Systemic lupus erythematosus
In 2008, the Food and Drug Administration (FDA) warned that mycophenolate mofetil (CellCept, Myfortic) should not be used during pregnancy as it can cause miscarriages and birth defects.
Systematic Lupus Erythematosus (SLE) Overview
SLE is an autoimmune disease that causes a chronic inflammatory condition. The inflammation triggered by SLE affects many organs in the body, including skin, joints, kidneys, lung, and nervous system. Women, especially African-American and Asian women, are at highest risk for developing SLE.
Symptoms and Diagnosis
Not all patients with SLE experience the same symptoms. The most common symptoms are joint pain, skin rash, and fever. Symptoms can develop slowly or appear suddenly. Many patients with SLE have flares, in which symptoms suddenly worsen and then disappear for long periods of time. Diagnosing SLE is complicated because symptoms vary widely and can resemble other conditions. A doctor will base an SLE diagnosis on certain specific criteria including symptom history and the results of blood tests for antinuclear antibodies.
No drug can cure SLE, but many different drugs can help control symptoms and relieve discomfort. The choice of drugs depends on the severity of the condition as well as other factors. Patients with mild SLE may be helped by nonsteroidal anti-inflammatory drugs (NSAIDs) while patients with more severe SLE may require corticosteroids or immunosuppressants. Researchers are working to develop new drugs and treatments for SLE.
Living with SLE
Patients can make lifestyle changes to help cope with SLE. These include:
- Avoid excessive sunlight exposure, and wear sunscreen (ultraviolet light is the one of the main triggers of flares).
- Get plenty of rest (fatigue is another common SLE symptom).
- Engage in regular light-to-moderate exercise to help fight fatigue and heart disease, and to keep joints flexible.
Systemic lupus erythematosus (SLE) is a chronic, often life-long, autoimmune disease. It can be mild to severe, andaffects mostly women. SLE may affect various parts of the body, but it most often manifests in the skin, joints, blood, and kidneys. SLE was first described in 1828. Its very name helps define the disease:
- Systemic is used because the disease can affect organs and tissue throughout the body.
- Lupus is Latin for wolf. It refers to the rash that extends across the bridge of the nose and upper cheekbones and was thought to resemble a wolf bite.
- Erythematosus is from the Greek word for red and refers to the color of the rash.
Lupus has many different symptoms. Common ones include:
- Joint pain or swelling
- Skin rashes
Systemic lupus erythematosus is a complex disorder that most likely results from a combination of processes and factors.
Environmental factors, such as viruses, exposure to chemicals, or sunlight, trigger inflammatory or immune activity. This immune activation may begin as an appropriate response to an unwanted "invader." But, because of a combination of genetic factors, an individual with lupus develops an ongoing immune response that does not shut itself off appropriately. This leads to waxing and waning flares of inflammation that can involve various organs of the body, depending on specific features of this self-perpetuating immune response in individual patients.
The exact combination of genes that predispose individuals to SLE may differ somewhat from patient to patient, but probably share certain common features which tend to impair the ability of the body to get rid of immune-triggering particles and which tend to prolong or increase the degree of immune responsiveness to these triggers.
A major characteristic of lupus is that it is an autoimmune response in which immune factors, called autoantibodies, attack the person's own cells. Some autoantibodies are normal in a well-balanced immune system, and serve various roles to help the body dispose of wastes, protect from infectious invaders, and to keep blood vessels clear. In healthy people, autoantibodies tend to be well-regulated and well "masked," or covered up, until needed. Therefore, it is probably the high activity and high detestability of autoantibodies that makes lupus unique, not the fact that they exist.
The Inflammatory Process and Autoimmunity
The Normal Immune System Response. The inflammatory process is a byproduct of the activity of the body's immune system, which fights infection and heals wounds and injuries:
- When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign proteins, such as a virus.
- The masses of blood cells that gather at the injured or infected site produce factors to fight any infections.
- In the process, the surrounding area becomes inflamed and some healthy tissue is injured. The immune system is then called upon to repair wounds by clotting any bleeding blood vessels and initiating fiber-like patches to the tissue.
- Under normal conditions, the immune system has special factors that control and limit this inflammatory process.
The Infection Fighters. B cells and T cells are two important components of the immune system that play a role in the inflammation associated with lupus. Both B cells and T cells belong to a family of immune cells called lymphocytes. Lymphocytes help fight infection.
