Scleroderma
by Carwile LeRoy, M.D.
Forms of the disease / Cause / Major organ involvement
Diagnosis / Treatment and Management / Emotional well-being / Progress in research
Scleroderma (Greek for 'hard skin') is a chronic disease characterized by sclerosis ('hardening') and scarring of the skin and of certain internal organs. First described in a paper published in 1753 by Carlo Curzio In Naples, Italy, scleroderma has since come to be recognized as one of the more than 100 types of arthritis, distinguished from one another by their associated symptoms and physical signs and by diagnostic tests. Most of these forms of arthritis are associated with an imbalance In the body's immune system and are therefore classified as autoimmune diseases.
The human immune system is composed of specialized cells (lymphocytes, monocytes) and molecules (antibodies, interleukins, interferons, and others). Their function is to ward off foreign substances by recognizing their foreignness, mounting a response, and destroying the substance, whether it be a bacteria or virus, a chemical agent, or a transplanted organ. When the immune system responds to and destroys substances that are not foreign but are a part of the body's own healthy tissues, the result is an autoimmune injury. In autoimmune forms of arthritis, Including scleroderma, this injury may be persistent and severe.
Forms of the disease
There are two major kinds of scleroderma: localized and generalized. In localized scleroderma, or morphea, one or more rounded patches of hardened skin appear. These patches may be shiny and flattened and may itch; their color may be lighter or darker than that of the surrounding skin, depending on the individual's normal skin pigmentation. Localized, scleroderma may also take another form, that of a band of hardened skin extending from leg to toe or from face to trunk, called linear scleroderma. Often found on only one side of the body, linear lesions usually affect the skin served by one major nerve root from the spinal cord. Tissue underneath the hardened skin may shrink, tighten, and become withered. Linear scleroderma sometimes develops in childhood. When this is the case, normal growth of involved limbs may be disrupted. When linear scleroderma involves the face, it has the appearance of an injury sustained in a fencing duel, hence the designation en coup de sabre ('as from the slash of a saber), which is sometimes used to describe this manifestation of the disease. Morphea and linear scleroderma typically occur In the second and third decades of life and are more common in females than in males. Those who have localized scleroderma usually do not develop generalized disease.
Generalized scleroderma, is also called systemic sclerosis to emphasize that it is not limited to the skin. The first signs of illness are episodes of skin discoloration-blanching (whitening), blueness, and subsequent reddening-accompanied by uncomfortable feelings of numbness, tingling, and fullness. The fingers are usually the first to be affected, although the toes, nose, and ears may sometimes be involved. These episodes are triggered by exposure to cold or by stress. First described by the Parisian physician Maurice Raynaud in the mid-19th century, they are called Raynaud's phenomenon. Not all individuals with Raynaud's phenomenon will develop scleroderma; the former is a vascular event (i.e., related to blood flow), not specific for any one disease. Following a variable period of time, weeks, months, or even years, after the appearance of Raynaud's phenomenon, the few individuals who do develop scleroderma will occasionally notice a full or puffy feeling of the hands, feet, or face. This may evolve into a continuous feeling of taut skin of the fingers, hands, and face and may gradually or abruptly involve other skin areas.
Two types of problems, which may evolve independently, usually occur: injury to the blood vessels and fibrotic changes, or scarring, in various organs and tissues throughout the body. The extent of these problems may vary from extremes of severe vascular injury with no tissue scarring to severe scarring with no vascular features. Usually the patient has a mixture of the two problems. Vascular features include Raynaud's phenomenon; a reduced tone of the fingertip tissue; ulcers, or sores, on fingertips, knuckles, or elbows; unusual patterns of visible capillaries around the nail fold of the fingernails or toenails; calcinosis, or deposition of calcium beneath the surface of the skin, which sometimes forms lumps or nodules; and changes In the blood vessels that supply such Internal organs as the lungs, the heart, the intestines, and the kidneys, which may be affected separately or together.
