Drug-induced Myopathy Research Articles

Steroid myopathy in patients with myasthenia gravis: a literature review

Steroid myopathy is a common drug-induced non-inflammatory myopathy that affects patients requiring long-term glucocorticoid treatment for various autoimmune, inflammatory and oncological diseases. According to the neurology clinical practice guidelines, non-fluorinated glucocorticoids are the first-line pathogen-directed therapy for a number of dysimmune neuromuscular disorders, including myasthenia gravis. Long-term high-dose steroid treatment regime for myasthenia gravis leads to both acute and chronic development of glucocorticoids-induced proximal muscle weakness and atrophy. Steroid myopathy, along with other undesirable side effects of glucocorticoids therapy, impact health-related quality of life, patient satisfaction and adherence to treatment. Hence, further studies are required to expand our knowledge of clinical evaluation, diagnostic testing and prevention approaches for glucocorticoids-induced myopathy. The aim of this literature review is to analyze existing data on pathogenesis, diagnostic tools and treatment strategies for steroid myopathy.

Causality analysis of myopathy secondary to dapagliflozin therapy in type II Diabetes – A case study

Diabetes mellitus is a chronic metabolic condition that is becoming more prevalent globally. Diabetic patients must maintain adequate glycemic control in order to avoid or postpone diabetic complications. Diabetes care has evolved since the introduction of sodium-glucose co-transporter 2 inhibitors (SGLT2i). Postmarketing surveillance has shown cases of diabetic ketoacidosis and increased bone fracture risk associated with the use of SGLT2 inhibitors. We present a case of a 55-year-old female with a 6-year history of diabetes who exhibited weakness, muscular pains, and a burning feeling in her left thigh as a result of Dapagliflozin. Before initiating dapagliflozin treatment, the patient's fasting blood sugar (FBS) was 314 mg/dl and postprandial blood sugar (PPBS) was 343 mg/dl. After adding dapagliflozin as part of the therapy, the FBS improved to 179.24 mg/dl, and the PPBS decreased to 214.39 mg/dl, indicating a significant reduction in blood glucose levels. The introduction of Dapagliflozin in the treatment reduces the therapeutic gap compared to earlier treatment schedule, but retain the same side effect and became rechallenge. The instance of myopathy linked to dapagliflozin was confirmed following the causality evaluation by WHO Schales. It exemplifies the need for detecting drug-induced myopathy. Recently, minimal evidence has emerged showing a link between prolonged SGLT2 inhibitor use and accelerated myopathy. Myopathy is the generalised loss of skeletal muscle mass and function that occurs with ageing. Its existence is linked to negative health outcomes such as physical impairment, low quality of life, and death. Clinically, no other cause of myopathy was detected, and biochemical analysis indicated that dapagliflozin was the cause of her myopathy.

Drug-Induced Myopathies: A Comprehensive Review and Update.

Drug-induced myopathies are a common cause of muscle pain, and the range of drugs that can cause muscle side effects is constantly expanding. In this article, the authors comprehensively discuss the diagnostic and therapeutic process in patients with myalgia, and present the spectrum of drug-induced myopathies. The review provides a detailed analysis of the literature on the incidence of myopathy during treatment with hypolipemic drugs, beta-blockers, amiodarone, colchicine, glucocorticosteroids, antimalarials, cyclosporine, zidovudine, and checkpoint inhibitors, a group of drugs increasingly used in the treatment of malignancies. The article considers the clinical course of the different types of myopathies, their pathogenesis, histopathological features, and treatment methods of these disorders. The aim of this paper is to gather from the latest available literature up-to-date information on the course, pathophysiology, and therapeutic options of drug-induced myopathies, to systematize the knowledge of drug-induced myopathies and to draw the attention of internists to the fact that these clinical issues are an important therapeutic problem.

