PURPOSE OF REVIEW: The majority of patients with systemic sclerosis (SSc) will experience involvement of their gastrointestinal over the course of their disease. Despite the high prevalence of gastrointestinal involvement in SSc, the strategies pertaining to the assessment and treatment for this clinical dimension of SSc have historically been limited. However, the present review highlights recent research contributions that enhance our understanding of SSc-GI patient subsets and provides updates on pathogenic mechanisms of disease, assessment and symptom-directed management. RECENT FINDINGS: In the past few years, several studies have identified risk factors for more severe gastrointestinal disease in SSc and have provided insight to optimize diagnosis and management of SSc-GI symptoms. This article also provides a review of currently available investigations and therapies for individual SSc-GI disease manifestations and reflects on actively evolving areas of research, including our understanding the role of the gut microbiome in SSc. SUMMARY: Here, we provide important updates pertaining to the risk stratification, assessment, diagnosis and management of SSc patients with gastrointestinal symptoms. These findings provide opportunities to enhance patient care and highlight exciting opportunities for future research.

INTRODUCTION: Systemic sclerosis (SSc) is a multi-dimensional connective tissue disease of unknown etiology. Given the immense clinical complexity of SSc, the treatment of this condition is not standardized and considerable heterogeneity exists in SSc management approaches. The purpose of this article is to highlight novel therapeutic strategies and new medications under development for the treatment of systemic sclerosis (SSc). AREAS COVERED: Herein, the authors focus primarily on recently completed clinical trials and phase 3 and 4 clinical trials of therapeutic agents that show promise in SSc. This review is organized by the clinical complications that occur in SSc, for which novel treatment strategies are under study. EXPERT OPINION: Combining therapies to address the individual manifestations of SSc is a cornerstone to the comprehensive management of this condition. Therapeutic strategies must take into account the organs involved, the level of disease activity in each area, and the disease stage. Controlling the complex biological network, progressive vasculopathy and fibrosis, as well as manifestations of end-organ dysfunction are all critical considerations when determining the best treatment approach for SSc.

PURPOSE: The primary aim is to identify the micronutrient deficiencies commonly reported in SSc. The exploratory aim is to evaluate associations between micronutrient deficiencies and SSc clinical manifestations. PATIENT AND METHODS: We conducted a scoping review of all published reports on SSc and nutrition in PubMed from its inception to August 2020. Clinical trials, observational studies, meta-analyses, and case series (with ≥20 cases) containing data on nutritional deficiency and SSc were included. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for reporting our findings. Two reviewers (ADN and ERV) studied the titles and abstracts of all search results with pre-specified inclusion and exclusion criteria. RESULTS: Among 790 retrieved publications, 35 full-length articles and 3 abstracts met the inclusion/exclusion criteria. Included studies took place across multiple geographic locations and included patients with both diffuse and limited cutaneous SSc. Vitamin D deficiency was the most commonly reported deficiency described in SSc, followed by vitamin B12, vitamin B9, selenium, zinc, and iron. In addition, some small studies found deficiencies in vitamins B1, B6, C, E, and A. While some studies reported associations between specific micronutrient deficiencies and SSc disease features (eg, interstitial lung disease was commonly associated with vitamin D deficiency and elevated homocysteine [Hcy]), the evidence to support these associations was not robust. CONCLUSION: Micronutrient deficiencies are common in SSc and are associated with specific SSc features. Routine screening for micronutrient deficiencies may lead to early detection of malnutrition. Future studies are needed to understand how interventions to replete micronutrient deficiencies affect patient outcomes in SSc.

OBJECTIVE: Systemic sclerosis (SSc)-associated gastrointestinal (GI) complications are attributed to a variety of factors, including diet, microbiota dysbiosis, or GI transit abnormalities. Our objective was to examine the contribution of abnormal GI transit to SSc Medsger GI severity scores and/or University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA GIT) 2.0 symptoms. METHODS: Patients with SSc and GI symptoms (n = 71) and healthy controls (n = 18) underwent whole gut transit (WGT) scintigraphy to assess transit from the esophagus to the colon. The presence of delayed transit and percent emptying in each GI region were measured. We compared the WGT measurements between categories of the Medsger GI severity score (0-4) and across UCLA GIT 2.0 domains and total score (0-3). RESULTS: A total of 88% of patients had >1 abnormal region of the gut on WGT scintigraphy. All patients requiring total parenteral nutrition had delayed small bowel transit, compared to only approximately 11% of patients in other Medsger GI severity groups (P ≤ 0.01). Severe colonic transit delays were more likely in patients with Medsger GI scores of 3 (pseudo-obstruction and/or malabsorption) compared to other Medsger GI groups (P = 0.02). Seventy-percent of these patients had ≤30% colonic emptying at 72 hours. Modest associations were noted between gastroesophageal reflux disease symptoms and delayed esophageal (r = -0.31, P = 0.05) and gastric emptying (r = -0.32, P = 0.05). CONCLUSION: These data are important in providing evidence that SSc bowel disease affects transit of GI content and that delay in transit accounts in part for both bowel symptoms and Medsger GI severity. Prospective studies examining the benefit of early therapeutic intervention targeting GI transit abnormalities in patients at high risk for severe GI complications are needed.

