Final Diagnosis

Mild Toxic Myopathy Induced by Statin Use

Patient Follow-up

The diagnosis of a mild toxic myopathy induced by statin use was discussed with the patient. He was reassured that his muscle symptoms would continue to improve with time. A repeat muscle biopsy was not needed. He was instructed to take coenzyme Q10 (CoQ10) and multivitamins. Six months later, he returned for follow-up. He reported near-complete resolution of his muscle symptoms. Examination showed no weakness. His CK level was minimally elevated at 283 U/L. His hyperlipidemia was relatively controlled by ezetimibe, low-fat diet, and daily exercise.

Discussion

Statin drugs, the HMGCR inhibitors , have been widely used for treating dyslipidemia and reducing the risk for cardiovascular and cerebrovascular diseases [1]. Muscle symptoms , including myalgia, fatigue, and weakness, represent a major side effect of this class of drugs, which can be seen in up to 20% of statin users [2]. Statin drugs can cause rhabdomyolysis, an immune-mediated necrotizing myopathy, and more commonly a mild toxic myopathy [3–8]. All statin drugs on the market can cause myopathy, which include lovastatin, simvastatin, pravastatin, atorvastatin, and fluvastatin [9]. The risk factors for statin-induced myopathies include age at or above 65 years, comorbidities such as diabetes mellitus, renal dysfunction, and cardiovascular disease, co-administration of certain drugs, and SLCO1B1 gene variants [10–12].

Rhabdomyolysis induced by statin is a very rare but serious type of myopathy [13, 14]. It is caused by the direct myotoxicity of statin. It can occur when initiating a statin drug or after increasing the dosage of a statin drug. These cases are mainly encountered in an emergency department or in an inpatient setting. Besides acute management of rhabdomyolysis, statin use should be discontinued immediately.

Immune-mediated necrotizing myopathy induced by statin is an autoimmune myopathy [15]. It is caused by the autoimmunity triggered by statin use [4–6]. The disease is characterized by progressive, symmetric, and proximal limb weakness, marked CK elevation, the presence of HMGCR autoantibody, muscle biopsy features of a necrotizing myopathy with diffuse or multifocal myofiber upregulation of class I major histocompatibility complex (MHC-1), and the need for immunosuppressive therapy [4–6]. The mean age of onset is 64.7 years in one series [4] and 55 years in the other [16]. The proximal limb weakness may develop weeks or years after statin exposure or even after statin withdrawal [4]. The initial serum CK while taking statin is markedly elevated, ranging from 3,000 to 17,280 U/L in one series of 25 patients [4]. Mean CK upon initial presentation is 6,853 U/L according to a systemic review of 100 published cases with immune-mediated necrotizing myopathy induced by statin [17]. This review also shows that HMGCR antibody is present in all cases tested [17]. HMGCR antibody is not present in asymptomatic statin users or statin users who develop self-limited mild toxic myopathy [18], which makes this autoantibody a useful marker for immune-mediated necrotizing myopathy induced by statin. HMGCR antibody can also be present in statin-naïve patients with autoimmune myopathy [19]. EMG in patients with immune-mediated necrotizing myopathy induced by statin often shows irritable myopathy with the presence of abnormal spontaneous activities in the forms of fibrillation potentials, positive sharp waves, and myotonic or pseudomyotonic discharges [4]. Muscle biopsy shows a necrotizing myopathy with minimal or absent lymphocytic infiltrates but with diffuse or multifocal myofiber upregulation of MHC-1 [6]. The disease course is characterized by the lack of improvement or worsening of muscle symptoms and CK elevation after statin withdrawal, the need for immunosuppressive therapy, and frequent relapse after tapering off immunosuppressive therapy [4, 6].

Mild toxic myopathy as seen in the present case is much more common than rhabdomyolysis and immune-mediated necrotizing myopathy induced by statin. It is caused by the direct myotoxicity of statin. The disease usually manifests muscle pain, fatigue, and/or mild weakness which predominantly affects proximal limb muscles. By using the development of muscle symptoms after statin use with no other causes of muscle symptoms identified as the definition for statin myopathy, and by excluding patients with rhabdomyolysis or immune-mediated necrotizing myopathy induced by statin use, we identified a cohort of 69 patients with mild toxic myopathy induced by statin (mild statin myopathy) to characterize their clinical features and outcomes after statin withdrawal [8]. Myalgia was the most common muscle symptom, as over 90% of the patients in our cohort reported myalgia. This is consistent with the finding by another study [20]. Although 68.1% of our patients also reported muscle weakness, only 26.1% had mild proximal limb weakness detectable by exam. CK was normal in nearly 25% of our patients, mildly elevated at or below 1,000 U/L in 52.2%, and above 1,000 U/L in 23.2%, with the highest CK level being 2,607 U/L. Despite that all of our patients had muscle symptoms and over 75% had CK elevation, only 25% of the patients who underwent EMG showed myopathic changes on EMG [8]. NCS/EMG is useful to rule out other neuromuscular disorders, but it is relatively insensitive to detect mild statin myopathy.

