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ObjectivesSystemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases.MethodsWe performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes.ResultsWe identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10−10 and 6.6×10−10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell.ConclusionsGSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

To describe various demographic, clinical, laboratory, and capillaroscopic features of Egyptian patients with systemic sclerosis (SSc) and to explore the relation between various capillaroscopic features and internal organ involvement as well as other disease parameters. In this cross-sectional multi-centric prospective analysis, two hundred twenty-two adult patients with SSc were recruited. Data regarding general and rheumatological examination including the modified Rodnan skin score (MRSS), internal organ involvement and related imaging and laboratory investigations were collected. Both activity and severity indices were measured. Nail fold capillary microscopy (NFC) was performed for 144 patients. Out of 222 patients; 139 (62.6%) had limited type while 83 (37.4%) had diffuse type, middle aged females were predominant (91%). Peripheral vascular, pulmonary, gastrointestinal and general manifestations were the most frequently documented affection with high activity, severity profiles and bad prognostic features in more than half of the patients. MRSS was above 20 in 122 patients (55%), and 126 patients (56.8%) had pulmonary hypertension (SPAP) while 78.4% had ILD which showed a weak correlation to age and disease duration (r = 0.135, r = − 0.152 respectively). Significant weak correlations were found between disease duration and SPAP (r = 0.134), Medseger’s severity score (r = 0.189), peripheral vascular, skin, and GIT affection severity (r = 0.210, 0.135, and 0.196 respectively). Significant difference was observed between different NFC patterns and antibodies, severity scale, some disease manifestations i.e.: general, gastrointestinal, myopathy, and digital ulceration while no significance was found between NFC patterns and the type of SSc. This study provided a comprehensive clinical and laboratory characterization of a large cohort of Egyptian patients with SSc which reflects a more severe disease with unfavorable prognostic aspects compared to the available world-wide reports. Nail fold capillaroscopy showed many associations to different aspects of the disease especially in late and active capillaroscopic features, if introduced early, it may improve the disease outcome.

Idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) differ in the predominant demographics and identified genetic risk alleles of effected patients, however both diseases frequently progress to respiratory failure and death. Contrasting advanced SSc-ILD to IPF provides insight to the role dysregulated immunity may play in pulmonary fibrosis. To analyze cell-type specific transcriptome commonalities and differences between IPF and SSc-ILD, we compared single-cell RNA-sequencing (scRNA-seq) of 21 explanted lung tissue specimens from patients with advanced IPF, SSc-ILD, and organ donor controls. Comparison of IPF and SSc-ILD tissue identified divergent patterns of interferon signaling, with interferon-gamma signaling upregulated in the SPP1 hi and FABP4 hi macrophages, cytotoxic T cells, and natural kill cells of IPF, while type I interferon signaling and production was upregulated in the corresponding SSc-ILD populations. Plasmacytoid dendritic cells were found in diseased lungs only, and exhibited upregulated cellular stress pathways in SSc-ILD compared to IPF. Alveolar type I cells were dramatically decreased in both IPF and SSc-ILD, with a distinct transcriptome signature separating these cells by disease. KRT5 - /KRT17 + aberrant basaloid cells exhibiting markers of cellular senescence and epithelial-mesenchymal transition were identified in SSc-ILD for the first time. In summary, our study utilizes the enriched capabilities of scRNA-seq to identify key divergent cell types and pathways between IPF and SSc-ILD, providing new insights into the shared and distinct mechanisms between idiopathic and autoimmune interstitial lung diseases.

