Nuclear-penetrating scleroderma autoantibody inhibits topoisomerase 1 cleavage complex formation.

The contributions of anti-Topoisomerase 1 (Top1) autoantibodies to the pathophysiology of diffuse cutaneous systemic sclerosis (dcSSc), the most aggressive scleroderma subtype, are unknown. Top1 catalyzes DNA relaxation and unwinding in cell nuclei, a site previously considered inaccessible to antibodies. The discovery of autoantibodies in systemic lupus erythematosus that penetrate nuclei and inhibit DNA repair raised the possibility that nuclear-penetrating autoantibodies contribute to mechanisms of autoimmunity. Here we show that an anti-Top1 autoantibody produced by a single B cell clone from a patient with dcSSc penetrates live cells and localizes into nuclei. Functionally, the autoantibody inhibits formation of the Top1 cleavage complex necessary for DNA nicking, which distinguishes it from cytotoxic camptothecin Top1 inhibitors used in cancer therapy that trap the cleavage complex rather than preventing its formation. Discovery of a patient-derived cell-penetrating scleroderma anti-Top1 autoantibody that inhibits Top1 cleavage complex formation supports the hypothesis that anti-Top1 autoantibodies contribute to cellular dysfunction in dcSSc and offers a valuable antibody reagent resource for future studies on anti-Top1 autoantibody contributions to scleroderma pathophysiology.

Phenotypes of patients with systemic sclerosis in the Chinese Han population: a cluster analysis.

OBJECTIVE: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is commonly subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) based on the extent of skin involvement. This subclassification may not reflect the full range of clinical phenotypic variation. This study aimed to investigate clinical features and aggregation of patients with SSc in Chinese based on SSc manifestations and organ involvements, in order to achieve precise treatment of SSc early prevention of complications. METHODS: In total 287 SSc patients were included in this study. A cluster analysis was applied according to 13 clinical and serologic variables to determine subgroups of patients. Survival rates between obtained clusters and risk factors affecting prognosis were also compared. RESULT: In this study, six clusters were observed: cluster 1 (n = 66) represented the skin type, with all patients showing skin thickening. In cluster 2 (n = 56), most patients had vascular and articular involvement. Cluster 3 (n = 14) individuals mostly had cardiac and pulmonary involvement. In cluster 4 (n = 52), the gastrointestinal type, 50 patients presented with stomach symptoms and 28 patients presented with esophageal symptoms. In cluster 5 (n = 50), patients barely had any major organ involvement. Cluster 6 (n = 49) included 46% of all patients presenting with renal crisis. CONCLUSION: The results of our cluster analysis study implied that limiting SSc patient subgroups to those based only on skin involvement might not capture the full heterogeneity of the disease. Organ damage and antibody profiles should be considered when identifying homogeneous patient groups with a specific prognosis. Key Points • Provides a new method of categorizing SSc patients. • Can better explain disease progression and guide subsequent treatment.

[Systemic sclerosis]. / Systemische Sklerose.

BACKGROUND: Systemic sclerosis (SSc) is a very heterogeneous, chronic, rare, but socioeconomically important disease with a severe disease course and severe impairment of the quality of life of affected patients. OBJECTIVES: Overview of the current state of research on the pathogenesis, diagnosis and therapy of SSc. METHODS: A literature search was performed. RESULTS: The pathogenesis of SSc is not fully understood. ACR/EULAR criteria allow the diagnosis of early forms of SSc. Classification into limited cutaneous SSc and diffuse cutaneous SSc is of prognostic and therapeutic relevance. New organ-specific treatment options for SSc have led to improved quality of life and prognosis.

Development and validation of a new diagnostic prediction model of ENHO and NOX4 for early diagnosis of systemic sclerosis.

