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•	Scleroderma

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Scleroderma

Highlights

Overview:

The name scleroderma comes from the Greek words skleros, which means hard, and derma, meaning skin. The disease is categorized as a rheumatologic disorder because it affects the connective tissues in the body.

Treatment News:

• Results from the Scleroderma Lung Study show that cyclophosphamide, a drug used to suppress the immune system, improves the lung condition of scleroderma patients with lung complications. The improvements lasted for 2 years (the duration of the study).
• A Phase I trial of reduced-intensity stem cell transplant showed the procedure is safe and effective. Patients' skin improved significantly, and their heart, lung, and kidney functions remained stable during the 12-month study.

Current Research:

• Scientists found that antibodies often present in patients with scleroderma and systemic lupus erythematosus (SLE) bind to different parts of a single protein. Scientists hope this finding will one day lead to a specific diagnostic test for scleroderma.
• 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 already used in cancer treatments, can some day be used to stop these DNA changes.
• In mice, scientists found that stopping a chemical messenger called TGF-beta halted a scleroderma-like condition in the animals.

Introduction

The name scleroderma comes from the Greek words skleros, which means hard, and derma, which means skin. The disease is categorized as a rheumatologic disorder because it affects the connective tissues in the body. Scleroderma is a rare disease marked by the following:

• Damage to the cells lining the walls of small arteries
• An abnormal build-up of tough scar-like tissue in the skin

Patients with scleroderma may develop either a localized or a systemic (body-wide) form of the disease.

Localized Scleroderma

Localized scleroderma usually affects only the skin on the hands and face. Its course is very slow and it rarely, if ever, becomes systemic or causes serious complications. There are two main forms of localized scleroderma: morphea and linear scleroderma.

Morphea Scleroderma. In morphea scleroderma, patches of hard skin form and can last for years. Eventually, however, they may improve or even disappear. There is less than a 1% chance that this disorder will progress to systemic scleroderma.

Linear Scleroderma. Linear scleroderma causes bands of hard skin across the face or on a single arm or leg. Linear scleroderma may also involve muscle or bone. In rare cases, if this type of scleroderma affects children or young adults, it may interfere with growth and cause severe deformities in the arms and legs.

Systemic Scleroderma

Systemic scleroderma is also called systemic sclerosis. This form of the disease may affect the organs of the body, large areas of the skin, or both. This form of scleroderma has two main types: limited and diffuse scleroderma. Both forms are progressive, although most often the course in either one is slow.

Limited Scleroderma (also called CREST Syndrome). Limited scleroderma is a progressive disorder. It is classified as a systemic disease because its effects can be widespread. It generally differs from diffuse scleroderma in the following ways:

• Most often the internal organs are not affected.
• Patients with scleroderma have a good outlook unless pulmonary hypertension develops (a particular danger with the CREST syndrome). Pulmonary hypertension is high blood pressure in the lungs (see the Lung Complications section).

Limited scleroderma is commonly referred to by the acronym CREST, whose letters are the first initials of characteristics that are usually found in this syndrome:

• Calcinosis. With this condition, mineral crystal deposits form under the skin usually around the joints. Skin ulcers filled with a thick white substance may form over the deposits.
• Raynaud's phenomenon. In this syndrome, the fingers of both hands are very sensitive to cold, and they remain cold and blue-colored after exposure to low temperatures. This occurs in nearly all cases of scleroderma, both limited and diffuse. It is caused by abnormal changes in small blood vessels. These changes cause the vessels to narrow, and blood flow is temporarily interrupted, usually in the fingers.
• Esophageal motility dysfunction. The esophagus carries food from the mouth to the stomach. In esophageal motility dysfunction, the muscles in the esophagus become scarred by scleroderma and do not contract normally. This can cause severe heartburn and other symptoms of gastroesophageal reflux disorder (GERD).
• Sclerodactylia (also called acrosclerosis). This is the stiffness and tightening of the skin of the fingers, a classic symptom of scleroderma. Bone loss may occur in the fingers and toes.
• Telangiectasia. In this situation, widening of small blood vessels causes numerous flat red marks on the hands, face, and tongue.

Click the icon to see an image of symptoms that are known as CREST.

In general, people with limited scleroderma experience a long duration of Raynaud's phenomenon before they develop any of the other symptoms mentioned above. It should be noted that one or more of the CREST conditions can also occur in other forms of scleroderma.

Diffuse Scleroderma. Diffuse scleroderma, the other systemic sclerosis, has the following characteristics:

• It can affect wide areas of the skin, connective tissue, and other organs.
• It can have a very slow course, but it also may have a rapid beginning, which may be marked by swelling of the whole hand. If it gets worse quickly early on, it can affect internal organs and become very severe, even life threatening.
• Diffuse scleroderma may overlap with other autoimmune diseases, including systemic lupus erythematosus and polymyositis. In such cases, the disorder is referred to as mixed connective disease.

Click the icon to see an image of systemic lupus erythematosus.

Symptoms

Raynaud's Phenomenon

Raynaud's phenomenon is often the first sign of the scleroderma disease process. With this condition, small blood vessels narrow in the fingers, toes, ears, and even the nose.

Typically, the fingers go through three color changes:

• First, they become very pale.
• As the blood flow is cut off, they turn a bluish color, usually in the top two sections of the second and third fingers.
• Finally, when blood flow returns, the fingers become red.
• Tingling and pain may occur in the affected regions.

Click the icon to see an image of Raynaud's phenomenon.

Attacks of Raynaud's phenomenon can occur several times a day, and are often brought on or made worse by cold. Warmth relieves these attacks. In severe cases, attacks may develop regardless of the temperature. Severe cases may also cause open sores or damage to the skin and bones, if the circulation is cut off for too long. The syndrome may also be triggered by stress.

It is important to note that over 80% of cases of Raynaud's phenomenon are harmless. It is very common and occurs in 3 - 5% of the general population. This condition is more likely to be a symptom of scleroderma or some other connective tissue disease if it develops after age 30, if it is severe, and if it is accompanied by other symptoms (such as skin changes and arthritis).

Skin Changes

Course of Typical Skin Changes. The primary symptoms of scleroderma occur in the skin. They often take the following course:

• Typically, pitted scars appear first on the hands. The skin begins to thicken and harden on the hands, feet, and face. The fingers may swell. This condition is called sclerodactylia or acrosclerosis. Patients with diffuse scleroderma may have whole hand swelling before the skin significantly thickens.
• Thickened or hardened patches on other areas of the body may also develop. (Their appearance on the trunk and near the elbows or knees tends to be a sign of a more severe condition.)
• For the first 2 or 3 years, the skin continues to thicken and feel puffy.
• This process then stops, and can even get better. The skin may soften.
• As the disease progresses further, however, the skin loses its ability to stretch, and becomes shiny as it tightens across the underlying bone, particularly in the fingers, toes, and around the mouth.
• Eventually, in severe cases, fingers may lose the ability to move, and can be difficult to bend. The hands and feet may curl from the tightness of the skin. It may be difficult to open the mouth widely.

