Lupus: Systemic Lupus Erythematosus (SLE)

Lupus: Systemic Lupus Erythematosus (SLE)

1 Overview

Summary and Quick Facts

  • Lupus is an autoimmune disease. Managing inflammation is a primary treatment goal for people with lupus.
  • This protocol summarizes how lupus develops and how it’s diagnosed and treated. Dietary, lifestyle and supplement approaches that complement conventional treatment options will be summarized, as well.
  • When combined with conventional treatments, the dietary and lifestyle strategies outlined in this protocol may help ease inflammation that contributes to lupus symptoms.
  • Vitamin D has been shown in several studies to support a healthy immune system and inflammatory response.

What is Lupus?

Lupus is a systemic autoimmune disease driven by inflammation. The term “lupus” generally refers to systemic lupus erythematosus (SLE), but other forms exist as well. Parts of the body frequently affected by lupus include the skin, kidneys, heart and vascular system, nervous system, connective tissues, musculoskeletal system, and other organ systems.

As lupus can cause complications in many organ systems, people with lupus have a significantly higher risk of heart attacks, diabetes, kidney disease, osteoporosis, blood disorders, and others.

Natural interventions such as vitamin D and omega-3 fatty acids may help relieve symptoms of lupus and improve quality of life.

What are Risk Factors for Lupus?

  • Female of childbearing age (eg, between 15 and 44 years old)
  • Ethnicity—more common in African American, Asian American, Native American, and Latina women than in Caucasians

What are the Signs and Symptoms of Lupus?

  • Intense fatigue
  • Painful and/or swollen joints
  • Muscle pain
  • Red rash on the face (often in response to sitting in the sun)
  • Pain in the chest after taking a deep breath
  • Unexplained fever
  • Edema (swelling), often in the legs or around the eyes
  • Mouth sores
  • Unexplained hair loss
  • Raynaud’s phenomenon (characterized by cold fingers and/or toes that are pale or purple in color)
  • Headaches
  • Impaired cognitive function—memory loss, confusion, and/or difficulty concentrating

Note: Lupus often presents in different ways, varying between individuals.Symptoms may cease during periods of remission, then worsen during flares.

What are Conventional Medical Treatments for Lupus?

  • Anti-inflammatory drugs (eg, corticosteroids and non-steroidal anti-inflammatory drugs [NSAIDs])
  • Anti-malarial drugs (eg, chloroquine and hydroxychloroquine)
  • Immune system modulators (eg, azathioprine and cyclophosphamide)
  • Monoclonal antibodies (eg, belimumab and rituximab)

What are Emerging Therapies for Lupus?

  • Stem cell therapy to replace “self-attacking” B and T cells

What Dietary and Lifestyle Changes Can Be Beneficial for Lupus?

  • Eat a healthy, well-balanced diet
  • Manage stress effectively
  • Avoid exposure to sunlight
  • Exercise regularly (aerobic or gentle range-of-motion)

What Natural Interventions May Be Beneficial for Lupus?

  • Vitamin D. Vitamin D may be important in reducing the risk of lupus. Deficiency is more prevalent in those with lupus than in healthy people, so supplementation is advisable.
  • Omega-3 fatty acids. Omega-3 fatty acids reduce inflammation. Some clinical studies have shown that fish oil supplementation diminished the severity of lupus.
  • Vitamin E. Vitamin E has been shown to reduce markers of inflammation, stabilize immune cells to prevent autoimmune attacks, and reduce levels of autoantibodies in lupus patients.
  • Vitamin A. Retinol, the active form of vitamin A, is important for healthy skin, bones, and soft tissues, and supports healthy immune function.
  • Curcumin. Curcumin, a potent anti-inflammatory, was shown to be effective at reducing lupus-related proteinuria (protein in urine, indicative of kidney damage) and improving symptoms of some autoimmune diseases.
  • Ginkgo biloba. Ginkgo biloba extract has been used for thousands of years in traditional Chinese medicine. Supplementation has been shown to reduce the number of Raynaud’s phenomenon attacks, which are common in lupus.
  • Pine bark extract. Pine bark extract may help improve inflammatory symptoms of lupus. A small study showed that adding pine bark extract to prescription therapy improved symptoms.
  • White peony extract. A number of studies have shown that compounds from white peony root have immunomodulatory, anti-inflammatory, and pain-relieving properties.
  • Dehydroepiandrosterone (DHEA). Low levels of DHEA-sulfate (DHEA-s), a metabolite of DHEA, have been observed in patients with lupus and other inflammatory diseases. Supplementation has been shown to reduce the amount of flares, improve emotional and mental well-being, and improve bone mineral density in lupus patients.

2 Introduction

Lupus is a systemic autoimmune disease driven by inflammation in which the immune system indiscriminately attacks "self-tissues" throughout the body. It is estimated that more than 16,000 people are diagnosed with lupus each year in the United States. Approximately 1.5 million Americans, and 5 million people worldwide, currently live with lupus.1

Lupus autoimmunity can cause variable symptoms from person to person. Parts of the body frequently affected by lupus include the skin, kidneys, heart and vascular system, nervous system, connective tissues, musculoskeletal system, and other organ systems.

The immune system is the primary facilitator of lupus; therefore, its treatment requires a strategy that successfully targets immune cells. Unfortunately, conventional medicine typically relies on global immune suppression to accomplish this goal, inadvertently predisposing patients to potentially deadly infections and a host of troubling side effects.

However, advancements in medical technology in recent years have led to the development of promising new medical therapies for lupus. These include the use of monoclonal antibodies targeted against cells of the immune system responsible for lupus autoimmunity, and stem cell therapy, which aims to replace aberrant immune cells with healthy immune cells in order to suppress autoreactivity.

Moreover, mounting evidence suggests that vitamin D may be a critical missing link in virtually all autoimmune diseases, including lupus. Vitamin D is capable of modulating the activity of immune cells, and studies have identified widespread vitamin D deficiency in lupus patients.2,3 For example, one study found that a mere 1.2% of lupus patients had adequate vitamin D levels, compared to 45% of healthy controls4; another found that lower vitamin D levels were linked with more aggressive lupus autoimmunity.5

Life Extension’s strategy is centered upon easing inflammation and combines several scientifically studied nutrients to complement the immunomodulatory role of vitamin D. Additionally, avoiding inflammatory foods high in omega-6 fatty acids in favor of healthy omega-3’s provides a nutritional foundation ideal for balancing an inappropriately reactive immune system.

3 Epidemiology

The population most affected by lupus is women of childbearing age—that is, women between the ages of 15 and 44 years-of-age.1 Lupus is also more likely to develop in African-American, Asian American, Native American, and Latina women compared with Caucasian women.6 However, it is possible for lupus to develop in people of any age group, race, or either gender.

Women with lupus are more likely to have high-risk pregnancies than those without this chronic disease. One study found that these women have a 3- to 7- fold greater risk of developing low platelet levels (thrombocytopenia), infection, and developing blood clots (thrombosis).7 Women who experience a "flare" within six months of conception are much more likely to experience complications during the pregnancy affecting the mothers’ health. Additionally, the fetuses and neonates of individuals who experience a flare during pregnancy are more likely to have complications.8 Consequently, doctors generally advise women with lupus to plan pregnancies after 12 to 18 months of remission, and definitely not before six months of remission.9

4 Types of Lupus

The term "lupus" commonly refers to systemic lupus erythematosus, or SLE, but there are other types of lupus as well, each with distinct signs and symptoms.10

Systemic Lupus Erythematosus (SLE)

This is the disease often simply referred to as “lupus.” The word "systemic" refers to the fact that connective tissues throughout the body are affected; "erythematosus" is a clinical state in which red, raised patches develop on the skin. When referring to lupus elsewhere in this protocol, we are referring to this form of the disease.

Discoid Lupus Erythematosus

This form of lupus is distinct from SLE in that the symptoms are only skin related; discoid lupus erythematosus causes a red rash ("erythematosus"), often developing on the face and/or scalp. People with discoid lupus often also have SLE, or develop SLE in the future.

Drug-Induced Lupus

Certain medications can potentially cause lupus, but the condition generally goes away after stopping the triggering drug. The medications that can possibly cause drug-induced lupus include some oral birth control drugs, certain blood pressure-lowering drugs, and antibiotics and antifungal medications.

