Current treatments of s-l-e

by Nathan Wei, MD, FACP, FACR

Nathan Wei is a nationally known board-certified rheumatologist and author of the Second Opinion Arthritis Treatment Kit. It's available exclusively at this website... not available in stores.

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder.

Information from the Arthritis Branch, National Institutes of Health, Bethesda, Maryland.

It causes fatigue and joint pain and can adversely affect nearly any internal organ. It also increases the risk of cardiovascular disease. A recent Canadian study in the journal, Arthritis and Rheumatism found that the incidence of heart attack and stroke in SLE patients was 7 to 17 times higher than what would be predicted based on traditional cardiovascular risk factors, such as elevated cholesterol, hypertension, diabetes, and smoking. Although SLE usually affects young women in their childbearing years, a large number of older adults have the condition. About 15% of cases are first diagnosed after age 55.

Systemic lupus is an immune system disorder. Normally, the immune system protects the body by attacking foreign invaders such as viruses and bacteria. In SLE, however, the body produces auto-antibodies that attack and destroy normal cells, causing inflammation, injury, and pain in various tissues and organs.

Although the exact cause of SLE is unknown, genetic and environmental factors are thought to play a role.

Hallmarks of the disease include:

• Joint pain.

• Skin disorders such as a butterfly rash across the cheeks and bridge of the nose (50% of patients), ulcers in the mouth and nose, and hair loss. About 30% develop Raynaud’s phenomenon, a disorder that is caused by poor circulation in the small blood vessels of the extremities.

• Fatigue or fever.

• Kidney involvement. About half of patients develop lupus nephritis- persistent inflammation of the kidneys.

• Blood issues. 85% of patients have low red and white cell and platelet counts or other blood disorders. An antibody called the lupus anticoagulant predisposes the blood to clot, increasing the risk of venous and arterial thrombosis, heart attack, and stroke.

• Many patients develop pleurisy (inflammation of the membrane lining the lung) and pleural effusion (accumulation of fluid between the lung and the pleura).

• Neurological disorders affect about a quarter of patients.

Most symptoms are mild and consist of anxiety, irritability, depression, and mild memory impairment. However, seizures and psychosis can occur.

Long-term corticosteroid therapy, often needed to control disease symptoms, also contributes to the higher cardiovascular risk in SLE patients. High doses of corticosteroids for long periods can raise blood pressure, increase lipid levels, cause weight gain, and raise the risk of diabetes. These put lupus patients at greater risk for heart disease and stroke.

Conservative treatment of SLE include avoiding excessive sun exposure and using a sunscreen with a Sun Protection Factor (SPF) of at least 15. All patients with lupus should obtain sufficient rest (8 to 10 hours of sleep nightly and a nap, if needed, during the day), regular exercise, and a healthy diet. Immunizations to protect against influenza and pneumonia are recommended, and prompt treatment of infections is essential.

Early diagnosis and treatment can greatly improve outcome. With treatment, the 20-year survival rate is about 80%.

Patients should generally be followed by a rheumatologist—even when they feel well. Although there is no cure, combination therapy can control symptoms. For some patients with mild disease, the only medication needed may be aspirin or a non-steroidal anti-inflammatory drug (NSAID) to relieve muscle and joint pain and arthritis. For others with more severe symptoms, stronger medications may be required, at least on a short-term basis. They include:

• Corticosteroids, which reduce inflammation and suppress the immune system. They are used to control severe or life-threatening complications such as kidney disease, central nervous system involvement, and hemolytic anemia. Some people need corticosteroids for brief periods; others may require long-term therapy. Combining corticosteroids with other drugs can sometimes reduce the risk of serious side effects because the corticosteroid dose can be reduced.

• Cytotoxic drugs, which also suppress immune function and are most commonly used to manage widespread lupus flares and to treat serious kidney, neurological, and arthritic symptoms. They can, however, produce anemia, a low white blood count, and an increased risk of infection; they may also increase the risk of cancer later in life, although the risk appears to be very small.

• Antimalarial drugs, which are frequently given to treat the skin and joint symptoms associated with lupus. Side effects, though rare, include diarrhea and rashes. Because about 1 of every 5,000 people taking hydroxychloroquine may develop retinal changes, periodic eye examinations are recommended.

Researchers are investigating more targeted SLE therapies that can avoid the potentially dangerous side effects associated with current treatments. Medications currently being investigated include dehydroepiandrosterone (DHEA), a mild male hormone; bromocriptine, which reduces prolactin levels (a pituitary hormone that is elevated in SLE); LJP 394 and leflunomide (Arava), which zeros in on particular aspects of the immune system (such as the antibodies responsible for lupus kidney disease or the immune cells responsible for inflammation); genetically cloned (monoclonal) antibodies to immune system proteins, which are thought to play a role in triggering SLE; and transplantation of blood-forming stem cells (which produce red and white blood cells and platelets) in conjunction with cyclophosphamide (Cytoxan), a cytotoxic drug. It now appears that short-term high-dose cyclophosphamide therapy can be effective without stem cell transplantation.