Click the icon to see an image of sclerodactyly.

Other Skin Changes. The following skin symptoms may also occur:

• Flat red marks, known as telangiectasis, may appear in various locations, usually the face, palms, lips, or the inside of the mouth.

Click the icon to see an image of telangiectasia.

• In calcinosis, small white lumps form beneath the skin, sometimes oozing a white substance that looks like toothpaste. Calcinosis can lead to infections.
• The base of the fingernails may show loss of small blood vessels in some places, and widening of small blood vessels in others. This is an indication that internal organs might be involved.
• The entire surface of the skin may get darker over time, and contain patches of abnormally pale skin.
• Hair loss may occur.
• About 1% of patients have Sjogren syndrome, a group of symptoms that include dry eyes and dry mucous membranes (such as those in the mouth).
• Inside the mouth, scleroderma can also cause changes that impair gum healing.

Bone and Muscle Symptoms

Changes in bones, joints, and muscles may cause the following symptoms:

• Mild arthritis. The condition is usually distributed equally on both sides of the body.
• Bone loss in the fingers. The destruction is not as severe as it is in rheumatoid arthritis, although the fingers may shorten over time.
• Trouble bending the fingers, if the disease has affected the tendons and joints.
• Muscles weakness may occur, especially near the shoulder and hip.

Symptoms in the Digestive Tract

The development of digestive symptoms depend on the extent of the condition:

• Symptoms of gastroesophageal reflux disorder (heartburn and difficulty in swallowing) are common in the upper part of the digestive tract.
• If the lower part of the digestive tract is affected, patients may become constipated. If scarring in the lower intestine is very severe, watery diarrhea may develop. Many patients do not have lower digestive tract symptoms, although the disease commonly affects this region.

Symptoms in the Lungs

In severe cases, the lungs may be affected, causing shortness of breath or difficulty in taking deep breaths. Shortness of breath may be a symptom of pulmonary hypertension, an uncommon but life-threatening complication of systemic scleroderma.

Click the icon to see an image of the respiratory system.

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 cells 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.

Antigens are large molecules (usually proteins) on the surface of cells, viruses, fungi, bacteria, and some non-living substances such as toxins, chemicals, drugs, and foreign particles. The immune system recognizes antigens and produces antibodies that destroy substances containing antigens.

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.

Risk Factors

Scleroderma is uncommon -- it afflicts about 150,000 Americans. The cause of scleroderma has not been determined, and there are few specific risk factors. The incidence tends to be higher in certain groups, however.

Age. Systemic scleroderma usually develops between the ages of 35 and 55. Localized scleroderma is more common in children than adults, but is extremely rare even in the young age group. It occurs in between 0.2 and 0.4 per 100,000 people. Systemic scleroderma in children is even more rare.

Gender. The incidence of scleroderma is three to eight times higher in women than in men. Of possible importance was a 2002 study reporting that the disease tended to be less severe in women who developed it in middle age after being pregnant. Women who had an earlier onset and did not have a history of pregnancy had a much higher rate of complications. This may reflect a different cause of the disease in these two groups. (It should be noted that pregnancy itself is not a risk factor for scleroderma.)

Family History. A family history is the strongest risk factor for scleroderma, but even among family members, the risk is very low (less than 1%).

Genetics. Preliminary research suggests that patients with certain gene variations may be more susceptible to scleroderma than those who do not carry these variations.

Ethnicity. Limited data on risk by ethnic group in the United States suggests that the risk from highest to lowest is the following: Choctaw Native Americans (highest), African-Americans, Hispanics, Caucasians, Japanese Americans.

African-Americans have a higher rate of diffuse scleroderma, lung involvement, and a worse prognosis than Caucasians. Other studies also found lower survival rates among Japanese Americans. A 2003 study further reported that even though African-Americans with scleroderma tended to have more severe problems, they received poorer care than Caucasian patients at major medical centers.

Genetic factors affect population groups differently. Studies are finding, for instance, that ethnic groups differ in the number of specific scleroderma-related antibodies they produce. Caucasians, for instance, have a higher rate of anti-centromere antibodies, which are associated with limited disease, while African-American patients have higher rates of autoantibodies and genetic factors that are associated with a more severe condition.

Geography. There appears to be certain geographic clusters of scleroderma, or specific types of scleroderma related to geography. This may suggest an infectious or genetic factor at work, but the reasons are largely unknown. The following are some examples:

• Studies reported significantly higher than average scleroderma mortality rates in male patients (both African-American and Caucasian) who live in two specific regions of the Southeast: one cluster around Coffee, Tennessee, and two others near Northampton, North Carolina.
• A cluster of scleroderma cases has been observed in South Boston, Massachusetts.
• There is a higher incidence of scleroderma cases among Choctaw Native Americans in Oklahoma. In the case of the Choctaw Native Americans, the cluster appears to have a strong genetic component. In most cases of geographic clusters, however, the disease is unlikely to be inherited, and family members of patients are not at higher risk.

Prognosis

At this time there is no cure for scleroderma and no treatment to change its course, but outlook varies widely. Many patients, even many with systemic scleroderma, can expect a normal lifespan.

General Outlook of Localized Scleroderma. Localized scleroderma nearly always carries a good prognosis and a normal life span. Even localized scleroderma, however, can cause some severe effects in children, including impaired growth, limb imbalance, and problems in flexing and bending muscles.

General Outlook of Systemic Scleroderma

• Limited Scleroderma. Patients with limited CREST scleroderma can usually expect a favorable outlook and normal lifespan if the disease affects only the hands and face. The course of this type of scleroderma still tends to be slowly progressive and, in some cases, may affect internal organs.
• Diffuse Scleroderma. The severity of diffuse scleroderma varies widely, and it is very difficult to predict its course. It generally follows one of two paths: If it is acute or rapidly progressing, it may be a life-threatening condition that affects internal organs. The most critical period for rapid progression is usually within the first 2 - 5 years of the start of the disease. In the absence of rapid progression, or if the patient survives the initial acute progression, the disease tends to progress very slowly. The more severe the condition of the skin is at the start of the disease, the poorer the survival rates.

Many patients with systemic scleroderma experience a plateau in which the condition stabilizes. This plateau is followed by a period of improvement and skin softening. No one knows why this occurs, and it can happen regardless of treatment. In one study, patients with systemic scleroderma who experienced such improvements also had better survival rates (80% at 10 years) than those whose skin did not improve (60% 10-year survival rate).

Lung Complications

Lung problems are usually the most serious complications of systemic scleroderma. They are now the leading cause of death in scleroderma patients. Two major lung conditions associated with scleroderma, pulmonary fibrosis and pulmonary hypertension, can occur either together or independently.

