Sarcoidosis.

Introduction

Sarcoidosis is a disease due to inflammation. It can appear in almost any body organ, but most often starts in the lungs or lymph nodes.

No one yet knows what causes sarcoidosis. The disease can appear suddenly and disappear. Or it can develop gradually and go on to produce symptoms that come and go, sometimes for a lifetime.

As sarcoidosis progresses, small lumps, or granulomas, appear in the affected tissues. In the majority of cases, these granulomas clear up, either with or without treatment.

In the few cases where the granulomas do not heal and disappear, the tissues tend to remain inflamed and become scarred (fibrotic).

Sarcoidosis was first identified over 100 years ago by two dermatologists working independently, Dr. Jonathan Hutchinson in England and Dr. Caesar Boeck in Nonway. Sarcoidosis was originally called Hutchinson's disease or Boecks disease. Dr. Boeck went on to fashion today's name for the disease from the Greek words "sark" and "oid," meaning flesh-like. The term describes the skin eruptions that are frequently caused by the illness.

Usual Symptoms

Shortness of breath (dyspnea) and a cough that won't go away can be among the first symptoms of sarcoidosis. But sarcoidosis can also show up suddenly with the appearance of skin rashes. Red bumps (erythema nodosum) on the face, arms, or shihs, and inflammation of the eves are also common symptoms. It is not unusual, however, for sarcoidosis symptoms to be more general. Weight loss, fatigue, night sweats, fever, or just an overall feeling of ill health can also be clues to the disease.

Who Gets Sarcoidosis?

Sarcoidosis was once considered a rare disease. We now know that it is a common chronic illness that appears all over the world. Indeed, it is the most common of the fibrotic lung disorders, and occurs often enough in the United States for Congress to have declared a national Sarcoidosis Awareness Day in 1990.

Anyone can get sarcoidosis. It occurs in all races and in both sexes. Nevertheless, the risk is greater if you are a young black adult, especially a black woman, or of Scandinavian, German, Irish, or Puerto Rican origin. No one knows why.

Because sarcoidosis can escape diagnosis or be mistaken for several other diseases, we can only guess at how many people are affected. The best estimate today is that about 5 in 100,000 white people in the United States have sarcoidosis. Among black people, it occurs more frequently, in probably 40 out of 100,000 people.

Overall, there appear to be 20 cases per 100,000 in cities on the east coast and somewhat fewer in rural locations. Some scientists, however, believe that these figures greatly underestimate the percentage of the U.S. population with sarcoidosis.

Sarcoidosis mainly affects people between 20 to 40 years of age. White women are just as likely as white men to get sarcoidosis, but the black female gets sarcoidosis two times as often as the black male.

Sarcoidosis also appears to be more common and more severe in certain geographic areas. It has long been recognized as a common disease in Scandinavian countries, where it is estimated to affect 64 out of 100,000 people. But it was not until the mid-1940s--when a large number of cases were identified during mass chest x-ray screening for the Armed Forces--that its high prevalence was recognized in North America.

What Sarcoidosis is Not

Much about sarcoidosis remains unknown. Nevertheless, if you have the disease, you can be reassured about several things.

Sarcoidosis is usually not crippling. It often goes away by itself, with most cases healing in 24 to 36 months. Even when sarcoidosis lasts longer, most patients can go about their lives as usual.

Sarcoidosis is not a cancer. It is not contagious, and your friends and family will not catch it from you. Although it can occur in families, there is no evidence that sarcoidosis is passed from parents to children.

Some Things We Don't Know About Sarcoidosis

Sarcoidosis is currently thought to be associated with an abnormal immune response. Whether a foreign substance is the trigger; whether that trigger is a chemical, drug, virus, or some other substance; and how exactly the immune disturbance is caused are not known.

Researchers supported by the National Heart, Lung, and Blood Institute are trying to solve some of these mysteries. Among the research questions they are trying to answer are:

* Does sarcoidosis have many causes, or is it produced by a single agent?

* In which body organ does sarcoidosis actually start?

* How does sarcoidosis spread from one part of the body to another?

* Do heredity, environment, and lifestyle play any role in the appearance, severity, or length of the disease?

* Is the abnormal immune response seen in patients a cause or an effect of the disease?

* How can sarcoidosis be prevented?

Course of the Disease

In general, sarcoidosis appears briefly and heals naturally in 60 to 70 percent of the cases, often without the patient knowing or doing anything about it. From 20 to 30 percent of sarcoidosis patients are left with some permanent lung damage. In 10 to 15 percent of the patients, sarcoidosis can become chronic.