There is a growing body of scientific evidence linking female hormones (for example, estrogen) to lupus and other autoimmune disorders. In lupus, the ratio of females to males with the disease is about 9:1 during childbearing age. At menopause, the numbers drop markedly. Menopause, of course, involves changes in the amount of estrogen produced by the female body. This has led some to speculate that estrogen levels within the body may have something to do with lupus. Further supporting the idea that female hormones play a role in SLE is the fact that female patients with SLE often have abnormal estrogen levels, while male lupus patients tend to have decreased serum testosterone levels.

Sixteen to 26% of women with SLE have increased levels of the hormone prolactin which stimulates milk production in the breast. Studies of lupus, using animals, have shown that increasing estrogen and prolactin levels worsens lupus, while many male hormones seem to have beneficial effects. This suggests that controlling prolactin production through drugs may be a promising new treatment for SLE. As for male hormones, decreased levels of testosterone and dehydroepiandrosterone (DHEA) have been observed in male lupus patients and there is some evidence that increasing the levels of these hormones may slow down the disease.

Someone is said to have severe or life-threatening SLE when the disease has damaged or destroyed one of the body's organ systems. Typical examples include severe kidney disease; neuropsychiatric symptoms such as personality change, epilepsy and psychosis; major blood disorders; and problems with the lung, heart and pancreas. The standard treatment for these patients has been high doses of corticosteroids, sometimes together with immunosuppressive drugs (such as azathioprine or cyclophosphamide). These drugs are often effective, but there is a down side. Long-term use of these powerful chemotherapy drugs can cause side effects such as high blood pressure, hyperglycemia (elevated blood sugar), osteoporosis, cataracts, weight gain and emotional instability. The immune system suppressant, cyclophosphamide, has further side effects such as infertility and birth defects.

The shortcomings of these conventional therapies for severe SLE have led researchers to look for new drugs that zero in on particular aspects of the immune system, rather than suppressing the entire immune response, which, for obvious reasons, can be very dangerous. Because explanations of how these new therapies work is very technical, patients with severe SLE should discuss these therapies with their doctor. Here are the names of the therapies and the new drugs.

Cytotoxic agents such as cyclophosphamide, azathioprine and cyclosporine are only used for severe SLE, as they can cause many serious side effects. Other drugs in this class are mycophenolate mofetil (MMF), fludarabine and cladribine.

In addition, Benlysta, a B-cell therapy approved by the FDA has also been used with modest success in severe lupus.

The immune system is generated from cells in the bone marrow known as stem cells. Many researchers believe that dysfunctional stem cells may be the cause of SLE. If they are right, then destroying these disease-producing stem cells and replacing them with healthy stem cells might be a way to stop or eliminate SLE. With stem cell therapy, doctors target bone marrow with radiation or various drugs and then transplant healthy stem cells. While few of these procedures have been done, the early results appear promising.

Intravenous immunoglobulin (IVIg) is a substance that has the ability to regulate lupus activity. IVIg has also been reported to be an effective treatment for arthritis, thrombocytopenia and the neuropsychiatric mainifestations of lupus.

Other new experimental therapies target various stages of the immunoinflammatory response. Therapies you may hear about include inhibition of costimulatory pathways, manipulation of the complement system and manipulation of cytokines.

Another potential treatment is human stem cell transplant (HSCT). The theory behind the use of allogeneic HSCT in autoimmune disease is that it can potentially have a positive impact on eradicating memory cells, acquiring tolerance, re-setting of the disease to an earlier stage, replacing the immune system, and creating graft-versus autoimmunity. Autologous HSCT may provide some of these benefits. A recently submitted study found that there was a 67% rate of sustained response, a 29% rate of transient response, and a 4% rate of no response among 51 cases of autologous HSCT in SLE patients. Scientists believes that the use of autologous HSCT in severe SLE patients using high-dose cytoxan-based regimens is a promising approach--it appears to be effective, relatively safe (with total-related mortality of less than 10%), and durable (with responses that last up to four years). However, relapses do occur (approximately 25% of the time) and the trials to date have been poorly standardized and controlled. In addition, the response mechanisms are unknown while cures are uncertain. In short, there is a need to better understand the pathogenesis and pathophysiology of SLE and the HSCT treatment.