Pulmonary hypertension is the narrowing of the pulmonary arteries within the lung. The narrowing of the arteries creates resistance and an increased work load for the heart. The heart becomes enlarged from pumping blood against the resistance. Some symptoms include chest pain, weakness, shortness of breath, and fatigue. The goal of treatment is control of the symptoms, although the disease usually develops into congestive heart failure.

Pulmonary Fibrosis. Scleroderma in the lung causes scarring (pulmonary fibrosis). Pulmonary fibrosis occurs in up to 80% of scleroderma patients, although the progression is very slow and patients have with a wide range of symptoms:

• Some patients may not experience any symptoms.
• When pulmonary fibrosis progresses, patients develop a dry cough, shortness of breath, and reduced exercise ability.
• Severe pulmonary fibrosis occurs in about 16% of patients with diffuse scleroderma. About half of these patients experience the most profound changes within the first 3 years. In such cases, lung function gets worse rapidly over that period, and then the progression slows down.

One of the most serious complications of pulmonary fibrosis is interstitial lung disease, which causes breathing difficulties and a decline in lung function. This condition also places the patient at higher risk for lung cancer. One study suggested that interstitial lung disease may be due to severe dysfunction in the esophagus, which causes patients to breathe in tiny amounts of stomach acid.

The most important indication of future worsening in the lungs appears to be evidence of inflammation in the small airways (alveolitis). Doctors detect alveolitis by using a lung test called bronchoalveolar lavage.

Pulmonary Hypertension. Pulmonary hypertension occurs in about half of scleroderma patients. In this condition, blood pressure in the lungs increases, in some cases to a dangerous level. The primary symptom is shortness of breath, which is often severe.

Pulmonary hypertension can develop in one of two ways:

• As a complication of pulmonary fibrosis
• As a direct outcome of the scleroderma process itself. In this case, it is most likely to develop in patients with limited scleroderma after many years.

Pulmonary hypertension can be very serious in the short- and long-term.

• If pulmonary hypertension develops suddenly it can cause respiratory failure, which is life threatening.
• Over time, pulmonary hypertension may cause a condition called cor pulmonale, in which the right side of the heart increases in size. In some cases, this enlargement can lead to heart failure.

Click the icon to see an image of cor pulmonale.

Kidney Complications

Signs of kidney problems, such as increased levels of protein in the urine and mild hypertension, are common in scleroderma. As with pulmonary hypertension, the degree of severity depends on whether the kidney problems are acute or chronic.

Slow Progression. The typical course of scleroderma in the kidney is a slow progression that may produce some damage. Such damage does not usually require dialysis.

Renal Crisis. The most serious kidney complication in scleroderma is renal crisis. It is a rare event that occurs in a small number of patients with diffuse scleroderma, most often early in the course of the disease. This syndrome includes a life-threatening condition called malignant hypertension, a sudden increase in blood pressure that can cause rapidly advancing kidney failure. This condition may be fatal. However, if the condition is successfully treated, recurrence is rare.

Until recently, renal crisis was the most common cause of death in scleroderma. Aggressive treatment with drugs that lower blood pressure, particularly those known as ACE inhibitors, is proving to be successful in reducing this risk.

Heart Complications

Many patients with even limited scleroderma have some sort of functional heart problem, although severe complications are uncommon and occur in only about 15% of patients with diffuse scleroderma. As with other serious organ complications, they are more likely to occur within 3 years of the onset of the disease.

Fibrosis of the Heart. The most direct effect that scleroderma has on the heart is fibrosis (scarring). It may be very mild or it can cause pain, low blood pressure, or other complications. By damaging muscle tissue, the scarring increases the risk for heart rhythm problems, problems in electrical conduction, and heart failure. The membrane around the heart can become inflamed, causing a condition called pericarditis.

Click the icon to see an image of pericarditis.

Effects of Pulmonary Hypertension. Pulmonary hypertension and kidney problems associated with scleroderma can also affect the heart.

Gastrointestinal Complications

The following complications may occur in the digestive tract:

Complications in the Upper Digestive Tract.

• Gastroesophageal reflux disorder (heartburn and trouble swallowing) is a common problem and much more severe than in the general public. This disorder, also known as GERD, develops when scarring in muscles of the esophagus causes them to lose the ability to contract normally. Some experts believe that patients with severe GERD may breathe in microscopic amounts of stomach acid, which in turn may be a major cause of lung scarring.
• About 80% of patients also experience impaired stomach activity, with a delay in stomach emptying being very common.
• Some patients develop "watermelon stomach" (medically referred to as CAVE syndrome), in which the stomach develops red streaked areas from widened blood vessels. This causes a slow bleeding that can cause anemia over time.
• There may be a higher risk for stomach cancer.

Complications in the Lower Digestive Tract. Complications in the lower tract can develop but are uncommon. They can include the following:

• Scarring can cause blockage and constipation. In rare cases, constipation can become so severe that the bowel develops holes or tears, which can be life threatening.
• Scarring can also damage the absorption of fats in the intestines. This can lead to an increase in the number of bacteria, which causes watery diarrhea.
• Fecal incontinence (the inability to control bowel movements) may be more common than studies indicate, since patients are reluctant to report it.

Many patients, however, have few or even no lower gastrointestinal symptoms.

Impact on Quality of Life

The many complications of scleroderma can have a major impact on the person's sense of well-being. Patients are greatly concerned about changes in their appearance, particularly alterations caused by tightening of the facial skin. A 2002 study on scleroderma patients reported that 63% of scleroderma patients experienced at least mild pain, and half of them had some degree of depression. Depression had the greatest impact, even more than pain, in reducing patients' ability to function socially.

Other Complications

Other complications of scleroderma may include the following:

• Patients with CREST may be at increased risk for biliary cirrhosis, an inflammatory autoimmune disorder of the liver.
• Nerve damage may occur in the extremities (legs and feet, arms and fingers), causing numbness and pain. This damage can be progressive and lead to severe ulcerations (open sores), particularly in the hands. The feet are less often affected, but when they are, the disease tends to affect the joints and cause pain.
• Bone loss (osteoporosis) can occur because of impaired blood flow.
• About half of the patients develop hypothyroidism.

Click the icon to see an image of hypothyroidism.

• Impotence, usually due to scarring of the penis, may be one of the first complications of the disease in men.
• There is some evidence of changes in the elastic properties of large arteries, such as those leading into the legs and up to the brain, in patients with scleroderma. Such changes theoretically increase the risk for stroke. Current evidence does not reveal an elevated risk.
• Some studies, using imaging techniques, have found changes in brain tissue, but because the brain has little connective tissue, scleroderma appears to have little effect on mental functioning, except possibly in late stages of severe disease.
• Systemic scleroderma does not generally affect fertility in women. Pregnant women with scleroderma, however, have a slightly increased risk of premature birth and low birth weight babies.