The Genesis of Dyspnea in Patients After COVID-19

Post-COVID syndrome is an actual problem at the present time. The shortness of breath is one of the most common complaints in this group of patients. Dyspnea is one of the most significant disabling symptoms that negatively affect the quality of life of patients. The causes and mechanisms for the development of dyspnea in the post-COVID period are varied. In particular, one of the main causes of dyspnea is fibrosis-like and fibrous changes in the. Fatigue and / or muscle weakness, in particular of the respiratory muscles, can also be the cause of dyspnea. Direct SARS-CoV-2 infection of skeletal muscles, drug-induced myopathy, prolonged immobilization of hospitalized patients may also result in muscle weakness. Increased risks of thrombosis and pulmonary embolism (PE) after COVID-19, creating conditions for the development of chronic thromboembolic pulmonary hypertension, represent another factors for the development of shortness of breath. In patients with no abnormalities in blood gases or any other parameters that assess the functioning of the cardiovascular and respiratory systems, hyperventilation syndrome can be the cause of dyspnea. Thus, studying pathogenetic and molecular mechanisms of dyspnea development is an urgent problem, due to the need for specialists to choose the right tactics and select effective drugs and non-drug therapy for managing patients with this complaint.

Reporting of Drug-Induced Myopathies Associated with the Combination of Statins and Daptomycin: A Disproportionality Analysis Using the US Food and Drug Administration Adverse Event Reporting System.

Myopathy is one of the most common adverse reactions of daptomycin and statins. We aimed to evaluate the muscular toxicity of the combination therapy of daptomycin and statins in a large pharmacovigilance database. This was a retrospective disproportionality analysis based on real-world data. All cases reported between the first quarter of 2004 and the fourth quarter of 2022 where daptomycin and statins were reported were gathered from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Disproportionality analyses were conducted by estimating the proportional reporting ratios (PRRs), reporting odds ratio (ROR), and information component (IC). A total of 971,861 eligible cases were collected from the FAERS database. Data analysis showed that rosuvastatin (ROR: 124.39, 95% CI: 87.35-178.47), atorvastatin (ROR: 68.53, 95% CI: 51.93-90.43), and simvastatin (ROR: 94.83, 95% CI: 71.12-126.46) combined with daptomycin increased the reporting frequency of myopathy. Moreover, myopathy was reported more frequently with the 3-drug combination (ROR: 598.01, 95% CI: 231.81-1542.71). For rhabdomyolysis, the frequency of reports also increased when daptomycin was combined with rosuvastatin (ROR: 156.34, 95% CI: 96.21-254.05), simvastatin (ROR: 72.65, 95% CI: 47.36-111.44), and atorvastatin (ROR: 66.31, 95% CI: 44.06-99.81). The combination of daptomycin and statins increased the association of myopathy and rhabdomyolysis, especially with rosuvastatin, simvastatin, and atorvastatin.

Safety monitoring of drug-induced muscle injury and rhabdomyolysis: a biomarker-guided approach for clinical practice and drug trials.

Skeletal muscle tissue (SKM) may be damaged due to mechanical, metabolic, and exertional causes. However, drug-induced myopathy is among the most frequent causes of muscle disease. The clinical picture of drug-induced myopathies may be highly variable. It may present as asymptomatic or mild myalgias, with or without muscle weakness, which are likely underreported. However, it may also appear as chronic myopathy with severe weakness and, rarely, even as massive rhabdomyolysis with acute kidney injury (AKI). Unfortunately, the available biomarkers for SKM injury do not fully meet the needs for satisfactory detection of drug-induced damage, both in clinical and research settings, mainly due to their low sensitivity and specificity. Therefore, the present study proposes a strategy for drug safety monitoring using the available biomarkers of SKM injury. Moreover, we will discuss mechanisms of drug-induced SKM injury, traditional laboratory testing for SKM injury, and novel skeletal myocyte biomarkers under investigation. This can be incredibly useful in both clinical practice and for de-challenge/re-challenge investigational trials where the risk of drug-induced SKM injury is present.

