidural injection of glucocorticoids has rarely been reported in the literature [20]. 5. Laboratory tests and complementary tests In patients with glucocorticoid-induced myopathy, muscle enzyme levels are habitually normal or slightly high. The levels of aldolase and aminotransferases are usually within the range of normality. In the acute phase, however, the levels of creatine kinase and aldolase might be quite high. In critical patients, serum creatine kinase levels can rise by approximately 50%. Electroneuromyography results are typically normal in the early stages of the disease, whereas a myopathic pattern, with short-duration polyphasic action potentials of small amplitude and no spontaneous activity upon needle insertion, is often observed in the later stages [21]. A muscle biopsy can reveal the following: nonspecific atrophy of type IIb muscle fibers, which are fibers of high glycolytic activity and low oxidative activity; absence of inflammatory infiltrate; variations in fiber size with centrally placed nuclei; and, more rarely, signs of muscle necrosis. Another recent tool for the diagnosis of myopathy is magnetic resonance imaging (MRI) that has been used in inflammatory myopathy diagnosis and follow-up. However, in patients whose glucocorticoids are originally prescribed for idiopathic inflammatory myopathy and continued, proximal muscle weakness is observed, Lovitt et al. suggest that it may be difficult to distinguish the underlying myopathy from a corticosteroid-induced myopathy. Furthermore, MRI has not been performed in patients who have corticosteroid-induced myopathy [22]. 6. Chronic glucocorticoid-induced myopathy versus inflammatory myopathy When inflammatory myopathies (polymyositis and dermatomyositis) are treated with glucocorticoids, it is difficult to distinguish between exacerbation of the underlying disease and a worsening of the condition (additional muscle weakness) attributable to the glucocorticoid. Some of the factors that can aid in the differential diagnosis are shown in Table 1. 7. Treatment In patients with glucocorticoid-induced myopathy, the use of glucocorticoids should be discontinued or reduced, except in cases in which the clinical status of the patient contra-indicates such a change. An increase in muscle strength can be observed within 3 to 4 weeks after discontinuation of the glucocorticoid. In the treatment regimen of such patients, fluorinated glucocorticoids such as dexamethasone should be replaced with non fluorinated glucocorticoids such as prednisone, and the lowest recommended dose should be used. The following are some of the experimental treatments that have been used: IGF-I; branched-chain amino acids; creatine; androgens such as testosterone, nandrolone and dehydroepiandrosterone (DHEA); and glutamine. As previously
R.M.R. Pereira, J. Freire de Carvalho / Joint Bone Spine 78 (2011) 41–44
43
Table 1 Differential diagnosis between chronic glucocorticoid-induced myopathy and inflammatory myopathy. Finding/event/test
Glucocorticoid-induced myopathy
Inflammatory myopathy
Occurrence of muscle weakness Cushingoid manifestations Muscle enzyme levels Dose reduction/discontinuation of the glucocorticoid Urinary creatine
≥ 1 month after glucocorticoid initiation Present Normal or slightly elevated Improvement within 3–4 weeks Elevated, but reduces when glucocorticoid is discontinued Normal or small-amplitude polyphasic action potentials without spontaneous activity upon needle insertion
During disease activity Present or absent Elevated Worsening Elevated, but increases further when glucocorticoid is discontinued Small-amplitude and high-frequency polyphasic action potentials with spontaneous activity upon needle insertion and spontaneous fibrillation Endomysial or perivascular inflammatory infiltrate (polymyositis) and perifascicular atrophy (dermatomyositis) Early disease: T2 weighted relatively symmetrical proximal muscle edema-like changes that can be either diffuse or focal Chronic disease: relatively symmetrical T1 and T2 weighted hyperintensities representing areas of fat deposition
Electroneuromyography
Muscle biopsy
Atrophy of type IIb muscle fibers
Magnetic resonance imaging
No studies