Specific drugs most frequently associated with drug-induced lupus include:

  • Procainamide—antiarrhythmic drug
  • Hydralazine—blood pressure lowering drug
  • Quinidine—antiarrhythmic drug

Neonatal Lupus

As the name indicates, this form of lupus develops in newborn infants. This form of lupus is quite rare, and is caused by autoantibodies being transmitted from a mother with lupus to the baby.11 Although most of the babies born of women with lupus are healthy,6 more than half of infants with neonatal lupus have problems with their skin, heart, and/or gallbladder.12,13 Neonatal lupus may spontaneously resolve over the first few months of life, but can sometimes cause serious complications. Death occurs in approximately 10% of neonatal lupus cases, the major causes of which are typically pneumonia or heart complications.13

5 Signs, Symptoms, and Diagnosis

Lupus is a complex disease with varying manifestations. Some people have several different symptoms; others have few. The symptoms in some individuals are severe, while those in others remain mild. Both genetic (inherited) and environmental factors influence the development and severity of lupus symptoms. Because of these characteristics, doctors sometimes have difficulty in correctly diagnosing lupus.

People with lupus have periods in which they are feeling well, called remission, and periods of worsening symptoms, called flares. Lupus patients can often predict the onset of flares due to specific warning signs, such as worsening fatigue and/or onset of headache, fever, dizziness, rash, and/or pain.14 Being able to recognize warning signs is important because catching and treating flares early can prevent them from becoming severe.

The most commonly occurring symptoms of lupus include10,15:

  • Intense fatigue
  • Painful and/or swollen joints
  • Muscle pain
  • Red rash on the face and/or in response to sitting in the sun
  • Pain in the chest after taking a deep breath
  • Unexplained fever
  • Edema (swelling), often in the legs or around the eyes
  • Mouth sores
  • Unexplained hair loss
  • Raynaud’s phenomenon, which is characterized by cold fingers and/or toes that are pale or purple in color.

In 1982, the American College of Rheumatology published a method for doctors to use for diagnosing lupus (Table 1). They then updated these criteria in 1997, and they have remained the same ever since. Lupus is generally diagnosed when a person exhibits four or more of these criteria.

Table 1. Eleven criteria used for the diagnosis of lupus, as defined by the American College of Rheumatology.

These criteria are based on the common lupus signs and symptoms. Lupus is diagnosed when any four or more criteria are present.15,16

CRITERION

SIGNS/SYMPTOMS

TEST

Malar rash A red rash on the cheeks and the bridge of the nose; often called a "butterfly rash" Physical exam, medical history
Discoid rash Raised, hard patches of scaly skin Physical exam, medical history
Photosensitivity A red skin rash caused by exposure to sunlight Physical exam, medical history
Oral ulcers Sores in the mouth, usually painless Physical exam, medical history
Nonerosive arthritis Inflammation in one or more joints, making them feel tender and swollen. Cartilage, which is protective tissue surrounding the bone, remains intact Physical exam, medical history, X-ray
Pleuritis and/or pericarditis Inflammation of the lining of the lung or heart, respectively; may cause pain when breathing deeply; growing tired easily Lung function test; chest X-ray to look for fluid in the lungs; cardiac stress test; echocardiogram, which uses sound waves to visualize the heart
Neurologic disorder Reduced or abnormal brain function, headaches, seizures, memory loss, difficulty concentrating Physical exam, medical history, brain MRI (magnetic resonance imaging); produces a high-resolution image of the brain.
Kidney disorder Usually no symptoms; signs are blood or high levels of protein in the urine. Urinalysis
Blood disorder Anemia (low red blood cell levels) with associated fatigue, dizziness, shortness of breath; increased susceptibility to infection; slow clotting, excessive bleeding CBC (complete blood count); test for abnormal cell counts of platelets, red blood cells, lymphocytes, and/or leukocytes
Immunologic disorder Possible increased susceptibility to infection, inflammation in various organ systems Assorted tests to detect antibodies from a blood sample.
Positive anti-nuclear antibodies Possible increased susceptibility to infection, inflammation in various organ systems ANA (antinuclear antibody) test; test for the presence of antibodies that bind the cell nucleus, which is where the DNA that make up genetic material is stored

Doctors assess lupus severity by calculating a SLEDAI score, which stands for Systemic Lupus Erythematosus Disease Activity Index. Based on the presence or absence various lupus signs and symptoms over the proceeding 10 days, a total score is calculated. For example, protein present in the urine would result in 1 point, and another point would be added if a new rash had appeared. One point is assigned for each symptom or sign present and the greater the score, the more severe the disease at that time. A mild or moderate flare is defined as a change in SLEDAI score of 3 or more points; a severe flare is diagnosed when the SLEDAI score has increased by 12 or more points.15,16

6 Lupus Pathophysiology and Manifestations

Inflammation and Tissue Injury

The principle cause of lupus-mediated tissue injury is inflammation triggered by autoantibody complexes.

B cells, so-called because these immune cells originate in the Bone marrow, produce and secrete the antibodies, which are specialized proteins that bind to other molecules. The immune system generates millions of different antibodies that target an extremely large variety of molecules on the surface of microbes, such as bacteria and viruses. The antibody binds its specific molecule on a microbe in similar fashion to a key in a certain lock. When the "key" (antibody) and "lock" (microbe) fit together, the antibody sticks tightly to the microbe and marks it to be removed from the body. In people with lupus, many of the B cells secrete autoantibodies, which means that these antibodies bind to molecules on otherwise healthy tissues instead of molecules on microbes.

T cells, which are generated in the Thymus, produce various proteins called cytokines that help B cells grow, become activated, and stimulate B cells to produce antibodies. Other immune cells, including macrophages and neutrophils, migrate to the site of inflammation and produce tissue damaging reactive oxygen species (ROS), as well as engulf microbes and cells through a process called phagocytosis. One of the ways macrophages know when to engulf a microbe is by sensing that antibodies are stuck to their surface. All of these cells collectively are called leukocytes or white blood cells because of their lack of color. B and T cells are a subset of leukocytes called lymphocytes.

The types of self-molecules ("the lock") that stick to autoantibodies ("the key") vary in each case of lupus. Self-molecules common in lupus often are associated with the cell nucleus, which is the compartment within a cell that contains DNA and other proteins that make up genes.

Lupus-mediated tissue damage can be summarized as follows:

  1. B cells become activated and produce autoantibodies that bind various self-molecules.
  2. Activated T cells produce proteins called cytokines that help activate more B cells.
  3. Large complexes of antibodies stuck to self-molecules are formed.
  4. These complexes become lodged in various tissues throughout the body, such as the kidney and joints.
  5. The complexes cause an influx of neutrophils, macrophages, and other B cells and T cells into the tissue
  6. Proinflammatory cells secrete damaging reactive oxygen species and more proteins that cause tissue damage.
  7. If the inflammation is not treated and persists over time, the tissue may become permanently damaged.

Vitamin D Balances Immune Reactivity in Autoimmune Diseases

Vitamin D intervenes in the process of autoimmunity by tilting the properties of T and B cells towards "tolerance" of self-tissues. Tolerance is a phenomenon orchestrated by a variety of highly specialized cytokines and other cell-signaling molecules.

Early in the developmental process of immune cells, they are directed to become either "effector" or "regulatory" immune cells. In other words, to become immune cells that promote tissue destruction, or those that suppress tissue destruction.

Patients with lupus have elevated numbers of effector cells and lower numbers of regulatory cells. Moreover, the regulatory cells of lupus patients are malfunctional.17 Vitamin D exerts multiple actions at the cellular level to balance the population of effector cells and regulatory cells.18 In a 2012 study, 20 lupus patients with initially low vitamin D blood levels received 100,000 IU of vitamin D weekly for four weeks, followed by 100,000 IU monthly for six months. The treatment resulted in significantly increased vitamin D blood levels (from 18 ng/mL at baseline to 51 ng/mL at 2- and 6-month follow-ups), decreased effector T-cell counts and anti-DNA antibodies, and increased regulatory T cells. Over the 6-month follow-up period, no disease flares were noted.19 These lines of evidence establish a very strong case for the importance of maintaining sufficient vitamin D blood levels to combat lupus disease activity. Life Extension suggests an optimal vitamin D blood level of 50–80 ng/mL (measured as 25-hydroxyvitamin D).

