Using the Immune System to Fight Lupus

Biologic therapy options for lupus should continue to grow

/ Author:  / Reviewed by: Dominique Brooks, M.D Beth Bolt, RPh

(RxWiki News) Only one new treatment for lupus has been approved in 50 years, but that one approval has sparked new optimism for effective therapies.

Systemic lupus erythematosis (SLE) is a complicated disease that involves many parts of the body’s immune system. It is an autoimmune disease in which the immune system functions improperly and reacts with some of the body’s own tissue.

Controlling the immune system’s activity in lupus has recently become the focus of new treatments.

A new review of biologic agents developed for lupus and other autoimmune diseases has highlighted several new therapies that have shown some promise for use in SLE.

"Ask your rheumatologist about new lupus treatments."

This review of biologic therapies for SLE was written by William Stohl, MD, PhD, of the Division of Rheumatology at the University of Southern California Keck School of Medicine in Los Angeles, CA.

The US Food and Drug Administration's (FDA) approval of belimumab (brand name Benlysta) in 2011 marked the first approval of a biologic agent for treatment of systemic lupus erythematosis (SLE) and the first new medication approved for SLE in 50 years. Several new therapies are under development and target different parts of the immune system that are active in the SLE disease process.

The reasons how and why SLE develops are not clear. What is known is that cells of the immune system target cells of the body as foreign and fight them with cells and antibodies of the immune system.

Cells that are active in this process are white blood cells called T lymphocytes and B lymphocytes. The job of T cells and B cells is to recognize foreign cells, bacteria and viruses in the body. Once they recognize a foreign invader, they start a process designed to try to eliminate it.

B cells make antibodies to neutralize the foreign cells, bacteria or viruses. Some T cells can kill infected cells and some T cells produce cytokines. Cytokines are also produced by B cells. Cytokines are proteins that act as mediators of the immune system. Some cytokines increase the immune response and call in T and B cells to create an inflammatory reaction to foreign invaders and some cytokines stop inflammation.

Because SLE is an autoimmune disease, the immune system reacts with cells of the body as if they are foreign. Stopping different parts of the immune response that are overactive in SLE has been the goal of biologic therapy. This is a delicate process because if normal immune processes are interrupted by the therapy, the body may not be able to fight infectious agents.

Rituximab (brand name Rituxan) targets B cells to decrease their number. It has been approved for use in leukemias, lymphomas and autoimmune diseases involving B cells. However, a clinical trial using rituximab in 257 SLE patients failed to show a decrease in disease symptoms after 52 weeks of treatment. There were some problems with the design of this trial. One problem was that minor symptom flare-ups were counted as failure of rituximab to control SLE so some small improvements in SLE by rituximab may have been missed. Several other clinical trials are underway with different experimental designs.

Another antibody active against B cells, ocrelizumab, was tested in 381 patients with kidney disease due to lupus. It appeared that ocrelizumab might have helped the kidney disease in these lupus patients, but serious infections caused the study to be stopped early. A third B cell antibody, ofatumumab, has not been tested in SLE patients.

An antibody that prevents B cells from multiplying, preliminarily named ASKP 1240, is currently in clinical trials in patients with moderate-to-severe plaque psoriasis. If these trials show good results, it is hoped that these antibodies will be tested in SLE patients as well.

A therapy aimed at T cells was developed that involves decreasing the immune activity of T cells to recognize foreign cells. Two antibodies, teplizumab and otelixizumab, have shown some effectiveness in studies with patients who had type 1 diabetes, another disease of the immune system. Since these antibodies work on steps in the immune process that occur early in disease, Dr. Stohl reported in his review that teplizumab and otelixizumab probably would not be useful in patients with SLE unless they could be diagnosed early in the disease.

Medications that block the action of T cells to become activated to fight foreign cells have also been developed. Two of these, abatacept (brand name Orencia) and belatacept  (brand name Nuloji)  have been approved by the FDA for rheumatoid arthritis, another autoimmune disease. Two clinical trials using abatacept in SLE patients have been reported. Abatacept did not decrease SLE disease symptoms in these studies, although there was an improvement in kidney function. Serious reactions were seen in patients getting abatacept in these studies.

Other T cell antibodies, efalizumab (brand name Raptiva) and natalizumab (brand name Tysabri), will not be considered for use in SLE because their use has been associated with the development of progressive multifocal leukoencephalopathy (PML). PML is a damaging inflammation of the brain that often results in death.

Targeting the chemicals, called cytokines, that help make B cells overactive in lupus has been the focus of other therapies. The BAFF protein works in the cytokine response and has been the target of recent immune therapies. One medication, atacicept, that interrupts BAFF activity was used in a clinical study where 49 patients were treated. Patients who took the medication had a 30 percent decrease in immune globulin proteins in the serum. Immune globulins are antibodies, so a decrease in antibodies that react against normal tissue might mean fewer SLE symptoms. However, the lowering of immune proteins made the patients susceptible to infections, and in an separate study, two of four lupus patients treated with atacicept developed pneumonia and the clinical trial was stopped.

The one biologic agent approved by the FDA for use in SLE patients, belimumab, decreases B cells by targeting the BAFF cytokine. Belimumab was proven effective to help fight the symptoms of SLE when it was given to a total of 1,684 patients in two clinical trials. A limitation of those studies was that the antibody was not given to SLE patients who had central nervous system involvement of their disease. Therefore, some of the sickest lupus patients do not know if this biologic will work for them.

Bispecific antibodies target two different parts of the immune process in one antibody. One bispecific antibody, part of which is directed at BAFF, showed good inhibition of B cell activity in lab experiments and is expected to be in clinical trials in the future.

Antibodies have also been made against two other cytokines, IL-6 and TNF. Tocilizumab (brand name Actemra) is an anti-IL6 agent that has been approved for use in rheumatoid arthritis. When it was tested in 16 patients, 50 percent of them had a decrease in their SLE disease activity. A side effect was that some patients had a decrease in their total white cell counts. Normal white cell counts are important to fight infection from bacteria and viruses.

An antibody to TNF has been used to treat SLE with some success. This treatment, however, had some serious side effects, with patients developing infection, central nervous system lymphoma and deep vein thrombosis. 

Because SLE is a complicated disease with many cells and body systems involved, there are many potential targets for development of treatments. Some have not proven effective, but some have had some success, although with some serious side effects.

Dr. Stohl concluded, “First, when one deals with a disorder as heterogeneous and complex as SLE, there should be no expectation for any single therapeutic intervention (biologic or nonbiologic) to be 100 percent effective in 100 percent of patients.” This was not intended to be discouraging, but to point out that there may be many options for different therapies that will effectively treat SLE.

The author left the reader with advice for future treatment options. He said, “Keeping an open mind and heeding the clinical data rather than being married to any preconceived notions will ultimately lead to success.”

The author disclosed associations with Eli Lilly, Novartis and Xencor.

This review was published in the December issue of Nature Reviews Rheumatology.

Review Date: 
December 27, 2013
Last Updated:
December 30, 2013