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Systemic Sclerosis (SSc)

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Risk Factors

Systemic sclerosis (SSc) is a rare, autoimmune, connective tissue disorder characterized by excessive collagen deposition and vascular abnormalities affecting the skin and/or internal organs.1 

The exact etiology of the condition is unknown. As with many autoimmune conditions, the causative factors are believed to be a combination of environmental and genetic factors. Therefore, risk factors for the condition include these potential causative environmental and genetic factors.1

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Demographic Risk Factors

Systemic sclerosis demonstrates an increased prevalence among groups with the following demographic characteristics2-5: 

  • Female sex 
  • Age between 45 and 64 years
  • Individuals living in North America or Europe (in studies compared to Japan or China)
  • Individuals of Choctaw Native American heritage from Oklahoma (20 times higher prevalence than the general population)
  • Family history of the disease

Many of these epidemiological demographics suggest genetic underpinnings as a risk factor for the development of SSc.

Read more about SSc epidemiology

Genetic Risk Factors

Ancestry-predominant human leukocyte antigen (HLA) gene alleles correlate more strongly with the specific autoantibody subtypes responsible for scleroderma, but they also identify the risk of developing the disease. African ancestry-predominant HLA alleles, HLA-DRB1*08:04 and HLA-DRB1*11:02, increase the risk of developing SSc. HLA-DRB1*08:04 correlates with the more severe antifibrillarin antibody (AFA) SSc subtype, which causes increased disease severity and higher mortality among the Black American population. HLA-DRB1*11:02 correlates with overall SSc prevalence in the Black American population, but not with any specific autoantibody subtype.6 

In White Americans, the alleles, HLA-DPB1*13:01 and HLA-DRB1*07:01, strongly correlate with the antitopoisomerase and anticentromere antibody SSc subtypes, respectively. These correlations between HLA alleles and antibody subtypes are stronger than the correlation with the risk of developing the disease. However, a direct association between HLA-DPB1*13:01 allele frequency and the prevalence of SSc across all ethnicities and races has been observed.6

While specific HLA alleles are most commonly related to certain autoantibody subtypes and SSc disease occurrence, severe non-HLA genes have also been associated with SSc. These genes include PTPN22, IRF5, IRF8, and TNFAIP3 (A20).5

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Microchimerism may be one of many factors increasing the risk of SSc pathogenesis. Women who have given birth, especially to male children, are more likely to develop SSc. Microchimerism occurs more commonly in those with SSc than in control individuals (35% vs 20%). Microchimerism may accelerate SSc disease development.2,7

Several occupational exposures have been found to increase the risk of developing SSc, especially silica and organic solvents. However, most of these studies were performed on small samples of men.3,8

Multiple sources indicate a significant association between the onset of SSc and environmental exposure to crystalline silica as well as cumulative silica exposures.2,3,8,9 Occupational exposure to organic solvents, including white spirits, ketones, trichloroethylene, aromatic hydrocarbon solvents, and chlorinated solvents, also correlate with SSc disease onset and more severe forms of the disease.9 

Due to small sample sizes, there is insufficient evidence suggesting that other environmental exposures increase the risk of SSc. Possible exposures include2,8,9:

  • Other chemical agents (such as pesticides, organic solvents, hair dyes, personal care products, epoxy resins, and welding fumes)
  • Physical agents (such as ultraviolet radiation, ionizing radiation, electrical fields, magnetic fields, and hand-arm vibrations)
  • Biological agents (such as specific or contaminated foods, infections, and diet)

Specific environmental exposures listed under these 3 categories that have been potentially associated with an increased risk of SSc include petroleum-related products, vinyl chloride, L-tryptophan, and contaminated rapeseed oil.5,10

Read more about SSc diagnosis

A systematic review of the literature published in 2018 reported that cigarette smoking, alcohol consumption, and infections did not increase the risk of developing SSc.2 In a study published in 2007, individuals with SSc reported a history of hepatitis B, rheumatic fever, or herpes zoster slightly more often than controls with musculoskeletal conditions, such as tendonitis, osteoarthritis, or fibromyalgia; however, these differences between groups were not statistically significant. Vaccinations in adulthood and infections within 1 year of SSc onset and diagnosis were not found to increase the risk of SSc development compared to the control group.11

Read more about SSc prognosis

Exposure to the cancer medication Blenoxane® (bleomycin) and the analgesic Talwin® (pentazocine) may increase the risk of developing SSc.10

References

  1. De Martinis M, Ciccarelli F, Sirufo MM, Ginaldi L. An overview of environmental risk factors in systemic sclerosis. Expert Rev Clin Immunol. 2016;12(4):465-478. doi:10.1586/1744666X.2016.1125782
  2. Abbot S, Bossingham D, Proudman S, de Costa C, Ho-Huynh A. Risk factors for the development of systemic sclerosis: a systematic review of the literature. Rheumatol Adv Pract. 2018;2(2):rky041. doi:10.1093/rap/rky041
  3. Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24(2):165-170. doi:10.1097/BOR.0b013e32834ff2e8
  4. Schwartz RA. Systemic sclerosis: epidemiology. Medscape. Updated April 16, 2021. Accessed April 25, 2023.
  5. Varga J. Risk factors for and possible causes of systemic sclerosis (scleroderma). UpToDate. Updated April 14, 2023. Accessed April 25, 2023.
  6. Gourh P, Safran SA, Alexander T, et al. HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry. Proc Natl Acad Sci U S A. 2020;117(1):552-562. doi:10.1073/pnas.1906593116
  7. Sahin A, Ozkan T, Türkçapar N, et al. Peripheral blood mononuclear cell microchimerism in Turkish female patients with systemic sclerosis. Mod Rheumatol. 2014;24(1):97-105. doi:10.3109/14397595.2013.854052
  8. Dospinescu P, Jones GT, Basu N. Environmental risk factors in systemic sclerosis. Curr Opin Rheumatol. 2013;25(2):179-183. doi:10.1097/BOR.0b013e32835cfc2d
  9. Marie I, Gehanno JF. Environmental risk factors of systemic sclerosis. Semin Immunopathol. 2015;37(5):463-473. doi:10.1007/s00281-015-0507-3
  10. Nevares AM. Systemic sclerosis (scleroderma). Merck Manual Professional Version. Updated October 2022. Accessed April 25, 2023.
  11. Pope JE, Goodwin JL, Ouimet JM, Krizova A, Laskin M. Infections are not increased in scleroderma compared to non-inflammatory musculoskeletal disorders prior to disease onset. Open Rheumatol J. 2007;1:12-17. doi:10.2174/1874312900701010012

Reviewed by Kyle Habet, MD, on 4/30/2023.

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