• Home

Home > Medical Reference > Patient Education

• Highlights
• Introduction
• Symptoms
• Causes
• Risk Factors
• Prognosis
• Diagnosis
• Treatment
• Medications
• Other Treatments
• Treatment for Raynaud's Phenomenon
• Treatment for Skin Thickening
• Treatment for Lung Complications
• Treatment for Gastrointestinal Problems
• Treatment for Other Complications
• Resources
• References

Scleroderma

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of scleroderma.

Alternative Names

Systemic sclerosis

Causes

The disease process leading to scleroderma appears to occur as an autoimmune response, where an abnormal immune system attacks the body itself. In scleroderma, this response produces inflammation (swelling) and an overproduction of collagen. Collagen is the tough protein that helps build connective tissues such as tendons, bones, and ligaments. Collagen also participates in the formation of scar tissue. Most likely this disease is caused by a number of inherited (genetic) abnormalities, with environmental factors as the trigger. Research published in 2005 also showed that the growth of new blood vessels is abnormal in people with scleroderma, particularly those with disease affecting the blood vessels in the lungs. Researchers now know that cells in the blood vessels and skin of scleroderma patients make too much of certain chemicals, and not enough of others. Studies revealed that the cause is an alteration in the DNA, the hereditary material. These changes "turn off" some genes and "turn up" others. It is hoped that certain drugs, some of which are already used in cancer treatments, can some day be used to stop these DNA changes.

Inflammatory Response and Autoimmunity

The Normal Immune System Response. The inflammatory process is a result of the body's immune system, which fights infection and heals wounds and injuries:

• When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign material, such as a virus.
• Large groups of blood cells gather at the injured or infected site to perform different tasks. These tasks include selecting and destroying harmful substances, breaking down the remains of the foreign invaders, and healing any injuries to the tissue by forming clots and scar tissue.
• In the process, the area around the injury or infection becomes swollen and irritated, and some healthy tissue is injured.
• Under normal conditions, the immune system has other factors that control and limit injuries to healthy tissue.

The Infection Fighters. The primary infection-fighting units are two types of white blood cells: lymphocytes and leukocytes.

Lymphocytes include two subtypes known as T cell s and B cells. Both types of cells are designed to recognize foreign invaders ( antigens ) and start an offensive or defensive action against them:

• B cells make antibodies , which can either ride along with a B cell or travel on their own to attack the antigen.
• T cells have special receptors attached to their surface. These receptors recognize the specific antigen.

T cells are further categorized as killer T cells or helper T cells (TH cells).

• Killer T cells directly attack antigens.
• Helper T cells also recognize antigens, but their role is twofold. They cause B cells and other white cells to attack the antigen. They also produce cytokines , powerful immune factors that have an important role in the inflammatory response and subsequent cell overgrowth, primarily in the skin.

Helper T Cells and Autoantibodies. The actions of the helper T cells are of special interest in scleroderma. For some unknown reason, the T cells become overactive in scleroderma and mistake the body's own collagen as an antigen. This triggers a series of immune responses to destroy the collagen:

• TH cells stimulate B cells to produce antibodies. In the case of scleroderma, however, they appear to direct the B cells to produce autoantibodies .
• Autoantibodies are the main factors in the autoimmune process. They are designed to fight specific cells in the person's own body (self antigens ). They also remain in circulation to continue the defense against these cells.
• Several autoantibodies associated with scleroderma are also common in other autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. They include rheumatoid factor, anti-single-stranded DNA, and antihistone antibodies. Some antibodies known as antinuclear antibodies (ANAs) attack RNA or DNA, the genetic material itself.
• Most patients with systemic scleroderma (but not localized scleroderma) have one or more of three other autoantibodies. They do not appear at the same time and seem to relate to different phases of the disease process. They are anti-RNA polymerase III, anti-topoisomerase I (also called anti-DNA topo I), and anti-centromere antibodies (ACA). For example, anti-DNA topo I is particularly associated with diffuse skin scleroderma and lung complications. Anti-centromere antibodies, on the other hand, are associated with a less severe form of the disease.
• Patients with both systemic and localized scleroderma tend to have higher than normal levels of autoantibodies to fibrillin 1, a protein found in muscle and other connective tissues. This autoantibody in localized scleroderma is more common in some groups (such as Japanese and Native American) than in others (Caucasians, for example). It is not found in other autoimmune diseases.

