Fellows’ Forum Case Report: Necrotizing Autoimmune Myopathy

Figure 2B: This acid phosphatase stain of Patient 2’s muscle biopsy shows large numbers of necrotic fibers (highlighted in the center of the image).

Because our patient was in respiratory distress, we evaluated him for cardiac dysfunction and respiratory involvement. Transthoracic echocardiography showed 40% ejection fraction with mild to moderate left ventricular systolic and diastolic dysfunction. His chest CT demonstrated no evidence of interstitial lung disease (ILD), and his NIF measured <-15, highlighting significant respiratory muscle involvement. His arterial blood gas revealed hypoxic hypercapnic respiratory failure, and we intubated him after he failed a bilevel positive airway pressure (BiPAP) trial.

We started the patient on a combination of high-dose steroids and IVIG, because he had severe muscle weakness with profound respiratory muscle involvement leading to respiratory failure. During hospitalization, his weakness improved and his CPK levels trended down to 800 U/L. We continued him on steroids and monthly IVIG. On his follow-up visit two months later, his respiratory status and muscle strength had significantly improved.

Triggered by Statins?

Unlike other statin-associated myopathies, HMGCR Ab-related IMNM features a complex pathogenesis characterized by extensive myocyte necrosis with scarce phlogistic infiltration in biopsy and the presence of HMGCR antibodies.^8,9 The recently discovered HMGCR Ab is composed of 200 kDa and 100 kDa proteins with specificity for the carboxy terminus of the HMGCR enzyme.¹⁰ Based on immunoprecipitation assays, these antibodies may be a causal link between statin exposure and IMNM.¹⁰ A study by Mammen et al reports the prevalence of these HMGCR antibodies in all patients suspected of inflammatory myopathy to be around 6%, making it the second most common myositis-specific antibody after the anti-Jo1 antibody.¹¹

The proposed pathogenesis of statins is through upregulation of the expression of MHC1 and the HMGCR enzyme in regenerating muscle fibers.^2,7,12 Overexpression of MHC1 may result from endoplasmic reticulum stress induced by HMGCR inhibition, leading to depletion of metabolic intermediates.^12,13 Endoplasmic reticulum stress leads to activation of the NF-kB pathway, which in turn activates the cytokine and chemokine production involved in immune processes.

Muscle Attack

After the initial trigger of the autoimmune process, researchers hypothesize muscle damage is sustained by overexpression of HMGCR in regenerating muscle even after statins are discontinued.^11,14 This supposition is supported by the discovery of upregulated HMCGR expression in cells expressing neural cell adhesion molecules (NCAM) in regenerating muscle fibers.¹¹ This explains the progressive weakness found in these patients even after statin discontinuation.