Introduction
Scleroderma is a rare autoimmune disease that involves the hardening of the skin. Scleroderma can cause problems relating to the internal organs and blood vessels. Scleroderma causes inflammation and overproduction of collagen which accumulates and creates thick, waxy skin. There are two major types of scleroderma: localized scleroderma and systemic sclerosis (SSc). Localized scleroderma only affects the skin and structures directly under the skin (Mayo Foundation for Medical Education and Research, 2024). The two most general patterns that localized scleroderma appears in are either patches of scleroderma that may be half an inch or larger in diameter called morphea, or linear scleroderma where the thickened skin occurs in a line (U.S. Department of Health and Human Services, 2023). Linear scleroderma usually extends down the arms or legs, however, sometimes it can also run down the forehead and face (American Academy of Dermatology Association [AAD], n.d.) On the other hand, systemic sclerosis is a more serious type of scleroderma that damages blood vessels and internal organs, such as the lungs, kidney, heart, or anywhere along the digestive system (AAD, n.d.). Systemic sclerosis is classified as limited or diffuse based on the level of involvement with the skin (Johns Hopkins Medicine [JHM], n.d.-a). Limited sclerosis, also known as CREST syndrome, involves symptoms such as calcinosis, Raynaud’s syndrome, esophageal dysfunction, sclerodactyly, and telangiectasias (Cleveland Clinic [CC], n.d.). It gradually affects the skin on the patient’s fingers, hands, face, lower arms, and sometimes legs below the knees. In contrast, diffuse sclerosis can rapidly spread and be found over large areas of an individual’s chest, abdomen, thighs, arms, legs, and face (CC, n.d.). This type of sclerosis is more dangerous as it causes more internal damage.
Scleroderma is diagnosed based on the symptoms such as skin hardening by certified dermatologists. One challenge in diagnosing scleroderma is its overlap in symptoms with other diseases. As a result, a skin biopsy is usually performed by dermatologists to examine thickened skin. Other types of tests such as X-rays, blood tests, and CAT scans are also done to assist in the diagnosis of scleroderma (Corbin et al., 2023).
Anyone can get scleroderma, but certain groups have a higher risk of developing the disease. Sex, age, and race are all factors that can play a part in the development of scleroderma. Though we do not know the exact cause of scleroderma, it is believed that genetic makeup, environmental factors, changes in the immune system, and even hormones may be risk factors in the development of scleroderma (JHM, n.d.-b).
Currently, there is no cure for scleroderma, however, there are some treatments that can slow the progression of the disease and relieve symptoms (AAD, n.d.). Treatments usually work best at early stages of scleroderma. Treatments such as phototherapy, and medicines such as methotrexate or cyclosporine, improve the immune system and help reduce the symptoms of scleroderma (Corbin et al., 2023). Other treatments such as physical therapy are usually carried out to maintain the ability to move joints and minimize the tightening of skin over joints (Corbin et al., 2023). Treatment is prescribed based on the type of scleroderma a patient is dealing with and the level of involvement of scleroderma. Our current knowledge of scleroderma is scarce due to the rare and unpredictable nature of the disease.
Methods
This systematic review was conducted using modified PRISMA guidelines, with the main modification being this was a single-author review. PubMed was searched for the MeSH filters “‘systemic sclerosis’ or ‘scleroderma’ AND risk factors AND progression of disease.'” The search strategy included studies published from various countries ranging from January 2000 to July 2024. Studies that researched modifiable or non-modifiable risk factors in adult patients diagnosed with systemic sclerosis were included. Studies that discussed disease progression, development of complications, or the morbidity and mortality of scleroderma were also included. On the other hand, studies that focused on pediatric patients, localized cutaneous scleroderma, and other diagnoses were excluded. Additionally, case reports, popular press reports, non-peer-reviewed reports, articles in foreign languages, studies that did not include the development of complications or disease progression, and other reviews were also excluded. A full list of inclusion and exclusion criteria can be found in Table 1.
