Managing and Treating Lupus

Important note: The information presented here is intended only to educate and not to be used as therapeutic advice. Therapeutic decisions should be made closely with your treating rheumatologist, as there is no one-size-fits-all therapy.

Systemic lupus erythematosus (lupus): A brief overview

SLE 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 people of African descent than in Caucasians. The most common symptoms of lupus are skin rashes, and pain and inflammation in the joints.. However, about 30% to 50% of lupus patients will develop clinically significant lupus 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 a person's own proteins) are usually present in people with this disease. Examples of these auto-antibodies include antinuclear antibodies (ANA), anti-double stranded DNA, anti-Smith (anti-Sm), and antiphospholipid antibodies (aPL).

Several cytokines (proteins produced by the immune system that affect the function of many body cells and tissues), such as interferon, have been found in high levels in the blood of patients with lupus and contribute to disease causation.

The goals of lupus disease management

The overarching objective is to preserve a normal lifespan without disabilities. The rheumatologist works together with the lupus patient, as a team, to achieve two principal treatment goals:

  1. The first goal of treatment is to minimize disease activity or even cause disease remission by using an intense therapeutic regimen called induction therapy. This therapeutic regimen consists of one or more immunosuppressive medicines and is tailored to the needs of the specific patient treated.
  2. After achieving good disease control, the second goal of therapy is to keep the disease at a low level of activity (or no disease activity) and minimize adverse side effects of medications by using a less intense therapeutic regimen. This is called maintenance therapy.

Indirect goals of lupus management include the prevention of hospitalizations and 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.

Treatment aims to control lupus by suppressing the overactive immune system just enough without risking compromise of the body’s defenses against infection or tumors.

Early intervention

Early therapeutic intervention is needed to minimize damage from uncontrolled disease. At the same time, the treatment should address comorbidities (other conditions or diseases the patient has) and aim to prevent complications from the disease or medications. Examples of such interventions include the control of cardiovascular disease risk factors (such as 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 habits that will facilitate best outcomes with their doctor’s approval. Key habits include the following:

  • staying informed about lupus
  • keeping doctors’ appointments
  • taking medication
  • following a healthy eating pattern
  • quitting smoking
  • getting aerobic exercise
  • receiving pregnancy/contraception counseling
  • developing strategies to effectively manage stress
  • participating in social support groups (such as the SLE Workshop at HSS)

Medications for lupus

Only a few drugs are currently approved by the US Food and Drug Administration (FDA) for treatment of lupus. However, due to the more rapid pace of clinical research, this is expected to change. Currently approved drugs include hydroxychloroquine (Plaquenil), aspirin, glucocorticoids (steroids) and belimumab (Benlysta – see below). Other drugs used for lupus, such as methotrexate, leflunomide, mycophenolate and cyclophosphamide, have not been approved by the FDA for the treatment of lupus because their therapeutic value has not been proven in rigorous clinical trials. However, these medications are considered effective by rheumatologists and are frequently used to treat the disease. All these medications may have significant adverse effects, so we still need new medications that will be effective against the disease but with less toxicity.

Immunosuppressive medications

Immunosuppressive medications lower the activity of the immune system. These medications help in lupus because the immune system is excessively active in this disease. However, 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

This is used for relatively mild or moderate disease flares. To achieve this, doctors typically prescribe low-dose glucocorticoids. In the case of prednisone, low-dose translates to 7.5 mg per day or less. Glucocorticoids have a relatively quick action (within hours), but they often cause significant adverse side 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 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

This is used for more severe flares of the disease. To achieve this, we typically use medium-dose glucocorticoids: roughly 10mg to 20 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), cyclosporine (Gengraf, Neoral or Sandimmune), and tacrolimus (Prograf). These drugs are considered somewhat more potent than methotrexate and are particularly useful for kidney disease (lupus nephritis). Belimumab (Benlysta) is a newer drug for treating lupus (approval by the FDA in March of 2011), and it may be used for medium-level immunosuppression even before using methotrexate and the other drugs, always according to the clinical judgment of the treating rheumatologist. Belimumab was recently also shown to be effective in a Phase III lupus nephritis trial and hopefully will soon get an approval for this condition as well.

High-level immunosuppression

This is used for severe or life- and organ-threatening flares of the disease, such as severe lupus nephritis, central nervous system (CNS) lupus (lupus that affects the brain) or lupus vasculitis (lupus that affects blood vessels). In this case, glucocorticoids are used in high doses (>20 mg prednisone) and are often given as very high doses (known as “pulse steroids”) by intravenous infusion. Other drugs used in this category include cyclophosphamide (Cytoxan). This is a chemotherapy medication that is often prescribed to treat cancers such as leukemia and lymphoma. It may be given intravenously every month for four to six months to treat severe lupus. Mycophenolate and azathioprine may also be used for this purpose, but typically in higher doses than for medium-level immunosuppression, and/or in combination with cyclosporine or tacrolimus (particularly for those with lupus nephritis). Rituximab (see below) may also be used for severe lupus cases. Finally, a new drug, voclosporin, which belongs to the same family of drugs as cyclosporine and tacrolimus, has shown success in both Phase II and III trials of lupus nephritis and seems to be very close to getting FDA approval.

