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BackgroundThe EULAR recommendations for the treatment of systemic sclerosis (SSc) were updated in 2017, informed by a systematic literature review (SLR) completed in 2014.ObjectivesThe aim of this new SLR was to provide the most up-to-date literature to underpin contemporary EULAR recommendations for the management of SSc.Methods30 searches for 30 interventions (including several outcomes/clinical questions), and 1 dedicated search (with several interventions) for calcinosis were prioritised by the task force. Three types of questions were defined: type I questions, unchanged as compared with the previous recommendations; type II questions exploring interventions already mentioned in the previous recommendations but with new outcomes; type III questions for new interventions.Results14 490 abstracts were retrieved from the databases on 31 March 2022 and 2021 abstracts were retrieved on 11 October 2022. 483 new full texts were evaluated and 172 new articles were included for the first search and 9 for the second search. The majority of the questions covered by this SLR explored new interventions (40% of type III questions) or new outcomes (26% of type II questions). New interventions included targeted therapies such as abatacept, Janus kinase inhibitors or nintedanib, and updated questions incorporated the results from key game-changing randomised controlled trials including trials on tocilizumab, mycophenolate or rituximab in SSc-interstitial lung disease.ConclusionsThis SLR provides and summarises the highest level of evidence for the new EULAR recommendations for the treatment of SSc, providing an unprecedented comprehensive overview of recent knowledge on SSc treatments and participating in defining the future research agenda.

Oxidative stress linked to vascular damage plays an important role in the pathogenesis of systemic sclerosis (SSc). Indeed, vascular damage at nailfold capillaroscopy in patients with Raynaud’s Phenomenon (RP) is a major risk factor for the development of SSc together with the presence of specific autoantiobodies. Here, we investigated the effects of the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, currently used in the management of RP, in modulating the proinflammatory response of dermal fibroblasts to oxidative stress in vitro. Human fibroblasts isolated from SSc patients and healthy controls were exposed to exogenous reactive oxygen species (ROS) (100 µM H2O2), in the presence or absence of sildenafil (1 µM). Treatment with sildenafil significantly reduced dermal fibroblast gene expression and cellular release of IL-6, known to play a central role in the pathogenesis of tissue damage in SSc and IL-8, directly induced by ROS. This reduction was associated with suppression of STAT3-, ERK-, NF-κB-, and PKB/AKT-dependent pathways. Our findings support the notion that the employment of PDE5i in the management of RP may be explored for its efficacy in modulating the oxidative stress-induced proinflammatory activation of dermal fibroblasts in vivo and may ultimately aid in the prevention of tissue damage caused by SSc.

Background Skin is the largest organ in the body, representing an important interface to monitor health and disease. However, there is significant variation in skin properties for different ages, genders and body regions due to the differences in the structure and morphology of the skin tissues. This study aimed to evaluate the use of non‐invasive tools to discriminate a range of mechanical and functional skin parameters from different skin sites. Materials and methods A cohort of 15 healthy volunteers was recruited following appropriate informed consent. Four well‐established CE‐marked non‐invasive techniques were used to measure four anatomical regions: palm, forearm, sole and lower lumbar L3, using a repeated measures design. Skin parameters included trans‐epidermal water loss (TEWL), pH (acidity), erythema, stratum corneum hydration and stiffness and elasticity using Myoton Pro (skin and muscle probe). Differences between body locations for each parameter and the intra‐rater reliability between days were evaluated by the same operator. Results The results indicate that parameters differed significantly between skin sites. For the Myoton skin probe, the sole recorded the highest stiffness value of 1006 N/m (SD ± 179), while the lower lumbar recorded the least value of 484 N/m (SD ± 160). The muscle indenter Myoton probe revealed the palm's highest value of 754 N/m (± 108), and the lower lumbar recorded the least value of 208 N/m (SD ± 44). TEWL values were lowest on the forearm, averaging 11 g/m2/h, and highest on the palm, averaging 41 g/m2/h. Similar skin hydration levels were recorded in three of the four sites, with the main difference being observed in the sole averaging 13 arbitrary units. Erythema values were characterised by a high degree of inter‐subject variation, and no significant differences between sites or sides were observed. The Myoton Pro Skin showed excellent reliability (intra‐class correlation coefficients > 0.70) for all sites with exception of one site right lower back; the Myoton pro muscle probes showed good to poor reliability (0.90–017), the corneometer showed excellent reliability (>0.75) among all the sites tested, and the TEWL showed Good to poor reliability (0.74–0.4) among sites. Conclusion The study revealed that using non‐invasive methods, the biophysical properties of skin can be mapped, and significant differences in the mechanical and functional properties of skin were observed. These parameters were reliably recorded between days, providing a basis for their use in assessing and monitoring changes in the skin during health and disease.

