Genetics of systemic sclerosis: an update.
Current rheumatology reports
Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune cell activation, and fibrosis of the skin and internal organs. Over the past few years, a role for genetics in the susceptibility for SSc has been established. This review aims to provide an update on the progress made in the past year or so within the field of SSc genetics research. This year has been of particular interest due to the publication of a large genome-wide association study, further investigations into gene-gene interactions, and the tendency to validate genetic results in functional models.
10.1007/s11926-011-0221-7
Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis.
Moinzadeh Pia,Aberer Elisabeth,Ahmadi-Simab Keihan,Blank Norbert,Distler Joerg H W,Fierlbeck Gerhard,Genth Ekkehard,Guenther Claudia,Hein Ruediger,Henes Joerg,Herich Lena,Herrgott Ilka,Koetter Ina,Kreuter Alexander,Krieg Thomas,Kuhr Kathrin,Lorenz Hanns-Martin,Meier Florian,Melchers Inga,Mensing Hartwig,Mueller-Ladner Ulf,Pfeiffer Christiane,Riemekasten Gabriela,Sárdy Miklós,Schmalzing Marc,Sunderkoetter Cord,Susok Laura,Tarner Ingo H,Vaith Peter,Worm Margitta,Wozel Gottfried,Zeidler Gabriele,Hunzelmann Nicolas,
Annals of the rheumatic diseases
BACKGROUND:Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. OBJECTIVES:To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). METHODS:The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. RESULTS:Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. CONCLUSIONS:These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.
10.1136/annrheumdis-2013-204487
Encapsulating Peritoneal Sclerosis in Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Systemic Sclerosis.
Internal medicine (Tokyo, Japan)
We encountered a 57-year-old Japanese woman with encapsulating peritoneal sclerosis (EPS) in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis. The patient was admitted to our hospital because of ascites retention. Administration of tocilizumab, an anti-interleukin-6 receptor antibody, for her RA reduced the refractory ascites remarkably; however, she developed sudden acute gastrointestinal bleeding and died a year later. On autopsy, sclerotic thickening of the peritoneum showed diffuse infiltration of podoplanin-positive fibroblast-like cells, and a diagnosis of EPS was made. EPS rarely occurs in SLE, and tocilizumab may be a new treatment candidate for EPS.
10.2169/internalmedicine.9793-22
Epidemiology of systemic sclerosis and systemic sclerosis-associated interstitial lung disease.
Bergamasco Aurore,Hartmann Nadine,Wallace Laura,Verpillat Patrice
Clinical epidemiology
Interstitial lung disease (ILD) is one of the leading causes of mortality in patients with systemic sclerosis (SSc). To further understand this patient population, we present the first systematic review on the epidemiology of SSc and SSc-associated ILD (SSc-ILD). Bibliographic databases and web sources were searched for studies including patients with SSc and SSc-ILD in Europe and North America (United States and Canada). The systematic review was limited to publications in English, German, French, Spanish, Italian, and Portuguese, published between January 1, 2000 and February 29, 2016. For all publications included in the review, the methodologic quality was assessed. For each dimension and region, data availability in terms of quantity and consistency of reported findings was evaluated. Fifty publications reporting epidemiologic data (prevalence, incidence, demographic profile, and survival and mortality) were included; 39 included patients with SSc and 16 included patients with SSc-ILD. The reported prevalence of SSc was 7.2-33.9 and 13.5-44.3 per 100,000 individuals in Europe and North America, respectively. Annual incidence estimates were 0.6-2.3 and 1.4-5.6 per 100,000 individuals in Europe and North America, respectively. Associated ILD was present in ~35% of the patients in Europe and ~52% of the patients in North America. In Europe, a study estimated the prevalence and annual incidence of SSc-ILD at 1.7-4.2 and 0.1-0.4 per 100,000 individuals, respectively. In both Europe and North America, SSc-ILD was diagnosed at a slightly older age than SSc, with both presentations of the disease affecting 2-3 times more women than men. Ten-year survival in patients with SSc was reported at 65-73% in Europe and 54-82% in North America, with cardiorespiratory manifestations (including ILD) associated with poor prognosis. This systematic review confirms that SSc and SSc-ILD are rare, with geographic variation in prevalence and incidence.