mentioned, IGF-I stimulation and myostatin inhibition seem to be promising therapeutic targets in glucocorticoid-induced muscle atrophy. In animal models, increased expression of IGF-I and a deletion in the myostatin gene have both been shown to prevent glucocorticoid-induced muscle atrophy [8]. The administration of branched-chain amino acids can mimic the full effect of a mixture of amino acids in stimulating protein synthesis in skeletal muscle [23]. However, it has been shown that neither branched-chain amino acid supplementation nor leucine supplementation provide any benefit [24]. Experimental studies have demonstrated that creatine supplementation can attenuate muscle loss and enhance exercise performance in animals treated with glucocorticoids [25,26]. DHEA is the principal androgenic hormone produced by the adrenal gland. Its secretion decreases with age and with severe chronic diseases such as rheumatoid arthritis and systemic lupus erythematosus. The administration of glucocorticoids inhibits the secretion of adrenocorticotropic hormone, which leads to the involution of the adrenal cortex and, consequently, to a decrease in DHEA levels. It has been suggested that the administration of DHEA can reduce the catabolic effects of glucocorticoids, including myopathy [27]. Glutamine is a conditionally essential amino acid in catabolic states. Glutamine and alanyl-glutamine have been reported to prevent glucocorticoid-induced muscle atrophy [28]. There are few data in the literature regarding the role of physical activity in the prevention and treatment of glucocorticoid-induced myopathy. Only a few studies have demonstrated that aerobic and resistance exercises are effective in attenuating muscle atrophy in patients with glucocorticoid-induced myopathy [29,30]. Conflicts of interest None of the authors has any conflicts of interest to declare. Acknowledgments This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (305691/2006-6 to RMR Pereira) and Federico Foundation to JF Carvalho. References [1] Cushing H. The basophil adenoma of the pituitary body and their clinical manifestation. Johns Hopkins Med 1932;50:137. [2] Miller ML. Glucocorticoid-induced myopathy. Up to Date, version 16.3, 2009.
[3] Batchelor T, Taylor L, Thaler H, et al. Steroid myopathy in cancer patients. Neurology 1997;48:1234–8. [4] Anagnos A, Ruffi RL, Kaminski H. Endocrine myopathies. Neurol Clin 1997;15:673–96. [5] Löfberg E, Gutierrez A, Wernerman J, et al. Effects of high doses of glucocorticoids on free amino acids, ribosomes and protein turnover in human muscle. Eur J Clin Invest 2002;32:345–53. [6] Schakman O, Gilson H, Thissen JP. Mechanisms of glucocorticoid-induced myopathy. J Endocrinol 2008;197:1–10. [7] Hasselgren PO, Fischer JE. Muscle cachexia: current concepts of intracellular mechanisms and molecular regulation. Ann Surg 2001;233:9–17. [8] Van Balkom RH, van Der Heijden HF, van Herwaarden CL, et al. Corticosteroidinduced myopathy of the respiratory muscles. Neth J Med 1994;45:114–22. [9] Mitsui T, Azuma H, Nagasawa M, et al. Chronic corticosteroid administration causes mitochondrial dysfunction in skeletal muscle. J Neurol 2002;249:1004–9. [10] Zochodne D. Myopathies in the intensive care unit. Can J Neurol Sci 1998;25:S40–2. [11] Guis S, Mattéi JP, Lioté F. Drug-induced and toxic myopathies. Best Pract Res Clin Rheumatol 2003;17:877–907. [12] Fernandez-Sola J, Cusso R, Picado C, et al. Patients with chronic glucocorticoid treatment develop changes in muscle glycogen metabolism. J Neurol Sci 1993;117:103–6. ´ [13] Owczarek J, Jasinska M, Orszulak-Michalak D. Drug-induced myopathies. An overview of the possible mechanisms. Pharmacol Rep 2005;57:23–34. [14] Bowyer SL, Lamothe MP, Hollister JR. Steroid myopathy: incidence and detection in a population with asthma. J Allergy Clin Immunol 1985;76: 234–42. [15] Natsui K, Tanaka K, Suda M, et al. High-dose glucocorticoid treatment induces rapid loss of trabecular bone mineral density and lean body mass. Osteoporos Int 2006;17:105–8. [16] Qian T, Guo X, Levi AD, et al. High-dose methylprednisolone may cause myopathy in acute spinal cord injury patients. Spinal Cord 2005;43:199–203. [17] Steinberg KP, Hudson LD, Goodman RB, et al. National heart, lung, and blood institute acute respiratory distress syndrome (ARDS) clinical trials network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671–84. [18] Dropch EJ, Soong SJ. Steroid-induced weakness in patients with primary brain tumors. Neurology 1991;41:1235–9. [19] Herzog AG. Proximal myopathy associated with inhaled steroids. JAMA 1999;281:37. [20] Boonen S, Van Distel G, Westhovens R, et al. Steroid myopathy induced by epidural triamcinolone injection. Br J Rheumatol 1995;35:385–6. [21] Ruff RL, Weissmann J. Endocrine myopathies. Neurol Clin 1988;6:575–92. [22] Lovitt S, Marden FA, Gundogdu B, et al. MRI in myopathy. Neurol Clin 2004;22:509–38. [23] Kimball SR, Jefferson LS. Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. J Nutr 2006;136:227S–31S. [24] Rieu L, Sornet C, Grizard J, et al. Glucocorticoid excess induces a prolonged leucine resistance on muscle protein synthesis in old rats. Exp Gerontol 2004;39:1315–21. [25] Menezes LG, Sobreira C, Neder L, et al. Creatine supplementation attenuates corticosteroid-induced muscle wasting and impairment of exercise performance in rats. J Appl Physiol 2007;102:698–703. [26] Campos AR, Serafini LN, Sobreira C, et al. Creatine intake attenuates corticosteroid-induced impairment of voluntary running in hamsters. Appl Physiol Nutr Metab 2006;31:490–4.
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[27] Robinzon B, Cutolo M. Should dehydroepiandrosterone replacement therapy be provided with glucocorticoids? Rheumatology (Oxford) 1999;38:488–95. [28] Hickson RC, Wegrzyn LE, Osborne DF, et al. Alanyl-glutamine prevents muscle atrophy and glutamine synthetase induction by glucocorticoids. Am J Physiol 1996;71:R1165–72.
[29] Lapier TK. Glucocorticoid-induced muscle atrophy. The role of exercise in treatment and prevention. J Cardiopulm Rehabil 1997;17:76–84. [30] Horber FF, Scheidegger J, Grünig BE, et al. Evidence that prednisoneinduced myopathy is reversed by physical training. J Clin Endocrinol Metab 1985;61:83–8.
Review
Glucocorticoid-induced myopathy Rosa Maria Rodrigues Pereira ∗ , Jozélio Freire de Carvalho Rheumatology Division, Faculdade de Medicina, Universidade de São Paulo, avenue Dr. Arnaldo, 455, 3 andar, sala 3105, São Paulo, 01246-903, Brazil
a r t i c l e
i n f o
Article history: Accepted 3 February 2010 Available online 14 May 2010 Keywords: Myopathy Glucocorticoid Muscle weakness Muscle Type II fiber atrophy
a b s t r a c t Glucocorticoid-induced myopathy, characterized by muscle weakness without pain, fatigue and atrophy, is an adverse effect of glucocorticoid use and is the most common type of drug-induced myopathy. This muscle disturbance has a frequency of 60%, and it has been most often associated with fluorinated glucocorticoid preparations. Glucocorticoids have a direct catabolic effect on muscle, decreasing protein synthesis and increasing the rate of protein catabolism leading to muscle atrophy. In clinical practice, it is important to differentiate myopathy due to glucocorticoid from muscle inflammatory diseases. The treatment is based on reduction or, if possible, on discontinuation of the steroid. Fluorinated glucocorticoids such as dexamethasone should be replaced with nonfluorinated glucocorticoids such as prednisone. Other experimental treatments may be tried such as IGF-I, branched-chain amino acids, creatine, androgens such as testosterone, nandrolone and dehydroepiandrosterone (DHEA), and glutamine. © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Glucocorticoid-induced myopathy was first described in 1932 by Harvey Cushing, in Cushing’s syndrome [1]. The introduction of glucocorticoids as therapeutic agents, in 1950, made clinicians more aware of glucocorticoid-induced myopathy. Glucocorticoidinduced myopathy, characterized by muscle weakness without pain, fatigue and atrophy, is an adverse effect of glucocorticoid use and is the most common type of drug-induced myopathy. Although glucocorticoid-induced myopathy can affect any individual, cancer patients and the elderly are most at risk for this muscle disorder [2]. The reported incidence of glucocorticoid-induced myopathy is 60% [3], and it has been most often associated with fluorinated glucocorticoid preparations [4]. 2. Pathogenesis Glucocorticoids have a direct catabolic effect on muscle, decreasing protein synthesis and increasing the rate of protein catabolism, thereby leading to muscle atrophy [5,6]. The catabolic effect of glucocorticoids might result from different mechanisms: inhibition of amino acid transport within the muscle, affecting protein synthesis; inhibition of the stimulatory action of insulin, insulin-like growth factor I (IGF-I) and amino acids (leucine in particular) in the phosphorylation of two factors that play a key role in the protein synthesis machinery, eIF4E-binding protein 4E-BP1 and
∗ Corresponding author. Tel.: +55 11 3061 7490; fax: +55 11 3061 7490. E-mail address: [email protected] (R.M.R. Pereira).
