Risk Of Systemic Sclerosis Research Articles

Impact of Plasminogen Activator Inhibitor-1 Serum Levels and the -675 4G/5G Variant in the SERPINE1 Gene on Systemic Sclerosis in a Mexican Population.

Systemic sclerosis (SSc) is characterized by a complex interplay of vascular damage, inflammation, and fibrosis, affecting the skin and internal organs. Plasminogen activator inhibitor-1 (PAI-1), a protein encoded by the SERPINE1 gene, is a potential biomarker of SSc because it is primarily involved in fibrinolysis and is associated with the severity of some autoimmune diseases. This study aimed to determine the association between SERPINE1 variant -675 4G/5G and soluble PAI-1 (sPAI-1) levels with the clinical characteristics and risk of SSc in a Mexican population. This cross-sectional study included 56 SSc patients and 114 control subjects (CSs). The variant was genotyped via the PCR-RFLP method and the levels of sPAI-1 were determined using enzyme-linked immunosorbent assays (ELISAs). The -675 4G/5G variant was not associated with SSc risk or sPAI-I levels. However, higher sPAI-1 levels were observed in SSc patients than in CSs (p = 0.045); these levels were significantly correlated with age, platelets, glucose, and serum levels of transforming growth factor (TGF)-β1, 2, and 3. The SERPINE1 -675 4G/5G variant did not show any association with SSc risk or sPAI-I levels. However, our study shows a possible alteration of sPAI-1 in this disease, which could be associated with the fibrotic and thrombotic processes in SSc.

Prediction of prognosis in patients with systemic sclerosis based on a machine-learning model.

The clinical manifestations of systemic sclerosis (SSc) are highly variable, resulting in varied outcomes and complications. Diverse fibrosis of the skin and internal organs, vasculopathy, and dysregulated immune system lead to poor and varied prognoses in patients with SSc subtypes. Therefore, this study aimed to develop a personalized tool for predicting the prognosis of patients with SSc. A cohort of 517 patients with SSc were recruited between January 2009 and November 2021 at Xijing Hospital in China, and 266 patients completed the follow-up and performed in the survival analysis. Risk factors for death were identified using Cox survival analysis and random survival forest-based machine-learning methods separately. The consistency index, area under the curve (AUC), and integrated Brier scores were used to compare the predictive performance of the different prognostic models. The results of Cox-based multivariate regression analysis suggested that pulmonary arterial hypertension, digital ulcer, and Modified Rodnan Skin Score (mRSS) were independent risk factors for poor prognosis in patients with SSc and significant risk factors in random survival forest (RSF) surveys. A nomogram was plotted to evaluate the prognostic risk to facilitate clinical assessment; the RSF model had better predictive performance than the Cox model, with 3- and 5-year AUCs of 0.74 and 0.78, respectively. Machine-learning models can help us better understand the prognosis of patients with SSc and comprehensively evaluate the clinical characteristics of each individual. The early identification of the characteristics of high-risk patients can improve the prognosis of those with SSc. Key Points • Regarding predictive performance, the random survival forest model was more effective than the Cox model and had unique advantages in analyzing nonlinear effects and variable importance. • Machine learning using the simple clinical features of patients with systemic sclerosis (SSc) to predict mortality can guide attending physicians, and the early identification of high-risk patients with SSc and referral to experts will assist rheumatologists in monitoring and management planning.

Associations of the circulating levels of cytokines with risk of systemic sclerosis: a bidirectional Mendelian randomized study.

