Case Study: Autoimmune-Mediated Necrotizing Myositis Due to Statin Therapy

Muscle symptoms in patients on statin therapy are prevalent and offer a complicated differential for providers to entertain. Symptoms range from relatively mild aches and pains to severe and debilitating weakness and pain. Statins are taken by more than 25 million patients across the globe and have been clearly associated with such complaints. The range of muscle complaints attributed to statin use extends from myalgia — a subjective complaint without creatine kinase (CK) elevation (the most common scenario) — to rhabdomyolysis, which is myonecrosis with myoglobinuria with or without acute renal failure.¹ These definitions were developed in 2014 by the National Lipid Association’s (NLA) Muscle Safety Expert Panel.

Parallel to the NLA’s work on developing these definitions, a multidisciplinary international group of experts also convened in 2014 as part of the Phenotype Standardization Project to categorize the wide clinical spectrum of muscle symptoms related to statin therapy (Table 1). They identified categories ranging from myalgias with or without CK elevation to the relatively new identification of statin-induced necrotizing autoimmune myopathy (SINAM).² This classification mirrors the NLA definitions, with the addition of asymptomatic CK elevations and of autoimmune-mediated necrotizing myonecrosis. The autoimmune condition is differentiated from myopathy alone by the presence of 3-hydroxy-3- methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) auto-antibodies, their expression on muscle biopsy, and incomplete resolution on cessation of statin therapy. Incidence of SINAM is estimated to be two patients per million per years.²

We present a case of a 62-year-old man with complaints of severe lower extremity weakness, edema, paresthesias in his hands and difficulty swallowing. He was found to have significant CK elevation and serologic confirmation of autoimmune-mediated necrotizing myonecrosis, SRM 6.

Case Study
The patient is a 62-year-old man with a past medical history significant for hypertension, hyperlipidemia, and type 2 diabetes mellitus. He initially was admitted with complaints of muscle aches, weakness, and a sore throat. He was diagnosed with rhabdomyolysis with a CK elevation peaking at 36,734 u/L. He was given intravenous fluids and steroids, and monitored for eight days. He clinically improved and was discharged from the hospital when his CK was trending downward to 24,046 u/L. The evaluation included a negative antinuclear antibody (ANA) panel and a normal serum creatinine. A gastrocnemius muscle biopsy was sent to the Mayo Clinic neuromuscular lab. Findings demonstrated type II fiber atrophy and possible re-innervation by type I motor neurons.

Of note, the patient indicated he had been on statin therapy for approximately 10 years and had intermittent myalgias; however, they had become more severe recently. His outpatient physician had discontinued his atorvastatin a few weeks prior to this admission because of myalgias, but the patient’s weakness progressed despite cessation of the medication. His only other home medication was Lisinopril 10mg daily. He denied regular use of over-the-counter medications, alcohol, or other drug use, and tobacco.

Two days following his discharge, he returned to the hospital having trouble speaking and swallowing. CK was measured at 26,665 u/L and he was weaker than he had been two days when discharged from the hospital.

Physical exam revealed a weak patient in no respiratory distress. He was afebrile and had a resting blood pressure of 156/80 mmHg. His sclerae were non-icteric and his cardiopulmonary exam was normal. An abdominal exam showed no distention, splenomegaly, hepatomegaly, or ascites.

There was bilateral pitting edema from his ankles up to his knees. Neurological exam revealed symmetrical bilateral proximal shoulder girdle and thigh weakness.

Initial laboratory work-up demonstrated a CK level of 26,665 units, creatinine 0.8 mg/dL, AST 1187 units/L, ALT 870 units/L, total bilirubin 1.2 mg/dL, WBC of 9.1 k/ mm3, Hgb 13.3 g/dL, platelet count 308 k/mm3. His vitamin D 25-hydroxy was <12.8 ng/mL. Plain film imaging revealed mild degenerative changes of the cervical spine and no subglottic or epiglottic edema. A chest X-ray showed low lung volumes.