Idiopathic polymyositis in renal transplant recipient

Introduction and aim Myositis is a rare complication following renal transplant and is most commonly the result of a drug-mediated myotoxicity, but the idiopathic cause is still the most common. After kidney transplant, the differential diagnosis of polymyositis includes autoimmune disease, drug-induced viral infections, and rhabdomyolysis associated with electrolyte imbalance. We aimed to report a case of idiopathic polymyositis in a renal transplant recipient and review the literature for similar cases. Case report A 31-year-old male patient developed polymyositis three years following live-related kidney transplantation. Electromyography confirmed myopathic changes. The clinical features and course, MRI findings, electromyography features, positive anti-MI-2 antibody, and the response to high-dose steroid therapy are matched with immune-mediated acute polymyositis, especially after excluding viral infections and drug-induced myopathy. Conclusion Acute polymyositis may occur after a kidney transplant. Possible mechanisms include viral antigen transmission or a localized graft versus host disease. Muscle biopsy is not mandatory before prompt initiation of high-dose steroid therapy, which leads to clinical and biochemical recovery.

Creatine phosphokinase enzyme elevation in two third-level hospitals of Córdoba

HyperCKemia is defined as the elevation of creatine phosphokinase (CK) levels greater than 1.5 times the upper limit (CK>285 U/L), being produced by multiple causes, which vary according different populations. The main objective of the study was to know the frequency of hyperCKemia in two hospitals in Córdoba and its main causes. Retrospective analytical study in two hospitals in Córdoba, Argentina, where all patients over 18 years of age who presented CK values ​​greater than 285 U/L on at least 2 occasions in a period between 1 and 4 weeks were identified, between the years 2015 and 2017. 254 patients with hyperCKemia were identified, the majority were male (n=181, 71.3%) and their median age was 65 years (interquartile range 25-75%=50-73 years). The main causes of hyperCKemia were ischemic myopathy in 99 (39%) patients and drug-induced myopathies in 45 (17.7%), with statins being the most frequently involved drugs in 31 cases. In only 3.1% of the cases the final diagnosis was not reached. Drug-induced hyperCKemias, when compared to other causes, occurred more frequently in patients with a history of chronic kidney disease (9/45 [20%] vs 18/209 [8.6%], p = 0.025) and in non-smokers (41/45 [91.1%] vs. 157/209 [75.1%], p=0.019). 254 cases of hyperCKemia were observed, the main causes being of ischemic origin and secondary to drug use, especially statins.

Drug-induced Myopathies.

Differential diagnosis of muscle pain and weakness is extensive, including neurological, vertebral, arthrogenic, vascular, traumatic, immunological, endocrine, genetic and infectious aetiologies, as well as medication or toxin-related causes. Muscles are highly sensitive to a large number of drugs, especially with high doses. Although many drug classes can cause toxic myopathy, a significant number of cases are caused by lipid-lowering drugs, long-term use of corticosteroids, and, most often, alcohol misuse. Some drug interactions, e.g. those that are metabolised via the enzyme CYP3A4, can increase the serum levels of the drugs and drug-induced toxicity. A careful history of patient's drug and alcohol consumption is therefore vital. Clinical symptoms depend on the drug, dosage and patient's sensitivity. They can vary from asymptomatic increase in serum levels of creatine kinase, mild myalgia and cramps to muscle weakness, rhabdomyolysis, kidney failure and even death. The pathogenesis is often only partially known and multifactorial. Toxic myopathy is often reversible once the drug is discontinued, alternative drug therapy is started or a different dosage regimen is chosen. Complications such as acute kidney failure must be avoided, and analgesic therapy may be indicated.

Telmisartan Induced Myotoxicity: A Case-Report

The precise incidence of drug-induced myopathy is still not known, only few reports with the use of Telmisartan. There are likely around 150 agents that are associated to cause myotoxicity like statins, corticosteroids, anti-retroviral, and immunosuppressants. Therefore, as recommended by the guidelines, therapeutic drug monitoring of Telmisartan is required after the initiation of the therapy. However, the rise in serum creatinine up to 20-30% is accepted. But if serum creatinine level increases >30% then withdrawal of the therapy is recommended.
 Suspicious with the previous therapy of Tab. Telmisartan as no other pathology could be detected. A causality analysis was done using the Naranjo’s algorithm and WHO-UMC Scale and the present ADR was found to be ‘Probable’ with Telmisartan. Tab. Telmisartan was withdrawn completely and was switched by another Antihypertensive -Tab. Enalapril (5mg). Gradually, the condition of the patient showed improvement in terms of both- the clinical symptoms and laboratory abnormalities. However, re-challenge of the drug was not performed in order to avoid further toxicity. After 15 days, the patient had visited Medicine Outpatient Department (OPD) again the creatinine and uric acid levels where checked which were normal and further advised to follow up every month. To be conclude, adverse drug reaction of myotoxicity associated with telmisartan is rare but quite significant. So, close monitoring is necessary to ensure safety of drug therapy especially in long term use.

