Silvia Bellando-Randone

Objective: To identify the specific gastrointestinal (GI) symptoms associated with clinically relevant fatigue in systemic sclerosis (SSc), beyond the established association between overall GI involvement and fatigue. Methods: We conducted a cross-sectional study including consecutive patients with SSc fulfilling the 2013 ACR/EULAR classification criteria. Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue) scale, with clinically relevant fatigue defined as a score ≤ 30. Demographic, clinical, laboratory, and organ involvement data were collected. Individual GI symptom domains (GERD, dysphagia, bloating, diarrhea and constipation), together with the Medsger GI severity score, were analyzed. Bivariate analyses and multivariable logistic regression analyses were performed to evaluate symptom-specific associations with clinically relevant fatigue. Results: Among 115 patients, clinically relevant fatigue was observed in 42 (36.5%). Patients with FACIT-Fatigue ≤ 30 more frequently reported GERD (90.5% vs 60.3%), dysphagia (40.5% vs 16.4%), bloating (66.7% vs 15.1%), and diarrhea (28.6% vs 11.0%) (all p < 0.05). No statistically significant between-group differences were detected in the available objective disease measures. In the primary Firth penalized logistic regression model, bloating (OR 9.11, 95% CI 3.53–25.71) and GERD (OR 4.08, 95% CI 1.29–15.44) were associated with clinically relevant fatigue. Dysphagia showed a directionally consistent but less precise association. In a continuous-outcome sensitivity analysis, GERD, dysphagia, and bloating were associated with lower FACIT-Fatigue scores. Conclusions: Clinically relevant fatigue in SSc was associated with a distinct profile of patient-reported GI symptoms, particularly bloating and GERD. These findings provide a more granular characterization of fatigue-related GI burden in SSc. Key Points • This study moves beyond aggregate gastrointestinal involvement by examining symptom-specific correlates of fatigue in systemic sclerosis. • Bloating and GERD were independently associated with FACIT-Fatigue ≤ 30, whereas dysphagia was associated with greater fatigue severity only in the continuous-outcome sensitivity analysis. • Clinically relevant fatigue in SSc appears to cluster more closely with patient-reported GI and functional burden than with conventional measures of disease severity.

Systemic sclerosis (SSc) is a rare and heterogeneous disease. SSc pathobiology is complex and it occurs in a genetically susceptible host. Our aim was to describe potential environmental and occupational exposures relevant to SSc. An online survey was developed in English to collect detailed information about relevant current/past environmental and occupational exposures. Individuals with SSc were invited to participate through international patient associations and social media. Participation was voluntary and no identifiable information was collected. We used descriptive statistics to summarize our data. In total, 478 evaluable individuals (93% female; 81% ≥ 51 years old) from 19 countries [mostly USA (68%) and UK (23%)] completed the survey. Concerning SSc subtype, 137 had diffuse and 178 limited cutaneous SSc; and around one-fifth mixed connective tissue disease/SSc overlap (n = 84). The majority had a long-established diagnosis of SSc (>10 years 50%, 5-10 years 20%). One-third were in active employment (full-time 23%, part-time 10%), 4.6% were self-employed, and 42% were retired. The most frequently reported current and past work-related exposures (reported by >10% of participants) included outdoor sun exposure, paint/varnishes/lacquers, weedkillers, wet work/cleaning agents, paint thinners/removers, biological agents, pesticides, solvents/degreasers, and ionizing radiation. Exposures previously implicated in SSc were also reported, including silica/quartz, PVC/plasticizers, vinyl chloride, and epoxy resins, although less frequently. We benchmark potential environmental and occupational factors in SSc. A novel finding was the identification of several important potential industrial/chemical agent exposures. These data could inform future SSc research concerning occupational/environmental triggers.

Background: Gastrointestinal (GI) involvement is the most frequent visceral complication of systemic sclerosis (SSc), affecting up to 90% of patients, yet it remains poorly understood compared to pulmonary or cutaneous manifestations. The aim of this review is to integrate current knowledge on the cellular mechanisms underlying GI disease in SSc and to identify research priorities. Methods: A narrative literature review was conducted through a systematic PubMed search up to September 2025, complemented by manual reference screening. Results: Histopathological and functional evidence consistently demonstrates that neuromuscular alterations, including degeneration of enteric neurons, loss of interstitial cells of Cajal, and smooth muscle atrophy, can precede fibrosis, challenging the traditional “fibrosis-first” paradigm. Fibroblast and myofibroblast activation are present in gastric and colonic samples, sustained by profibrotic mediators such as TGF-β, CTGF, and endothelin-1, although the cellular origins of these stromal cells remain uncertain. Additional pathogenic contributions include autonomic dysfunction, barrier dysfunction with dysbiosis, impaired vascular reserve of vessels perfusing the gut, and functional autoantibodies targeting interneural and neuromuscular function and communication. Compared with skin and lung, the GI tract displays less fibrosis and fewer inflammatory infiltrates, but immune-derived mediators and autoantibodies suggest distinct immunopathogenic pathways are activated. Conclusions: Collectively, these findings depict GI involvement in SSc as a multi-compartmental process integrating neural, epithelial, endothelial, stromal, and immune alterations. Addressing the lack of validated biomarkers, mechanistic models, and biomarker-stratified trials will be essential to move beyond symptomatic care and toward precision medicine approaches for SSc-related GI disease.

