Prevalence and Clinical Characteristics of Systemic Sclerosis in Alaska Native and American Indian Peoples in Alaska

Abstract

Objective

Systemic sclerosis (SSc) is known to exhibit significant epidemiologic and clinical variation. This study aimed to describe the clinical and epidemiologic characteristics of SSc in Alaska Native and American Indian (AN/AI) individuals in Alaska.

Methods

Adults with a potential diagnosis of SSc were identified through an electronic health record query for SSc‐related codes from 2012 to 2019 in the participating tribal health organizations in the Alaska Tribal Health System (ATHS). Detailed medical record abstraction was performed to confirm diagnoses and clinical characteristics, including demographics, SSc subtype, organ involvement, serologic test results, and medications. The denominator for prevalence was the 2019 ATHS user population aged ≥18 years.

Results

The age‐adjusted prevalence of SSc was 354 (95% confidence interval [CI] 241–504) per 1,000,000 adults overall, 503 (95% CI 323–752) per 1,000,000 in women, and 188 (95% CI 82–379) per 1,000,000 in men. Of the 36 adults identified with SSc, the mean age at diagnosis was 59.9 years (median 62 years), with a female predominance (28 [77.8%]; female‐to‐male ratio 3.5:1). Diffuse SSc prevalence was 95 (95% CI 44–184), and limited SSc prevalence was 258 (95% CI 164–391) per 1,000,000. Although most clinical features appear to be similar to other populations, a high prevalence of pulmonary arterial hypertension, gastrointestinal manifestations, and telangiectasias were notable.

Conclusion

This is the first study to describe the epidemiology and clinical characteristics of SSc in AN/AI individuals in Alaska. The prevalence, average age at onset, female predominance, and most clinical features are generally similar to those in studies of SSc in other populations.

INTRODUCTION

Systemic sclerosis (SSc), also known as scleroderma, is a complex multisystem autoimmune disorder characterized by vascular dysfunction and progressive fibrosis of skin and internal organs. Examples of vascular dysfunction–related pathology include clinical manifestations such as Raynaud phenomenon, telangiectasias, gastric antral vascular ectasia, and pulmonary arterial hypertension (PAH). Similarly, examples of fibrotic manifestations may include skin thickening and interstitial lung disease (ILD). However, in many cases, organs exhibit both vascular and fibrotic pathologies; for example, esophageal dysmotility is thought to result from a complex interplay of fibrosis, vasculopathy, and autonomic nerve dysfunction, contributing to the clinical manifestations. SSc is classified into two main subtypes based on the extent of skin involvement: limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc). ¹ The pathogenesis of SSc is thought to involve a complex interplay of genetic, environmental, and immunologic factors. ² , ³

SIGNIFICANCE & INNOVATIONS.

• This is the first study to describe the prevalence and clinical characteristics of systemic sclerosis (SSc) among Alaska Native and American Indian (AN/AI) peoples in Alaska.

• Our findings suggest a potentially similar prevalence of SSc in AN/AI peoples of Alaska when compared to other populations.

• Potentially higher‐than‐expected prevalence of pulmonary arterial hypertension, gastrointestinal manifestations, and telangiectasias was observed in comparison to studies of other populations.

Globally, SSc exhibits significant epidemiologic variation. Reported prevalence rates range widely, from 38 to 469 cases per million in most population‐based studies, with studies generally suggesting lower prevalence in Asia compared to North America, Europe, and Australia. ² , ³ , ⁴ Notably, higher prevalence has been observed in certain populations, including Black and Indigenous North American (INA) groups. ⁵ , ⁶ , ⁷ A high prevalence was reported in one American Indian tribe (660 per 1,000,000); however, the study was based on a small number of patients (n = 14). ⁶ Studies in Canada have reported a higher prevalence of SSc among First Nations women over 45 years of age. ⁷

Clinical features of SSc also vary across different populations studied. Black and Hispanic individuals tend to experience a more aggressive disease course, earlier age at onset, and a higher likelihood of dcSSc and pulmonary fibrosis. ² , ⁸ , ⁹ , ¹⁰ Similar trends of increased dcSSc and pulmonary fibrosis have been observed in one American Indian tribe. ⁶ A Canadian study of First Nations individuals with SSc reported more severe gastrointestinal (GI) involvement and Raynaud phenomenon in this population. ¹¹ These variations in SSc prevalence and clinical presentation underscore the potential influence of genetic and environmental factors on disease susceptibility and expression across diverse racial, ethnic, and geographic contexts.

Despite this recognition of racial, ethnic, and geographic variation in SSc, there is a significant gap in knowledge regarding the epidemiology and clinical characteristics of SSc in INA populations. These populations experience disparities in other autoimmune diseases, making it crucial to understand the prevalence and specific clinical presentation of SSc within this group. Therefore, this study aimed to describe the prevalence of SSc among AN/AI adults in Alaska. Our secondary objective was to determine common clinical manifestations of SSc in AN/AI adults in Alaska.

