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Sarcoidosis (cont.)

How is sarcoidosis treated?

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, corticosteroid drugs 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 lung scarring (fibrosis) that might be present in advanced sarcoidosis. More than one test is needed to diagnose sarcoidosis.

Tests can also show if patients with sarcoidosis are getting better. Occasionally, a blood test will show a high blood level of calcium accompanying sarcoidosis. The reasons for this are not clear. When it does occur, the patient may be advised to avoid calcium-rich foods, vitamin D, or sunlight, or to take prednisone (this corticosteroid usually quickly reverses the condition).

Because sarcoidosis can disappear even without therapy, even 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 corticosteroid.

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 corticosteroid, various other drugs have been tried, but their effectiveness has not been established in controlled studies. These drugs include chloroquine (Aralen) and D-penicillamine. Several drugs such as chlorambucil (Leukeran), azathioprine (Imuran), methotrexate (Rheumatrex, Trexall), and cyclophosphamide (Cytoxan), 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 must be compared closely with the benefits in preventing organ damage by the disease. They are not to be used by 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. More recently, thalidomide (Thalomid) has been used successfully in a limited number of patients and seemed to improve lung function and heal skin lesions. Infliximab (Remicade) has been reported recently as effective in treating patients with sarcoidosis.

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 characterized the disease is the major aim of researchers of 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 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 sarcoidosis patients show that many of the immune functions associated 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 substances, 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, cytokines, 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 bronchoalveolar technique, it also has become possible for researchers 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 macrophage. This pronounced, 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-1, interleukin-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 cytomegalovirus (CMV), a common disease-causing virus, were introduced into lymphocytes, 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 responsible for the production of interleukin-1. Since interleukin-1 levels are found to increase in alveolar macrophage from patients with sarcoidosis, this 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.

Currently, thalidomide is being studied as a treatment for sarcoidosis. Future research with viral models may provide clues to the molecular mechanisms that trigger alterations in white blood cell (lymphocyte and macrophage) regulation leading to sarcoidosis.

For difficult to treat (refractory) sarcoidosis and sarcoidosis involving the nervous system (neurosarcoidosis), recent research using biologic medications that inhibit tumor necrosis factor (TNF-blockers) has been beneficial. The TNF-blockers used were adalimumab (Humira) and infliximab.