Investigational Treatments for Lupus
Before any drug can be approved for use as a medical treatment, it must undergo a series of research studies, called clinical trials, to determine if it is safe and effective. Clinical trials are done in several phases, and this period of testing can take as many as 15 years. Sometimes, as part of the clinical trial design, not all of the volunteers receive the investigational drug being studied. Instead they are given already approved medications or a placebo (a chemically inactive compound, sometimes referred to as a "sugar pill").
People with serious illnesses who are not responding to already available treatments sometimes enroll in clinical trials to gain access to medical treatments that could be helpful. However, there is no guarantee that an investigational product will provide any benefit, and of course there are always risks with all drugs, whether investigational or well-known.
Many medications and drug products, both old and new, are now being studied in people with either cutaneous or systemic lupus. We have categorized these drugs depending upon their mechanism of action or how they were developed.
Biologics are genetically engineered compounds that interfere with the action of cells involved in the immune response. Monoclonal antibodies are considered biologics, but we have included them in a separate category.
Abatacept (Orencia®) acts like an antibody, with the job of ridding the body of harmful agents. It attaches to a protein on the surface of T cells. By doing so it prevents the activation of the T cells, blocking both the production of new T cells and the production of the chemicals that destroy tissue and cause the symptoms and signs of rheumatoid arthritis (RA). Abatacept has been approved for RA because it slows damage to bones and cartilage and relieves arthritis symptoms.
LJP 394 (Riquent™) may be able to block the production of the anti-double-stranded DNA (dsDNA) antibodies believed to promote lupus kidney disease, without suppressing the entire immune system or causing adverse side effects.
CD154 (CD40L) was designed to bind to a surface protein called CD40, which normally appears briefly on activated T cells. This binding action interferes with lymphocyte activation.
Atacicept (TACI-Ig) was designed to interrupt several stages of B cell development and may inhibit cells responsible for making antibodies.
Prasterone (Prestara™), a synthetic form of the mild male hormone, dehydroepiandrosterone (DHEA), is being studied as a treatment for corticosteroid-induced osteoporosis in women with lupus.
Triptorelin, a type of hormonal therapy developed to treat advanced prostate cancer, is being studied for the protection of the ovaries in women who are receiving cyclophosphamide therapy for lupus.
Immunosuppressives (Immune Modulators)
Leflunomide (Arava®) was developed to treat rheumatoid arthritis. It also appears to help with the arthritis caused by lupus. A disease-modifying anti-rheumatic drug, it works by stopping the body from producing too many of the immune cells responsible for swelling, inflammation, stiffness, and joint pain.
Thalidomide (Thalomid®) is an oral medication that has been increasingly accepted as a second-line therapy for the types of lupus that affect the skin. It has been shown to greatly improve cutaneous lupus even in people who have not responded to numerous other treatments.
Monoclonal Antibodies (mAbs)
The monoclonal antibody approach has been used to target both B and T lymphocytes, the white blood cells responsible for autoantibody production in lupus.
Rituximab (Rituxan®, anti-CD20) targets a specific protein known as CD20 that appears on the surface of B cells. Rituxan binds to CD20 and is believed to work with the body’s own immune system to attack and kill the marked B cells.
Epratuzumab is an anti-CD22 antibody designed to bind to the CD22 antigen on B cells and may control lupus disease by depleting B cells and by controlling or modulating B cell function.
Anti-IL6. Elevated levels of Interleukin 6 (IL-6) in blood, urine, and kidneys have been seen in people with active lupus. Treatment with anti-IL-6 may be able to suppress inflammation induced by autoreactive B cells and autoreactive T cells.
MEDI-545 (anti-interferon-alpha) targets interferon-alpha by binding to multiple INF-alpha subtypes seen in the serum of people with lupus. Levels of interferon-alpha are elevated in active lupus and other autoimmune disorders, and may be associated with disease activity.
Eculizumab (anti C5a) was developed to inhibit the complement component C5. Complement is a collection of proteins that can become overactive or misdirected by autoantibodies in a disease like lupus.
Anti-TNF therapies (Enbrel®, Humira®, Remicade®) are primarily used in RA. Although these drugs have been found to cause drug-induced lupus in some people (reversible when the medicine is stopped), they have also been shown to be effective in treating the arthritis that can occur in lupus.
Anti-IL10 is an antibody that blocks the activity of IL10, which is important in the activation of B cells in lupus.
