Comparative utility of LC3, p62 and TDP-43 immunohistochemistry in differentiation of inclusion body myositis from polymyositis and related inflammatory myopathies

Annie Hiniker,Marta Margeta,Han S Lee,Brianne H Daniels

doi:10.1186/2051-5960-1-29

Abstract

BackgroundInclusion body myositis (IBM) is a slowly progressive inflammatory myopathy of the elderly that does not show significant clinical improvement in response to steroid therapy. Distinguishing IBM from polymyositis (PM) is clinically important since PM is steroid-responsive; however, the two conditions can show substantial histologic overlap.ResultsWe performed quantitative immunohistochemistry for (1) autophagic markers LC3 and p62 and (2) protein aggregation marker TDP-43 in 53 subjects with pathologically diagnosed PM, IBM, and two intermediate T cell-mediated inflammatory myopathies (polymyositis with COX-negative fibers and possible IBM). The percentage of stained fibers was significantly higher in IBM than PM for all three immunostains, but the markers varied in sensitivity and specificity. In particular, both LC3 and p62 were sensitive markers of IBM, but the tradeoff between sensitivity and specificity was smaller (and diagnostic utility thus greater) for LC3 than for p62. In contrast, TDP-43 immunopositivity was highly specific for IBM, but the sensitivity of this test was low, with definitive staining present in just 67% of IBM cases.ConclusionsTo differentiate IBM from PM, we thus recommend using a panel of LC3 and TDP-43 antibodies: the finding of <14% LC3-positive fibers helps exclude IBM, while >7% of TDP-43-positive fibers strongly supports a diagnosis of IBM. These data provide support for the hypothesis that disruption of autophagy and protein aggregation contribute to IBM pathogenesis.

Highlights

Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy of the elderly that does not show significant clinical improvement in response to steroid therapy
Sporadic inclusion body myositis (IBM) is a common inflammatory myopathy that classically presents in older individuals with proximal lower extremity and finger flexor weakness; the clinical course is generally slow but progressive and unresponsive to immunosuppressive therapy, leading to significant disability
Autophagy impairment leads to accumulation of autophagosomes, which can be detected by immunohistochemistry for autophagy proteins LC3 and p62/SQSTM1; we have recently shown that immunostaining for either LC3 or p62 can replace electron microscopy in the diagnosis of drug-induced autophagic vacuolar myopathies [18,22]

Summary

Introduction

Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy of the elderly that does not show significant clinical improvement in response to steroid therapy. Sporadic inclusion body myositis (IBM) is a common inflammatory myopathy that classically presents in older individuals with proximal lower extremity and finger flexor weakness; the clinical course is generally slow but progressive and unresponsive to immunosuppressive therapy, leading to significant disability. IBM shows chronic myopathic changes in a background of T cell-rich endomysial inflammation [1,2,3]. The distinction between sporadic IBM and other myopathies with RVs is fairly straightforward: IBM shows a prominent T cell-rich endomysial inflammatory infiltrate and diffuse upregulation of major histocompatibility complex I (MHC-1) in muscle fibers; other myopathies with RVs do not [1]. The current pathologic criteria for IBM are specific but not sensitive for diagnosis; in the absence of supporting clinical information, a significant fraction of IBM patients is misdiagnosed with chronic polymyositis, leading to unnecessary steroid treatment

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