Diagnosis

There are no specific tests for scleroderma. The doctor may suspect scleroderma after taking a history of the symptoms and performing a physical examination. As part of this examination, the doctor does the following:

• Checks the skin for thickened and hardened areas. The major clinical clues to scleroderma are hardening and thickening of the skin in any areas on the fingers and toes.
• Presses affected tendons and joints to detect crackling or grating sensations, which can indicate sclerodermic changes beneath the skin.
• Examines the fingernails underneath a microscope. The doctor may find changes in capillaries that are characteristic of scleroderma and mixed connective tissue disease.

Scientists recently found that antibodies often present in patients with scleroderma and systemic lupus erythematosus (SLE) bind to different parts of a single protein. Scientists hope this finding will one day lead to a specific diagnostic test for scleroderma.

Tests for Antinuclear Antibodies

Tests may be conducted to detect immune factors called antinuclear antibodies (ANAs). Elevated levels of ANA are found in 95% of patients with scleroderma. Antinuclear antibodies, however, are also strongly present in patients with many other autoimmune diseases, including systemic lupus erythematosus. Many people can also have high levels and never develop any of these diseases.

Detecting ANA subtypes may provide some weight in diagnosing scleroderma. Such subtypes include the following:

• Anti-topoisomerase antibodies (TOPO)
• Anti-centromere antibodies. The centromere is an important factor in cell division, and 50 - 80% of people with CREST have antibodies to centromeres.

These antibodies are also found in other rheumatologic disorders, however, so detecting them does not necessarily prove scleroderma. At the same time, studies have found that specific antibodies are associated with specific aspects of the disease. Therefore, identifying their presence could help diagnose, treat, and monitor people with scleroderma. For example, the presence of anti-U1-RNP and anti U3-RNP is associated with muscle inflammation. Pulmonary hypertension and vascular disease is common with ACA. Pulmonary fibrosis is associated with TOPO. Severe interstitial fibrosis rarely occurs in the presence of RNA Polymerase III (Pol 3), although this autoantibody is strongly present in patients with renal crisis. Among patients who have diffuse scleroderma, those with Pol 3 have the best survival rate.

Ultrasound

High frequency ultrasound may be used to detect the effects of scleroderma in patients' hands.

Diagnosing Systemic Complications

Diagnosing Lung Complications. Changes in the lungs may occur early in scleroderma lung disease, and prompt treatment is very important to prevent complications. For this reason, once a diagnosis is made, the doctor will check for lung changes:

• Using a stethoscope, the doctor will first listen for specific lung sounds. Rales (a crackling sound) heard at the base of the lungs while breathing in is a sign of pulmonary fibrosis even if breath function is normal.
• Respiratory function tests determine lung capacity.
• A chest x-ray is usually done. X-rays, however, do not always find lung disease, especially in children.
• In another test, patients inhale nitric oxide to test the ability of blood vessels to open. (According to a small 2002 study, this test may cause complications in patients with CREST syndrome, who should be tested with caution.)
• More extensive tests, such as high resolution computed tomography (CT) scans and bronchoalveolar lavage, may be needed if severe lung scarring is suspected.

Right heart catheterization involves the passage of a catheter (a thin flexible tube) into the right side of the heart to obtain diagnostic information about the heart and for continuous monitoring of heart function in critically ill patients.

Diagnosing Heart Complications. Patients with suspected heart complications should have the following tests:

• Electrocardiography (ECG): A test of the heart's electrical activity
• Echocardiography: A look at the beating heart through the use of sound waves
• Radionucleotide ventriculography: An evaluation of the working heart using a radioactive dye

Advanced imaging techniques, which provide a more detailed picture of the heart, may also be useful to determine the extent of heart complications in scleroderma patients.

Diagnosing Pulmonary Hypertension. Echocardiography is a noninvasive imaging technique for detecting pulmonary hypertension, a common and life-threatening complication of scleroderma. (A non-invasive procedure is one where no materials or equipment are put into the body.) To confirm the diagnosis, doctors sometimes use an invasive procedure called right-heart catheterization. However, a newer, noninvasive technique called cardiac MRI is now becoming available at many centers. Studies have shown that cardiac MRI is more accurate than either echocardiography or right heart catheterization.

Diagnosing Gastrointestinal (Digestive) Complications. Gastrointestinal problems may be detected using endoscopy. Endoscopy is an invasive procedure in which a tube is inserted down the esophagus. The tube contains a small camera and other instruments. Another diagnostic test is manometry, a test that measures the pressure that the muscles in the esophagus apply. Electrogastrography (EGG) measures the electrical activity in muscles in the stomach, and may be an effective method for detecting stomach problems.

Diagnosing problems in growth of blood vessels. Capillaroscopy is the microscopic examination of blood vessels under the skin. It is now considered a useful tool for identifying problems with the growth of blood vessels. Such problems can show the severity and progression of scleroderma.

Click the icon to see an image about endoscopy.

Ruling out Other Conditions

Other Autoimmune and Connective Tissue Disorders. Several other autoimmune conditions that affect connective tissue can strongly resemble, and even occur together, with scleroderma. They include the following:

• Rheumatoid arthritis
• Systemic lupus erythematosus
• Polymyositis

Symptoms of such diseases may also include fever, arthritis, muscle aches, rash, and lung and heart problems.

Eosinophil Fasciitis. Eosinophilic fasciitis is a muscle disorder that is known to occur after intense hard work. It can cause symptoms similar to scleroderma, including pain, swelling, and tenderness in the hands and feet, as well as skin thickening. The disorder can be ruled out if blood tests show elevated sedimentation rate and no antinuclear antibodies.

Although Raynaud's phenomenon occurs in most scleroderma patients, over 80% of the cases of Raynaud's phenomenon are harmless. In one study, only 12% of Raynaud's cases were associated with some other condition, and few of those were scleroderma. The following are other problems that might accompany or cause Raynaud's phenomenon:

• Other autoimmune connective tissue diseases
• Diabetes. Patients with diabetes may develop Raynaud's phenomenon and other scleroderma-like symptoms.
• Certain drugs including bleomycin, ergot derivatives (used for migraines), and methysergide
• Hereditary hemorrhagic telangiectasia is very similar to CREST syndrome and poses a diagnostic problem for the doctor, although it is very rare.
• Keloids are areas of scarring overgrowth on the skin that develop at the site of skin injuries. They are caused by genetic factors and are most likely to occur in African-Americans. Extensive keloids may be mistaken for scleroderma.

Click the icon to see an image of a keloid.

• Repetitive stress injuries (particularly from vibrating tools)
• Hypothyroidism

Treatment

Because scleroderma is so variable, treatments vary depending on the patient.

The first step is to determine what form the disease has taken:

• Is it local or systemic, and if systemic, is it limited or diffuse?
• If the disease is systemic, what organs, if any, are involved?

