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Scleroderma–Systemic Sclerosis

John Varga, Fredrick M. Wigley

Systemic sclerosis (SSc) is a chronic multisystem connective tissue with other autoimmune diseases, particularly systemic lupus
disease characterized by autoimmunity and inflammation, erythematosus (SLE), and are involved in immune regulation
widespread functional and structural abnormalities in small and innate immune responses, highlighting the potential impor-
blood vessels, and progressive fibrosis of the skin and visceral tance of immune dysregulation in the pathogenesis of SSc. 3
organs. Multiple cell types and their products interact to mediate
the pathogenetic processes that underlie the diverse clinical Environmental Factors
manifestations of SSc. Although the etiology if SSc is unknown, microbial exposures
and exposure to environmental and occupational agents, dietary
PREVALENCE AND EPIDEMIOLOGY factors, and drugs have been implicated as potential triggering
factors. Patients with SSc have increased serum levels of antibodies
SSc is a sporadic disease with worldwide distribution. Incidence directed against the human cytomegalovirus (hCMV). Evidence
estimates in the United States range from 9 to 19 cases per million for a potentially pathogenic role for CMV, Epstein-Barr virus
per year, and prevalence rates range from 28 to 253 cases per (EBV), and parvovirus B19 infection or reactivation, as well as
million. According to the revised American College of Rheumatol- Helicobacter pylori infection, has also been presented. These studies
ogy classification criteria, which are more sensitive for identifying need confirmation, and the etiological role of microbial patho-
early stage of disease, the prevalence estimates are expected to gens in SSc remains a conjecture. Although reports of apparent
1
be considerably higher. Age, gender, and ethnicity are important geographical clustering of SSc cases suggest shared environmental
2
factors that determine disease susceptibility. Like other connective exposures, careful investigations have generally not been able to
tissue diseases, SSc is more prevalent in women, with the most substantiate these clusters. Epidemic outbreaks of apparently
common age of onset in the range of 40–60 years. Disease onset novel multisystemic illnesses with SSc-like features have been
tends to occur at an earlier age among patients of African descent linked to environmental exposures, such as contaminated rapeseed
than among whites. Furthermore, black patients are more likely cooking oils in Spain (the toxic oil syndrome) and l-tryptophan
to have diffuse skin involvement, digital ulcers, pulmonary dietary supplements (eosinophilia–myalgia syndrome) in the
4
hypertension (PH), and pulmonary fibrosis, and have a worse United States. The incidence of SSc is increased among miners
prognosis. and others with occupational exposure to silica. Additional
occupational exposures linked to increased risk of SSc include
ETIOLOGY AND PATHOGENESIS polyvinyl chloride, trichloroethylene, and organic solvents. Drugs
potentially implicated in SSc-like illnesses include bleomycin,
The pathogenesis of SSc involves dynamic interplay among taxane, pentazocine, cocaine, and anorexigens associated with
inherited genetic risk factors, environmentally induced stable pulmonary artery hypertension. The apparent association of
epigenetic modifications, and acute or subacute environmental SSc with silicone breast implants originally raised concern,
exposures. but epidemiological investigations have not substantiated the
hypothesis of an increased risk. 5
Genetic Factors
Systemic sclerosis is not inherited in a mendelian fashion, and Pathology
disease concordance rates among both monozygotic and dizygotic The hallmark pathological features of SSc are a noninflammatory
twins are relatively low (<5%). Nonetheless, 1.6% of patients obliterative microangiopathy in multiple vascular beds and fibrosis
with SSc have a first-degree relative with the disease (relative of the skin and internal organs. In early-stage disease, cellular
risk of 13), indicating an important role for genetic background infiltrates may be prominent in many organs. In skin, inflam-
in SSc disease susceptibility. Specific human leukocyte antigen matory cells are located predominantly around blood vessels.
(HLA) haplotypes show strong association with distinct SSc- With disease progression, these infiltrates become sparse.
specific autoantibody responses. Genetic investigations in SSc Vascular injury is the earliest and possibly primary event in
have focused on candidate genes and genome-wide association the pathogenesis of SSc. Patients with established SSc show
studies (GWAS). Candidate genes shown to be associated with widespread vascular lesions characterized by bland intimal
SSc include those implicated in interferon (IFN) signaling, T- and proliferation in the small- and medium-sized arteries (Fig. 55.1).
B-cell activation, DNA clearance, and innate immunity (Table In late stages, perivascular adventitial fibrosis and generalized
55.1). It is remarkable that a majority of these genes are shared capillary rarefaction are prominent.

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