Objective: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis. The challenge of early diagnosis, along with the lack of effective treatments for fibrosis, contribute to poor therapeutic outcomes and high mortality of SSc. Therefore, there is an urgent need to identify suitable biomarkers for early diagnosis of SSc. Methods: Three skin gene expression datasets of SSc patients and healthy controls were downloaded from Gene Expression Omnibus (GEO) database (GSE130955, GSE58095, and GSE181549). GSE130955 (48 early diffuse cutaneous SSc and 33 controls) were utilized to screen differentially expressed genes (DEGs) between SSc and normal skin samples. Least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM-RFE) were performed to identify diagnostic genes and construct a diagnostic prediction model. The results were further validated in GSE58095 (61 SSc and 36 controls) and GSE181549 (113 SSc and 44 controls) datasets. Receiver operating characteristic (ROC) curves were applied for assessing the level of diagnostic ability. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to verify the diagnostic genes in skin tissues of out cohort (10 SSc and 5 controls). Immune infiltration analysis were performed using CIBERSORT algorithm. Results: A total of 200 DEGs were identified between SSc and normal skin samples. Functional enrichment analysis revealed that these DEGs may be involved in the pathogenesis of SSc, such as extracellular matrix remodeling, cell-cell interactions, and metabolism. Subsequently, two critical genes (ENHO and NOX4) were identified by LASSO and SVM-RFE. ENHO was found down-regulated while NOX4 was up-regulated in skin of SSc patients and their expression levels were validated by above three datasets and our cohort. Notably, these differential expressions were more pronounced in patients with diffuse cutaneous SSc than in those with limited cutaneous SSc. Next, we developed a novel diagnostic model for SSc using ENHO and NOX4, which demonstrated strong predictive power in above three cohorts and in our own cohort. Furthermore, immune infiltration analysis revealed dysregulated levels of various immune cell subtypes within early SSc skin specimens, and a negative correlation was observed between the levels of ENHO and Macrophages M1 and M2, while a positive correlation was observed between the levels of NOX4 and Macrophages M1 and M2. Conclusion: This study identified ENHO and NOX4 as novel biomarkers that can be serve as a diagnostic prediction model for early detection of SSc and play a potential role in the pathogenesis of the disease.

Systemic Sclerosis in Individuals With Exposure to World Trade Center Ground Zero Rescue and Recovery Efforts: A Case Series.

OBJECTIVE: The World Trade Center (WTC) attack in New York resulted in a dust plume containing silica, hydrocarbons, and asbestos. Autoimmune disorders have been reported among those with WTC site exposure. The characteristics of individuals developing systemic sclerosis (SSc) have not been previously described. The purpose of this study was to describe the features of patients with SSc with WTC exposure. METHODS: Data were collected from 11 patients with SSc or SSc spectrum conditions who reported exposure to the WTC site. Seven patients completed an exposure assessment. RESULTS: Of the 11 patients, the majority (n = 8) were female. The median (range) for age at diagnosis was 46 (36-75) years, time between exposure and first non-Raynaud phenomenon SSc symptom was 8 (1-19) years, and time between exposure and diagnosis was 11 (2-18) years. Fifty-five percent had SSc onset > 5 years from WTC exposure. Five patients had limited cutaneous SSc, 3 patients had diffuse cutaneous SSc, 1 patient with SSc features met criteria for mixed connective tissue disease (CTD), and 2 patients had undifferentiated CTD with features of SSc. Four patients had overlapping features with other CTDs. Interstitial lung disease (ILD) was present in 10 patients. Five of 11 patients had a history of tobacco use. Seven of 7 patients who completed the questionnaire reported other hazardous exposures outside of WTC. Of these, only 2 patients reported personal protective equipment use. CONCLUSION: A high frequency of ILD and overlap features were observed among patients with SSc with WTC exposure. Future studies are needed to characterize this association.

Standardized mortality ratios in systemic sclerosis: a meta-analysis assessing overall and sex- and disease subtype-specific differences.

