3. Statin induced immune mediated necrotising myopathy: a case report

Abstract

IntroductionStatins are a commonly used group of drugs which lowers low density lipoprotein (LDL) levels by competitively inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Though they are effective and safe, about 0.1% patients on statins can develop severe myonecrosis or immune mediated necrotising myopathy (IMNM).Here we present a case of IMNM secondary to atorvastatin exposure, resulting in severe muscle weakness and prolonged hospitalisation, and positive treatment response to intravenous immunoglobulin (IVIG).Case descriptionA 59-year-old Caucasian lady with a history of hypothyroidism and hyperlipidaemia, presented with 5 weeks’ history of progressive weakness in both upper and lower limbs which was preceded by flu like symptoms. She was also having swallowing difficulty and had neck-flexor weakness. There was MRC grade 2 power around hips, knees and shoulders, with normal power distally. She had been started on atorvastatin 10 mg 6 months ago, which was stopped due to myalgia.She was admitted to the hospital, and soon developed respiratory muscle weakness. She had serial SVC assessment and required nasogastric feeding. Electromyography suggested myositis. MRI of the thighs showed extensive myositis, muscle biopsy confirmed necrotising myopathy. Autoantibodies were negative, but she had high titre HMGcoA reductase antibodies (anti-HMGCR).Creatine kinase levels on presentation was 24230 U/L, which increased to 31000 U/L. Initial SVC was 33% of predicted. CT scan of chest abdomen and pelvis did not reveal any malignancy. Cardiac MRI did not reveal myocarditis, though her troponin-T levels were raised 1096 ng/L.She was non responsive to 3 pulses of 1 gm methyl-prednisolone. She was treated with IVIG, cyclophosphamide infusions and oral prednisolone. She made steady progress and was discharged with SVC of 70%, CK of 664 U/I, proximal muscle strength of 3/5 and feeding orally. She received 9 cycles of 900 mg cyclophosphamide followed by mycophenolate mofetil 2gm/day.However, her CK levels plateaued to between 650 and 700; proximal lower limb power was fluctuating between 4 and 3. She received another course of IVIG- 6 months after the onset of myositis which significantly improved her power, which sustained for around 4 months. The plan is to manage her with serial IVIG infusions.DiscussionStatins can cause adverse muscle related events, ranging from mild myalgia to severe myopathy and rhabdomyolysis. Rarely, patients can develop immune mediated necrotising myositis, as in our patient. IMNM can cause persisting myositis with predominantly proximal muscle weakness, and runs a protracted course. Statin-induced IMNM is associated with presence of anti HMGCR antibodies.There are no clinical trials to guide therapeutic decisions in IMNM, however some case series and observational studies have shown improvement with immunosuppression. IVIG have been shown to be effective in anti HMGCR associated IMNM, as in our case.Even after stopping statins, IMNM can progress and patients can have prolonged weakness requiring immunosuppression. Around 50% patients continue to have significant weakness even after 2 years of treatment, indicating an unfavourable prognosis.Our patient continues to have waxing waning weakness with persistently raised CK, and IVIG infusions seems to give a rapid clinical response , though sustaining for 3 to 4 months, indicating a need for repeated infusions. The other treatment option remains rituximab, which has shown to have some efficacy in anti-SRP positive IMNM.Our patient had hypothyroidism, which is known to potentiate statin induced myopathy, however, strong association with IMNM is not established.Around 80% patients with anti HMGCR associated myositis have prior statin exposure, however, a subgroup of patients, especially among Asians, can have anti-HMGCR antibody and myositis even without statin exposure. This indicates a possible a genetic susceptibility to statins. Also, exposure to oyster mushroom and red yeast rice have been reported to be associated with anti-HMGCR antibodies in this subgroup of patients.Key learning pointsStatins can cause muscle related adverse events. 2-11% patients can have mild myalgia and myopathy, however necrotising myopathy is extremely rare (0.1%). Anti-HMCGCR antibodies are associated with statin induced IMNM. IMNM has a protracted course and can continue for years after stopping statins. Long term Immunosuppression is required in IMNM. IVIG is effective in refractory cases. Anti-HMCGCR antibodies can be found in statin naïve patients. Hypothyroidism can potentiate statin induced myopathy. The risk of muscle injury is higher when taking a statin which is extensively metabolised by cytochrome P450 3A4 (CYP3A4) - like simvastatin and atorvastatin, with CYP3A4 inhibitors. Pravastatin, rosuvastatin are preferred in these cases.Conflict of interestThe authors declare no conflicts of interest.