IL18-containing 5-gene signature distinguishes histologically identical dermatomyositis and lupus erythematosus skin lesions.

Lam C Tsoi,J Michelle Kahlenberg,Matthew T Patrick,Allison C Billi,Celine C Berthier,Johann E Gudjonsson,Tori Nault,Shannon N Estadt,Grace A Hile,Mehrnaz Gharaee-Kermani,Lori Lowe,Tamra J Reed,Rachael Wasikowski

doi:10.1172/jci.insight.139558

Abstract

Skin lesions in dermatomyositis (DM) are common, are frequently refractory, and have prognostic significance. Histologically, DM lesions appear similar to cutaneous lupus erythematosus (CLE) lesions and frequently cannot be differentiated. We thus compared the transcriptional profile of DM biopsies with CLE lesions to identify unique features. Type I IFN signaling, including IFN-κ upregulation, was a common pathway in both DM and CLE; however, CLE also exhibited other inflammatory pathways. Notably, DM lesions could be distinguished from CLE by a 5-gene biomarker panel that included IL18 upregulation. Using single-cell RNA-sequencing, we further identified keratinocytes as the main source of increased IL-18 in DM skin. This study identifies a potentially novel molecular signature, with significant clinical implications for differentiating DM from CLE lesions, and highlights the potential role for IL-18 in the pathophysiology of DM skin disease.

Highlights

Dermatomyositis (DM) is an autoimmune disease characterized by a skin rash and accompanied by prominent muscle weakness
We report a DM-specific 5-gene signature that, in combination, distinguishes DM from cutaneous lupus erythematosus (CLE), further validated in independent samples. These results suggest that IL-18 is a novel player in DM skin disease and illustrate its potential clinical impact to serve as a biomarker, differentiating DM and CLE
A total of 43 cutaneous lesional biopsies from 36 validated DM patients were collected from the University of Michigan (U-M) Archives of Pathology & Laboratory Medicine (Table 1)

Summary

Introduction

Dermatomyositis (DM) is an autoimmune disease characterized by a skin rash and accompanied by prominent muscle weakness. Histopathologic factors common to cutaneous DM lesions, including vacuolar interface dermatitis, perivascular inflammation, increased dermal mucin, and dyskeratotic keratinocytes [3], are seen in cutaneous lupus erythematosus (CLE) lesions, making DM-associated skin eruptions difficult to distinguish from CLE, especially in the absence of obvious muscle disease or lesional pathognomonic patterns. Similar to systemic lupus erythematosus (SLE) and CLE, research on DM pathogenesis has identified a strong type I IFN blood signature that correlates with the severity of skin activity [4, 5]. Type I IFNs are upregulated in lesional skin [6] and are thought to play a pathogenic role in destruction of muscle tissue [7]. Previous research examining the roles of B cells, T cells, and DCs has focused primarily on muscle pathology The inflammatory cell contributions in DM skin have not yet been thoroughly examined

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Conclusion