The Hormone Connection

The link between sex hormones as lupus disease activity has been the subject of debate for decades. The fact that women are considerably more likely to develop autoimmune diseases than men suggests that steroid hormones, especially estrogen and progesterone, influence the immune system.

Estrogen actions tend to be proinflammatory, while the actions of progesterone, androgens, and glucocorticoids are anti-inflammatory.20 Studies have documented low progesterone levels in women with lupus, suggesting that a relative imbalance in favor of estrogen may contribute to immune reactivity in some female patients.21

Accordingly, studies in women with lupus revealed an increased rate of mild to moderate intensity disease flares associated with estrogen-containing hormone replacement therapy.22 Experimental studies have suggested that testosterone may suppress immune reactivity in lupus animal models and in cells from patients with lupus.23,24

Based on the available data, Life Extension suggests that women with lupus evaluate their sex hormone levels and ensure that progesterone and testosterone levels are sufficient. If progesterone or testosterone levels are found to be low, women should consider using bioidentical progesterone or and/or testosterone creams to restore levels to a normal range.25

Kidneys

Kidney disease is a common complication in people with lupus; in fact, almost 50% of those with lupus have some degree of kidney disease.6 Like other affected tissues in lupus, damaging inflammation from autoimmune attack causes a kidney disease called lupus nephritis.

The circulatory system delivers blood to the glomeruli, which are the small filtering units of the kidneys, through small capillaries. Glomeruli help to regulate blood pressure and electrolytes by removing or reabsorbing fluids and salt according to the body’s needs. In people with lupus, the large autoantibodies/antigen complexes that circulate in the blood can become lodged in the glomeruli and cause damaging inflammation. The onset of kidney complications generally occurs at least five years after the onset of lupus symptoms.

A healthy kidney only allows small molecules like salts to be removed from the body, and allows large protein molecules to remain in the blood. However, kidney disease—including that caused by lupus nephritis—causes proteins to leak out of the kidney into urine. High levels of protein in the urine, clinically called proteinuria, are indicative of kidney damage. A normal level of protein in a 24-hour urine sample is below 300 mg.26

Heart and Cardiovascular

People with lupus are at a significantly increased risk of developing coronary artery disease (CAD). One study found that women between the ages of 35 and 44 who had lupus were 50 times more likely to have a heart attack than similar aged women without lupus.27 Additionally, heart disease is actually one of the most common causes of death for people with lupus.28 This increased heart disease risk in people with lupus is caused by a several different factors,29 including:

  1. Lupus-mediated inflammation can directly damage the endothelium, the lining of blood vessels, ultimately leading to atherosclerosis.
  2. Type 2 diabetes, high blood pressure, and high cholesterol are more likely to be present in people with lupus, all of which make the risk of heart disease greater.
  3. People with lupus are often less active because of various symptoms such as fatigue, joint pain and muscle pain. A low degree of activity is associated with unhealthy weight gain and high blood pressure, both of which are risk factors of heart disease.

People with lupus should be sure to do everything they can to take care of their heart and vascular system. The Life Extension Magazine article entitled "How to Circumvent 17 Independent Heart Attack Risk Factors" is an excellent resource to help ensure that every risk factor for cardiovascular disease is addressed.

Nervous System

Lupus may also damage the nervous system. The possible signs and symptoms include confusion, excessive tiredness, seizures, difficulty concentrating, and/or headaches.30 The exact mechanisms causing nervous system damage in lupus are still being investigated, but are likely due to two principle factors10,31:

  1. Specific autoantibodies may inappropriately target molecules on nerve cells, causing inflammation and subsequent nerve damage.
  2. Inflammation in and around blood vessels prevents the delivery of the nutrients and oxygen nerves need to stay healthy.

Additional signs and symptoms of nervous system involvement in lupus include a very stiff neck reminiscent of meningitis, a high fever, psychosis, and/or seizures.32 Severe neurological disease in lupus can lead to coma and even death and therefore immediate emergency medical attention should be sought at the first sign of these symptoms.

Muscles

Lupus also causes muscle pain, but fortunately, the strength of the muscle is not affected. Up to 16% of people with lupus experience this painful symptom, which commonly affects the arms and upper thighs.33

Bones

Loss of bone density is more common in people with lupus, which can lead to osteoporosis and a greater risk of fracture. The disease itself, and/or disease-related inactivity, can contribute to osteoporosis risk. However, exercise is often difficult or painful for individuals with lupus because of joint and muscle pain and stiffness. Additionally, certain conventional medications used to treat lupus, such as corticosteroids, can also accelerate bone loss.6

Blood Disorders

These disorders are, unfortunately, very common in people with lupus. Four potentially severe lupus-associated complications are blood count abnormalities. Blood cell counts are typically measured as number of cells in cubic millimeter of blood.

Anemia. Too few red blood cells. A complete blood count (CBC) is a common blood test in which all of the blood cell types are counted in a fixed volume. Normal results for men are 4.7 to 6.1 million red blood cells/µL of blood and normal results for women are 4.2 to 5.4 million red blood cells/µL.34

Thrombyocytopenia. Too few platelets in the blood. Platelets are small cell fragments that, when activated, stick together to form blood clots. Too few platelets may cause a delay in clot formation and excessive bleeding. Normal levels are between 150,000 to 450,000 platelets per cubic millimeter35; thrombocytopenia in context of lupus is defined as platelet levels below 100,000 per cubic millimeter.36

Leukopenia. A reduced level of leukocytes, also called white blood cells due to their lack of color. Defined as a count below 4,000 per cubic millimeter.36 Leukopenia increases the risk of potentially severe infections.

Lymphopenia. A reduced level of a subset of white blood cells called lymphocytes, defined as a count below 1,500 per cubic millimeter.36 B and T cells fall broadly into the leukocyte group and can be more specifically defined lymphocytes. Lymphopenia also increases the risk of severe infections.

7 Conventional Medicine’s Approach to Lupus Treatment

Since lupus potentially targets multiple organ systems, the type of treatment should be tailored for each individual person. Doctors may prescribe one, two, or more medicines at a time to maximize treatment response. An effective overall treatment strategy includes maintaining a healthy lifestyle—which may include conventional medicine, complementary medicine, exercise, good nutrition, and avoiding smoking and excessive sunlight—in order to reduce the frequency and severity of lupus flares. It is important to consider both the positive and detrimental effects of any treatment type before commencing a treatment plan.

Anti-Inflammatory Drugs

Several categories of conventional medications are available that reduce inflammation, which is the chief cause of symptoms in lupus. Many of these medicines are often quite effective at reducing symptoms and preventing severe flare-ups. Unfortunately, these medicines are commonly associated with significant adverse long-term side effects.

Corticosteroids. Corticosteroids (glucocorticoids) are one type of steroid with powerful, anti-inflammatory effects. Synthetic corticosteroids mimic the effects of natural corticosteroids produced in the body and effectively reduce inflammation in people with lupus.

The most common corticosteroid medicine prescribed to treat lupus is prednisone. It may be taken orally in pill form, or injected into the skin to treat rashes, or intramuscularly (IM) to treat muscle inflammation. Other corticosteroids include hydrocortisone, dexamethasone, and methylprednisolone.

