Discussion
Immune-mediated necrotizing myopathy (IMNM) can be caused by cancer, viral infection, connective tissue diseases, and medications, especially statin, anti-HMGCR, and anti-SRP autoantibodies, resulting in skeletal muscle injury3. Antibodies against HMGCR, the statins target, are found more often in patients with necrotizing myopathy with statin exposure; thus, the positive antibody supports the autoimmune process2. There have been many proposed mechanisms for the pathogenesis underlying the statin-induced IMNM; however, the true mechanism is not well understood 2,4.
Anti-HMGCR IMNM presents clinically as a subacute or chronic progressive symmetrical proximal muscle weakness. Dysphagia, like our patient, occurs in approximately one-third of patients. Muscle weakness persists despite discontinuing statins and CK levels, usually exceeding 10 times the upper normal limit1,2. Extramacular manifestations like those of dermatomyositis can be present5. However, malignancy-associated anti-HMGCR IMNM was unclear; there was no statistically significant relation6,7.
Musculoskeletal MRI and EMG can be done prior to antibody assay or muscle biopsy. EMG usually shows signs of irritable myopathic patterns but is not possible to differentiate the type of inflammatory myositis. MRI with STIR sequence in statin-induced IMNM demonstrates diffuse and symmetrical muscle edema and signs of fibro-adipose tissue replacement2,3. A report by Mammen proposed an algorithm for evaluating potential cases of statin-associated autoimmune myopathy2. The presence of muscle necrosis and regeneration with sparse inflammatory infiltrates on muscle biopsy are the prominent histologic features2.
There is no definite cutoff point on how long after taking statins patients would develop IMNM—it can range from months to years8. In our case, the patient developed weakness a few months after statin initiation and continued to deteriorate even after statin discontinuation. Compared to other statins, atorvastatin was more frequently reported to be a cause of statin-induced IMNM, likely due to its high lipophilic property resulting in better penetration to peripheral and liver tissues9. Symptoms are milder at onset 50-60 years old while younger patients appear to be more severe and, regardless of statin use, are more recalcitrant to treatment.7
Serum levels of the anti-HMGCR antibody are correlated with creatinine kinase and inversely associated with the degree of muscle weakness7,10. However, anti-HMGCR titers remain positive even in the remission of the disease and CK level normalizes. Together with being a more expensive test, there is no need to monitor anti-HMGCR levels practically7.
No definite guideline has been available on how long a patient should be on the treatment. The first step is to discontinue statins. Unlike self-limited forms of statin myopathy, statin-induced IMNM very rarely improves spontaneously after stopping statins. Only a few reported statin-induced IMNM patients with positive anti-HMGCR antibodies spontaneously resolved2. The most common therapy is prednisolone combined with at least another agent like methotrexate, azathioprine, or mycophenolate mofetil5,6,8. IVIg or rituximab can be added to support the treatment but preferentially IVIG3,11,12 Our case, the patient received triple therapy which comprises IVIg, systemic corticosteroids, and a non-steroidal immunosuppressant, which has been described as in the literature2,5. Symptom resolution time was approximately twelve months and might take longer in females at 16 months9. Most of the patients responded well to immunosuppressive treatment. Symptoms monitoring is required following tapering doses of immunosuppressants due to the autoimmunity which may cause disease relapse.
Statins are contraindicated in this group of patients. To substitute the need for statins, aside from fenofibrate or ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can be used and are safe in patients with anti-HMGCR myopathy9.