Naomi F. Rothfield, researchers at the University of Connecticut Health Center's division of rheumatic diseases, provided this medical outline:
"The fundamental cause of scleroderma is unknown at the present time, but medical researchers are making strides in diagnosing and treating it. There are three main components of the disease: vascular, fibrotic, and autoimmune.
"Vascular component. The hallmark of the vascular component of scleroderma is a set of physiological changes known as the Raynaud's phenomenon. This phenomenon is a blanching of the body's extremities when exposed to the cold, followed by a skin-color change to purple-blue and/or red. It is generally the first manifestation of the disease.
"There are a couple of secondary vascular symptoms. The constant recurrent constriction of the small vessels leads to pulmonary hypertension. Associated gastrointestinal problems can also occur. Constrictions of the small blood vessels around the nerves that control the muscles of the esophagus can lead to problems when swallowing food. Patients may have a sensation of choking, with food getting trapped in the upper-middle chest. In rare instances, the decreased motility may involve not only the esophagus but also lower segments of the gastrointestinal tract. The slow progression of food through the lower tract may allow excessive growth of bacteria and produce diarrhea and abdominal cramps.
"Fibrotic component. Fibrosis is a process that follows chronic inflammation in the progression of scleroderma. Fibrotic tissue is a scar tissue, which is thick and rigid because of excess accumulation of the protein (collagen). Initially, the excess of collagen produces thick, tight skin and resultant pain and burning. This problem is easily diagnosed and requires no laboratory or special testing.
"Fibrotic changes within the lung tissue may parallel the changes in the skin, giving rise to symptoms of chronic inflammation. Using high-resolution computed tomography (CT) of the lungs, researchers can evaluate thin sections of the lungs for early signs of inflammation. (A discussion of this work, along with CT images showing the effects of scleroderma, are available online from research group at at Los Alamos National Laboratory.) Repeated testing of the lung function allows the doctor to follow the response to treatment.
"Autoimmune component. The immune system is designed to attack foreign proteins (viruses, bacteria, parasites, etc.). To do this, it must distinguish 'self' (the substances of the body) from 'non-self' (substances from other sources). When this fine distinction is no longer made by the immune system, the cells that mediate immunity (the B and T cells) are directed toward self proteins, or components of them. Autoimmunity is the term used to explain this reactivity to self by the immune system; scleroderma is an autoimmune disease. Most of the patients suffering from scleroderma have antibodies (produced by the B cells) that bind self components. There are two main kinds of antibodies involved in scleroderma, anticentromere antibodies, and anti-topoisomerase-I antibodies.
"The treatment of scleroderma follows the various aspects of the disease as just described. The change in skin color associated with Raynaud's phenomenon indicates a dramatic loss of the normal blood supply to the fingers, which should be avoided or treated immediately. A warm bath is one of the fastest and most effective ways to warm the fingers. In emergency situations, the fingers can be placed under the warmer parts of the body, such as the armpits and the abdomen. If the Raynaud's phenomenon is not treated, the patient may develop digital ulcers or sores, requiring amputation of the finger tips in extreme cases.
"Changes in daily habits that preserve the body heat--such as dressing in multiple layers of clothing and wearing hats and scarves--can help prevent Raynaud's phenomenon. Treatment of the disorder centers on the mechanism that causes it: when exposed to cold, small blood vessels contract. Hence, Raynaud's phenomenon is treated with medications that produce vasodilatation (expansion or opening of the blood vessels). The most common vasodilators used in Raynaud's phenomenon go by the commercial names Procardia XL, Altace, Norvasc, Trental and Cardizem. Sometimes the skin ulcers associated with Raynaud's phenomenon may become infected and require antibiotics.
"For symptoms associated with pulmonary artery problems, the most appropriate drug treatment is Procardia XL. Pulmonary hypertension may produce no symptoms, so periodic echocardiograms should be performed to estimate the pressures within the pulmonary artery. It is essential that people suffering from scleroderma stop smoking to lessen the risk of pulmonary hypertension. When a patient is diagnosed with pulmonary hypertension, he or she should receive anticoagulation medications and should reduce physical activities (thereby decreasing the body's demand for oxygen). If the pulmonary pressure continues to increase, the patient may need to receive nasal oxygen.