Systemic sclerosis(SSc) remains unclear, studies suggest that inflammation may be linked to its pathogenesis. Hence, we conducted a bidirectional Mendelian randomization (MR) analysis to evaluate the association between cytokine and growth factor cycling levels and the risk of SSc onset. In our study, the instrumental variables(IVs) for circulating cytokines were sourced from the genome-wide association study (GWAS) dataset of 8293 Finnish individuals. The SSc data comprised 302 cases and 213145 controls, and was included in the GWAS dataset. We employed four methods for the MR analysis: MR Egger, Inverse variance weighted (IVW), Weighted medium, and Weighted Mode, with IVW being the primary analytical method. Sensitivity analyses were performed using heterogeneity testing, horizontal pleiotropy testing, and the Leave One Out (LOO) method. We also conducted a reverse MR analysis to determine any reverse causal relationship between SSc and circulating cytokines. After Bonferroni correction, MR analysis revealed that the Interleukin-5 (IL-5) cycle level was associated with a reduced risk of SSc [odds ratio (OR)=0.48,95% confidence interval (CI): 0.27-0.84, P=0.01]. It also indicated that the Stem cell growth factor beta (SCGF-β) cycling level might elevate the risk of SSc (OR = 1.36, 95% CI: 1.01-1.83, P = 0.04). However, the reverse MR analysis did not establish a causal relationship between SSc and circulating cytokine levels. Additionally, sensitivity analysis outcomes affirm the reliability of our results. Our MR study suggests potential causal relationships between IL-5, SCGF-β, and the risk of SSc. Further research is essential to determine how IL-5 and SCGF-β influence the development of SSc.

Association between systemic sclerosis and venous thromboembolism, pulmonary embolism, and deep vein thrombosis: ameta-analysis.

This study aimed to analyze the published data pertaining to the correlation between venous thromboembolism (VTE) and systemic sclerosis (SSc). We conducted manual searches and explored MEDLINE, EMBASE, and Cochrane databases to review papers reporting the risk of VTE in patients with SSc. Ameta-analysis was performed exploring the relative risks (RRs) of deep vein thrombosis (DVT), pulmonary embolism (PE), and VTE in these individuals. Six trials that included 41,105 patients with SSc were eligible for inclusion. Ameta-analysis of the six included studies revealed astatistically significant correlation (RR 2.372, 95% confidence interval [CI] = 1.608-3.500, p < 0.001) between the risk of VTE and SSc. Regional subgroup study revealed astrong correlation between SSc and VTE risk in Americans, Europeans, and Asians. Additionally, asignificant correlation between SSc and PE risk was observed (RR 3.154, 95% CI = 1.320-7.539, p = 0.010). Finally, the meta-analysis revealed asubstantial correlation (RR 5.190, 95% CI = 1.513-17.01, p = 0.009) between the risk of DVT and SSc. This meta-analysis showed that SSc is linked to an increased risk of DVT, PE, and VTE. This finding underscores the importance of close monitoring for the emergence of these conditions in patients with SSc.

The Impact of Tobacco Smoking on Systemic Sclerosis, Idiopathic Inflammatory Myositis, and Systemic Lupus Erythematosus.

This narrative review aims specifically to explore the relationship between tobacco exposure and systemic sclerosis (SSc), idiopathic inflammatory myositis (IIM), and systemic lupus erythematosus (SLE). Relevant articles were obtained by searching key terms such as "tobacco," "smoking," "scleroderma," "myositis," "lupus," and "Sjögren's" in PubMed and Google Scholar databases. The selected articles ranged from the years 2010 to 2023. Inclusion criteria were based on the relevance and contribution to the field of study. Systemic sclerosis is a complex condition involving multiple immune cell lines that can be influenced by tobacco. However, the existing literature does not provide sufficient evidence to support an increased risk of SSc in smokers or the impact on treatment options. Cigarette smoking does increase the risk of skin ulcerations in SSc patients. In addition, cigarette smoking has been associated with IIM through genetic and molecular mechanisms. Smokers with dermatomyositis or polymyositis are at an elevated risk of atherosclerosis and interstitial lung disease. Similarly, smoking in patients with SLE increases the risk of organ damage, thrombosis, and disease severity compared with non-smokers. Smokers with SLE also have more difficulty in controlling disease flares compared with non-smokers. Tobacco exposure can lead to secondary complications in patients with IIM and SLE, although the course of treatment may not differ significantly. No definitive conclusions can be drawn to the clear relationship between tobacco smoking and Sjögren's's syndrome.