OBJECTIVE: This study aims to evaluate the overall and sex- and illness subtype-specific standardized mortality ratios (SMRs) in patients with systemic sclerosis (SSc). METHODS: We searched and examined studies that compared the overall and sex- and illness subtype-specific SMRs in patients with SSc to those in the general population using MEDLINE, EMBASE, and Cochrane databases (until May 2023). We then conducted a meta-analysis of the overall and sex- and illness subtype-specific SMRs in patients with SSc. RESULTS: Overall, 29 studies including 30,673 patients with SSc and 5582 deaths met the inclusion criteria. Patients with SSc had a higher overall SMR than that in the general population (SMR: 2.742, 95% confidence interval [CI]: 2.224-3.38091, p < 0.001). The SMR significantly increased in populations from Europe, North America, Asia, and Oceania according to regional stratification. A sex-specific meta-analysis revealed a substantial increase in the SMR in both men and women (SMR: 3.598, 95% CI: 3.097-4.180, p < 0.001; SMR: 2.833, 95% CI: 2.4384-3.292, p < 0.001, respectively) and the mortality rate was higher in men compared to women. A substantial increase in the SMR in diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) was observed in a disease subtype-specific meta-analysis. In addition, the SMR in the dcSSc group was higher than that in the lcSSc group (SMR: 4.726, 95% CI: 3.795-5.885, p < 0.001; SMR: 1.987, 95% CI: 1.586-2.489, p < 0.001, respectively). CONCLUSION: Our findings demonstrated that the mortality rate in patients with SSc was 2.74-times greater than that in the general population. The mortality rate was higher in men compared to women. Additionally, compared to patients with lcSSc, those with dcSSc showed much higher fatality rates.

Is cyclophosphamide still the gold standard in early severe rapidly progressive systemic sclerosis?

Cyclophosphamide (CYC) has been a gold standard of treatment for severe progressive Systemic Sclerosis (SSc), especially in patients with concomitant interstitial lung disease (ILD). This approach was based on results of several interventional studies, including randomized control trials, which mainly addressed SSc-ILD as a primary end point and skin involvement as a second one. The use of CYC is time-limited due to significant adverse events. More recently, other immunosuppressive and biological agents showed efficacy but better safety profile in patients with SSc and SSc-ILD. With regards to other end-points, post-hoc analyses, systematic reviews and metalysis showed that CYC had limited influence on patients' quality of life, event-free survival and mortality. Comprehensive patient's stratification according to a molecular, cellular and phenotypic pattern may help in choosing of personalized medicine with more ambitious treatment effect and should be the future direction. According to the above available data and even if scientific evidence may be missing, experts' opinion has changed the attitude to CYC as an anchor drug in the management of severe SSc. Indeed, CYC has been pushed to the second and even third treatment option after mycophenolate mofetil, tocilizumab or rituximab. This position became obvious during debate on this topic at CORA meeting 2023.

Performance of myotonometer in the assessment of skin involvement in systemic sclerosis.

OBJECTIVES: A clinically practical tool to assess skin biomechanical properties rapidly and accurately is still lacking. Our aim was to examine the intra- and inter-observer reproducibility of a myotonometer for objective skin property assessment in systemic sclerosis (SSc), comparing it with the modified Rodnan skin score (mRSS), and distinguishing patients from healthy controls. METHOD: Thirty-four patients (21 limited and 13 diffuse SSc), and 31 age and gender-matched healthy controls were enrolled. Skin tone and stiffness were measured at four different anatomical sites (the forearm, hand, leg, and foot) using a myotonometer. The correlation between the mRSS and skin properties was assessed. Also, hand functionality was evaluated for possible correlations between the variables. The differences in skin properties between dcSSc and lcSSc patients, and healthy controls were assessed using variance analysis. RESULTS: Intra- and inter-examiner reproducibility were excellent (ICC = 0.70 to 0.98) for tone and stiffness except for non-dominant hand tone, which showed good reliability (ICC = 0.64 to 0.74). Stiffness and tone values of the hands, forearms, and feet significantly correlated with mRSS total score (r = 0.40 to 0.71, p < 0.05). Additionally, tone and stiffness of the hands and forearms moderately correlated with hand function (p < 0.05). Tone and stiffness values increased in patients with dcSSc compared to healthy controls, or patients with lcSSc, at the hands, forearms, and legs (p < 0.05). CONCLUSIONS: Our findings emphasize the potential utility of the myotonometer for assessing skin properties and differentiating SSc patients from controls, demonstrating its promise as a valuable clinical evaluation tool in this context. Key Points •The myotonometer displayed excellent intra- and inter-examiner reproducibility for assessing skin properties. •Skin tone and stiffness parameters well correlated with the mRSS scores. •The myotonometer can distinguish patients with diffuse cutaneous SSc from healthy controls.

Flemish network on rare connective tissue diseases (CTD): patient pathways in systemic sclerosis. First steps taken.

Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

Human leukocyte antigen association in systemic sclerosis patients: our experience at a tertiary care center in North India.

Introduction: Systemic sclerosis (SSc) is a chronic multisystem autoimmune rheumatic disease of unknown etiology. Several studies have established that SSc is triggered by a dynamic interplay between genetic factors and environmental stimuli. In the present study, we aimed to study the association of human leukocyte antigen (HLA) with familial and non-familial SSc patients [limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc)] from North India. Methods: The HLA-A, B, DRB1, and DQB1 genotyping of 150 (70 lcSSc and 80 dcSSc) adult-onset SSc patients and 150 age-gender-matched healthy controls were performed with sequence-specific oligonucleotide (SSO) typing kits using the luminex platform. HLA typing for HLA class I (A, B, and C) and II (DRB1, DQB1, and DPB1) in five North Indian families consisting of parent-child/sibling pairs affected with SSc or overlap syndrome was performed by Next Generation Sequencing (NGS) with Illumina MiniSeq. Rseults: Among the non-familial SSc patients, HLA- DRB1*11 (P = 0.001, OR: 2.38, P c = 0.01) was identified as a risk allele, and DRB1*12 (P = .0001, OR: 0.00, P c = 0.001) as a protective allele. There was no statistical association found with HLA-DQB1*. Also, no significant association was observed between HLA antigens and different clinical subsets (lcSSc and dcSSc) of SSc. Two cases of familial SSc patients had the DRB1*11 allele. The DRB1*12 allele was absent in all the familial SSc patients. Discussion: HLA DRB1*11 (risk allele) and DRB1*12 (protective allele) were found to be strongly associated with non-familial SSc patients and partially explain the disease's familial clustering, supporting the susceptible genetic background theory for SSc development. The study also indicates the HLA allele as a common genetic risk factor in distinct autoimmune diseases contributing to overlap syndrome or polyautoimmunity.

Anti-Ro52 positivity is associated with progressive interstitial lung disease in systemic sclerosis-an exploratory study.

BACKGROUND: Interstitial lung disease (ILD) is the most common cause of death in patients with systemic sclerosis (SSc). Prognostic biomarkers are needed to identify SSc-ILD patients at risk for progressive pulmonary fibrosis. This study investigates autoantibodies measured in bronchoalveolar lavage (BAL) fluid and in serum in reference to the clinical disease course of SSc-ILD. METHODS: Fifteen patients with new onset SSc-ILD underwent bronchoscopy. Autoantibody levels were analyzed using addressable laser bead immunoassay from BAL fluid and the serum. In a separate longitudinal cohort of 43 patients with early SSc-ILD, autoantibodies in serum were measured at baseline and pulmonary function tests were performed at least 2 times over the course of at least 2 or more years. Linear mixed effect models were created to investigate the relationship between specific autoantibodies and progression of SSc-ILD. Finally, lung tissue from healthy controls and from subjects with SSc was analyzed for the presence of the Ro52 antigen using immunohistochemistry. RESULTS: Among SSc-ILD patients who were positive for anti-Ro52 (N = 5), 3 (60%) had enrichment of anti-Ro52 in BAL fluid at a ratio exceeding 50x. In the longitudinal cohort, 10/43 patients (23%) were anti-Ro52 positive and 16/43 (37%) were anti-scl-70 positive. Presence of anti-Scl-70 was associated with a lower vital capacity (VC) at baseline (-12.6% predicted VC [%pVC]; 95%CI: -25.0, -0.29; p = 0.045), but was not significantly associated with loss of lung function over time (-1.07%pVC/year; 95%CI: -2.86, 0.71; p = 0.230). The presence of anti-Ro52 was significantly associated with the loss of lung function over time (-2.41%pVC/year; 95% CI: -4.28, -0.54; p = 0.013). Rate of loss of lung function increased linearly with increasing anti-Ro52 antibody levels (-0.03%pVC per arbitrary units/mL and year; 95%CI: -0.05, -0.02; p < 0.001). Immunohistochemical staining localized the Ro52 antigen to alveolar M2 macrophages in peripheral lung tissue both in subjects with and without SSc. CONCLUSIONS: This study suggests that antibodies targeting Ro52 are enriched in the lungs of patients with new-onset SSc-ILD, linking Ro52 autoimmunity to the pulmonary pathology of SSc. Clinical and immunohistochemical data corroborates these findings and suggest that anti-Ro52 may serve as a potential biomarker of progressive SSc-ILD.