Articles were screened for information relating to risk factors such as lifestyle habits, everyday risk factors, and health factors, which the author extracted. Each article was also analyzed for factors contributing to the progression of disease or complications related to systemic sclerosis. The author independently performed a quality assessment, and any papers not from peer-reviewed, quality sources were excluded.
Results
Literature Search and Study Characteristics
The initial search consisted of 297 articles. After applying an inclusion and exclusion criteria, 83 articles were assessed for full-text review. Of the 83 articles reviewed, 38 articles were selected for inclusion, with participating patients from foreign studies Acosta-Herrera et al., 2019; Allanore et al., 2015; Apipattarakul et al., 2018; Beall et al., 2007; Becker & Riemekasten, 2016; Bose et al., 2015; Bossini-Castillo et al., 2015; Bussone et al., 2011; Chang et al., 2006; Chowaniec et al., 2018; Ciaffi et al., 2024; Denton & Hachulla, 2011; Faludi et al., 2014; Giucă et al., 2021; Gumkowska-Sroka et al., 2024; Hesselstrand et al., 2005; Hosing et al., 2011; Hui, Duan, et al., 2024; Hui, Zhou, et al., 2024; Hussein et al., 2014; Jang et al., 2023; Khanna et al., 2020, 2023; Kolb & Vašáková, 2019; Koschik et al., 2012; Liem et al., 2023; MacGregor et al., 2001; Mihai et al., 2018; Morisset et al., 2017; Nevskaya et al., 2017; Ouchene et al., 2021; Radić et al., 2010; Simeón-Aznar et al., 2015; Volkmann, 2020; Wareing et al., 2023; Yaqub & Chung, 2013; Yu et al., 2023; Zuhur et al., 2012.
A Framework of Non-modifiable and Modifiable Factors Contributing to the Development and Progression of Scleroderma
After analyzing the eligible articles, it was revealed that risk factors pertaining to systemic sclerosis development can be attributed to non-modifiable factors as well as modifiable factors. Non-modifiable factors are defined as an individual’s genetics, sex, age, race, and the autoantibodies found within them. Modifiable factors are defined as environmental risk factors and a history of smoking.
Non-modifiable Factors
Age
Eighteen of the 38 articles selected for inclusion revealed that age was a common non-modifiable risk factor in the development and progression of complications related to systemic sclerosis (Apipattarakul et al., 2018; Beall et al., 2007; Becker & Riemekasten, 2016; Bose et al., 2015; Chang et al., 2006; Denton & Hachulla, 2011; Faludi et al., 2014; Giucă et al., 2021; Gumkowska-Sroka et al., 2024; Hui, Zhou, et al., 2024; Jang et al., 2023; Khanna et al., 2020; MacGregor et al., 2001; Morisset et al., 2017; Nevskaya et al., 2017; Simeón-Aznar et al., 2015; Yaqub & Chung, 2013; Zuhur et al., 2012).
These articles found that increased age was a common risk factor in the development and progression of both complications associated with systemic sclerosis and systemic sclerosis. Some complications associated with systemic sclerosis discussed in the article review include interstitial lung disease (ILD), pulmonary hypertension (PAH), left ventricular diastolic dysfunction (LVDD), tricuspid gradient (TG), and scleroderma renal crisis (SRC). Specifically, patients who are above 60 years old are at a greater risk of developing systemic sclerosis and such complications with more severe progressions. Interestingly, one study discussed contrasting ideas stating that diffuse cutaneous systemic sclerosis tends to develop at a younger age in African Americans (Beall et al., 2007). Five articles revealed that increased age is also associated with increased mortality among SSc patients as there may be more underlying diseases affecting older patients (Apipattarakul et al., 2018; Bose et al., 2015; Jang et al., 2023; Khanna et al., 2020; Simeón-Aznar et al., 2015). Furthermore, age is associated with higher mortality rates due to more severe degrees of skin involvement, for example, rapidly progressive skin hardening in patients with SRC.