Higher gamma-glutamyl transferase levels are associated with an increased risk of incident systemic sclerosis: a nationwide population-based study

Gamma-glutamyl transferase (GGT) is known to promote oxidative stress. As oxidative stress is a key component in the pathogenesis of systemic sclerosis (SSc), we investigated whether GGT levels are associated with the risk of incident SSc. A cohort of individuals without SSc who underwent national health examination in 2009 were extracted from the Korean National Health Insurance Service database. The incidence rate of SSc during the observation period, between 2009 and 2019, was estimated. GGT levels measured in 2009 were categorized into quartiles (Q1 [lowest], Q2, Q3, and Q4 [highest]). Multivariable Cox proportional hazard models were used to estimate the risk of incident SSc according to the quartiles of GGT, using Q1 as the reference. A total of 6,091,788 individuals were included. Incidence rate of SSc was 1.16 per 100,000 person-years over a mean observation period of 9.2 years. After adjusting for age, sex, body mass index, economic income, smoking status, alcohol consumption, physical activity, hypertension, type 2 diabetes, dyslipidemia, and chronic kidney disease, higher quartiles of GGT levels were significantly associated with a higher risk of incident SSc (Q4: adjusted hazard ratio [aHR] 1.807, 95% confidence interval CI 1.446–2.259; Q3: aHR 1.221, 95% CI 0.971–1.536; and Q2: aHR 1.034, 95% CI 0.807–1.324; p for trend < 0.001). Higher GGT levels were associated with a higher risk of incident SSc. These findings could lead to a closer monitoring for high risk individuals and an earlier diagnosis and treatment.

Association Between Lipid Profile and Risk of Incident Systemic Sclerosis: A Nationwide Population-Based Study.

Lipid metabolism is altered in systemic sclerosis (SSc), mediating activation of immune cells and fibroblasts. However, it is unclear whether altered lipid profile is associated with a risk of developing SSc. We aimed to assess the association between lipid profile and risk of incident SSc. From a Korean nationwide database, individuals without SSc who underwent national health check-ups in 2009 were selected and followed-up through 2019. Serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride were measured on the health check-up date in 2009. Individuals who developed SSc during follow-up were identified. Multivariable Cox models were performed to estimate the risk of incident SSc according to TC, HDL-C, LDL-C, and triglyceride levels, respectively. Of the 9,894,996 individuals selected, 1355 individuals developed SSc during a mean follow-up of 9.2 years (incidence rate=1.49 per 100,000 person-years). Levels of TC (adjusted hazard ratio [aHR] 0.959, 95% confidence interval [CI] 0.945-0.974), HDL-C (aHR 0.968, 95% CI 0.950-0.987), LDL-C (aHR 0.968, 95% CI 0.952-0.983) were inversely associated with the risk of incident SSc, whereas no significant association was observed between levels of triglyceride (aHR 1.004, 95% CI 0.998-1.011) and risk of incident SSc. Serum levels of TC, HDL-C, and LDL-C were inversely associated with the risk of incident SSc. Our findings provide new insights that altered lipid profile could be considered a non-causal biomarker associated with incident SSc, which could help early diagnosis. The underlying mechanism for this association needs further studies.

Contribution of Telomere Length to Systemic Sclerosis Onset: A Mendelian Randomization Study.

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], p = 0.031) and the Mendelian randomization pleiotropy residual sum and outlier method (OR = 0.716 [95% CI 0.563-0.911], p = 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 TERC and TERT genes, respectively. Our findings suggest an influence of telomere length in leukocytes on the development of SSc.

Clinical Risk Factors for Dysphagia and Esophageal Dysmotility in Systemic Sclerosis.

Systemic sclerosis (SSc) is often associated with dysphagia and esophageal dysmotility; however, only a few clinical studies on this topic have been conducted. Patients with SSc who underwent swallowing examinations and esophagography at our institution between 2010 and 2022 were included. A retrospective evaluation of the patients' backgrounds, autoantibody positivity, swallowing function, and esophageal motility was performed using medical charts. The association between dysphagia and esophageal dysmotility in patients with SSc and respective risk factors was investigated. Data were collected from 50 patients. Anti-topoisomerase I antibodies (ATA) and anti-centromere antibodies (ACA) were detected in 21 (42%) and 11 (22%) patients, respectively. Dysphagia was present in 13 patients (26%), and esophageal dysmotility in 34 patients (68%). ATA-positive patients had a higher risk for dysphagia (p = 0.027); ACA-positive patients had a significantly lower risk (p = 0.046). Older age and laryngeal sensory deficits were identified as risk factors for dysphagia; however, no risk factors for esophageal dysmotility were identified. No correlation was found between dysphagia and esophageal dysmotility. Esophageal dysmotility is more common in patients with SSc than in those with dysphagia. Autoantibodies can be predictors of dysphagia, and dysphagia must be carefully considered in ATA-positive and elderly patients with SSc.

