Systemic Sclerosis and Cardiovascular Disease-related Mortality in the United States: An Analysis of Trends and Disparities, 1999-2022

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Data regarding SSc-related CVD mortality in the United States (US) population has not been studied. We aim to analyze the mortality rate related to SSc and cardiovascular disease in the US adult population and differences across different demographic and geographic subgroups. Methods Systemic Sclerosis-associated CVD mortality data were extracted from the Center for Disease Control and Prevention Wide-ranging Online Data Epidemiologic Research (CDC WONDER) database. We extracted age-adjusted mortality rates (AAMR) per 1,000,000 people for population age ≥15 and calculated annual change percentage (APC) using Joinpoint regression. The data were stratified into demographic (gender, race, age groups) and geographic (census region, and state) groups to analyze differences between the trends. Results Between 1999 and 2022, 25,727 deaths were related to SSc and CVD deaths. The overall AAMR for SSc-associated CVD mortality decreased significantly from 5.39 in 1999 to 3.58 in 2022. AAMR decreased by 39.33% from 1999 to 2019, increased by 10.50% from 2019 to 2022. Sex disparities were identified, with females experiencing a higher AAMR (6.01) compared to males (1.63). NH Blacks or African Americans had the highest overall AAMR (5.76), followed by Hispanics (4.14), and NH Whites (3.76). Age disparities were identified with the Elderly (≥75) having the highest overall AAMR (18.70), followed by Middle Age (45-74) (6.15), and Young (15-44) (0.59). Geographically, all regions had similar AAMR. Conclusion Overall, from 1999 to 2022, CVD-related mortality associated with SSc decreased in the US, with a brief and modest increase seen during the COVID-19 pandemic. Despite this overall decline, substantial disparities were identified with NH Black people, women, and people ≥ 75 exhibiting significantly higher AAMRs. Cardiovascular disease Systemic Sclerosis Mortality Trends Disparities United States Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Fibrotic changes in connective tissue characterize systemic sclerosis (SSc), although its exact causes remain unclear. However, in recent years, our understanding of this condition has progressed to include other organ systems, including the heart, lungs, kidneys, and gastrointestinal tracts.[1] The heterogeneity of the presentation poses a significant challenge, particularly in the management and prediction of the SSc disease course. The severity of internal organ manifestations is an important indicator for the overall prognosis of SSc patients. Because manifestations can be unpredictable in terms of the prognosis of the patient population, it creates a unique challenge for both patients and clinicians.[2] Cardiopulmonary involvement is the leading cause of mortality in SSc, with cardiac complications accounting for 26% of SSc-related deaths.[2] SSc involves the heart in various ways, ranging from arrhythmias to heart failure.[2] Notably, the prevalence of heart failure is significantly higher in SSc patients compared to the similar age group. In multiple studies, diastolic dysfunction prevalence in those with SSc is on average at 18-62%, while similarly aged groups’ prevalence in diastolic dysfunction is at 1.4-38.1%.[3–5] Additionally, cardiac dysfunction secondary to SSc is associated with worse outcomes compared to those without SSc.[6] Beyond structural cardiac changes, SSc leads to endothelial damage, vascular remodeling, and macro- and microvascular dysfunctions.[7] These changes result in vascular pathologies, including myocardial infarction, peripheral vascular diseases, pulmonary hypertension, and renal crisis.[7,8] Data regarding SSc-related CVD mortality in the United States (US) population has not been studied. We aim to analyze the mortality rate related to SSc and cardiovascular disease in the US adult population and differences across different demographic and geographic subgroups. Methods Study design and database The Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) was used to identify SSc and CVD-related deaths in the United States. This database has been used to study trends and disparities for various cardiovascular and non-cardiovascular diseases. 9,10,11,12 The Multiple Cause of Death public use records of death certificates were extracted, which listed SSc and CVD as an underlying or contributing cause on nationwide death certificate records.[ 13 ] We extracted data regarding SSc and CVD-related deaths and population sizes from 1999 to 2022. The International Classification of Diseases, 10th Revision, Clinical Modification codes M34 and I00-I99 were used to identify deaths from SSc and CVD, respectively.[ 14 ] The study was exempt from institutional review board approval because the CDC WONDER database contains anonymized, publicly available data. Demographic and geographical study groups Data extracted for analysis included biological sex, race and ethnicity, age groups, region, and state. Biological sex included men and women. Race and ethnicity groups were divided into non-Hispanic (NH) white, NH Black people, and Hispanic or Latino. Age groups included adults aged ≥ 15, which were divided into young (15–44), middle age (45–74), and elderly (≥ 75) age groups. We extracted data for four census regions (Northeast, Midwest, South, and West), classified by the Census Bureau definitions. Statistical analysis SSc and CVD-related deaths and age-adjusted mortality rates (AAMR) per 1,000,000 were used for analysis, which adjusts for the variation in the population's size and age distribution, enabling better data comparison. The study used the Joinpoint Regression Program (Joinpoint version 5.3.0) available from the National Cancer Institute, Bethesda, Maryland) to analyze mortality trends from 1999–2023.[ 15 ] Significant changes in annual mortality trends by fitting models of linear segments are used to calculate annual percentage change (APC) with 95% confidence intervals (CIs) for the age-adjusted mortality rates (AAMRs) for the line segments. The weighted average of the APCs was calculated and reported as average annual percentage changes (AAPCs), along with corresponding 95% CIs, to summarize the reported mortality trend for the entire study period. APCs and AAPCs were identified as increasing or decreasing based on whether the change in mortality over the time interval significantly differed from zero using a 2-tailed t-test. Statistical significance was set at p ≤ 0.05 and is represented by an asterisk ‘*’ in the results and figures (Table 1 ). Table 1 Systemic Sclerosis and Cardiovascular Disease-related total number of deaths and AAMR in the US from 1999 to 2022, annual AAMRs for 1999 and 2022, and AAPC from 1999 to 2022. AAMR: Age-adjusted mortality rate; AAPC = Average annual percent change; 95% CI: 95% Confidence interval; * = significantly different from 0 with p < 0.05 Deaths, 1999 to 2022 (percentage, %) AAMR, 1999 to 2022 (95% CI) 1999 AAMR (95% CI) 2022 AAMR (95% CI) AAPC from 1999 to 2022 (95% CI) Overall 25965 4.02 (3.96 to 4.09) 5.39 (5.08 to 5.70) 3.58 (3.37 to 3.79) -1.54* (-2.09 to -1.21) Sex stratified Male 4811 (18.52) 1.63 (1.57 to 1.69) 2.17 (1.87 to 2.47) 1.58 (1.38 to 1.79) -1.74* (-2.42 to -1.19) Female 21154 (81.47) 6.01 (5.91 to 6.11) 7.99 (7.48 to 8.50) 5.27 (4.92 to 5.61) -1.46* (-2.07 to -1.07) Race Stratified NH Black or African American 3909 (15.05) 5.76 (5.53 to 5.99) 8.04 (6.83 to 9.25) 4.71 (3.97 to 5.46) -2.44* (-3.07 to -1.82) NH White 18762 (72.25) 3.76 (3.69 to 3.82) 4.99 (4.66 to 5.32) 3.40 (3.16 to 3.64) -1.42* (-2.09 to -1.00) Hispanic 2408 (9.27) 4.14 (3.92 to 4.36) 6.88 (5.42 to 8.61) 3.97 (3.3 to 4.64) -1.74 (-3.53 to 0.12) Census Region Northeast 5308 (20.44) 4.31 (4.17 to 4.46) 5.47 (4.78 to 6.16) 3.60 (3.12 to 4.09) -2.02* (-2.50 to -1.59) Midwest 5865 (22.58) 4.12 (3.99 to 4.25) 4.88 (4.27 to 5.49) 3.80 (3.34 to 4.27) -0.83* (-1.31 to -0.21) South 8950 (34.46) 3.77 (3.68 to 3.87) 5.68 (5.15 to 6.22) 3.22 (2.90 to 3.54) -1.94* (-2.71 to -1.36) West 5842 (22.49) 4.16 (4.03 to 4.30) 5.47 (4.77 to 6.16) 3.97 (3.51 to 4.42) -1.73* (-2.36 to -1.10) Age Groups Young (15–44) 1715 (6.60) 0.59 (0.56 to 0.63) 0.78 (0.64 to 0.95) 0.43 (0.32 to 0.57) -2.42* (-3.35 to -1.60) Middle Age (45–74) 15588 (60.03) 6.15 (6.03 to 6.27) 9.19 (8.53 to 9.86) 4.98 (4.59 to 5.37) -2.33* (-3.15 to -1.77) Elderly (≥ 75) 8662 (33.36) 18.70 (18.20 to 19.20) 20.59 (18.40 to 22.79) 19.68 (17.90 to 21.45) -0.30 (-1.07 to -0.17) Results From 1999 to 2022, there were 43,010 systemic sclerosis-related deaths in the United States ( Supplemental Table 1 ). Overall, systemic sclerosis AAMR per 1,000,000 decreased significantly from 8.98 (95% CI: 8.58 to 9.38) in 1999 to 5.44 (95% CI: 5.18 to 5.70) in 2022 (AAPC − 2.30* (95% CI: -2.55 to -2.09). AAMR decreased from 1999 to 2019 (APC: -2.89*, 95% CI: -3.13 to -2.72) and stayed stable from 2019 to 2022 (APC: 1.74, 95% CI: -1.15 to 5.72) (Fig. 1 ). Of the 43,010 SSc deaths, 25,965 (64.47%) were associated with cardiovascular disease. Within CVD, the major subcategories associated with SSc-related deaths were Pulmonary heart disease and diseases of pulmonary circulation (22.16%), Heart failure (15.02%), Ischemic heart disease (12.06%), and Hypertensive diseases (10.73%) ( Supplement Table 5 ). The overall AAMR for SSc-associated CVD mortality decreased significantly from 5.39 (95% CI: 5.08 to 5.70) to 3.58 (95% CI: 3.37 to 3.79) in 2022 (AAPC of -1.54* (95% CI: -2.09 to -1.21). AAMR decreased significantly from 1999 to 2019 (APC: -2.37*, 95% CI: -3.12 to -2.01) and then increased from 2019 to 2022 (APC: 4.11, 95% CI: -1.24 to 19.23) (Table 1 , Fig. 1 , Supplemental Fig. 1, Supplemental Fig. 2 ). Gender-stratified trend for Systemic Sclerosis-associated CVD