PATIENTS AND METHODS

Ethics approval

This observational study was approved by the Alaska Area Institutional Review Board (AAIRB) as expedited research with a waiver of informed consent (AAIRB# 2019‐03‐021). Tribal approval for the study was obtained from the Alaska Native Tribal Health Consortium (ANTHC), the Southcentral Foundation Board of Directors, and other participating regional tribal health organizations (THOs). ANTHC, the Southcentral Foundation Board of Directors, and participating regional THOs also reviewed and approved the manuscript before journal submission.

Study population

This study included adults receiving care within the Alaska Tribal Health System (ATHS), a network of THOs across the state of Alaska operating self‐governed health programs under compact with the United States Indian Health Service. Rheumatology health services are available at the Alaska Native Medical Center (ANMC), a tertiary health center in Anchorage, Alaska. People with rheumatologic disease within the ATHS are referred to ANMC or regional field clinics conducted by rheumatologists from the ANMC. This study was developed using existing data within the electronic health record collected for nonresearch purposes (ie, medical services).

Data collection

AN/AI adults aged ≥18 years with a potential diagnosis of SSc were identified from electronic health record encounter data between January 1, 2012, and December 31, 2019, based on queries of the electronic health record for the presence of International Classification of Diseases (ICD) codes. Specific codes queried included ICD‐9 codes 710.1 and 701.0 and ICD‐10 codes M34.0, M34.1, M34.2, M34.8, M34.9, M34.82, M34.83, M34.89, L94.0, and L94.1. Although the initial query included codes for localized scleroderma (L94.0 and L94.1) to ensure comprehensive case findings, patients with diagnoses of localized scleroderma or morphea without concomitant SSc were excluded during the subsequent medical record review and rheumatologist confirmation step. For participating THOs using a shared electronic health record platform in the ATHS (Cerner), a combined query of the shared platform was conducted. For participating THOs not on the shared electronic health record, we used the same methods for local electronic health record queries.

Data from the electronic health record queries were compiled into one database using REDCap hosted on a secure ANTHC server for analysis. ¹² Research nurses trained by the principal investigator performed medical record abstraction to confirm the diagnosis of SSc and determine associated features. The medical record abstraction followed a standardized data dictionary. Abstracted data elements included diagnosis, demographics, laboratory studies, clinical characteristics, and associated rheumatologic conditions reported in clinician notes. Data were reviewed by EDF and VRM for quality assurance with respect to diagnosis of SSc and select clinical characteristics.

Statistical analysis

Adults were included in the study analysis of prevalence and clinical characteristics if the diagnosis of SSc was endorsed by a rheumatologist and confirmed by December 31, 2019. Only individuals alive on December 31, 2019, contributed to the prevalence calculations; however, all adults with an SSc diagnosis during the entire study period were included in the descriptive analysis of clinical characteristics regardless of date of death. The population used for prevalence calculations was the 2019 ATHS adult (≥18 years of age) user population for participating THOs, defined as the number of adults receiving medical or dental care within the ATHS once during the previous three fiscal years.

Analysis was performed using R (version 4.4.1). ¹³ Unadjusted prevalence was calculated as the number of adults with the condition at the end of 2019 divided by the corresponding ATHS user population in 2019. Prevalence was age adjusted to the 2000 projected US population. ¹⁴ Confidence intervals (CIs) were calculated using the method of Clopper and Pearson for unadjusted prevalence ¹⁵ and the method of Fay and Kim for age‐adjusted prevalence. ¹⁶ To protect confidentiality, data were not reported for groups or categories with a sample size of less than five.

RESULTS

The flowchart for the inclusion of potential cases is presented in Figure 1. The 2019 ATHS user population (aged ≥18 years old) of participating THOs (denominator for prevalence) was 93,720.

Figure 1.

Flow diagram of included patients. Prevalence calculations for December 31, 2019, are based on the 29 patients alive on that date. The analysis of clinical characteristics includes all 36 patients identified during the study period. ICD, International Classification of Diseases.

A total of 36 patients with SSc were included in this study, with demographic and clinical features presented in Table 1. Seven patients (19.4%) died during the study period and were therefore excluded from the 2019 point prevalence calculations, which are based on the remaining 29 prevalent cases. The mean age at diagnosis was 59.9 years (median 62 years). The majority of patients were female (77.8%, n = 28), resulting in a female‐to‐male ratio of 3.5:1.

Table 1.