Systemic sclerosis occurs worldwide and Is seen in all climates and among all racial and ethnic groups. In the U.S. alone, there are between 500,00 and 700,00 people with various forms of scleroderma, depending on the criteria used for classification. (Some 20 million people in the U.S. suffer from Raynaud's phenomenon.) Women are three to four times more likely to be affected than men, except in areas where occupational exposure (coal mining, plastics manufacturing, or the use of heavy vibrating machinery) Increases the proportion of male patients. While scleroderma is not inherited, there is some evidence of a genetic predisposition for the disease.
Cause
In most cases of scleroderma, the cause is unknown. There may, in fact, be more than one cause of the disease, or possibly there are multiple factors working together. The underlying processes are complex, and the order of events is not yet clearly understood. As mentioned above, two kinds of injury or damage seem to be involved--vascular injury and proliferation of scar tissue. Blood vessel spasms are believed to be responsible for the impaired blood flow in tissues affected by scleroderma. Current research seems to indicate that the spasms are the result of prior Injury to blood vessels, caused by ,any of several immune system substances or, perhaps, by exposure to a pathogen, such as a virus, bacteria, or to toxic substances in the environment. The characteristic thickening of the skin and buildup of excessive scar tissue is also believed to be triggered by a complex interaction of various substances produced by the immune system, possibly assisted or activated by a pathogen or a toxic agent.
What is known, however, is that several types of environmental and occupational exposure are associated with the scleroderma-like disease. Coal and gold miners exposed to silica, workers who use vibrating tools Jackhammer operators, loggers), factory workers exposed to vinyl chloride or trichloroethylenes, cancer patients treated with the drugs bleomycin or cisplatin, bone marrow recipients who develop chronic rejection reactions, and people who consumed a contaminated cooking oil in Spain in 1981--individuals in all of these diverse groups have been known to develop a scleroderma-like illness. What these various exposures have in common is unknown, but it is known that the chemical agents cited above create toxic products of oxygen metabolism that injure cells and tissue.
Major organ involvement
Generalized scleroderma, or systemic sclerosis, is a highly variable disease. There are many different symptoms, and they may appear one at a time or in a variety of combinations. The course of the disease is, therefore, highly variable. Fortunately, most types of scleroderma are not serious and do not involve the life-essential organs. The most serious form of the disease, diffuse cutaneous systemic sclerosis, involves scarring of the skin of the trunk (chest or abdomen). Patients with this form of scleroderma are at highest risk for developing potentially serious critical organ involvement. Organs that may be affected include the kidneys, the heart, the lungs, and all parts of the digestive tract. In addition, the patient may experience a tightening of the skin on the face, especially around the mouth; dryness of the eyes and mouth as a result of a decrease in secretions by the salivary and lachrymal (tear) glands called Sjoren’s Syndrome; painful joint inflammation; and flexion contractures, which are joints tightened and contractures, which are joints tightened and immobilized, in a bent position by tightening and hardening of the skin and adjacent connective tissues.
Renal failure--the inability of the kidneys to cleanse the blood of waste products—was until fairly recently the most feared complication of scleroderma. Now, with access to dialysis, the success of kidney transplantation, and the advent of drugs that effectively control high blood pressure, the outlook has improved for the scleroderma patient with kidney involvement. Early diagnosis is extremely important in the successful treatment of renal scleroderma.
Patients with diffuse systemic sclerosis are also at risk for lung involvement, which may be a result of fibrosis of the lung tissue, damage to blood vessels, or weakening of the respiratory muscles. The damaged lung tissue has a reduced capacity for both air movement and gas diffusion. Scarring of the blood vessels of the lung causes pulmonary hypertension elevation in blood pressure due to increased resistance to blood flow through the lungs-which, in turn, causes further scarring of the blood vessels and strains the pumping capacity of the heart. The formation of scar tissue in the lungs is usually a slow process, however, and many years may elapse before respiratory problems become severe. Scarring of the heart muscle itself may overload the heart's pumping capacity, creating the potential for heart failure.
