HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.

/pdf/statin-adverse-effects-a-review-of-the-literature-and-5byfkzyay5.pdf

Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism

Rhabdomyolysis: an evaluation of 475 hospitalized patients.

We report patients from two neuromuscular centers who were evaluated between the years 2000 and 2008 and met the following criteria: (1) proximal muscle weakness occurring during or after treatment with statins; (2) elevated serum creatine kinase (CK); (3) persistence of weakness and elevated CK despite discontinuation of the statin; (4) improvement with immunosuppressive agents; and (5) muscle biopsy showing necrotizing myopathy without significant inflammation. Twenty-five patients fulfilled our inclusion criteria. Twenty-four patients required multiple immunosuppressive agents. Fifteen patients relapsed after being tapered off immunosuppressive therapy. Exposure to statins prior to onset was significantly higher in patients with necrotizing myopathy (82%) as compared to those with dermatomyositis (18%), polymyositis (24%), and inclusion-body myositis (38%) seen in the same time period. The lack of improvement following discontinuation of statins, the need for immunosuppressive therapy, and frequent relapse when treatment was tapered suggest an immune-mediated etiology for this rare, statin-associated necrotizing myopathy.

Immune-mediated necrotizing myopathy associated with statins.

The different autoimmune myopathies-for example, dermatomyositis, polymyositis, and immune-mediated necrotizing myopathies (IMNM)-have unique muscle biopsy findings, but they also share specific clinical features, such as proximal muscle weakness and elevated serum levels of muscle enzymes. Furthermore, around 60% of patients with autoimmune myopathy have been shown to have a myositis-specific autoantibody, each of which is associated with a distinct clinical phenotype. The typical clinical presentations of the autoimmune myopathies are reviewed here, and the different myositis-specific autoantibodies, including the anti-synthetase antibodies, dermatomyositis-associated antibodies, and IMNM-associated antibodies, are discussed in detail. This Review also focuses on a newly recognized form of IMNM that is associated with statin use and the production of autoantibodies that recognize 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the pharmacological target of statins. The contribution of interferon signaling to the development of dermatomyositis and the potential link between malignancies and the initiation of autoimmune myopathies are also assessed.

Autoimmune myopathies: Autoantibodies, phenotypes and pathogenesis

Anti-HMGCR myopathy was first recognized and characterized in patients with a history of statin exposure and immune-mediated necrotizing myopathy. After the discovery of anti-HMGCR autoantibodies, several international groups identified and characterized more patients, expanding the phenotypic spectrum of this disease to include pediatric patients and young adults without statin exposure and those with a chronic myopathy resembling limb-girdle muscular dystrophy. We provide a summary of clinical findings, pathologic features, muscle imaging, and immunogenetic risk factors of the disease. We also discuss the current treatment strategies and approaches to monitoring the therapeutic response. Lastly, we briefly summarize the current understanding of the pathophysiology of the disease and postulate a model for autoimmunity initiation and propagation in this disease.

Anti-HMGCR Myopathy.

Purpose Rhabdomyolysis and myositis are rare, dose-related complications of statins and fenofibrates. The outcome is favorable as a rule with rapid regression after stopping the responsible drug. Recently, various auto-immune disease with evidence of hypersensitivity to HMG-CoA reductase inhibitors or fibrates drugs have been reported. Less than ten cases of dermatomyositis and polymyositis due to cholesterol-lowering drugs (CLD) have been previously reported. Five more cases polymyositis associated with CLD are reported. Methods Symptoms were compatible with diagnosis of polymyositis according to Bohan and Peter and with previous reported criteria for drug-induced myopathy in all cases. None of these patients had previous other connective tissue disorders. Results Five patients (median age 68 [54-78], female N =4) with CLD treatment (statin N =4, fenofibrates N =1) have developed iatrogenic polymyositis. All of them presented both proximal muscular weakness and increased muscle enzyme levels. One patient had iatrogenic antisynthetase syndrome characterized by mechanic's hand, Raynaud's phenomenon and anti JO1 antibodies. One other had sclerodermic hand oedema. Antinuclear antibodies were positive in 4 cases and muscle biopsy revealed polymyositis infiltrate in 4 cases. CLD treatment was discontinued with partial clinical improvement in 3 cases. Clinical remission was obtained with corticosteroid (N =5) in association with immunosuppresive agents in 3 cases. Conclusion Muscular symptoms in patient with CLD treatment could be the first symptom of a polymyositis revealed or increased by this treatment and must encourage physician with antinuclear antibodies screening especially in case of proximal muscular weakness and increased muscle enzyme levels.

[Polymyositis induced or associated with lipid-lowering drugs: five cases].

Polymyosites induites ou associées aux traitements hypolipémiants

Resume L'atteinte valvulaire de la maladie lupique est le plus souvent une decouverte echographique et son retentissement hemodynamique reste rare, le remplacement valvulaire exceptionnel. Nous rapportons l'observation d'une patiente ayant eu un double remplacement valvulaire aortique et mitral precedant la decouverte d'anticorps antiphospholipides associes a 4 criteres de l'ARA de maladie lupique. L'etude histopathologique devait confirmer l'endocardite specifique de Libman et Sachs. La presence d'anticorps antiphospholipides fait discuter leur role dans la physiopathologie des atteintes valvulaires et des accidents vasculaires presentes par la patiente. Le chevauchement entre les criteres diagnostiques du lupus et du syndrome primaire des antiphospholipides est discute. L'atteinte valvulaire peut etre un des modes d'entree dans le syndrome des antiphospholipides.

Double remplacement valvulaire révélateur d'un syndrome des antiphospholipides

We present a case of retroperitoneal fibrosis associated with scleroderma (CREST syndrome). The pathogenic implications of such association with systemic vasculitis and connective tissue disease is discussed.

Fibrose rétropéritonéale et sclérodermie. Association fortuite ou mécanisme commun

There are few reports of amyloidosis diagnosed by deliberate biopsy of accessory salivary glands. Usually, a biopsy performed for dry mouth syndrome reveals an unsuspected amyloidosis. We report the case of 2 patients with lambda-type light chain monoclonal gammapathy complicated by generalized amyloidosis and in whom biopsy of the accessory salivary glands showed signs of amyloidosis. In the first patient accessory salivary gland biopsy was performed because these glands were enlarged, and the monoclonal dysglobulinaemia was subsequently diagnosed by serum immunoelectrophoresis. In the second patient with nephrotic syndrome, renal biopsy could not be carried out owing to the presence of a renal malformation; amyloidosis was confirmed by periumbilical fat aspiration, and a systematic biopsy of accessory salivary glands also showed evidence of amyloidosis. Biopsy of accessory salivary glands seems to be a particularly simple and safe method to detect generalized amyloidosis in patients with chronic inflammatory disease or monoclonal dysglobulinaemia.

Intérêt de la biopsie de glandes salivaires accessoires pour le diagnostic d'amylose

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