Cytokines and the Inflammatory Response. TH cells also release or fuel the production of powerful immune factors called cytokines . In small amounts, cytokines are necessary for healing. If overproduced, however, they can cause serious damage, including inflammation and injury during the scleroderma process.

A cytokine known as connective transforming growth factor (CTGF) appears to be particularly important. It acts together with another compound called TGF-beta to stimulate the growth of fibroblasts . Fibroblasts are immature cells that regulate production of collagen. In mice, scientists found that stopping TGF-beta halted a scleroderma-like condition in the animals.

Other cytokines that may have major roles in scleroderma include tumor necrosis factor and interleukins.

Neutrophils. Cytokines attract to the scene large numbers of other white blood cells known as neutrophils . Neutrophils bring about the activation of chemicals known as leukotrienes. Scleroderma patients have high levels of specific leukotrienes called LTB(4) and LTE(4). LTB(4) and LTE(4) may contribute specifically to lung disease in scleroderma.

Fetal Cell Theory and Microchimerism

A growing body of research supports microchimerism as a cause of scleroderma . The theory arose from the fact that scleroderma occurs mostly in women, and that its symptoms resembled those of graft-versus-host disease (GVHD). GVHD occurs in bone marrow transplant patients. The bone marrow is responsible for producing certain types of immune system cells. GVHD happens when the transplanted donor immune cells launch an attack against the patient's cells.

To understand the process, it is useful to define chimerism , which occurs when cells from two different individuals exist in the same body. When there is a low number of cells of one body in another, the condition is referred to as microchimerism .

The theory that links microchimerism to scleroderma is as follows:

• During any pregnancy, cells of both the pregnant mother and the unborn child pass naturally back and forth between them through blood circulation. This causes microchimerism, with low levels of both the mother's and the baby's cells existing in each other's body.
• In most mothers, the immune system removes these foreign cells within a few months of the birth of the child.
• Some studies on women with scleroderma, however, have detected small but significant numbers of fetal cells decades after pregnancies with male babies. Furthermore, the DNA in such fetal cells often closely matches the mother's own DNA.
• This suggests, then, that the mother's immune system may not have recognized the fetal cells as being foreign and so did not remove them after birth. In addition, the similarity between the mother's and the baby's cells confused the immune system, so that the mother's own antibodies learned to attack not only the fetal cells but also her own.

Ongoing research is detecting fetal cells in women with scleroderma more often than in the general population. In 2002, for example, researchers detected microchimerism in the saliva gland cells of 45% of women with systemic sclerosis who had a history of pregnancy with male babies.

The following has been suggested to explain how microchimerism may trigger scleroderma in men, or in women who had never been pregnant:

• The mother's cells pass into and stay in the bloodstream of the fetus. Her child then becomes at risk for scleroderma later on.
• Cells pass within the womb from one twin to another.
• Cells are transferred during blood transfusions or transplant procedures.

However, if microchimerism plays a role, it most likely does so only in a subset of patients.

Triggering the Immune Response

It is still not clear why the immune system responds abnormally. Some experts believe that environmental factors, such as a virus or a chemical, may trigger the response in individuals with a genetic vulnerability.

Oxygen-Free Radicals and Abnormal Metal Accumulation. Another focus for researchers involves an observation that in scleroderma, as blood vessels narrow and become inflamed, destructive particles known as oxygen-free radicals are produced. Oxygen-free radicals are made by natural processes in the body. They cause harm in the following way:

• Because they are missing an electron, oxygen-free radicals tend to bind with other molecules in the body, therefore disrupting other processes.
• Environmental toxins, infections, and other factors may cause very high amounts of these oxygen-free radicals to build up in the body.
• In such cases, too many of these radicals can set off a chemical chain reaction. Such a reaction can damage any type of cell in the body, including nerve cells in the brain. The reaction can even interfere with DNA in the cells.