The possible side effects of corticosteroids include easy bruising; fat redistribution leading to an increase in fat around the abdomen; weight-gain and insulin resistance; and psychological changes ranging from irritability and depression to euphoria. They may also lead to increased risk of complications from diabetes, high blood pressure, glaucoma, and may cause elevated triglyceride and cholesterol levels. If taken over the long term, corticosteroids cause bone loss and therefore leads to an elevated risk of bone fracture. Due to effects on triglyceride and cholesterol, long-term corticosteroid use could also contribute to an increased risk for atherosclerosis.37

Due to these potentially severe side effects, the lowest dose of corticosteroids that provides symptom relief is prescribed. Injected corticosteroids are usually only used to treat very severe disease flares; once symptoms come under control, oral administration is resumed.37,38

Non-steroidal anti-inflammatory drugs. Like corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) also suppress inflammation. However, NSAIDs are less effective for individuals with severe lupus than corticosteroids. NSAIDs, of which there are more than 20 types available, are both anti-inflammatory and analgesic, meaning they provide pain relief as well as reduce inflammation. Examples of NSAIDs include ibuprofen and naproxen. Although adverse effects are possible, and these risks are elevated in people with lupus, administration of NSAIDS with close monitoring by physicians can be helpful.39

NSAIDs operate by inhibiting the secretion of leukotrienes and prostaglandins that cause inflammation and pain. Possible side effects include stomach upset, nausea, and even gastrointestinal bleeding; fluid retention; kidney damage, and increases in blood pressure and heart attack risk.40

Aspirin may be particularly helpful in individuals who have anti-phospholipid antibodies, which can make blood particularly "sticky" and prone to clotting. In the case of patients who are discovered to have anti-phospholipid antibodies without any known thrombotic problems, the question of preventative (prophylactic) treatment is unresolved. Currently, aspirin is the general recommendation.41

Due to aspirin’s blood thinning, anti-inflammatory, and analgesic effects, doctors may recommend taking low-dose aspirin to reduce the risk of heart disease in people with lupus and relieve the pain of aching joints.42

Anti-Malarial Drugs

Although the original purpose was to treat the parasitic disease malaria, it was discovered more than 50 years ago that anti-malarial drugs were also effective in treating the symptoms of lupus through minor immune suppression. In people with lupus, these drugs have been shown to reduce inflammation in the lining of the lung (pleurisy) and heart (pericarditis), improve joint and muscle pain, and reduce fever and fatigue. Examples of anti-malarial drugs include chloroquine, hydroxychloroquine, and quinacrine.43-45

Possible side effects include gastrointestinal symptoms like nausea, vomiting, diarrhea, stomach cramps; headache, dizziness, and irritability; and the skin may darken in color and become very dry.45

Immune System Modulators

Immune system modulators treat lupus by altering the number or function of immune cells. As lupus is an immune-mediated disease, this approach is often effective.

Some immune system modulating drugs globally suppress the immune system, and are thus called immunosuppressive drugs. While the self-reactive immune cells are suppressed, the cells that fight against infections are also inhibited, which can lead to increased susceptibility to infections. Potentially severe side effect may occur with all immunosuppressive drugs. Examples of commonly prescribed immunosuppressive drugs include the following:

Cyclophosphamide. Cyclophosphamide has been used for several decades and is quite effective in treating lupus-related kidney disease. However, the side effects of cyclophosphamide can be severe and include nausea, vomiting, infertility, and hair loss. One study indicates that low-dose cyclophosphamide is still effective in treating individuals with lupus nephritis.46

Mycophenolate mofetil. This medicine is newer, more effective, and causes fewer side effects than cyclophosphamide. Due to these positive characteristics, mycophenolate mofetil has replaced cyclophosphamide as the first-line drug for the treatment of lupus.47-49

Azathioprine. Azathioprine is an immunosuppressive drug that also has fewer severe side effects than cyclophosphamide, and overall, data suggest it is similar in effectiveness.50

Monoclonal Antibodies

When an antibody "sticks" to the surface of a cell, it either blocks its function and/or tags the cell for removal from the body. Scientists have taken advantage of this quality of antibodies to design ones that stick to and induce the clearance of many different cell types, including B and T cells.

Monoclonal antibodies are created through a complex process involving culturing specialized immune cells with disease-specific stimuli (antigens) and purifying the antibodies that are produced as a result.

Monoclonal antibodies represent one of the greatest advancements in lupus treatment in recent history. The advent of monoclonal antibodies targeted towards receptors on the surface of B cells allows physicians to turn the immune system against itself, in a sense, and eradicate self-reactive B cells that underlie lupus pathology.

The Food and Drug Administration (FDA) has approved a few of these drugs to treat some diseases, especially certain types of cancer. Monoclonal antibodies also show promise as drugs to treat lupus.

One monoclonal antibody drug recently approved by the FDA to treat lupus is belimumab, which targets B-cell activating factor (BAFF), a protein involved in activation, differentiation, and proliferation of B cells.51-53 The FDA’s approval of belimumab for the treatment of lupus is a groundbreaking achievement, as this is the first new drug developed specifically for lupus that has been approved for the last 50 years.51 Belimumab is co-marketed by Human Genome Sciences and GlaxoSmithKline under the name Benlysta, with cost estimates exceeding $30,000 annually. However, insurance should cover this therapy in most cases, as few new therapeutic options for lupus exist.54

Rituximab is also a monoclonal antibody drug that targets a receptor on B-cell surfaces called CD20, thereby causing the immune system to destroy B cells. It was originally approved to treat lymphoma, and may be effective in other diseases characterized by too many or malfunctional B cells, including lupus. Currently, studies are mixed as to whether this drug is effective in treating lupus.55 Rituximab is not approved to treat lupus, but is often used off-label for this purpose by many physicians.

Other monoclonal antibody drugs that may be effective in treating lupus and are still being studied include epratuzumab, abetimus, ocrelizumab, and atacicept, all of which target B cells.55 Additional drugs are being developed and tested with targets such as T cells and pro-inflammatory proteins.

Currently, monoclonal antibody drugs face several challenges and may cause adverse reactions in some patients. However, scientists are quickly elucidating the role of particular proteins and receptors in the molecular physiology of lupus and it is very likely that monoclonal antibody therapy will become much more efficacious in the near future.

8 A Novel Approach: Stem Cells

A stem cell is unique in that it is a nonspecific cell type and has the potential to develop into many different types of specialized cells. These cells can divide and produce another stem cell to replenish itself or grow into a specialized cell, such as a nerve cell, brain cell, or a B cell.

Stem cell transplantation has the potential to revolutionize the treatment of several types of diseases. In this procedure, stem cells are taken from a person, grown in the laboratory into specialized cells, and then transplanted back into the individuals to replace diseased cells. To treat lupus, one approach is to take blood stem cells from a person with lupus and grow them in the laboratory into healthy new B and T cells that do not attack self-tissues. The next step is to replace the autoimmune B and T cells in an individual with the individual’s own new, healthy B and T cells.

This general approach is called autologous hematopoietic stem cell transplantation. The word "autologous" refers to the fact that the transplanted blood cells are derived from the person’s own stem cells; "hematopoietic" refers to the fact that the type of stem cell used is the precursor of blood cells like B and T cells. As of 2011, approximately 200 stem cell transplantations for the treatment of lupus have taken place.56

Data regarding the safety and efficacy of autologous stem cell transplantation is not yet plentiful, but some studies suggest that this treatment approach may be promising.

For example, in one small clinical study conducted in China, the disease status of almost 65% of patients did not get any worse over seven years.57 A comprehensive review of several studies that investigated autologous hematopoietic stem cell transplantation revealed that, in total, 81% of those that survived at least three years beyond the procedure showed some positive response to treatment.58 However, it is important to note that this analysis also found that an average of 11% of people who participated in these types of studies ultimately died because of transplant-related causes.

Stem cell transplantation is currently reserved for individuals with very severe disease who have not responded to conventional lupus treatments. In this population specifically, a remarkable 50% probability of 5-year disease free survival was achieved in the two largest studies to date exploring stem cell transplantation as a therapeutic option for lupus.56

9 The Influence of Lifestyle on Disease Activity

Lifestyle, including diet, physical activity, and stress levels, can have a potent effect on many different chronic diseases, including lupus. A healthy lifestyle is an important factor in preventing flares, reducing disease severity, and improving overall quality-of-life.

The level of stress an individual with lupus experiences can significantly affect disease. Whether this stress comes from work, finances, relationships, or from managing this chronic disease, it can trigger flares or worsen lupus severity. A recent study found that the people with lupus who had a greater ability to cope with stress reported a greater quality-of-life.59 Additional data suggest people who participate in a short stress-management program may have less pain.60

Ultra-violet (UV) light from the sun can cause or exacerbate the skin lesions often associated with lupus, and therefore avoiding or reducing exposure to the sun may be necessary for some people to avoid triggering these symptoms. One study found that photosensitivity was tightly linked with lupus disease, irrespective of the type of lupus, the level of serum autoantibodies, and use of anti-inflammatory medications.61 Fortunately, avoiding sun exposure or applying sunscreen is quite effective in preventing the damaging effects of UV light.62 Ironically, the need to avoid exposure to sunlight may exacerbate the widespread vitamin D deficiency in lupus patients.

