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有关硬皮症的原因、诊断和治疗的深入报道(一)  

2017-03-12 01:57:20|  分类: 疾病与治疗 |  标签: |举报 |字号 订阅

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Description

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


Alternative Names

Systemic sclerosis; Localized scleroderma


Highlights

Overview
Scleroderma is an uncommon, complex, autoimmune disease. The body's immune system attacks its own tissues. It affects the skin by causing hardened tissue or ulcers and may harm the internal organs.
Doctors have made progress developing treatments to reduce symptoms, but there is no cure.
There are two major forms of the disease. Systemic scleroderma is a serious condition, while localized scleroderma carries a good prognosis and normal lifespan. In children, localized scleroderma is three times more common than the systemic form of the disease.
The cause and course of the disease is unclear, and more research is needed to assess treatment options.

Treatment

Treatment involves a combination approach to treat the immune response, improve circulation, and stop the progression of skin symptoms. Several medications and therapies are in the very early phases of study for scleroderma. These agents show some promise, but additional study is needed to define their use:


Bosentan is currently under study in the US for systemic scleroderma. It is already approved by the Food and Drug Administration (FDA) for the treatment of pulmonary hypertension. Two trials have demonstrated a reduction of new skin ulcers for certain scleroderma patients after taking Bosentan. The drug was approved in Europe in 2007 for the treatment of skin ulcers related to scleroderma.
Early study results on a very small number of patients show some promise after non-myeloablative autologous haemopoietic stem-cell transplantation (HSCT) for those with severe disease. Longer follow up and further study is needed to learn if this treatment works and for which patients, as well as to evaluate its safety.
Some biologic drugs -- such as rituximab (Rituxan) and Imatinib mesylate (Gleevac), used to treat certain cancers and illnesses that involve an overactive immune system -- may play a role in treating scleroderma. However, larger scale, randomized, multi-center studies are necessary to determine whether they are beneficial.

New Guidelines


The Canadian Scleroderma Research Group (CSRG) convened an expert panel in the area of nutrition to develop new recommendations in the screening and management of nutritional disorders related to scleroderma. Recommendations cover areas of evaluation, referral, medications, and nutritional therapies.
The European League Against Rheumatism (EULAR), with experts from Europe, the United States, and Japan, has developed 14 evidence-based recommendations for the treatment of scleroderma.
The American College of Rheumatology has developed guidelines for improved diagnostic accuracy and consistency.


Introduction

The name scleroderma comes from the Greek words skleros, which means hard, andderma, which means skin. The disease is categorized as a rheumatologic disorder because it affects the connective tissues in the body. It is rare, with an annual incidence of 18 - 20 new cases per million persons.

Scleroderma is 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, spreads throughout the body (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. Rarely, 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 of the disease in both types 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 throughout the body. It generally differs from diffuse scleroderma in the following ways:


In most cases the internal organs are not affected.
Patients with limited scleroderma have a less serious course, unless they develop pulmonary hypertension (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 to form on the hands, face, and tongue.
 
CREST syndrome
 Click the icon to see an image of symptoms that are known as CREST. 

In general, people with limited scleroderma develop Raynaud's phenomenon long before they develop any of the other symptoms. One or more of the CREST conditions can also occur in other forms of scleroderma.

Diffuse Scleroderma. Diffuse scleroderma, the other type of 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 start quickly and be accompanied by swelling of the whole hand. If it gets worse quickly early on, the condition can affect internal organs and become very severe -- even life threatening.
Diffuse scleroderma can overlap with other autoimmune diseases, including systemic lupus erythematosus and polymyositis. In such cases, the disorder is referred to asmixed connective disease.


Risk Factors

Scleroderma is not common. It afflicts about 300,000 Americans, about a third of whom have the systemic form of the disease. 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. It is extremely rare in children. Localized scleroderma is more common in children than adults, but is extremely rare even in the young age group.

Gender. The prevalence of scleroderma is about four times higher in women than men, and it's higher during child-bearing years. This may reflect different causes of the disease in these two genders. (It should be noted that pregnancy itself is not a risk factor for scleroderma and that women in general are more susceptible to autoimmune diseases than men.)

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. Genetic factors appear to play a role in triggering the disease, but most cases are unlikely to be inherited. Preliminary research suggests that genes and gene to gene interactions play a role.

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.

