Systemic sclerosis (SSc) is a rare systemic autoimmune rheumatic disease frequently associated with gastrointestinal (GI) involvement. GI manifestations are heterogeneous, may occur throughout the entire tract from the very early stages of the disease and are often associated with a significant burden of symptoms and complications, leading to high morbidity and mortality. Diagnosis often remains challenging due to the lack of sensitive instruments for early detection and the reliance on invasive or expensive diagnostic tools. In recent years, ultrasound (US) has become an increasingly important tool for GI evaluation across a wide range of conditions, including chronic inflammatory bowel diseases, appendicitis and diverticulitis as well as rarer diseases and functional conditions. The aim of this scoping review is to provide an updated overview of the role of gastrointestinal ultrasound (GIUS) in the assessment and monitoring of GI involvement in SSc. A systematic search of MEDLINE and Scopus identified 25 eligible studies. The available evidence is unevenly distributed across the GI tract: thirteen studies addressed the upper GI tract, seven the anorectum, six the gallbladder and five the mesenteric vessels. For each segment, we summarize how US can detect changes in wall structure, vascularization and motility. The evidence base is limited by small, predominantly single-center and cross-sectional studies, heterogeneous acquisition protocols and reference standards and a scarcity of reproducibility data. Further prospective and multicenter studies are therefore needed to validate the role of GIUS, standardize protocols and establish its integration into the clinical management of SSc patients.

A prompt and accurate diagnosis is essential because the management of thrombotic microangiopathy (TMA) depends on its underlying etiology. We report a case of diffuse cutaneous systemic sclerosis (dcSSc) in which scleroderma renal crisis-associated TMA preceded the development of overt skin sclerosis. A 53-year-old woman presented with TMA and severe renal dysfunction. She tested positive for anti-RNA polymerase III antibodies and subsequently developed skin sclerosis, leading to a diagnosis of dcSSc. Angiotensin-converting enzyme inhibitor therapy resulted in a clinical improvement in the patient. Therefore, systemic sclerosis should be considered in the differential diagnosis of TMA, even in the absence of skin manifestations at presentation.

Gastrointestinal (GI) involvement is among the most common and clinically important manifestations of systemic sclerosis (SSc), affecting up to 90% of patients and substantially contributing to morbidity and reduced quality of life. SSc-related GI disease results from microvascular injury, enteric nervous system dysfunction, and progressive smooth muscle atrophy with fibrosis, producing widespread dysmotility throughout the gastrointestinal tract. Clinical involvement can extend from the oral cavity to the anorectum, with esophageal dysfunction, gastroesophageal reflux disease (GERD), gastroparesis, small intestinal bacterial overgrowth (SIBO), and intestinal pseudo-obstruction among the major manifestations. Recent diagnostic advances, including high-resolution esophageal manometry (HRM), ambulatory pH-impedance monitoring, and improved imaging, have strengthened early detection and characterization of GI involvement. Treatment remains largely supportive and symptom-directed, including acid suppression, prokinetic therapy, nutritional optimization, and endoscopic or surgical management of complications. Growing evidence on the gut microbiome, immune-mediated mechanisms, and the gut-brain axis is expanding understanding of disease pathophysiology and may guide future targeted therapies. This review synthesizes current evidence on the epidemiology, pathophysiology, clinical manifestations, and management of gastrointestinal involvement in systemic sclerosis, emphasizing early recognition and multidisciplinary care. We conclude by outlining persistent management challenges and future directions to improve diagnostic precision, therapeutic development, and patient-centered outcomes.