Zebrafish as a Model for the Study of Lipid-Lowering Drug-Induced Myopathies.

Drug-induced myopathies are classified as acquired myopathies caused by exogenous factors. These pathological conditions develop in patients without muscle disease and are triggered by a variety of medicaments, including lipid-lowering drugs (LLDs) such as statins, fibrates, and ezetimibe. Here we summarise the current knowledge gained via studies conducted using various models, such as cell lines and mammalian models, and compare them with the results obtained in zebrafish (Danio rerio) studies. Zebrafish have proven to be an excellent research tool for studying dyslipidaemias as a model of these pathological conditions. This system enables in-vivo characterization of drug and gene candidates to further the understanding of disease aetiology and develop new therapeutic strategies. Our review also considers important environmental issues arising from the indiscriminate use of LLDs worldwide. The widespread use and importance of drugs such as statins and fibrates justify the need for the meticulous study of their mechanism of action and the side effects they cause.

The toxic effects of chloroquine and hydroxychloroquine on skeletal muscle: a systematic review and meta-analysis

The aim of this systematic review was to perform qualitative and quantitative analysis on the toxic effects of chloroquine (CQ) and hydroxychloroquine (HCQ) on skeletal muscles. We designed the study according to PRISMA guidelines. Studies for qualitative and quantitative analyses were selected according to the following inclusion criteria: English language; size of sample (> 5 patients), adult (> age of 18) patients, treated with CQ/HCQ for inflammatory diseases, and presenting and not presenting with toxic effects on skeletal muscles. We collected data published from 1990 to April 2020 using PubMed, Cochrane Library, EMBASE, and SciELO. Risk of bias for observational studies was assessed regarding the ROBIN-I scale. Studies with less than five patients (case reports) were selected for an additional qualitative analysis. We used the software Comprehensive Meta-Analysis at the confidence level of 0.05. We identified 23 studies for qualitative analysis (17 case-reports), and five studies were eligible for quantitative analysis. From case reports, 21 patients presented muscle weakness and confirmatory biopsy for CQ/HCQ induced myopathy. From observational studies, 37 patients out of 1,367 patients from five studies presented muscle weakness related to the use of CQ/HCQ, and 252 patients presented elevated levels of muscle enzymes (aldolase, creatine phosphokinase, and lactate dehydrogenase). Four studies presented data on 34 patients with confirmatory biopsy for drug-induced myopathy. No study presented randomized samples. The chronic use of CQ/HCQ may be a risk for drug-induced myopathy. There is substantiated need for proper randomized trials and controlled prospective studies needed to assess the clinical and subclinical stages of CQ/HCQ -induced muscle myopathy.

Indicators of Isotretinoin-Induced Myopathy: Neutrophil/Lymphocyte Ratio, Cobb Angle of Spine

Objective: There are many side effects of isotretinoin on the musculoskeletal system, liver, nervous system and dermatological side effects. To investigate usage and side effects of isotretinoin (13-cis retinoic acid), which is popularly recommended by dermatologists for the treatment of acne vulgaris, on young patients admitted to the hospital with severe low back and neck pains.Methods: We evaluated 61 patients who, using isotretinoin for the treatment of acne vulgaris for an average of eight months, experienced cervical and lumbar pain between 2017-2019. The age range of patients was between 16 and 38 years, there were 45 female and 16 male patients. These patients used isotretinoin at a dose of 0.5-0.8 mg/kg/day for the treatment of acne vulgaris for about eight months. The patients were questioned about cervical and lower back pain, joint pain, muscle weakness, myoglobinuria, creatine phospo-kinase (CPK), Visual Analog Scale (VAS), inflammation myopathy, neutrophil/lymphocyte ratio (Neu/Lymp ratio), and Cobb angle of the spine during monthly controls.Results: The VAS and Neu/Lymp ratio, cervical and lumbar Cobb angles of the patients were statistically analyzed and the relationship between them was shown.Conclusion: The Neu/Lymp ratio and Cobb angle of the cervical and lumbar spine should be considered as an alternative or additional parameter to diagnose drug-induced myopathy.