mortality From 1999 to 2022, systemic sclerosis-associated CVD deaths in the United States, 4811 (18.55%) were in men and 21,154 (81.45%) in women ( Supplemental Table 1) . Women consistently had higher AAMR than men throughout the study, though both followed a similar overall downtrend. From 1999 to 2022, the AAMR in women decreased with an AAPC of -1.46* (95% CI: -2.07 to -1.07). The AAMR in women decreased by -39.79% from 7.99 (95% CI: 7.48 to 8.50) in 1999 to 4.81 (95% CI: 4.47 to 5.15) in 2019 (APC: -2.22*, 95% CI: -3.52 to -1.76) followed by a 9.56% increase to 5.27 (95% CI: 4.92 to 5.61) in 2022. From 1999 to 2022, men had a significant reduction in mortality as well (AAPC: -1.74*, 95% CI: -2.42 to -1.19). The AAMR in men decreased from 2.17 (95% CI: 1.87 to 2.47) in 1999 to 1.21 (95% CI: 1.03 to 1.40) in 2017 (APC: -3.00*, 95% CI: -4.26 to -2.41), followed by an increase to 1.58 (95% CI: 1.38 to 1.79) in 2022 (Table 1 , Supplemental Fig. 1 , Fig. 2 , Supplemental Table 2 ). Race-stratified trend for Systemic Sclerosis-associated CVD mortality Of the total SSc and CVD-related deaths, 3903 (15.57%) were NH black, 2408 (9.60%) were Hispanic or Latino, and 18751 (74.81%) were NH White. Overall, NH black people had the highest AAMR but also witnessed the most significant reduction in mortality (AAPC − 2.44*, 95% CI: -3.07 to -1.82). NH black individuals’ AAMR decreased from 8.04 (95% CI: 6.83 to 9.25) in 1999 to 4.71 (95% CI: 3.97 to 5.46) in 2022. Hispanic people had a relative lesser reduction in AAMR from 6.88 (95% CI: 5.42 to 8.61) in 1999 to 2.53 (95% CI: 1.97 to 3.19) in 2017, with an APC of -3.41 (95% CI: -12.71 to 53.27) with an increase in AAMR to 3.97 (95% CI: 3.30 to 4.64) in 2022 with an APC of 4.50 (95% CI: -2.83 to 37.80). For the NH White population, the AAMR decreased, though to a lesser extent, compared to NH black people, from 1999–2022 with an AAPC − 1.42* (95% CI: -2.09 to -1.00). Their AAMR initially decreased from 4.99 (95% CI: 4.66 to 5.32) in 1999 to 3.01 (95% CI: 2.79 to 3.24) in 2019 (APC of -2.36*, 95% CI: -3.39 to -1.92) and then increased to 3.40 (95% CI: 3.16 to 3.64) in 2022 (APC of 5.10, 95% CI: -1.27 to 24.16). (Table 1 , Supplemental Fig. 2, Supplemental Table 2 , Fig. 3 ). Age-group Stratified trend for Systemic Sclerosis-associated CVD mortality All age groups witnessed a reduction in AAMR from 1999 to 2019. The older age group (≥ 75 years) had a non-significant reduction in mortality from 1999 to 2022 (AAPC − 0.30, 95% CI: -1.07 to 0.174). Those 75 years and older had the highest AAMR throughout the study duration, which decreased from 20.59 (95% CI: 18.40 to 22.79) in 1999 to 16.59 (95% CI: 14.91 to 18.28) in 2019 (APC: -1.36*, 95% CI: -2.66 to -0.80) followed by an increased to 19.68 (95% CI: 17.90 to 21.45) in 2022 with an APC of 7.00 (95% CI: -0.49 to 26.39). The young age-group (15–44) had a significant reduction in mortality from 1999 to 2022 (AAPC − 2.42*, 95% CI; -3.35 to -1.60). The middle-aged group (45–74) also had a significant reduction in mortality from 1999 to 2022 (AAPC − 2.33*, 95% CI: -3.15 to -1.77). Their AAMR decreased from 9.19 (95% CI: 8.53 to 9.86) in 1999 to 4.83 (95% CI: 4.44 to 5.21) in 2018 with an APC of -2.97 (95% CI: -6.63 to 15.16) and similar AAMR of 4.98 (95% CI: 4.59 to 5.37) by 2022 (2018–2022 APC 0.75, 95% CI: -10.69 to 15.23). (Table 1 , Supplemental Table 2, Supplemental Fig. 3 , Fig. 5 ). Region-Stratified trend for Systemic Sclerosis-associated CVD mortality All four census regions of the US saw a decrease in AAMR from 1999 to 2022, with the South seeing the most significant reduction of -43.30% (AAPC − 1.94*, 95% CI: -2.72 to -1.36). AAMR for South region decreased from 5.68 (95% CI: 5.15 to 6.22) in 1999 to 2.93 (95% CI: 2.62 to 3.25) in 2018 (APC: -3.00*, 95% CI: -4.86 to -2.41) and with an increase in AAMR 3.22 (95% CI: 2.90 to 3.54), APC of 3.25 (95% CI: -2.00 to 22.05) from 2018 to 2022. The northeast and west regions followed this. West region saw the AAMR decrease from 5.47 (95% CI: 4.77 to 6.16) in 1999 to 3.97 (95% CI: 3.51 to 4.42) in 2022 (AAPC − 1.73*, 95% CI: -2.36 to -1.10) followed by the Northeast with similar AAMR of 5.47 (95% CI: 4.78 to 6.16) in 1999 which decreased to 3.60 (95% CI: 3.12 to 4.09) in 2022 (AAPC: -2.02*, 95% CI: -2.50 to -1.59). In the Midwest, the AAMR initially stayed stable from 4.88 (95% CI: 4.27 to 5.49) in 1999 to 4.64 (95% CI: 4.08 to 5.20) in 2009 (APC: -0.39, 95% CI: -1.50 to 3.61). This was followed by a decrease in AAMR from 4.64 (95% CI: 4.08 to 5.20) in 2009 to 3.43 (95% CI: 2.97 to 3.89) in 2016 with an APC of -4.41* (95% CI: -14.11 to -2.44) and an increase in AAMR to 3.80 (95% CI: 3.34–4.27) by 2022 with an APC of 2.73* (95% CI: 0.07 to 10.51). (Table 1 , Supplemental Table 3 , Fig. 4 , Supplemental Fig. 4 ) State-level trend A marked overall difference in AAMR was observed among the states. From 1999 to 2023, Nebraska had the highest AAMR of 5.35 compared to New Hampshire with the lowest AAMR of 2.47. States in the upper 90th percentile of SSc associated CVD-related mortality included Nebraska, South Dakota, Oklahoma, Colorado, and Rhode Island which had more than twice the AAMRs compared to states in the lower 10th percentile of SSc associated CVD-related deaths which included New Hampshire, Louisiana, Arizona, Alabama, Arkansas ( Supplemental Table 4 ). Discussion Our analysis, spanning multiple decades of US mortality, revealed several insights. CVD was associated with approximately two-thirds of all SSc-related deaths. Overall, there was a decrease in SSc-associated CVD-related deaths during the study period, with a modest increase in AAMRs observed from 2019 to 2022 in overall and most subgroup trends. Females had higher AAMR compared to men throughout the study. The NH Black population had the highest AAMR, while the NH White population had the lowest. Regionally, the Northeast, South, Midwest, and West had similar AAMRs with a decreasing trend. Our findings align with previous research, showing a steady decline in SSc mortality from 1968 to 2015. 1,2 We observed that SSc mortality is highly associated with CVD, with approximately two-thirds of all SSc deaths related to CVD from 1999 to 2022. In our study, among CVD, Pulmonary heart disease, and diseases of pulmonary circulation were associated with the most SSc deaths. Data from EUSTAR has also shown that 26% of SSc deaths were related to pulmonary hypertension.[ 2 ] Heart failure was the second most common CVD associated with SSc mortality in our study, aligning with EUSTAR findings that report heart failure as the cause of 10% of SSc deaths. Ischemic heart disease also contributed to increased mortality in our cohort, with EUSTAR data indicating it accounts for 5% of SSc-related deaths. Finally, hypertensive renal crisis was found to be a significant contributor to mortality in our study, consistent with EUSTAR data, attributing 4% of SSc deaths to renal crisis. Moreover, in a systematic review, coronary artery disease has been established to manifest more frequently in SSc compared to controls, consistent with our findings.[ 17 ] We found an overall downtrend in the SSc-associated CVD mortality from 1999 to 2022. This trend is likely due to a multitude of factors. Overall, there has been an ongoing decrease in ischemic heart disease mortality that may be explained by better treatment of cardiovascular risk factors or by an improvement in health care systems, such as cardiac catheterization and improved medical management.[ 11 ] This supports our data with the decrease in SSc-associated CVD mortality. Another potential reason for the reduction in mortality could be explained by the most common cardiac involvement in SSc, which is pulmonary arterial hypertension (PAH).[ 18 , 19 ] With the development of new therapies for PAH, such as Phosphodiesterase-5 Inhibitors (sildenafil and tadalafil), guanylate cyclase stimulator (riociguat), and endothelin receptor antagonists.[ 18 ] Cardiac arrhythmias are a less common presentation of SSc, yet account for a disproportionate number of SSc-associated deaths.[ 2 ] Non-specific arrhythmic and conduction abnormalities are detected in 50% of SSc patients on resting ECG.[ 2 , 20 ] Both atrial and ventricular arrhythmias arise throughout the disease course, with QT prolongation hypothesized as a contributing reason causing disturbed ventricular repolarization.[ 20 , 21 ] Additionally, SSc is linked with dysfunction of the autonomic nervous system, triggering ventricular arrhythmias and associated with a five-fold increased risk of cardiovascular mortality and increased risk of SCD.[ 20 ] Lastly, another risk for SSc mortality is renal crisis, which is a life-threatening condition. With the advent of angiotensin-converting enzyme inhibitor (ACEi) therapy, mortality has improved, which is consistent with our study.[ 8 ] An increase in AAMRs was observed from 2019 to 2022 overall and in most subgroup trends. The advent of the COVID-19 pandemic likely contributed to the increased SSc-associated CVD mortality. In a single-center study, the prevalence of COVID-19 in patients with SSc was 12.5%, and the COVID-19-specific mortality rate among SSc patients was 3.1%. In the general population, prevalence was 6.8% with a mortality of 0.07%, illustrating the increased risk of both COVID-19 infection and death with SSc.[ 22 ] The probable cause of this increased mortality is due to the underlying mechanism of SSc-associated CVD. SSc-associated CVD and COVID-19 share a similar pathogenesis of microvascular damage, which is endothelial cell activation/injury and dysfunction. SSc patients hospitalized with COVID-19 had higher odds of left heart failure, cardiac arrest, and ventricular arrhythmias. COVID-19 has been associated with many cardiac complications and an increased risk of long-term complications such as heart failure, arrhythmias, and myocarditis.