B cells and T cells are involved in the immune system's response to infection. Antigens are foreign bodies (such as bacteria and viruses) that stimulate the immune system to produce autoantibodies. When a T cell recognizes an antigen it will produce chemicals (cytokines) that cause B cells to multiply and release many immune proteins (antibodies). These antibodies circulate widely in the bloodstream, recognizing the foreign particles and triggering inflammation in order to rid the body of the invasion.
For reasons that are still not completely understood, both the T cells and B cells become overactive in lupus patients. In lupus, a complex interaction between activated immune cells and an impaired antigen-elimination process leads to a greater than normal range of what the antibodies recognize. Eventually, antibodies are made that recognize more of the body's own tissues in a stronger or more persistent manner than is healthy, and inflammatory responses are mounted in these tissues.
Autoantibodies. In the majority of patients with SLE, antinuclear antibodies (ANA) are detectable. Such autoantibodies may be present in individuals up to 7 years prior to their developing symptoms of lupus. Some subtypes of ANA are found in lupus patients and only rarely in people without lupus. These include:
- Anti-ds DNA. An autoantibody called anti-double stranded DNA (anti-ds DNA) may play an important role in some lupus patients.
- Anti-Sm antibodies. This antibody is found most often in lupus patients of African descent and is almost never detected in people without lupus.
- Anti-Ro (SSA) and Anti-La (SSB)
- Antiphospholipid antibodies
Cytokines. Most immune cells secrete or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are indispensable for maintaining the balance of the body during immune responses, including:
- Tissue repair
- Blood clotting
- Clearing of debris from inflamed blood vessels
- Other aspects of healing.
If overproduced, however, they can cause serious damage, including dangerous levels of inflammation and cellular injury. Specific cytokines called interferons and interleukins play a critical role in SLE by regulating the secretion of autoantibodies by B cells.
Complement. Another immune factor of high interest in SLE is the complement system. This is comprised of more than 30 proteins and is important for defending and regulating the immune response. Inherited deficiencies in certain complement components (C1q, C1r, C1s, C4, and C2) have long been associated with SLE.
SLE is a complex disorder and researchers are still in the early stages of unraveling how genetic factors may alter and affect the immune system. Researchers estimate that 20 - 100 different genetic factors may make a person susceptible to SLE.
The number of people diagnosed with lupus has more than tripled over the past four decades. This may simply indicate a greater degree of doctor training in recognizing the syndrome.
About 90% of lupus patients are women, most diagnosed when they are in their childbearing ages. Hormones may be an explanation. After menopause, women are only 2.5 times as likely as men to contract SLE. Flares also become somewhat less common after menopause in women who have chronic SLE.
African-Americans are three to four times more likely to develop the disease than Caucasians and to have severe complications. Hispanics and Asians are also more susceptible to the disease.
A family history plays a strong role in SLE. A brother or sister of a patient with the disorder has 20 times the risk as someone without an immediate family member with SLE.
Risk Factors in Children
The disease is rare in childhood. When it does occur, it is often associated with thrombotic thrombocytopenia purpura, a condition resulting from abnormally low levels of blood platelets. SLE in children may also be caused by certain medications, including minocycline and zafirlukast.
Presence of Other Autoimmune Disorders
Rheumatoid Arthritis. Studies have investigated the relationship among hormones, SLE, and rheumatoid arthritis, another autoimmune disease. Higher levels of estrogen are associated with SLE, while lower levels are associated with rheumatoid arthritis. Some research suggests that some patients, in fact, progress from one disease to the other, and that such transitions occur during major hormonal shifts, such as the onset of menopause or pregnancy.
Many prescription drugs can cause lupus-like skin symptoms. These include high blood pressure (hypertension) medications, including hydrochlorothiazide, angiotensin-converting-enzyme inhibitors, and calcium-channel blockers. About 40 different drugs have been linked to lupus onset. Anyone diagnosed with cutaneous lupus erythematosus should be sure to tell their doctors all the medications (including herbs and supplements) that they are taking.
Smoking. Smoking may be a risk factor for triggering SLE and can increase the risk for skin and kidney problems in women who have the disease.
Possible SLE Triggers
In genetically susceptible people, there are various external factors that can provoke an immune response. Possible SLE triggers include colds, fatigue, stress, chemicals, sunlight, and certain drugs.
Viruses. Patients with SLE may be more likely to have been exposed to certain viruses than the general population. These viruses include the Epstein-Barr virus (the cause of mononucleosis), cytomegalovirus, and parvovirus-B1. In particular, some research suggests a strong association between Epstein-Barr virus (EBV) and increased risk of lupus, particularly for African-Americans.