Sex
Eighteen of the 38 articles selected for inclusion also reveal that sex plays a role in the likelihood of developing systemic sclerosis as well as complications associated with systemic sclerosis (Allanore et al., 2015; Beall et al., 2007; Bose et al., 2015; Chang et al., 2006; Chowaniec et al., 2018; Ciaffi et al., 2024; Denton & Hachulla, 2011; Giucă et al., 2021; Hussein et al., 2014; Khanna et al., 2020, 2023; MacGregor et al., 2001; Mihai et al., 2018; Nevskaya et al., 2017; Simeón-Aznar et al., 2015; Volkmann, 2020; Yaqub & Chung, 2013; Zuhur et al., 2012). Progression and severity of systemic sclerosis and its related complications can also be attributed to sex. Specifically, Male sex is a risk factor associated with the development and progression of SSc and its complications. In 8 of the 17 articles, it was revealed that males are more likely to develop SSc, SSc-ILD, and SSc-PAH (Chang et al., 2006; Chowaniec et al., 2018; Giucă et al., 2021; Hussein et al., 2014; Khanna et al., 2020, 2023; Volkmann, 2020; Yaqub & Chung, 2013). In 2 articles, the mortality rates of males are revealed to be higher than females, with males more likely developing diffuse SSc and ILD, leading to a worse prognosis (Ciaffi et al., 2024; Hussein et al., 2014). Compellingly, 3 articles reveal that women are at a higher risk of developing SSc-PAH during the post-menopausal period and childbearing years (Denton & Hachulla, 2011; Hussein et al., 2014; Yaqub & Chung, 2013). This could be potentially linked to a decrease in the protective effects of estrogen in females. Similarly, in one article, systemic sclerosis was found to predominantly affect women, specifically middle-aged women with a pooled prevalence of 33.99 per 100,00 compared to men who had only 6.0 per 100,000 (Gumkowska-Sroka et al., 2024).
Biomarkers
Seventeen of the 38 articles selected for full-text review identified genetics, autoantibodies, and blood neutrophil count as risk factors in the development and progression of SSc and SSc-related complications (Acosta-Herrera et al., 2019; Allanore et al., 2015; Becker & Riemekasten, 2016; Bose et al., 2015; Bossini-Castillo et al., 2015; Bussone et al., 2011; Gumkowska-Sroka et al., 2024; Hesselstrand et al., 2005; Hui, Duan, et al., 2024; Hui, Zhou, et al., 2024; Khanna et al., 2023; Kolb & Vašáková, 2019; Koschik et al., 2012; Liem et al., 2023; Nevskaya et al., 2017; Wareing et al., 2023; Yu et al., 2023). In three articles, genes in the HLA region showed the strongest link to SSc susceptibility (Acosta-Herrera et al., 2019; Bossini-Castillo et al., 2015; Gumkowska-Sroka et al., 2024). These genes affect immune processes, such as the presentation of autoantigens and cytokine production, thus strongly influencing disease development and progression (Gumkowska-Sroka et al., 2024). HLA-DRB1*1104 has shown strong associations with certain SSc subtypes (Bossini-Castillo et al., 2015). The TYK2 gene, part of the JAK family is recognized as a genetic risk factor (Gumkowska-Sroka et al., 2024). Genome-wide association studies have also identified multiple single-nucleotide polymorphisms associated with SSc, particularly in the MHC class II region (Hussein et al., 2014).