[ 23 , 24 ] Our analysis revealed differences in AAMRs across gender and racial groups. Females had almost three times higher AAMRs compared to men, which is in accordance with previous research that the incidence of SSc is higher in women.[ 25 ] Though women have a higher incidence, other studies have shown that men diagnosed with SSc have a higher rate of premature death than their female counterparts.[ 26 , 27 ] In two studies, male sex was independently associated with left ventricular dysfunction, pulmonary fibrosis, and heart failure in SSc.[ 28 , 29 ] This highlights that men with SSc have more severe manifestations of cardiovascular involvement than women, who have higher overall SSc-associated CVD mortality, which is likely due to SSc disproportionately affecting females, leading to a higher AAMR. Racial groups also exhibited marked disparities, with NH Black people having twice that of NH White, who had the lowest rate. The gap between the NH Black and NH White populations narrowed over the past two decades, but there is still room for improvement. NH Blacks have an elevated risk of SSc-associated CVD stemming from an increased susceptibility due to an imbalance of pro-fibrotic and anti-fibrotic factors. This is alluded to racial difference expression of transforming growth factor-β1 (TGF-β1) and caveolin-1, as well as differences in the expression of hepatocyte growth factor (HGF) and PPAR-γ.[ 30 ] Beyond genetic predisposition, this ethnicity experiences low socioeconomic standing and limited healthcare access, which further exacerbate the dichotomy in the AAMR trends. 25 The age group with the highest mortality was the elderly, which could be secondary to cumulative toxicities of medications over time in SSc, leading to higher mortality. Additionally, if diagnosed at a late age (> 65 years), there are greater risks of pulmonary hypertension, renal impairment, and cardiac disease, leading to increased mortality.[ 31 ] Our analysis showed that all regions in the United States had similar AAMR and experienced a net decrease from 1999 to 2022. Nebraska, South Dakota, and Oklahoma had the highest mortality rates. Higher mortality rates are anticipated in regions with higher disease incidence; however, mortality data alone cannot be used to infer incidence rates directly. The clustering of disease-related deaths in specific geographic areas suggests that environmental and genetic factors may play a role, but further research is needed to confirm this. These findings highlight essential concerns regarding SSc care in disadvantaged populations, emphasizing the need to investigate the factors driving these disparities and public health efforts to tackle these differences. To address these issues, it is crucial to implement targeted interventions that meet these vulnerable groups' specific needs and challenges. Limitations CDC WONDER data is compiled from death certificates, which rely on ICD codes for disease identification; thus, a potential for misclassification bias is present. Though we used validated ICD codes, SSc is under-coded on death certificates, leading to potential underestimation. This study could only analyze racial disparities for NH white, NH Black, and Hispanic or Latino. NH Asian or Pacific Islander and NH American Indian or Alaska Native could not be analyzed because of suppressed data in these subgroups for most of the years. CDC suppresses the counts of fewer than 10 in CDC WONDER data to protect confidentiality, and death rates are marked unreliable for a count less than 20 per the CDC WONDER data use agreement. Other characteristics of the study population, such as social determinants of health that could contribute to the patient’s death, are not available in the data files for analysis. Moreover, despite the physiological plausibility of the association between SSc and CVD, due to the ecological nature of our study, a causal relationship cannot be established based on the findings of this study. Conclusion Overall, from 1999 to 2022, CVD-related mortality associated with SSc decreased in the US, with a brief and modest increase seen during the COVID-19 pandemic. Despite this overall decline, substantial disparities were identified with NH Black people, women, and people ≥ 75 exhibiting significantly higher AAMRs. Abbreviations SSc Systemic Sclerosis CVD Cardiovascular Disease AAMR Age-Adjusted Mortality Rate APC Annual Percent Change AAPC Average Annual Percent Change NH Non-Hispanic PAH Pulmonary Arterial Hypertension ECG Electrocardiogram SCD Sudden Cardiac Death Declarations Ethics approval and consent to participate: Not applicable Consent for publication : Not applicable Availability of data and materials : all data is available at: https://wonder.cdc.gov/ Competing Interests: Not applicable Funding : Not applicable Authors' Contributions: ABAJ: Conceptualization, Methodology, Acquisition, Analysis, Interpretation of data, Visualization; Writing- Original draft preparation, Reviewing and Editing; WT: Interpretation of data, Visualization; Writing- Original draft preparation, Reviewing and Editing. MC Writing- Original draft preparation; KG: Writing- Original draft preparation. AA: Supervision, Writing- Reviewing and Editing. Acknowledgements Not applicable References Rodnan GP, Benedek TG. An historical account of the study of progressive systemic sclerosis (diffuse scleroderma). Ann Intern Med. 1962;57:305–19. Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010;69(10):1809–15. Tennøe AH, Murbræch K, Andreassen JC, Fretheim H, Garen T, Gude E, et al. Left Ventricular Diastolic Dysfunction Predicts Mortality in Patients With Systemic Sclerosis. J Am Coll Cardiol. 2018;72(15):1804–13. Vemulapalli S, Cohen L, Hsu V. Prevalence and risk factors for left ventricular diastolic dysfunction in a scleroderma cohort. Scand J Rheumatol. 2017;46(4):281–7. Fernández-Codina A, Simeón-Aznar CP, Pinal-Fernandez I, Rodríguez-Palomares J, Pizzi MN, Hidalgo CE, et al. Cardiac involvement in systemic sclerosis: differences between clinical subsets and influence on survival. Rheumatol Int. 2017;37(1):75–84. Sun G, Yafasova A, Andersson C, McMurray JJV, Jhund PS, Docherty KF, et al. Gender- and age-specific rates of heart failure and other adverse cardiovascular outcomes in systemic sclerosis. Rheumatol Oxf Engl. 2022;61(11):4374–83. Kawaguchi Y, Kuwana M. Pathogenesis of vasculopathy in systemic sclerosis and its contribution to fibrosis. Curr Opin Rheumatol. 2023;35(6):309–16. Cole A, Ong VH, Denton CP. Renal Disease and Systemic Sclerosis: an Update on Scleroderma Renal Crisis. Clin Rev Allergy Immunol. 2023;64(3):378–91. Abdul Jabbar AB, May MT, Deisz M, Tauseef A. Trends in heart failure-related mortality among middle-aged adults in the United States from 1999–2022. Curr Probl Cardiol. 2025;50(3):102973. Morrissey R, Lee J, Baral N, Tauseef A, Sood A, Mirza M, et al. Demographic and regional trends of sepsis mortality in the United States, 1999–2022. BMC Infect Dis. 2025;25(1):504. Abdul Jabbar AB, Klisares M, Gilkeson K, Aboeata A. Acute Myocardial Infarction Mortality in the Older Population of the United States: An Analysis of Demographic and Regional Trends and Disparities from 1999 to 2022. J Clin Med. 2025;14(7):2190. Abdul Jabbar AB, Khan DA, Li-Jedras M, Kabach A, Aboeata A. Trends of infective endocarditis mortality in young adult population of US: A concerning rise and its association with substance abuse. Int J Cardiol Cardiovasc Risk Prev. 2025;25:200404. Multiple. Cause of Death, 1999–2020 Request [Internet]. [cited 2024 Nov 8]. Available from: https://wonder.cdc.gov/mcd-icd10.html Organization WH. ICD-10: international statistical classification of diseases and related health problems : tenth revision [Internet]. World Health Organization; 2004 [cited 2025 Feb 7]. Available from: https://iris.who.int/handle/10665/42980 Joinpoint Regression Program [Internet]. [cited 2025 Jan 5]. Available from: https://surveillance.cancer.gov/joinpoint/ Yen EY, Singh DR, Singh RR. Trends in Systemic Sclerosis Mortality Over Forty-Eight Years, 1968–2015: A US Population-Based Study. Arthritis Care Res. 2021;73(10):1502–10. Ungprasert P, Charoenpong P, Ratanasrimetha P, Thongprayoon C, Cheungpasitporn W, Suksaranjit P. Risk of coronary artery disease in patients with systemic sclerosis: a systematic review and meta-analysis. Clin Rheumatol. 2014;33(8):1099–104. Almaaitah S, Highland KB, Tonelli AR. Management of Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis. Integr Blood Press Control. 2020;13:15–29. Ross L, Prior D, Proudman S, Vacca A, Baron M, Nikpour M. Defining primary systemic sclerosis heart involvement: A scoping literature review. Semin Arthritis Rheum. 2019;48(5):874–87. Ross L, Paratz E, Baron M, La Gerche A, Nikpour M. Sudden Cardiac Death in Systemic Sclerosis: Diagnostics to Assess Risk and Inform Management. Diagn Basel Switz. 2021;11(10):1781. Saramet EE, Cojocaru DC, Ungurianu S, Negru RD, Ancuta C. QT Interval Prolongation in Patients with Systemic Sclerosis-Are the Holter ECG Recordings a Better Option for QT Interval Evaluation? Med Kaunas Lith. 2021;57(3):295. Poormoghim H, GaffariRad F, Rahmani S, Mohtasham N, Almasi S, Sobhani A, et al. Prevalence & Impact of COVID-19 in Systemic Sclerosis Patients and Assessment of the Demographic & Clinical Features in Cases Associated with Worse Prognosis: Results of a Single Centre Registry. Mediterr J Rheumatol. 2023;34(2):172–9. Matucci-Cerinic M, Hughes M, Taliani G, Kahaleh B. Similarities between COVID-19 and systemic sclerosis early vasculopathy: A viral challenge for future research in scleroderma. Autoimmun Rev. 2021;20(10):102899. Chaisrimaneepan N, Thiravetyan B, Nakaphan P, Puchongmart C. The impact of systemic sclerosis on hospitalized COVID-19 patients: Analysis of the US nationwide inpatient sample (2021). J Scleroderma Relat Disord. 