Myofibroblasts are the key effector cells responsible for the exaggerated tissue fibrosis in Systemic Sclerosis (SSc). Despite their importance to SSc pathogenesis, the specific transcriptome of SSc myofibroblasts has not been described. The purpose of this study was to identify transcriptome differences between SSc myofibroblasts and non-myofibroblastic cells. Alpha smooth muscle actin (α-SMA) expressing myofibroblasts and α-SMA negative cells were isolated employing laser capture microdissection from dermal cell cultures from four patients with diffuse SSc of recent onset. Total mRNA was extracted from both cell populations, amplified and analyzed employing microarrays. Results for specific genes were validated by Western blots and by immunohistochemistry. Transcriptome analysis revealed 97 differentially expressed transcripts in SSc myofibroblasts compared with non-myofibroblasts. Annotation clustering of the SSc myofibroblast-specific transcripts failed to show a TGF-β signature. The most represented transcripts corresponded to several different genes from the Neuroblastoma Breakpoint Family (NBPF) of genes. NBPF genes are highly expanded in humans but are not present in murine or rat genomes. In vitro studies employing cultured SSc dermal fibroblasts and immunohistochemistry of affected SSc skin confirmed increased NBPF expression in SSc. These results indicate that SSc myofibroblasts represent a unique cell lineage expressing a specific transcriptome that includes very high levels of transcripts corresponding to numerous NBPF genes. Elevated expression of NBPF genes in SSc myofibroblasts suggests that NBPF gene products may play a role in SSc pathogenesis and may represent a novel therapeutic target.

Systemic sclerosis (SSc) is characterized by microangiopathy with impaired reparative angiogenesis and fibrosis. Epidermal Growth Factor Like-domain 7 (EGFL7), firstly described in endothelial cells plays a pivotal role in angiogenesis. Fibroblasts (FBs) are involved in vascular remodeling, under physiological and pathological conditions. In this study, we investigated: (i) the expression of EGFL7 and its miR-126 in patients affected by diffuse cutaneous SSc (dcSSc); (ii) the ability of Transforming Growth Factor-beta (TGF-β) to modulate EGFL7 expression; (iii) the ability of EGFL7 to modulate COL1A1 expression and proliferation/migration, and (iv) the functional role of EGFL7 on angiogenesis. Patients were divided in 2 subsets: patients fulfilling the classification criteria in less than one year from Raynaud’s Phenomenon onset (Early Onset Subset–EOS), and all the others (Long Standing Subset–LSS). We show that EGFL7 expression is increased in EOS dcSSc skin and cultured FBs. EGFL7 is inducible by TGF-β on Healthy Controls (HC) FBs but not in SSc-FBs. EGFL7 decreases COL1A1 expression in EOS SSc-FBs while EGFL7 silencing up-regulates COL1A1 expression. EGFL7 promotes migration/invasion of EOS SSc-FBs but not proliferation. Finally, SSc-FBs, partially inhibit angiogenesis in organotypic coculture assays, and this is reversed by treatment with human recombinant (rh)EGFL7. We conclude that EGFL7 and its specific microRNA miR-126 may be involved in the pathogenesis of SSc vasculopathy and fibrosis.

: 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. : A narrative literature review was conducted through a systematic PubMed search up to September 2025, complemented by manual reference screening. : 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. : 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.

Oxidative stress plays a key role in systemic sclerosis (SSc) pathogenesis, and an altered redox homeostasis might be responsible for abnormal inflammatory status, fibrosis and tissue damage extension. In this study, we explored the effect of the phosphodiesterase type 5 inhibitor sildenafil in modulating the activation of the CXCL-9, -10, -11/CXCR3 axis, which is fundamental in the perpetuation of inflammation in different autoimmune diseases, in the cell culture of SSc human dermal fibroblasts exposed to a pro-oxidant environment. We observed that sildenafil significantly reduced gene expression and release of CXCL-9, -10 and -11, inhibited the CXCR3 action and suppressed the activation of STAT1-, JNK- and p38MAPK pathways. This in vitro study on dermal fibroblasts supports clinical studies to consider the efficacy of sildenafil in preventing tissue damage and fibrosis in SSc by targeting central biomarkers of disease progression, vascular injuries and fibrosis and reducing the pro-inflammatory activation induced by oxidative stress.