When either the granulomas or fibrosis seriously affect the function of a vital organ--the lungs, heart, nervous system, liver, or kidneys, for example-sarcoidosis can be fatal. This occurs 5 to 10 percent of the time.

No one can predict how sarcoidosis will progress in an individual patient. But the symptoms the patient experiences, the doctor's findings, and the patient's race can give some clues.

For example, a sudden onset of general symptoms such as weight loss or feeling poorly are usually taken to mean that the course of sarcoidosis will be relatively short and mild. Dyspnea and possibly skin sarcoidosis often indicate that the sarcoidosis will be more chronic and severe.

White patients are more likely to develop the milder form of the disease. Black people tend to develop the more chronic and severe form.

Sarcoidosis rarely develops before the age of 10 or after the age of 60. However, the illness--with or without symptoms--has been reported in younger as well as in older people. When symptoms do appear in these age groups, the symptoms are those that are more general in nature, for example, tiredness, sluggishness, coughing, and a general feeling of ill health.

Diagnosis

Preliminary diagnosis of sarcoidosis is based on the patient's medical history, routine tests, a physical examination, and a chest x-ray.

The doctor confirms the diagnosis of sarcoidosis by eliminating other diseases with similar features. These include such granulomatous diseases as berylliosis (a disease resulting from exposure to beryllium metal), tuberculosis, farmer's lung disease (hypersensitivity pneumonitis), fungal infections, rheumatoid arthritis, rheumatic fever, and cancer of the lymph nodes (lymphoma).

* Signs and Symptoms

In addition to the lungs and lymph nodes, the body organs more likely than others to be affected by sarcoidosis are the liver, skin, heart, nervous system, and kidneys, in that order of frequency. Patients can have symptoms related to the specific organ affected, they can have only general symptoms, or they can be without any symptoms whatsoever. Symptoms also can vary according to how long the illness has been under way, where the granulomas are forming, how much tissue has become affected, and whether the granulomatous process is still active.

Even when there are no symptoms, a doctor can sometimes pick up signs of sarcoidosis during a routine examination, usually a chest x-ray, or when checking out another complaint. The patient's age and race or ethnic group can raise an additional red flag that a sign or symptom of illness could be related to sarcoidosis. Enlargement of the salivary or tear glands and cysts in bone tissue are also among sarcoidosis signals.

Lungs. The lungs are usually the first site involved in sarcoidosis. Indeed, about 9 out of 10 sarcoidosis patients have some type of lung problem, with nearly one-third of these patients showing some respiratory symptoms--usually coughing, either dry or with phlegm, and dyspnea. Occasionally, patients have chest pain and a feeling of tightness in the chest.

It is thought that sarcoidosis of the lungs begins with alveolitis (inflammation of the alveoli), the tiny sac-like air spaces in the lungs where carbon dioxide and oxygen are exchanged. Alveolitis either clears up spontaneously or leads to granuloma formation. Eventually fibrosis can form, causing the lung to stiffen and making breathing even more difficult.

Eyes. Eye disease occurs in about 20 to 30 percent of patients with sarcoidosis, particularly in children who get the disease. Almost any part of the eye can be affected--the membranes of the eyelids, cornea, outer coat of the eyeball (sclera), retina, and lens. The eye involvement can start with no symptoms at all or with reddening or watery eyes. In a few cases, cataracts, glaucoma, and blindness can result.

Skin. The skin is affected in about 20 percent of sarcoidosis patients. Skin sarcoidosis is usually marked by small, raised patches on the face. Occasionally the patches are purplish in color and larger. Patches can also appear on limbs, face, and buttocks.

Other symptoms include erythema nodosum, mostly on the legs and often accompanied by arthritis in the ankles, elbows, wrists, and hands. Erythema nodosum usually goes away, but other skin problems can persist.

Nervous system. In an occasional case (I to 5 percent), sarcoidosis can lead to neurological problems. For example, sarcoid granulomas can appear in the brain, spinal cord, and facial and optic nerves. Facial paralysis and other symptoms of nerve damage call for prompt treatment.

* Laboratory Tests

No single test can be relied on for a correct diagnosis of sarcoidosis. X-rays and blood tests are usually the first procedures the doctor will order. Pulmonary function tests often provide clues to diagnosis. Other tests may also be used, some more often than others.

Many of the tests that the doctor calls on to help diagnose sarcoidosis can also help the doctor follow the progress of the disease and determine whether the sarcoidosis is getting better or worse.