The digestive tract also can be affected in scleroderma. Scarring and vascular change disrupt the smooth muscular propulsion of food and interfere with the muscular gates, or sphincters, that separate the esophagus, stomach, and intestines. Failure of the lower esophageal sphincter to close properly can result in a reflux (backfiow) of stomach acid into the esophagus. When this happens, the patient experiences the disagreeable and sometimes painful sensation known as heartburn. Involvement of the muscles of the esophagus may cause difficulty in swallowing. Digestion and nutrition may also be affected by changes In the intestinal lining that interfere with proper absorption of digested food. Weakness of the intestinal muscles disrupts the normal muscle contractions that propel food through the intestine and colon, The result may be diarrhea or constipation or a combination of both.
Diagnosis
In its early stages, when symptoms are infrequent and of short duration and findings are not specific, scleroderma is difficult to diagnose. Later, however, when skin scarring is present, the leathery character of the skin is unmistakable. There is no single test that confirms the presence of scleroderma, but several tests are helpful in establishing an early diagnosis. A careful physical examination is important for the detection of edema (swelling), unusual skin pigmentation, and heart and lung problems. A nail fold capillaroscopy--or a microscopic exam of the skin at the nail fold (the sensitive vascular skin layer at the margin of fingernails and toenails)--to reveal unusual capillaries can provide important early evidence of the disease. While conventional chest X-rays and pulmonary function tests may fail to demonstrate lung involvement, some relatively recently developed techniques--such as bronchial alveolar lavage (lung "washing" by means of a bronchoscope inserted into the lungs)-may be useful in detecting early signs of inflammation.
Blood tests for the presence of three autoimmune antibodies can also aid in early diagnosis. These antibodies, called antinuclear antibodies, react with three components of the cell nucleus: an organizing region, a chromosomal region, and an enzyme that coils and uncoils DNA. Why these structures of the cell nucleus are reactive-and why thousands of other nuclear substances are not-is unknown; nonetheless, these tests help to establish the diagnosis.
Many symptoms of scleroderma are also characteristic of other diseases, thus making them difficult to distinguish from one another. Other disorders with which scleroderma may be confused include rheumatoid arthritis, systemic lupus erythematosus, and reflex sympathetic dystrophy, a neurological disorder. An experienced physician can apply the appropriate tests and sort out the various diseases. Consultation with a rheumatologist (a specialist in connective tissue disorders) and a dermatologist (skin specialist) may be recommended.
Treatment and management
Until the cause is known, the cure for scleroderma will remain elusive. Most of the environmental causes of the disease are unavoidable unless the patient is able to make major changes in his or her life. Treatment is supportive, and practical attention to life-style is important. The patient should avoid sudden changes in temperature both indoors and outdoors, minimize stress, eliminate tobacco in all its forms, maintain optimal body weight, distribute daily food intake over four or more meals, keep alcohol intake to the equivalent of two ounces per day or less, and obtain adequate sleep. He or she can prepare for unavoidable exposure to cold by wearing extra layers of clothing over the trunk to increase blood flow and warmth to the face and extremities; some patients use battery-powered heated garments during prolonged exposure,
Specific therapies are available for reducing blood vessel constriction and improving blood flow. So-called vasodilators (drugs that block the transmission of nerve impulses that would otherwise constrict blood vessels) and drugs that work by directly relaxing the blood vessels (e.g., the calcium-channel-blocker family of compounds) are effective in improving the vascular features of scleroderma. Tissue scarring is another problem, however. At present, there are no agents capable of removing scarring after it has formed, but since most scarring follows immune-driven inflammation, controlling inflammation wherever it occurs may at least reduce scarring. Aspirin and similar nonsteroidal anti-inflammatory drugs, cortisonelike compounds, D-penicillamine, and methotreate photopheresis cytoxen have all been used in scleroderma with variable effects. Because of this variability, it is difficult to conduct controlled clinical trials that prove or disprove that a given drug is indeed beneficial.
Exercise is another method of improving blood circulation, which is vital to the tissues that are affected by scleroderma. A program of physical therapy and regular exercise, with an emphasis on stretching and limbering, is very important. Such programs not only improve the circulation to the skin (a special problem for persons who have scleroderma) but they also protect the joints from becoming stiff and immobile. In addition, a daily regimen of range-of-motion exercises of all of the affected joints helps to keep those joints flexible.