Sunlight. Ultraviolet (UV) rays found in sunlight are important SLE triggers. When they bombard the skin, they can alter the structure of DNA in cells below the surface. The immune system may perceive these altered skin cells as foreign and trigger an autoimmune response against them. UV light is categorized as UVB or UVA depending on the length of the wave. Shorter UVB wavelengths cause the most harm.
Chemicals. Clusters of SLE cases have occurred in populations with high exposure to certain chemicals. Chlorinated pesticides and crystalline silica are two suspects. A number of other chemicals are under investigation. However, it is very difficult to determine a causal role for any specific chemicals. (Silicone breast implants have been under intense scrutiny as a possible trigger of autoimmune diseases, including SLE. The weight of evidence to date, however, finds no support for this concern.) Some drugs have been associated with a temporary lupus syndrome (drug-induced lupus), which resolves when these drugs are stopped.
Hormones. Cytokines, major immune factors that are active in SLE, are directly affected by sex hormones. In general, estrogen enhances antibody production, and testosterone reduces antibody production, although their exact role in SLE may be more complicated than that since there are various ways in which each hormone might influence various immune cells. Women with SLE may have lower levels of several active male hormones (androgens), and some men who are affected by SLE may also have abnormal androgen levels.
Premature menopause, and its accompanying symptoms (such as hot flashes), is common in women with SLE. Hormone replacement therapy (HRT), which is used to relieve these symptoms, increases the risk for blood clots and heart problems. It is not clear whether HRT triggers SLE flares. Women should discuss with their doctors whether HRT is an appropriate and safe choice. Guidelines recommend that women who take HRT use the lowest possible dose for the shortest possible time. Women with SLE who have active disease, antiphospholipid antibodies, or a history of blood clots or heart disease should not use HRT.
Oral Contraceptives. Female patients with lupus used to be cautioned against taking oral contraceptives (OCs) due to the possibility that estrogen could trigger lupus flare-ups. However, recent evidence indicates that OCs are safe, at least for women with inactive or stable lupus. Women who have been newly diagnosed with lupus should avoid OCs. Lupus can cause complications in its early stages. For this reason, women should wait until the disease reaches a stable state before taking OCs. In addition, women who have a history of, or who are at high risk for, blood clots (particularly women with antiphospholipid syndrome) should not use OCs. The estrogen in OCs increases the risk for blood clots.
SLE symptoms may develop slowly over months or years, or they may appear suddenly. Symptoms tend to be worse during winter months, perhaps because prolonged exposure to sunlight in the summer causes a gradual build-up of factors that trigger symptoms months later.
The most common symptom is joint pain, which occurs in about 90% of patients with SLE. Characteristics of this symptom vary widely:
- It is often accompanied by swelling and redness.
- It can last from hours to months.
- It may be mild or severe.
- It can occur in one joint, move from one to another, or flare erratically.
- Pain often occurs in the morning and improves during the day, only to return later when the patient tires.
- The joints most affected are fingers, wrists, elbows, knees, and ankles. (Joints in the spine and neck are not affected.)
Children may experience these symptoms as growing pains, and, in all patients, they may be the only symptoms for many years.
Fever occurs in 90% of patients with SLE and is usually caused by the inflammatory process of the disease, not by infection. It is low-grade except during an acute lupus crisis.
Three-quarters of patients with SLE have skin inflammation and skin lesions (ulcers, rashes, or other injured areas). About half of these lesions are photosensitive; that is, they are aggravated by ultraviolet (UV) radiation from sunlight, even from light coming through a window. (UV radiation may even trigger systemic flares in patients with SLE.)
A number of different skin conditions have been described in patients with SLE.
Discoid Lupus Erythematosus. About 20% of patients have discoid lesions. In such cases, the condition is often known as discoid lupus erythematosus (DLE). Patients with this condition may have the following skin abnormalities:
- Discoid means coin-shaped, so these lesions are round and raised. They are also scaly. Untreated, the margins gradually extend outward as the center dries out and shrivels, causing severe scarring. If discoid lesions appear on the scalp, they can plug hair follicles and cause irreversible hair loss. Discoid lesions can also appear on the upper body.
- A butterfly-shaped rash across the face may accompany this condition. This rash causes little scarring, although spidery, branching lines of swollen capillaries (the tiniest blood vessels) may appear.
Most patients with this condition have only a limited skin disorder. In only about 10% of cases does discoid lupus develop into full-blown SLE.