Genetic factors affect population groups differently. Studies are finding 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. The condition is also more severe in Native Americans.


Symptoms and Complications


Raynaud's Phenomenon

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

Attacks of Raynaud's phenomenon can occur several times a day, and are often brought on or worsened by exposure to cold. Warmth relieves these attacks. In severe cases, attacks can 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.

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 can occur in the affected regions.

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

Raynaud's is very common and occurs in 3 - 5% of the general population. It's important to note that more than 80% of patients with Raynaud's phenomenon do not have scleroderma, lupus, rheumatoid arthritis, or other serious illnesses. Raynaud's 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 calledsclerodactylia or acrosclerosis. Patients with diffuse scleroderma may have swelling of the whole hand before the skin significantly thickens.
Thickened or hardened patches may also develop on other areas of the body. (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, the 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.
 
Sclerodactly
 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.
 
Telangiectasia
 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.
Small blood vessels at the base of the fingernails may be severely narrowed in some places, and may widen in other places. 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 Sj?gren syndrome, a group of symptoms that include dry eyes and dry mucus 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 can 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.
Muscle weakness may occur, especially near the shoulder and hip.
Digestive Tract Symptoms and Complications

Complications in the Upper Digestive Tract.


Esophageal motility disorder develops when scarring in the muscles of the esophagus causes them to lose the ability to contract normally, resulting in trouble swallowing, heartburn, and gastroesophageal reflux (also known as GERD). Some experts believe that patients with severe GERD may aspirate (breathe in) tiny amounts of stomach acid, which in turn may be a major cause of lung scarring.
About 80% of patients also experience impaired stomach activity. A delay in stomach emptying is 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 lead to anemia (low red blood cell counts) over time.
There may be a higher risk for stomach cancer.
Problems with movement of the food (motility) through the intestines also develop. Patients may experience an increase in bacteria levels in their intestines as a result, and have trouble absorbing nutrients from foods through their intestines.

Complications in the Lower Digestive Tract. Complications in the lower digestive tract are uncommon. If they do occur, they can include the following:


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

Digestive complications can put scleroderma patients at risk for malnutrition and/or incomplete absorption of nutrients. Many patients, however, have few or even no lower gastrointestinal symptoms.


Lung Symptoms and Complications

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.

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.

Interstitial Pulmonary Fibrosis. Scleroderma involving the lung causes scarring (pulmonary fibrosis). Pulmonary fibrosis occurs in about 20% of scleroderma patients with limited skin disease and 80% of scleroderma patients with
more severe disease (diffuse cutaneous), although its progression is very slow and patients have a wide range of symptoms:


Some patients may not have any symptoms.
When pulmonary fibrosis progresses, patients develop a dry cough, shortness of breath, and reduced ability to exercise.
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 of diagnosis. In such cases, lung function worsens rapidly over that period, and then the progression slows down.

Pulmonary fibrosis also places the patient at higher risk for lung cancer. This condition may be due to severe dysfunction in the esophagus, which causes patients to aspirate tiny amounts of stomach acid.

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


Primary pulmonary hypertension

Pulmonary hypertension is the narrowing of the pulmonary arteries in the lung. The narrowing of the arteries creates resistance and increases the workload of 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 to control the symptoms, although the disease usually develops into heart failure.


Pulmonary Hypertension. Pulmonary hypertension is the narrowing of the pulmonary arteries in the lung. The narrowing of the arteries creates resistance to blood flow and increases the workload of the heart. The heart becomes enlarged from pumping blood against this resistance. Some symptoms of pulmonary hypertension include shortness of breath, chest pain, weakness, and fatigue. Shortness of breath, the primary symptom of pulmonary hypertension, worsens over time. The goal of treatment is to control the symptoms, although the disease eventually produces heart failure, usually after about 10 years.

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.
 
Cor pulmonale
 Click the icon to see an image of the cor pulmonale.
Kidney Symptoms and Complications

Signs of kidney problems, such as increased amounts of protein in the urine and high blood pressure (hypertension), are common in scleroderma (but somewhat less common in children). As with pulmonary hypertension, the degree of severity depends on whether the kidney problems are acute or chronic.

Slow Progression. The typical course of kidney involvement in scleroderma is a slow progression that may produce some damage but does not usually lead to kidney failure.

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 rapid kidney failure. This condition may be fatal. However, if the condition is successfully treated, it rarely recurs.