OBJECTIVE: Up to 50% of patients with systemic sclerosis (SSc) experience slow colonic transit, which may be associated with severe outcomes. Our objective, therefore, was to identify specific clinical features associated with slow colonic transit in SSc. METHODS: SSc patients with gastrointestinal symptoms were prospectively enrolled and completed a scintigraphy-based whole gut transit study. Clinical features were compared between patients with and without slow colonic transit in univariate and multivariable logistic regression analyses. RESULTS: Forty-eight of 100 patients (48%) in our cohort had slow colonic transit. In the univariate analyses, slow colonic transit was positively associated with female sex (odds ratio [OR] 12.61 [95% confidence interval (95% CI) 1.56-101.90]), telangiectasia (OR 4.00 [95% CI 1.32-12.10]), anticentromere antibodies (OR 3.25 [95% CI 1.25-8.44]), prior or current smoking (OR 2.56 [95% CI 1.06-6.21]), and a Medsger gastrointestinal severity score of ≥3 (OR 3.94 [95% CI 1.16-13.36]). Patients were less likely to have significant restriction on pulmonary function tests (OR 0.23 [95% CI 0.09-0.63]). In our multivariable model, the association between slow colonic transit and telangiectasia (OR 3.97 [95% CI 1.20-13.20]) and less restrictive lung disease on pulmonary function tests (OR 0.28 [95% CI 0.09-0.86]) remained statistically significant, though a trend with smoking remained (OR 2.16 [95% CI 0.82-5.75]). Interestingly, there were no significant associations between slow colonic transit and delayed transit in other regions of the gastrointestinal tract. CONCLUSION: Distinct clinical features are associated with slow colonic transit in SSc. Such features may provide insight in risk stratification and the study of disease mechanism in more homogeneous subgroups.

OBJECTIVE: The gastrointestinal tract is commonly involved in patients with systemic sclerosis (SSc) with varied manifestations. As our understanding of SSc gastrointestinal disease pathogenesis and risk stratification is limited, we sought to investigate whether patterns of esophageal dysfunction associate with specific clinical phenotypes in SSc. METHODS: Patients enrolled in the Johns Hopkins Scleroderma Center Research Registry who completed high-resolution esophageal manometry (HREM) studies as part of their clinical care between 2011 and 2020 were identified. Associations between esophageal abnormalities on HREM (absent contractility [AC], ineffective esophageal motility [IEM], hypotensive lower esophageal sphincter [hypoLES]) and patient demographic information, clinical characteristics, and autoantibody profiles were examined. RESULTS: Ninety-five patients with SSc had HREM data. Sixty-five patients (68.4%) had AC (37 patients with only AC, 28 patients with AC and a hypoLES), 9 patients (9.5%) had IEM, and 11 patients (11.6%) had normal studies. AC was significantly associated with diffuse cutaneous disease (38.5% versus 10.0%; P < 0.01), more severe Raynauds phenomenon, including digital pits, ulcers, or gangrene (56.9% versus 30.0%; P = 0.02), and reduced median diffusing capacity of lung for carbon monoxide (50.6% versus 72.2%; P = 0.03). AC was observed in most of the patients who died (13 of 14; P = 0.06). These findings were not seen in patients with IEM. CONCLUSION: Among patients with SSc, AC is associated with a significantly more severe clinical phenotype. IEM may associate with a milder phenotype. Further studies are needed to evaluate AC, IEM, and their clinical impact relative to the timing of other end-organ complications in SSc.