Mitochondrial dysfunction drives scleroderma pathogenesis. The mitochondria-associated endoplasmic reticulum membrane (MAM) regulates mitochondrial function. Parthenolide (PTL) has protective effects on mitochondria. However, its specific role and mechanisms in localized scleroderma (LoS) remain unclear. This study investigates whether PTL reduces senescence and skin fibrosis by stabilizing MAM in LoS and examines the protective effects of a synthesized thermosensitive controlled-release hydrogel (F127@PLGA@PTL) against LoS. We employed transmission electron microscopy (TEM) to observe MAM abnormalities in LoS skin lesions. Other multiple molecular biology experiments were conducted to investigate how PTL protects against LoS in TGF-β-induced human dermal fibroblasts (HDFs) and a murine model of LoS. RNA sequencing, molecular docking-based inverse virtual screening, and surface plasmon resonance (SPR) were used to find possible targets of PTL. Emulsification-volatilization was used to prepare the PTL-loaded PLGA nanoparticles. MAM's calcium ion transport function is enhanced, and its quantity increases in LoS. PTL can ameliorate senescence and fibrosis in TGF-β-induced HDF cells and the bleomycin-induced LoS model by regulating the IP3R1/Grp75/VDAC1 complex and repairing mitochondrial damage. Notably, mechanistically, this protective effect was mediated through Ero1L suppression, with ARG-449 identified as the critical residue for PTL-Ero1L binding. Ero1L overexpression reversed the protective effects of PTL. Additionally, Ero1L knockdown also exhibits anti-senescence and antifibrotic effects on TGF-β-induced HDFs. Furthermore, F127@PLGA@PTL demonstrates excellent sustained-release properties and significant therapeutic efficacy in the mouse model of LoS. The study demonstrates that PTL alleviates fibrosis of LoS by regulating Ero1L-mediated MAM stabilization.

Antiphospholipid syndrome (APS) and systemic sclerosis (SSc) are distinct autoimmune diseases, but both are characterized by immune dysregulation, persistent inflammation, and vascular injury. To explore whether they also share blood transcriptional features, we analyzed peripheral blood datasets from GEO (GSE102215, APS: nine patients/nine controls; GSE231691, SSc: 49 patients/18 controls). Differential expression analysis performed separately in each cohort using edgeR with cohort-specific fold-change thresholds and nominal p < 0.05 identified 281 genes that were altered in the same direction in both diseases, including 100 upregulated and 181 downregulated genes. Enrichment analyses in both cohorts consistently pointed to interferon-related, cytokine, and inflammatory pathways. We then combined random forest and a single-hidden-layer artificial neural network as exploratory feature-prioritization approaches and identified five shared candidate genes: S100A8, IER5L-AS1, LTK, PRR5-ARHGAP8, and PCDH1. All five genes showed significant case-control expression differences in both datasets (p < 0.001). Given the small APS cohort, the machine-learning analyses were considered exploratory and were not interpreted as evidence of validated diagnostic performance. CIBERSORT suggested that both diseases have a blood immune profile enriched for myeloid signals, particularly neutrophils and monocyte/macrophage populations, whereas SSc showed relatively stronger CD4+ T-cell and NK-cell signals. S100A8 expression was positively correlated with inferred neutrophil abundance in both datasets (APS r = 0.62; SSc r = 0.58; p < 0.05). Finally, miRNA prediction and DSigDB enrichment pointed to possible upstream regulators and candidate compounds, including miR-155, miR-146a, celecoxib, tamibarotene, HMN-176, and XMD14-99. These findings represent concordant signals observed across two parallel disease cohorts rather than independent cross-disease validation and therefore require confirmation in independent cohorts.