Reference value for the 6-min walking distance in women with systemic sclerosis considering the impact of muscle strength.

BACKGROUND: Early triage, the search for new therapies, and closer monitoring of patients with systemic sclerosis before their lung function irreversibly deteriorates are urgent concerns. Because it is an independent predictor of systemic sclerosis-related mortality, the 6-min walk test is a potentially useful tool to evaluate outcomes, along with pulmonary function and computed tomography. This study aimed to establish a reference value for the 6-min walking distance in women with diffuse cutaneous systemic sclerosis-associated interstitial lung disease that takes into account the effects of muscle and lung function. METHODS: This was a cross-sectional study in which 69 women with systemic sclerosis underwent the 6-min walk test, Health Assessment Questionnaire-Disability Index, pulmonary function, handgrip strength test, and quadriceps strength test. FINDINGS: The mean 6-min walking distance was 447 ± 78 m, and 43.5% of the participants did not reach 80% of their predicted value. 6-min walking distance correlated positively with quadriceps strength (r = 0.418, P = 0.0004), forced vital capacity (r = 0.306, P = 0.011), pulmonary diffusion (r = 0.360, P = 0.002), maximum inspiratory pressure (r = 0.268, P = 0.029), and maximum expiratory pressure (r = 0.288, P = 0.019) and negatively with age (r = -0.378, P = 0.001), body mass index (r = -0.248, P = 0.039), and Health Assessment Questionnaire-Disability Index (r = -0.438, P = 0.0001). In the multiple linear regression analysis, quadriceps strength, body mass index, pulmonary diffusion, age, and maximum expiratory pressure explained 72% of the 6-min walking distance variability. INTERPRETATION: Muscle function and, to a lesser extent, lung function are key contributors in determining the reference value for the 6-min walking distance in women with diffuse cutaneous systemic sclerosis-associated interstitial lung disease.

Single-cell analysis reveals key differences between early-stage and late-stage systemic sclerosis skin across autoantibody subgroups.

OBJECTIVES: The severity of skin involvement in diffuse cutaneous systemic sclerosis (dcSSc) depends on stage of disease and differs between anti-RNA-polymerase III (ARA) and anti-topoisomerase antibody (ATA) subsets. We have investigated cellular differences in well-characterised dcSSc patients compared with healthy controls (HCs). METHODS: We performed single-cell RNA sequencing on 4 mm skin biopsy samples from 12 patients with dcSSc and HCs (n=3) using droplet-based sequencing (10× genomics). Patients were well characterised by stage (>5 or <5 years disease duration) and autoantibody (ATA+ or ARA+). Analysis of whole skin cell subsets and fibroblast subpopulations across stage and ANA subgroup were used to interpret potential cellular differences anchored by these subgroups. RESULTS: Fifteen forearm skin biopsies were analysed. There was a clear separation of SSc samples, by disease, stage and antibody, for all cells and fibroblast subclusters. Further analysis revealed differing cell cluster gene expression profiles between ATA+ and ARA+ patients. Cell-to-cell interaction suggest differing interactions between early and late stages of disease and autoantibody. TGFß response was mainly seen in fibroblasts and smooth muscle cells in early ATA+dcSSc skin samples, whereas in early ARA+dcSSc patient skin samples, the responding cells were endothelial, reflect broader differences between clinical phenotypes and distinct skin score trajectories across autoantibody subgroups of dcSSc. CONCLUSIONS: We have identified cellular differences between the two main autoantibody subsets in dcSSc (ARA+ and ATA+). These differences reinforce the importance of considering autoantibody and stage of disease in management and trial design in SSc.

Clinical correlates of a subset of anti-fibroblast antibodies in systemic sclerosis.

