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The State of Lupus Research

 

Introduction

Lupus erythematosus-whether systemic,involving any part of the body (SLE), or discoid (cutaneous), involving only the skin (DLE)-is a chronic inflammatory disease that can affect variousparts of the body, especially the skin, joints, blood,and kidneys.

Currently there are few drug therapiesspecifically approved for lupus by the Food and Drug Administration (FDA). All of the following therapies are investigational and are in various stages of research and/or clinical trials.

How Lupus Affects the Body

The body's immune system normally makes proteins called "antibodies" to protect the body against foreign materials, or "antigens," such as viruses and bacteria. In an autoimmune disorder such as lupus, the immune system loses the ability to tell the difference between its own cells and tissues and the unwelcome antigens. The immune system then makes antibodies directed against "self." These "autoantibodies" react with the self antigens to form "immune complexes," which build up in tissues and can cause inflammation, injury to tissues, and pain.

The course of lupus appears to depend heavily upon the activity of autoimmune "lymphocytes," including B cells that produce autoantibodies, and T Cells which regulate the B cells in the development of the immune response.

Current therapies for lupus try to suppress the entire immune system and to reduce inflammation. The aim of the future is to determine the specific mechanisms of inflammation and autoimmunity, in order to better target therapies to what is going wrong, without suppressing the whole immune system. Medical research is ongoing on the treatments listed here.

 

Biologic Agents and Immune-Suppressants

DHEA (PrestaraT)

It is thought that androgens (male hormones) may reduce lupus disease activity. DHEA is a mild male hormone, which appears in abnormally low levels in persons with lupus. Studies have shown that DHEA was helpful in treating mild to moderate lupus, and may be particularly useful for persons experiencing cognitive dysfunction and fatigue. Study results also showed a significant increase in bone density.

The FDA did not approve DHEA for use in lupus, on the basis of studies that tested its ability to reduce disease activity. However, the agency has approved ongoing studies to further test the product's safety and effectiveness in protecting the bones.

LJP 394

Some persons with lupus produce antibodies to double-stranded DNA (dsDNA). This response is believed to promote lupus kidney disease, which is one of the more serious complications of lupus. The drug candidate LJP 394 has been developed to lower the levels of these antibodies and is currently being studied to see whether it can reduce kidney flares.

Antibody to CD40 Ligand

Research in this area has focused on proteins located on B cells and T cells that are important for the stimulation of these cells. White blood cells help fight off foreign intruders, but can be overactive in lupus. One way in which this happens is that a T cell protein known as CD40L might over-stimulate a B cell protein known as CD40. By blocking the communications between these proteins, it may be possible to help correct the hyper-activity of the immune system which is characteristic of lupus. Anti-CD40L antibodies for SLE are proteins much like those our bodies produce, but they are designed to target CD40L and block its increased activity in lupus. The concept here is that autoantibodies are not necessarily bad in the right dose and with the right target. Unfortunately, these drugs are not being actively developed for lupus anymore, because of a significant risk of blood clotting problems in previous trials. It is not yet known whether these blood clotting problems could be prevented and if these drugs could be safely used in patients.

BlyST

Several companies are now studying this new treatment strategy for lupus. This antibody targets another B cell-regulating protein which is found on a different white blood cell called a monocyte. The product that is furthest along is an antibody to BlyS (short for B Lymphocyte Stimulator) and seems to control how reactive a B cell might be to a T cell. The purpose of this new medication is to try and dampen that process.

Bromocriptine (Parlodel TM )

This molecule has been shown to suppress the secretion of prolactin, and to suppress circulating prolactin. Prolactin, or PRL, is believed to be involved in the onset and progression of lupus. (Prolactin is best known as a hormone that promotes and supports lactation in mammals.) In studies, prolactin was found to be necessary to maintain normal immune function. Therefore, bromocriptine's ability to suppress both prolactin and circulating prolactin might lead to suppression of the immune system and autoimmune disease.

High Dose Intravenous Immunoglobulins

One way to regulate, rather than suppress, the body's immune response is by manipulating the autoantibodies. Giving high doses of immunoglobulins (a mixture of normal antibodies) intravenously, known as IVIg or IVIG antibodies, has been used for lupus kidney disease and other serious manifestations of lupus for ten years.

Mycophenolate mofetil (CellCept®)

Mycophenolate mofetil is approved to prevent rejection after organ transplants. This is important to persons with lupus since some people with serious kidney disease may require a transplant. Physicians have now begun to use CellCept to control the activity of various rheumatic diseases. Anecdotal reports suggest that it might be effective in lupus kidney disease. There is an ongoing FDA-sponsored trial to compare mycophenolate mofetil with Cytoxan for this purpose.

Cyclosporine (Sandimmune®, Neoral®)

This potent immunosuppressive drug is frequently used in the therapy of autoimmune diseases, including systemic lupus. Small, uncontrolled studies have shown significant improvement in disease activity and consistent reduction in corticosteroid dosage, often by as much as 50 percent. Toxicity does occur, especially in individuals with hypertension and kidney impairment, but usually reverses as the dose is reduced or an antihypertensive agent is added.

Thalidomide (Thalomid®)

Thalidomide, developed as a sleep aid in the 1950s, has been increasingly accepted as a second-line therapy for the types of lupus that affect the skin, producing marked improvement even in patients who have not responded to numerous other treatments.

Rituximab (Rituxan®)

Anti-CD20, known as rituximab, or Rituxan, is a new genetically- engineered monoclonal antibody that targets a receptor called CD20, found on some B cells. The antibody marks the B cells for destruction by the immune system, after which new B cells are generated by stem cells. Stem-cells and B cells bearing antibodies are spared by Rituxan, since they lack the CD20 antigen.

 

Processes to Cleanse the Immune System

Apheresis, or Plasmapheresis

This is a safe but expensive and labor-intensive procedure, whereby plasma is separated from whole blood in order to remove undesirable substances from the blood. Some of the reasons one might undertake plasmapheresis for systemic lupus are to remove circulating immune complexes and autoantibodies and to improve the functioning of suppressor cells and the cells that kill bacteria. Anecdotal reports have suggested that this treatment might be helpful for individuals who are quite ill.

Hematopoietic Stem Cell Transplantation

In this procedure, stem cells harvested from the person are "cleansed" and returned to repopulate the bone marrow. It is thought that they might also contribute to organ repair over the following years. The underlying concept is based on the theory that, for most people, lupus is not simply an inherited disease. That means that the body's primitive, immature, and undifferentiated "stem" cells are not inherently "lupus" stem cells. The disease develops because a person carries a genetic predisposition to lupus, and certain factors in their environmental and hormonal make-up compound that risk, allowing the disease to come forth. Therefore, if a person's stem cells are allowed to develop in a safer environment, a more normal immune response might emerge

 
 

 

 
 

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