Exercising regularly is important for everyone’s health, but is especially important for individuals with lupus. Exercise helps prevent inflamed joints from becoming excessively stiff and keeps muscles, bones, and cartilage strong.63 Physical activity has also been shown to improve physical fitness in individuals with lupus, but can also help improve feelings of depression and overall quality-of-life.64 Exercise can be daunting to those who are already feeling ill because of lupus, but remaining active is an important part of remaining as healthy as possible, even during flares. Those feeling too ill for more vigorous exercise can participate in gentle range-of-motion exercises so that muscles and joints can remain as flexible as possible.

One small pilot study with individuals with lupus confirmed that both aerobic exercise and the more gentle range-of-motion exercises are safe for people with lupus and did not worsen signs or symptoms.65

10 Nutrition and Lupus Disease Activity

Vitamin D

Vitamin D is an essential nutrient, and the precursor to the active form is produced in the skin after absorbing ultra-violet light. Other sources of vitamin D include fatty fish like salmon and mackerel; fortified foods like margarine, milk, and breakfast cereals; and vitamin D supplements.66

Studies have shown that vitamin D may be important in reducing the risk of lupus.67 It has been shown that higher blood levels of vitamin d are associated with less severe lupus disease activity.68

Two observational studies found that women with systemic lupus erythematosus have significantly lower levels of 25-hydroxy vitamin D.2,69 Another study found that, while 22% of healthy control women had a deficiency in vitamin D, 69% of women with lupus exhibited a deficiency in this vitamin.5

Reduced levels of vitamin D in people with lupus may be due to one or both of two possible scenarios:

  1. The deficiency is related to the disease itself; or
  2. The deficiency is caused/exacerbated by avoiding sun exposure due to increased photosensitivity of individuals with lupus.

As previously discussed, lupus and some of its treatments can cause bone loss and lead to osteoporosis. Healthy levels of vitamin D are necessary to help the body absorb calcium and keep bones as strong as possible and this is especially important in individuals with lupus.

Life Extension suggests that 25-hydroxyvitamin D levels be kept between 50 and 80 ng/mL for optimal health. This usually necessitates supplementation with 5,000–8,000 IU vitamin D daily for most individuals. However, supplemental doses should always be determined based upon blood test results.

Fish Oil

The oil from fatty fish, such as mackerel, tuna, salmon, and halibut, is especially rich in omega-3 fatty acids.70 Fish oil is rich in two types of omega-3 fatty acids: docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

Omega-3 fatty acids, also sometimes referred to as polyunsaturated fatty acids (PUFAs), promote health in a number of ways. EPA and DHA are of particular interest in autoimmune diseases, including lupus.

Similar to vitamins, the body needs EPA and DHA, but can only produce them in very limited quantities. Therefore, these fatty acids must be included in the diet in adequate amounts.71

Recent evidence has revealed a critical role for EPA and DHA in establishing balanced immunity in autoimmune disease. Experimental studies found that EPA was able to induce immune cells into a regulatory phenotype, thus countering the action of aggressive effector immune cells.72

Two clinical studies found that taking fish oil reduced lupus severity.73,74 Another study found that taking fish oil reduced the level of serum lipids in people with lupus,75 which may be useful as they are at a greater risk of developing heart disease.

The ratio between inflammatory omega-6 fatty acids and anti-inflammatory omega-3 fatty acids in the blood is of critical importance in autoimmune diseases. If the ratio is too high, disease activity may increase.76 Life Extension recommends that everyone strive to maintain an omega-6 to omega-3 ratio of 4:1 or lower. Readers can learn more about the importance of the omega-6 to omega-3 ratio and how to test it in the Life Extension Magazine article entitled "Optimize Your Omega-3 Status."

Vitamin E

There are several forms of vitamin E, four tocopherols and four tocotrienols, each of which has different levels of activity in the human body. Vitamin E has been shown to reduce several different markers of inflammation in the body, including inflammatory cytokines.77 Since inflammation is responsible for the widespread tissue damage in lupus, antioxidant vitamins may aid in prevention or delay of the disease.

Vitamin E helps stabilize membranes of lysosomes, or immune cells that contain destructive enzymes used to fight intruders. When membranes are unstable, these enzymes cause damage to surrounding healthy tissue. Vitamin E can help prevent the onset of autoimmune attacks by stabilizing membranes of lysosomes.78 The symptoms of mice with lupus that were treated with vitamin E greatly improved. The mice lived longer, immune cell activity was normalized, anti-DNA antibodies were reduced, and kidney function improved.79

One study indicates that vitamin E can reduce the level of autoantibodies in lupus patients,80 but further studies are needed to confirm these effects. A case report of two patients indicates that a topical formula containing vitamin E improves the health of skin in people with discoid lupus erythematosus.45

Vitamin A

The active form of vitamin A, called retinol, is important for healthy skin, bones, and soft tissues,81 and supports healthy immune function.82 Since people with lupus have an abnormally functioning immune system and a higher risk of osteoporosis, healthy vitamin A levels are especially important for this population. Interestingly, one study showed that people with lupus consumed less vitamin A in their diets than age-matched healthy controls, which may contribute to a vitamin A deficiency.83

Consumption of beta-carotene, a vitamin A precursor, is an ideal way to ensure that vitamin A levels are sufficient while simultaneously avoiding vitamin A toxicity. The body will convert beta-carotene into active vitamin A as necessary and excrete any excess.

Plants and Herbs

Curcumin. Curcumin, a bioactive derivative of the spice turmeric, has been tested over the last several years for its antioxidant, anti-cancer, and anti-inflammatory clinical properties. Curcumin decreases the ability of lupus autoantibodies to bind their specific antigens an average of 52%.84 The damaging inflammation of lupus-mediated injury is facilitated by the binding of autoantibodies to protein and nucleic acid antigens. Therefore, successful blocking of antigen/autoantibody binding suppresses inflammation before it even begins.

Experimental studies have revealed a considerable role for curcumin in modulating inflammatory cross-talk between cells of the immune system by suppressing cytokines such as IL-1beta, IL-6, IL-12 and tumor necrosis factor-alpha (TNF-α).85 Moreover, a recent animal model of an autoimmune disease identified nuclear factor-kappa beta (NF-kβ) suppression as a key mechanism behind curcumin’s anti-inflammatory action.

A clinical trial tested the effects of curcumin in 24 patients with the lupus-associated kidney disease lupus nephritis. One group of patients took 500 mg of turmeric daily over a 3-month period, which is equivalent to a daily curcumin dose of 22.1 mg. Compared with the placebo group, the turmeric group exhibited significant improvement in proteinuria.86

Although some clinical studies have been conducted showing some signs and symptoms are reduced in some autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, clinical studies have not yet been conducted to determine if curcumin has a similar effect with lupus.85 However, these results are promising and suggest potential beneficial effects of curcumin in people with lupus.

Ginkgo. Ginkgo biloba, or more simply "ginkgo," is an herb that has been used for thousands of years in traditional Chinese medicine. This nutrient is often prepared by making an extract from the dried leaves. These extracts contain high concentrations of molecules called flavonoids and terpenoids, which are antioxidants and improve blood flow, respectively.87

A clinical study revealed that taking 120 mg of Ginkgo biloba extract three times per day for 10 weeks significantly reduced the number of Raynaud’s phenomenon attacks, a set of symptoms that often affect people with lupus.88

Pine bark extract. There is evidence that extract from the bark of the pine tree (Pinus pinaster) helps improve lupus inflammation, although more information is likely needed to make definite conclusions about this ingredient.

One study found that administration of pine bark extract reduced oxidative stress and improved lupus signs and symptoms in six patients that received the supplement in addition to prescription medications compared to a placebo group.89 Specifically, the patients who took pine bark extract exhibited a reduction in SLEDAI score, meaning that disease as a whole was decreased.