ribosomal protein S6-kinase 1; inhibition of myogenesis through the downregulation of myogenin, a transcription factor involved in the differentiation of satellite cells into muscle fibers. The inhibition of protein synthesis by glucocorticoids is mainly due to the mammalian target of rapamycin, a kinase responsible for the phosphorylation of 4E-BP1 and S6-kinase 1 [6]. The catabolic effect of glucocorticoids results from the activation of the most important cellular proteolytic systems: ubiquitin-proteasome system, lysosomal system (cathepsins) and calcium-dependent system (calpains). Protein degradation by glucocorticoids primarily affects myofibrillar proteins, as evidenced by an increase in urinary 3-methyl-histidine excretion. Because proteasomes cannot degrade intact myofibrils, it is believed that actin and myosin must be dissociated from myofibrils before they are broken down by the ubiquitin-proteasome system [7]. Some in vivo studies suggest that caspase-3 might be involved in glucocorticoidinduced muscle breakdown. The signaling pathways present in this protein breakdown are the forkhead box class O transcription factor and glycogen-synthase kinase 3 beta [6]. Local factors might also be involved in the physiopathology of glucocorticoid-induced myopathy. In addition, glucocorticoids can cause muscle atrophy because they affect the production of growth factors that exert local control over muscle development. Glucocorticoids inhibit muscle production of IGF-I, a factor that stimulates muscle development by increasing protein synthesis and myogenesis, as well as decreasing apoptosis and proteolysis. On the other hand, glucocorticoids stimulate muscle production of myostatin, a factor that inhibits muscle development through the downregulation of protein synthesis, as well as of the proliferation and differentiation of satellite cells [8]. Another mechanism related to myostatin that induces muscle atrophy is reversing
1297-319X/$ – see front matter © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2010.02.025
42
R.M.R. Pereira, J. Freire de Carvalho / Joint Bone Spine 78 (2011) 41–44
the IGF-I/PI3K/Akt hypertrophy pathway. Moreover, myostatin increases the levels of active FOXO allowing increased expression of atrogenes through inhibition of Akt phosphorylation [6]. This hypothesis has been confirmed by disruption of myostatin gene expression in mice that lead to dramatic increase in skeletal muscle mass due to fiber hyperplasia and/or hypertrophy [6]. Additional mechanism to glucocorticoid induced myopathy is mitochondrial dysfunction. Previous studies demonstrated that mitochondria are enlarged or aggregated and GC also reduces mitochondrial oxidative capacity [9].