Since around 2010, great advances in science have allowed the development of a new class of drugs, which we often call targeted therapies (because they are specifically constructed to target certain key parts of the immune system). These drugs are discussed in a later section below and may also be used by physicians for high level of immunosuppression.

Risks of glucocorticoids

Glucocorticoids, though very effective, have many adverse effects that are directly associated with the dosage level used. The higher the dose and the longer they are used, the more likely and more severe their adverse effects. Using immunosuppressive medications allows the physician to minimize the use and adverse effects of glucocorticoids.

Adverse side effects associated with glucocorticoids such as prednisone, methylprednisolone (Medrol) or dexamethasone include:

  • Osteoporosis (weakening of the bones) and potential spine and hip fractures as a result: Patients should speak to their doctors about this possibility and discuss diagnostic tests such as bone density, as well as preventive measures, such as calcium, vitamin D, or even stronger therapy, such as bisphosphonates.
  • Osteonecrosis (also known as avascular necrosis, this is the development of dead bone areas that may collapse and cause joint damage): The hip is often affected by osteonecrosis, and patients will develop relatively quickly a painful groin despite having no active arthritis from lupus. Sometimes, this complication requires joint replacement surgery.
  • Infection, as a result of the suppression of the immune system: Infections could be due to a virus (such as shingles), fungus (such as mouth thrush) or bacteria (such as pneumonia). Patients who develop fever or sudden sickness should speak to their doctors regarding this possibility. Immediate therapy with an antibiotic and discontinuation of some immunosuppressive medications may be needed for optimal results.
  • Weight gain and/or puffiness in the face: This is a reversible complication that improves when the dosage of glucocorticoids is lowered.
  • Loss of control of diabetes and blood pressure: This particularly affects patients who already suffer from diabetes, hypertension (high blood pressure) or kidney disease.
  • Adrenal fatigue (sometimes called “lazy adrenals”): Our bodies normally produce glucocorticoids – which are essential for life – especially in periods of stress, such as after surgery or a serious illness. Patients who take glucocorticoids lose their ability to produce their own glucocorticoids. These patients may get very sick after surgery or another illness; doctors need to give them extra doses of glucocorticoids to prevent this.

Decreasing the glucocorticoid doses as fast as disease will allow is the strategy rheumatologists use to minimize these adverse events. All drugs (including glucocorticoids) that are used for medium- or high-level immunosuppression may increase the risk for infection and, rarely, tumors. The latter is mainly related to cyclophosphamide. Because of the relatively higher potential for infection, tumors, and infertility, this drug is typically reserved for the most severe forms of disease. Immunosuppressive medications may have additional adverse effects specific to each of them. Please discuss medication safety profiles with your doctors.

Targeted medications

Targeted medications are modern, carefully designed drugs that bind and block a specific target that is considered very important in a given disease such as lupus. These can be of two types: biologics and kinase inhibitors.

  • Biologic drugs are manufactured using molecular biology techniques in order to target certain cell membrane receptors or circulating cytokines of the immune system. These are either monoclonal antibodies (-mab suffix used in their name) or soluble truncated cell membrane receptors (-cept suffix used in their name) and are administered either as an infusion or injection under the skin.
  • Kinase inhibitors are small chemicals that are designed to block the function of specific key enzymes (kinases) inside cells and thus not allow them to activate inflammation signals within the cell. These are administered by mouth.

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 people with lupus, many B cells also produce self-harming antibodies called autoantibodies. B cell targeted therapies either directly kill B cells (these are called B cell depleting agents) or block cytokines that help autoimmune B cells survive and multiply (these are called B cell inhibitors). The first B cell depleting 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 whether the design of those clinical trials may be responsible for these failures. Belimumab (Benlysta), the newest FDA-approved drug for lupus, is a B cell inhibitor that blocks the cytokine B lymphocyte stimulator (BLyS). Other promising agents in this category include the B cell inhibitor, telitacicept (promising Phase II trial), and the more potent B cell depleting agent, obinutuzumab (Phase II results in lupus nephritis very promising).

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. Some T cell targets under investigation include CD40 ligand, inducible T cell costimulatory (ICOS), and others.

Cytokine targeted therapies: Several cytokines other than BLyS have been considered potentially good treatment targets for lupus, including the Type I Interferons and interleukins IL-12 and IL-23. The closest to FDA approval is probably a drug called anifrolumab, a monoclonal antibody that blocks interferon activity and has shown great promise in recent Phase II and III clinical trials.

Kinase inhibitors under development for lupus include baricitinib, which blocks the Janus kinases JAK-1 and Jak-2, and Bruton-tyrosine kinase inhibitors.

Lupus is a complex disease that requires careful, individualized treatment by a skilled rheumatologist in order to obtain optimal health results for each patient. Treatment challenges are numerous. However, with the development of newer drugs to manage the disease, doctors and researchers are hopeful of offering patients more options that improve the quality of life and minimize poor outcomes. Lupus patients who partner with their doctors on their medical treatment plan and who adopt healthy lifestyle behaviors have the best chance for a normal lifespan free of disabilities.

Authors

Image - Photo of Kyriakos A. Kirou, MD, DSc, FACP
Kyriakos A. Kirou, MD, DSc, FACP
Director, Lupus Nephritis Program, Hospital for Special Surgery
Clinical Co-Director, Mary Kirkland Center for Lupus Care, Hospital for Special Surgery
     

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