In addition to genes, in 14 articles autoantibody presence was discussed as a risk factor in SSc development and progression (Becker & Riemekasten, 2016; Bose et al., 2015; Bussone et al., 2011; Chowaniec et al., 2018; Gumkowska-Sroka et al., 2024; Hesselstrand et al., 2005; Hui, Duan, et al., 2024; Hui, Zhou, et al., 2024; Khanna et al., 2020; Kolb & Vašáková, 2019; Liem et al., 2023; Nevskaya et al., 2017; Volkmann, 2020; Yu et al., 2023). The presence and positivity of specific antibodies: anti-Scl-70, anti-topoisomerase I, anti-RNA polymerase III, anti-centromere, anti-neutrophil cytoplasmic, anti-phospholipid antibodies were all identified as potential risk factors for development and progression. These types of autoantibodies are associated with higher risks of SSc and SSc-ILD. However, in contrast to the other articles, one article found that the absence of the anti-centromere antibody indicated an increased likelihood of progressive ILD (Khanna et al., 2020). 1 article revealed that patients with the anti-PM-Scl antibodies are associated with better survival rates compared to patients without the antibody (Koschik et al., 2012). One article found that higher neutrophil count & neutrophil-to-lymphocytes ratio predicted a decline in lung function (Wareing et al., 2023).
Race/Ethnicity
In seven articles, race and ethnicity were found to be risk factors in the development and progression of SSc and SSc-related complications (Allanore et al., 2015; Beall et al., 2007; Bose et al., 2015; Khanna et al., 2020; Nevskaya et al., 2017; Volkmann, 2020; Zuhur et al., 2012). Five of these articles reported that SSc and its related complications – such as diffuse cutaneous SSc, SSc-PAH, SRC, and SSc-ILD – were more prevalent in Black and African Americans than any other race (Allanore et al., 2015; Beall et al., 2007; Bose et al., 2015; Khanna et al., 2020; Zuhur et al., 2012). African American patients experienced more severe disease progression while also showing higher rates of mortality and morbidity (Allanore et al., 2015). This is further supported in one more article, which discusses the relationship between ethnicity and SSc-ILD (Volkmann, 2020). In this article, Afro-Caribbean patients were more at risk of developing SSc-ILD compared to European, South/ East Asian, Hispanic, Arab, North American Indigenous, and Persian patients due to autoantibody positivity discussed previously. In one of the seven articles, patients of South Asian ethnicity experienced more severe cardiac involvement relating to SSc because they experienced longer disease duration (Nevskaya et al., 2017).
Modifiable Factors
Smoking
In four articles, smoking was identified as a notable risk factor in the development and progression of SSc and SSc-related complications (Ciaffi et al., 2024; Hui, Duan, et al., 2024; Hui, Zhou, et al., 2024; Morisset et al., 2017). According to these articles, smoking is a notable risk factor associated with the development and progression of SSc, SSC-ILD, and digital gangrene. In one article, smoking is associated with increased mortality in male patients but not in female patients (Ciaffi et al., 2024). However, women who have a history of smoking have a higher risk for disease progression in SSc. People who have smoked at least once in their lives are at a higher risk than those who have never smoked of developing SSc-ILD, and digital ischemia, while also experiencing more severe cardiac or gastrointestinal involvement.
Medications
Two articles discussed certain medications and treatments that may be risk factors in developing and progressing SSc and other related complications (Bussone et al., 2011; Hosing et al., 2011). One article explored the effects of corticosteroid treatments and their relationship to SSc progression. Corticosteroids, particularly in high doses, are associated with an increased risk of SRC as a complication (Bussone et al., 2011). In another article, patients who received high doses of immunosuppression followed by autologous or allogeneic hematopoietic cell transplantation may be at further risk for developing renal complications due to the administration of calcination inhibitors and high doses of corticosteroids for the prevention treatment of graft-versus-host diseases (Hosing et al., 2011).
Environmental and Occupational Factors
Four articles discuss the environmental and occupational risk factors that may be associated with the development and progression of SSc and SSc-related complications (Allanore et al., 2015; Gumkowska-Sroka et al., 2024; Ouchene et al., 2021; Radić et al., 2010). Three articles discussed that environmental and occupational factors significantly influence disease development with various chemical compounds implicated (Allanore et al., 2015; Gumkowska-Sroka et al., 2024; Hesselstrand et al., 2005). These compounds include silica, pesticides, organic solvents, and epoxy resins. Occupational exposure to silica dust, vinyl chloride, asbestos, and particulate air pollution may play a part and favor increased risks of SSc development (Allanore et al., 2015; Hesselstrand et al., 2005). Workers in cleaning industries have a higher risk of disease development and progression because they are at significant risk of absorbing solvents through the skin and airways. These organic solvents may contribute to developing autoimmune diseases through tissue injury and immune alteration by impeding cell proliferation and apoptosis (Ouchene et al., 2021). Bacterial and viral infections may also contribute to disease initiation, not as a causative agent, but rather as a permissive factor.2 In terms of viruses, Parvovirus B19 has been implicated in the pathogenesis of SSc due to its potential to cause vascular injury (Radić et al., 2010). The same article also found that high percentages of patients are infected with the virulent CagA strain of H. Pylori, suggesting a potential role in disease pathogenesis (Radić et al., 2010).