3. Clinical manifestations Glucocorticoid-induced myopathy can occur in an acute form or a chronic form, either at the initiation of or during the maintenance phase of glucocorticoid treatment, the dose being increased in the latter phase due to exacerbation of the underlying disease. The acute form of glucocorticoid-induced myopathy most often occurs in the intensive care unit setting. It is clinically characterized by rapidly progressive weakening of the proximal and distal muscle groups. The respiratory muscles can also be affected, and recovery can take months [8]. Intensive care unit patients, who can present nutritional deficiencies concomitantly with sepsis, as well as potentially being on mechanical ventilation and receiving neuromuscular non depolarizing agents, are generally treated with high doses of glucocorticoids [10]. Chronic myopathy caused by the use of steroids is characterized by muscle weakness that is painless or only mildly painful and progresses slowly, affecting the proximal muscles, particularly the pelvic girdle muscles, and, more rarely, the distal muscles [11]. Chronic myopathy can lead to muscle atrophy that regresses only after a matter of weeks or months [12,13]. Clinical manifestations of Cushing’s syndrome, such as moon face, diabetes mellitus, mood disorders, fragile skin and osteoporosis, are common but not always present [14]. Regarding to osteoporosis/fractures, Natsui et al. showed that high-dose glucocorticoid treatment induces rapid loss of trabecular bone mineral density and lean body mass and suggested that decreased lean mass may be also responsible for the increased risk of fracture [15]. The population at risk for glucocorticoid-induced myopathy is composed of the elderly, cancer patients, patients with diseases that affect the respiratory muscles, patients with negative nitrogen balance before the initiation of glucocorticoid treatment and patients who are physically inactive [2].
4. Myopathy: glucocorticoid presentation and dose Glucocorticoid-induced myopathy is more frequently associated with the use of fluorinated glucocorticoid preparations, such as dexamethasone, betamethasone and triamcinolone, than with the use of nonfluorinated preparations, such as prednisone and prednisolone. The glucocorticoid dose that can induce glucocorticoid-induced myopathy varies greatly among patients. Some might present with muscle weakness after a low dose of steroids, whereas others might not suffer from such weakness even if they are treated with high doses of steroids for months or years. However, the following are typically observed: the use of prednisone or equivalent drugs in doses of lower than 10 mg/day are rarely associated with glucocorticoid-induced myopathy; higher glucocorticoid doses result in more rapid onset of clinically significant muscle weakness, which can be observed within 2 weeks after the initiation of corticosteroid therapy; the use of prednisone or equivalent drugs in doses of 40–60 mg/day for at least 1 month results in some degree of muscle weakness [2].
Treatment with non fluorinated glucocorticoids, especially methylprednisolone, has been shown to cause acute muscle weakness in situations of stress, such as acute spinal cord injury or acute respiratory distress syndrome [16,17]. It is noteworthy that, when the glucocorticoid dexamethasone is used in combination with the anticonvulsant phenytoin, the risk of developing glucocorticoidinduced myopathy is significantly lower. It is argued that phenytoin can induce hepatic corticosteroid metabolism [18]. Inhaled corticosteroids are rarely associated with myopathy; if such myopathy occurs, it can be quickly reversed by interrupting the steroid treatment [19].Glucocorticoid-induced myopathy following epidural injection of glucocorticoids has rarely been reported in the literature [20]. 5. Laboratory tests and complementary tests In patients with glucocorticoid-induced myopathy, muscle enzyme levels are habitually normal or slightly high. The levels of aldolase and aminotransferases are usually within the range of normality. In the acute phase, however, the levels of creatine kinase and aldolase might be quite high. In critical patients, serum creatine kinase levels can rise by approximately 50%. Electroneuromyography results are typically normal in the early stages of the disease, whereas a myopathic pattern, with short-duration polyphasic action potentials of small amplitude and no spontaneous activity upon needle insertion, is often observed in the later stages [21]. A muscle biopsy can reveal the following: nonspecific atrophy of type IIb muscle fibers, which are fibers of high glycolytic activity and low oxidative activity; absence of inflammatory infiltrate; variations in fiber size with centrally placed nuclei; and, more rarely, signs of muscle necrosis. Another recent tool for the diagnosis of myopathy is magnetic resonance imaging (MRI) that has been used in inflammatory myopathy diagnosis and follow-up. However, in patients whose glucocorticoids are originally prescribed for idiopathic inflammatory myopathy and continued, proximal muscle weakness is observed, Lovitt et al. suggest that it may be difficult to distinguish the underlying myopathy from a corticosteroid-induced myopathy. Furthermore, MRI has not been performed in patients who have corticosteroid-induced myopathy [22]. 