Mesenchymal stem cell (MSC) transplantation has emerged as a potential therapeutic strategy for systemic sclerosis (SSc), a rare autoimmune disease characterized by inflammation, fibrosis, and vasculopathy. Recent evidence suggests that the therapeutic benefits of MSCs do not depend directly on their ability to proliferate but rather on their capacity to release extracellular nanovesicles known as exosomes (MSC-Exos). MSC-Exos are rich in bioactive molecules such as microRNAs, which can modulate gene expression and trigger significant biological responses, playing a central role in modulating immune responses, inhibiting fibrotic pathways and promoting tissue repair and angiogenesis. Preclinical studies have demonstrated that MSC-Exos can attenuate fibrosis, modulate macrophage polarization, suppress autoreactive lymphocyte activity, and even reverse pulmonary arterial hypertension in animal models of SSc. Compared to cell-based therapies, MSC-Exos offer several advantages, including lower immunogenicity and better safety profile. This review provides an overview of the immunomodulatory, antifibrotic, and angiogenic properties of MSC-Exos and explores their potential as novel cell-free therapy for SSc.

To evaluate the use of hydroxychloroquine (HCQ) and its impact on the Health Assessment Questionnaire disability index(HAQ-DI) and the Cochin Hand Function Status(CHFS) in a large Systemic Sclerosis (SSc) cohort. SSc patients from the European Scleroderma Trials and Research (EUSTAR) database treated with HCQ for at least 6 months were evaluated and compared to a matched group of SSc patients not using HCQ. Demographic and clinical data, concomitant drugs, HAQ-DI and CHFS (at least 2 evaluations) were recorded and were the outcome variables of interest. Statistical analysis was performed using propensity score matching for age, gender, disease duration, corticosteroids, immunosuppressives, vasoactive drugs in a 3:1 control: HCQ ratio. Standard descriptive statistics and Student’s t-test and Chi-square test were used to assess the propensity-matched groups. Out of 17,805 SSc patients evaluated, 468 (2.6%) used HCQ and constituted the HCQ group. Among them, 50 (10.7%) had at least a baseline and follow-up HAQ-DI evaluation and 44 (9.4%) had at least a baseline and follow-up CHFS evaluation. Propensity matching assured that patients were matched for female gender (HCQ vs. control 92.0% vs. 85.3%), mean age (49.8 vs. 50.0 years) disease duration (8.3 vs. 9.1 years), limited disease (55.3 vs. 62.6%) as well as background medications (all P > 0.1). We did not find any significant differences among the two groups in the change of HAQ-DI or CHFS, over up to 365 days (all P > 0.05). Results from the EUSTAR registry showed that HCQ was used by 2.6% of SSc patients. HCQ use did not improve the HAQ-DI, or CHFS when comparing HCQ users to non-HCQ users.

Synovitis–acne–pustulosis–hyperostosis–osteitis (SAPHO) syndrome is a rare disease characterized by a sterile inflammatory osteitis and/or arthritis associated with a wide range of dermatological manifestations, such as acne, palmoplantar pustulosis, and psoriasis. This review, providing up-to-date knowledge on this disease, aims at informing researchers and clinicians to help them program future studies in order to improve patients’ care. Due to the vast clinical heterogeneity that characterizes this disease, SAPHO syndrome has received various names; among these, chronic recurrent multifocal osteomyelitis represents the most used one. The various nomenclatures in use also reflect different approaches to its management. Indeed, considering the world-wide distribution and the vast onset age (from children to late adulthood), in addition to the multiform clinical presentation, its diagnosis and treatment are often challenging for clinicians. In this review, we provide valuable insights on SAPHO syndrome, delving into its many aspects: epidemiology, pathogenesis, clinical presentation, diagnosis, and classification. Most importantly, this paper addresses the continuously changing treatment panorama of this disease, from established drugs to newly introduced ones. Furthermore, a peculiar focus regards nonpharmacologic approaches, including traditional Chinese medicine, the apheresis technique, and surgery. Similarly, this review also discusses patients’ lifestyle, including quality of life. To improve SAPHO syndrome’s management, different knowledge gaps should be filled, such as its current epidemiology and pathogenesis. In turn, perfected knowledge in these fields could also advance research in therapy.