Discussion
Systemic sclerosis is a rare disease that humanity has yet to fully decipher. More research has to be done in medicine to prevent and develop more effective treatments for the disease to understand the characteristics and risk factors associated with the disease. In this paper, we conducted a systematic review of articles retrieved from the PubMed database to uncover the modifiable and non-modifiable factors contributing to the development and progression of systemic scleroderma. Through the screening of several articles, the authors discovered the most common modifiable factors involved with the development and progression of scleroderma were smoking, environmental and occupational factors, as well as medication and treatments. In addition to modifiable risk factors, researchers also found that age, sex, genetics, autoantibodies, blood neutrophil count, and race were the most common non-modifiable factors.
It is important to research the risk factors associated with systemic sclerosis because little is known about this rare disease. This systematic review contributes to the current state of knowledge relevant to scleroderma development and progression through a synthesis of various risk factors, possibly influencing other researchers to start their own studies in identifying other risk factors relating to the same topic. The objective of this review is to promote awareness of scleroderma research, enabling the development of new ideas and methods towards how to approach the generation of treatments for scleroderma through the incorporation of current knowledge on specific risk factors influencing systemic sclerosis.
Newer studies of risk factors discussed in this systematic review heavily overlap with older ones. This suggests that further research should be done on the risk factors covered in this review to solidify their role pertaining to the development and progression of scleroderma and its related complications. Once specific risk factors have been identified and agreed upon, doctors and researchers can direct their attention toward better understanding why and how these factors, such as smoking or race, relate to scleroderma. This can ultimately guide medicine in the direction of advancements in treatments or preventative measures for scleroderma. For example, in the case of systemic lupus erythematosus (SLE), unprotected sun exposure was identified as a risk factor in the formation of skin lesions.45 Patients with SLE are now counseled on sun-avoidant behaviors to reduce the risk of skin lesions and exacerbation of disease. A similar understanding of risk factors for scleroderma may allow patients to slow the progression or development of their disease.
This systematic review identified that age is the most common of all risk factors for disease development and progression. This may be secondary to older patients usually having weaker immune systems as well as underlying health issues impacting the susceptibility of scleroderma. For example, these sources suggest scleroderma is worsened by pulmonary hypertension, which is more common in the elderly (Apipattarakul et al., 2018; Chang et al., 2006; Giucă et al., 2021; Rutkowska-Sak et al., 2021; Yaqub & Chung, 2013). Systemic sclerosis is rare in children and teenagers, further suggesting age is a reliable risk factor in the pathogenesis of systemic sclerosis (Launay et al., 2017).
Another common non-modifiable risk factor worth noting is race and ethnicity, specifically those of African American or Black descent. Several overlapping studies have shown that African Americans have the highest rates of susceptibility to scleroderma. This may be associated with the genome and autoantibodies found in African Americans, two other non-modifiable risk factors associated with scleroderma (Volkmann, 2020). These factors may further influence the development of other complications such as pulmonary hypertension (Beall et al., 2007). Besides age and race, genetics is also a common risk factor. The male sex has been considered a huge risk factor as several studies included in this paper have supported this claim. This may be due to differences in the X and Y chromosomes which may regulate an individual’s immune system. Therefore, it may be worth researching how these chromosomes play a part in the pathogenesis of scleroderma (JHM, n.d.-a). Because of these reasons, it may be important to closely monitor male African American patients of older age as they are the most likely to develop scleroderma. With this in mind, future researchers may unlock more complex findings associated with older age, race, genetics, and autoantibodies. Despite these findings, further research must be done to confirm them.
