Scleroderma is caused by a combination of genetic susceptibility, immune system dysfunction, and environmental triggers that together drive the body to overproduce collagen, the protein that gives skin and connective tissue their structure. No single cause has been identified. Instead, the disease appears to unfold through a chain of events: something activates the immune system in a genetically vulnerable person, blood vessels sustain damage, and the body’s wound-healing machinery gets stuck in overdrive, depositing scar-like tissue in the skin and sometimes in internal organs.
The disease strikes women nearly five times more often than men, with the average age of onset around 47 to 50 years. It rarely develops after age 75.
Genetic Risk Factors
Scleroderma is not directly inherited, but certain gene variants make a person more vulnerable. The strongest genetic links involve the HLA system, a group of genes that help the immune system distinguish the body’s own cells from foreign invaders. Specific HLA variants, particularly HLA-DRB1*11:04 and HLA-DPB1*13:01, are found at significantly higher rates in people with scleroderma compared to the general population. People carrying HLA-DRB1*11:04 have roughly 2.8 times the usual risk, and HLA-DPB1*13:01 raises risk by about 2.2 times.
These genetic associations are even more pronounced in patients who produce a specific autoantibody called anti-topoisomerase (sometimes called anti-Scl-70). In that subgroup, carrying HLA-DPB1*13:01 increases risk nearly eightfold. This suggests the genetic blueprint doesn’t just make scleroderma more likely in general; it shapes which form of the disease a person develops.
The Immune System Turns on Itself
Scleroderma is an autoimmune disease, meaning the immune system mistakenly attacks the body’s own tissues. A hallmark of this misdirected response is the production of autoantibodies, proteins that target normal cellular components. Two autoantibodies are particularly associated with scleroderma and help distinguish its subtypes.
Anti-centromere antibodies appear in roughly 57% of people with the limited form of the disease (sometimes called CREST syndrome), which primarily affects the skin of the hands, face, and forearms. Anti-topoisomerase I antibodies (anti-Scl-70) are found in about 40% of people with the diffuse form, which involves more widespread skin thickening and carries a higher risk of organ damage. These two antibodies almost never appear together in the same patient, and about 40% of scleroderma patients test negative for both. A third antibody, anti-RNA polymerase III, is also linked to the diffuse form and is associated with a higher risk of kidney involvement.
Beyond antibodies, the broader immune response is disrupted. Immune cells infiltrate the skin and blood vessel walls early in the disease, releasing chemical signals that push fibroblasts (the cells responsible for making collagen) into a permanently activated state.
Blood Vessel Damage Comes Early
Injury to the inner lining of blood vessels appears to be one of the earliest events in scleroderma, often occurring before noticeable skin changes. The cells lining small arteries and capillaries become dysfunctional, triggering a cascade of problems: the vessel walls thicken, capillaries break down, and some blood vessels become completely blocked.
This vascular damage explains why Raynaud’s phenomenon, where fingers turn white or blue in response to cold or stress, is often the very first symptom. It can precede other signs of scleroderma by years. The ongoing loss of small blood vessels also deprives tissues of oxygen and nutrients, which contributes to skin ulcers on the fingertips and, in severe cases, damage to the lungs, kidneys, and heart.
How Fibrosis Takes Hold
The defining feature of scleroderma is fibrosis: the relentless buildup of collagen and other structural proteins in the skin and organs. This process is driven primarily by a signaling molecule called TGF-beta, which normally plays a controlled role in wound healing. In scleroderma, TGF-beta signaling becomes persistent and self-reinforcing.
Here’s what happens at a cellular level. TGF-beta activates fibroblasts and transforms them into myofibroblasts, aggressive collagen-producing cells that normally appear only during wound repair and then die off. In scleroderma, these cells don’t shut down. They establish a feedback loop: TGF-beta triggers the production of a protein called CCN2, which in turn amplifies TGF-beta’s effects, keeping the fibroblasts locked in their overproductive state. Meanwhile, the natural brakes on this process are weakened. Scleroderma fibroblasts show reduced levels of several molecules that normally restrain collagen production, including one called PTEN. When researchers have studied mice lacking PTEN, their fibroblasts produce excess collagen and readily convert into myofibroblasts, mirroring what happens in scleroderma.
This combination of an accelerator stuck on and brakes that don’t work explains why fibrosis in scleroderma is so difficult to reverse once established.
Environmental Triggers
Genetics loads the gun, but something in the environment often pulls the trigger. The best-studied occupational exposure is silica dust. A meta-analysis of available studies found that silica exposure is a significant risk factor for developing scleroderma, with the association particularly strong in men. Workers in mining, sandblasting, construction, and ceramics face the highest exposure levels.
Organic solvents, including those used in painting, degreasing, and chemical manufacturing, have also been linked to increased risk, though the evidence is less consistent than for silica. The common thread among these exposures is that they can cause direct tissue damage or trigger abnormal immune activation in susceptible individuals.
Viral Infections as Possible Triggers
Several viruses have been investigated as potential triggers for scleroderma in genetically predisposed people. The strongest laboratory evidence involves parvovirus B19, a common virus best known for causing “fifth disease” in children. Research published in Rheumatology demonstrated that parvovirus B19 can infect human skin fibroblasts and push them into a state of premature aging called cellular senescence. These senescent fibroblasts then produce inflammatory and fibrotic signals that spread to neighboring cells, potentially setting off a chain reaction of tissue scarring.
Other viruses, including cytomegalovirus (CMV) and Epstein-Barr virus, have been found at higher rates in scleroderma patients, though a direct causal relationship hasn’t been proven. The idea is that viral infection may serve as the initial insult that, in combination with genetic vulnerability, pushes the immune system toward the autoimmune and fibrotic cascade.
The Microchimerism Theory
One intriguing hypothesis for why scleroderma disproportionately affects women involves fetal microchimerism. During pregnancy, small numbers of fetal cells cross the placenta and take up permanent residence in the mother’s body. In women with scleroderma who previously gave birth to male children, researchers have found male fetal immune cells in their skin and blood. These fetal cells produce high levels of IL-4, an immune signal associated with fibrosis.
The theory is that these foreign cells could trigger a reaction resembling chronic graft-versus-host disease, where the body mounts an immune response either against the foreign cells or, confused by their presence, against its own tissues. This could help explain the strong female predominance of the disease and why onset often occurs during or after childbearing years. The hypothesis remains unproven, but the biological evidence is compelling enough to sustain ongoing research interest.
Localized vs. Systemic: Different Diseases, Overlapping Biology
When people search for “scleroderma,” they may be looking at two distinct conditions. Localized scleroderma (morphea) affects only the skin and underlying tissue, producing patches or bands of thickened skin. Systemic sclerosis involves the skin plus internal organs and blood vessels.
The two conditions share some biology, particularly the end result of excessive collagen deposition and similar skin biopsy findings. But they differ in important ways. Systemic sclerosis features Raynaud’s phenomenon, characteristic autoantibodies, and abnormal nail-fold capillaries. Localized scleroderma generally lacks all three. The trigger for localized scleroderma is thought to be a vascular injury that spirals into overactive collagen production, but without the widespread immune dysregulation seen in systemic disease. Some researchers consider them two ends of a single disease spectrum, though they behave as separate conditions in clinical practice.