"Gastrointestinal problems can be treated with antacid medications such as Maalox, Mylanta, Tums, Tagamet, Pepcid, Zantac, Prilosec or Prevacid. To prevent late complications, people experiencing gastrointestinal symptoms should stick to a soft diet, abstain from alcohol and other stomach irritants (including hot and spicy food) and discontinue smoking. Radiological studies of the esophagus may be deemed necessary if the symptoms of heartburn worsen, or if there are new symptoms of choking or the sensation of food stuck in the chest. If bacterial overgrowth occurs, it may be necessary to start a course of antibiotics for one or two months every six to 12 months, as deemed necessary by a doctor. The most commonly used antibiotics are erythromycin, tetracycline and doxycycline.
"For the fibrotic component of scleroderma, part of the treatment focuses on skin fibrosis. At the first stages of skin tightening on the fingers, hands and legs, occupational and physical therapy are important for preventing and ameliorating irreversible contractures of the fingers. Protecting the hand and fingers with gloves while doing physical activities (washing the dishes or gardening, for instance) prevents trauma that may break the skin and slow the healing of finger ulcers. Oral hygiene may become difficult if the facial skin becomes tight. Several medications can be administered if the skin-tightening progresses quickly or involves the chest and abdomen. The most commonly used drugs are Cuprimine (D-penicillamine) and Methotrexate. No drug has been shown to revert the skin hardness effectively and consistently; on the other hand, there are numerous anecdotal reports of spontaneous remission. A promising new drug, Relaxin, is currently being tested. Any therapy for skin fibrosis should be carefully evaluated and followed by the primary rheumatologist. All of these drugs also require frequent laboratory monitoring for toxicity and secondary effects.
"The skin tightening associated with scleroderma may occur rapidly, producing a sudden increase in the pressure under the skin and a rubbing of the muscles and tendons below the skin. This condition may lead to inflammatory muscle disease (myositis). In these cases, a blood test will show elevated levels of muscle enzymes. Such symptoms demand an immediate cessation of exercise. Low-dose oral steroids are used to treat myositis.
"Fibrosis also affects the lungs. Once doctors detect, or even suspect, the presence of an inflammatory lesion, the present consensus is that treatment with the oral drug Cytoxan is justified, but the proper dosage has not yet been established in double-blind studies. In our experience, it can be started at 150 milligrams per day, quickly lowered to as little as 25 milligrams per day and continued for less than one year. Patients on Cytoxan require careful monitoring of their blood and urine. Other drug treatments for lung fibrosis include Cuprimine and Methotrexate, but trials to test their efficacy in reverting early lung inflammation or late fibrosis remain to be done."
Nicole Gardner of the Scleroderma Research Foundation has made some additional information available to Scientific American:
"The past year has yielded research advances that hold the promise of a cure for scleroderma. And it isn't decades away; it's just around the corner. This work is being supported by the Scleroderma Research Center, which funds two collaborative research center, one at Johns Hopkins University and one at the University of California, San Francisco.
"The following segment from the Scleroderma Research Center's 'End of the Year Research Program Update' describes some of this work:
"Thanks to the unprecedented success of our research centers, 1996 was the most productive and exciting year of scleroderma research ever. We have achieved amazing breakthroughs in both understanding Scleroderma as well as targeting disease interventions which will soon allow us to treat scleroderma effectively and, for the first time, prevent people from dying of this devastating disease."One of the most noteworthy results from the east coast Center came from a study conducted by Livia Casciola-Rosen, Fred Wigley and Antony Rosen of Johns Hopkins University; their work was published in the January 6, 1997 issue of The Journal of Experimental Medicine ("Scleroderma Autoantigens are Uniquely Fragmented by Metal-Catalyzed Oxidation Reactions: Implications for Pathogenesis." Vol. 185, No. 1, pages 71-80). The following is a brief summary of the results.