Background Early diffuse cutaneous systemic sclerosis (dcSSc) has the highest case fatality among rheumatic diseases. We report baseline characteristics, current immunosuppressive therapies, progression of skin and internal organ involvement, and mortality in a multicenter prospective cohort from the United States (US) of America. Methods We performed a longitudinal analysis of participants from 12 US centers, from April 2012 to July 2020. All participants had early dcSSc or were at-risk for dcSSc, with ≤2 years since the first non-Raynaud’s phenomenon (RP) symptom. Results Three hundred one patients were included with a baseline median disease duration of 1.2 years since RP and a mean modified skin score of 21.1 units. At baseline, 263 (87.3%) had definite dcSSc and 38 (12.7%) were classified as at-risk; 112 (49.6%) patients were positive for anti-RNA polymerase III antibodies. The median follow-up duration was 24.5 months (IQR = 10.3–40.7 months). One hundred ninety (63.1%) participants were treated with an immunosuppressive therapy, of which mycophenolate mofetil was most used at baseline and follow-up. Of 38 who were classified as at-risk at baseline, 27 (71%) went on to develop dcSSc; these patients were characterized by higher baseline mean HAQ-DI (0.8 versus 0.4, p = 0.05) and higher baseline mRSS (8.8 versus 4.4, p < 0.01) in comparison with those who remained as limited cutaneous SSc. In the overall cohort, 48 participants (21.1%) had clinically significant worsening of skin fibrosis, mainly occurring in the first year of follow-up; 41 (23.3%) had an absolute forced vital capacity decline of ≥10%. Twenty participants (6.6%) died, of which 18 died in the first 3 years of follow-up. Cardiac involvement (33.3%), gastrointestinal dysmotility (22.2%), and progressive interstitial lung disease (ILD) (16.7%) were the main causes of death. Conclusion This US cohort highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement.

ObjectivesTo determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc).MethodsWe evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression.ResultsOf 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09).ConclusionsProgressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice.

Background Skin fibrosis is a cardinal manifestation of systemic sclerosis (SSc) and is routinely measured by modified Rodnan skin score (mRSS), which is however limited by its operator-dependence and may not reflect the complex disease biology at the cutaneous compartment. A recent high dimensional multi-omic analysis identified 3 serum proteins independently associated with mRSS: tenascin C (TENC), cartilage oligomeric matrix protein (COMP), and collagen type IV alpha 1 (COL4A1). The aim of our study was to evaluate the relationship between these analytes as cross-sectional and dynamic biomarkers for skin involvement, as well as to capture potential correlations with type of immunosuppressive treatment. Methods We selected 21 patients from 2 Dutch centres who participated in the Autologous Stem Cell Transplantation International Scleroderma trial - a phase 3, multicentre, randomized study comparing autologous stem cell transplantation (HSCT) to cyclophosphamide (CYC) in diffuse cutaneous (dc)SSc. Serum concentrations of the three analytes were measured with ELISAs at baseline, 12 and 24 months. We employed linear mixed-effects models to assess cross-sectional correlation between mRSS, analyte concentrations and time. A multivariable linear regression model (independent of time) was used to formulate a composite biomarker score to predict mRSS. Results There were 11 patients in the CYC arm, and 10 to the HSCT arm. Serum concentrations of COMP and COL4A1, but not TENC, showed significant correlation with mRSS at the mixed model; COL4A1 correlation with mRSS remained significant at multivariable analysis (β = 0.01, p  = 0.001). We derived a composite biomarker formula score to predict mRSS with good performance at Bland Altman plot. As dynamic biomarkers, only changes in concentrations of COMP were associated with mRSS change ( r  = 0.013; p  = 0.012). It is notable that there was greater reduction in COL4A1 concentration at 24 months in the HSCT group compared with CYC (-81 ng/mL vs. -27.4 ng/mL in CYC group; p  = 0.029). Conclusion Our composite biomarker score showed a moderate cross-sectional correlation with mRSS and potentially complement mRSS in the assessment of skin activity. The differential variations for serum COL4A1 across treatment groups warrant further evaluation as a predictive marker of immunotherapeutic response in dcSSc.

Systemic sclerosis (SSc) is rare, severe connective tissue disease characterized by endothelial and vascular damage, immune activation, and resulting in inflammation and fibrosis of skin and internal organs, including the heart. SSc is associated with high morbidity and mortality. Cardiac involvement is frequent in SSc patients, even though often asymptomatic at early stages, and represents one of the major causes of SSc-related mortality. Heart involvement has a variable clinical presentation, and its pathogenesis is not completely understood. Myocardial fibrosis is traditionally considered the immunopathologic hallmark of heart involvement in SSc. This unique histological feature is paralleled by distinctive clinical and prognostic features. The so-called “vascular hypothesis” represents the most credited hypothesis to explain myocardial fibrosis. More recently, the prominent role of an inflammatory myocardial process has been identified as a cardinal event in the evolution to fibrosis, thus also delineating an “inflammation-driven pathway to fibrosis”. The pro-inflammatory cytokine interleukin (IL)-1 has an apical and cardinal role in the myocardial inflammatory cascade and in cardiac dysfunction. The primary aim of this perspective article is: to present the emerging evidence on the role of IL-1 and inflammasome in both SSc and heart inflammation, to review the complex interplay between cellular metabolism and inflammasome activation, and to discuss the rationale for targeted inhibition of IL-1 for the treatment of SSc-heart involvement, providing preliminary experimental and clinical data to support this hypothesis.