Compared to the non-modifiable risk factors, there were fewer studies overall discussing modifiable risk factors. Nevertheless, some studies overlapped, which suggests there is some validity to these factors. Specifically, smoking and environmental factors were found to be the most common of the modifiable risk factors. Patients and adults with a history of smoking were found to be more susceptible to a more severe progression of scleroderma and one of its specific complications, interstitial lung disease (ILD) (Ciaffi et al., 2024). Though we do not know whether smoking is a direct factor that influences the likelihood of developing scleroderma, the symptoms relating to SSc-ILD such as shortness of breath and chest pain suggest that smoking may play a factor in these symptoms as it causes lung damage. This may lead to a more severe prognosis of SSc-ILD. Aside from smoking, environmental factors may be an important factor contributing to the susceptibility of scleroderma. Occupational chemicals such as silica dust and epoxy resin that enter through the skin and airways may weaken the immune system or cause tissue injury. These can then lead to an increased likelihood of developing or worsening systemic sclerosis. This suggests that workers who are in close contact with organic solvents should be closely monitored as high-risk patients. Nonetheless, there is still a chance of uncertainty, thus further studies need to be done to confirm these risk factors.
There were various strengths to this systematic review. One of these strengths was the number of papers included in the paper. With so many papers, a great deal of information was able to be gleaned from across various research papers. In addition to this strength, many articles overlapped with each other implying there is a connection between the results. Another strength of this paper is the use of only one database. As all articles were pulled from a trusted source, PubMed, all the articles included in this paper are from credible authors. In addition to the large amounts of articles reviewed and the use of one single database, this paper followed modified PRISMA guidelines to be very systematic while ensuring structure and organization.
A weakness of this paper is there is only one author. This may result in bias in certain articles and ideas in this paper. Furthermore, with only one author reviewing and screening all articles, there is a high chance of inevitable error and inaccuracy in parts of the synthesis and analysis of the articles, especially as there was a substantial number of articles to review and analyze.
We must continue to research scleroderma, including its symptoms, how the disease progresses, and the risk factors associated with the disease. Once we have a better understanding of the disease, it will be easier to develop more effective treatments, or possibly even a cure for the disease. However, as of right now, we have yet to reach a complete understanding of the disease so treatments are unlikely. Because of this, researchers need to continue brainstorming and researching how and why certain factors can influence the pathogenesis of scleroderma. In addition to the causes of scleroderma, doctors should also research how to prevent scleroderma with our present knowledge of risk factors. We should also question the effects of certain risk factors on the immune system as scleroderma is an autoimmune disease. Furthermore, as collagen buildup is a huge problem in scleroderma, we should investigate how we can control the collagen buildup. Overall, we have come a long way and gathered great information on scleroderma, nevertheless, our current findings are only hints and lead to greater knowledge that has yet to be unearthed.
Conclusion
Scleroderma, also known as systemic sclerosis, is a rare, autoimmune disease that causes an overproduction of collagen, resulting in the hardening and thickening of the skin. With little established knowledge of the cause of the disease and its pathogenesis, this paper inquired what modifiable and non-modifiable risk factors may affect the development and progression of scleroderma. To answer this question, a systematic review utilizing a modified PRISMA guideline and the PubMed database was conducted to recover possible risk factors pertaining to scleroderma. Ultimately, this paper revealed that the most common non-modifiable risk factors consisted of older age, male sex, genetics, and African American race. Modifiable risk factors included a history of smoking, environmental and occupational risk factors, as well as certain medicines or treatments. While the exact etiology of scleroderma is still unknown, understanding the risk factors related to the development and progression of systemic sclerosis can provide greater insight into predicting the cause of scleroderma, with hopes that effective treatments can eventually be developed.