"The Treatment of Scleroderma, 2004 and Beyond"

by Richard Silver, M.D., Professor of Medicine and Pediatrics, Medical University of South Carolina, (originally published in "Scleroderma Voice," 2004 #2)

The ultimate goal of scleroderma research is to discover the cause(s) of and the pathogenic pathway(s) leading to localized and systemic scleroderma.

Although much progress has been made in our understanding of certain aspects of scleroderma, the underlying cause and pathogenesis remains unclear and, thus, prevention and cure remain a quest rather than a reality. Nevertheless, significant progress is being made and patients, now more than ever before, can expect to live a longer and better quality of life.

Disease-specific therapy versus organ-specific therapy

Treatment for scleroderma can be divided into disease-specific therapy and organ-specific therapy. Disease-specific therapy is still in the developmental stage. Any such treatment must address each of the three cardinal features of scleroderma: the vascular system, the immune system, and activated fibroblast (a cell that makes collagen). For now, no single drug addresses all three of these important elements, but that is the goal for which those of us in the scleroderma research community strive.

Treating Vascular Abnormalities

An increasing number of drugs are aimed at ameliorating the vascular abnormalities of systemic sclerosis, such as calcium-channel blocking agents, angiotensin-converting enzyme (ACE) inhibitors and prostaglandin analogues.

Within the past few years three new drugs (Flolan, Tracleer, and Remodulin) have been approved by the FDA for the management of pulmonary arterial hypertension, a potentially lethal vascular complication of systemic scleroderma. More are under study now.

Other drugs, such as sildenafil (Viagra) and related compounds, may also prove to be effective in the management of various vascular complications of scleroderma, e.g. digital ischemia and pulmonary hypertension.

Immune Suppression Treatments

Since autoimmunity is believed to play a role in the pathogenesis of scleroderma, a number of drugs and treatments designed to suppress the immune system are currently under investigation.

The Scleroderma Lung Study, funded by the National Heart Lung and Blood Institute (NHLBI), is designed to test the hypothesis that cyclophosphamide (Cytoxan) will improve lung function in scleroderma patients with active lung inflammation. This study has completed enrollment and early data analysis is anticipated by the end of this year.
The National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS) branch of the National Institutes of Health (NIH) is sponsoring another multicenter study of immune suppression, the Oral Type I Collagen for Relieving Scleroderma Study, designed to determine whether or not exogenous (occurring outside the body) collagen can induce tolerance in scleroderma lymphocytes (a type of white blood cell), thereby reducing the degree of immune activation and subsequent fibrosis. Another powerful immunosuppressive treatment, autologous stem cell transplantation, is currently under study in both the U.S. and Europe.

Other Treatment Approaches

One of the most exciting areas of therapeutic research is the interest in biological agents to reduce the quantity of collagen produced by scleroderma fibroblasts. Antibodies designed to bind to and inhibit growth factors have been synthesized and administered to patients in early clinical trials. Thus far, preliminary studies suggest this therapy is safe, but it remains to be determined whether or not such drugs will prove to be effective treatments for scleroderma.

Another approach currently under study is to administer drugs that block receptors on the cell surface of fibroblasts and other cells believed to play important roles in the pathogenesis of scleroderma. One such study, BUILD2 (Tracleer, Actelion), is currently recruiting study participants.

Progress in Managing Organ-Specific Complications

While we await a disease-specific treatment, it is important to appreciate the incredible progress made in the management of organ-specific complications of scleroderma.
For example, the introduction of ACE-inhibitors for the prevention and treatment of scleroderma renal crisis was a major breakthrough for scleroderma patients. Newer drugs may prove to have a similar impact on preventing death from pulmonary hypertension.

The proton pump inhibitors that suppress gastric acid secretion not only reduce the severity of gastro-esophageal reflux but may also prevent complications such as stricture formation and Barrett’s esophagus, a pre-malignant lesion.

This Is An Exciting Time

For those of us who manage patients with localized and systemic scleroderma, this is indeed an exciting era. At no time has there been more interest in the development of new and novel therapeutic agents for scleroderma. While the quest toward cure continues, we are confident that significant disease-specific treatment will be developed.

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