A RARE CASE OF STATIN-INDUCED NECROTIZING AUTOIMMUNE MYOPATHY

Abstract

Objective:

Necrotizing autoimmune myopathy (NAM) is a rare side-effect of statin therapy. We report the case of a patient who developed statin-induced NAM with a review of the clinical presentation and management of this rare entity. The case illustrates the importance of including NAM in the differential diagnosis of persistent myopathy in a statin-exposed individual.

Methods:

A 74-year-old male was referred to endocrinology for hypercholesterolemia management in the context of a statin contraindication. He previously developed myositis and rhabdomyolysis secondary to statin therapy, but continued to have persistent proximal lower limb muscle weakness despite statin discontinuation. Rheumatologic and metabolic work-up were negative and neurologic work-up was negative except for a myopathic pattern in the glutei found on electromyography.

Results:

Due to the persistence of proximal myopathy despite statin discontinuation and myopathic pattern seen on electromyography, NAM was suspected and antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase were sent and came back positive. The patient was treated with the immunosuppressant azathioprine, which resulted in clinical improvement. The patient was started on a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolucumab for hypercholesterolemia, which resulted in significant improvement in his lipid panel.

Conclusion:

The case illustrates the presentation and management of statin-induced NAM. We demonstrate the necessity for prompt diagnosis and timely management, as statin therapy is contraindicated and immunosuppressive therapy is warranted. Statin-induced NAM is rare however, it should be included in the differential diagnosis of persistent myopathy despite statin discontinuation. PCSK9 inhibitors are the only alternative therapy for hypercholesterolemia management in patients with statin-induced NAM.

INTRODUCTION

Statins are the first line therapy for primary hypercholesterolemia to prevent atherosclerotic cardiovascular and cerebrovascular disease. The mechanism of action of statins involves inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) enzyme, which is the rate-limiting step of the cholesterol synthesis pathway (1). Although statins are generally well-tolerated, musculoskeletal manifestations are well-recognized side-effects. This can range from myalgias and/or mild creatine kinase (CK) elevation to myotoxicity including self-limited myotoxicity, rhabdomyolysis, and the rare recently recognized side-effect of necrotizing autoimmune myopathy (NAM). NAM is a rare autoimmune condition which is characterized by proximal muscle weakness, elevated CK level, myopathic pattern on electromyography, and necrosis and inflammation seen on muscle biopsy, with elevation in anti-HMGCR antibodies (1–5). It has also been reported in patients who are statin-naïve (1,3–5). Its distinguishing features from other musculoskeletal side-effects of statins are the persistence of proximal muscle weakness and elevated CK level despite statin discontinuation, evidence of muscle necrosis, and elevated anti-HMGCR antibodies. The pathophysiology of NAM is poorly understood however, it is hypothesized that the interaction between statins and HMGCR enables immunogenic HMGCR proteins to be expressed, which in turn triggers autoimmunity against the enzyme (1). NAM is a condition which requires prompt diagnosis and timely management and should be included in the differential diagnosis for persistent myopathy in statin-exposed individuals despite stain discontinuation.