Associations Between Patterns of Esophageal Dysmotility and Extra-Intestinal Features in Patients With Systemic Sclerosis.

The gastrointestinal tract is commonly involved in patients with systemic sclerosis (SSc) with varied manifestations. As our understanding of SSc gastrointestinal disease pathogenesis and risk stratification is limited, we sought to investigate whether patterns of esophageal dysfunction associate with specific clinical phenotypes in SSc. Patients enrolled in the Johns Hopkins Scleroderma Center Research Registry who completed high-resolution esophageal manometry (HREM) studies as part of their clinical care between 2011 and 2020 were identified. Associations between esophageal abnormalities on HREM (absent contractility [AC], ineffective esophageal motility [IEM], hypotensive lower esophageal sphincter [hypoLES]) and patient demographic information, clinical characteristics, and autoantibody profiles were examined. Ninety-five patients with SSc had HREM data. Sixty-five patients (68.4%) had AC (37 patients with only AC, 28 patients with AC and a hypoLES), 9 patients (9.5%) had IEM, and 11 patients (11.6%) had normal studies. AC was significantly associated with diffuse cutaneous disease (38.5% versus 10.0%; P < 0.01), more severe Raynaud's phenomenon, including digital pits, ulcers, or gangrene (56.9% versus 30.0%; P=0.02), and reduced median diffusing capacity of lung for carbon monoxide (50.6% versus 72.2%; P=0.03). AC was observed in most of the patients who died (13 of 14; P=0.06). These findings were not seen in patients with IEM. Among patients with SSc, AC is associated with a significantly more severe clinical phenotype. IEM may associate with a milder phenotype. Further studies are needed to evaluate AC, IEM, and their clinical impact relative to the timing of other end-organ complications in SSc.

Vitiligo and systemic sclerosis: Are they associated?- Lessons from a population-based study.

The epidemiological relationship of vitiligo with systemic sclerosis (SSc) remains to be precisely evaluated. To investigate the bidirectional association between vitiligo and SSc. A population-based study was carried out to compare vitiligo patients (n= 20,851) with age-, sex- and ethnicity-matched control subjects (n= 102,475) regarding the incidence of new-onset and the prevalence of preexisting SSc. Adjusted hazard ratios (HRs) and adjusted odds ratios (ORs) were calculated by the Cox regression and logistic regression, respectively. The incidence rate of new-onset SSc was calculated at 2.4 (95% CI, 1.6-3.4) and 0.4 (95% CI, 0.3-0.6) cases per 10,000 person-years among patients with vitiligo and controls, respectively. Patients with vitiligo had an increased risk of SSc (fully adjusted HR, 5.37; 95% CI, 3.03-9.54; p< 0.001). Correspondingly, a history of SSc predicted elevated odds of developing vitiligo (fully adjusted OR, 2.09; 95% CI, 1.23-3.55; p= 0.006). Relative to other patients with vitiligo, those with vitiligo and comorbid SSc were older and had a higher prevalence of ischaemic heart disease, hyperlipidaemia, and hypertension. A robust bidirectional association exists between vitiligo and SSc. This knowledge is valuable for physicians managing patients with both conditions. Patients with vitiligo and comorbid SSc might be monitored for cardiovascular and metabolic comorbidities.

Several genetic variants associated with systemic sclerosis in a Chinese Han population.