Organ Transplant Anti-Rejection Drugs
Some drugs that were developed to stop the body from rejecting a transplanted organ have been found to help certain kinds of lupus. They mainly target the white blood cells that initiate and increase inflammation and tissue damage in the joints, skin, and kidneys of people with lupus. Side effects of these medications range from headaches, anemia, and low white blood cell counts to liver disease and increased risk for infection and cancer.
Mycophenolate mofetil (CellCept®), designed to help prevent rejection after organ transplants, is proving effective in treating lupus kidney disease.
Prograf® is used to help prevent organ rejection in individuals receiving liver, kidney, or heart transplants and works by interfering with T cell function.
Cyclosporine (cyclosporin A, Neoral®, Sandimmune®) was the first immunosuppressive drug that allowed the body to regulate T cell activity without causing too much damage to the immune system. Cyclosporine enabled routine organ transplantation that until then had only been done experimentally. Cyclosporine is also used alone or with methotrexate to treat the symptoms of RA in people whose symptoms are not relieved by methotrexate alone, and to treat psoriasis (a skin disease) in people who have not been helped by other treatments.
Sirolimus (rapamycin, Rapamune®) is an immunosuppressive used in combination with other medications to prevent rejection of kidney transplants, and works by suppressing the body’s immune system.
Stem Cell Transplantation
Both hematopoietic and autologous stem cell transplantation have been used in Europe and in the U.S. to treat autoimmune conditions that have not responded to any other treatments. Both procedures are currently in clinical trials for severe lupus. Stem cell transplantation is a high-risk procedure. Although it can be effective, and symptoms of lupus may become more easily controlled, some people will experience a recurrence of their lupus over time.
Topical Immunomodulators (TIMs)
This new class of drugs has been developed to treat serious skin conditions without the side effects found in corticosteroids.
Tacrolimus (Protopic™) and pimecrolimus (Elidel™) are creams that have been shown to suppress the activity of the immune system in the skin, including the "butterfly" rash, subacute cutaneous lupus erythematosus, and possibly even discoid lupus skin lesions.
Frequently Asked Questions
Has the use of Imuran been linked to cancer (particularly sarcoma) in those with lupus?
Many patients are concerned about the risk of cancer after having lupus for a long time, or after being treated for many years with immunosuppressive drugs such as Imuran. A study including almost 10,000 patients with lupus found that the risk to develop cancer is mostly related to non-Hodgkin's lymphoma, which affects the lymph system, lung cancer, and liver and bile duct cancers. Smoking increases the risk for cancer in lupus patients, just as it does in other people. So far, there is no good evidence for a link between Imuran and cancer in lupus patients.
I have done so much research on the effects of Imuran on fertility and I can't find a definitive answer. Most sites speak of the MALE fertility and not the female and how it is affected. These sites speak about pregnancy only, not the actual effects of this drug on fertility of a female. I am 40 years old and need to start Imuran or CellCept to get off high steroids. I do not have children and wish to know the answer to this ongoing question.
There is no study that can definitively answer the question about azathioprine (Imuran) and infertility. Many lupus patients do get pregnant after taking azathioprine, and it is not thought to be a major issue with this agent. CellCept falls in a similar category; however CellCept should definitely be stopped at least 90 days before attempting to conceive. Although most doctors are not enthusiastic about continuing azathioprine during pregnancy if this can be avoided, it has been used safely in some patients throughout pregnancy, and there are fewer worries if a patient becomes accidentally pregnant on azathioprine.
Can you please tell me about the efficacy and use of Rituximab in people with Systemic Lupus? I have had a recent severe flare which included brain involvement. We hope this treatment will help with my CNS symptoms.
Rituximab is approved by the FDA for use in rheumatoid arthritis. Because it acts to suppress B cells, (a kind of white blood cell that has an important role in lupus), it makes sense that this agent is currently being tested now to see whether it is appropriate for use in lupus patients. There are some reports about the use of Rituximab for some patients with lupus or similar conditions, but it is not yet known how effective this is, we must wait for the results of current studies. It is never optimal to be taking treatments that are not fully studied for your condition. On the other hand, because there have been no new treatments approved specifically for lupus in decades, it is not unreasonable for doctors to try some of the new immune system suppressors that seem to work in rheumatoid arthritis, especially in patients with serious conditions for whom the more usual treatments are not working. However, all medicines that suppress the immune system have potentially serious side effects. Only your doctors can determine whether the next step for you should be the use of this kind of treatment.