Unadjusted and age‐adjusted 2019 point prevalence of systemic sclerosis in AN/AI adults^*

Category	2019 prevalent cases, n	2019 unadjusted (95% CI)	2019 age‐adjusted (95% CI)
All systemic sclerosis	29	309 (207–444)	354 (241–504)
Female	22	452 (283–685)	503 (323–752)
Male	7	155 (62–320)	188 (82–379)
Age, y
18–24	<5	–	–
25–44	<5	–	–
45–64	16	609 (348–989)	–
>65	10	828 (397–1,522)	–
Limited cutaneous systemic sclerosis	21	224 (139–342)	258 (164–391)
Diffuse cutaneous systemic sclerosis	8	85 (37–168)	95 (44–184)

^*Per 1,000,000 adults aged ≥18 years old, unless otherwise specified. AI, American Indian; AN, Alaska Native; CI, confidence interval.

Prevalence estimates

The age‐adjusted overall prevalence of SSc was estimated to be 354 per 1,000,000 population (95% CI 241–504). The prevalence was significantly higher in women (503 per 1,000,000, 95% CI 323–752) compared to men (188 per 1,000,000, 95% CI 82–379). The highest prevalence was observed in individuals older than 65 years (828 per 1,000,000, 95% CI 397–1,522). The prevalence of dcSSc was estimated at 95 per 1,000,000 (95% CI 44–184), whereas the prevalence of lcSSc was 258 per 1,000,000 (95% CI 164–391; Table 1).

Clinical characteristics

The clinical subtypes of SSc were as follows: 27 patients (75%) had lcSSc, and 9 patients (25%) had dcSSc. The most common clinical manifestations are summarized in Table 2. Sclerodactyly (91.7%), Raynaud phenomenon (86.1%), telangiectasia (69.4%), and GI involvement (91.7%) were noted to be frequent (Table 2).

Table 2.

Demographics and clinical characteristics of systemic sclerosis (n = 36)^*

Characteristics	Value
Mean age at diagnosis, y	59.9
Female, n (%)	28 (77.8)
Limited cutaneous systemic sclerosis, n (%)	27 (75)
Diffuse cutaneous systemic sclerosis, n (%)	9 (25)
Skin/vascular involvement, n (%)
Sclerodactyly	33 (91.7)
Digital ulcers	13 (36.1)
Digital loss	7 (19.4)
Telangiectasia	25 (69.4)
Raynaud phenomenon	31 (86.1)
Calcinosis	15 (41.7)
Pulmonary manifestations, n (%)
Pulmonary arterial hypertension	6 (16.7)
Interstitial lung disease	13 (36.1)
Gastrointestinal manifestations, n (%)
Esophageal dysmotility	20 (55.6)
GERD	28 (77.8)
Serologic findings, n (%)
ANA positive	32 (88.9)
Anticentromere antibody	15 (41.7)
Anti–topoisomerase I antibody	6 (16.7)
Anti‐RNP antibody	5 (13.9)
RNA polymerase III antibody	<5

^*ANA, antinuclear antibodies; GERD, gastroesophageal reflux disease.

Serologic findings

Antinuclear antibodies (ANAs) were positive in 32 patients (88.9%). Specific autoantibodies were detected as follows: anticentromere antibodies in 15 patients (41.7%), anti–topoisomerase I antibody in 6 patients (16.7%), and anti‐RNP antibodies in 5 patients (13.9%). RNA polymerase III antibodies were detected in fewer than five patients.

Organ involvement

As shown in Table 2, GI involvement was highly prevalent, affecting 33 patients (91.7%). Esophageal dysmotility and gastroesophageal reflux disease were observed in 20 (55.6%) and 28 (77.8%) patients, respectively. PAH and ILD were present in 6 (16.7%) and 13 (36.1%) patients, respectively. Cardiac and renal involvement each occurred in fewer than 5 patients and are therefore reported as <5.

DISCUSSION

This study provides valuable epidemiologic and clinical data on SSc in AN/AI adults in Alaska. Population‐based studies on SSc prevalence in AN/AI populations are notably lacking, making our findings particularly relevant for understanding the burden of this disease in this population. Our findings reveal an age‐adjusted overall prevalence of 354 per 1,000,000 (95% CI 241–504), with a significantly higher prevalence in women (503 per 1,000,000, 95% CI 323–752) compared to men (188 per 1,000,000, 95% CI 82–379). The highest prevalence was observed in individuals over 65 years of age (828 per 1,000,000, 95% CI 397–1,522). These estimates, although based on a relatively small sample size, offer initial insights into the epidemiology of SSc in this unique population. Direct comparison with other studies is challenging due to variations in methodology, study populations, and the scarcity of data specifically on Indigenous populations in North America. Existing epidemiologic studies have reported global prevalence ranging from 38 to 469 cases per million, with higher estimates often reported in North America. ¹ , ² , ³ Our findings suggest a potentially similar or even higher prevalence in AN/AI peoples of Alaska, particularly in older individuals and women. The observed female predominance (77.8%) in our study aligns with global trends, in which SSc is significantly more prevalent in women, with female‐to‐male ratios ² ranging from 3:1 to 9:1.