Systemic sclerosis (SSc) is a connective tissue disease with ethnic differences. Single-nucleotide polymorphisms (SNPs) in the ARID3A, CXCR5, and TNFSF8 genes have been reported to be associated with various autoimmune diseases. The aim of this study was to investigate the association between these SNPs and susceptibility to SSc in a Chinese Han population. A case-control study was conducted in 342 patients with SSc and 694 ethnically matched healthy controls. SNPs in ARID3A, CXCR5, and TNFSF8 were genotyped using a Sequenom MassArray iPLEX system, and allele association analyses were performed using the PLINK v1.90 software. Our study demonstrated that the ARID3A rs10415976 G and CXCR5 rs77871618 T alleles were suggestively associated with patients with SSc (P = 0.049 and P = 0.024, respectively) and TNFSF8 rs1555457 T allele was strongly associated with SSc (P = 0.003). Patients carrying the ARID3A rs350146 TT and TNFSF8 rs1555457 TT genotypes had a significant increased risk of SSc (P = 0.03 and P = 0.004, respectively). Moreover, rs10415976, rs77871618, and rs1555457 were associated with SSc in an additive genetic model (P < 0.05). rs62132345 and rs1555457 were associated with SSc in the dominant genetic model (P < 0.05). rs350146 was associated with SSc in the recessive genetic model (P = 0.029). ARID3A rs10415976, ARID3A rs350146, and CXCR5 rs77871618 were suggestively associated with SSc and TNFSF8 rs1555457 was strongly associated with SSc in the Chinese Han population in this study. Key Points •This case-control study determined that ARID3A rs10415976, ARID3A rs350146 and CXCR5 rs77871618 were suggestively associated with SSc and TNFSF8 rs1555457 was strongly associated with SSc in the Chinese Han population. •The differences in these results compared with previous studies may be a result of ethnic and racial differences.

Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes.

Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual’s underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.

Genetic Association between TNFA Polymorphisms (rs1799964 and rs361525) and Susceptibility to Cancer in Systemic Sclerosis.

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that plays an important role in the pathogenesis of autoimmune diseases. The aim of the study was to establish an association between TNF-α promoter variability and systemic sclerosis (SSc). The study included 43 SSc patients and 74 controls. Four single nucleotide polymorphisms (rs361525, rs1800629, rs1799724, and rs1799964) located at the promoter of the TNFA gene were genotyped using commercially available TaqMan allelic discrimination assays with real-time PCR. The rs1799724 allele was associated with an increased SSc susceptibility (p = 0.028). In turn, none of the polymorphisms studied were related to the clinical and laboratory parameters of SSc patients, except for a higher prevalence of anti-Ro52 antibodies in the AG rs1800629 genotype in comparison to GG carriers (p = 0.04). Three of four cancer patients had both CT rs1799964 and AG rs361525 genotypes; thus, both of them were related to the increased risk of cancer, as compared to the TT (p = 0.03) and GG carriers (p = 0.0003), respectively. The TNFA C rs1799724 variant is associated with an increased risk of SSc, while the CT rs1799964 and AG rs361525 genotypes might enhance cancer susceptibility in SSc patients, although large observational and experimental studies are needed to verify the above hypothesis.

Precursors to Systemic Sclerosis and Systemic Lupus Erythematosus: From Undifferentiated Connective Tissue Disease to the Development of Identifiable Connective Tissue Diseases.

The pathogenesis of connective tissue diseases (CTDs), such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), is characterized by derangements of the innate and adaptive immune system, and inflammatory pathways leading to autoimmunity, chronic cytokine production, and chronic inflammation. The diagnosis of these diseases is based on meeting established criteria with symptoms, signs and autoantibodies. However, there are pre-clinical states where criteria are not fulfilled but biochemical and autoimmune derangements are present. Understanding the underlying processes responsible for disease pathogenesis in pre-clinical states, which place patients at increased risk for the development of established connective tissue diseases, represents an opportunity for early identification and potentially enables timely treatment with the goal of limiting disease progression and improved prognosis. This scoping review describes the role of the innate and adaptive immune responses in the pre-clinical states of undifferentiated CTD at risk for SSc and prescleroderma, the evolution of antibodies from nonspecific to specific antinuclear antibodies prior to SLE development, and the signaling pathways and inflammatory markers of fibroblast, endothelial, and T cell activation underlying immune dysregulation in these pre-clinical states.

Risk of rheumatic disease in breast implant users: a qualitative systematic review.

