This summary, the first segment of this two-part presentation, focuses on lupus. For more information on antiphospholipid syndrome, please read Recent Developments in Managing and Treating Lupus and Antiphospholipid Syndrome (APS): Part II – APS.
Important Note: Information presented here is intended only to educate you and not to be used as therapeutic advice. Therapeutic decisions should be made closely with your treating rheumatologist, as there is not one-size-fits-all therapy.
Systemic Lupus Erythematosus or “lupus” is a disease that mainly affects young or middle-aged women (approximately 1 per 1000 women). The ratio of female/male affected is 9:1, and the disease is more frequent and often more severe in African Americans than in Caucasians. The most common symptoms of lupus are skin and joint manifestations. However, about 30-50% of lupus patients will develop clinically significant nephritis (kidney inflammation), usually within the first six months to three years of the disease.
Although the cause of lupus is not known, genetic risk factors and infections have been implicated as important predisposing factors. Several auto-antibodies (antibodies that are produced by the immune system which attack the individual’s own proteins, as further discussed in Part II of this presentation, focusing on Antiphospholipid Syndrome)are characteristically present in the disease. Examples of these auto-antibodies include antinuclear antibodies (ANA), anti-double stranded DNA, anti-Sm, anti-Ro, and antiphospholipid antibodies (aPL).
Several cytokines (proteins that affect cell function), such as interferon, have been found in high levels in the blood of patients with lupus and contribute to disease causation.
The rheumatologist works together with the lupus patient, as a team, to achieve two principal treatment goals:
Additionally, indirect goals of lupus management include the prevention of hospitalizations/emergency room visits, the control of disabling symptoms such as pain and fatigue, and the preservation of functionality such as continued attendance at (or a return to) work and/or school. In other words, the goal is to preserve a normal lifespan without disabilities.
The treatment aims to control lupus by suppressing the overactive immune system just enough without risking to compromise body defense against infection or tumors. Early therapeutic intervention is needed to minimize damage from uncontrolled disease. At the same time, the treatment should address co-morbidities (other important diseases present) and aim to prevent complications from the disease or medications. Examples of such interventions include the control of cardiovascular disease risk factors (e.g., high blood pressure, high cholesterol), repletion of calcium/vitamin D to protect bones, and vaccination for influenza and pneumonia to prevent infection.
In addition, it is important that patients adopt lifestyle changes that will facilitate best outcomes. Key changes include the following:
Immunosuppressive medications lower the activity of the immune system. These medications help in lupus because the immune system is excessively active in this disease. It is important to note, however, that too much suppression of the immune system might cause susceptibility to infections or tumor development. Below is a classification of the various types of immunosuppression: low, medium, and high levels. The patient’s physician determines the level of immunosuppression needed based on the severity of the patient’s disease.
Low level immunosuppression is used for relatively mild or moderate disease flares. To achieve this, we typically use low dose glucocorticoids (also known as steroids). In the case of prednisone, this translates to less than 10mg per day. Glucocorticoids have a relatively quick action (within hours), but they often cause significant adverse effects as the dose increases to higher levels. For this level of immunosuppression, we also often use hydroxychloroquine (Plaquenil®). This medication is usually very well tolerated with only few potential adverse effects, but it takes up to three months to work well. Hydroxychloroquine has been shown to decrease the risk of a lupus flare and it usually improves symptoms of fatigue, arthritis, and skin rash.
Medium level immunosuppression is used for more severe flares of the disease. To achieve this, we typically use medium dose glucocorticoids: roughly 10-40 mg of prednisone per day. In addition, we use other drugs to allow us to decrease doses of glucocorticoids. A frequently used drug that is generally well-tolerated is methotrexate, which is especially effective for arthritis. Other drugs include mycophenolate (Cellcept®, or Myfortic®), azathioprine (Imuran® or Azasan®), and cyclosporine (Gengraf®, Neoral® or Sandimmune®). These drugs are considered somewhat more potent than methotrexate and are particularly useful for kidney disease (lupus nephritis).
High level immunosuppression is used for severe or life/organ threatening flares of the disease, such as severe lupus nephritis or lupus affecting the brain. In this case glucocorticoids are used in high doses (>40 mg prednisone) and often given as very high doses by intravenous route in the infusion room ( known as “pulse steroids”). Other drugs used in this category include cyclophosphamide (Cytoxan®). This is a “chemotherapy” type of medication that is given usually intravenously every month for 3-6 months to treat severe lupus. Mycophenolate and azathioprine may also be used here, but typically in higher doses than for medium level immunosuppression.
In the last decade, great advances in science have allowed the development of a new class of drugs, which we often call biologics or targeted therapies (because they are specifically constructed to target certain key parts of the immune system). These drugs are discussed below and may also be used by physicians for high level of immunosuppression.
Of note, a very important reason why we use immunosuppressive medications in lupus is the fact that glucocorticoids, although very effective, have many adverse effects that are directly associated with the dosage level used. In other words, the higher the dose of glucocorticoids and the longer they are used, the more likely and more severe their adverse effects will be. Using immunosuppressive medications allows the physician to minimize the use and adverse effects of glucocorticoids.