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder, characterized by multisystem involvement, vasculopathy, and fibrosis. An increased risk of malignancy is observed in SSc (including breast and lung cancers), and in a subgroup of patients with specific autoantibodies (i.e., anti-RNA polymerase III and related autoantibodies), SSc could be a paraneoplastic syndrome and might be directly related to an immune response against cancer. Herein, we reviewed the literature, focusing on the most recent articles, and shed light onto the potential relationship between cancer and scleroderma regarding temporal and immunological dimensions.

Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common complication of SSc and a major contributor to SSc-related deaths. Besides nintedanib and tocilizumab, there are currently no clinically approved drugs for SSc-ILD, highlighting the urgent need for new treatment strategies. Previous studies have shown that cyclic adenosine monophosphate (cAMP) plays a crucial role in the pathogenesis of SSc and lung fibrosis. Phosphodiesterases (PDEs) are enzymes that specifically hydrolyze cAMP, making PDE inhibitors promising candidates for SSc-ILD treatment. Nerandomilast, a preferential phosphodiesterase 4B (PDE4B) inhibitor currently undergoing phase III clinical trials for idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung diseases (PF-ILD), has good preference for PDE4B but lacks studies for SSc-ILD. Our research demonstrates that nerandomilast effectively inhibits skin and lung fibrosis in a bleomycin-induced mouse model of SSc-ILD. For lung fibrosis, we found that nerandomilast could improve bleomycin-induced SSc-ILD through inhibiting PDE4B and the TGF-β1-Smads/non-Smads signaling pathways, which provides a theoretical basis for potential therapeutic drug development for SSc-ILD.

Background Systemic sclerosis (SSc) is a rare connective tissue disorder with heterogeneous manifestations. Two predominant subtypes, limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc), are distinguished based on skin involvement distribution. A comprehensive conceptual SSc model is needed to support measurement strategies for outcome studies. This qualitative study aimed to explore key SSc disease concepts and develop a conceptual disease model capturing the heterogeneous lived experiences of patients with SSc. Methods Patient- and clinician-reported concepts specific to dcSSc (more severe and faster-progressing than lcSSc) were identified via a targeted literature review and used to develop a preliminary dcSSc symptom model and a semi-structured qualitative interview guide. The guide was used in concept elicitation interviews with adults with lcSSc and dcSSc. A final conceptual SSc symptoms model was refined based on interview results. Results Disease concepts were retrieved from 35 peer-reviewed articles and 17 clinical trials focusing on patients with dcSSc. The preliminary dcSSc symptom model included skin, hand, gastrointestinal, pain, joint, muscle, mouth, sexual, lung, cardiovascular, cognitive, ocular, and other symptoms. During concept elicitation interviews, participants (n = 44) reported 112 unique symptoms (within 13 domains). Twenty-six symptoms had not previously been identified in pertinent literature. Hand and skin symptoms were reported by all participants. Over 95% of participants reported at least one gastrointestinal and pain symptom, around 80% reported joint and mouth symptoms, 70% reported muscle symptoms, and over 50% reported ocular symptoms. Cognitive, lung, sexual, and cardiac symptoms were reported by fewer than half of participants. Participants with dcSSc reported a broader variety of symptoms than those with lcSSc. However, concepts relevant to patients with dcSSc and lcSSc strongly overlapped, suggesting that a single conceptual model is appropriate to map symptoms for both subtypes. The overlap was further reflected in the most bothersome symptoms, which included skin fibrosis and hand symptoms for both populations. Conclusions The final conceptual model captures the heterogeneous symptoms of SSc and reflects the lived experience of patients with SSc. It covers both clinical SSc subtypes and can support the choice and/or development of instruments to measure patient experiences in clinical trials.