(This information is from 2006 and the study may no longer be available for new candidates; however, the theory behind it pinpoints the direction that lupus research is taking as far as therapeutics)

A National Institutes of Health protocol is underway to evaluate this therapy. The protocol (NIH protocol 04-C-0095: A Pilot Study of Intensified Lymphodepletion Followed by Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Systemic Lupus Erythematosus) is an attempt to develop a highly effective but less toxic treatment. Guiding principles behind the protocol are as follows:

• Lymphoselective (i.e., focused on the lymphoid system without excessive toxic side effects).

• Strictly defined in terms of inclusion criteria, efficacy endpoints, and definitions of flare and success. To be eligible, patients must be between the ages of 15 and 40, fulfill American College of Rheumatology (ACR) criteria for SLE, have acceptable organ function, and have any of four types of active, treatment-resistant SLE (kidney, central nervous system, lungs, or anemia/thrombocytopenia). The primary efficacy endpoint is complete clinical response at 24 months post-transplant, maintained for at least 3 months. Complete response is defined as complete response in the target organ, no signs of active lupus (SLEDAI less than or equal to 3), and use of 10 grams or less of prednisone at 6 months and 5 grams or less at 12 months or later.

• Based on existing studies and knowledge of biology.The combination of agents is expected to be superior in efficacy to high-dose cyclophosphamide without added toxicity. It is hoped that this protocol can serve as a foundation for cellular immunotherapy (including both autologous and allogeneic approaches) for autoimmune diseases, with the ultimate goal being to treat or cure disease and to improve immune reconstitution. To facilitate that goal, many patients’ blood samples are being studied to examine immune function and the effects of therapies on patients with normal and autoreactive responses.

The following key points came out of a discussion at the NIH:

• No patients have been enrolled in the trial. Recruitment remains a challenge, although a number of potential candidates have been identified. Several candidates chose not to enroll for personal reasons. The protocol's sponsors are engaged in a variety of activities to inform the public and physicians about the protocol, including working through patient advocacy organizations.

• There was some concern that use of fludarabine during the conditioning phase could cause pulmonary toxicity in patients with pulmonary disease. Dr. Pavletic- one of the principal investigator- noted that fludarabine is not often used in patients with autoimmune diseases, but has been used frequently in hematology/oncology patients, including older individuals, without pulmonary toxicity side effects. Immunosuppression is the main effect. In the protocol, fludarabine is used in combination with cyclophosphamide; this combination can cause cardiac toxicity in some patients.

• While the cutoff for evaluating patient benefits is 2 years, patients will be followed for 5 years.

• To ensure safety, participating patients will be hospitalized for 3 weeks, which includes the conditioning and recovery stages. Patients would not normally need to be hospitalized for this long.

• Participating patients must have failed standard cytoxan therapy for severe SLE for 3 to 6 months depending on the type of SLE present, but cannot have organ dysfunction or otherwise be critically ill. If they are too sick, they will not respond well to the treatment protocol.

• No control group is planned. The comparison will be a "before" and "after" analysis of the patient's condition. A randomized controlled trial may be conducted once there is an opportunity to improve the protocol.

• Information on the trial is being distributed through print materials, on relevant web sites, and through patient advocacy organizations. An article on the protocol recently appeared in Lupus Now magazine.

Ellen Goldmuntz, M.D., Medical Officer in the Division of Allergy, Immunology and Transplantation of the National Institute of, Allergies and Infectious Diseases (NIAID, an NIH Institute), presented an overview of a stem cell transplant, specifically a NIAID-sponsored protocol that is currently under development. Based on a Phase I trial conducted at Northwestern University in Chicago, IL, this new protocol will be tested in a Phase II trial that will compare the use of stem cell transplantation to currently available therapies for SLE. The primary objective is to test the safety of this approach; as a result, measures such as overall and transplant-related mortality, infection rates, and rates of engraftment will be analyzed. Because the focus is on the long term, the trial will not be stopped unless mortality rates are 10% or higher at the 6-month mark. The trial will also focus on the long-term efficacy of the stem cell transplant approach, with a Phase III trial planned for the future. Because the goal is to achieve a durable response to treatment, efficacy endpoints include: independence from all SLE drugs other than low-dose prednisone, quality-of-life indicators, disease/system assessments, and neuropsychiatric measures.

The goal is to enroll 100 patients who will be randomly assigned to the intervention group or the regular-care group. Participants will be treated in six transplant sites around the country, supported by a network of 20 "feeder" sites (large rheumatology practices housed at academic medical centers). Feeder sites were chosen so that they might enroll participants from across socioeconomic classes and racial and ethnic groups. Participants in the intervention group will undergo the transplant at one of the six sites, and then go home for follow-up care at one of the supporting rheumatology centers. Participants will make annual follow-up visits to the transplant center.