The diagnosis of mild statin myopathy can be made based on clinical grounds. Muscle biopsy is not needed as there is no muscle pathology signature for this condition. Among 16 patients in our cohort who underwent muscle biopsies, 3 showed rare degenerating and regenerating fibers, 2 showed occasional regenerating fibers, 3 showed rare COX-deficient fibers, and 1 showed mild type 2 fiber atrophy. EM only showed a mild increase in mitochondrial number in rare fibers in 3 cases, and it was completely normal in the others [8]. These findings are very mild and non-specific. Therefore, muscle biopsy is not helpful in diagnosing mild statin myopathy. The muscle biopsy in our patient also showed mild non-specific changes, but his clinical presentation was consistent with a mild statin myopathy. The purpose of a muscle biopsy is mainly to rule out immune-mediated necrotizing myopathy induced by statin and other underlying myopathies unmasked by statin use. The muscle pathology features of immune-mediated necrotizing myopathy are illustrated in the chapter of immune-mediated necrotizing myopathy.

Mild statin myopathy can be differentiated from immune-mediated necrotizing myopathy induced by statin based on the clinical features . Unlike immune-mediated necrotizing myopathy, mild statin myopathy is characterized by mild or no muscle weakness, normal or mildly elevated CK, absent HMGCR autoantibody, improvement of muscle symptoms and CK elevation after statin withdrawal, and no need for immunosuppressive therapy. However, we still frequently receive requests for performing muscle biopsies for patients with mild statin myopathy. The most common reason for referring physicians to request muscle biopsies is to rule out immune-mediated myopathy induced by statin use or other myopathies unmasked by statin use, as patients’ CK elevation or muscle symptoms do not resolve as fast as expected after statin withdrawal. To avoid unnecessary muscle biopsies in this clinic setting and to obtain data to guide the biopsy threshold, we studied the outcomes of mild statin myopathy after statin withdrawal [8].

For the duration of follow-up (Mean ± SD: 29.6 ± 33.1 months) in our cohort of 69 patients, muscle symptoms completely recovered in 50/69 (72.5%), improved in 9/69 (13.0%), and did not change in 10/69 (14.5%). None of our patients reported worsening of muscle symptoms. Among the 10 patients who reported no change of their muscle symptoms, only 1 showed mild, persistent, detectable proximal weakness, and CK trended down in all. Among 50/69 (72.5%) patients who had their muscle symptoms completely resolved, the recovery was achieved within 1 month in 12 (24.0%), 3 months in 31 (62.0%), 6 months in 45 (90.0%), 1 year in 48 (96.0%), 3 years in 49 (98.0%), and 5 years in all (100%). 13/69 (18.8%) patients had muscle symptoms lingering beyond 14 months. Therefore, the symptom recovery in mild statin myopathy can be prolonged. One may hold muscle biopsy especially in those who have mild improving muscle symptoms even the improvement is relatively slow. The outcomes of mild statin myopathy after statin withdrawal do not correlate with the duration of statin exposure, duration of follow-up, initial CK elevation or myopathic changes on EMG [8]. There are no features that would allow us to accurately determine who may have a prolonged recovery course. The confounding factors of muscle symptoms should be screened, such as thyroid dysfunction, connective tissue diseases, and administration of non-statin myotoxic drugs.

Although 85.5% of our patients had muscle symptoms completely resolved (72.5%) or improved (13.0%) for the duration of follow up, the CK level remained elevated, although trended down, in 41/52 (78.8%). Baseline CK levels (before statin exposure) were retrievable in 34/69 (49.3%) patients, and they were all normal. The findings suggest that the normalization of CK often lags behind the improvement or resolution of muscle symptoms after statin withdrawal. Mild persistent CK elevation alone should not be an indication for muscle biopsy.

Management of patients with mild statin myopathy may include statin withdrawal and CoQ10 supplementation. Statin drugs should be immediately discontinued when the diagnosis of rhabdomyolysis or immune-mediated necrotizing myopathy is made. The decision of discontinuing statin in mild toxic myopathy should be made by weighing the benefits and risks. In some cases, the muscle symptoms are very mild, but the benefit of statin use to reduce the risk of cardiovascular and cerebrovascular diseases is significant. Such patients may be managed by close monitoring. If their muscle symptoms become significantly worse with time, the decision of statin withdrawal should be reconsidered. In this setting, treating neurologists should make a decision by discussing the benefits and risks of statin withdrawal not only with patients but also with physicians who treat patients with statin. It has been shown that CoQ10 can reduce muscle symptoms but not serum CK [21], and it may be offered to patients with mild statin myopathy.

Pearls