2025;23971983251342065. Hughes M, Pauling JD, Armstrong-James L, Denton CP, Galdas P, Flurey C. Gender-related differences in systemic sclerosis. Autoimmun Rev. 2020;19(4):102494. Clinical. and epidemiological differences between men and women with systemic sclerosis: a study in a Spanish systemic sclerosis cohort and literature review [Internet]. Clin Exp Rheumatol. [cited 2025 May 25]. Available from: https://www.clinexprheumatol.org/abstract.asp?a=11910 Peoples C, Medsger TA, Lucas M, Rosario BL, Feghali-Bostwick CA. Gender differences in systemic sclerosis: relationship to clinical features, serologic status and outcomes. J Scleroderma Relat Disord. 2016;1(2):177–240. Allanore Y, Meune C, Vonk MC, Airo P, Hachulla E, Caramaschi P, et al. Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis. Ann Rheum Dis. 2010;69(1):218–21. Moinzadeh P, Aberer E, Ahmadi-Simab K, Blank N, Distler JHW, Fierlbeck G, et al. Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2015;74(4):730–7. Silver RM, Bogatkevich G, Tourkina E, Nietert PJ, Hoffman S. Racial Differences between Blacks and Whites with Systemic Sclerosis. Curr Opin Rheumatol. 2012;24(6):642–8. Yen EY, Singh DR, Singh RR. Steady decrease in systemic sclerosis mortality rates at younger ages over the past five decades. Rheumatol Oxf Engl. 2024;63(2):466–71. Additional Declarations No competing interests reported. Supplementary Files table1.docx SupplementalFiguresandTablesSSCVD.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 05 Oct, 2025 Reviews received at journal 02 Oct, 2025 Reviewers agreed at journal 25 Sep, 2025 Reviewers agreed at journal 24 Sep, 2025 Reviews received at journal 24 Sep, 2025 Reviewers agreed at journal 18 Sep, 2025 Reviewers agreed at journal 18 Sep, 2025 Reviewers invited by journal 18 Sep, 2025 Editor assigned by journal 15 Sep, 2025 Editor invited by journal 25 Aug, 2025 Submission checks completed at journal 23 Aug, 2025 First submitted to journal 23 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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p\u0026lt;.05\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7323176/v1/226d21a20a06f17e0b224213.png"},{"id":92412423,"identity":"d5b82527-e3b0-403f-85d1-950c17f343a2","added_by":"auto","created_at":"2025-09-29 12:48:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1036076,"visible":true,"origin":"","legend":"\u003cp\u003eSSc + CVD-related Age-adjusted mortality rate (AAMR) per 100,000, overall and stratified by gender, 1999-2022. APC = annual percent change, * = significantly different from 0 with p \u0026lt; 0.05.\u003c/p\u003e\n\u003cp\u003eSSc: Systemic Sclerosis; CVD: Cardiovascular Disease; AAMR: Age-adjusted mortality rate; APC = annual percent\u003cstrong\u003e change; AAPC: Average APC; * = significantly different from 0 with p \u0026lt; 0.05\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7323176/v1/51cef7fdbc5a3b783ac837d9.png"},{"id":92412427,"identity":"60ff7faa-6958-4044-ba04-dcb4dc524a6f","added_by":"auto","created_at":"2025-09-29 12:48:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1279753,"visible":true,"origin":"","legend":"\u003cp\u003eSSc + CVD-related Age-adjusted mortality rate (AAMR) per 100,000, stratified by race and ethnicity, 1999-2022. SSc: Systemic Sclerosis; CVD: Cardiovascular Disease; AAMR: Age-adjusted mortality rate; APC = annual percent change; AAPC: Average APC; * = significantly different from 0 with p \u0026lt; 0.05\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7323176/v1/e3a8acf0ec728d5ff6f0524d.png"},{"id":92414452,"identity":"ba857367-537a-42a4-8730-525ab943cb7f","added_by":"auto","created_at":"2025-09-29 13:12:54","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1732216,"visible":true,"origin":"","legend":"\u003cp\u003eSSc + CVD-related Age-adjusted mortality rate (AAMR) per 100,000, stratified by the US census regions, 1999-2022. SSc: Systemic Sclerosis; CVD: Cardiovascular Disease; AAMR: Age-adjusted mortality rate; APC = annual percent change; AAPC: Average APC; * = significantly different from 0 with p \u0026lt; 0.05\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-7323176/v1/5663b96aad3ed6e5e6e083be.png"},{"id":92413549,"identity":"efd796c4-d456-4f62-b9a1-96c5114bc52a","added_by":"auto","created_at":"2025-09-29 12:56:54","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2688039,"visible":true,"origin":"","legend":"\u003cp\u003eSSc + CVD-related Age-adjusted mortality rate (AAMR) per 100,000, stratified by age groups, 1999-2022 a) young (15-44 years) age group; b) middle age (45 to 74 years) and elderly (≥75) age groups. SSc: Systemic Sclerosis; CVD: Cardiovascular Disease; AAMR: Age-adjusted mortality rate; APC = annual percent change; AAPC: Average APC; * = significantly different from 0 with p \u0026lt; 0.05\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-7323176/v1/94798538cfee068166a452a1.png"},{"id":92415419,"identity":"40d4bf35-757a-441e-b3b8-d55a2cdd52a5","added_by":"auto","created_at":"2025-09-29 13:20:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7607302,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7323176/v1/4f6a0184-f8ab-4f6e-9c65-4278a6f5d705.pdf"},{"id":92413770,"identity":"06e3c9eb-11e9-46a0-93f7-f8d97bf91c6c","added_by":"auto","created_at":"2025-09-29 13:04:54","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":24103,"visible":true,"origin":"","legend":"","description":"","filename":"table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7323176/v1/6610679b9c24c554a7fc81d0.docx"},{"id":92412436,"identity":"def2ed86-dcfb-49a6-a89a-fa0362dbdedf","added_by":"auto","created_at":"2025-09-29 12:48:54","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":507426,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalFiguresandTablesSSCVD.docx","url":"https://assets-eu.researchsquare.com/files/rs-7323176/v1/8a03fb5db891a26790537185.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Systemic Sclerosis and Cardiovascular Disease-related Mortality in the United States: An Analysis of Trends and Disparities, 1999-2022","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFibrotic changes in connective tissue characterize systemic sclerosis (SSc), although its exact causes remain unclear. However, in recent years, our understanding of this condition has progressed to include other organ systems, including the heart, lungs, kidneys, and gastrointestinal tracts.[1]\u0026nbsp;The heterogeneity of the presentation poses a significant challenge, particularly in the management and prediction of the SSc disease course. The severity of internal organ manifestations is an important indicator for the overall prognosis of SSc patients. Because manifestations can be unpredictable in terms of the prognosis of the patient population, it creates a unique challenge for both patients and clinicians.[2]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCardiopulmonary involvement is the leading cause of mortality in SSc, with cardiac complications accounting for 26% of SSc-related deaths.[2]\u0026nbsp;SSc involves the heart in various ways, ranging from arrhythmias to heart failure.[2]\u0026nbsp;Notably, the prevalence of heart failure is significantly higher in SSc patients compared to the similar age group. In multiple studies, diastolic dysfunction prevalence in those with SSc is on average at 18-62%, while similarly aged groups’ prevalence in diastolic dysfunction is at 1.4-38.1%.[3–5]\u0026nbsp;Additionally, cardiac dysfunction secondary to SSc is associated with worse outcomes compared to those without SSc.[6]\u0026nbsp;Beyond structural cardiac changes, SSc leads to endothelial damage, vascular remodeling, and macro- and microvascular dysfunctions.[7]\u0026nbsp; These changes result in vascular pathologies, including myocardial infarction, peripheral vascular diseases, pulmonary hypertension, and renal crisis.[7,8]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData regarding SSc-related CVD mortality in the United States (US) population has not been studied. We aim to analyze the mortality rate related to SSc and cardiovascular disease in the US adult population and differences across different demographic and geographic subgroups.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and database\u003c/h2\u003e\u003cp\u003eThe Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) was used to identify SSc and CVD-related deaths in the United States. This database has been used to study trends and disparities for various cardiovascular and non-cardiovascular diseases.\u003csup\u003e9,10,11,12\u003c/sup\u003e The Multiple Cause of Death public use records of death certificates were extracted, which listed SSc and CVD as an underlying or contributing cause on nationwide death certificate records.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] We extracted data regarding SSc and CVD-related deaths and population sizes from 1999 to 2022. The International Classification of Diseases, 10th Revision, Clinical Modification codes M34 and I00-I99 were used to identify deaths from SSc and CVD, respectively.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] The study was exempt from institutional review board approval because the CDC WONDER database contains anonymized, publicly available data.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDemographic and geographical study groups\u003c/h3\u003e\n\u003cp\u003eData extracted for analysis included biological sex, race and ethnicity, age groups, region, and state. Biological sex included men and women. Race and ethnicity groups were divided into non-Hispanic (NH) white, NH Black people, and Hispanic or Latino. Age groups included adults aged\u0026thinsp;\u0026ge;\u0026thinsp;15, which were divided into young (15\u0026ndash;44), middle age (45\u0026ndash;74), and elderly (\u0026ge;\u0026thinsp;75) age groups. We extracted data for four census regions (Northeast, Midwest, South, and West), classified by the Census Bureau definitions.