Recent studies on the risk of rheumatic disease among breast implant users have reported conflicting results. The primary objective of this study was to provide a systematic and critical review of the literature on the association between breast implants and the risk of rheumatic disease. A qualitative systematic review was conducted in PubMed, MEDLINE, EMBASE, EBM-Reviews and CINAHL Complete from database inception to June 23rd, 2021. Eligible papers were full-length articles in English or French reporting original data on the incident risk of rheumatic disease among individuals with and without breast implants. Data were extracted from published reports and appraised using the Newcastle-Ottawa scale. The main outcome was incident risk of systemic sclerosis (SSc), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), fibromyalgia and other rheumatic disorders and symptoms. Out of 3,425 identified citations, 86 met inclusion criteria. Two cohort studies suggested a two-fold increase in risk of SSc, whereas three case-control studies showed no increase in risk. Three cohort studies did not find an increased risk of incident and confirmed SS among breast implant users, however symptoms of sicca, myalgia and fatigue were reported more frequently. A meta-analysis of heterogenous studies reported a less than two-fold increase in risk of RA. Studies did not support an association with SLE. Insufficient evidence was available for autoimmune myositis and other rheumatic diseases. Implant rupture detected on imaging was not clearly associated with incident rheumatic disease, although no studies specifically examined the risk associated with acute/traumatic rupture. Little data was available on the safety of saline breast implants. Explantation often led to temporary improvement. Based on a small number of high-quality and methodologically robust studies, an association between breast implants and a small increase in risk of SSc and RA could not be excluded. Symptoms of sicca, myalgia and fatigue were reported more frequently among breast implant users. Overall, there remains much uncertainty in regard to the association between breast implants and the risk of incident rheumatic diseases. Individuals considering the placement of breast implants should be informed of this uncertainty. This study was registered in the PROSPERO database (#CRD42019133616).

Association between Appendicitis and Incident Systemic Sclerosis.

Objective: This nationwide study aimed to investigate the association between newly diagnosed systemic sclerosis (SSc) and previous appendicitis history. Methods: A total of 1595 patients who were newly diagnosed with SSc were recruited as the SSc cases from the 2003 to 2012 claims data of the entire population in Taiwan. The other 15,950 individuals who had never been diagnosed with SSc during 2003 and 2012 were selected as the non-SSc controls to match the SSc cases. We defined that the index date as the first date of SSc diagnosis of SSc cases and the first date of ambulatory visit for any reason of non-SSc controls. Conditional logistic regression analysis was applied for the association between appendicitis and the risk of the incident SSc, tested by estimating odds ratios (ORs) with 95% confidence intervals (CIs). Potential confounders, including the Charlson comorbidity index (CCI), a history of periodontal disease, salmonella infection, and intestinal infection, were controlled. We further designed sensitivity analyses by varying the definition of appendicitis according to the status of receiving primary appendectomy. Results: The mean age was 51 years in the case and control groups. Females accounted for 77.5%. A total of 17 (1.1%) out of 1595 SSc cases and 81 (0.5%) out of 15,950 non-SSc controls had a history of appendicitis before the index date had a history of appendicitis. A significant association between appendicitis and the risk of SSc was confirmed (OR, 2.03; 95% CI, 1.14–3.60) after adjusting potential confounders. CCI ≥ 1 (OR, 8.48; 95% CI, 7.50–9.58) and periodontal disease (OR, 1.55; 95% CI, 1.39–1.74) were also significantly associated with the risk of SSc. The association between appendicitis and SSc risk remained robust using various definitions of appendicitis. Conclusion: Our study demonstrated appendicitis was associated with the incident SSc. CCI ≥ 1 and periodontal disease also contributed to the risk of developing SSc.

Comparative characteristics of the clinical and laboratory features of the primary Sjogren’s syndrome associated with anticentromere antibodies and the “classic” subtype of the disease