Anti-fibroblast antibodies (AFA) have been reported in systemic sclerosis (SSc) and are known to promote fibroblast activation. Aim of this study was to characterize the fine specificity of AFA and to analyze any correlations with clinical parameters associated to fibrosis. To this end, AFA were affinity-purified from a patient with diffuse cutaneous SSc (dcSSc) and interstitial lung disease (ILD). Panning of a phage display peptide library with purified AFA identified the motif . The peptide p121, bearing the AFA-specific motif, was used in ELISA to screen sera from 186 SSc patients and 81 healthy donors. Anti-p121 Ab serum levels were statistically higher in SSc than in healthy groups, and directly associated with dcSSc, reduced FVC (FVC < 70), and ILD. Given these clinical correlates, this study lays the groundwork for the identification of the antigen recognized by anti-p121 Ab, which might represent a novel therapeutic target for ILD.

Cutaneous Manifestations, Clinical Characteristics, and Prognosis of Patients With Systemic Sclerosis Sine Scleroderma: Data From the International EUSTAR Database.

Importance: Systemic sclerosis (SSc) sine scleroderma (ssSSc) is a subset of SSc defined by the absence of skin fibrosis. Little is known about the natural history and skin manifestations among patients with ssSSc. Objective: To characterize the clinical phenotype of patients with ssSSc compared with patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) within the EUSTAR database. Design, Setting, and Participants: This longitudinal observational cohort study based on the international EUSTAR database included all patients fulfilling the classification criteria for SSc assessed by the modified Rodnan Skin score (mRSS) at inclusion and with at least 1 follow-up visit; ssSSc was defined by the absence of skin fibrosis (mRSS = 0 and no sclerodactyly) at all available visits. Data extraction was performed in November 2020, and data analysis was performed from April 2021 to April 2023. Main Outcomes and Measures: Main outcomes were survival and skin manifestations (onset of skin fibrosis, digital ulcers, telangiectasias, puffy fingers). Results: Among the 4263 patients fulfilling the inclusion criteria, 376 (8.8%) were classified as having ssSSc (mean [SD] age, 55.3 [13.9] years; 345 [91.8%] were female). At last available visit, in comparison with 708 patients with lcSSc and 708 patients with dcSSc with the same disease duration, patients with ssSSc had a lower prevalence of previous or current digital ulcers (28.2% vs 53.1% in lcSSc; P < .001; and 68.3% in dcSSc; P < .001) and puffy fingers (63.8% vs 82.4% in lcSSc; P < .001; and 87.6% in dcSSc; P < .001). By contrast, the prevalence of interstitial lung disease was similar in ssSSc and lcSSc (49.8% and 57.1%; P = .03) but significantly higher in dcSSc (75.0%; P < .001). Skin telangiectasias were associated with diastolic dysfunction in patients with ssSSc (odds ratio, 4.778; 95% CI, 2.060-11.081; P < .001). The only independent factor for the onset of skin fibrosis in ssSSc was the positivity for anti-Scl-70 antibodies (odds ratio, 3.078; 95% CI, 1.227-7.725; P = .02). Survival rate was higher in patients with ssSSc (92.4%) compared with lcSSc (69.4%; P = .06) and dcSSc (55.5%; P < .001) after up to 15 years of follow-up. Conclusions and Relevance: Systemic sclerosis sine scleroderma should not be neglected considering the high prevalence of interstitial lung disease (>40%) and SSc renal crisis (almost 3%). Patients with ssSSc had a higher survival than other subsets. Dermatologists should be aware that cutaneous findings in this subgroup may be associated with internal organ dysfunction. In particular, skin telangiectasias in ssSSc were associated with diastolic heart dysfunction.

A rare case of signet ring cell carcinoma with diffuse cutaneous systemic sclerosis: A case report.

Systemic sclerosis, an autoimmune disease characterized by fibrosis and vasculopathy of the skin and other multiple organs has been associated with an increased risk of malignancy. We present the case of a 74-year-old woman who had diffused cutaneous systemic sclerosis and uterine cervical cancer. The patient was initially diagnosed with stage IIB squamous cell carcinoma and concurrent chemoradiotherapy was planned. However, cisplatin could not be administered due to acute renal failure, so the patient was treated solely with radiotherapy. However, complications of systemic sclerosis progressed rapidly, and the patient died 63 days later from pulmonary edema. An autopsy later revealed that uterine cervix had primary signet ring cell carcinoma. We suspected that this patient had a combination of signet ring cell carcinoma and squamous cell carcinoma, with squamous cell carcinoma disappearing after radiotherapy. This case highlighted the importance of systemic management for cancers associated with systemic sclerosis.