There are limited data on SSc prevalence and clinical features in INA populations. In a study of an American Indian tribe in Oklahoma, people of one tribe were found to have SSc prevalence of 660 per 1,000,000, which is one of the highest reported prevalences of SSc. Of note, other American Indian people living in the same region did not have as high a prevalence. ⁵ However, this study included a small sample size of only 14 individuals based on which high prevalence was reported. Notably, this cohort exhibited a high proportion with dcSSc, and a majority were noted to have ILD. A high mortality rate was reported, with five deaths occurring within the study period. Based on a case‐control study, the authors reported a unique HLA haplotype as a possible risk factor in this population. In Alberta, Canada, First Nations individuals were estimated to have an SSc prevalence of 580 cases per 1,000,000 women and 100 per 1,000,000 men, which is slightly higher than the prevalence found in our study but within CIs for our estimate. ⁶ Another Canadian study comparing INA people with SSc to White people with SSc found that INA individuals were younger at disease onset, showed a trend toward more diffuse disease, experienced more severe Raynaud symptoms, had a trend toward a greater burden of digital ulcers, and reported more GI symptoms. ¹⁰

The clinical and serologic features observed in our study provide important insights for clinicians. The mean age at diagnosis (59.9 years) is consistent with the typical onset of SSc in the fourth to sixth decades of life. Although a high prevalence of dcSSc compared to lcSSc has been noted in Black and certain INA populations, our study found dcSSc in 25% (n = 9) and lcSSc in 75% (n = 27) of patients, which is similar to findings in other studies of White populations. ⁶ , ⁸ , ¹⁰ Sclerodactyly (91.7%), Raynaud phenomenon (86.1%), telangiectasia (69.4%), and GI involvement (91.7%) were particularly frequent. Most clinical features seem consistent with other studies, although the high proportion of telangiectasia and GI involvement observed here is notable. Esophageal dysmotility was noted to be present in 55.6% of individuals, which appears to be on the higher side compared to other studies, ranging from 20% to 75% of people with SSc. ⁸ , ¹⁰ ILD and PAH, present in 36.1% and 16.7% of individuals, respectively, are serious complications of SSc and important contributors to morbidity and mortality. PAH appears to be more prevalent in AN/AI people with SSc compared to other studies, in which PAH has been reported to be present in 3% to 12% of people with SSc, with no ethnic or racial predilection reported. ⁸ , ⁹ The prevalence of ILD in SSc can vary anywhere from 20% to 75% in the literature depending on the study methods, with a high prevalence noted in Black and some INA populations. The rates of ILD in our study appear to be overall similar to those of other populations. ⁷

Serologically, the antibody profile in the AN/AI population appears to be overall similar to that in other populations. Most studies report an ANA positivity rate of >80%. Anticentromere antibody is usually reported to be more prevalent, but higher rates of anti–topoisomerase I antibody positivity have been reported in populations with a high prevalence of dcSS. ⁵ , ⁶ , ⁷ , ⁸ , ⁹ In this study of the AN/AI population, positive ANA was detected in 88.9% of adults with SSc. The prevalence of specific autoantibodies varied: anticentromere antibodies (41.7%), anti–topoisomerase I antibodies (16.7%), and anti‐RNP antibodies (13.9%).

This study has some limitations, primarily its small sample size, which limits the precision of estimates. In addition, the study relied on data in the existing electronic health record using detailed medical record abstraction for specific elements but without direct contact with individuals to confirm clinical findings. Furthermore, although we abstracted data on organ involvement, the specific diagnostic modalities used (eg, right‐sided heart catheterization for PAH, high‐resolution computed tomography for ILD, or manometry for esophageal dysmotility) were not systematically collected; we relied on the clinician's diagnosis documented in the chart. This study is also limited by its inability to assess unique regional factors. We did not collect data on environmental factors, socioeconomic status, lifestyle factors, or the challenges with access to specialist care in Alaska's vast geography. Further research into these multifaceted influences is critical for understanding and mitigating SSc‐related health disparities in this population. Finally, as an observational study, the findings are descriptive and do not identify causal pathways.

This study represents the first investigation of SSc in AN/AI individuals in Alaska. We estimated an age‐adjusted overall prevalence of 354 per 1,000,000, with higher rates in women (503 per 1,000,000) and those aged over 65 years (828 per 1,000,000). Although many clinical and serologic features aligned with existing studies of SSc, we noted a somewhat high prevalence of GI involvement and telangiectasia. More research is needed to identify and address health disparities, risk and protective factors for developing SSc, and potential interventions to improve clinical outcomes.

AUTHOR CONTRIBUTIONS

All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Ferucci confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.