Chest x-ray. A picture of the lungs, heart, as well as the surrounding tissues containing lymph nodes, where infection-fighting white blood cells form, can give the first indication of sarcoidosis. For example, a swelling of the lymph glands between the two lungs can show up on an x-ray. An xray can also show which areas of the lung are affected.

Pulmonary function tests. By performing a variety of tests called pulmonary function tests (PFT), the doctor can find out how well the lungs are doing their job of expanding and exchanging oxygen and carbon dioxide with the blood. The lungs of sarcoidosis patients cannot handle these tasks as well as they should; this is because granulomas and fibrosis of lung tissue decrease lung capacity and disturb the normal flow of gases between the lungs and the blood.

One PFT procedure calls for the patient to breathe into a machine, called a spirometer. It is a mechanical device that records changes in the lung size as air is inhaled and exhaled, as well as the time it takes the patient to do this.

Blood tests. Blood analyses can evaluate the number and types of blood cells in the body and how well the cells are functioning. They can also measure the levels of various blood proteins known to be involved in immunological activities, and they can show increases in serum calcium levels and abnormal liver function that often accompany sarcoidosis.

Blood tests can measure a blood substance called angiotens in converting enzyme (ACE). Because the cells that make up granulomas secrete large amounts of ACE, the enzyme levels are often high in patients with sarcoidosis. ACE levels, however, are not always high in sarcoidosis patients, and increased ACE levels can also show up in other illnesses.

Bronchoalveolar lavage. This test uses an instrument called a bronchoscope--a long, narrow tube with a light at the end--to wash out, or lavage, cells and other materials from inside the lungs. This wash fluid is then examined for the amount of various cells and other substances that reflect inflammation and immune activity in the lungs. A high number of white blood cells in this fluid usually indicates an inflammation in the lungs.

Biopsy. Microscopic examination of specimens of lung tissue obtained with a bronchoscope, or of specimens of other tissues, can tell a doctor where granulomas have formed in the body.

Gallium scanning. In this procedure, the doctor injects the radioactive chemical element gallium-67 into the patients vein. The gallium collects at places in the body affected by sarcoidosis and other inflammatory conditions. Two days after the injection, the body is scanned for radioactivity.

Increases in gallium uptake at any site in the body indicate that inflammatory activity has developed at the site and also give an idea of which tissue, and how much tissue, has been affected. However, since any type of inflammation causes gallium uptake, a positive gallium scan does not necessarily mean that the patient has sarcoidosis.

Kveim test. This test involves injecting a standardized preparation of sarcoid tissue material into the skin. On the one hand, a unique lump formed at the point of injection is considered positive for sarcoidosis. On the other hand, the test result is not always positive even if the patient has sarcoidosis.

The Kveim test is not used often in the United States because no test material has been approved for sale by the U.S. Food and Drug Administration. However, a few hospitals and clinics may have some standardized test preparation prepared privately for their own use.

Slit-lamp examination. An instrument called a slit lamp, which permits examination of the inside of the eye, can be used to detect silent damage from sarcoidosis.

Management

Fortunately, many patients with sarcoidosis require no treatment. Symptoms, after all, are usually not disabling and do tend to disappear spontaneously.

When therapy is recommended, the main goal is to keep the lungs and other affected body organs working and to relieve symptoms. The disease is considered inactive once the symptoms fade. After many years of experience with treating the disease, corticosteroids remain the primary treatment for inflammation and granuloma formation. Prednisone is probably the corticosteroid most often prescribed today. There is no treatment at present to reverse the fibrosis that might be present in advanced sarcoidosis.

Occasionally, a blood test will show a high blood level of calcium accompanying sarcoidosis. The reasons for this are not clear. Some scientists believe that this condition is not common. When it does occur, the patient may be advised to avoid calcium-rich foods, vitamin D, or sunlight, or to take prednisone; this corticosteroid quickly reverses the condition.

Because sarcoidosis can disappear even without therapy, doctors sometimes disagree on when to start the treatment, what dose to prescribe, and how long to continue the medicine. The doctor's decision depends on the organ system involved and how far the inflammation has progressed. If the disease appears to be severe--especially in the lungs, eyes, heart, nervous system, spleen, or kidneys--the doctor may prescribe corticosteroids.

Corticosteroid treatment usually results in improvement. Symptoms often start up again, however, when it is stopped. Treatment, therefore, may be necessary for several years, sometimes for as long as the disease remains active or to prevent relapse.