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eSSc and CVD-related deaths and age-adjusted mortality rates (AAMR) per 1,000,000 were used for analysis, which adjusts for the variation in the population's size and age distribution, enabling better data comparison. The study used the Joinpoint Regression Program (Joinpoint version 5.3.0) available from the National Cancer Institute, Bethesda, Maryland) to analyze mortality trends from 1999\u0026ndash;2023.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] Significant changes in annual mortality trends by fitting models of linear segments are used to calculate annual percentage change (APC) with 95% confidence intervals (CIs) for the age-adjusted mortality rates (AAMRs) for the line segments. The weighted average of the APCs was calculated and reported as average annual percentage changes (AAPCs), along with corresponding 95% CIs, to summarize the reported mortality trend for the entire study period. APCs and AAPCs were identified as increasing or decreasing based on whether the change in mortality over the time interval significantly differed from zero using a 2-tailed t-test. Statistical significance was set at p\u0026thinsp;\u0026le;\u0026thinsp;0.05 and is represented by an asterisk \u0026lsquo;*\u0026rsquo; in the results and figures (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSystemic Sclerosis and Cardiovascular Disease-related total number of deaths and AAMR in the US from 1999 to 2022, annual AAMRs for 1999 and 2022, and AAPC from 1999 to 2022. AAMR: Age-adjusted mortality rate; AAPC\u0026thinsp;=\u0026thinsp;Average annual percent change; 95% CI: 95% Confidence interval; * = significantly different from 0 with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDeaths, 1999 to 2022 (percentage, %)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAAMR, 1999 to 2022\u003c/p\u003e\u003cp\u003e(95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1999 AAMR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2022 AAMR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAAPC from 1999 to 2022 (95% CI)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOverall\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25965\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.02 (3.96 to 4.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.39 (5.08 to 5.70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.58 (3.37 to 3.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-1.54* (-2.09 to -1.21)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex stratified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4811 (18.52)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.63 (1.57 to 1.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.17 (1.87 to 2.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.58 (1.38 to 1.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-1.74* (-2.42 to -1.19)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21154 (81.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.01 (5.91 to 6.11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.99 (7.48 to 8.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.27 (4.92 to 5.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-1.46* (-2.07 to -1.07)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRace Stratified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNH Black or African American\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3909 (15.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.76 (5.53 to 5.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8.04 (6.83 to 9.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.71 (3.97 to 5.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-2.44* (-3.07 to -1.82)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNH White\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18762 (72.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.76 (3.69 to 3.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.99 (4.66 to 5.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.40 (3.16 to 3.64)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-1.42* (-2.09 to -1.00)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHispanic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2408 (9.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.14 (3.92 to 4.36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.88 (5.42 to 8.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.97 (3.3 to 4.64)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-1.74 (-3.53 to 0.12)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCensus Region\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNortheast\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5308 (20.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.31 (4.17 to 4.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.47 (4.78 to 6.16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.60 (3.12 to 4.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-2.02* (-2.50 to -1.59)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMidwest\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5865 (22.58)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.12 (3.99 to 4.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.88 (4.27 to 5.49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.80 (3.34 to 4.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.83* (-1.31 to -0.21)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSouth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8950 (34.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.77 (3.68 to 3.87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.68 (5.15 to 6.22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.22 (2.90 to 3.54)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-1.94* (-2.71 to -1.36)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWest\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5842 (22.49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.16 (4.03 to 4.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.47 (4.77 to 6.16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.97 (3.51 to 4.42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-1.73* (-2.36 to -1.10)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge Groups\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYoung (15\u0026ndash;44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1715 (6.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.59 (0.56 to 0.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.78 (0.64 to 0.95)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.43 (0.32 to 0.57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-2.42* (-3.35 to -1.60)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMiddle Age (45\u0026ndash;74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15588 (60.03)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.15 (6.03 to 6.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.19 (8.53 to 9.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.98 (4.59 to 5.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-2.33* (-3.15 to -1.77)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElderly (\u0026ge;\u0026thinsp;75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8662 (33.36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.70 (18.20 to 19.20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20.59 (18.40 to 22.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e19.68 (17.90 to 21.45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.30 (-1.07 to -0.17)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFrom 1999 to 2022, there were 43,010 systemic sclerosis-related deaths in the United States (\u003cb\u003eSupplemental Table\u0026nbsp;1\u003c/b\u003e). Overall, systemic sclerosis AAMR per 1,000,000 decreased significantly from 8.98 (95% CI: 8.58 to 9.38) in 1999 to 5.44 (95% CI: 5.18 to 5.70) in 2022 (AAPC \u0026minus;\u0026thinsp;2.30* (95% CI: -2.55 to -2.09). AAMR decreased from 1999 to 2019 (APC: -2.89*, 95% CI: -3.13 to -2.72) and stayed stable from 2019 to 2022 (APC: 1.74, 95% CI: -1.15 to 5.72) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Of the 43,010 SSc deaths, 25,965 (64.47%) were associated with cardiovascular disease. Within CVD, the major subcategories associated with SSc-related deaths were Pulmonary heart disease and diseases of pulmonary circulation (22.16%), Heart failure (15.02%), Ischemic heart disease (12.06%), and Hypertensive diseases (10.73%) (\u003cb\u003eSupplement Table\u0026nbsp;5\u003c/b\u003e). The overall AAMR for SSc-associated CVD mortality decreased significantly from 5.39 (95% CI: 5.08 to 5.70) to 3.58 (95% CI: 3.37 to 3.79) in 2022 (AAPC of -1.54* (95% CI: -2.09 to -1.21). AAMR decreased significantly from 1999 to 2019 (APC: -2.37*, 95% CI: -3.12 to -2.01) and then increased from 2019 to 2022 (APC: 4.11, 95% CI: -1.24 to 19.23) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eSupplemental Fig.\u0026nbsp;1, Supplemental Fig.\u0026nbsp;2\u003c/b\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eGender-stratified trend for Systemic Sclerosis-associated CVD mortality\u003c/h3\u003e\n\u003cp\u003eFrom 1999 to 2022, systemic sclerosis-associated CVD deaths in the United States, 4811 (18.55%) were in men and 21,154 (81.45%) in women (\u003cb\u003eSupplemental Table\u0026nbsp;1)\u003c/b\u003e. Women consistently had higher AAMR than men throughout the study, though both followed a similar overall downtrend. From 1999 to 2022, the AAMR in women decreased with an AAPC of -1.46* (95% CI: -2.07 to -1.07). The AAMR in women decreased by -39.79% from 7.99 (95% CI: 7.48 to 8.50) in 1999 to 4.81 (95% CI: 4.47 to 5.15) in 2019 (APC: -2.22*, 95% CI: -3.52 to -1.76) followed by a 9.56% increase to 5.27 (95% CI: 4.92 to 5.61) in 2022. From 1999 to 2022, men had a significant reduction in mortality as well (AAPC: -1.74*, 95% CI: -2.42 to -1.19). The AAMR in men decreased from 2.17 (95% CI: 1.87 to 2.47) in 1999 to 1.21 (95% CI: 1.03 to 1.40) in 2017 (APC: -3.00*, 95% CI: -4.26 to -2.41), followed by an increase to 1.58 (95% CI: 1.38 to 1.79) in 2022 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eSupplemental Fig.