Statin-Induced Autoimmune Myopathy: A Diagnostic Challenge in Muscle Weakness

Introduction

Statin-class medications are some of the most prescribed medications as they contribute to reduction in low-density lipoprotein cholesterol (LDL-C) via inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and improve atherosclerotic cardiovascular disease (ASCVD) scores [1]. Approximately 28% of adults age 40 and over are using a statin-class medication, with approximately 78 million US adults estimated to be on this medication [2,3]. The adverse effects profile of this class of medications is well known and muscle adverse-effects range from benign myalgia and myopathy without creatinine kinase (CK) elevation to severe drug-induced myopathy. The prevalence of benign clinical myopathy without evidence of CK increase is estimated to be approximately 10–25%, and it often leads to discontinuation of and aversion to this class of medication [4,5]. However, the incidence of drug-related clinically significant myonecrosis and rhabdomyolysis is less than 0.1% [5]. Here, we present a case report illustrating how statin-induced autoimmune myopathy often remains undiagnosed.

Case Report

A 69-year-old man with a past medical history of coronary artery disease, hypertension, hyperlipidemia, type 2 diabetes mellitus, and heart failure presented to the Emergency Department with muscle weakness and myalgias. About 2 months prior to admission, he began experiencing weakness with activity, which gradually worsened over time. He also reported cramping in the upper and lower extremities. He had been taking atorvastatin 80 mg once nightly for 5 years. Other home medications included carvedilol, sacubitril-valsartan, tamsulosin, finasteride, and aspirin, but no agents that can cause myopathy.

His physical exam was notable for significant weakness in bilateral proximal upper and lower extremities. On laboratory investigation, the patient had controlled diabetes with hemoglobin A1c of 5.3% and creatinine kinase at 8323U/L (reference range, 44–196 U/L). No renal insufficiency or myoglobinuria were noted. In light of the patient’s long history of statin usage, myalgias with muscle weakness, elevated creatinine kinase, and abnormal urinalysis, myopathy secondary to statin use was considered. Atorvastatin was held and the patient received intravenous (IV) fluid for management of rhabdomyolysis. His hospital course was complicated with respiratory failure necessitating intubation secondary to volume overload for a presumed rhabdomyolysis, despite careful monitoring with auscultation and oxygen saturation. He received 4200 cc total intravenous fluid since admission, and prior to intubation had an overall net negative balance. Given the respiratory failure in the setting of volume overload, acute decompensated heart failure was suspected, and the initial echocardiogram reflected heart failure with reduced ejection fraction of 40–45%. He also underwent cardiac catheterization to exclude any ischemic cause of heart failure.

Although the CK trended down to 3248 U/L, there was no significant improvement in muscular symptoms. At this point, given the patient’s muscle weakness and elevated CK, myositis was suspected. A myositis panel including anti-HMG Co-A reductase antibody was ordered and the patient was started on IV methylprednisolone. Anti-HMG Co-A reductase antibody was positive and the rest of myopathy workup was negative and there was no positive antibody against collagen disease. His muscle weakness significantly improved with IV methylprednisolone 40 mg every 8 hours during hospitalization. He was discharged with 60 mg of oral prednisone. On outpatient rheumatology follow-up, given incomplete improvement in myalgia and muscle weakness after 2 months of prednisone 60 mg, the steroid dose was tapered weekly and intravenous immunoglobulin (IVIG) 50 g every 4 weeks for 3 months was initiated. After 3 months of treatment with IVIG and tapering of prednisone, he regained his strength, and the CK level normalized to 28 U/L. A Figure 1 shows his clinical progress.

Discussion

Rhabdomyolysis can occur due to trauma or metabolic and exertional causes. It is important to find the cause and treat accordingly to prevent complications such as acute kidney injury [6]. Drug-induced rhabdomyolysis has been associated with multiple medications such as leflunomide, trabectedin, propofol, and daptomycin [7]. There are a few case reports of diphenhydramine, ecstasy, and baclofen inducing rhabdomyolysis in the pediatric population [8]. Statins can have adverse effects on muscles, including myalgia, myositis, and rhabdomyolysis, which can present with muscle pain, weakness, elevated creatinine kinase, myoglobinuria, and renal failure [9].

In our case, statin use induced rhabdomyolysis, which did not respond to the usual treatment of holding the inductive medication and administering intravenous fluid. Further investigation detected anti-HMGCR antibody and diagnosis of autoimmune myopathy. Statin-induced myopathy can be self-limited non-immune-mediated, which gradually improves after discontinuation of statin. However, immune-mediated myopathy caused by anti-HMGCR antibodies usually requires an immunosuppressant [10]. In a retrospective study in Lahore, about 50% of patients treated with statins had myalgia [11]. The incidence of statin-induced myopathy was reported at 11 cases in 100000 patients and the incidence of rhabdomyolysis caused by statins was reported to be about 4–7 in 100 000 cases [12]. The incidence of statin-associated autoimmune myopathy is estimated at 2–3 new cases per 100 000 patients [13]. Although rare, this etiology must be considered when muscle weakness or pain presents with elevations in CK ranging from 10x to 40x the upper limit of normal, defining myopathy and rhabdomyolysis, respectively [14]. However, the coincidence of autoimmune myopathy secondary to anti-HMG CoA reductase with other autoimmune disorders is not clear. A study of 82 participants with idiopathic inflammatory myopathy (IIM) reported that the prevalence of anti-HMG CoA reductase in these patients was unusually high [15]. It is crucial to have a clinical suspicion of this diagnosis in mind when the originally diagnosed disease is not responding to treatment, as it may not be as rare as thought, but rather may be widely undiagnosed. In patients not responding to statin withdrawal, the general approach is use of immunosuppressants such as steroids and intravenous immunoglobulins [16]. However, use of mycophenolate and tacrolimus in addition to steroids was also reported to be helpful [17,18].

Conclusions

In our case report, we highlighted the importance of evaluating anti-HMGCR antibodies in patients without adequate response to conservative therapy, including withdrawal of statins, and IV fluid therapy in the setting of rhabdomyolysis and renal injury. It is important to notice that the rarity of this phenomenon may not be due to low incidence but rather due to inadequate clinical suspicion for diagnosis and treatment of this condition.