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Lupus: Systemic Lupus Erythematosus (SLE)

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 (Lupus Foundation 2011).

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 lead 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 (Toloza 2010; Lemire 1992). For example, one study found that a mere 1.2% of lupus patients had adequate vitamin D levels, compared to 45% of healthy controls (Damanhouri 2009); another found that lower vitamin D levels were linked with more aggressive lupus autoimmunity (Ritterhouse 2011).

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.

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 (Lupus Foundation 2011). Lupus is also more likely to develop in African-American, Asian American, Native American, and Latina women compared with Caucasian women (Womenshealth.gov 2011). 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) (Clowse 2008). Women who experience a "flare" within 6 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 (Kwok 2011). Consequently, doctors generally advise women with lupus to plan pregnancies after 12 to 18 months of remission, and definitely not before 6 months of remission (Smyth 2009).

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 (Firestein 2009).

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 chapter, 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 (White 1994). Although most of the babies born of women with lupus are healthy (Womenshealth.gov 2011), more than half of infants with neonatal lupus have problems with their skin, heart, and/or gallbladder (Silverman 2010; Wisuthsarewong 2011). 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 (Wisuthsarewong 2011).

LUPUS 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 (Phillips 1991). 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 include (Firestein 2009; Griffiths 2005):

  • 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 an individual 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 (adapted from Griffiths 2005; Smith 2010).

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 ore 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 (Griffiths 2005; Smith 2010).

LUPUS PATHOPHYSIOLOGY

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 (Bonelli 2010). Moreover, the regulatory cells of lupus patients are malfunctional (Bonelli 2010). Vitamin D exerts multiple actions at the cellular level to balance the population of effector cells and regulatory cells (Bruce 2011). In a 2012 study, 20 lupus patients with initially low vitamin D blood levels received 100 000 IU of vitamin D weekly for 4 weeks, followed by 100 000 IU monthly for 6 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 (Terrier 2012) 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).

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 (Womenshealth.gov 2011). 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 5 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 (Levey 2005).

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 (Manzi 1997). Additionally, heart disease is actually one of the most common causes of death for people with lupus (Trager 2001). This increased heart disease risk in people with lupus is caused by a several different factors (Kahlenberg 2011), 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 (Nowicka-Sauer 2011). The exact mechanisms causing nervous system damage in lupus are still being investigated, but are likely due to two principle factors (Huizinga 2008; Firestein 2009):

  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 (Muscal 2010). 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 (Record 2011).

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 (Womenshealth.gov 2011).

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 1 mm3 (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 (MedlinePlus 2010).

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/mm3 (McCrae 2006); thrombocytopenia in context of lupus is defined as platelet levels below 100,000/mm3 (Hochberg 1997).

Leukopenia: A reduced level of leukocytes, also called white blood cells due to their lack of color. Defined as a count below 4,000/mm3 (Hochberg 1997). 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/ mm3 (Hochberg 1997). 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.

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 (Cutolo 2004). 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 (Shabanova 2008).

Accordingly, studies in women with lupus revealed an increased rate of mild to moderate intensity disease flares associated with estrogen-containing hormone replacement therapy (Buyon 2005). Experimental studies have suggested that testosterone may suppress immune reactivity in lupus animal models and in cells from patients with lupus (Walker 1994; Kanda 1997).

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 (Gompel 2007).