As indicated above, glucocorticoids (steroids) such as prednisone, methylprednisolone (Medrol®), or dexamethasone are often associated with significant adverse events:
Decreasing the glucocorticoid dose, as fast as disease will allow, is the strategy used for minimizing these adverse events. All drugs, including glucocorticoids, used for medium/high level immunosuppression may increase the risk for infection and, rarely, tumors (the latter is mainly related to cyclophosphamide). Cyclophosphamide - because of the relatively higher potential for infection, tumors, and infertility - is typically reserved for the most severe forms of disease. Immunosuppressive medications may have additional adverse effects specific to each one of them. Please discuss this with your doctors.
Only a few drugs are approved by the FDA for treatment of lupus. These include hydroxychloroquine (Plaquenil®), aspirin, glucocorticoids, and, since March 2011, belimumab (Benlysta®; see below). Other drugs used for lupus, such as methotrexate, mycophenolate, and cyclophosphamide, have not been approved for lupus because their therapeutic value has not been proven in clinical trials. However, these medications are considered effective by rheumatologists and are frequently used to treat the disease. As indicated above, these medications may have significant adverse effects, because they work by lowering the immune system. Therefore, we still need new medications that will be effective for the disease but less toxic.
As indicated above, novel and more specific immunosuppressive medications, that target only certain components of the immune system rather than the whole immune system, have been developed recently. These drugs are called biologics and are under intense investigation in clinical trials. Such clinical drug trials compare promising new drugs for lupus to the more conventional immunosuppressive medications already in use, for both effectiveness and safety. Patients and doctors are often not aware whether a particular patient is taking the active drug or a placebo (sham), in order to allow for more objective assessment of the new drug.
Drug trials have several phases of development:
For more information on lupus clinical trials, please visit:
Multiple therapeutic targets are being explored as potential new therapies for lupus. These include different cells of the immune system, as well certain key cytokines. An overview follows:
B cell targeted therapies. B cells are cells of the immune system that produce antibodies, which are proteins used for our defense against specific infectious agents. In lupus, many B cells also produce self-harming antibodies called autoantibodies. B cell targeted therapies block or eliminate B cells. The first such agent used in lupus has been rituximab. Although this agent failed in phase III drug trials for lupus and lupus nephritis, many experts still believe in its value and question the design of those trials for the failure. Belimumab (Benlysta®), the newest FDA-approved drug in lupus, is discussed below. Other promising agents in this category include epratuzumab (phase III trial in progress) and atacicept (phase III trial in progress).
T cell targeted therapies. T cells are cells of the immune system that are important for activation of other cells of the immune system, including the B cells. An example of such agent is abatacept (Orencia®). Although a phase II trial in SLE failed, data from a phase II/III trial in nephritis are pending.
Cytokine targeted therapies. Interferon alpha is a very important cytokine of the immune system that has been found in high levels in lupus and is considered to contribute to the disease. Several agents designed to block interferon alpha are in development, including sifalimumab and rontalizumab. Agents that target other cytokines, including interleukin-6, are also in development.
Other agents: Other promising agents capable of modulating the immune system - such as lupuzor and laquinimod - are also in development.
Benlysta® is a fully human monoclonal antibody that blocks the activity of a protein called B lymphocyte stimulator (BLyS). For this reason it is considered a “B cell targeted therapy.” BLyS protein has the ability to activate (and sustain the life of) B-cells that produce autoantibodies (antibodies against self antigens). Autoantibodies are thought to promote tissue damage and cause harm in lupus.
Two large phase III trials, BLISS-52 and BLISS-76, showed improvement in SLE with belimumab plus standard lupus therapy compared to standard therapy alone. The success of these trials led to the medication’s approval by the FDA in March of 2011.
Belimumab is given by monthly infusion after initial loading (one intravenous dose every two weeks for the first six weeks, then one infusion every four weeks). It is expected to be used in patients with active lupus despite other lupus therapies, especially if prednisone dosages cannot be lowered to levels below 10 mg/day. Benlysta has not been tested in severe lupus (such as in severe lupus nephritis or lupus affecting the nervous system) and therefore it is not currently indicated for such cases.
Although this medication is costly and its long-term safety still needs to be proven, it has been a great advance for the treatment of lupus and has been welcomed by both physicians and patients.
The goal of therapy in this case is to prevent kidney failure and the need for dialysis. Severe lupus nephritis requires aggressive induction therapy as early as possible to put it under control. We typically use high dose glucocorticoids plus either cyclophosphamide intravenously every month for six months or mycophenolate by mouth for six months. Once control (optimally remission) of disease is achieved, the goal is to keep it from flaring again with maintenance therapy. This can be achieved by using either mycophenolate or azathioprine.
A new trial (Aspreva Lupus Management Study or ALMS) has recently suggested that mycophenolate may be more effective than azathioprine for maintenance therapy (please note that this study has not yet been published).
Also read the second segment of this two-part presentation: Recent Developments in Managing and Treating Lupus and Antiphospholipid Syndrome (APS): Part II – APS.
Original summary by Stephen Rudolf, SLE Workshop Coordinator and Social Work Intern, with special acknowledgement to Pretima Persad, Manager, Mary Kirkland Center for Lupus Care, for her editorial review.