The intervention group will receive a nonmyeloablative conditioning regimen that includes treatment with cyclophosphamide and ATG followed by the stem cell transplant. The control group will receive any of a variety of "real-world" treatments for SLE, administered by rheumatologists at the feeder sites. The treatment for the control group was difficult and time-consuming to define. The ultimate decision, made by a panel of rheumatology experts, was for the control group to receive treatments based on current medical practice. Because there are little good data today on the efficacy of current practice, this trial may provide important information on the efficacy of current approaches (along with data on the risks and benefits of stem cell transplants).

The trial will follow participants for 5 years, with most key efficacy measures evaluated at 30 months. To be eligible for the trial, patients must be between the ages of 16 and 60 and meet the ACR criteria for SLE. They must be steroid-dependent and have no systemic end-organ damage or other organ problems that could significantly increase the chance of complications or death (e.g., cardiac disease, pulmonary disease). Participants must have failed standard therapy for 3 months.

Dr. Goldmuntz noted that the developers of this protocol are facing and/or will face a number of challenges, including how to keep patients engaged for the 5-year duration, how to educate physicians about stem cell transplantation (many are "afraid" of it), how to explain to patients assigned to the control group why they cannot receive stem cell transplants (many patients want the treatment), and how to satisfy FDA requirements related to the trial (e.g., ensuring comparability of care across sites).

The following key points came out of the discussion that followed Dr. Goldmuntz's presentation:

• Academic-based rheumatology centers are being used to ensure greater consistency in care delivery for the intervention and control group. The transplant centers can provide "back-up" assistance to these centers if needed. Selection of the six transplant centers has not yet been finalized.
• Third-party payers covered some of the costs of the Phase I trial. Since NIH cannot communicate directly with third-party payers, the individual centers will have to initiate discussions about coverage of the Phase II trials. Under the contract that Blue Cross/Blue Shield (BC/BS) has with the Federal Government to cover Federal employees, BC/BS will provide coverage for NIAID-approved trials that are designated as being "pivotal" studies. It is not clear whether BC/BS will provide financial support for smaller phase II studies supported by NIAID, including those related to SLE. Other insurers may follow BC/BS's lead on coverage.
• Both protocols (the NIAID protocol and the protocol described earlier by Dr. Pavletic) are "competing" for the same patients. While the regimens are different, the target patient populations are quite similar. In fact, the same individuals may well be offered participation in both trials, and thus have to decide which (if any) to enter. The goal will be to develop educational approaches that can help patients understand these and other trials so that they can make informed decisions. (The topic of patient education about trials may be appropriate for future LFWG meetings.) The NIAID trial may face more recruitment difficulties, since many would-be participants who are interested in stem-cell transplantation may not want to risk being assigned to the control group.

Another potential therapy...

Ann Rheum Dis 2001;60:112-115 ( February )

Extended report

UVA-1 cold light treatment of SLE: a double blind, placebo controlled crossover trial

M C A Poldermana, T W J Huizingab, S Le Cessiec, S Pavela

a Department of Dermatology, Leiden University Medical Centre, The Netherlands, b Department of Rheumatology, Leiden University Medical Centre, c Department of Medical Statistics, Leiden University Medical Centre

Correspondence to: Dr M C A Polderman, Department of Dermatology, B1-Q, Leiden University Medical Centre, PB 9600, 2300 RC, Leiden, The Netherlands

Accepted for publication 5 June 2000


OBJECTIVE Treatment of patients with systemic lupus erythematosus (SLE) often implies strong drugs with possibly serious side effects. Thus there is a need for new immunosuppressive treatments. Long wave ultraviolet A (UVA-1) cold light therapy is an anti-inflammatory, immunomodulatory treatment with a possible systemic effect and few side effects. In the current study low dose UVA-1 cold light treatment was tested to determine whether it reduces disease activity in SLE.

METHODS Eleven patients with SLE were treated with UVA-1 cold light treatment and a placebo light treatment in a double blind, placebo controlled, crossover study. In two consecutive 12 week periods the patients were treated in the first three weeks with UVA-1 and placebo treatment or vice versa. The primary variables were the SLE Disease Activity Index (SLEDAI) and SLE Activity Measure (SLAM).

RESULTS The mean SLAM and SLEDAI showed a significant decrease of 30.4% (p=0.0005) and 37.9% (p=0.016) respectively after three weeks of UVA-1 and a non-significant decline of 9.3% (p=0.43) and 12.2% (p=0.54) respectively after three weeks of placebo treatment. In this small trial the difference in reduction of the disease activity indices during UVA-1 compared with during placebo treatment failed to reach the conventional border of significance (p=0.07). The total score of quality of life measure RAND-36 did not improve significantly, but the subscore for vitality did improve.

CONCLUSION Low dose UVA-1 cold light treatment was strongly suggestive of lowering disease activity in this double blind placebo controlled study, and no side effects occurred.

(Ann Rheum Dis 2001;60:112-115)

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