Epidemiological studies have found that the prevalence of the disease among the relatives of the patients was significantly higher than that of normal population. It suggests this disease has a certain relationship with inheritance factors. Antibodies found in patients with SSc, which is specific to the disease, seem to have a close relationship with human HLA class-II genes. In acrosclerosis and CREST syndrome, the anti-centromere antibodies (ACA) have a closer relationship with the DQ genes in HLA-II.

A study of pregnant women showed that bidirectional cells traffic between fetus and mother during normal human pregnancy. Moreover, fetal cells have been found to persist in the maternal peripheral blood for decades after childbirth. Nelson put forward a hypothesis that microchimerism is involved in autoimmune diseases like SSc based on the observation that the incidence of SSc is higher in women and is increased in women following childbearing year, and that SSc has clinical similarities to chronic graft-versus-host disease, a condition of chimerism occurring after stem cell transplantation. Altlett et al found the embryonic CD3+ T cells in peripheral blood of patients with SSc, and also found the presence of embryonic cells in diseased tissues. Taraka and Evans found the relevance ratio of microchimera on peripheral blood mononuclear cells in women with SSc is higher than that in healthy women. Arelett et al found male DNA in CD4+T cells collected from women. In female patients of SSc, the positive rate of microchimerism in CD4+T cells was up to 82.9%, while 63.6% in the control group. And in diffuse sclerosis, the number of CD4+T cells with microchimerism was also significantly higher than the control. In the autopsy of female patients of SSc, Johnson examined several sites of organs and tissue, and found DNA of male in at least one site. The microchimerism was most commonly found in spleen, following by lymph nodes, lungs, adrenals and skin tissue. The only organ without DNA of male was pancreas. In the detection for the tissue of women without autoimmune disease, there was no male cells. Christner injected ethylene chloride into BALB/CJ infertile female mice and found the number of microchimera in peripheral blood increased 48 times after 20 days. Meanwhile, there was a number of mononuclear cells and fibroblasts infiltrating in derma, with enriched collagen fiber arranging in beam, and the content of collagen in each unit of skin increased 2 to 3 times than that of the control. This study shows that microchimerism seems to induce the skin inflammation and fibrosis, and may be the essential factor of autoimmune diseases such as SSc. Some scholars considered the change of HLA-II compatibility might cause the long-exist of microchimerism. Lambert's study suggested that long-term microchimerism in T lymphocytes was closely associated with maternal HLA-DQA1*0501, but even more closely with that of their sons. However, in some other scholars' studies, it showed no significant difference in the positive rate of microchimerism between female patients with SSc and the control group, and microchimerism also widely existed in the normal population. So the role of microchimerism in SSc still needed to be further clarified.

Although this disease seemed to has a sporadic trend, the incidence is still high in some occupations, such as uranium miners, workers who are often exposed to dust (especially silica dust) and organic solvent.

Many patients often present with a history of acute infection before onset, including angina, tonsillitis, pneumonia, scarlet fever, measles, and sinusitis. Paramyxovirus-like inclusions had been found in striated muscle and kidney of patients. In recent years, some people proposed Borrelia burgdorferi infection may be associated with the disease.

In addition, trauma, fatigue, cold and other factors may play a certain role in the formation and development of SSc.