Pregabalin-Induced Myopathy in a Double Lung Transplant Recipient

Pregabalin is a gamma-aminobutyric acid (GABA) derivative that was commercially approved by the Food and Drug Administration (FDA) in 2004. It is commonly used in the treatment of diabetic neuropathy, peripheral neuropathy, and spinal cord injury. We present the case of a 36-year-old Caucasian male double lung transplant recipient who presented with an 18-month history of fatigue and muscle weakness. He had elevated creatinine kinase level and his muscle biopsy showed evidence of drug-induced myopathy that improved after the cessation of pregabalin. We present a case of drug-induced myopathy as a rare complication of pregabalin therapy in a double lung transplant recipient.

Combination of atorvastatin and gemfibrozil plus physical activity: an animal model of statin/fibrate-induced myopathy

Introduction Drug-induced myopathy is among the most common causes of muscle disease. Lipid-lowering drugs, primarily the statins as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are a common cause of myopathy. Statin-fibrate combination potentially increases risk for myopathy and rhabdomyolysis. Blood levels of the enzymes creatine kinase (CK), aldolase and lactate dehydrogenase (LDH) increase during myopathy. Exercise may be a trigger for statin-associated muscle symptoms (SAMS). Methods In this study a model of myopathy induction was designed via combination of oral atorvastatin, gemfibrozil and exercise for ten days in rats. To maximise exercise, the rats were placed in a pool of water and allowed to swim before sinking in the last three days. Finally, the mean of swimming tolerance times and blood levels of creatine kinase, aldolase and lactate dehydrogenase were measured. Results The results showed a significantly (p < 0.05) decreased swimming tolerance time and elevated enzyme levels in rats receiving atorvastatin (ATV) and gemfibrozil (GMF) plus exercise compared with those rats in other groups. This animal model can be used to evaluate the effects of medication on reduction of statin/fibrate-induced myopathy.

The changing spectrum of drug-induced myopathies.

Drug-induced myopathies are a group of disorders whose importance lies in the fact that they are potentially treatable and usually reversible if the causative agent is identified and withdrawn. A wide variety of medications used in many different branches of medicine have been recognised as causing muscle adverse effects, ranging from myalgia and asymptomatic hyperCKaemia to severe weakness and at times fatal rhabdomyolysis. There has been increased awareness of these complications since the introduction of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor group of drugs (statins) in the 1980s, and their subsequent association with a range of necrotising and immune-mediated inflammatory myopathies and muscle symptoms. More recently, since the introduction of the immune checkpoint inhibitors for the treatment of advanced malignancies, it has been increasingly recognised that these drugs also have a propensity to induce or exacerbate a variety of immune-mediated myopathies, neuropathies, myasthenic disorders and atypical overlap syndromes, and it is anticipated that these complications will become even more prevalent with increasing use of these medications in the future. This review focusses mainly on these two groups of drugs, and on cytokine-based therapies and VEGF inhibitors which have also been implicated in the induction of immune-mediated inflammatory myopathies.

Pregabalin-induced focal myositis: A report of two cases and review of literature

Background: Drug-induced myopathy should be on the differential diagnosis in patients with non-traumatic muscle pain. It is important to consider the diagnosis as symptoms typically abate with removal of the offending agent. Case: Two elderly females presented separately with complaint of lower extremity pain and swelling. There was no elevation in inflammatory markers or muscle enzymes in either case. MRI revealed inflammatory changes on T2-weighted sequences. Both patients experienced rapid improvement of symptoms with discontinuation of pregabalin. Discussion: Medication-induced myositis should be considered in patients presenting with muscle complaints. Due to the overall high prevalence of pregabalin in the management of chronic pain, it is important to consider its role in the pathogenesis of focal myositis.