Elevated interleukin-11 in systemic sclerosis and role in disease pathogenesis.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease in which there is elevated inflammation, aberrant cytokine expression, and subsequent fibrosis. Interleukin-11 (IL-11) is a recently described profibrotic cytokine that can mediate fibrosis in the heart, lungs, and skin and is upregulated by transforming Growth Factor-ß (TGF-ß1). The objective of this study was to quantify the serum levels of IL-11 in early diffuse SSc patients. Also, if IL-11 could regulate the alarmin IL-33 in dermal fibroblasts was quantified. Early diffuse SSc patient sera was isolated and IL-11 was quantified by specific commercial ELISA compared to healthy control (n = 17). Healthy dermal fibroblasts were cultured in vitro and then serum starved and incubated with or without recombinant IL-11. At specific early and late time points the supernatant was quantified for the alarmin IL-33 by specific ELISA. In early diffuse SSc patients it was demonstrated that they have elevated IL-11 in their sera. In a subgroup of SSc patients with interstitial lung disease (ILD) this elevation was particularly pronounced compared to those devoid of fibrotic lung disease. In vitro incubation of healthy dermal fibroblasts led to a significant induction of IL-33 cytokine release into the cell media. IL-11 is a profibrotic cytokine that is elevated in early diffuse SSc and is particularly elevated in those with ILD. This suggests that IL-11 could be a possible biomarker of ILD in SSc. It was also found that IL-11 led to release of the cytokine alarmin IL-33 in fibroblasts at earlier time points but not late time points, suggesting early stimulation elicits an inflammatory response in the local microenvironment but prolonged stimulation leads to fibrosis.

Characteristics of ScleroID highlighting musculoskeletal and internal organ implications in patients afflicted with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a multi-organ disease with impaired health-related quality of life (HRQoL). The EULAR SSc Impact of Disease (ScleroID) is a newly introduced SSc-specific patient-reported outcome to evaluate HRQoL in SSc. OBJECTIVE: To investigate the correlation between the ScleroID and the involvement of organ systems as well as disease activity/damage in a SSc cohort from a large tertiary care centre. PATIENTS AND METHODS: The ScleroID and clinical characteristics including internal organ involvement and hand function were investigated in 160 consecutive patients with SSc (median age 46 (43;56) years; diffuse cutaneous SSc 55%). RESULTS: A strong correlation was found between the ScleroID and articular disease activity scores (DAS28-CRP, DAS28-ESR, CDAI, SDAI), a hand function performance test, the Hand Anatomy Index and muscle strength tests. Additionally, a strong significant correlation was discovered using instruments representing hand function and musculoskeletal disability including the Cochin Hand Function Scale, the Quick Questionnaire of the Disability of the Hands, Arms and the Shoulders and the Health Assessment Questionnaire Disability Index. A significant negative correlation was found between the ScleroID score and the 6-min walking test (6MWT) (rho - 0.444, p < 0.001). Clinically mild lung/heart disease did not show increased ScleroID values. The Mouth Handicap in the Scleroderma Scale and the University of California Los Angeles Scleroderma Clinical Trials Consortium gastrointestinal tract 2.0 also showed significant positive correlations to the ScleroID score (rho: 0.626, p < 0.001; rho: 0.646, p < 0.001, respectively). Patients experiencing oesophageal difficulties bore a significantly higher score compared to individuals with a normal functioning oesophagus (3.2/1.5;4.5/ vs. 2.2/1.0;3.2/, p = 0.011). Moreover, the ScleroID showed a significant positive correlation to the revised EUSTAR disease activity index and modified activity index. CONCLUSION: In a large single-centre cohort, the previously described ScleroID-related findings were confirmed. Furthermore, several organ involvement-related functional and performance tests showed a good correlation to the ScleroID including the 6MWT and gastrointestinal-related complaints. Many aspects of musculoskeletal damage, overall disease activity, pain and fatigue were also well represented in the ScleroID, which efficiently reflects the impact of organ involvement, disease activity and functional damage.