ARTHRITIS
April 15, 2006

A New Treatment for Lupus?

Elena Peeva, M.D., Liliane Min, M.D., and Peter Barland, M.D.
Dr. Peeva is Assistant Professor of Medicine and Dr. Min is a Fellow in Rheumatology at The Albert Einstein College of Medicine, New York.

Lupus, or systemic lupus erythematosus — SLE for short — is a devastating disease in which you produce antibodies that attack your cells and your tissues. This so−called autommune disorder can affect the joints, kidneys, heart, lungs, brain, blood and skin. It is chronic, staying with people throughout their lives and flaring up unpredictably.

Joint aches, fever, fatigue, and skin rashes are among the most common symptoms of lupus. Because these symptoms have so many possible causes and because they tend to vary from person to person and from time to time, SLE is often misdiagnosed even though it is fairly common, affecting about 1.5 million Americans, particularly adult women and African Americans.

SLE is often misdiagnosed even though it is fairly common, affecting about 1.5 million Americans, particularly adult women and African Americans.

No one knows exactly what causes SLE or why some people get it and others don't. It is thought to have a genetic component and is not contagious. As medical science learns more and more about how the disease works, there is increasing hope for better and safer drug treatments.

What's an Autoimmune Disease?
Autoimmune diseases occur when the immune system responsible for our ability to fight infections loses the ability to tell the difference between an outside health threat, such as a bacterial infection, and the body's own healthy tissue. As a result, the body's immune system attacks its own healthy tissue and organs just as it would attack an invading bacteria, virus or foreign substance.

The immune system is made up of a vast array of different kinds of cells. We know that SLE particularly affects one part of the immune system -- B cells. B cells identify viruses, bacteria and other threats to the body's health and then produce antibodies to attack and destroy those specific invaders. SLE causes B cells to become hyperactive and produce antibodies to healthy tissue. This leads to different kinds of damage, depending on which systems and organs are affected by the antibodies.


The SLE Drug Arsenal
The current arsenal of drugs available to doctors to treat SLE is inadequate. Safer and more focused treatments are desperately needed. Currently approved medications merely lessen the inflammation and tissue damage caused by the hyperactive B cells or suppress the entire immune system. The NSAIDS (non-steroidal anti-inflammatory drugs), and low to moderate doses of steroids are examples of drugs that suppress the inflammation caused by the self-directed antibodies while anti-malarials, high dose steroids and cytotoxic agents normally used in cancer chemotherapy are examples of drugs that suppress most of the different arms of the immune response.

We know that SLE particularly affects one part of the immune system, B cells. B cells identify viruses, bacteria and other threats to the body's health and...produce antibodies to attack and destroy... invaders.

Because these therapies, especially high-dose steroids and cytotoxic drugs, suppress the entire immune system, they can leave the body vulnerable to serious and even life-threatening infections. Not everyone is helped by these drugs. Some SLE sufferers respond poorly or not at all.

Two categories of drugs currently under study are designed to target B cell activity and leave the rest of the immune system to protect the body. One of these, B cell-depleting drugs, reduces the number of B cells and interferes with the functioning of those that remain. The other, called an anti-cytokine drug, blocks the action of B cell-stimulating cytokines, proteins within the immune system that regulate B cells and other parts of the immune response. Let's take a look at these studies and what they tell us about these two categories of drugs, so far.

B Cell-Depleting Therapies
There are two B cell-depleting drugs now being tested for use against SLE -- rituximab and epratuzumab. It is encouraging that rituximab has a good track record in treating another autoimmune disease, rheumatoid arthritis and non-Hodgkins lymphoma, a type of cancer that originates in B cells. Epratuzumab has also been looked at as a treatment for both non-Hodgkins lymphoma and SLE.

Both rituximab and epratuzumab have the advantage of reducing the number of B cells without affecting other cells that play a key role in the immune system.


B Cell-Depleting Therapies vs. SLE - What We Know Now

Rituximab
A groundbreaking 2002 pilot study provided the first evidence that rituximab can be safe and effective against SLE. Six women with SLE were given a combination of rituximab, the anti-cancer drug cyclophosphamide and the corticosteroid prednisolone. The women's symptoms -- inflammation of the lining of the lungs, heart and other internal organs (serositis); joint pain and arthritis; fatigue; and skin rashes -- improved. The number of B cells was reduced for all of the women, for periods ranging from a few months to nearly a year. The disease went into remission for an average of 12.6 months without any additional treatment with rituximab. Infection is a common problem with immunosuppressant drugs, and this group experienced a total of nine infections, but none was serious and all were successfully treated with antibiotics.

A second study of lupus patients treated with rituximab or rituximab and cyclophosphamide for four years found that after 19 months, patients' fatigue, joint pain, arthritis, serositis, kidney problems, thrombocytopenia (lowered blood platelet count) and anemia all improved. During nine months of follow-up, no serious infections developed.

Another trial of rituximab, used along with other drugs, found that of the 17 SLE patients who completed the study, 11 achieved a significant reduction in B cells and all showed improvement in two to three months which lasted twelve months or more. Seven people in this study suffered from kidney inflammation caused by SLE. One of these improved to the point of a complete return to normal kidney function. None of the group died or had any serious infections.

In a separate pilot study, rituximab was given to 11 people who had not been helped by conventional immunosuppressant drugs. All 11 received infusions of rituximab along with methylprednisolone, a steroid. Eight of the 11 completed the infusions and 6 of these saw a dramatic reduction in their B cell count and significant improvement in SLE symptoms. Two went into long-term remission.

Lupus can sometimes attack the nervous system producing headaches, seizures, depression and stroke. Scientists have named this disorder neuropsychiatric lupus. Rituximab also shows promise in controlling this disorder, one of the most serious and difficult to treat forms of SLE.


Epratuzumab
The other potential drug to treat SLE, epratuzumab, has also delivered significant improvement in symptoms in one small study. B cell counts in this group declined by 60% after four weeks of treatment and 40% after six months. The infusions themselves caused no significant problems, and only two subjects developed mild infections that were easily treated.

Anti-cytokine Therapy
Drug treatments for lupus which target cytokines, the proteins within the immune system that regulate B cells and other immune system components mentioned earlier, have focused on one particular cytokine, called BlyS or BAFF, known to stimulate B cell activity. There is evidence that this cytokine plays a key role in SLE., Studies of an anti-cytokine drug that neutralizes human BlyS. (belimumab) are ongoing and it is too early to determine its safety and effectiveness.

Conclusions
People with lupus/SLE have reason to be hopeful about the promise of these treatments but some hurdles remain. In a few cases, subjects taking the experimental drug rituximab developed antibodies to the drug itself, a development which would limit its effectiveness and perhaps cause further complications.

Another area of concern is the effect of these drugs on children with SLE because the drugs (particularly rituximab) significantly lower children's immunoglobulin levels, the antibodies needed to fight infection. Giving children IV immunoglobin may solve this problem.

Bit by bit we are making progress in our efforts to understand and treat lupus/SLE. Along the way we may also find the key to dealing with other autoimmune diseases. Drugs designed to reduce B cell activity by reducing the number of B cells themselves have shown the most promise. Even though the results so far have not been encouraging regarding the usefulness of drugs to control the cytokines stimulating B cells, this research is still in its infancy.
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