ContextThe very early diagnosis of systemic sclerosis (VEDOSS) criteria were developed to diagnose systemic sclerosis (SSc) at a very early stage. However, several studies have applied these criteria inconsistently, often using them to identify patients at a predisease stage. This use has created confusion between the concept of VEDOSS and pre-SSc. With growing interest in predisease states in autoimmunity, a consensus definition of pre-SSc is mandatory.ObjectiveAs a preliminary step towards such definition, this scoping review aimed to map existing definitions of pre-SSc and VEDOSS in the literature, identify item combinations used and capture conceptual variations.MethodsFollowing Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines, PubMed and Web of Science were searched using the terms ‘VEDOSS’ OR ‘very early diagnosis of systemic sclerosis’ OR ‘pre-scleroderma’ OR ‘pre-systemic sclerosis’ OR ‘pre-SSc’.ResultsOf 106 records screened, 40 full texts were included (eight on pre-SSc and 32 on VEDOSS). Most articles (80%) originated from Europe. Three distinct definitions of pre-SSc were identified, alongside 13 different applications of VEDOSS criteria. Although 62.5% of studies cited the 2011 VEDOSS consensus, only 31.3% applied the complete definition incorporating the three step 1 essential items and step 2 confirmation tools.ConclusionThis scoping review highlights the variability of the definitions of VEDOSS and pre-SSc that have been used in the literature. The absence of a consensus definition for pre-SSc contributes to overlapping and blurring boundaries between these concepts. A consensus effort is warranted to select a core set of items for a standardised definition of pre-SSc.

Systemic sclerosis (SSc), or scleroderma, is a rare, complex, systemic autoimmune disease of unknown aetiology, characterized by high morbidity and mortality often resulting from cardiopulmonary complications such as interstitial lung disease and pulmonary arterial hypertension. Despite substantial progress in unravelling the pathways involved in the pathogenesis of SSc and the increasing number of therapeutic targets tested in clinical trials, there is still no cure for this disease, although several proposed treatments might limit the involvement of specific organs, thereby slowing the natural history of the disease. A specific focus of recent research has been to address the plethora of unmet needs regarding the global management of SSc-related interstitial lung disease, including its pathogenesis, early diagnosis, risk stratification of patients, appropriate treatment regimens and monitoring of treatment response, as well as the definition of progression and predictors of progression and mortality. More refined stratification of patients on the basis of clinical features, molecular signatures, identification of subpopulations with distinct clinical trajectories and implementation of outcome measures for future clinical trials could also improve therapeutic management strategies, helping to avoid poor outcomes related to lung involvement.Interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) is associated with considerable morbidity and mortality. In this Review, various unmet needs in the management of SSc–ILD are discussed, and solutions are proposed to help improve outcomes for these patients.

ObjectiveTo determine the distribution of the EULAR SSc Impact of Disease (ScleroID) and its domain questions in very early (Ve), limited (lc) and diffuse cutaneous (dc) subsets, its value in reflecting clinical severity, and to assess its sensitivity to change and minimal clinically important difference (MCID) in a 12-month interval.MethodsPatients with ScleroID questionnaires from the observational cohort STRIKE were included in the study. Changes (Δ) were calculated as the difference between 12-month follow-up and compared MCIDs of the other measures.ResultsData were available for 271 patients, 69 with Ve, 139 lc and 63 dc systemic sclerosis (SSc). Median (IQR) ScleroID scores were progressively higher in the 3 subsets with 2.1 (3.6) for VeSSc, 3.4 (4.4) for lcSSc and 4.7 (4) for dcSSc (p<0.001). ScleroID showed strong content validity against clinical measures. Patients with high disease activity had significantly higher ScleroID scores than low ones (p=0.003). Presence of digital ulcers, pulmonary disease or small intestinal bacterial overgrowth was all reflected in higher scores in their relative domains (p<0.005 for all). Accordingly, ScleroID scores and its relative domains showed high correlations with all other patient-reported outcomes (PROs) (p<0.05). Changes in ScleroID strongly correlated with changes in clinical measures and other PROs with specific thresholds identified for MCID changes in Health Assessment Questionnaire Disability Index, the University of California Los Angeles Scleroderma Clinical Trials Consortium gastrointestinal tract 2.0 and Cochin Hand Function Scale.ConclusionScleroID demonstrates strong correlation with validated clinical measures and responsiveness to changes in standard of care, supporting its use in both clinical practice and trials. ScleroID captures the multidimensional burden of SSc regardless of disease subsets.