P.14.14 LC3, p62 and TDP-43 immunohistochemistry in differentiation of inclusion body myositis from other T-cell inflammatory myopathies

Abstract

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. Distinguishing IBM from polymyositis (PM) is clinically important since PM is steroid-responsive; however, the two conditions can show substantial histologic overlap. We performed quantitative immunohistochemistry for (1) autophagic markers LC3 and p62 and (2) protein aggregation marker TDP-43 on muscle biopsies from 53 subjects with PM, IBM, or two intermediate T cell-mediated inflammatory myopathies [polymyositis with COX-negative fibers (PM-COX) and possible IBM (pIBM)]. The percentage of stained fibers was significantly higher in IBM than PM for all three markers, but there were important differences in the overall pattern and degree of staining. The autophagy markers LC3 and p62 were both sensitive for IBM, but the tradeoff between sensitivity and specificity was smaller (and diagnostic utility thus greater) for LC3 than for p62. In PM-COX and pIBM groups, staining for LC3 and p62 was more heterogeneous, with both high- and low-staining biopsies present in each group; however, PM-COX cases were mostly LC3- and p62-negative, while pIBM cases were mostly LC3- and p62-positive. The protein aggregation marker TDP-43, in contrast, was highly specific for IBM but its sensitivity was low, with definitive staining present in only 67% (8 of 12) IBM biopsies, 8% (1 of 13) PM-COX biopsies, and 6% (1 of 16) pIBM biopsies. To differentiate IBM from PM, we thus recommend using a panel of LC3 and TDP-43 antibodies: the finding of 6% of TDP-43-positive fibers strongly supports the IBM diagnosis. These data suggest that accumulation of LC3 and p62 occurs early and accumulation of TDP-43 late in the IBM progression, providing support for the hypothesis that disruption of autophagy precedes florid protein aggregation in the IBM pathogenesis.