6. Chronic glucocorticoid-induced myopathy versus inflammatory myopathy When inflammatory myopathies (polymyositis and dermatomyositis) are treated with glucocorticoids, it is difficult to distinguish between exacerbation of the underlying disease and a worsening of the condition (additional muscle weakness) attributable to the glucocorticoid. Some of the factors that can aid in the differential diagnosis are shown in Table 1. 7. Treatment In patients with glucocorticoid-induced myopathy, the use of glucocorticoids should be discontinued or reduced, except in cases in which the clinical status of the patient contra-indicates such a change. An increase in muscle strength can be observed within 3 to 4 weeks after discontinuation of the glucocorticoid. In the treatment regimen of such patients, fluorinated glucocorticoids such as dexamethasone should be replaced with non fluorinated glucocorticoids such as prednisone, and the lowest recommended dose should be used. The following are some of the experimental treatments that have been used: IGF-I; branched-chain amino acids; creatine; androgens such as testosterone, nandrolone and dehydroepiandrosterone (DHEA); and glutamine. As previously
R.M.R. Pereira, J. Freire de Carvalho / Joint Bone Spine 78 (2011) 41–44
43
Table 1 Differential diagnosis between chronic glucocorticoid-induced myopathy and inflammatory myopathy. Finding/event/test
Glucocorticoid-induced myopathy
Inflammatory myopathy
Occurrence of muscle weakness Cushingoid manifestations Muscle enzyme levels Dose reduction/discontinuation of the glucocorticoid Urinary creatine
≥ 1 month after glucocorticoid initiation Present Normal or slightly elevated Improvement within 3–4 weeks Elevated, but reduces when glucocorticoid is discontinued Normal or small-amplitude polyphasic action potentials without spontaneous activity upon needle insertion
During disease activity Present or absent Elevated Worsening Elevated, but increases further when glucocorticoid is discontinued Small-amplitude and high-frequency polyphasic action potentials with spontaneous activity upon needle insertion and spontaneous fibrillation Endomysial or perivascular inflammatory infiltrate (polymyositis) and perifascicular atrophy (dermatomyositis) Early disease: T2 weighted relatively symmetrical proximal muscle edema-like changes that can be either diffuse or focal Chronic disease: relatively symmetrical T1 and T2 weighted hyperintensities representing areas of fat deposition
Electroneuromyography
Muscle biopsy
Atrophy of type IIb muscle fibers
Magnetic resonance imaging
No studies
mentioned, IGF-I stimulation and myostatin inhibition seem to be promising therapeutic targets in glucocorticoid-induced muscle atrophy. In animal models, increased expression of IGF-I and a deletion in the myostatin gene have both been shown to prevent glucocorticoid-induced muscle atrophy [8]. The administration of branched-chain amino acids can mimic the full effect of a mixture of amino acids in stimulating protein synthesis in skeletal muscle [23]. However, it has been shown that neither branched-chain amino acid supplementation nor leucine supplementation provide any benefit [24]. Experimental studies have demonstrated that creatine supplementation can attenuate muscle loss and enhance exercise performance in animals treated with glucocorticoids [25,26]. DHEA is the principal androgenic hormone produced by the adrenal gland. Its secretion decreases with age and with severe chronic diseases such as rheumatoid arthritis and systemic lupus erythematosus. The administration of glucocorticoids inhibits the secretion of adrenocorticotropic hormone, which leads to the involution of the adrenal cortex and, consequently, to a decrease in DHEA levels. It has been suggested that the administration of DHEA can reduce the catabolic effects of glucocorticoids, including myopathy [27]. Glutamine is a conditionally essential amino acid in catabolic states. Glutamine and alanyl-glutamine have been reported to prevent glucocorticoid-induced muscle atrophy [28]. There are few data in the literature regarding the role of physical activity in the prevention and treatment of glucocorticoid-induced myopathy. Only a few studies have demonstrated that aerobic and resistance exercises are effective in attenuating muscle atrophy in patients with glucocorticoid-induced myopathy [29,30]. Conflicts of interest None of the authors has any conflicts of interest to declare. Acknowledgments This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (305691/2006-6 to RMR Pereira) and Federico Foundation to JF Carvalho. References [1] Cushing H. The basophil adenoma of the pituitary body and their clinical manifestation. Johns Hopkins Med 1932;50:137. [2] Miller ML. Glucocorticoid-induced myopathy. Up to Date, version 16.3, 2009.
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