10.2147/CLEP.S191418
Association between systemic sclerosis and left ventricle dysfunction: Findings from observational studies.
Heliyon
Objectives:Cardiac involvement is common in systemic sclerosis (SSc) patients. In this study, we aimed to systematically evaluate the relationship between SSc and left ventricular dysfunction (LVD), especially the left ventricular diastolic dysfunction, by ultrasound and cardiac magnetic resonance data. Methods:We searched The Cochrane Library, PubMed and Embase databases collected studies about comparing LVD parameters in SSc patients and controls from establishment to January 2022. Furthermore, we also performed a two-sample MR using summary statistics from genome-wide association studies (GWAS) important LVD parameters, including left ventricular end-diastolic volume (LVEDV), left ventricular mass (LVM) and left ventricular ejection fraction (LVEF). Results:Our meta-analysis included 31 eligible studies with 1448 SSc patients. According to the results, SSc patients had lower peak of early diastolic flow velocity/peak of late diastolic flow velocity ratio (E/A ratio), E, -mitral early filling peak velocity (E'), and left ventricular end-diastolic diameter (LVEDD) compared to controls. The E/E' ratio, A, left ventricular isovolumetric relaxation time (IVRT), deceleration Time (DT) and left atrial (LA) diameter were higher in SSc patients in comparison with controls. Moreover, we observed that the SSc patients had lower LVEF than controls. And in MR analysis, we also found that SSc was causally correlated with LVEF (OR = 0.9966, 95% CI 0.9935-0.998, P = 0.0398). However, unfortunately, there was no significant correlation between SSC and LVM (OR = 1.0048, 95% CI 0.9919-1.0179, P = 0.4661) and LVEDV (LVEDV OR = 0.9976, 95%CI 0.9888-1.0066, P = 0.6019). Conclusion:SSc patients had diastolic/systolic dysfunction. However, MR analysis cannot confirm the genetic relationship between SSc and LVDD because of insufficient data. More research is needed to confirm the causal relationship between the two.
10.1016/j.heliyon.2023.e14110
Association between systemic sclerosis and risk of lung cancer: results from a pool of cohort studies and Mendelian randomization analysis.
Peng Haoxin,Wu Xiangrong,Wen Yaokai,Li Caichen,Lin Jinsheng,Li Jianfu,Xiong Shan,Zhong Ran,Liang Hengrui,Cheng Bo,Liu Jun,He Jianxing,Liang Wenhua
Autoimmunity reviews
BACKGROUND:Population-based cohort studies have indicated that systemic sclerosis (SSc) may be associated with an increased risk of lung cancer. However, there are few studies that comprehensively investigate their correlation and the causal effect remains unknown. METHODS:A systematic search of PubMed, Web of Science, Cochrane Library and Embase from the inception dates to December 1, 2019 was carried out. Meta-analysis was performed to calculate odds ratio (OR) and corresponding 95% confidence interval (CI) using random-effects models. Subgroup analyses were performed regarding gender. Two-sample Mendelian randomization (MR) was carried out with summary data from published genome-wide association studies of SSc (Neale Lab, 3871 individuals; UK Biobank, 463,315 individuals) and lung cancer (International Lung Cancer Consortium, 27,209 individuals; UK Biobank, 508,977 individuals). Study-specific estimates were summarized using inverse variance-weighted, weighted median, and MR-Egger method. RESULTS:Through meta-analysis of 10 population-based cohort studies involving 12,218 patients, we observed a significantly increased risk of lung cancer among patients with SSc (OR 2.80, 95% CI 1.55-5.03). In accordance with subgroup analysis, male patients (OR 4.11, 95% CI 1.92-8.79) had a 1.5-fold higher lung cancer risk compared with female patients (OR 2.73, 95% CI 1.41-5.27). However, using a score of 11 SSc-related single nucleotide polymorphisms (p < 5*10) as instrumental variables, the MR study did not support a causality between SSc and lung cancer (OR 1.001, 95% CI 0.929-1.100, p = 0.800). Specifically, subgroup MR analyses indicated that SSc was not associated with increased risks of non-small-cell lung cancer (OR 1.000, 95% CI 0.999-1.000, p = 0.974), including lung adenocarcinoma (OR 0.996, 95% CI 0.906-1.094, p = 0.927), squamous cell lung carcinoma (OR 1.034, 95% CI 0.937-1.140, p = 0.507), nor small-cell lung cancer (OR 1.000, 95% CI 0.999-1.000, p = 0.837). CONCLUSIONS:This study indicated an increased risk of lung cancer among patients with SSc by meta-analysis, whereas the MR study did not support a causality between the two diseases. Further studies are warranted to investigate the factors underlying the attribution of SSc to lung cancer risk.