Objectives: In systemic sclerosis (SSc), gastrointestinal involvement is one of the earliest events. We compared the gut microbiota (GM), its short-chain fatty acids (SCFAs) and host-derived free fatty acids (FFAs) in patients with very early diagnosis of SSc (VEDOSS) and definite SSc. Methods: Stool samples of 26 patients with SSc, 18 patients with VEDOSS and 20 healthy controls (HC) were collected. The GM was assessed through 16S rRNA sequencing, while SCFAs and FFAs were assessed by gas chromatography-mass spectrometry. Results: In patients with VEDOSS, an increase in Bacteroidales and Oscillospirales orders and a decrease in Bacilli class, Blautia, Romboutsia, Streptococcus and Turicibacter genera was detected in comparison with HC. In patients with SSc, an elevated number of Acidaminococcaceae and Sutterellaceae families, along with a decrease of the Peptostreptococcaceae family and Anaerostipes, Blautia, Romboutsia and Turicibacter genera was found in comparison with HC. Patients with SSc and VEDOSS had a significantly lower butyrate and higher acetate with respect to HC. In VEDOSS, an increase in Oscillospiraceae family and Anaerostipes genus, and a decrease in Alphaproteobacteria class, and Lactobacillales order was identified with respect to SSc. Moreover, patients with VEDOSS exhibited higher acetate and lower valerate compared with definite SSc. Conclusion: A GM dysbiosis with depletion of beneficial anti-inflammatory bacteria (especially butyrate-producing) and a significant decrease in faecal butyrate was identified in patients with VEDOSS. This early GM imbalance may foster the growth of inflammatory microbes, worsening intestinal dysbiosis and inflammation in early SSc stages. The potential butyrate administration in early disease phases might be considered as a novel therapeutic approach to mitigate gastrointestinal discomfort and progression preserving patient’s quality of life.

Osteoarthritis (OA) is a chronic, progressive, degenerative joint disease characterized by joint pain, stiffness, and limited movement. It presents significant intra- and inter-individual variability—in particular, between genders. Recent research has increasingly focused on the role of adipokines—especially leptin, adiponectin, and resistin—in the development of OA. Adipokines, peptide hormones primarily secreted by adipose tissue, are involved in crucial physiological processes related to metabolism and immunity. They can also impact bone and cartilage turnover by interacting with joint cells such as osteoblasts, osteoclasts, chondrocytes, and mesenchymal stem cells, thereby linking inflammation with bone cartilage homeostasis. This review aims to elucidate the structure and functions of various adipokines, their serum and synovial levels, and their association with clinical presentation and radiographic progression in OA patients, with a focus on differences between sexes. A narrative literature review was conducted using three databases specifically analyzing sex differences. OA patients generally show elevated serum and synovial levels of leptin, chemerin, and visfatin, as well as high plasma levels of resistin and visfatin. In contrast, synovial levels of adiponectin and omentin are reduced in OA patients compared to healthy individuals, with an inverse relationship to disease severity, suggesting a potential protective role. Resistin and leptin were positively correlated with pain severity and radiographic progression, while adiponectin’s role in OA remains controversial. Regarding sex differences, male OA patients exhibited higher serum levels of leptin, chemerin, and omentin compared to healthy controls, with a positive correlation to the BMI and estrogen levels, potentially explaining the sexual dimorphism observed in this condition. Studies on visfatin and lipocalin did not reveal significant differences in synovial or serum levels between the sexes. The role of resistin remains controversial. Adipokines influence the joint microenvironment and contribute to the progression of osteoarthritis (OA). However, the precise biological mechanisms are not yet fully understood due to the complex interactions between the metabolic, mechanical, and immune systems. Further research is needed to clarify their roles in OA and to identify targeted therapies for managing this degenerative disease.

The gut microbiota is a complex ecosystem of microorganisms residing in the human gastrointestinal tract, playing a crucial role in various biological processes and overall health maintenance. Dysbiosis, an imbalance in the composition and function of the gut microbiota, is linked to systemic autoimmune diseases (SAD). Short-chain fatty acids (SCFAs), especially butyrate, produced by the gut microbiota through the fermentation of dietary fibers, play a significant role in immunomodulation and maintaining intestinal homeostasis. Butyrate is essential for colonocyte energy, anti-inflammatory responses, and maintaining intestinal barrier integrity. Studies show reduced butyrate-producing bacteria in SAD patients, suggesting that increasing butyrate levels could have therapeutic benefits. Butyrate’s anti-inflammatory effects and its potential therapeutic role have been studied in rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, systemic sclerosis, and Behçet’s disease. Despite promising in vitro and animal model results, human studies are limited, and the optimal strategies for modulating dysbiosis in SADs remain elusive. This review explores the current evidence on the immunoregulatory role of butyrate and its potential therapeutic effects in SAD.