Specific drugs are used to help combat the various mechanisms and consequences of the disease.

• Some medications keep blood vessels open (prostacylins, ACE inhibitors and others) and are used to treat Raynaud's phenomenon, heart and kidney problems, and pulmonary hypertension.
• Others, notably cyclophosphamide, reduce inflammation and block damaging immune factors. These drugs are helpful for improving skin thickness and reducing scarring, even in the lungs.
• Doctors use other treatments for specific complications, such as proton pump inhibitors for gastrointestinal problems, or light treatments for skin thickening.
• Promising investigative approaches include stem-cell transplantation.

The patient should receive treatments for specific complications as early as possible in the course of the disease, to reduce progression before irreversible hardening of tissues occurs.

Problems in Developing Treatments for Scleroderma

There is no cure for scleroderma. Experimental work is ongoing to develop procedures or to find drugs that can treat the underlying processes that cause damage. Developing effective treatments for scleroderma is very problematic, however, for the following reasons:

• Scleroderma has an extremely unpredictable progression, making it one of the most difficult rheumatic diseases to treat. It also makes drug development complicated.
• The disease, when advanced, affects many organs. Designing treatment strategies that will improve symptoms in some organs without affecting others is very difficult.
• Many drugs that are useful in other autoimmune inflammatory disorders have not proven to be very effective for scleroderma.
• Many studies do not take seasonal temperature changes into consideration. Such temperature changes are major factors in scleroderma and can distort study results.
• The disease is so uncommon that there are few patients for clinical trials. Studies, then, are very small, sometimes having only four or five patients. It is very difficult to design studies that can provide strong evidence one way or the other on treatment effects. Drugs that seem promising on small groups of patients often fail to come through on larger groups. For example, of great disappointment was the failure of relaxin (ConXn) to produce significant benefits. It had been the first drug approved specifically for scleroderma.

Treating the Whole Patient

The course of scleroderma is difficult to predict. The disease can evolve slowly over time with few symptoms, or progress rapidly and become very severe. The patient, then, must live with considerable uncertainty and emotional stress. Support associations, non-medical aids to help relieve symptoms, and other life-style measures can be extremely important and helpful.

Medications

Drugs that relax and open blood vessels (vasodilators) have been a mainstay for treating and preventing complications in scleroderma. As more is known about the disease, however, additional new drugs are used to treat this difficult disease. Some of these drugs affect blood clotting and smooth muscles in the blood vessels.

Vasodilators. Vasodilators have been key medicines in the treatment of scleroderma. They relax and open blood vessels, and are important for treating most of the symptoms and complications of scleroderma. [These agents are also discussed under many of the sections covering complication of treatments.]

Calcium-Channel Blockers. Calcium-channel blockers are the standard vasodilating agents. Short- or sustained-release nifedipine (Adalat, Procardia) is the gold standard. Others used include diltiazem (Cardizem, Dilacor). Side effects vary among different preparations, and may include fluid accumulation in the feet, constipation, fatigue, impotence, gingivitis, flushing, and allergic symptoms. Grapefruit juice appears to boost the effects of these drugs.

• Nitrates. Nitrates relax smooth muscles and therefore open arteries. They are available as topical or in a form taken by mouth. Side effects of nitrates include headaches, dizziness, nausea, blurred vision, fast heartbeat, and sweating. Lying down with the legs elevated can relieve low blood pressure and dizziness. Alcohol, beta blockers, calcium-channel blockers, and certain antidepressants can significantly worsen these side effects. Withdrawal from nitrates should be gradual. Some severe reactions have occurred when people have stopped abruptly.

Prostacyclins (also called Prostaglandins). Prostacyclins open blood vessels and also have anti-blood clotting properties. Specific agents, such as iloprost, appear to reduce levels of connective tissue growth factor, a molecule important in the abnormal production of cells that cause collagen buildup. A 2005 study reported that prostavasin, a drug related to prostacyclins, improved circulation to the hands and feet. Several prostacyclins are being used for scleroderma, although none have been approved specifically for the condition. Iloprost has been studied the longest. Other promising prostacyclins or similar drugs include alprostadil (prostaglandin E1), epoprostenol (Flolan,), and treprostinil (Remodulin).

Endothelin Receptor Antagonists. Bosentan (Tracleer) is a drug taken by mouth. It is called an endothelin receptor antagonist. It controls endothelin, a powerful molecule that causes blood vessels to narrow. It improves blood flow and is becoming important for treating patients with scleroderma, especially for preventing finger ulcers and improving hand function. Although experts initially thought bosentan might help scleroderma patients with pulmonary hypertension, a 2005 study concluded that the drug did not work for such patients. In fact, the researchers found that bosentan might even make the condition worse.

ACE Inhibitors and Similar Agents for High Blood Pressure and Renal Crises

The most effective approach at this time for preventing renal crises is to institute aggressive blood pressure-lowering treatment before blood tests show kidney damage.

Angiotensin Converting Enzyme (ACE) Inhibitors. Many medications are available for controlling blood pressure, but ACE inhibitors appear to be the most effective for scleroderma patients, because of their protective actions in the kidney. ACE inhibitors include captopril (Capoten), enalapril (Vasotec), quinapril (Accupril), benazepril, and lisinopril (Prinivil, Zestril). Side effects are uncommon but may include an irritating cough, large drops in blood pressure, and allergic reactions. The drug picotamide can help reduce the frequency of coughs.

One rare but severe side effect, granulocytopenia, has been observed. This extreme reduction in white blood cells can be minimized with lower medication dosages. There has been some concern that ACE inhibitors may impair lung function, but studies to date have been reassuring.

Angiotensin II Receptor Antagonists. Angiotensin II receptor antagonists (losartan, candesartan cilexetil, and valsartan) have benefits similar to ACE inhibitors and may have fewer or less severe side effects, including coughing. They may also have positive effects on blood vessels. Small studies showing improvement in Raynaud's phenomenon warrant further research.

Immunosuppressive Treatments

One major approach to scleroderma is to use treatments that suppress the immune system, and therefore reduce the activity of the harmful processes leading to scleroderma. Such treatments are used effectively in other autoimmune diseases. Their use in scleroderma varies depending on the location and severity of the disease process.

An important 2002 study employed an approach called high-dose immunosuppressive therapy, which uses radiation, powerful immunosuppressant drugs, and other therapies to strongly suppress the immune system. This is a very toxic treatment, but improvements in skin and other indicators of scleroderma were more significant than those reported with other therapies. More research is needed.

Cyclophosphamide (Cytoxan) is the most important immunosuppressant currently used for scleroderma. A small study found that patients with scleroderma-related lung disease respond better to intravenous cyclophosphamide than those without such lung disease. Additionally, results from the Scleroderma Lung Study show that cyclophosphamide improves the lung condition of scleroderma patients with lung complications. Patients took a daily dose of cyclophosphamide, by mouth, for a full year. The improvements in energy levels and breathing lasted for 2 years (the duration of the study). When used with stem cell transplantation, high doses of cyclophosphamide are proving to be safe for patients with systemic sclerosis.

