Progressive myopathy with up-regulation of MHC-I associated with statin therapy
Introduction
The incidence of statin-induced myopathy is regularly quoted to be 0.1–0.2% [1], [2], [3]. The myopathy varies in severity from asymptomatic hyperCKaemia to severe widespread myalgia and weakness, and in some cases myoglobinuria and acute renal failure. Unlike other drug reactions, this can occur many months, or even years after initiation of the statins. Except for rare fatal cases of acute rhabdomyolysis, in most cases the muscle symptoms resolve upon cessation of the offending drug. In a prospective hospital-based case series of 20 patients who developed muscle symptoms on statins reported by Soininen et al. [4], symptoms resolved fully without treatment in all cases after stopping the drug.
There have been a limited number of case reports of myopathy during statin therapy with persistence or worsening of symptoms after cessation of the statin. We found reports in the literature of 7 cases of statin-induced polymyositis [5], [6], [7], [8], and 6 cases of statin-induced dermatomyositis [9], [10], [11], [12], [13], [14], in most cases requiring glucocorticoid or immunosuppressive therapy. There have been few detailed reports of the muscle pathology in such cases and there are limited data on MHC Class I and II expression.
We report 8 patients who developed a myopathy whilst on a statin, which persisted and in some cases progressed after withdrawal of the drug. The clinical and immunopathological findings in these cases are reviewed, and the possible underlying mechanisms of the myopathy are discussed.
Section snippets
Methods
Needle or open muscle biopsies were taken from the vastus lateralis, deltoid or gastrocnemius muscles (Table 1). Routine H&E, modified gomori trichrome stain and enzyme histochemical methods for mitochondria, (namely NADH, SDH, COX-SDH and cytochrome c oxidase) were performed. In addition, on 8 μm acetone fixed frozen sections the immunoperoxidase stains including MHC-I and II and MAC (Membrane Attack Complex) were performed using the streptavidin–biotin complex technique with diaminobenzidine
Clinical details
The patients ranged in age from 63 to 82 years and had been on a statin (5 on simvastatin, and 3 on atorvastatin) for periods ranging from 7 months to 9 years (Table 1). The dose of statin had been stable in all but one, (Case 8), in whom the dose of simvastatin had been increased 2 weeks prior to his presentation. None were taking any other medications associated with myopathy.
In 4 cases there was symmetric proximal weakness, (Cases 1, 4, 7 and 8), in one muscle pain only, (Case 3), and in the
Discussion
The present cases demonstrate two interesting and rarely reported phenomena: the continued progression of symptoms after cessation of the statin, and the histological finding of diffuse sarcolemmal MHC-1 expression in non-necrotic fibres in all patients. Although it is difficult to definitely attribute the cause of our patients’ muscle problems to the statin in every case, an alternative cause could not be found in any case. In a number of cases, (especially those with inflammatory
Note added in proof
The following reference was inadvertently omitted from the manuscript: Appleyard ST, Dunn MJ, Dubowitz V, Rose ML. Increased expression of HLA ABC class I antigens by muscle fibres in Duchenne muscular dystrophy, inflammatory myopathy, and other neuromuscular disorders. Lancet 1985;1:361–3.
Acknowledgements
We gratefully acknowledge the hard work and diligence of the technical assistants in the Department of Neuropathology at Royal Perth Hospital. Dr. M. Needham was supported by an NHMRC Postgraduate Medical Scholarship (number 392500).
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