The patient was re-admitted to the medical/surgical floor and was immediately given an IV bicarbonate infusion along with serial CK labs. Because of his long-term use of atorvastatin, a serum anti-HMGCR antibody was drawn. A neuromuscular specialist consultation was obtained and the patient was started on methyl- prednisolone 1000mg IV daily for three days for worsening proximal muscle weakness and a CK that increased to 34,745 units/L. Azathioprine 50 mg daily and prednisone 100 mg daily were initiated after his pulse dose IV steroid regimen was complete. The patient developed severe anemia, so azathioprine was discontinued. This was compounded by respiratory failure and worsening weakness, including dysphagia. Subsequently, his anti-HMGCR AB was strongly positive at more than 200 units (strong positive is considered >60 U). Thus, we decided to start rituximab 1,000 mg IV weekly for four weeks followed by IVIG 30 gm IV daily for five days. His acute kidney injury was deemed the result of sucrose nephropathy from the level of sucrose in IVIG. This reversed quickly when changed to an IVIG infusion with lower sucrose levels, and his renal function normalized. The patient was then given another round of pulse-dosed IV methylprednisolone for five days.

As the patient’s clinical picture began to improve, he was extubated. His liver function tests normalized. He was able to regain some physical strength and was able to stand and sit upright. His dysphagia was still severe and he was dependent on a percutaneous endoscopic gastrostomy (PEG) tube for nutrition. Finally, his CK levels began to decrease after initiating rituximab. After five weeks of combined therapy with Rituximab, steroids, and intermittent IVIG infusions, his CK levels were in the normal range.

Discussion
Statins are among the most prescribed medications in the world because of the excellent evidence demonstrating efficacy in primary and secondary prevention of cardiovascular events. Muscle complaints are common in patients treated with these medications, affecting up to 20 percent of treated patients.⁴ Estimates from randomized controlled clinical trials suggest the incidence of true myotoxicity is 1.5 to 2.5 percent.⁵ Most cases of muscle symptoms in statin treated patients are mild and improve with cessation of therapy or a change to a different statin or non-statin lipid lowering therapy. The incidence of hospitalization-requiring myotoxicity in one analysis was one in 22,727 patients per year.⁶

We have presented a case of a patient with severe myotoxicity because of autoimmune-mediated necrotizing myositis. This patient had severe muscular weakness, rendering him unable to swallow or breathe on his own, and dependent upon supportive care with endotracheal intubation and a PEG tube.

HMG CoA reductase is a key component of cholesterol biosynthesis, catalyzing the conversion of HMG CoA into mevalonate, a precursor of cholesterol. Its inhibition by statin therapy is key to their efficacy, and may also be responsible for muscular symptoms due to impaired synthesis of ubiquinone and other cell components. Antibodies to HMG-CoA (anti-HMGCR) develop rarely in patients on statin therapy.⁴ However, this may lead to the development of statin-associated myopathy that does not resolve with cessation of statin therapy. These auto-antibodies can be detected using a specific serologic assay and may be detected by muscle biopsy of the affected cells.⁷ Regenerating muscle cells express high levels of HMGCR and may sustain the autoimmune response even after statins are discontinued.

Though statin-induced autoimmune- mediated necrotizing myonecrosis is rare, it is important to consider it as a possible etiology for severely ill patients and for patients whose muscle symptoms do not resolve with cessation of statin therapy. Because this autoimmune condition does not resolve with cessation of therapy, aggressive immunosuppressive treatment is needed. In reported cases, weaning off of steroid therapy, even months later, often resulted in a relapse of weakness, elevated CK and hospitalization.⁷

Figure 1 depicts a useful algorithm for the assessment of patients with suspected statin-induced muscle symptoms and allows for consideration of the rare but serious condition found in our patient.

Disclosure statement: Elizabeth Jackson received speakers bureau honorarium from Sanofi/Regeneron. Dr. Chafizadeh has no disclosures to report. Dr. Pham has no disclosures to report.

References are listed on page 36 of the PDF.