Scleroderma isn’t something you catch or develop from a single cause. It’s an autoimmune condition where the immune system mistakenly attacks the body’s own connective tissue, triggering cells called fibroblasts to produce too much collagen. This excess collagen builds up in the skin and sometimes in internal organs, causing the thickening and scarring that define the disease. No one factor explains why it happens, but a growing body of research points to a combination of genetic susceptibility, environmental exposures, hormonal influences, and blood vessel damage that together set the disease in motion.
What Happens Inside the Body
The process starts with the immune system overreacting and causing inflammation that injures the cells lining small blood vessels. This early vascular damage is now considered one of the first events in the disease. Once those blood vessel walls are injured, they release signaling molecules that cause the vessels to narrow and restrict blood flow. This is why Raynaud’s phenomenon, where fingers turn white or blue in response to cold, is often the earliest visible sign and can appear years before other symptoms.
The vascular injury also triggers a chain reaction in the surrounding tissue. Fibroblasts, the cells responsible for building connective tissue, shift into an overactive state and begin producing collagen at an abnormal rate. Some of the damaged blood vessel cells themselves actually transform into these collagen-producing cells, compounding the problem. The result is progressive fibrosis: tissue that should be soft and flexible becomes thick, stiff, and scarred.
Genetic Susceptibility
Scleroderma is not directly inherited, but your genes influence how likely you are to develop it. The strongest genetic links involve a set of immune system genes called HLA genes, which help your body distinguish its own cells from foreign invaders. Specific variations in these genes can increase scleroderma risk anywhere from two to seven times, depending on the variant and the person’s ancestry.
These genetic effects vary significantly across populations. In people of African descent, two specific HLA variants carry odds ratios of 3.2 and 2.3 for developing scleroderma. In people of European descent, different variants are involved, with one raising risk by about 2.6 times. Notably, one variant found in European Americans is actually protective, cutting the risk roughly in half. The genetic picture becomes even more striking when researchers look at specific subtypes of the disease. One HLA variant associated with a severe subtype involving lung scarring showed an odds ratio of 13.7 in European Americans, meaning carriers were nearly 14 times more likely to develop that particular form.
Having these gene variants doesn’t mean you’ll get scleroderma. Most people who carry them never do. But the variants create a biological backdrop that makes the immune system more prone to the kind of misfiring that leads to the disease, especially when combined with the right environmental trigger.
Environmental Triggers
Among all environmental exposures studied, silica dust and organic solvents have the strongest evidence linking them to scleroderma. People who work in hard rock mining, coal mining, stone cutting, concrete mixing, and mineral crushing face the highest silica exposure and, correspondingly, elevated risk. Organic solvents used in manufacturing and industrial cleaning have also been consistently implicated.
Certain medications can trigger scleroderma-like symptoms as well. Bleomycin, a chemotherapy drug, is the best-established pharmaceutical trigger and can induce fibrosis in animal models. Other cancer drugs, including taxane-based agents, vinblastine, and pembrolizumab (an immunotherapy drug), have shown significant associations in pharmacovigilance data. Outside of oncology, older drugs like pentazocine (a painkiller) and D-penicillamine have also been linked to scleroderma-like changes. These drug-associated cases are uncommon, but they offer a window into how external substances can push the body toward the same fibrotic process.
Why Women Are Affected More Often
Women develop scleroderma at least three times more often than men, with some studies reporting ratios as high as 8:1 or even higher. This dramatic skew points to hormonal factors playing a role. Estrogen activates signaling pathways involved in immune response and can promote autoimmunity. Research on scleroderma skin cells in the lab has shown that female sex hormones directly stimulate fibroblasts to produce more collagen.
A large population-based study found that women using hormone replacement therapy had a 42% increased risk of developing scleroderma compared to those who didn’t. Combination therapy with both estrogen and a progestogen carried a 50% increased risk. These findings don’t mean hormone therapy causes scleroderma outright, but they add to evidence that estrogen and related hormones can tip a susceptible immune system toward the disease.
Ethnicity, Age, and Disease Severity
Scleroderma affects people of all backgrounds, but it doesn’t affect them equally. Compared to white Americans, African Americans tend to develop the disease at a younger age, are more likely to have the diffuse form (which affects larger areas of skin and more internal organs), and experience more severe lung involvement. They are also less likely to carry anticentromere antibodies, a marker associated with milder disease. These differences appear to reflect both genetic factors, including the distinct HLA variants described above, and broader health disparities.
Women in their 30s through 50s represent the most commonly affected group, though the disease can appear at any age. Men who do develop scleroderma tend to have outcomes comparable to women with similar disease subtypes, but the overall male experience is less well studied simply because fewer men are diagnosed.
The Epigenetic Bridge
One of the more compelling explanations for how genes and environment work together involves epigenetics: chemical modifications that sit on top of your DNA and control which genes are turned on or off, without changing the DNA sequence itself. Think of it as a layer of switches that environmental exposures can flip.
In scleroderma, researchers have found abnormal patterns in these switches. Some genes involved in inflammation and collagen production appear to be stuck in the “on” position. Three main types of epigenetic changes have been identified: modifications that silence genes by attaching chemical tags to DNA, alterations to the proteins that DNA wraps around (which control how accessible genes are), and small RNA molecules that interfere with gene activity. These epigenetic changes can be influenced by environmental exposures like silica or solvents, potentially explaining why two people with the same genetic risk can have very different outcomes depending on what they’ve been exposed to over their lifetime.
How the Diagnosis Comes Together
Because scleroderma develops gradually and can look different from person to person, diagnosis relies on a combination of findings rather than a single test. Rheumatologists use a standardized point system. Skin thickening on the fingers that extends past the knuckles toward the wrist is considered sufficient on its own to classify someone as having the disease. When that finding isn’t present, doctors add up points from a checklist that includes skin thickening limited to the fingers, fingertip ulcers or scarring, tiny dilated blood vessels visible on the skin (telangiectasia), abnormal capillaries visible at the base of the fingernails, lung involvement, Raynaud’s phenomenon, and specific autoantibodies found through blood tests.
The particular autoantibodies present help predict which form of the disease someone has and which organs are most at risk. This is where genetics circles back into the clinical picture: the HLA variants a person carries strongly influence which autoantibodies they produce, which in turn shapes the course of their disease.