Progressive myopathy with up-regulation of MHC-I associated with statin therapy.
Statins can cause a necrotizing myopathy and hyperCKaemia which is reversible on cessation of the drug. What is less well known is a phenomenon whereby statins may induce a myopathy, which persists or may progress after stopping the drug. We investigated the muscle pathology in 8 such cases. All had myofibre necrosis but only 3 had an inflammatory infiltrate. In all cases there was diffuse or multifocal up-regulation of MHC-I expression even in non-necrotic fibres. Progressive improvement occurred in 7 cases after commencement of prednisolone and methotrexate, and in one case spontaneously. These observations suggest that statins may initiate an immune-mediated myopathy that persists after withdrawal of the drug and responds to immunosuppressive therapy. The mechanism of this myopathy is uncertain but may involve the induction by statins of an endoplasmic reticulum stress response with associated up-regulation of MHC-I expression and antigen presentation by muscle fibres.
Needham
Merrilee
M
Centre for Neuromuscular and Neurological Disorders, Queen Elizabeth II Medical Centre, University of Western Australia, Australia. needhm01@uwa.edu.au
Fabian
Victoria
V
Knezevic
Wally
W
Panegyres
Peter
P
Zilko
Paul
P
Mastaglia
Frank L
FL
D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000069059:Atorvastatin; D003402:Creatine Kinase / Q000097:blood; D005260:Female; D005493:Folic Acid Antagonists / Q000627:therapeutic use; D005805:Genes, MHC Class I / Q000235:genetics*; D006538:Heptanoic Acids / Q000009:adverse effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D007150:Immunohistochemistry; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000473:pathology; D018908:Muscle Weakness / Q000139:chemically induced / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D011239:Prednisolone / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects; D012508:Sarcolemma / Q000378:metabolism; D019821:Simvastatin / Q000009:adverse effects; D015854:Up-Regulation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D005493:Folic Acid Antagonists; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D011239:Prednisolone; D000069059:Atorvastatin; D019821:Simvastatin; D003402:Creatine Kinase; D008727:Methotrexate