The Spectrum of Statin Myopathy

Abstract and Introduction

Abstract

Purpose of review: This review discusses the spectrum of myopathies associated with statin use, with special attention given to a recently identified statin-associated autoimmune-necrotizing myopathy. The clinical characteristics of these patients, pathologic findings, associated autoantibody and immunogenetic risk factors are discussed.

Recent findings: In the past several years, a novel form of autoimmunemyopathy associated with statin use has been described. Patients with this form of myositis have unique clinical, pathologic and pathophysiologic features when compared with those with self-limited statin toxic myopathy. An autoantibody directed against HMG-CoA reductase (HMGCR), the pharmacologic target of statins, characterizes the disease and can be used in clinical practice to identify these patients and direct therapy. Still, many questions remain to be answered regarding the pathogenic mechanisms at play, risk factors for developing the disease, long-term prognosis and effects of rechallenge with statins or other cholesterol-lowering drugs.

Summary: Statins can cause a spectrum of muscle diseases, most of which are self-limited and improve with discontinuation of the offending agent. In a subgroup, an autoimmune necrotizing myopathy develops that persists after discontinuation of statins. Specific autoantibody testing can help identify these patients in clinical practice and determine the need for immunosuppressive therapy.

Introduction

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors, remain one of the most effective treatments for atherosclerotic disease and reduce mortality and disability from cardiovascular and cerebrovascular disease. Although generally well tolerated, 5–20% of patients do not tolerate the side effects of statins, resulting in discontinuation of therapy.^[1,2] These patients commonly report self-limited musculoskeletal symptoms that most often resolve after discontinuation of the offending agent. In these patients, statins are thought to cause a direct toxicity to muscle fibres that is self-limited, here referred to as toxic statin myopathy. In contrast, a small number of patients with concurrent statin use develop a progressive, autoimmune necrotizing myopathy.^[3,4] This disorder is characterized by progressive muscle weakness, elevated muscle enzymes, specific auto-antibodies against the target of statins, HMGCR and progression of symptoms and signs despite discontinuation of statins.^[5,6,7] Muscle biopsy typically shows a necrotizing myopathy, without severe inflammation. This provides an update of recent findings that have expanded the spectrum of statin-associated myopathy, with a focus on comparing self-limited toxic statin myopathy and the newly discovered autoimmune statin-associated necrotizing myopathy.

Table 1. comparison of toxic statin myopathy with statin-associated autoimmune myopathy
	Toxic statin myopathy	Statin-associated autoimmune myopathy
Symptoms	Myalgias common; Weakness infrequent	Myalgias common; Weakness common
Maximum creatine kinase (IU/l)	Normal (with mild disease) to >100 000 (with rhabdomyolysis)	1000–50 000 IU/I
Muscle biopsy	Mild disease: cytochrome oxidase negative fibres, vacuolization; Severe disease: myofiber necrosis and regeneration with minimal inflammation	Myofiber necrosis and regeneration with minimal inflammation; MHC class up-regulation; MAC deposition on nonnecrotic fibers
Genetic risk factors	SNP in SLCO1B1 gene	HLA-DRB1_11:01
Anti-HMGCR antibody	Absent	Present
Clinical course after statin discontinuation	Improvement	Persistent/progressive weakness and CK elevation
Appropriate therapy	Statin withdrawal (or dose reduction)	Statin withdrawal and immunosuppressive therapy

CK, creatine kinase; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme reductase; MHC, major histocompatibility complex; SNP, single nucleotide polymorphism.