OBJECTIVE: To assess adverse events (AEs) in relation to baseline body mass index (BMI) and the risk of malnutrition in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) treated with nintedanib. METHODS: Among patients with SSc-ILD randomized to receive nintedanib or placebo in the SENSCIS trial, we assessed AEs in subgroups by baseline BMI ≤20 kg/m2 and BMI >20 kg/m2 , and the risk of malnutrition using a modified version of the Malnutrition Universal Screening Tool (MUST), over 52 weeks. RESULTS: The AE profile of nintedanib was similar between subgroups with a baseline BMI ≤20 kg/m2 (n = 61) and a baseline BMI >20 kg/m2 (n = 515). In these subgroups, respectively, AEs led to treatment discontinuation in 16.7% and 15.9% of the nintedanib group and 13.5% and 8.0% of the placebo group, respectively. Based on the modified MUST, the proportions of patients who had a low risk of malnutrition at baseline and at their last assessment were 74.0% in the nintedanib group and 78.1% in the placebo group, while the proportions who were classified as at low risk at baseline but at high risk by their last assessment were 4.5% in the nintedanib group and 1.0% in the placebo group. CONCLUSION: In the SENSCIS trial, most patients with SSc-ILD remained at low risk of malnutrition over 52 weeks, but the proportion at high risk was higher in patients who received treatment with nintedanib compared to those who received placebo. Management of disease manifestations and AEs that may be associated with weight loss is important to reduce the risk of malnutrition in patients with SSc-ILD.

Objective

Autoimmune responses to DNA topoisomerase I (topo I) are found in a subset of scleroderma patients who are at high risk for interstitial lung disease (ILD) and mortality. Anti-topo I antibodies (ATAs) are associated with specific HLA-DRB1 alleles, and the frequency of HLA-DR-restricted topo I-specific CD4+ T cells is associated with the presence, severity, and progression of ILD. Although this strongly implicates the presentation of topo I peptides by HLA-DR in scleroderma pathogenesis, the processing and presentation of topo I has not been studied.

Methods

We developed a natural antigen processing assay (NAPA) to identify putative CD4+ T cell epitopes of topo I presented by monocyte-derived dendritic cells (mo-DCs) from 6 ATA-positive patients with scleroderma. Mo-DCs were pulsed with topo I protein, HLA-DR-peptide complexes were isolated, and eluted peptides were analyzed by mass spectrometry. We then examined the ability of these naturally presented peptides to induce CD4+ T cell activation in 11 ATA-positive and 11 ATA-negative scleroderma patients.

Results

We found that a common set of 10 topo I epitopes was presented by Mo-DCs from scleroderma patients with diverse HLA-DR variants. Sequence analysis revealed shared peptide-binding motifs within the HLA-DRβ chains of ATA-positive patients and a subset of topo I epitopes with distinct sets of anchor residues capable of binding to multiple different HLA-DR variants. The NAPA-derived epitopes elicited robust CD4+ T cell responses in 73% of ATA-positive patients (8 of 11), and the number of epitopes recognized correlated with ILD severity (P = 0.025).

Conclusion

These findings mechanistically implicate the presentation of a convergent set of topo I epitopes in the development of scleroderma.

Background

Alterations in gastrointestinal (GI) microbial composition have been reported in patients with systemic sclerosis (SSc). However, it is unclear to what degree these alterations and/or dietary changes contribute to the SSc-GI phenotype.

Objectives

Our study aimed to 1) evaluate the relationship between GI microbial composition and SSc-GI symptoms, and 2) compare GI symptoms and GI microbial composition between SSc patients adhering to a low versus non-low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet.

Methods

Adult SSc patients were consecutively recruited to provide stool specimens for bacterial 16S rRNA gene sequencing. Patients completed the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (GIT 2.0) and the Diet History Questionnaire (DHQ) II and were classified as adhering to a low or non-low FODMAP diet. GI microbial differences were assessed using three metrics of alpha diversity (species richness, evenness, and phylogenetic diversity), as well as beta diversity (overall microbial composition). Differential abundance analysis was performed to identify specific genera associated with SSc-GI phenotype and low versus non-low FODMAP diet.

Results

Of the 66 total SSc patients included, the majority were women (n = 56) with a mean disease duration of 9.6 years. Thirty-five participants completed the DHQ II. Increased severity of GI symptoms (total GIT 2.0 score) was associated with decreased species diversity and differences in GI microbial composition. Specifically, pathobiont genera (e.g., Klebsiella and Enterococcus) were significantly more abundant in patients with increased GI symptom severity. When comparing low (N = 19) versus non-low (N = 16) FODMAP groups, there were no significant differences in GI symptom severity or in alpha and beta diversity. Compared with the low FODMAP group, the non-low FODMAP group had greater abundance of the pathobiont Enterococcus.

Conclusion

SSc patients reporting more severe GI symptoms exhibited GI microbial dysbiosis characterized by less species diversity and alterations in microbial composition. A low FODMAP diet was not associated with significant alterations in GI microbial composition or reduced SSc-GI symptoms; however, randomized controlled trials are needed to evaluate the impact of specific diets on GI symptoms in SSc.