Other drugs used to suppress the immune system may be useful in specific cases. They include D-penicillamine (which may be useful for skin symptoms), methotrexate (Rheumatrex), corticosteroids, cyclosporine (Sandimmune, Neoral), and chlorambucil (Leukeran). All of these agents have potentially severe side effects.

Other Treatments

Interferons. Interferons include drugs that are used in hepatitis. Such drugs have helped reduce liver scarring. Early research is suggesting interferon gamma (for example, Actimmune) may reduce scarring in scleroderma. In one early study, 5-year survival was 85% for patients with diffuse systemic sclerosis who took interferon gamma. In addition, 40% of patients said their skin got softer. It should be noted, however, that interferon alpha appears to trigger the development of scleroderma in some people with hepatitis.

Tumor-Necrosis Factor Modifiers. Tumor-necrosis factor (TNF) modifiers are major breakthroughs in the treatment of rheumatoid arthritis. They interfere with specific parts of TNF, a powerful immune factor. Researchers believe they should be tested in other inflammatory conditions, including scleroderma. The current agents include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira).

Halofuginone. Halofuginone, a drug that slows down the synthesis of collagen, is showing some promise in preventing scarring. The drug blocks production of certain collagen types involved in cell production.

Minocycline. Although this drug is an antibiotic, in low doses it has anti-inflammatory characteristics that may help slow down skin symptoms. Small studies suggested it provides slow and progressive symptom improvement, but other studies reported that minocycline is not effective for systemic scleroderma.

Investigative Procedures

Blood Exchange (Plasmapheresis). Plasmapheresis is a process in which the liquid part of the blood, called plasma, is separated from blood cells. The procedure involves first withdrawing blood from the patient. The plasma, which contains the active immune factors, is discarded and replaced with other fluids. The blood is then returned to the patient. In a small 2001 study, this procedure appeared to slow down the course of severe progressive scleroderma. Other studies are underway.

Autologous Stem-Cell Transplantation. Researchers are investigating a possible benefit using transplantation of the patient's own stem cells (an autologous transplant). (Patients with autoimmune diseases cannot be given cells from donors.) Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). The transplant procedures introduce normal white blood cells that replace the abnormal autoimmune cells. The procedure has improved or stabilized systemic scleroderma in some patients, with remissions lasting up to 4 years. Initial results of ASTIS, a major study evaluating stem-cell transplants and high-dose immunosuppressive therapy in severe scleroderma, indicate that this combination has significant benefits with few toxic side effects. Additional research will compare stem cell transplants to monthly cyclophosphamide therapy.

There are significant risks with stem cell transplants:

• Transplantation does not work in all patients.
• It cannot reverse all damage that may have been done during the disease process.
• The treatment carries significant dangers. The mortality rate from the procedure itself is 10% in scleroderma patients, which is higher than in other patient groups who are given transplants.

Because the procedure has serious side effects, experts suggest that the best candidates would be those at high risk for complications from scleroderma. In general, such patients would have diffuse scleroderma whose first symptoms occurred within the previous three years and who have evidence of at least mild abnormalities in the heart, lungs, or kidney. In general, patients with advanced scleroderma would not be the best candidates, because their condition is usually stable. In such cases, the risks of the procedure would outweigh the risks from the disease.

A Phase I trial of reduced-intensity stem cell transplant showed the procedure is safe and appears effective. A reduced-intensity stem cell transplant does not destroy the bone marrow, and therefore avoids many of the risks associated with the full-strength procedure. In this trial of 10 patients, survival rate was 90% (9 out of 10 people). Seven out of 10 people (70%) showed no progression of the disease during follow-up examination. Patients' skin improved significantly, and their heart, lung, and kidney functions remained stable during the 12-month study.

Intermittent pneumatic compression (IPC) pump therapy. During this therapy, a band wrapped around the arm is inflated and deflated. This helps stimulate blood flow. Experts are studying the use of IPC pump therapy for patients with ulcers on their arms. Medications usually do not work for such ulcers, and amputation is usually the only option for such patients. However, a small pilot study has shown that IPC pump therapy for an average of 5 hours per day healed 96% of ulcers.

Intravenous immunoglobulin (IVIg).Animal studies have found that administration of IVIg, an agent that modifies the immune system, may reduce the severity of scleroderma and other autoimmune diseases. Early studies in patients with scleroderma found it can improve skin fibrosis.

Alternative Treatments and Diet

Some patients avoid high-fiber diets (which include fruits and vegetables) and so their diets may lack enough nutrients. Supplements may be needed, but patients should consult someone experienced in dietary conditions associated with scleroderma. Because of reports that oxygen-free radicals may play a role in the development of sclerosis, some researchers recommend taking antioxidant supplements (for example, selenium, beta-carotene, vitamin C, vitamin E, and methionine). Though studies have not reported much benefit from such supplements, there have not been long-term trials, and some studies may have been started too late in the course of the disease to have much effect.

Because of the difficulty of the disease, many patients are tempted to try high-dose supplements or other alternative treatments. It is very important to note that this approach is not without its dangers.

Treatment for Raynaud's Phenomenon

The following are some lifestyle tips for managing Raynaud's phenomenon:

• Keeping warm is the primary goal for preventing the onset of Raynaud's phenomenon. Air-conditioning and exposure to refrigeration can trigger this syndrome. If patients go out in cold weather, they should dress warmly with many layers. Wearing a hat is essential.
• Living in a warm climate may help relieve symptoms, although a recent study found that weather changes themselves had little effect on the disorder.
• Exercise is helpful in maintaining a sense of well-being, in keeping warm, and in helping to sustain skin flexibility. Patients with Raynaud's phenomenon may want to avoid exercising outdoors in cold weather, however.
• Quitting smoking is, of course, essential for anyone, but it is critical for people with scleroderma.
• Patients might want to learn relaxation and anti-stress techniques, which might help reduce some triggers of Raynaud's phenomenon. Many effective methods are available.
• Moisturizers and antibiotic ointments may be helpful for keeping skin flexible and preventing infections in the fingers.
• Patients should avoid certain medications that could aggravate Raynaud's phenomenon, including nonselective beta blockers (e.g., propranolol), certain common cold preparations, and narcotics.