Researchers found abnormal molecules in cells that are damaged by free radicals. These molecules seem to occur only with abnormally high levels of certain metals, particularly iron and copper. Researchers suggest that these abnormal molecules may be the antigens targeted by some of the autoantibodies that trigger the development of scleroderma. Abnormally high levels of copper and iron in the body might play a role in the development or worsening of scleroderma.

Chemicals. Occupational exposure to certain chemicals can cause blood vessel constriction and attacks of Raynaud's phenomenon. Although some cases of actual scleroderma are believed to be related to a person's work, no specific factors have been proven to cause the disorder itself. Industrial and pharmaceutical chemicals being investigated include the following:

• Silica: Silicone is derived from silica. Silicone breast implants have been under intense scrutiny as a possible trigger of autoimmune diseases, including scleroderma. Evidence to date is inconclusive about breast implants, although silica dust in stone quarries or other settings is associated with a high risk of scleroderma in workers.
• Plastic materials such as epoxy resins and vinyl chloride
• Detergents
• Herbicides
• Organic solvents such as trichloroethane, benzene, and carbon tetrachloride
• Various drugs such as bleomycin, amphetamine, cocaine, amfepramone, docetaxel, pentazocine, and penicillamine
• Asbestos

It is nearly impossible to determine if specific chemicals may actually cause systemic scleroderma, primarily because few people develop scleroderma, while many people are exposed to such chemicals. In addition, research has been unable to consistently repeat studies that have reported links with chemicals.

Studies have found, however, that certain industrial toxins are significantly associated with severe pulmonary problems in people with scleroderma. Those most likely to be associated with severe disease include epoxy resins, white spirit, solvents, and silica mixed with welding fumes.

Repetitive Stress Injuries. Raynaud's phenomenon and symptoms of scleroderma have been associated with jobs that require intense repetitive hand and arm movements, such as working jackhammers or other vibrating tools. As with chemical industries, many workers are involved in such occupations, but scleroderma is very rare, even in this group. If there is a link, the disease would most likely develop in individuals with genetic factors that make them susceptible to disease in the first place.

Radiation. Radiation therapy has been reported to induce morphea (local scleroderma patches) or make preexisting scleroderma worse in a few patients. In some cases, it may occur years after treatments.

Infections

Researchers think that infections may play a role in triggering the process leading to some cases of scleroderma. There is no significant evidence of any single organism that might be responsible, although some are of particular interest.

Some studies reported an association between Borrelia burgdorferi , the cause of Lyme Disease, and some cases of morphea (localized scleroderma). However, the evidence is weak. If there is a connection, it is possibly limited to a specific type of the bacteria in Europe and Asia. There is no connection between systemic scleroderma and Lyme disease.

Parvovirus. In one study there was a higher frequency of antibodies to a virus called parvovirus 19 in patients with scleroderma than in patients without the disorder. The association probably warrants more research.

Hepatitis C. Scleroderma has been reported in some patients with hepatitis C, although a cause and effect relationship is unclear.

Genetic Factors

Genetic factors appear to play a role in triggering the disease, but most cases are unlikely to be inherited. There are some exceptions. Scientists in 1999 discovered a probable link between the gene for the protein fibrillin-1 and the development of scleroderma in certain populations. The gene was detected in Choctaw Native Americans, who have a higher risk for scleroderma than other groups. Elevated levels of autoantibodies to this protein have also been detected in other ethnic groups, including African-American and Japanese patients, but not in Caucasians.

• Review Date: 12/14/2006
• Reviewed By: Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is the first of its kind, requiring compliance with 53 standards of quality and accountability, verified by independent audit. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial process . A.D.A.M. is also a founding member of Hi-Ethics (www.hiethics.com) and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2007 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.