CASE REPORT

We report the case of a 74-year-old male with a past medical history of primary hypercholesterolemia and hypertension, who was referred to endocrinology for the management of hypercholesterolemia in the setting of a statin contraindication. His initial lipid panel revealed a total cholesterol of 7.18 mmol/L (normal, <5.2 mmol/L), low-density lipoprotein (LDL) cholesterol of 4.87 mmol/L (normal, <2 mmol/L), and non-high-density lipoprotein (HDL) cholesterol of 6.15 mmol/L (normal, <2.6 mmol/L), which warranted the initiation of a statin given his elevated 10-year risk of cardiovascular disease based on the Framingham risk score. He was started on simvastatin in 2002, which was discontinued as he developed myositis rapidly after initiation. Three months later, he was prescribed atorvastatin which was also discontinued due to the development of rhabdomyolysis. A few years later in 2011, he was prescribed rosuvastatin 5 mg daily, to which he developed another episode of rhabdomyolysis. Finally, he was trialed back on atorvastatin at 40 mg daily and developed his third episode of rhabdomyolysis with a slowly progressive onset, presenting with generalized myalgia, elevated CK levels which peaked at 1,029 U/L (normal, 57 to 208 U/L), renal failure with creatinine at 140 μmol/L (normal, 67 to 117 μmol/L), estimated glomerular filtration rate of 43 mL/min/m² (normal, >60 mL/min/m²), and myoglobinuria. Atorvastatin was discontinued in 2015, and the patient's myalgias subsided immediately however, he developed persistent proximal lower extremity muscle weakness in 2017 which prompted him to seek medical attention. His blood work demonstrated CK levels ranging from 482 to 813 U/L (normal, 44 to 275 U/L). Rheumatologic work-up for autoimmune myopathies was negative including erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, antinuclear antibody, and extractable nuclear antigen panel. Other metabolic causes of proximal muscle weakness or neuropathy were ruled out including diabetes with a hemoglobin A1c of 5.6% (38 mmol/mol normal, <6% [<42 mmol/mol]), vitamin B12 deficiency with vitamin B12 of 216 pmol/L (normal, 140 to 650 pmol/L), and thyroid disease with thyroid-stimulating hormone of 3.72 mIU/L (normal, 0.32 to 4.0 mIU/L). Nerve conduction studies were normal, but electromyography demonstrated rare small myopathic units in the glutei muscles indicating myopathy. Due to the persistence of symptoms and elevated CK levels despite statin discontinuation and negative work-up otherwise for rheumatologic, metabolic, or neurologic etiologies, NAM was suspected. Anti-HMGCR antibodies were tested and were strongly positive with a titer of 4,000 (normal, <2,500), confirming the diagnosis of statin-induced NAM. The patient was initially treated with intravenous immune globulin (IVIg) however, this was discontinued due to uncontrolled hypertension secondary to IVIg. He was then started on the immunosuppressant azathioprine along with a 5-day course of prednisone, which resulted in symptomatic improvement within a few days, and a reduction in CK level to 180 U/L (normal, 44 to 275 U/L). He demonstrated significant improvement to almost normal strength in his lower extremities at the following clinic visit 3 months later. At the time of initial consultation with endocrinology, his lipid panel revealed total cholesterol at 5.78 mmol/L (normal, <5.2 mmol/L), LDL cholesterol 3.69 mmol/L (normal, <2 mmol/L), and non-HDL cholesterol 4.94 mmol/L (normal, <2.6 mmol/L). He was not on any cholesterol-lowering agent at the time. The Framingham risk score predicting his 10-year risk of a cardiovascular event was elevated at 43%. Given his elevated LDL cholesterol and Framingham risk score, a cholesterol-lowering agent was warranted and the patient was started on a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, evolocumab 140 mg every 2 weeks subcutaneously. A lipid panel following initiation of the PCSK9 inhibitor improved and demonstrated a total cholesterol level of 3.27 mmol/L (normal, <5.2 mmol/L), LDL cholesterol level of 1.56 mmol/L (normal, <2 mmol/L), and non-HDL cholesterol level of 2.11 mmol/L (normal, <2.6 mmol/L). The patient tolerated evolocumab well and did not have any adverse effects.