Objective: to compare clinical and laboratory manifestations in 2 groups of patients with primary Sjogren’s syndrome (pSS): with and without anticentromere antibodies (ACA); compare the incidence, clinical and laboratory characteristics of lymphomas in these two groups.Materials and methods. We examined 119 patients with ACA-positive pSS (pSS-ACA+). pSS was diagnosed based on Russian 2001 criteria, systemic sclerosis (SSc) – criteria ACR/EULAR 2013. To diagnose liver diseases, the level of transaminases, alkaline phosphatase and antimitochondrial antibodies (AMA) was determined, as well as liver biopsy. The diagnosis of primary biliary cholangitis (PBC) was established according to the recommendations of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association and the Russian Society for the Study of the Liver. Lymphomas were diagnosed according to histological, immunohistochemical and molecular studies of affected organs biopsies, according to the classification of the World Health Organization. A combination of pSS and SSc was diagnosed in 37 patients, and they were excluded from further analysis. We compared clinical and laboratory features in patients with pSS-ACA+ (n=82) and ACA-negative pSS (pSS-ACA–, n=64) and characterized lymphomas in the pSS-ACA+ (n = 14) and pSS-ACA– (n=10) groups.Results and discussion. In patients with pSS-ACA+, a later age of disease onset was revealed, the duration of the disease before lymphoma development did not differ. In patients with pSS-ACA+, we found a lower frequency of rheumatoid factor (RF), antibodies to Ro (anti-Ro) and La (anti-La), decreased C3-complement, hypergammaglobulinemia, increased IgG concentration, CRP, increased ESR, leukopenia and anemia. 51.2% of patients with pSS-ACA+ were seronegative for anti-Ro, anti-La and RF. Patients with pSS-ACA+ had a higher frequency of AMA and elevated IgM. The incidence of cryoglobulinemia and paraproteinemia did not differ. The frequency of recurrent parotitis in pSS-ACA+ was significantly lower, there were no differences in the frequency and severity of other signs of salivary and lacrimal gland damage. PBC and epitheliitis of the biliary ducts in patients with pSS-ACA+ were detected significantly more often. Damage to the peripheral nervous system, lungs, hypergammaglobulinemic purpura, arthralgia and autoimmune thyroiditis were significantly more often detected in the group of patients with pSS-ACA–. In the pSS-ACA+ group, Raynaud’s phenomenon was significantly more frequent, mainly with scleroderma-type capillaroscopic abnormalities. There was no difference in the frequency of other signs characteristic of SSc. MALT lymphomas were diagnosed in the study groups with the same frequency. Patients with lymphomas in the pSS-ACA+ group were characterized by significantly higher laboratory activity. All patients with lymphomas in both groups showed persistent parotid salivary gland enlargement. Lymphomas in both groups developed in patients with late stage salivary and lacrimal gland damage, systemic manifestations of pSS in both groups were rare.Conclusion. pSS-ACA+ is an independent subtype of pSS, which has a number of significant clinical and laboratory differences from the “classic” variant of the disease. ACA in pSS are associated with a low frequency of anti-Ro, anti-La, and RF, as well as an increased risk of PBC and limited SSc. MALT lymphomas in the pSS-ACA+ and pSS-ACA– groups developed with the same frequency and were associated with the progression of glandular damage, regardless of the presence of systemic manifestations.

Geographic distribution and environmental triggers of systemic sclerosis cases from 2 large academic tertiary centers in Massachusetts