Medications Used in the Treatment of Raynaud's Phenomenon

Vasodilators. Vasodilators open blood vessels and so are important for Raynaud's phenomenon. Some studies reporting their effects including the following:

• Calcium-channel blockers, including diltiazem (Cardizem, Dilacor) and nifedipine (Adalat, Procardia) are the standard vasodilating agents used for Raynaud's phenomenon. Side effects vary among different preparations, and may include fluid accumulation in the feet, constipation, fatigue, impotence, gingivitis, flushing, and allergic symptoms. Grapefruit juice appears to boost the effects of these drugs.
• Nitrates, available in forms that are topical or taken by mouth, are vasodilators that are also used for Raynaud's phenomenon. For example, in a 2002 study, a nitroglycerin tape improved circulation within an hour. A gel containing nitric oxide was found effective in a 1999 study in improving the blood circulation in hands and arms of Raynaud's patients. A single application increased circulation to the arms 10-fold, tripled the circulation to the fingers, and caused no serious side effects.

Prostacylins. Iloprost and other prostacylins are proving to be effective agents for Raynaud's phenomenon. A 2001 analysis reported that intravenous iloprost was effective for treating Raynaud's phenomenon, reduced the frequency of attacks, and prevented and healed ulcers. The form of iloprost taken by mouth was not as effective. One earlier comparison study found that iloprost was even more effective than the calcium channel blocker nifedipine.

Anti-Platelet Drugs. Aspirin, dipyridamole, and other drugs that prevent blood clotting and keep blood flowing freely are sometimes recommended to patients with Raynaud's phenomenon.

Estrogen Therapy in Women. Short-term treatment with estrogen may benefit older women with Raynaud's phenomenon and scleroderma. It is important to note, however, that hormone replacement therapy can increase a woman's risk for breast cancer, heart attacks, strokes, and blood clots.

Treatment for Skin Thickening

Nitroglycerin is a rapidly acting nitrate and is used as an ointment (Nitro-Bid, Nitrol, Nitrong, Nitrostat) to treat hardened skin. Before applying it, any ointment that remains from the previous application should be removed.

Phototherapy

UVA-1 Phototherapy. Phototherapy (light therapy) is now considered by some experts to be the treatment of choice for local scleroderma. Specifically, doctors favor an approach called ultraviolet A-1 (UVA-1) radiation. This treatment produces long UVA wave lengths that do not cause sunburn and may actually repair DNA in damaged skin cells. Research suggests that UVA-1 therapy blocks inflammatory immune factors and the process leading to over-production of collagen, addressing the underlying mechanisms of scleroderma. The procedure is effective for all stages of morphea. It increases skin elasticity and in some cases, achieves complete clearance of symptoms. In one small study, patients with localized scleroderma received 30 treatments over a period of 12 weeks. In a majority of the patients, 80% of the skin patches disappeared or significantly improved. There were no side effects.

UVA-1 phototherapy is quite expensive and requires a special light source not readily available everywhere. In addition, studies are reporting an increased risk with UVA radiation. Whether this applies to UVA-1 phototherapy is not yet clear. Nonetheless, phototherapy is still an effective and important treatment of scleroderma. It may prove to be even more beneficial when combined with certain medications, such as calcipotriene (Dovonex), a form of vitamin D3.

PUVA. An alternative phototherapy regimen called PUVA uses drugs taken by mouth known as psoralens before UVA treatment. It has been used for other skin diseases, including psoriasis. It may prove to be useful for patients with early-onset diffuse scleroderma. In one study, most of those treated with PUVA for 2 days a month for up to 8 years experienced improvement or stabilization in nearly all scleroderma symptoms. Tests for kidney function remained normal. This treatment is known to increase the risk for skin cancer.

Phototherapy with Psoralen Water Bath. Yet another procedure uses UVA light therapy after patients take a bath containing a solution of the psoralen 8-methoxypsoralen (8-MOP). It is safe and well tolerated, although benefits appear to be minor and occur only in a small subset of patients.

Extracorporeal Photopheresis. Another phototherapy treatment under investigation is called extracorporeal photopheresis. It involves withdrawing the patient's blood and treating it with ultraviolet light. Little data exists on its effectiveness, and experts do not recommend it at this time. Still, some experts argue that some initial promise in its use warrants more research.

Vitamin D3 Analogs

A form of vitamin D3, calcipotriene (Dovonex), appears to help block skin cell production. This vitamin is also called calcipotriol in Europe. It also has anti-inflammatory properties and is being investigated as a rub-on treatment and a form taken by mouth for local scleroderma. It may prove to be beneficial when combined with low-dose ultraviolet A1 phototherapy.

Immunosuppressive Agents

D-penicillamine is proving to be an effective agent for softening skin and reducing thickness. (Improvements in thickness with this drug have also been associated with improved survival.)

Methotrexate (Rheumatrex) is another agent commonly used may be even more effective than penicillamine.

Corticosteroids taken by mouth, such as prednisolone and prednisone, are also often employed.

Treatment for Lung Complications

Pulmonary Fibrosis

Cyclophosphamide. Cyclophosphamide (Cytoxan), an immunosuppressive agent, may be effective for preventing lung deterioration and is the important agent for treating pulmonary fibrosis. Cyclophosphamide, available in forms that are intravenous and taken by mouth, blocks some of the destructive actions of scleroderma in the lung. Intravenous cyclophosphamide can be life-saving for patients with pneumonia resulting from interstitial lung disease. Side effects include hair loss, infection, and bleeding into the urinary tract. To date, no other immunosuppressive agents have proven to have any significant benefits.

Use of this drug may improve survival in patients who show early signs of lung deterioration, notably inflammation in the small lung airways (alveolitis). The drug is not recommended for patents with existing stable pulmonary fibrosis and no signs of inflammation. In one study, patients with early signs of lung inflammation were given a course of intravenous pulses of the corticosteroid methylprednisolone (MP) and cyclophosphamide. Nearly all patients experienced improvement or stabilization during the first year, although the disease had progressed in two-thirds of them by the end of 2 years.

Pulmonary Hypertension

Several types of drugs are used to treat pulmonary hypertension. Anticoagulants taken by mouth, such as warfarin (Coumadin), are a standard treatment used to prevent blood clot formation. Diuretic treatment and supplemental oxygen are recommended for patients with fluid retention and low blood oxygen, respectively.

Vasodilators help to open blood vessels and relieve pressure in arteries in the lungs. Vasodilators used to treat pulmonary hypertension fall into several different drug classes:

Calcium Channel Blockers (CCBs). Some patients with pulmonary hypertension benefit from these drugs. They help relax blood vessels in the heart and lungs, and increase the supply of oxygen. However, calcium channel blockers are only appropriate for patients who meet certain diagnostic criteria, including absence of right-sided heart failure.

Prostacyclins (Prostaglandins). Prostacyclins, which open blood vessels, are now the primary agents for treating pulmonary hypertension.

