Detecting gastrointestinal manifestations in patients with systemic sclerosis using anti-gAChR antibodies

Shunya Nakane,Osamu Higuchi,Kunihiro Ichinose,Hidenori Matsuo,Yasuhiro Maeda,Akihiro Mukaino,Atsushi Kawakami,Hideki Nakamura,Masataka Umeda,Shin-Ya Kawashiri

doi:10.1186/s13075-020-2128-z

Abstract

BackgroundPatients with systemic sclerosis (SSc) complicated by gastrointestinal dysmotility are difficult to treat and have high mortality. To clarify the pathogenesis of gastrointestinal manifestations, we aimed to demonstrate the association among the clinical features of SSc, the serological markers, the autoantibodies against nicotinic acetylcholine receptor at autonomic ganglia (gAChR).MethodsFifty patients were enrolled and divided into two groups according to the presence or absence of gastrointestinal manifestations, and the characteristics were analyzed between these two groups. We measured biomarkers and the autoantibodies against two gAChRα3 and β4 subunits to test sera samples. Furthermore, patients were classified based on the presence or absence of anti-gAChR autoantibodies, and their clinical features were compared.ResultsIn patients with SSc and gastrointestinal manifestations, digital ulcers were more frequent (p = 0.050) and VEGF expression was significantly higher (p = 0.038). Seven subjects with SSc were seropositive for α3 subunit, whereas one patient was seropositive for β4 subunit. The mean level of anti-gAChRα3 autoantibodies in SSc patients with gastrointestinal manifestations was significantly higher than that in SSc patients without gastrointestinal manifestations (p = 0.001). The group of patients with SSc and gAChR autoantibodies had significantly higher endostatin levels (p = 0.046).ConclusionsThis study is the first to demonstrate that clinical characteristics of SSc patients with seropositivity for gAChR autoantibodies. Patients with SSc have circulating autoantibodies against gAChR, which may contribute to gastrointestinal manifestations associated with this disease, suggesting that gAChR-mediated autonomic neurotransmission may provide a pathomechanism for gastrointestinal dysmotility in SSc.

Highlights

Patients with systemic sclerosis (SSc) complicated by gastrointestinal dysmotility are difficult to treat and have high mortality
We reviewed clinical survey data and summaries for the patients whether they had any of the following symptoms, which would indicate dysfunction of the autonomic system: orthostatic hypotension (OH) or orthostatic intolerance (OI), arrhythmia, pupillary dysfunction, coughing episodes, dryness of the skin, hypohidrosis or anhidrosis associated with heat intolerance, appetite loss, nausea/ vomiting, early satiety, postprandial abdominal pain, and gastroparesis associated with dysfunction of the upper gastrointestinal system, diarrhea or constipation, and paralytic ileus associated with dysfunction of the lower gastrointestinal system, dysuria or urinary retention associated with bladder dysfunction, and sexual dysfunction
Anti-gAChRα3 antibodies were detected in 7 samples, whereas anti-gAChRβ4 antibodies were detected in 1 sample (2%, 1 of 50)

Summary

Introduction

Patients with systemic sclerosis (SSc) complicated by gastrointestinal dysmotility are difficult to treat and have high mortality. Systemic sclerosis (SSc), a multi-systemic disorder of the connective tissues, is characterized by widespread vascular damage and fibrosis of the skin and visceral organs [13, 14] Gastrointestinal (GI) manifestations occur frequently in patients with SSc [15,16,17]. The pathogenesis of GI involvement is thought to include early vascular damage to the vasa nervorum [28]. This leads to neurological dysfunctions, those involving autonomic pathways

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