To describe real-world management of connective tissue disease-associated interstitial lung disease (CTD-ILD) and explore associations between progressive pulmonary fibrosis (PPF) onset and clinical outcomes. This international, retrospective cohort included adults with rheumatoid arthritis (RA), systemic sclerosis (SSc), mixed connective tissue disease, and other CTD with associated ILD. PPF was identified using INBUILD and/or ATS/ERS/JRS/ALAT criteria applied in routine care. Analyses were descriptive and exploratory; time-to-event methods assessed selected outcomes and factors associated with PPF onset. Among 357 patients (mean age 61.6 years; 58% female), SSc-ILD (31%) and RA-ILD (29%) were most common. At ILD diagnosis, 21.6% had no respiratory symptoms. During a mean follow-up of 60.5 months, 147 patients (41.2%) met the PPF criteria, at a median of 30.6 months after CTD-ILD diagnosis. Following PPF onset, the most frequently prescribed therapies were corticosteroids (72.8%), mycophenolate mofetil (52.4%), and antifibrotics (51.0%). Lung function data were available for 37.8% at diagnosis and 53.7% at year 5. PPF was associated with greater observed lung function decline compared to non-PPF patients. ILD-related hospitalizations was numerically more frequent within PPF patients (37.4% vs. 28.6%), but the difference was not statistically significant (P = 0.078). Among patients with PPF, earlier versus later onset, defined by a subtype-specific median split, was associated with poorer observed survival (P < 0.001). In this retrospective cohort, PPF was observed frequently in CTD-ILD patients, particularly those with SSc-ILD, and was associated with greater lung function decline and higher healthcare utilisation. Earlier PPF onset was associated with higher mortality risk, but missing lung function data, surveillance differences, time-related bias, and residual confounding limit causal interpretation. Prospective studies using harmonised PPF adjudication and time-dependent analyses are needed.

Tumoral calcinosis (TC) is a rare disorder characterized by periarticular ectopic calcium deposition, with spinal involvement being exceptionally uncommon. We report a rare case of facet-destructive cervical TC causing progressive cervical myelopathy in a patient with diffuse systemic sclerosis and review the current literature on its pathogenesis, diagnosis, and management. A 51-year-old woman with diffuse systemic sclerosis presented with progressive neck pain, worsening cervical kyphosis, and cervical myelopathy. Computed tomography and magnetic resonance imaging demonstrated multilobulated calcific masses involving the posterior elements and facet joints from C3 to C6, resulting in severe cervical canal stenosis. She underwent C3-6 decompressive laminectomy with posterior instrumented fusion. Intraoperatively, the lesions had extensively replaced the bilateral lateral masses and posterior elements from C3 to C5 and were densely adherent to the dura, precluding complete excision. Adequate decompression was achieved through careful internal debulking and lateral release of the calcified masses, with intraoperative ultrasonography confirming satisfactory decompression. Postoperatively, her neck pain resolved and neurological function improved progressively; independent ambulation was regained by six months. Although rare, spinal TC should be considered in the differential diagnosis of calcified spinal lesions, particularly in patients with connective tissue disease. Surgical decompression with stabilization remains the treatment of choice for patients presenting with neurological compromise.

Background/Objectives: Reduced hand function significantly contributes to disability in patients with systemic sclerosis (SSc). We aimed to evaluate the effects on hand function and quality of life of a multicomponent hand rehabilitation program in patients with longstanding SSc. Methods: This prospective, controlled, interventional pilot study enrolled adults with SSc, disease duration >5 years and ≥1 upper limb joint contracture. The intervention consisted of 10 sessions over 5 weeks, including paraffin wax therapy and individualized hand rehabilitation. The allocation to the intervention or control group was based on the patients' availability to participate in the program. Hand mobility/function and health-related quality of life were assessed through validated outcome measures at baseline and after 5 weeks. Results: Sixteen patients were included (intervention N = 10; control N = 6), with a median disease duration of 19.5 (15.3-24.3) years. Within the intervention group, significant improvements were observed in right-hand Hand Mobility in Scleroderma (HAMIS) score (p = 0.033) and in the Short Form (SF)-36 domains of "Energy/fatigue" (p = 0.008), "Emotional well-being" (p = 0.009), "Pain" (p = 0.020), and "General health" (p = 0.050). Compared with controls, significant benefit was observed in the SF-36 "Energy/fatigue" (p = 0.002; d = 1.97) and "General health" (p = 0.011; d = 1.50) domains. Between-group differences in hand function measures did not reach statistical significance, although moderate-to-large effect sizes favored rehabilitation across several outcomes. Conclusions: In this pilot study, a multicomponent hand rehabilitation program was associated with improvements in quality of life in patients with longstanding SSc, despite limited effects on hand mobility. These preliminary findings suggest a potential benefit of hand rehabilitation even in advanced disease.

