Recent evidence suggests a link between autoimmunity and the intestinal microbial composition in several rheumatic diseases including systemic sclerosis (SSc). The objective of this study was to investigate the prevalence of intestinal dysbiosis in SSc and to characterise patients suffering from this potentially immunomodulatory deviation. This study consisted of 98 consecutive patients subject to in-hospital care. Stool samples were analysed for intestinal microbiota composition using a validated genome-based microbiota test (GA-map™ Dysbiosis Test, Genetic Analysis, Oslo, Norway). Gut microbiota dysbiosis was found present as per this standardised test. Patients were examined regarding gastrointestinal and extraintestinal manifestations of SSc by clinical, laboratory, and radiological measures including esophageal cineradiography, the Malnutrition Universal Screening Tool (MUST), levels of plasma transthyretin (a marker of malnutrition) and faecal (F-) calprotectin (a marker of intestinal inflammation). A majority (75.5%) of the patients exhibited dysbiosis. Dysbiosis was more severe (rs = 0.31, p = 0.001) and more common (p = 0.013) in patients with esophageal dysmotility. Dysbiosis was also more pronounced in patients with abnormal plasma levels of transthyretin (p = 0.045) or micronutrient deficiency (p = 0.009). In 19 patients at risk for malnutrition according to the MUST, 18 exhibited dysbiosis. Conversely, of the 24 patients with a negative dysbiosis test, only one was at risk for malnutrition. The mean ± SEM levels of F-calprotectin were 112 ± 14 and 45 ± 8 μg/g in patients with a positive and negative dysbiosis test, respectively. Dysbiosis was more severe in patients with skin telangiectasias (p = 0.020), pitting scars (p = 0.023), pulmonary fibrosis (p = 0.009), and elevated serum markers of inflammation (p < 0.001). However, dysbiosis did not correlate with age, disease duration, disease subtype, or extent of skin fibrosis. In this cross-sectional study, intestinal dysbiosis was common in patients with SSc and was associated with gastrointestinal dysfunction, malnutrition and with some inflammatory, fibrotic and vascular extraintestinal features of SSc. Further studies are needed to elucidate the potential causal relationship of intestinal microbe-host interaction in this autoimmune disease.

Andréasson K, Scheja A, Saxne T, Ohlsson B, Hesselstrand R (Section for Rheumatology; Section for Gastroenterology and Hepatology, Lund University, Lund, Sweden). Faecal calprotectin: a biomarker of gastrointestinal disease in systemic sclerosis. J Intern Med 2011; 270: 50–57. Background. Assessment of gastrointestinal (GI) involvement in systemic sclerosis (SSc) is difficult. Measurement of calprotectin in faeces is a valuable tool for the assessment of inflammatory bowel diseases. Calprotectin is an intracellular protein found in leucocytes and is a potent activator of the innate immune system. Objective. To determine whether faecal calprotectin (F-calprotectin) could serve as a biomarker of GI disease in SSc. Design. In a cross-sectional study, F-calprotectin and plasma calprotectin were measured in patients with SSc using an enzyme-linked immunosorbent assay. F-calprotectin concentrations were evaluated in relation to cineradiography, medical records, laboratory measurements and patients’ subjective GI symptoms. Setting. The study was conducted at a tertiary referral centre for SSc. Subjects. The study comprised 81 consecutive patients with SSc. Results. A majority of the patients had pathological levels of F-calprotectin when compared to accepted clinical reference values for healthy adults. F-calprotectin did not correlate with calprotectin levels in plasma. F-calprotectin was associated with the following patient characteristics: pathological cineradiography, history of referral to another clinic because of GI disease, treatment of vitamin or mineral deficiency and use of proton pump inhibitors. We did not find any significant correlation between F-calprotectin and patient-reported GI symptoms. Conclusion. Faecal calprotectin is increased in a majority of patients with SSc. It correlates with objective and clinically important features of GI disease, and faecal concentrations do not vary with plasma concentrations. We suggest that F-calprotectin is a promising objective non-invasive biomarker of GI involvement in SSc.

High-frequency ultrasound offers a potential for objective and quantitative assessment of skin thickness and skin echogenicity in systemic sclerosis (SSc). Few studies have however assessed the longitudinal changes of skin involvement using ultrasound. The aim of the study was to investigate changes in skin thickness in early SSc using high frequency ultrasound during one year of follow-up in comparison to other measurements of skin fibrosis. This retrospective study comprised 75 consecutive patients with disease duration shorter than 3 years, in whom ultrasound examination of skin thickness was performed at baseline and at the one year follow-up at five predefined sites. Repeated ultrasound examination identified significant changes in a majority of patients. In 21 patients, the total sum of skin thickness (TST) increased, while TST decreased in 37 patients. On a group level there were significant decreases in skin thickness of the chest (p = 0.024) and in the TST (p = 0.011) during the observation time. Both baseline and follow-up TST correlated to serum-COMP (rS: 0.41; p = 0.001; rS: 0.49; p < 0.001), modified Rodnan skin score (mRSS; rS: 0.48; p < 0.001; rS: 0.48; p < 0.001) and hand mobility in scleroderma (HAMIS; rS: 0.30; p = 0.043; rS: 0.64; p < 0.001). Changes in TST correlated with changes in serum-COMP (rS: 0.30; p = 0.034), changes in mRSS (rS: 0.43; p < 0.001) and changes in HAMIS (rS: 0.53; p = 0.001) during follow-up. In early SSc, skin thickness measured by high frequency ultrasound develops in parallel with serum-COMP, mRSS and the HAMIS test. Ultrasound examination of the skin allows for objective assessment of one facet of the complex process of skin fibrosis in early SSc.