White peony extract. White peony (Paeonia lactiflora) root is a traditional Chinese medicinal herb that contains bioactive compounds called glucosides. A water and alcohol extract of the peony root, known as total glucosides of peony, has more than 15 identified compounds. The most active and abundant of these is paeoniflorin, which represents more than 90% of the total glucosides of peony.90,91 A number of studies have shown paeoniflorin and total glucosides of peony have immunomodulatory, anti-inflammatory, and pain-relieving properties, and provide supportive evidence for peony’s historical use in the treatment of autoimmune conditions, including lupus.90-92

One study that examined case histories of lupus patients treated with total glucosides of peony found that consistent treatment for five years or more was associated with lower medication dosages and lower disease activity compared with patients who had not used peony extract.93 In a mouse model of lupus, levels of lupus antibodies decreased significantly and disease-associated kidney damage was reduced after 15 and 30 days of treatment with total glucosides of peony.94

Laboratory and animal investigations indicate in conditions of immune over-activation, total glucosides of peony strengthen immune regulation and quiet immune over-activity.91 Total glucosides of peony was found in a laboratory study to induce the differentiation of immune cells affected by lupus into regulatory cells capable of quieting immune over-activity.95 Paeoniflorin alone has also demonstrated immune-regulatory effects in immune cells.96,97

Other Natural Therapies

Dehydroepiandrosterone. Dehydroepiandrosterone (DHEA) is a hormone naturally produced by the adrenal gland and is converted into sex hormones. In addition to being produced in the body, DHEA can be derived from the Mexican yam.81

Low levels of DHEA-s, a plentiful metabolite of DHEA in humans, have been observed in patients with lupus and other inflammatory diseases.98 DHEA and its various metabolites exert considerable influence over immune system activity by regulating production of multiple cytokines including IL-2, IL-1, IL-6 and TNF-α.98

In a clinical trial, when individuals with lupus took 200 mg of DHEA daily for 24 weeks, the number of patients who experienced lupus flares was significantly reduced.99 In another study, the same investigators showed that taking 200 mg of DHEA daily for 24 weeks reduced blood levels of the cytokine IL-10, which enhances antibody production.100 This reduction in IL-10 may have contributed to the reduced incidence of lupus flares seen in the first study.

Another double-blind, randomized, controlled trial involving 41 women found that six months treatment with 20–30 mg DHEA daily improved mental and emotional well-being in lupus patients.101 Also, at a dose of 200 mg daily, DHEA improved bone mineral density in postmenopausal women with lupus.102

Life Extension suggests that DHEA-s blood levels be kept between 350–490 µg/dL for men and 275–400 µg/dL for women in order to achieve optimal immunomodulatory action.

Plants to Avoid

Alfalfa

The seeds of the alfalfa plant have the potential to cause transient lupus-like symptoms, including autoimmune-related anemia, in certain people and primates.103,104 Alfalfa seeds are rich in the amino acid L-canavanine, which was shown to be the responsible triggering agent in humans, and in certain types of mice.103,105 Due to these potential effects, people with lupus should avoid alfalfa seeds.

Echinacea

Echinacea is an herb that has long been used to promote a strong immune system to prevent and/or infections like the flu and colds.106 Considering that lupus is a disease characterized by an overactive immune system, people with lupus would likely benefit from staying away from echinacea, which has been shown to be an immune system stimulant. While studies have not yet been conducted to determine the effect of echinacea specifically on lupus, case studies have shown that taking this herb can exacerbate the severity of other autoimmune diseases.107 Additionally, a number of studies have shown that echinacea can induce human immune cells to secrete proinflammatory cytokines that are known to play a role in lupus disease.108 People with lupus should avoid echinacea.

Tripterygium wilfordii (Thunder God Vine)

Some reports exist in the scientific literature suggesting that using Thunder God Vine, a Chinese herbal, may ameliorate symptoms associated with autoimmune diseases.109 Due to these reports, Thunder God Vine is sometimes suggested by alternative health resources to those with lupus. However, Life Extension has reviewed the available scientific literature and concluded that, in most cases, the risk outweighs the potential benefit with this plant.

Several reports of severe toxicity and even death associated with the use of Thunder God Vine are available, and it appears that the dose required for clinical effectiveness is very close to that required to cause toxicity.110,111 Another report linked Thunder God Vine use with low bone mineral density in women.112

Life Extension does not suggest that use of Tripterygium wilfordii outside of a clinical setting. If a healthcare practitioner decides to use this therapy with patients, only a standardized extract of the skinned root should be used, as other parts of the plant are highly toxic.113

