Systemic sclerosis-associated myositis features minimal inflammation and characteristic capillary pathology

Elise Siegert,Vincent Casteleyn,Jakob Höppner,Carsten Dittmayer,Corinna Preuße,Gerd R Burmester,Udo Schneider,Werner Stenzel,Felix Kleefeld,Kathrin Hahn,Hans-Hilmar Goebel,Rieke Alten,Akinori Uruha

doi:10.1007/s00401-021-02305-3

Abstract

Systemic sclerosis represents a chronic connective tissue disease featuring fibrosis, vasculopathy and autoimmunity, affecting skin, multiple internal organs, and skeletal muscles. The vasculopathy is considered obliterative, but its pathogenesis is still poorly understood. This may partially be due to limitations of conventional transmission electron microscopy previously being conducted only in single patients. The aim of our study was therefore to precisely characterize immune inflammatory features and capillary morphology of systemic sclerosis patients suffering from muscle weakness. In this study, we identified 18 individuals who underwent muscle biopsy because of muscle weakness and myalgia in a cohort of 367 systemic sclerosis patients. We performed detailed conventional and immunohistochemical analysis and large-scale electron microscopy by digitizing entire sections for in-depth ultrastructural analysis. Muscle biopsies of 12 of these 18 patients (67%) presented minimal features of myositis but clear capillary alteration, which we termed minimal myositis with capillary pathology (MMCP). Our study provides novel findings in systemic sclerosis-associated myositis. First, we identified a characteristic and specific morphological pattern termed MMCP in 67% of the cases, while the other 33% feature alterations characteristic of other overlap syndromes. This is also reflected by a relatively homogeneous clinical picture among MMCP patients. They have milder disease with little muscle weakness and a low prevalence of interstitial lung disease (20%) and diffuse skin involvement (10%) and no cases of either pulmonary arterial hypertension or renal crisis. Second, large-scale electron microscopy, introducing a new level of precision in ultrastructural analysis, revealed a characteristic capillary morphology with basement membrane thickening and reduplications, endothelial activation and pericyte proliferation. We provide open-access pan-and-zoom analysis to our datasets, enabling critical discussion and data mining. We clearly highlight characteristic capillary pathology in skeletal muscles of systemic sclerosis patients.

Highlights

Systemic sclerosis (SSc) is a rare connective tissue disease, characterized by the pathophysiological triad of fibrosis, vasculopathy and autoimmune phenomena in the form of inflammatory cell infiltrates and disease-specific diagnostic antibodies
Cardiac involvement was present in 31% of all patients, while 38% had a history of digital ulcers
We precisely characterized muscle pathology in SSc using histological, enzyme histochemical and immunohistochemical procedures in conjunction with an innovative electron microscopy (EM) technology that allows unrestricted in-depth analysis of entirely digitized ultrathin sections

Summary

Introduction

Systemic sclerosis (SSc) is a rare connective tissue disease, characterized by the pathophysiological triad of fibrosis, vasculopathy and autoimmune phenomena in the form of inflammatory cell infiltrates and disease-specific diagnostic antibodies. There are structural alterations of vessels: Microscopic evaluation of capillaries at the nailfold typically shows both capillary enlargement and reduced capillary density, and there is well-known obliterative vasculopathy in SSc-associated digital ulcers, pulmonary arterial hypertension (PAH) and scleroderma renal crisis (SRC) [4, 40]. These lesions consist of concentric intimal proliferation, leading to luminal obstruction, and inflammatory cell infiltration [10]. There are socalled plexiform lesions, which are believed to be caused by hyper-proliferation of endothelial cells in the lung [6]

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