Radiation-induced morphea (RIM) is a rare, immune-mediated late complication of breast radiotherapy that may clinically mimic radiation fibrosis, malignancy, or other inflammatory dermatoses. Diagnosis is particularly challenging in patients with pre-existing cutaneous T-cell lymphoma (CTCL), in whom new post-radiation skin lesions may raise concern for lymphoma involvement or progression. To the best of our knowledge, based on a non-systematic search of the available literature, this is the first reported case of radiation-induced morphea occurring in a patient with pre-existing mycosis fungoides (MF). A 55-year-old woman with a history of MF and right breast invasive lobular carcinoma underwent bilateral mastectomy followed by adjuvant chest wall radiotherapy. Approximately 6.5 years later, she developed a progressive erythematous, indurated plaque within the irradiated field. Given her history of MF, cutaneous lymphoma involvement and radiation-associated sarcoma were important diagnostic considerations. Punch biopsy demonstrated dermal collagen homogenization with a mixed inflammatory infiltrate, while immunohistochemistry showed preserved pan-T-cell antigen expression without an aberrant phenotype, supporting RIM rather than lymphoma. The patient was treated with topical corticosteroids followed by methotrexate, with mild-to-moderate improvement in erythema without complete resolution; subsequent reconstructive revision was followed by further improvement in erythema, breast softness, and cosmesis. This case highlights the diagnostic overlap between RIM and CTCL and underscores the importance of prompt biopsy and careful clinicopathological correlation in evaluating persistent or atypical post-radiation skin changes.

Background: Autoantibodies are central to the diagnosis and risk stratification of systemic sclerosis (SSc), but their prevalence and clinical associations may vary across populations. This study aimed to evaluate the prevalence and immuno-clinical associations of different autoantibodies in the Rheumatic Diseases Portuguese Register systemic sclerosis cohort. Methods: This was a multicentre observational registry-based study that used data from the Reuma.pt SSc module. Patients were divided according to autoantibody status, and associations between autoantibody expression and clinical data were assessed using appropriate statistical tests, with Bonferroni correction applied for multiple comparisons. Multivariable binary logistic regression was performed for clinically relevant outcomes, with adjustment for sex, age at diagnosis and disease duration. Results: A total of 1080 patients were included, 87.5% female, with a mean age at last evaluation of 60.2 ± 14.6 years and a mean disease duration of 12.4 ± 10.0 years. Limited cutaneous SSc was the most frequent clinical category (57.4%), followed by diffuse cutaneous SSc (17.7%), very early diagnosis of systemic sclerosis (VEDOSS; 12.3%), overlap syndromes (9.8%) and SSc sine scleroderma (2.8%). Antinuclear antibodies were present in 93.4% of patients. Anti-centromere antibodies (ACAs) were the most frequent SSc-specific autoantibodies (54.6%), followed by topoisomerase I antibodies (ATAs; 21.8%). ACA positivity was associated with limited cutaneous disease; older age at diagnosis; and lower frequency of interstitial lung disease (ILD), myositis and flexion contractures. ATA positivity was associated with diffuse cutaneous disease, male sex, higher modified Rodnan skin score (mRSS), digital ulcers, flexion contractures, oesophageal involvement and ILD. Among less frequent autoantibodies, anti-Pm/Scl antibodies were associated with myositis, joint involvement, calcinosis and ILD; anti-U1RNP antibodies with younger age, MCTD overlap, myositis and joint involvement; anti-RNA polymerase III antibodies (ARAs) with scleroderma renal crisis and higher mRSS; anti-U3RNP antibodies with diffuse cutaneous disease and renal involvement; and anti-Ku antibodies with overlap syndromes. Conclusions: In this large real-world SSc cohort, autoantibody status was strongly associated with distinct clinical phenotypes, confirming its value for disease stratification. While most established immuno-clinical associations were reproduced, some differences from international cohorts were observed, supporting the need for population-specific validation of autoantibody associations in SSc.