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

  1. Lupus Foundation of America. Understanding Lupus. 2011 8/11//2011]; Available from: http://www.lupus.org/clinicaltrials/understanding-lupus.html.
  2. Toloza, S.M., et al., Vitamin D insufficiency in a large female SLE cohort. Lupus, 2010. 19(1): p. 13-9.
  3. Lemire, J.M., Immunomodulatory role of 1,25-dihydroxyvitaminD3. Journal of cellular biochemistry, 1992. 49(1): p. 26-31.
  4. Damanhouri LH. Vitamin D deficiency in Saudi patients with systemic lupus erythematosus. Saudi Med J. 2009. 30(10): p. 1291-5.
  5. Ritterhouse, L.L., et al., Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus. Annals of the rheumatic diseases, 2011. 70(9): p. 1569-74.
  6. Womenshealth.gov. Lupus Fact Sheet. 2011 9/24/2011]; Available from: http://www.womenshealth.gov/publications/our-publications/fact-sheet/lupus.cfm.
  7. Clowse, M.E., et al., A national study of the complications of lupus in pregnancy. American journal of obstetrics and gynecology, 2008. 199(2): p. 127 e1-6.
  8. Kwok, L.W., et al., Predictors of maternal and fetal outcomes in pregnancies of patients with systemic lupus erythematosus. Lupus, 2011. 20(8): p. 829-36.
  9. Smyth, A. and V.D. Garovic, Systemic lupus erythematosus and pregnancy. Minerva urologica e nefrologica = The Italian journal of urology and nephrology, 2009. 61(4): p. 457-74.
  10. Firestein, G.S. and W.N. Kelley, Kelley's textbook of rheumatology. 8th ed2009, Philadelphia, PA: Saunders/Elsevier.
  11. White, P.H., Pediatric systemic lupus erythematosus and neonatal lupus. Rheumatic diseases clinics of North America, 1994. 20(1): p. 119-27.
  12. Silverman, E. and E. Jaeggi, Non-cardiac manifestations of neonatal lupus erythematosus. Scandinavian journal of immunology, 2010. 72(3): p. 223-5.
  13. Wisuthsarewong, W., J. Soongswang, and R. Chantorn, Neonatal lupus erythematosus: clinical character, investigation, and outcome. Pediatric dermatology, 2011. 28(2): p. 115-21.
  14. Phillips, R.H., Coping with lupus : a guide to living with lupus for you and your family1991, Garden City Park, N.Y.: Avery Pub. Group. xii, 276 p.
  15. Griffiths, B., M. Mosca, and C. Gordon, Assessment of patients with systemic lupus erythematosus and the use of lupus disease activity indices. Best practice & research. Clinical rheumatology, 2005. 19(5): p. 685-708.
  16. Smith, P.P. and C. Gordon, Systemic lupus erythematosus: clinical presentations. Autoimmunity reviews, 2010. 10(1): p. 43-5.
  17. Bonelli M et al. Treg and lupus. Ann Rheum Dis. 2010 Jan;69Suppl1:i65-66.
  18. Bruce D et al. Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling. IntImmunol. 2011 Aug;23(8):519-28. Epub 2011 Jun 22.
  19. Terrier B, Derian N, Schoindre Y, et al. Costedoat-Chalumeau N. Restoration of regulatory and effector T cell balance and B cell homeostasis in systemic lupus erythematosus patients through vitamin D supplementation. Arthritis research & therapy. Oct 17 2012;14(5):R221.
  20. Cutolo M et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus. 2004;13(9):635-8.
  21. Shabanova SS et al. Ovarian function and disease activity in patients with systemic lupus erythematosus. ClinExpRheumatol. 2008 May-Jun;26(3):436-41.
  22. Buyon JP, Petri MA, et al. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med . 2005 Jun 21;142(pt 1):953-62.
  23. Walker SE et al. Accelerated deaths from systemic lupus erythematosus in NZB x NZWF1 mice treated with the testosterone-blocking drug flutamide. J Lab Clin Med. 1994;124(3):401-7.
  24. Kanda N et al. Testosterone suppresses anti-DNA antibody production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1703-11.
  25. Gompel A et al. Systemic lupus erythematosus and hormone replacement therapy. Menopause Int. 2007 Jun;13(2):65-70.
  26. Levey, A.S., et al., Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney international, 2005. 67(6): p. 2089-100.
  27. Manzi, S., et al., Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. American journal of epidemiology, 1997. 145(5): p. 408-15.
  28. Trager, J. and M.M. Ward, Mortality and causes of death in systemic lupus erythematosus. Current opinion in rheumatology, 2001. 13(5): p. 345-51.
  29. Kahlenberg, J.M. and M.J. Kaplan, The interplay of inflammation and cardiovascular disease in systemic lupus erythematosus. Arthritis research & therapy, 2011. 13(1): p. 203.
  30. Nowicka-Sauer, K., et al., Neuropsychological assessment in systemic lupus erythematosus patients: clinical usefulness of first-choice diagnostic tests in detecting cognitive impairment and preliminary diagnosis of neuropsychiatric lupus. Clinical and experimental rheumatology, 2011. 29(2): p. 299-306.
  31. Huizinga, T.W. and B. Diamond, Lupus and the central nervous system. Lupus, 2008. 17(5): p. 376-9.
  32. Muscal, E. and R.L. Brey, Neurologic manifestations of systemic lupus erythematosus in children and adults. Neurologic clinics, 2010. 28(1): p. 61-73.
  33. Record, J.L., T. Beukelman, and R.Q. Cron, High prevalence of myositis in a southeastern United States pediatric systemic lupus erythematosus cohort. Pediatric rheumatology online journal, 2011. 9: p. 20.
  34. MedlinePlus. CBC. 2010 09/04/11]; Available from: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm.
  35. McCrae, K.R., Thrombocytopenia. Basic and clinical oncology2006, New York: Taylor & Francis. xii, 315 p.
  36. Hochberg MC et al. American College of Rheumatology. American College of Rheumatology Revised Criteria for Classification of Systemic Lupus Erythematosus. 1997 (Update from 1982) 09/04/11]; Available from: http://www.rheumatology.org/practice/clinical/classification/SLE/ 1997_update_of_the_1982_acr_revised_criteria_for_classification_of_sle.pdf.
  37. Doria, A., et al., Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Annals of the rheumatic diseases, 2003. 62(11): p. 1071-7.
  38. Cameron, J.S., Lupus nephritis. Journal of the American Society of Nephrology : JASN, 1999. 10(2): p. 413-24.
  39. Horizon, A.A. and D.J. Wallace, Risk:benefit ratio of nonsteroidal anti-inflammatory drugs in systemic lupus erythematosus. Expert opinion on drug safety, 2004. 3(4): p. 273-8.
  40. Bjarnason, I., et al., Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology, 1993. 104(6): p. 1832-47.
  41. Bruce IN. Cardiovascular disease in lupus patients: should all patients be treated with statins and aspirin? Best Pract Res ClinRheumatol. 2005 Oct;19(5):823-38.
  42. Verheugt, F.W. and A.C. Bolte, The role of aspirin in women's health. International journal of women's health, 2011. 3: p. 151-66.
  43. Ben-Zvi, I., et al., Hydroxychloroquine: From Malaria to Autoimmunity. Clinical reviews in allergy & immunology, 2011.
  44. Chang, A.Y., et al., Response to Antimalarial Agents in Cutaneous Lupus Erythematosus: A Prospective Analysis. Archives of dermatology, 2011.
  45. Yildirim-Toruner, C. and B. Diamond, Current and novel therapeutics in the treatment of systemic lupus erythematosus. The Journal of allergy and clinical immunology, 2011. 127(2): p. 303-12; quiz 313-4.
  46. Mitwalli, A.H., et al., Comparison of high and low dose of cyclophosphamide in lupus nephritis patients: A long-term randomized controlled trial. Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia, 2011. 22(5): p. 935-40.
  47. Walsh, M., et al., Mycophenolatemofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis. Clinical journal of the American Society of Nephrology : CJASN, 2007. 2(5): p. 968-75.
  48. Shum, K. and A. Askanase, Treatment of lupus nephritis. Current Rheumatology Reports. 2011. 13(4): p. 283-90.
  49. Hahn, B.H., Targeted therapies in systemic lupus erythematosus: successes, failures and future. Annals of the rheumatic diseases, 2011. 70 Suppl 1: p. i64-i66.
  50. Houssiau, F.A., et al., Azathioprine versus mycophenolatemofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Annals of the rheumatic diseases, 2010. 69(12): p. 2083-9.
  51. Thanou-Stavraki, A. and A.H. Sawalha, An update on belimumab for the treatment of lupus. Biologics : targets & therapy, 2011. 5: p. 33-43.
  52. Food and Drug Administration (FDA). Medication Guide: Benlystaj (beliimumab) -- Injection for intravenous use. 2011 09/28/11]; Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM247030.pdf.
  53. Sabahi, R. and J.H. Anolik, B-cell-targeted therapy for systemic lupus erythematosus. Drugs, 2006. 66(15): p. 1933-48.
  54. Pollack A. "F.D.A. Panel Backs Drug for Lupus". New York Times 11/17/2010. Available at http://www.nytimes.com/2010/11/17/health/17drug.html.
  55. Haubitz, M., New and emerging treatment approaches to lupus. Biologics : targets & therapy, 2010. 4: p. 263-71.
  56. Illei, G.G., et al., Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus. Annals of the rheumatic diseases, 2011.
  57. Song, X.N., et al., Autologous stem cell transplantation for systemic lupus erythematosus: report of efficacy and safety at 7 years of follow-up in 17 patients. Transplantation proceedings, 2011. 43(5): p. 1924-7.
  58. Gratwohl, A., et al., Autologous hematopoietic stem cell transplantation for autoimmune diseases. Bone marrow transplantation, 2005. 35(9): p. 869-79.
  59. Hyphantis, T., et al., Coping with health-stressors and defence styles associated with health-related quality of life in patients with systemic lupus erythematosus. Lupus, 2011. 20(9): p. 893-903.
  60. Greco, C.M., T.E. Rudy, and S. Manzi, Effects of a stress-reduction program on psychological function, pain, and physical function of systemic lupus erythematosus patients: a randomized controlled trial. Arthritis and rheumatism, 2004. 51(4): p. 625-34.