DISCUSSION

Statins are one of the most widely prescribed lipid-lowering medications which act by inhibiting the HMGCR enzyme, which is the key enzyme in the rate limiting-step in the cholesterol synthesis pathway (1). According to the Canadian Cardiovascular Society and the American College of Cardiology/American Heart Association guidelines, statins are the first-line therapy for primary hypercholesterolemia and prevention of atherosclerotic cardiovascular disease (6,7). Musculoskeletal side-effects are the most common reason for statin discontinuation, ranging from self-limited myalgias to myotoxicity, rhabdomyolysis, and rarely NAM (1,8,9). These side-effects almost always subside with statin discontinuation, except NAM. NAM is a rare side-effect of statins and is an autoimmune condition with a prevalence of 2 to 3 new cases for every 100,000 statin-exposed individuals (1,8,9). It is associated with human leukocyte antigen DRB1*11:01 in adults and DRB1*07:01 in children and it is due to the development of antibodies against HMGCR (1,2,8). Anti-HMGCR antibodies were first discovered in 2010 by Mammen et al (10) and have a reported sensitivity and specificity of 94.4% and 99.3%, respectively (1,2,8–10). NAM is characterized by persistent proximal lower limb weakness and CK elevation despite statin discontinuation, a myopathic pattern on electromyography, and muscle necrosis and inflammation on muscle biopsy. Rheumatologic, neurologic, and metabolic causes of proximal lower limb muscle weakness or neuropathy should be ruled out, as described in the case presentation. There are no clinical trials to guide the management of statin-induced NAM, however, immunosuppressive therapy is the cornerstone of treatment. Selva-O'Callaghan et al (1) report that IVIg appears to be the best option for treating statin-induced NAM as it is the only agent which has been proven effective for treating inflammatory myopathies. Nichols et al (2) on the other hand, discuss the use of IVIg only in cases which are refractory to immunosuppressive therapy or cases that are particularly severe at diagnosis. Other immunosuppressive agents such as azathioprine and methotrexate have also been used with good effect, as well as calcineurin antagonists and mycophenolate mofetil less commonly (1,2,5). Although a clear association between specific statins and the development of NAM has not been shown, previous reports have demonstrated a greater propensity with atorvastatin and simvastatin (2). Our patient was prescribed 3 statins on 4 different occasions, and therefore it is difficult to ascertain whether any one statin, or rather multiple trials of different statins, predisposed him to develop NAM. It is also unclear why he was prescribed statins multiple times despite a clear history of myositis/rhabdomyolysis. Interestingly, NAM has also been shown to occur in patients with no prior statin exposure (1,3). In our case, the patient was tested for anti-HMGCR antibodies given several previous exposures to statins and persistence of proximal lower limb myopathy with no clear rheumatologic, metabolic, or neurologic diagnoses.

PCSK9 inhibitors are monoclonal antibodies which can be used as an alternate agent if statins are contraindicated, such as in the case of statin-induced NAM. PCSK9 is a protein which regulates LDL cholesterol levels via internalization and degradation of LDL receptors (LDLR), thereby reducing the number of LDLR available to bind LDL cholesterol (11). PCSK9 inhibitors work by inhibiting PCSK9, which results in a greater number of LDLR available to bind LDL cholesterol and thereby reducing circulating LDL levels (11). In patients with statin-induced NAM, PCSK9 inhibitors are the treatment of choice which can be used for hypercholesterolemia and primary prevention of cardiovascular and cerebrovascular disease. In our case report, we demonstrated the improvement in total cholesterol and LDL cholesterol levels to target with the use of the PCSK9 inhibitor, evolocumab.

CONCLUSION

In conclusion, NAM is a rare side-effect of statin therapy and is increasingly being recognized within the “statin-induced myopathy” spectrum. Exclusion of more common autoimmune myopathic conditions, metabolic, and neurologic causes of proximal lower limb myopathy or neuropathy is essential for the diagnosis of NAM. This condition should be included in the differential diagnosis of persistent myopathy and CK elevation in statin-exposed individuals, particularly despite statin discontinuation. NAM necessitates a prompt diagnosis as immunosuppressive therapy is warranted and statin therapy is contraindicated. PCSK9 inhibitors are the agents of choice for treatment of hypercholesterolemia and cardiovascular/cerebrovascular protection in patients who have a statin contraindication. Further studies are important to identify which individuals are at risk for developing statin-induced NAM, for whom statin therapy should be avoided altogether.

Abbreviations

CK

creatine kinase

HDL

high-density lipoprotein

HMGCR

3-hydroxy-3-methylglutaryl-coenzyme A reductase

IVIg

intravenous immune globulin

LDL

low-density lipoprotein

LDLR

low-density lipoprotein receptors

NAM

necrotizing autoimmune myopathy

PCSK9

proprotein convertase subtilisin/kexin type 9