\u0026nbsp;1\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cb\u003eSupplemental Table\u0026nbsp;2\u003c/b\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eRace-stratified trend for Systemic Sclerosis-associated CVD mortality\u003c/h3\u003e\n\u003cp\u003eOf the total SSc and CVD-related deaths, 3903 (15.57%) were NH black, 2408 (9.60%) were Hispanic or Latino, and 18751 (74.81%) were NH White. Overall, NH black people had the highest AAMR but also witnessed the most significant reduction in mortality (AAPC \u0026minus;\u0026thinsp;2.44*, 95% CI: -3.07 to -1.82). NH black individuals\u0026rsquo; AAMR decreased from 8.04 (95% CI: 6.83 to 9.25) in 1999 to 4.71 (95% CI: 3.97 to 5.46) in 2022. Hispanic people had a relative lesser reduction in AAMR from 6.88 (95% CI: 5.42 to 8.61) in 1999 to 2.53 (95% CI: 1.97 to 3.19) in 2017, with an APC of -3.41 (95% CI: -12.71 to 53.27) with an increase in AAMR to 3.97 (95% CI: 3.30 to 4.64) in 2022 with an APC of 4.50 (95% CI: -2.83 to 37.80). For the NH White population, the AAMR decreased, though to a lesser extent, compared to NH black people, from 1999\u0026ndash;2022 with an AAPC \u0026minus;\u0026thinsp;1.42* (95% CI: -2.09 to -1.00). Their AAMR initially decreased from 4.99 (95% CI: 4.66 to 5.32) in 1999 to 3.01 (95% CI: 2.79 to 3.24) in 2019 (APC of -2.36*, 95% CI: -3.39 to -1.92) and then increased to 3.40 (95% CI: 3.16 to 3.64) in 2022 (APC of 5.10, 95% CI: -1.27 to 24.16). (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eSupplemental Fig.\u0026nbsp;2, Supplemental Table\u0026nbsp;2\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eAge-group Stratified trend for Systemic Sclerosis-associated CVD mortality\u003c/h2\u003e\u003cp\u003eAll age groups witnessed a reduction in AAMR from 1999 to 2019. The older age group (\u0026ge;\u0026thinsp;75 years) had a non-significant reduction in mortality from 1999 to 2022 (AAPC \u0026minus;\u0026thinsp;0.30, 95% CI: -1.07 to 0.174). Those 75 years and older had the highest AAMR throughout the study duration, which decreased from 20.59 (95% CI: 18.40 to 22.79) in 1999 to 16.59 (95% CI: 14.91 to 18.28) in 2019 (APC: -1.36*, 95% CI: -2.66 to -0.80) followed by an increased to 19.68 (95% CI: 17.90 to 21.45) in 2022 with an APC of 7.00 (95% CI: -0.49 to 26.39). The young age-group (15\u0026ndash;44) had a significant reduction in mortality from 1999 to 2022 (AAPC \u0026minus;\u0026thinsp;2.42*, 95% CI; -3.35 to -1.60). The middle-aged group (45\u0026ndash;74) also had a significant reduction in mortality from 1999 to 2022 (AAPC \u0026minus;\u0026thinsp;2.33*, 95% CI: -3.15 to -1.77). Their AAMR decreased from 9.19 (95% CI: 8.53 to 9.86) in 1999 to 4.83 (95% CI: 4.44 to 5.21) in 2018 with an APC of -2.97 (95% CI: -6.63 to 15.16) and similar AAMR of 4.98 (95% CI: 4.59 to 5.37) by 2022 (2018\u0026ndash;2022 APC 0.75, 95% CI: -10.69 to 15.23). (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eSupplemental Table\u0026nbsp;2, Supplemental Fig.\u0026nbsp;3\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eRegion-Stratified trend for Systemic Sclerosis-associated CVD mortality\u003c/h2\u003e\u003cp\u003eAll four census regions of the US saw a decrease in AAMR from 1999 to 2022, with the South seeing the most significant reduction of -43.30% (AAPC \u0026minus;\u0026thinsp;1.94*, 95% CI: -2.72 to -1.36). AAMR for South region decreased from 5.68 (95% CI: 5.15 to 6.22) in 1999 to 2.93 (95% CI: 2.62 to 3.25) in 2018 (APC: -3.00*, 95% CI: -4.86 to -2.41) and with an increase in AAMR 3.22 (95% CI: 2.90 to 3.54), APC of 3.25 (95% CI: -2.00 to 22.05) from 2018 to 2022. The northeast and west regions followed this. West region saw the AAMR decrease from 5.47 (95% CI: 4.77 to 6.16) in 1999 to 3.97 (95% CI: 3.51 to 4.42) in 2022 (AAPC \u0026minus;\u0026thinsp;1.73*, 95% CI: -2.36 to -1.10) followed by the Northeast with similar AAMR of 5.47 (95% CI: 4.78 to 6.16) in 1999 which decreased to 3.60 (95% CI: 3.12 to 4.09) in 2022 (AAPC: -2.02*, 95% CI: -2.50 to -1.59). In the Midwest, the AAMR initially stayed stable from 4.88 (95% CI: 4.27 to 5.49) in 1999 to 4.64 (95% CI: 4.08 to 5.20) in 2009 (APC: -0.39, 95% CI: -1.50 to 3.61). This was followed by a decrease in AAMR from 4.64 (95% CI: 4.08 to 5.20) in 2009 to 3.43 (95% CI: 2.97 to 3.89) in 2016 with an APC of -4.41* (95% CI: -14.11 to -2.44) and an increase in AAMR to 3.80 (95% CI: 3.34\u0026ndash;4.27) by 2022 with an APC of 2.73* (95% CI: 0.07 to 10.51). (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eSupplemental Table\u0026nbsp;3\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cb\u003eSupplemental Fig.\u0026nbsp;4\u003c/b\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eState-level trend\u003c/h2\u003e\u003cp\u003eA marked overall difference in AAMR was observed among the states. From 1999 to 2023, Nebraska had the highest AAMR of 5.35 compared to New Hampshire with the lowest AAMR of 2.47. States in the upper 90th percentile of SSc associated CVD-related mortality included Nebraska, South Dakota, Oklahoma, Colorado, and Rhode Island which had more than twice the AAMRs compared to states in the lower 10th percentile of SSc associated CVD-related deaths which included New Hampshire, Louisiana, Arizona, Alabama, Arkansas (\u003cb\u003eSupplemental Table\u0026nbsp;4\u003c/b\u003e).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur analysis, spanning multiple decades of US mortality, revealed several insights. CVD was associated with approximately two-thirds of all SSc-related deaths. Overall, there was a decrease in SSc-associated CVD-related deaths during the study period, with a modest increase in AAMRs observed from 2019 to 2022 in overall and most subgroup trends. Females had higher AAMR compared to men throughout the study. The NH Black population had the highest AAMR, while the NH White population had the lowest. Regionally, the Northeast, South, Midwest, and West had similar AAMRs with a decreasing trend.\u003c/p\u003e\u003cp\u003eOur findings align with previous research, showing a steady decline in SSc mortality from 1968 to 2015.\u003csup\u003e1,2\u003c/sup\u003e We observed that SSc mortality is highly associated with CVD, with approximately two-thirds of all SSc deaths related to CVD from 1999 to 2022. In our study, among CVD, Pulmonary heart disease, and diseases of pulmonary circulation were associated with the most SSc deaths. Data from EUSTAR has also shown that 26% of SSc deaths were related to pulmonary hypertension.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Heart failure was the second most common CVD associated with SSc mortality in our study, aligning with EUSTAR findings that report heart failure as the cause of 10% of SSc deaths. Ischemic heart disease also contributed to increased mortality in our cohort, with EUSTAR data indicating it accounts for 5% of SSc-related deaths. Finally, hypertensive renal crisis was found to be a significant contributor to mortality in our study, consistent with EUSTAR data, attributing 4% of SSc deaths to renal crisis. Moreover, in a systematic review, coronary artery disease has been established to manifest more frequently in SSc compared to controls, consistent with our findings.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eWe found an overall downtrend in the SSc-associated CVD mortality from 1999 to 2022. This trend is likely due to a multitude of factors. Overall, there has been an ongoing decrease in ischemic heart disease mortality that may be explained by better treatment of cardiovascular risk factors or by an improvement in health care systems, such as cardiac catheterization and improved medical management.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] This supports our data with the decrease in SSc-associated CVD mortality. Another potential reason for the reduction in mortality could be explained by the most common cardiac involvement in SSc, which is pulmonary arterial hypertension (PAH).[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] With the development of new therapies for PAH, such as Phosphodiesterase-5 Inhibitors (sildenafil and tadalafil), guanylate cyclase stimulator (riociguat), and endothelin receptor antagonists.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] Cardiac arrhythmias are a less common presentation of SSc, yet account for a disproportionate number of SSc-associated deaths.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Non-specific arrhythmic and conduction abnormalities are detected in 50% of SSc patients on resting ECG.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Both atrial and ventricular arrhythmias arise throughout the disease course, with QT prolongation hypothesized as a contributing reason causing disturbed ventricular repolarization.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] Additionally, SSc is linked with dysfunction of the autonomic nervous system, triggering ventricular arrhythmias and associated with a five-fold increased risk of cardiovascular mortality and increased risk of SCD.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Lastly, another risk for SSc mortality is renal crisis, which is a life-threatening condition. With the advent of angiotensin-converting enzyme inhibitor (ACEi) therapy, mortality has improved, which is consistent with our study.