Frequent checkups are important so that the doctor can monitor the illness and, if necessary, adjust the treatment. Corticosteroids, for example, can have side effects--mood swings, swelling, and weight gain because the treatment tends to make the body hold on to water; high blood pressure; high blood sugar; and craving for food. Long-term use can affect the stomach, skin, and bones. This situation can bring on stomach pain, an ulcer, or acne, or cause the loss of calcium from bones. However, if the corticosteroid is taken in carefully prescribed, low doses, the benefits from the treatment are usually far greater than the problems.

Besides corticosteroids, various other drugs have been tried, but their effectiveness has not been established in controlled studies. These drugs include chloroquine and D-penicillamine.

Several drugs such as chlorambucil, azathioprine, methotrexate, and cyclophosphamide, which might suppress alveolitis by killing the cells that produce granulomas, have also been used. None have been evaluated in controlled clinical trials, and the risk of using these drugs is high, especially in pregnant women.

Cyclosporine, a drug used widely in organ transplants to suppress immune reaction, has been evaluated in one controlled trial. It was found to be unsuccessful.

Living with Sarcoidosis

The cause of sarcoidosis still remains unknown, so there is at present no known way to prevent or cure this disease. However, doctors have had a great deal of experience in management of the illness.

If you have sarcoidosis, you can help yourself by following sensible health measures. You should not smoke. You should also avoid exposure to other substances such as dusts and chemicals that can harm your lungs.

Patients with sarcoidosis are best treated by a lung specialist or a doctor who has a special interest in sarcoidosis. Sarcoidosis specialists are usually located at major research centers.

If you have any symptoms of sarcoidosis, see your doctor regularly so that the illness can be watched and, if necessary, treated. If it heals naturally, sarcoidosis is unlikely to recur. Nevertheless, if you have had sarcoidosis, or are suspected of having the illness but have no symptoms now, be sure to have physical checkups every year, including an eye examination.

Although severe sarcoidosis can reduce the chances of becoming pregnant, particularly for older women, many young women with sarcoidosis have given birth to healthy babies while on treatment. Patients planning to have a baby should discuss the matter with their doctor. Medical checkups all through pregnancy and immediately thereafter are especially important for sarcoidosis patients. In some cases, bed rest is necessary during the last 3 months of pregnancy.

In addition to family and close friends, a number of local lung organizations, other nonprofit health organizations, and self-help groups are available to help patients cope with sarcoidosis. By keeping in touch with them, you can share personal feelings and experiences. Members also share specific information on the latest scientific advances, where to find sarcoidosis specialists, and how to improve one's self-image.

RELATED ARTICLE: Research Status in Sarcoidosis: Goals of the National Heart, Lung, and Blood Institute

There are many unanswered questions about sarcoidosis. Identifying the agent that causes the illness, along with the inflammatory mechanisms that set the stage for the alveolitis, granuloma formation, and fibrosis that characterize the disease, is the major aim of the National Heart, Lung, and Blood Institute's program on sarcoidosis. Development of reliable methods of diagnosis, treatment, and, eventually, the prevention of sarcoidosis is the ultimate goal.

Originally, scientists thought that sarcoidosis was caused by an acquired state of immunological inertness (anergy). This notion was revised a few years ago, when the technique of bronchoalveolar lavage provided access to a vast array of cells and cell-derived mediators operating in the lungs of sarcoidosis patients. Sarcoidosis is now believed to be associated with a complex mix of immunological disturbances involving simultaneous activation, as well as depression, of certain immunological functions.

Immunological studies on sarcodiosis patients show that many of the immune functions association with thymus-derived white blood cells, called T-lymphocytes or T-cells, are depressed. The depression of this cellular component of systemic immune response is expressed in the inability of the patients to evoke a delayed hypersensitivity skin reaction (a positive skin test), when tested by the appropriate foreign substance, or antigen, underneath the skin.

In addition, the blood of sarcoidosis patients contains a reduced number of T-cells. These t-cells do not seem capable of responding normally when treated with substances known to stimulate the growth of laboratory-cultured T-cells. Neither do they produce their normal complement of immunological mediators, cytokins, through which the cells modify the behavior of other cells.

In contrast to the depression of the cellular immune response, humoral immune response of sarcoidosis patients is elevated. The humoral immune response is reflected by the production of circulating antibodies against a variety of exogenous antigens, including common viruses. This humoral component of systemic immune response is mediated by another class of lymphocytes known as B-lymphocytes, or B-cells, because they originate in the bone marrow.

In another indication of heightened humoral response, sarcoidosis patients seem prone to develop autoantibodies (antibodies against endogenous antigens) similar to rheumatoid factors.

With access to the cells and cell products in the lung tissue compartments through the brochoalveolar technique, it also has become possible for researches to complement the above investigations at the blood level with analysis of local inflammatory and immune events in the lungs.