We previously demonstrated that patients with scleroderma or systemic sclerosis (SSc) have elevated autoreactive transitional B cells, including against topoisomerase I (anti-topoisomerase I autoantibody [ATA[+]]). This suggests that defective transitional B cell tolerance could drive autoimmunity in SSc. To investigate this, we used single-cell transcriptomic and B cell receptor (BCR) sequencing on sorted transitional B cells from treatment-naive SSc patients and healthy controls (HCs). Four transitional B cell clusters were identified as T1, T2, CD27[+], and marginal zone precursors (MZPs). T1 B cells were significantly expanded in SSc with a 2-fold increase compared with HCs. Additionally, pro-survival genes (IL4R, TCL1A, and S100A10) and IFN-responsive genes (IFITM1 and IFITM2) were upregulated in SSc. BCR analysis revealed increased complementarity determining region 3 (CDR3) hydrophobicity and altered κ/λ ratios with proximal Jκ gene usage in the SSc patients. Collectively, our findings support divergent transitional B cell development and activation in SSc with an AKT-driven pathway likely promoting autoreactive transitional B cell survival.

Systemic sclerosis (SSc) frequently causes visible changes in physical appearance that may adversely affect body image and quality of life. Although dermocosmetic and aesthetic procedures are increasingly used to improve appearance and function in selected patients with SSc, little is known about patients' knowledge, attitudes, and expectations regarding these interventions. This study aimed to evaluate patients' attitudes toward dermocosmetic and aesthetic procedures using a purpose-designed questionnaire. In this cross-sectional study, 70 patients fulfilling the 2013 ACR/EULAR classification criteria for SSc completed a purpose-designed questionnaire. Demographic data were obtained from the questionnaire, while clinical characteristics were verified using medical records. The questionnaire evaluated knowledge, attitudes, previous experiences, future intentions, appearance-related concerns, perceived effects on self-confidence, willingness to consult a rheumatologist before aesthetic procedures, and preferred anatomical sites for potential interventions. The mean age was 54.6 ± 13.3 years, 90.0% were female, and 55.7% had diffuse cutaneous SSc. Disease-related changes in physical appearance were reported by 70.0% of participants, and 41.4% expressed discomfort with these changes. Nearly half (47.1%) reported no knowledge of any dermocosmetic procedure, and 85.7% had not previously undergone a dermocosmetic/medical aesthetic procedure. Nevertheless, 61.4% expressed positive attitudes toward dermocosmetic procedures, and 64.3% believed that these procedures could improve self-confidence. Nearly all participants (97.2%) stated that they would consult their rheumatologist before undergoing a dermocosmetic or aesthetic procedure. After false discovery rate (FDR) correction, diffuse cutaneous SSc remained associated with greater appearance-related discomfort than limited disease (53.8% vs. 25.8%; FDR-adjusted p = 0.032). Participants with at least a high school education more frequently expressed positive attitudes (83.9% vs. 43.6%; FDR-adjusted p = 0.014) and reported plans for future dermocosmetic/medical aesthetic (45.2% vs. 20.5%; FDR-adjusted p = 0.038) and surgical aesthetic procedures (22.6% vs. 2.6%; FDR-adjusted p = 0.032). In multivariable logistic regression adjusted for age and SSc subtype, higher education remained independently associated with a positive attitude (adjusted OR 6.43, 95% CI 1.73-23.91, p = 0.006). Appearance-related concerns are common among patients with SSc and represent an important yet often overlooked aspect of patient care. Despite limited knowledge, patients generally expressed favorable attitudes toward dermocosmetic and aesthetic procedures and strongly preferred consulting their rheumatologists before considering such interventions. These findings support the integration of appearance-related counselling into routine, patient-centered rheumatology care.