• Iloprost (Ventavis) is available in inhaled and intravenous forms. Studies suggest that the inhaled form improves exercise capacity and survival in some patients with pulmonary hypertension. In addition, infusions of iloprost remain effective over long periods (up to 3 years) of use.
• Treprostinil (Remodulin) is similar to epoprostenol but is more stable. It can also be administered using a portable pump that delivers the drug under the skin. This is less expensive, cumbersome, and invasive than the delivery methods for epoprostenol.
• Epoprostenol (Flolan), which is administered intravenously, has improved exercise capacity and symptoms in both the short and long term in a number of patients. In some patients, survival is increased significantly. However, not all patients respond to this agent. The implanted catheter needed to deliver the agent can also cause serious complications.

Endothelin Receptor Antagonists. Bosentan (Tracleer) was the first drug taken by mouth that was approved for pulmonary hypertension. Bosentan controls endothelin, a powerful molecule that causes blood vessels to narrow. Studies have reported improved exercise capacity in patients with pulmonary hypertension.

PDE5 Inhibitors. Sildenafil (Revatio) was approved in 2005 as the first pill for patients with early-stage pulmonary hypertension. Sildenafil is the same agent contained in the erectile dysfunction drug Viagra. However, Revatio is prescribed at a lower dosage than Viagra, and is a different color and shape than Viagra pills.

Other Treatments. Lung transplantation may offer hope for people with advanced pulmonary hypertension that does not respond to conservative measures.

Treatment for Gastrointestinal Problems

Treatments for abnormalities in the esophagus and stomach are generally the same as those for gastroesophageal reflux (GERD) or heartburn. Many non-prescription agents are available for the relief of heartburn.

Proton-pump or acid-pump inhibitors are probably the best agents for GERD related to scleroderma. They work by inhibiting the so-called gastric acid pump that is required for the stomach's cells to release acid. The standard drug has been omeprazole (Prilosec). Newer ones, including lansoprazole (Prevacid), pantoprazole (Protonix), esomeprazole (Nexium), and rabeprazole (Aciphex), are more potent, but few comparison studies have been done.

Side Effects. Side effects are uncommon, but can include an allergic reaction, headache, stomach pain, diarrhea, and flatulence. Of some concern was a report of a very severe and wide spread skin rash induced by omeprazole in a woman with scleroderma. It should be noted that this is only one incident, but patients should be cautious about any skin change when taking this agent.

Long-Term Complications. The use of proton-pump inhibitors by people with H. pylori may reduce acid secretion sufficiently to cause a condition called atrophic gastritis (chronic inflammation of the stomach).

Agents for Impaired Stomach Muscle Contractions

Metoclopramide. Metoclopramide (Reglan) is sometimes used for patients who have delayed stomach emptying.

Octreotide. Octreotide (Sandostatin) is related to a natural hormone that suppresses growth hormone, and may prove to be very helpful. Small studies have reported improvement in weight and nutrition with the use of this agent. It may even help other symptoms of scleroderma. In one case report, adding the antibiotic erythromycin in combination with octreotide allowed normal nutrition for at least 2 years.

Agents for Constipation

Prokinetics. Prokinetics improve the muscle action of the esophagus and enhance stomach emptying. Prucalopride is an investigative pro-kinetic agent that showed significant improvement in symptoms and relief from constipation. Similar agents, such as cisapride (Propulsid), are showing promise. Such agents can have serious side effects.

Treatments for Malabsorption

Antibiotics may be effective for the malabsorption syndrome.

Surgeries

Strictures (abnormally narrowed regions in the esophagus) may need to be opened with surgery.

Treatment for Other Complications

Pilocarpine (Salagen) has been approved for treating dry mouth found in people with scleroderma and Sjogren syndrome. In one study, patients with Sjogren syndrome experienced increased salivation after the first dose. Patients reported improvement in being able to speak, sleep, and swallow food without drinking. Side effects include sweating, increased need to urinate, chills, and flushing.

Surgical Treatments for Problems of the Hands

Sympathectomy and Hand Surgeries. Sympathectomy uses procedures that block or removes the nerve responsible for narrowing blood vessels in the hand. The result is increased blood flow in the hand.

The local anesthetics lidocaine or bupivacaine may be very effective in temporarily restoring blood flow and reducing pain.

For finger ulcers that won't heal and are resistant to standard treatments, sympathectomy surgery may be performed.

Other Surgeries. Disabling deformity of the hand is a common feature of scleroderma. Various surgical procedures can relieve pain, prevent tissue loss, protect hand function, and improve the appearance of hands.

Resources

• www.scleroderma.org -- Scleroderma Foundation
• www.srfcure.org -- Scleroderma Research Foundation
• www.arthritis.org -- The Arthritis Foundation
• www.niams.nih.gov -- National Institute of Arthritis and Musculoskeletal and Skin Diseases
• www.rheumatology.org -- American College of Rheumatology
• www.sclero.org -- International Scleroderma Network
• www.sctc-online.org -- Scleroderma Clinical Trials Consortium
• www.phassociation.org -- Pulmonary Hypertension Association
• www.thoracic.org -- American Thoracic Society

References

Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006; 354(25):2655-66

Barr WG, Oyama Y, Statkute L, et al. Autologous Non-Myeloablative Peripheral Blood Stem Cell Transplantation in Patients with Systemic Sclerosis. American College of Rheumatology Annual Meeting, 2006. Presentation 688.

National Institute of Arthritis, Musculoskeletal, and Skin Diseases. Scleroderma: Summaries of Research. November 2006. Last accessed on 1 December, 2006.

Casciola-Rosen L, Wigley F, and Rosen A. Scleroderma Autoantigens Are Uniquely Fragmented by Metal-catalyzed Oxidation Reactions: Implications for Pathogenesis. J. Exp. Med. 1997; 185 (January): 71-80. Last accessed on 27 November, 2006.

van Laar JM. Autologous Stem cell Transplantation International Scleroderma (ASTIS) trial: hope on the horizon for patients with severe systemic sclerosis. Ann Rheum Dis. 2005; 64(10): 1515.

van Laar JM. High-dose immunosuppressive therapy and autologous progenitor cell transplantation for systemic sclerosis. Best Pract Res Clin Haematol. 2004; 17(2): 233-45.

Crofford LJ. Immunomodulatory therapy for SSc: will high-intensity immunosuppression with stem cell rescue improve outcome? Curr Rheumatol Rep. 2005; 7(2): 142-9.

Toledano C, Henegar C, Ilie D et al. Cardiopulmonary function before and after cyclophosphamide treatment in severe systemic sclerosis: comparison of monthly intravenous bolus and autologous haematopoietic stem cell transplantation. Rev Med Interne. 2005 Jun;26(6):444-52.

Pfizenmaier DH 2nd, Kavros SJ, Liedl DA, Cooper LT. Use of intermittent pneumatic compression for treatment of upper extremity vascular ulcers. Angiology. 2005 Jul-Aug;56(4):417-22.

Shoenfeld Y, Katz U. IVIg therapy in autoimmunity and related disorders: our experience with a large cohort of patients. Autoimmunity. 2005 Mar;38(2):123-37.

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