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 Symptoms and 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 after the disease begins. Research has shown that patients with systemic scleroderma have a higher risk of atherosclerosis than healthy individuals.

Fibrosis of the Heart. The most direct effect of scleroderma 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.

 
Pericarditis
 Click to see an image of blood pressure monitoring. 

Pulmonary hypertension and hypertension associated with kidney problems in scleroderma can also affect the heart.


Other Symptoms and 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, feet, arms, fingers, and toes), causing numbness and pain. This damage can progressively worsen and lead to severe open sores (ulcerations), 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 10-15% of scleroderma patients develop underactive thyroid gland (hypothyroidism).
 
Hypothyroidism
 Click the icon to see an image of hypothyroidism.
Erectile dysfunction, usually due to scarring of the penis, may be one of the first complications of the disease in men.
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. Although they can carry a baby to term, because complications such as kidney crisis can occur with the disease, pregnant women with scleroderma need to be monitored closely in a high-risk obstetric facility.
More than half of scleroderma patients are likely to experience significant depression. Researchers say it may be beneficial for scleroderma patients to be routinely screened for depression.
About 30% of scleroderma patients are estimated to be at medium to high risk for malnutrition due to swallowing problems and other digestive complications.


Causes

Most likely this disease is caused by several inherited (genetic) abnormalities, which are triggered by environmental factors.


Inflammatory Response and Autoimmunity

The disease process leading to scleroderma appears to occur as an autoimmune response, in which an abnormal immune system attacks the body itself. In scleroderma, this response produces swelling (inflammation) and too much production of collagen. Collagen is the tough protein that helps build connective tissues such as tendons, bones, and ligaments. Collagen also helps scar tissue form. When normal tissue from skin, lungs, the esophagus, blood vessels, and other organs is replaced by this type of abnormal tissue, none of these body parts work as well, and many of the symptoms previously described occur.


Antibodies

Antigens are large molecules (usually proteins) on the surface of many cells -- both human cells, and cells of viruses, fungi, bacteria, and some non-living substances such as toxins, chemicals, drugs, and foreign particles. When the immune system recognizes an antigen as being foreign (not part of the human body), it starts offensive and defensive actions against them by producing antibodies and other chemicals such as cytokines that destroy any cells in the area.


Much of this activity is directed by white blood cells known as T cells, which are subdivided into killer T cells and helper T cells (TH cells).

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 for a foreign antigen. This triggers a series of immune responses to destroy the collagen. When the body creates antibodies against itself in this way, it is called an autoimmune response.


Genetics

Research has demonstrated that systemic sclerosis is a polygenic (involving more than one gene) autoimmune (involving the immune system response) disease. Several genes and gene-gene interactions have been identified as playing a role in systemic sclerosis. Many of these same genes are linked to related diseases, such as rheumatoid arthritis and systemic lupus erythematosus.

The genes are involved in the regulation of the immune system.


Fetal Cell Theory and Microchimerism

A process called microchimerism has been proposed as one cause of scleroderma. The theory arose from the fact that scleroderma occurs mostly in women, and its symptoms resemble those of graft-versus-host disease (GVHD). GVHD occurs in bone marrow transplant patients who have received cells from another person. It happens when the transplanted immune cells of the donor launch an attack against the patient's body.

Chimerism occurs when cells from two different individuals exist in the same body, such as cells from a fetus left in its mother's body after she gave birth. When there are low numbers of the cells of one body in another, the condition is referred to as microchimerism.

However, if microchimerism plays a role in scleroderma, 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 in people with scleroderma. Some experts believe that environmental factors, such as a virus or a chemical, may trigger the response in individuals with a genetic vulnerability.

Chemicals. Occupational exposure to certain chemicals can cause blood vessel constriction and attacks of Raynaud's phenomenon. Despite the fact that women are at higher overall risk for scleroderma, among people who are exposed to solvents at work, men face a higher risk for the disease. However, no specific work-related factors have been proven to cause the disorder.

It is nearly impossible to determine whether specific chemicals may actually cause systemic scleroderma, primarily because few people develop the disease, even though 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 lung problems in people with scleroderma. The toxins most likely to be associated with severe disease include epoxy resins, white spirit, solvents, and silica mixed with welding fumes.

Radiation. Radiation therapy has been reported to cause local patches of scleroderma (morpheaa in patients. In some cases, scleroderma may occur years after radiation treatment

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