Objective: The study objective was to examine alterations in gastrointestinal (GI) microbial composition in patients with systemic sclerosis (SSc) and to investigate the relationship between SSc features and GI microbiota using two independent, international cohorts.Methods: Prospective patients with SSc from Lund University (LU), Sweden, from the University of California, Los Angeles (UCLA), United States, and control subjects provided stool specimens for 16S ribosomal RNA sequencing. Alpha and beta diversity analyses were performed. Multivariate negative binomial models identified differentially abundant genera between groups.Results: Patients from LU with SSc (n = 106) with recent SSc diagnosis (median disease duration 2.0 years) had lower abundance of commensal genera (eg, Faecalibacterium) and higher abundance of pathobiont genera (eg, Desulfovibrio) than LU‐controls (n = 85). Patients from UCLA with SSc (n = 71) had a similar prevalence of females, a similar body mass index, and similar age but an increased disease duration (median 7.1 years) compared with patients from LU with SSc. Factors associated with beta diversity in patients with SSc from both LU and UCLA included disease duration (P = 0.0016), interstitial lung disease (P = 0.003), small intestinal bacterial overgrowth (P = 0.002), and immunosuppression use (P = 0.014). In multivariable analysis, the UCLA‐SSc cohort had higher abundance of specific pathobiont genera (eg, Streptococcus) compared with the LU‐SSc cohort.Conclusion: Enrichments and depletions in certain microbial genera were observed in patients recently diagnosed with SSc, suggesting that dysbiosis is present in early SSc. Specific disease features were independently associated with fecal microbial composition in both cohorts. After controlling for these factors, the abundance of several pathobiont bacteria differed between the cohorts, suggesting that environmental factors, along with disease manifestations, should be considered in future SSc studies.

To examine faecal calprotectin (F-calprotectin) levels and presence of anti-Saccharomyces cerevisiae antibodies (ASCA) and their associations with disease subtype and current status in axial SpA (axSpA). F-calprotectin and ASCA in serum were compared between consecutive patients with a clinical axSpA diagnosis, classified as non-radiographic axSpA (nr-axSpA; n = 40) or AS (n = 90), and with healthy controls (n = 35). Furthermore, standard axSpA outcome measures were compared between axSpA patients (nr-axSpA and AS combined) with elevated vs normal F-calprotectin, ASCA IgA and IgG, respectively. Elevated F-calprotectin (⩾50 mg/kg) was observed in 27% of nr-axSpA patients, 38% of AS patients and 6% of controls. F-calprotectin was significantly higher in AS vs nr-axSpA [AS: geometric mean 41 (95% CI 32, 54) mg/kg; nr-axSpA: 24 (95% CI 16, 38) mg/kg; P = 0.037], and in each axSpA subtype vs controls. Overall, worse disease activity and physical function scores were observed among axSpA patients with elevated vs normal F-calprotectin levels, with significant differences regarding patient's visual analogue scale for global health, ASDAS using CRP, and BASFI (adjusted for age, sex, NSAID use, anti-rheumatic treatments, and CRP). ASCA titres and seropositivity (⩾10 U/ml) were similar in nr-axSpA (IgA/IgG-seropositivity: 8%/26%) and AS (7%/28%), and clinical outcome measures did not differ between patients with elevated vs normal ASCA IgA or IgG, respectively. Compared with controls (IgA/IgG-seropositivity: 0%/17%), ASCA IgA was significantly higher in both axSpA subtypes, and IgG was significantly higher in the AS group. In patients with axSpA, gut inflammation measured by elevated F-calprotectin is associated with worse disease activity and physical function, and may be a marker of more severe disease.

Primary Sjögren’s syndrome (pSS) is a systemic rheumatic disease in which gastrointestinal (GI) symptoms are common. Faecal calprotectin (FC) is a non-invasive biomarker that has been suggested to discriminate organic intestinal disease from functional disorders. The purpose of this study was to explore the usefulness of FC testing in patients with pSS. In total, 56 consecutive patients with pSS and 29 healthy control subjects were included in this cross-sectional study. FC was measured with a commercially available enzyme-linked immunosorbent assay kit. GI symptoms were evaluated with the Rome III questionnaire and the Visual Analogue Scale for Irritable Bowel Syndrome. In patients with pSS, disease activity was estimated using the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI), and patient-reported outcomes were evaluated with the EULAR Sjögren’s Syndrome Patient-Reported Index. Patients with pSS had higher levels of FC than healthy control subjects (median 54 μg/g, interquartile range [IQR 20–128]; vs. 20 μg/g [20–43]; p = 0.002). Concomitant organic GI disease was found in 14 patients with pSS and included inflammatory bowel disease (n = 3), colonic adenoma (n = 2) and GI lymphoma (n = 1). Patients with organic GI disease had higher FC levels than the other patients with pSS (median 274 μg/g [IQR 61–363] vs. median 34 μg/g [IQR 20–76]; p < 0.001). Although patients with pSS reported abdominal discomfort more frequently than healthy control subjects did, such symptoms were not associated with organic GI disease or elevated FC levels. FC correlated moderately with ESSDAI. Excluding patients with organic GI disease, we did not identify any significant association between ESSDAI and FC levels. GI symptoms are frequent in pSS. Contrary to patient-reported outcomes, elevated FC levels in pSS indicate possible organic GI disease that warrants further investigation.