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eAn increase in AAMRs was observed from 2019 to 2022 overall and in most subgroup trends. The advent of the COVID-19 pandemic likely contributed to the increased SSc-associated CVD mortality. In a single-center study, the prevalence of COVID-19 in patients with SSc was 12.5%, and the COVID-19-specific mortality rate among SSc patients was 3.1%. In the general population, prevalence was 6.8% with a mortality of 0.07%, illustrating the increased risk of both COVID-19 infection and death with SSc.[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] The probable cause of this increased mortality is due to the underlying mechanism of SSc-associated CVD. SSc-associated CVD and COVID-19 share a similar pathogenesis of microvascular damage, which is endothelial cell activation/injury and dysfunction. SSc patients hospitalized with COVID-19 had higher odds of left heart failure, cardiac arrest, and ventricular arrhythmias. COVID-19 has been associated with many cardiac complications and an increased risk of long-term complications such as heart failure, arrhythmias, and myocarditis.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eOur analysis revealed differences in AAMRs across gender and racial groups. Females had almost three times higher AAMRs compared to men, which is in accordance with previous research that the incidence of SSc is higher in women.[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] Though women have a higher incidence, other studies have shown that men diagnosed with SSc have a higher rate of premature death than their female counterparts.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] In two studies, male sex was independently associated with left ventricular dysfunction, pulmonary fibrosis, and heart failure in SSc.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] This highlights that men with SSc have more severe manifestations of cardiovascular involvement than women, who have higher overall SSc-associated CVD mortality, which is likely due to SSc disproportionately affecting females, leading to a higher AAMR. Racial groups also exhibited marked disparities, with NH Black people having twice that of NH White, who had the lowest rate. The gap between the NH Black and NH White populations narrowed over the past two decades, but there is still room for improvement. NH Blacks have an elevated risk of SSc-associated CVD stemming from an increased susceptibility due to an imbalance of pro-fibrotic and anti-fibrotic factors. This is alluded to racial difference expression of transforming growth factor-β1 (TGF-β1) and caveolin-1, as well as differences in the expression of hepatocyte growth factor (HGF) and PPAR-γ.[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] Beyond genetic predisposition, this ethnicity experiences low socioeconomic standing and limited healthcare access, which further exacerbate the dichotomy in the AAMR trends.\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe age group with the highest mortality was the elderly, which could be secondary to cumulative toxicities of medications over time in SSc, leading to higher mortality. Additionally, if diagnosed at a late age (\u0026gt;\u0026thinsp;65 years), there are greater risks of pulmonary hypertension, renal impairment, and cardiac disease, leading to increased mortality.[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eOur analysis showed that all regions in the United States had similar AAMR and experienced a net decrease from 1999 to 2022. Nebraska, South Dakota, and Oklahoma had the highest mortality rates. Higher mortality rates are anticipated in regions with higher disease incidence; however, mortality data alone cannot be used to infer incidence rates directly. The clustering of disease-related deaths in specific geographic areas suggests that environmental and genetic factors may play a role, but further research is needed to confirm this.\u003c/p\u003e\u003cp\u003eThese findings highlight essential concerns regarding SSc care in disadvantaged populations, emphasizing the need to investigate the factors driving these disparities and public health efforts to tackle these differences. To address these issues, it is crucial to implement targeted interventions that meet these vulnerable groups' specific needs and challenges.\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eCDC WONDER data is compiled from death certificates, which rely on ICD codes for disease identification; thus, a potential for misclassification bias is present. Though we used validated ICD codes, SSc is under-coded on death certificates, leading to potential underestimation. This study could only analyze racial disparities for NH white, NH Black, and Hispanic or Latino. NH Asian or Pacific Islander and NH American Indian or Alaska Native could not be analyzed because of suppressed data in these subgroups for most of the years. CDC suppresses the counts of fewer than 10 in CDC WONDER data to protect confidentiality, and death rates are marked unreliable for a count less than 20 per the CDC WONDER data use agreement. Other characteristics of the study population, such as social determinants of health that could contribute to the patient\u0026rsquo;s death, are not available in the data files for analysis. Moreover, despite the physiological plausibility of the association between SSc and CVD, due to the ecological nature of our study, a causal relationship cannot be established based on the findings of this study.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOverall, from 1999 to 2022, CVD-related mortality associated with SSc decreased in the US, with a brief and modest increase seen during the COVID-19 pandemic. Despite this overall decline, substantial disparities were identified with NH Black people, women, and people\u0026thinsp;\u0026ge;\u0026thinsp;75 exhibiting significantly higher AAMRs.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eSSc\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSystemic Sclerosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eCVD\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCardiovascular Disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eAAMR\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAge-Adjusted Mortality Rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eAPC\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAnnual Percent Change\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eAAPC\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAverage Annual Percent Change\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eNH\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNon-Hispanic\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003ePAH\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePulmonary Arterial Hypertension\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eECG\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eElectrocardiogram\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eSCD\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSudden Cardiac Death\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e: all data is available at: https://wonder.cdc.gov/\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eFunding\u003c/strong\u003e: Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eABAJ: Conceptualization, Methodology, Acquisition, Analysis, Interpretation of data, Visualization; Writing- Original draft preparation, Reviewing and Editing; WT: Interpretation of data, Visualization; Writing- Original draft preparation, Reviewing and Editing. MC Writing- Original draft preparation; KG: Writing- Original draft preparation. AA: Supervision, Writing- Reviewing and Editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements Not applicable\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRodnan GP, Benedek TG. An historical account of the study of progressive systemic sclerosis (diffuse scleroderma). Ann Intern Med. 1962;57:305\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTyndall AJ, Bannert B, Vonk M, Air\u0026ograve; P, Cozzi F, Carreira PE, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010;69(10):1809\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTenn\u0026oslash;e AH, Murbr\u0026aelig;ch K, Andreassen JC, Fretheim H, Garen T, Gude E, et al. Left Ventricular Diastolic Dysfunction Predicts Mortality in Patients With Systemic Sclerosis. J Am Coll Cardiol. 2018;72(15):1804\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVemulapalli S, Cohen L, Hsu V. Prevalence and risk factors for left ventricular diastolic dysfunction in a scleroderma cohort. Scand J Rheumatol. 2017;46(4):281\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFern\u0026aacute;ndez-Codina A, Sime\u0026oacute;n-Aznar CP, Pinal-Fernandez I, Rodr\u0026iacute;guez-Palomares J, Pizzi MN, Hidalgo CE, et al. Cardiac involvement in systemic sclerosis: differences between clinical subsets and influence on survival. Rheumatol Int. 2017;37(1):75\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSun G, Yafasova A, Andersson C, McMurray JJV, Jhund PS, Docherty KF, et al. Gender- and age-specific rates of heart failure and other adverse cardiovascular outcomes in systemic sclerosis. Rheumatol Oxf Engl. 2022;61(11):4374\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKawaguchi Y, Kuwana M. Pathogenesis of vasculopathy in systemic sclerosis and its contribution to fibrosis. Curr Opin Rheumatol. 2023;35(6):309\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCole A, Ong VH, Denton CP. Renal Disease and Systemic Sclerosis: an Update on Scleroderma Renal Crisis. Clin Rev Allergy Immunol. 2023;64(3):378\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbdul Jabbar AB, May MT, Deisz M, Tauseef A. Trends in heart failure-related mortality among middle-aged adults in the United States from 1999\u0026ndash;2022. Curr Probl Cardiol. 2025;50(3):102973.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMorrissey R, Lee J, Baral N, Tauseef A, Sood A, Mirza M, et al. Demographic and regional trends of sepsis mortality in the United States, 1999\u0026ndash;2022. BMC Infect Dis. 2025;25(1):504.