  61. Sanders, C.J., et al., Photosensitivity in patients with lupus erythematosus: a clinical and photobiological study of 100 patients using a prolonged phototest protocol. The British journal of dermatology, 2003. 149(1): p. 131-7.
  62. Kuhn, A., et al., Photoprotective effects of a broad-spectrum sunscreen in ultraviolet-induced cutaneous lupus erythematosus: a randomized, vehicle-controlled, double-blind study. Journal of the American Academy of Dermatology, 2011. 64(1): p. 37-48.
  63. Chilibeck, P.D., D.G. Sale, and C.E. Webber, Exercise and bone mineral density. Sports medicine, 1995. 19(2): p. 103-22.
  64. Carvalho, M.R., et al., Effects of supervised cardiovascular training program on exercise tolerance, aerobic capacity, and quality of life in patients with systemic lupus erythematosus. Arthritis and rheumatism, 2005. 53(6): p. 838-44.
  65. Ramsey-Goldman, R., et al., A pilot study on the effects of exercise in patients with systemic lupus erythematosus. Arthritis care and research : the official journal of the Arthritis Health Professions Association, 2000. 13(5): p. 262-9.
  66. Berdanier, C.D., J.T. Dwyer, and E.B. Feldman, Handbook of nutrition and food. 2nd ed2008, Boca Raton: Taylor & Francis. 1265 p.
  67. Cantorna, M.T. and B.D. Mahon, Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Experimental biology and medicine, 2004. 229(11): p. 1136-42.
  68. Amital, H., et al., Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D? Annals of the rheumatic diseases, 2010. 69(6): p. 1155-7.
  69. Borba, V.Z., et al., Vitamin D deficiency in patients with active systemic lupus erythematosus. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 2009. 20(3): p. 427-33.
  70. Kris-Etherton, P.M., et al., Polyunsaturated fatty acids in the food chain in the United States. The American journal of clinical nutrition, 2000. 71(1 Suppl): p. 179S-88S.
  71. Connor, W.E., Importance of n-3 fatty acids in health and disease. The American journal of clinical nutrition, 2000. 71(1 Suppl): p. 171S-5S.
  72. Iwami D, Nonomura K, Shirasugi N, et al. Immunomodulatory effects of eicosapentaenoic acid through induction of regulatory T cells. Int Immunopharmacol. 2011. 11(3): p. 384-9.
  73. Duffy, E.M., et al., The clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus. The Journal of rheumatology, 2004. 31(8): p. 1551-6.
  74. Walton, A.J., et al., Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus. Annals of the rheumatic diseases, 1991. 50(7): p. 463-6.
  75. Clark, W.F., et al., Fish oil in lupus nephritis: clinical findings and methodological implications. Kidney international, 1993. 44(1): p. 75-86.
  76. Simopoulos AP. The importance if the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood). 2008. 233(6): p. 674-88.
  77. Singh, U., S. Devaraj, and I. Jialal, Vitamin E, oxidative stress, and inflammation. Annual review of nutrition, 2005. 25: p. 151-74.
  78. Ayres S Jr, Mihan R. Is vitamin E involved in the autoimmune mechanism? Cutis. 1978 Mar;21(3):321-5.
  79. Weimann BJ, Hermann D. Inhibition of autoimmune deterioration in MRL/lpr mice by vitamin E. Int J VitamNutr Res . 1999 Jul;69(4):255-61.
  80. Maeshima, E., et al., The efficacy of vitamin E against oxidative damage and autoantibody production in systemic lupus erythematosus: a preliminary study. Clinical rheumatology, 2007. 26(3): p. 401-4.
  81. Coates, P.M., Encyclopedia of dietary supplements, 2010, Informa Healthcare,: New York. p. 1 online resource (xix, 898 p.).
  82. Harbige, L.S., Nutrition and immunity with emphasis on infection and autoimmune disease. Nutrition and health, 1996. 10(4): p. 285-312.
  83. Bae, S.C., S.J. Kim, and M.K. Sung, Impaired antioxidant status and decreased dietary intake of antioxidants in patients with systemic lupus erythematosus. Rheumatology international, 2002. 22(6): p. 238-43.
  84. Kurien, B.T., A. D'Souza, and R.H. Scofield, Heat-solubilized curry spice curcumin inhibits antibody-antigen interaction in in vitro studies: a possible therapy to alleviate autoimmune disorders. Molecular nutrition & food research, 2010. 54(8): p. 1202-9.
  85. Bright, J.J., Curcumin and autoimmune disease. Advances in experimental medicine and biology, 2007. 595: p. 425-51.
  86. Khajehdehi, P., et al., Oral Supplementation of Turmeric Decreases Proteinuria, Hematuria, and Systolic Blood Pressure in Patients Suffering from Relapsing or Refractory Lupus Nephritis: A Randomized and Placebo-controlled Study. Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation, 2011.
  87. McKenna, D.J., K. Jones, and K. Hughes, Efficacy, safety, and use of ginkgo biloba in clinical and preclinical applications. Alternative therapies in health and medicine, 2001. 7(5): p. 70-86, 88-90.
  88. Muir, A.H., et al., The use of Ginkgo biloba in Raynaud's disease: a double-blind placebo-controlled trial. Vascular medicine, 2002. 7(4): p. 265-7.
  89. Stefanescu, M., et al., Pycnogenol efficacy in the treatment of systemic lupus erythematosus patients. Phytotherapy research : PTR, 2001. 15(8): p. 698-704.
  90. Feng Z, Xu J, He G, Cao M, Duan L, Chen L, Wu Z. The Efficacy and Safety of the Combination of Total Glucosides of Peony and Leflunomide for the Treatment of Rheumatoid Arthritis: A Systemic Review and Meta-Analysis. Evidence-based complementary and alternative medicine: eCAM. 2016;2016:9852793.
  91. He DY, Dai SM. Anti-inflammatory and immunomodulatory effects of paeonia lactiflora pall., a traditional chinese herbal medicine. Frontiers in pharmacology. 2011;2:10.
  92. Zhang W, Dai SM. Mechanisms involved in the therapeutic effects of Paeonia lactiflora Pallas in rheumatoid arthritis. International immunopharmacology. Sep 2012;14(1):27-31.
  93. Zhang HF, Xiao WG, Hou P. [Clinical study of total glucosides of paeony in patients with systemic lupus erythematosus]. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine / Zhongguo Zhong xi yi jie he xue hui, Zhongguo Zhong yi yan jiu yuan zhu ban. Apr 2011;31(4):476-479.
  94. Ding ZX, Yang SF, Wu QF, et al. [Therapeutic effect of total glucosides of paeony on lupus nephritis in MRL/lpr mice]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University. Apr 2011;31(4):656-660.
  95. Zhao M, Liang GP, Tang MN, et al. Total glucosides of paeony induces regulatory CD4(+)CD25(+) T cells by increasing Foxp3 demethylation in lupus CD4(+) T cells. Clinical immunology (Orlando, Fla.). May 2012;143(2):180-187.
  96. Zhang J, Li H, Huo R, et al. Paeoniflorin selectively inhibits LPS-provoked B-cell function. Journal of pharmacological sciences. May 2015;128(1):8-16.
  97. Zhai T, Sun Y, Li H, et al. Unique immunomodulatory effect of paeoniflorin on type I and II macrophages activities. Journal of pharmacological sciences. Mar 2016;130(3):143-150.
  98. Sawalha AH et al. Dehydroepiandrosterone in systemic lupus erythematosus. CurrRheumatol Rep. 2008 Aug;10(4):286-91.
  99. Chang, D.M., et al., Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized, double-blind, placebo-controlled trial. Arthritis and rheumatism, 2002. 46(11): p. 2924-7.
  100. Chang, D.M., et al., Dehydroepiandrosterone suppresses interleukin 10 synthesis in women with systemic lupus erythematosus. Annals of the rheumatic diseases, 2004. 63(12): p. 1623-6.
  101. Nordmark G et al. Effects of dehydroepiandrosterone supplement on health-related quality of life in glucocorticoid treated female patients with systemic lupus erythematosus. Autoimmunity. 2005 Nov;38(7):531-40.
  102. Hartkamp A et al. The effect of dehydroepiandrosterone on lumbar spine bone mineral density in patients with quiescent systemic lupus erythematosus. Arthritis Rheum. 2004 Nov;50(11):3591-5.
  103. Montanaro, A. and E.J. Bardana, Jr., Dietary amino acid-induced systemic lupus erythematosus. Rheumatic diseases clinics of North America, 1991. 17(2): p. 323-32.
  104. Bardana, E.J., Jr., et al., Diet-induced systemic lupus erythematosus (SLE) in primates. American journal of kidney diseases : the official journal of the National Kidney Foundation, 1982. 1(6): p. 345-52.
  105. Akaogi, J., et al., Role of non-protein amino acid L-canavanine in autoimmunity. Autoimmunity reviews, 2006. 5(6): p. 429-35.
  106. Barrett, B., Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial. The Journal of pediatrics, 2004. 145(1): p. 135-6.
  107. Lee, A.N. and V.P. Werth, Activation of autoimmunity following use of immunostimulatory herbal supplements. Archives of dermatology, 2004. 140(6): p. 723-7.
  108. Spelman, K., et al., Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators. Alternative medicine review : a journal of clinical therapeutic, 2006. 11(2): p. 128-50.
  109. Chen YZ et al. Meta-analysis of Tripterygiumwilfordii Hook F in the immunosuppressive treatment of IgA nephropathy. Intern Med. 2010;49(19):2049-55. Epub 2010 Oct 1.
  110. Huang GZ et al. [Pathological study on autopsy died of Tripterygium intoxication--report of 4 cases]. ZhongguoZhong Xi Yi Jie He ZaZhi. 2009 Feb;29(2):165-8.
  111. Wang BX et al. [A tablet of Tripterygiumwilfordii in treating lupus erythematosus]. Zhong Xi Yi Jie He ZaZhi. 1989 Jul;9(7):407-8, 389.
  112. Huang L et al. Decreased bone mineral density in female patients with systemic lupus erythematosus after long-term administration of TripterygiumWilfordii Hook. F. Chin Med J (Engl). 2000 Feb;113(2):159-61.
  113. NCCAM. National Center for Complementary and Alternative Medicine. "Thunder God Vine". Available at: http://nccam.nih.gov/health/tgvine/ Accessed 10/18/2011.