Tissue-Engineered Human Myobundle System as a Platform for Evaluation of Skeletal Muscle Injury Biomarkers.

Traditional serum biomarkers used to assess skeletal muscle damage, such as activity of creatine kinase (CK), lack tissue specificity and sensitivity, hindering early detection of drug-induced myopathies. Recently, a novel four-factor skeletal muscle injury panel (MIP) of biomarkers consisting of skeletal troponin I (sTnI), CK mass (CKm), fatty-acid-binding protein 3 (Fabp3), and myosin light chain 3, has been shown to have increased tissue specificity and sensitivity in rodent models of skeletal muscle injury. Here, we evaluated if a previously established model of tissue-engineered functional human skeletal muscle (myobundle) can allow detection of the MIP biomarkers after injury or drug-induced myotoxicity in vitro. We found that concentrations of three MIP biomarkers (sTnI, CKm, and Fabp3) in myobundle culture media significantly increased in response to injury by a known snake venom (notexin). Cerivastatin, a known myotoxic statin, but not pravastatin, induced significant loss of myobundle contractile function, myotube atrophy, and increased release of both traditional and novel biomarkers. In contrast, dexamethasone induced significant loss of myobundle contractile function and myotube atrophy, but decreased the release of both traditional and novel biomarkers. Dexamethasone also increased levels of matrix metalloproteinase-2 and -3 in the culture media which correlated with increased remodeling of myobundle extracellular matrix. In conclusion, this proof-of-concept study demonstrates that tissue-engineered human myobundles can provide an in vitro platform to probe patient-specific drug-induced myotoxicity and performance assessment of novel injury biomarkers to guide preclinical and clinical drug development studies.

Myopathy secondary to empagliflozin therapy in type 2 diabetes.

SummarySodium/glucose co-transporter 2 (SGLT2) inhibitors are novel oral hypoglycaemic agents that are increasingly used in the management of type 2 diabetes mellitus (T2DM). They are now recommended as second-line pharmacotherapy (in conjunction with metformin) in patients with type 2 diabetes and established atherosclerotic heart disease, heart failure or chronic kidney disease due to their favourable effects on cardiovascular and renal outcomes. We report a case of a 69-year-old man who developed muscle pain, weakness and wasting after commencing the SGLT2 inhibitor empagliflozin. This persisted for 1 year before he underwent resistance testing, which confirmed muscle weakness. His symptoms resolved within weeks of ceasing empagliflozin, with improvement in muscle strength on clinical assessment and resistance testing and reversal of MRI changes. No other cause of myopathy was identified clinically, on biochemical assessment or imaging, suggesting that empagliflozin was the cause of his myopathy.Learning points:Empagliflozin, a commonly used SGLT2 inhibitor, was associated with myopathy.A high degree of suspicion is required to diagnose drug-induced myopathy, with a temporal relationship between starting the medication and symptom onset being the main indicator.Recognition of drug-induced myopathy is essential, as discontinuation of the offending drug typically improves symptoms.

Protocols for Enzymatic Fluorometric Assays to Quantify Phospholipid Classes.

Phospholipids, consisting of a hydrophilic head group and two hydrophobic acyl chains, are essential for the structures of cell membranes, plasma lipoproteins, biliary mixed micelles, pulmonary surfactants, and extracellular vesicles. Beyond their structural roles, phospholipids have important roles in numerous biological processes. Thus, abnormalities in the metabolism and transport of phospholipids are involved in many diseases, including dyslipidemia, atherosclerosis, cholestasis, drug-induced liver injury, neurological diseases, autoimmune diseases, respiratory diseases, myopathies, and cancers. To further clarify the physiological, pathological, and molecular mechanisms and to identify disease biomarkers, we have recently developed enzymatic fluorometric assays for quantifying all major phospholipid classes, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylinositol, phosphatidylglycerol + cardiolipin, and sphingomyelin. These assays are specific, sensitive, simple, and high-throughput, and will be applicable to cells, intracellular organelles, tissues, fluids, lipoproteins, and extracellular vesicles. In this review, we present the detailed protocols for the enzymatic fluorometric measurements of phospholipid classes in cultured cells.