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbdul Jabbar AB, Klisares M, Gilkeson K, Aboeata A. Acute Myocardial Infarction Mortality in the Older Population of the United States: An Analysis of Demographic and Regional Trends and Disparities from 1999 to 2022. J Clin Med. 2025;14(7):2190.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbdul Jabbar AB, Khan DA, Li-Jedras M, Kabach A, Aboeata A. Trends of infective endocarditis mortality in young adult population of US: A concerning rise and its association with substance abuse. Int J Cardiol Cardiovasc Risk Prev. 2025;25:200404.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMultiple. Cause of Death, 1999\u0026ndash;2020 Request [Internet]. [cited 2024 Nov 8]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://wonder.cdc.gov/mcd-icd10.html\u003c/span\u003e\u003cspan address=\"https://wonder.cdc.gov/mcd-icd10.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOrganization WH. ICD-10: international statistical classification of diseases and related health problems : tenth revision [Internet]. World Health Organization; 2004 [cited 2025 Feb 7]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://iris.who.int/handle/10665/42980\u003c/span\u003e\u003cspan address=\"https://iris.who.int/handle/10665/42980\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJoinpoint Regression Program [Internet]. [cited 2025 Jan 5]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://surveillance.cancer.gov/joinpoint/\u003c/span\u003e\u003cspan address=\"https://surveillance.cancer.gov/joinpoint/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYen EY, Singh DR, Singh RR. Trends in Systemic Sclerosis Mortality Over Forty-Eight Years, 1968\u0026ndash;2015: A US Population-Based Study. Arthritis Care Res. 2021;73(10):1502\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUngprasert P, Charoenpong P, Ratanasrimetha P, Thongprayoon C, Cheungpasitporn W, Suksaranjit P. Risk of coronary artery disease in patients with systemic sclerosis: a systematic review and meta-analysis. Clin Rheumatol. 2014;33(8):1099\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlmaaitah S, Highland KB, Tonelli AR. Management of Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis. Integr Blood Press Control. 2020;13:15\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoss L, Prior D, Proudman S, Vacca A, Baron M, Nikpour M. Defining primary systemic sclerosis heart involvement: A scoping literature review. Semin Arthritis Rheum. 2019;48(5):874\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoss L, Paratz E, Baron M, La Gerche A, Nikpour M. Sudden Cardiac Death in Systemic Sclerosis: Diagnostics to Assess Risk and Inform Management. Diagn Basel Switz. 2021;11(10):1781.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSaramet EE, Cojocaru DC, Ungurianu S, Negru RD, Ancuta C. QT Interval Prolongation in Patients with Systemic Sclerosis-Are the Holter ECG Recordings a Better Option for QT Interval Evaluation? Med Kaunas Lith. 2021;57(3):295.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePoormoghim H, GaffariRad F, Rahmani S, Mohtasham N, Almasi S, Sobhani A, et al. Prevalence \u0026amp; Impact of COVID-19 in Systemic Sclerosis Patients and Assessment of the Demographic \u0026amp; Clinical Features in Cases Associated with Worse Prognosis: Results of a Single Centre Registry. Mediterr J Rheumatol. 2023;34(2):172\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMatucci-Cerinic M, Hughes M, Taliani G, Kahaleh B. Similarities between COVID-19 and systemic sclerosis early vasculopathy: A viral challenge for future research in scleroderma. Autoimmun Rev. 2021;20(10):102899.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChaisrimaneepan N, Thiravetyan B, Nakaphan P, Puchongmart C. The impact of systemic sclerosis on hospitalized COVID-19 patients: Analysis of the US nationwide inpatient sample (2021). J Scleroderma Relat Disord. 2025;23971983251342065.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHughes M, Pauling JD, Armstrong-James L, Denton CP, Galdas P, Flurey C. Gender-related differences in systemic sclerosis. Autoimmun Rev. 2020;19(4):102494.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eClinical. and epidemiological differences between men and women with systemic sclerosis: a study in a Spanish systemic sclerosis cohort and literature review [Internet]. Clin Exp Rheumatol. [cited 2025 May 25]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.clinexprheumatol.org/abstract.asp?a=11910\u003c/span\u003e\u003cspan address=\"https://www.clinexprheumatol.org/abstract.asp?a=11910\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePeoples C, Medsger TA, Lucas M, Rosario BL, Feghali-Bostwick CA. Gender differences in systemic sclerosis: relationship to clinical features, serologic status and outcomes. J Scleroderma Relat Disord. 2016;1(2):177\u0026ndash;240.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAllanore Y, Meune C, Vonk MC, Airo P, Hachulla E, Caramaschi P, et al. Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis. Ann Rheum Dis. 2010;69(1):218\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoinzadeh P, Aberer E, Ahmadi-Simab K, Blank N, Distler JHW, Fierlbeck G, et al. Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2015;74(4):730\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSilver RM, Bogatkevich G, Tourkina E, Nietert PJ, Hoffman S. Racial Differences between Blacks and Whites with Systemic Sclerosis. Curr Opin Rheumatol. 2012;24(6):642\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYen EY, Singh DR, Singh RR. Steady decrease in systemic sclerosis mortality rates at younger ages over the past five decades. Rheumatol Oxf Engl. 2024;63(2):466\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cardiovascular disease, Systemic Sclerosis, Mortality, Trends, Disparities, United States","lastPublishedDoi":"10.21203/rs.3.rs-7323176/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7323176/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSystemic Sclerosis (SSc) increases cardiovascular disease (CVD) morbidity and mortality. Data regarding SSc-related CVD mortality in the United States (US) population has not been studied. We aim to analyze the mortality rate related to SSc and cardiovascular disease in the US adult population and differences across different demographic and geographic subgroups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSystemic Sclerosis-associated CVD mortality data were extracted from the Center for Disease Control and Prevention Wide-ranging Online Data Epidemiologic Research (CDC WONDER) database. We extracted age-adjusted mortality rates (AAMR) per 1,000,000 people for population age ≥15 and calculated annual change percentage (APC) using Joinpoint regression. The data were stratified into demographic (gender, race, age groups) and geographic (census region, and state) groups to analyze differences between the trends.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween 1999 and 2022, 25,727 deaths were related to SSc and CVD deaths. The overall AAMR for SSc-associated CVD mortality decreased significantly from 5.39 in 1999 to 3.58 in 2022. AAMR decreased by 39.33% from 1999 to 2019, increased by 10.50% from 2019 to 2022. Sex disparities were identified, with females experiencing a higher AAMR (6.01) compared to males (1.63). NH Blacks or African Americans had the highest overall AAMR (5.76), followed by Hispanics (4.14), and NH Whites (3.76). Age disparities were identified with the Elderly (≥75) having the highest overall AAMR (18.70), followed by Middle Age (45-74) (6.15), and Young (15-44) (0.59). Geographically, all regions had similar AAMR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, from 1999 to 2022, CVD-related mortality associated with SSc decreased in the US, with a brief and modest increase seen during the COVID-19 pandemic. Despite this overall decline, substantial disparities were identified with NH Black people, women, and people ≥ 75 exhibiting significantly higher AAMRs.\u003c/p\u003e","manuscriptTitle":"Systemic Sclerosis and Cardiovascular Disease-related Mortality in the United States: An Analysis of Trends and Disparities, 1999-2022","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-29 12:48:49","doi":"10.21203/rs.3.rs-7323176/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-10-06T01:08:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-03T03:51:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"10024584955563543101855546294002272446","date":"2025-09-25T20:06:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"288983976536773862917285789062746490545","date":"2025-09-24T15:04:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-24T10:46:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"157741789928245373966788474452786582138","date":"2025-09-18T09:17:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"249128484920452696284803485630241463344","date":"2025-09-18T09:08:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-18T09:00:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-15T09:34:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-25T10:16:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-23T06:35:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2025-08-23T06:32:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d1c7ff4f-6f93-4914-b745-a49076a462ae","owner":[],"postedDate":"September 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-09-29T12:48:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-29 12:48:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7323176","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7323176","identity":"rs-7323176","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}