In contrast to what is seen at the systemic level, the cellular immune response in the lungs seems to be heightened rather than depressed. The heightened cellular immune response in the diseased tissue is characterized by significant increases in activated T-lymphocytes with certain characteristic cell-surface antigens, as well as in activated alveolar macrophages.

This prononunced, localized cellular response is also accompanied by the appearance in the lung of an array of mediators that are thought to contribute to the disease process; these include interleukin-l, inteleukin-2, B-cell growth factor, B-cell differentiation factor, fibroblast growth factor, and fibronectin.

Because a number of lung diseases follow respiratory tract infections, ascertaining whether a virus can be implicated in the events leading to sarcoidosis remains an important area of research. Some recent observations seem to provide suggestive leads on this question. In these studies, the genes of cutomegalovirus (CMV), a common disease-causing virus, were introduced into lumphocytes, and the expression of the viral genes was studied. It was found that the viral genes were expressed both during acute infection of the cells and when the virus was not replicating in the cells. However, this expression seemed to take place only when the T-cells were activated by some injurious event.

In addition, the product of a CMV gene was found capable of activating the gene in alveolar macrophage responsive for the production of interleukin-1. Since interleukin-1 levels are found to increase in alveolar macrophages from patients with sarcoidosis, tis suggests that certain viral genes can enhance the production of inflammatory components associated with sarcoidosis. Whether these findings implicate viral infections in the disease process in sarcoidosis is unclear. Future research with viral models may provide clues to the molecular mechanisms that trigger alterations in lymphocyte and macrophage regulation leading to sarcoidosis.

For More Information

Additional Information on sarcoidosis is available from a number of sources.

For the names of U.S. scientists working on sarcoidosis or physicians specializing in the disease, write to:

National Heart, Lung, and Blood Institute

Division of Lung Diseases

5333 Westbard Avenue

Room 6A16

Bethesda, MD 20892

If you are interested in participating in clinical studies of sarcoidosis ongoing at the NHLBI, have your physician write to:

National Heart, Lung, and Blood Institute

Pulmonary Branch

9000 Rockville Pike

Building 10, Room 6D06

Bethesda, MD 20892

Information and publications for sarcoidosis patients and their families are available from:

National Institute of Allergy and Infectious Diseases

9000 Rockville Pike

Building 31, Room 7A32

Bethesda, MD 20892

Sarcoidosis Family Aid and Research Foundation

460A Central Avenue

East Orange, NJ 07018

Many local chapters of the American Lung Association host support groups for sarcoidosis patients. The address and telephone number of the chapter nearest to you should be in your local telephone directory. Or you can write or call the association's national headquarters:

American Lung Association

1740 Broadway

New York, NY 10019-4374

[phone]

Listed below are addresses of organizations that provide additional information and patient support groups on sarcoidosis:

Sarcoidosis Networking

13925 80th Street East

Puyallup, WA 98372

[phone]

National Sarcoidosis Resources Center

P.O. Box 1593

Piscataway, NJ 08855-1593

[phone]

Sarcoidosis Research Institute

3475 Central Avenue

Memphis, TN 38111

[phone]

Glossary

ACE                   Angiotensin-converting enzyme.
Alveoli               The tiny sac-like air spaces in the lung where
                      carbon dioxide and oxygen are exchanged.
Alveolitis            Inflammation of the alveoli.
Anergy                Absence of immune response to particular substances.
Berylliosis           A lung disease resulting from exposure to
                      beryllium metal.
Bronchoscope          A long, narrow tube with a light at the end that is
                      used by the doctor for direct observation of the
                      airways, as well as for suction of tissue and other
                      materials.
Dyspnea               Shortness of breath.
Enzyme                Substance, made by living cells, that causes
                      specific chemical changes.
Erythema nodosum      Red bumps that tend to appear on the face, arms,
                      and shins.
Fibrotic tissue       Inflamed tissue that has become scarred.
Granulomas            Small lumps in tissues caused by inflammation.
Inflammation          A basic response of the body to injury, usually
                      showing up in skin redness, warmth,
                      swelling, and pain.
Lavage                To wash out a body organ.
Lymph nodes           Small, bean-shaped organs of the immune system
                      distributed throughout the body tissue.
Lymphoma              Cancer of the lymph nodes.
PFT                   Pulmonary function test.
Pneumonitis          A disease caused by inhaling a wide variety, of
                     substances such as dusts and molds. Also called
                     "farmer's disease."
Sclera               Outer coat of the eyeball.

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