Early recognition of symptoms leads to early diagnosis and prompt initiation of treatment. In the case of scleroderma, both the disease and the medications presently used for treating it are slow-acting in nature; the sooner treatment is begun, the better the chances for a good result. Even after the diagnosis of scleroderma has been made, it is important for the patient to be alert to new manifestations of the disease. It a new symptom appears and seems to be persistent, It should be reported to the physician. This vigilance is part of the constant attempt to prevent tissue or organ damage.
Much can be done to alleviate the effects and the symptoms of scleroderma. As already noted, the symptoms very greatly from one patient to another, and the response to each therapy may also vary greatly. In addition, there are many different treatments to chose from. It is therefore extremely important that the patient work closely with his or her physician to develop an individualized treatment plan that Is optimal for the person, the stage of illness, and the degree of vascular and tissue involvement.
Emotional well-being
For patients newly diagnosed as having scleroderma an open expression of feelings is critical. Only when patients' anxieties and fears are expressed can help be obtained in resolving the many problems that can be expected. Keeping feelings inside can make thing worse, whereas sharing both triumphs and setback with family members and friends can be helpful. Trying to handle the psychological concerns without help places an undue burden on persons with scleroderma and all those close to them. "Can I cope?" is one question that many patients ask; professional counseling can be very helpful for patients, their families and their close friends. Many people who have scleroderma have found that squarely facing the realities the disease can add meaning and fullness to life that was not there previously.
Above all, persons with scleroderma should participate in their own care, trying to understand what is known about the disease and encouraging further understanding by physicians and other health professionals. In addition to having their own person support network, patients may want to seek o a support group whose members have experienced similar illness.
Progress in research
The study of the underlying processes in scleroderma continues in many laboratories around the world. dothelial cells, which form the lining of the blood vessels and can lead to vascular problems, and fibroblasts, which can cause scarring, are presently the subjects of intensive study.
One focus of current research is the possible role of immune system cells in triggering the overproduction of fibroblasts. Ordinarily, the fibroblast plays a part In the healing of wounded or damaged tissue. In scleroderma, however, the fibroblast makes too many of the molecules (collagens, fibronectin, proteoglycans) that form scar tissue; it seems to be unable to stop what is normally a short-lived and precisely regulated process. How the immune cells (lymphocytes, monocytes, mast cells) and the inflammatory cells (neutrophils, platelets) communicate with fibroblasts is not understood. Many components of the immune system-lymphokines (including the interleukins and interferons), growth factors, antibodies, and activated immune effector cells are potentially important sources of molecules that may play a role in scleroderma. Viral Interactions at the cell membrane and the activation and expression of genes at the level of the cell nucleus may be important. It is possible that environmental triggers activate viruses already present in the cell, or they may act directly on the cell, causing regulatory mechanisms to go awry. Until the normal regulation of fibroblast production and the accumulation of scar tissue are understood, the failure of the regulatory process in scleroderma will be difficult to correct.
A growth factor now being studied, called transforming growth factor beta (TGF-b; also called polyergin), has a negative influence on endothelial cells and stimulates fibroblasts to produce the molecules that form tissue. Scientists at Thomas Jefferson University, Philadelphia, supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, are now investigating the possible role of this growth factor in scleroderma Clearly, much more precise understanding of underlying processes will be needed before a treatment can be found for this major form of autoimmune arthritis.
Also being investigated are both hormonal factors and immunologic mediators before the onset of scleroderma. The proposed research design will eliminate the current dilemma of whether the variously reported hormonal and immunological abnormalities are a contributing cause or a result of the scleroderma process.
A natural occurring hormone, relaxin which is found in elevated levels during pregnancy and has biological effects which promote remodeling of connective tissues was injected into twenty-three men and women with SC was associated with softening of thickened skin, decreased frequency of Raynaud’s phenomenon and healing of skin ulcers. The double-blinded study is underway and already full. As we get the results will inform you. The studies look very promising.
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