10.1016/j.autrev.2020.102633
Contribution of Telomere Length to Systemic Sclerosis Onset: A Mendelian Randomization Study.
International journal of molecular sciences
Although previous studies have suggested a relationship between telomere shortening and systemic sclerosis (SSc), the association between these two traits remains poorly understood. The objective of this study was to assess the causal relationship between telomere length in leukocytes (LTL) and SSc using the two-sample Mendelian randomization approach, with the genome-wide association study data for both LTL and SSc. The results of inverse-variance weighted regression (OR = 0.716 [95% CI 0.528-0.970], = 0.031) and the Mendelian randomization pleiotropy residual sum and outlier method (OR = 0.716 [95% CI 0.563-0.911], = 0.035) indicate an association between telomere length and SSc. Specifically, longer genetically predicted LTL is associated with a reduced risk of SSc. Sensitivity tests highlight the significant roles of the variants rs10936599 and rs2736100 annotated to the and genes, respectively. Our findings suggest an influence of telomere length in leukocytes on the development of SSc.
10.3390/ijms242115589
Negative causal exploration of systemic sclerosis: a Mendelian randomization analysis.
Scientific reports
Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune-related connective tissue disease with a complex and unknown pathophysiological mechanism with genes association. Several articles have reported a high prevalence of thyroid disease in SSc patients, while one study suggested a potential contribution of appendicitis to the development of SSc. To investigate this causal association, we conducted Mendelian randomization (MR) analysis using instrumental variables (IVs) to assess exposure and outcome. In the MR study involving two cohorts, all analyses were conducted using the TwoSampleMR package in R (version 4.3.0). Single nucleotide polymorphisms (SNPs) meeting a statistically significant threshold of 5E-08 were included in the analysis. Multiple complementary approaches including MR-IVW, MR-Egger, weighted median, simple mode, and weighted mode were employed to estimated the relationship between the exposure and outcome. Leave-one-out analysis and scatter plots were utilized for further investigation. Based on the locus-wide significance level, all of the MR analysis consequences manifested no causal association between the risk of appendicitis with SSc (IVW OR 0.319, 95% CI 0.063-14.055, P = 0.966). Negative causal effects of autoimmune thyroiditis (AT) on SSc (IVW OR 0.131, 95% CI 0.816-1.362, P = 0.686), Graves' disease (GD) on SSc (IVW OR 0.097, 95% CI 0.837-1.222, P = 0.908), and hypothyroidism on SSc (IVW OR 1.136, 95% CI 0.977-1.321, P = 0.096) were derived. The reverse MR revealed no significant causal effect of SSc on thyroid disease. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates. The consequences indicated no significant association between AT, GD, and hypothyroidism with SSc. Similarly, there was no observed relationship with appendicitis.
10.1038/s41598-024-55808-w