Hepatobiliary involvement in systemic sclerosis and the cutaneous subsets: Characteristics and survival of patients from the Spanish RESCLE Registry

https://doi.org/10.1016/j.semarthrit.2017.10.004Get rights and content

Abstract

Objective

To assess the prevalence and causes of hepatobiliary involvement (HBI) in systemic sclerosis (SSc), to investigate the clinical characteristics and prognosis of SSc patients with HBI (SSc-HBI) and without HBI (SSc-non-HBI), and to compare both groups according to the cutaneous SSc subsets.

Methods

In all, 1572 SSc patients were collected in the RESCLE registry up to January 2015, and all hepatobiliary disturbances were recorded. We investigated the HBI-related characteristics and survival from the entire SSc cohort and according to the following cutaneous subsets: diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc).

Results

Out of 1572, 118 (7.5%) patients had HBI. Primary biliary cholangitis (PBC) was largely the main cause (n = 67, 4.3%), followed by autoimmune hepatitis (n = 19, 1.2%), and anti-mitochondrial negative PBC (n = 6, 0.4%). Other causes of HBI were as follows: secondary liver diseases (n = 11, 0.7%), SSc-related HBI (n = 7, 0.4%), nodular regenerative hyperplasia (n = 3, 0.2%), liver cirrhosis (n = 3, 0.2%), and HBI of unknown origin (n = 2, 0.1%). In multivariate analysis, HBI was independently associated to lesser risk of dcSSc (5.1% vs. 24.4%), and higher frequency of calcinosis (26% vs. 18%), left ventricular diastolic dysfunction (46% vs. 27%), sicca syndrome (51% vs. 29%), and anti-centromere antibodies (ACA, 73% vs. 44%). According to the cutaneous subsets, HBI was associated (1) in lcSSc, to longer time from SSc onset to diagnosis (10.8 ± 12.5 vs. 7.2 ± 9.3 years), sicca syndrome (54% vs. 33%), and ACA (80% vs. 56%); (2) in ssSSc, to sicca syndrome (44% vs. 19%), and (3) in dcSSc, no associations were found. HBI was the cause of death in 2.3% patients but the cumulative survival according to the presence or absence of HBI showed no differences.

Conclusions

HBI prevalence in SSc is 7.5% and dcSSc is the least involved subset. PBC is the main cause of HBI. Patients with SSc-HBI exhibited specific clinical and immunologic profile. Survival is similar for SSc patients with HBI.

Introduction

Systemic sclerosis (SSc) is a chronic autoimmune systemic disease characterized by an overlapping triad of autoimmunity, obliterative vasculopathy, and variable degrees of skin and visceral fibrosis that mainly depends on the cutaneous subsets and immunological status [1], [2]. Hepatobiliary involvement (HBI) associated to SSc was firstly described by Milbradt in 1934 [3]. Although liver disturbance is not a rare finding in scleroderma, its presence is not considered characteristic of SSc. Initially, autopsy series of SSc patients showed a similar prevalence of HBI compared to that of the control population [4], [5]. However, further investigations reported the presence of some clinical and biological liver disturbances in 37–52% of SSc patients. Formerly, these findings were assumed to be related to the coexistence with liver steatosis, viral infections, drug-induced toxicity, and other causes [4], [6], [7]. Nowadays, an organ-specific autoimmune disease such as primary biliary cholangitis (PBC) is considered the main cause of HBI in SSc patients [6], [7], [8], [9], [10], [11], [12], [13]. Although no common etiology has been established between SSc and the autoimmune liver disease, several arguments suggest a shared autoimmune basis. First, the presence of the characteristic SSc anti-centromere antibodies (ACA) in 9–30% of PBC patients [14], [15], [16], [17], [18], [19]; secondly, the presence of the characteristic PBC anti-mitochondrial antibodies (AMA) in 25% of SSc with no apparent HBI [20], [21], and thirdly, the relatively frequent association of SSc and PBC with other organ-specific and organ-nonespecific autoimmune conditions such as Hashimoto’s thyroiditis or Graves’ disease, and Sjögren’s syndrome [8], [10], [20], [21], [22], [23].

To our knowledge, studies addressed to investigate the prevalence, clinical characteristics, and prognosis related to the presence of HBI in SSc are scarce and heterogeneous. Moreover, no study has described neither the characteristics of SSc patients with HBI according to the cutaneous subsets nor its impact on survival. The present study is a cross-sectional analysis of a large cohort of SSc patients addressed to establish the prevalence of HBI in patients with SSc, to investigate the clinical characteristics and prognosis of SSc patients with and without HBI, and to compare both groups of patients according to the cutaneous subsets. We used a modification of the classification proposed by LeRoy and Medsger [24] on three subsets but patients with SSc sine scleroderma (ssSSc) were considered separately to evaluate whether they show any difference in HBI. Of note, no data are currently available on the characteristics of SSc patients with HBI (SSc-HBI) and without HBI (SSc-non-HBI) according to these four differentiated SSc subsets in a large population of patients.

Section snippets

Patients and methods

Twenty-one Spanish centers participated in the recruitment of 1572 SSc patients in a registry named RESCLE (Registro de ESCLErodermia as Spanish nomenclature) up to January 2015. All participating centers obtained the Ethics Committee approval and all patients signed the informed consent. We considered SSc diagnosis when patients fulfilled criteria of the modified classification proposed by LeRoy and Medsger [24] and/or the 2013 ACR/EULAR criteria for SSc [25]. Demographic, clinical,

Characteristics of SSc patients with and without HBI

Baseline demographic and clinical characteristics for the entire SSc cohort (N = 1572), according to the presence (n = 118, 7.5%) and absence (n = 1454, 92.5%) of HBI are shown in Table 1. Ninety six percent of patients were Caucasian. Gender was predominantly female (89%), and most patients were classified as lcSSc (n = 924, 59%) subset followed by dcSSc (n = 359, 22.9%), ssSSc (n = 166, 10.6%), and pre-SSc (n = 117, 7.5%) subsets. Taking into account the cutaneous subsets, results revealed

Multivariate analysis of HBI in SSc patients

A logistic regression model including significant associations in univariate analysis was performed for the whole SSc cohort and also according to the cutaneous subsets. Only variables with >75% of the data were included in the multivariate analysis that is summarized in Table 4. Independent variables from the SSc cohort associated to HBI were: lesser risk of dcSSc subset, longer elapsed time from SSc onset to its diagnosis and higher risk of calcinosis cutis, LV diastolic dysfunction, sicca

Discussion

In this cross-sectional analysis of 1572 SSc patients recruited in a large ongoing Spanish multicenter registry named RESCLE, HBI was recorded in 7.5% of patients. To our knowledge, this is the first study that best estimates the prevalence of HBI in a large series of patients with SSc and assesses the characteristics of SSc-HBI and SSc-non-HBI patients both from the entire cohort and according to the cutaneous subsets. Results from our study revealed that the prevalence of HBI was similar for

Acknowledgments

We gratefully acknowledge all investigators who form part of the RESCLE Registry. This project was possible thanks to an educational unrestricted scholarship granted by Laboratorios Actelion. We also thank the RESCLE Registry Coordinating Center, S&H Medical Science Service, for their quality control data, logistic and administrative support and Prof. Salvador Ortiz, Universidad Autónoma de Madrid and Statistical Advisor S&H Medical Science Service for the statistical analysis of the data

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    This Project was funded by an unrestricted educational scholarship granted by Laboratorios Actelion. Actelion had no access to the data of the RESCLE Registry database. The authors have no conflicts of interest to disclose.

    1

    A full list of the RESCLE investigators is given in the appendix.

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