To the Editor: Systemic sclerosis (SSc) is a chronic autoimmune sclerosing disease with the highest case fatality rate among connective tissue diseases.1Feghali-Bostwick C.A. Varga J. Systemic Sclerosis.in: Bradshaw R.A. Dennis E.A. Handbook of Cell Signaling. 2nd ed. Academic Press, 2010: 2913-2917Crossref Scopus (1) Google Scholar Since the 1980s, the annual incidence rates in North America have increased from 1.7 to 2.7 per 100,000 individuals.2Bergamasco A. Hartmann N. Wallace L. Verpillat P. Epidemiology of systemic sclerosis and systemic sclerosis-associated interstitial lung disease.Clin Epidemiol. 2019; 11: 257-273Crossref PubMed Scopus (66) Google Scholar Although the exact pathogenesis of SSc remains unclear, environmental triggers have been hypothesized to provoke disease development among genetically predisposed hosts.3Barnes J. Mayes M.D. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers.Curr Opin Rheumatol. 2012; 24: 165-170Crossref PubMed Scopus (212) Google Scholar,4McCormic Z.D. Khuder S.S. Aryal B.K. Ames A.L. Khuder S.A. Occupational silica exposure as a risk factor for scleroderma: a meta-analysis.Int Arch Occup Environ Health. 2010; 83: 763-769Crossref PubMed Scopus (82) Google Scholar The assessment of high-prevalence geographic clusters may be a crucial first step in cause identification. Our objectives were to analyze SSc hotspots in Massachusetts and identify possible environmental triggers. The research patient data registry was utilized to identify 4579 potential SSc cases and zip codes from medical records between 1989 and 2019 of Massachusetts General Hospital and Brigham and Women's Hospital. Cases confirmed by dermatologists or rheumatologists were included (n = 2196). The period prevalence was calculated based on the population per zip code. QGIS3.10, a geospatial program, was used to create and analyze SSc distribution and prevalence maps (Fig 1). These maps were compared to environmental toxins and social justice maps to determine trends in etiologic triggers and demographic clusters. Statistical analysis was performed using 2 sample t tests. Hazardous waste facilities (P = .0039) and oil release or disposal sites (P = .0203) were significantly associated with a higher SSc prevalence (Fig 2). Although the association between chemical release sites and SSc prevalence was not independently significant (P = .3166), a spatial correlation was found to exist. Exposure to all 3 sites together posed a significantly increased SSc risk (P = .0002). Disease hotspots showed greater particulate pollution levels and were in proximity to ash pollution and combustion facilities (Supplemental Fig 1 available via Mendeley at https://data.mendeley.com/datasets/59zfn6fdb2/2). The maps of low-income and minority communities demonstrated a spatial relationship with SSc hotspots, suggesting a possible association between socioeconomic factors and disease (Supplemental Fig 2 available via Mendeley at https://data.mendeley.com/datasets/59zfn6fdb2/2).5Environmental justice populations in Massachusetts | Mass.gov.https://www.mass.gov/info-details/environmental-justice-populations-in-massachusettsDate accessed: January 27, 2021Google Scholar The presence of SSc regional clustering and increased density of industry and waste sites in these areas suggest that environmental pollutants play a critical role in disease development. Additionally, the clustering of SSc hotspots and environmental pollutants around low-income and minority neighborhoods indicates that these residents face a disproportionate burden of toxin exposure and disease. High-SSc prevalence pockets in Central and Western Massachusetts with few or no direct toxin sites may be impacted by their surrounding environmental factors, such as water sources collecting precipitated pollutants from nearby facilities or by cross-state pollution, both waterborne and airborne. Another possible explanation for SSc regional clustering is the social drift hypothesis, suggesting that those with chronic diseases are more likely to reside in low-income areas because of disease burden. The study limitations include potential confounders contributing to disease, such as genetic predispositions, sociodemographic factors, and proximity bias. Finally, our study demonstrated a correlation but could not prove causation, making further study of this important topic crucial. Further investigations, including wider geographies and more diverse patient populations, are warranted. Ultimately, this research may provide a greater understanding of the potential role of environmental toxins in SSc onset. Furthermore, it may be used as an advocate for environmental and health policy reforms to protect communities disproportionately burdened by their exposure to environmental toxins and their adverse health effects. None disclosed.

New perspectives in the imaging of Raynaud's phenomenon.

The last 10-20 years have seen huge strides in imaging science. The aim of this review article is to share with the reader the key recent advances in non-invasive imaging of the digital (finger) vasculature in patients with Raynaud's phenomenon (RP), including in systemic sclerosis (SSc)-related digital vasculopathy. For the rheumatologist, seeing a patient with RP is an opportunity for early diagnosis of an underlying SSc-spectrum disorder or (conversely) for reassuring the patient with primary (idiopathic) RP. Non-invasive imaging techniques can help to provide diagnostic certainty. In addition, they can provide new insights into pathophysiology and have the potential to facilitate the development of much needed effective treatments by providing primary and secondary endpoints for randomized controlled trials: validation studies are ongoing. This review article focuses on nailfold capillaroscopy, thermography, and laser Doppler methods but also discusses (briefly) other technologies, including optical coherence tomography, multispectral imaging, and photoacoustic imaging. Key recent advances are the increasing use/availability of nailfold capillaroscopy (and better understanding of the role of low-cost hand-held devices), increased accessibility of thermography (including mobile phone thermography), and increased application of laser Doppler methods to the study of RP/digital vasculopathy (in particular of laser Doppler imaging and laser speckle contrast imaging, both of which measure blood flow over an area rather than at a single site). In an era of precision medicine, non-invasive imaging techniques can help stratify risk of (a) SSc in the patient with RP and (b) digital vascular disease progression in the patient with an SSc-spectrum disorder.