"Our West Coast Center, located in the San Francisco Bay Area, is focused on the goal of building a disease model of scleroderma and providing important insight into the collagen overproduction problem which causes so much of the organ damage associated with this disease. Perhaps the most important insight has been into the nature of fibrosis itself. Conventional theoretical constructs have long held that the rampant overproduction of collagen endemic to scleroderma is directly regulated by the immune system. Our research strongly suggests that fibrosis is a self-sustaining process built on an autocrine loop--a self-feeding positive feedback cycle. This breakthrough has led to the discovery of specific antigens which can interrupt and reverse the fibrosis process in vitro. The next vital step before therapeutic development is now in process--developing and testing in vivo mouse model fibrosis intervention.
"...As a result of the work now being done at the East Coast Center, it is now only a very short time before Raynaud's syndrome will be directly treated and whatever role it plays in the pathogenesis of scleroderma mitigated.
"Our investigators have also attempted to identify autoantibody responses which might constitute the body's memory of the early onset of scleroderma and therefore identify important elements of the disease's initial trigger. In groundbreaking investigation, researchers have found several key autoantibodies which cluster at the same cellular location and are unique to scleroderma. They have further discovered that these autoantibodies are sensitive to fragmentation by reactive oxygen species, generated when cells are deprived of oxygen and then receive it again, as occurs with Raynaud's syndrome. The role of certain metals in the cleavage of these autoantibodies in the nucleolini of cells holds great promise in identifying the environmental factors which lead to disease development, as well as pointing the way to locating the gene involved in its predisposition.
"...With our new insight into the disease process, there is no longer any doubt whether scleroderma can be conquered. The only question is how quickly we can grow our funding base to develop these exciting opportunities. We are growing increasingly confident that, if we can fund our research centers at adequate levels, the Foundation's research approach can lead to a cure for Scleroderma within a decade.
"Johns Hopkins scientists studying scleroderma may have identified the unique molecular footprints on the biochemical trail leading the immune system to attack its own tissue. The insight provides major clues into the early stages of the disease and provides a new way to study its development, which may lead to earlier diagnosis and improved treatment, and aid research into other autoimmune conditions, the Hopkins scientists say.
"Scleroderma causes blood vessels to narrow and become irritated; the repeated slowing, stopping and restarting of blood flow produces toxic oxygen products that damage tissues. To investigate how the tissue is damaged and how the immune system is activated, Hopkins scientists used antibodies from the blood of 60 people with scleroderma. They studied the effects of the toxic oxygen products on the specific tissue molecules recognized by the immune system in scleroderma.
"Results show that exposure to toxic oxygen products causes certain tissue molecules to break apart, but only in the presence of abnormal amount of iron, copper, zinc and other metals in the body. Fragmentation of these molecules exposes hidden parts of the molecules that the immune system has never seen. The immune system 'sees' the newly exposed parts as foreign invaders and produces the antibodies against them. This produces the symptoms of scleroderma.
"Scientists pieced together the likely chain reaction activating the immune system by analyzing the circumstances under which the fragments are produced. This reaction centers on the cell's nucleolus, in which both the fragmented molecules and the abnormal amounts of metals become concentrated.
"'The autoantibodies (antibodies produced by the immune system that attack the body's own tissue) are a long-lived immunologic memory of this unique reaction," says Antony Rosen, the study's senior author and an assistant professor of medicine, cell biology and anatomy. 'Our novel approach is to use autoantigens (the hidden molecules attacked by the immune system) and autoantibodies as molecular tools to visualize what happens at the start of the disease and to recreate and probe the original circumstances. It serves as a mirror of what is driving the immune system and as a memory of the event that switched on the immune system.'
"Clinical studies are underway. Hopkins scientists are investigating what causes the abnormal cellular metal accumulation and whether the abnormal metals cause the blood vessels to narrow. The team is also studying drugs that might prevent the autoantigens from being fragmented."