Subacute Cutaneous Lupus Erythematosus. Subacute cutaneous lupus erythematosus (SCLE) can cause skin lesions on parts of the body that are exposed to sunlight. These lesions do not cause scarring.
Vasculitis. Patients with SLE sometimes develop inflammation in the blood vessels (vasculitis) that may have the following effects on the skin:
- Red welts may form across large areas of the body.
- Sometimes deep red bumps may appear, particularly on the leg, where they may ulcerate.
- In some people, reddish-purple lesions appear on the pads of fingers and toes or near the nails of fingers and toes.
- Lesions caused by vasculitis may ulcerate or blister if they erupt on mucous membranes in the mouth, nose, or vagina and can be painful if they occur on the throat.
- Vasulitis can attack blood vessels in almost any other organ, including the brain, the heart, and the gastrointestinal tract.
Other SLE Symptoms
Other symptoms include:
- Loss of appetite, nausea, and weight loss
- Chest pain
- Menstrual irregularities
- Thought and concentration disturbances
- Personality changes
- Sleep disorders, such as restless legs syndrome and sleep apnea
- Dryness of the eyes and mouth
- Brittle hair or hair loss
Hair loss or breakage may also occur in about half of patients with SLE during severe flares or after pregnancy or severe illness. In such cases, hair grows back.
Raynaud's phenomenon is a condition in which cold or stress can cause spasms in impaired blood vessels, resulting in pain in fingers and toes. It occurs as part of the inflammatory response in blood vessels, which can narrow them and reduce circulation. In extreme cases, gangrene can result.
Conditions with Similar Symptoms
A number of conditions overlap with SLE:
- Scleroderma: Hardening of the skin caused by overproduction of collagen
- Rheumatoid arthritis: Inflammation of the lining of the joints
- Sjgren syndrome: Characterized by dry eyes and dry mouth
- Mixed connective tissue disorder: Similar to SLE, but milder
- Myositis: Inflammation and degeneration of muscle tissues
- Rosacea: Flushed face with pus-filled blisters
- Seborrheic dermatitis: Sores on lips and nose
- Lichen planus: Swollen rash that itches, typically on scalp, arms, legs, or in the mouth
- Dermatomyositis: Bluish-red skin eruptions on face and upper body
- Lyme disease: Bulls-eye rash, joint inflammation, and flu-like symptoms
Systemic lupus erythematosus (SLE) can cause systemic complications throughout the body.
Complications of the Blood
Almost 85% of patients with SLE experience problems associated with abnormalities in the blood.
Anemia. About half of patients with SLE are anemic. Causes include:
- Iron deficiencies resulting from excessive menstruation
- Iron deficiencies from gastro-intestinal bleeding caused by some of the treatments
- A specific anemia called hemolytic anemia, which destroys red blood cells
- Anemia of chronic disease
Hemolytic anemia can occur with very high levels of the anticardiolipin antibody. It can be chronic or develop suddenly and be severely (acute).
Antiphospholipid Syndrome. Between 34 - 42% of patients with SLE have antiphospholipid syndrome (APS). This is a specific set of conditions related to the presence of autoantibodies called lupus anticoagulant and anticardiolipin. These autoantibodies react against fatty molecules called phospholipids, and so are called antiphospholipids. Their actions have complex effects that include causing narrowing and abnormalities of blood vessels.
- Patients who have APS have a very incidence of blood clots, which most often occur in the deep veins in the legs. Blood clotting, in turn, puts patients at higher risk for stroke and pulmonary embolism (clots in the lungs).
- The effects on blood vessels have also been associated with confusion, headaches, and seizures. Leg ulcers can also develop.
- Patients with APS who become pregnant have a high incidence of pregnancy loss, especially in the late term.
Not all patients with APS carry both of the autoantibodies, and they can also wax and wane and so have varying effects. APS also occurs without lupus in about half of patients with the syndrome.
Thrombocytopenia. In thrombocytopenia, antibodies attack and destroy blood platelets. In such cases, blood clotting is impaired, which causes bruising and bleeding from the skin, nose, gums, or intestines. (This condition can also occur in APS, but it is not considered to be one of the standard features of the syndrome.)
Neutropenia. Neutropenia is a drop in the number of white blood cells. Patients with SLE often neutropenia, but the condition is usually harmless unless the reductions are so severe that they leave the patient vulnerable to infections.
Acute Lupus Hemophagocyte Syndrome. A rare blood complication of SLE that occurs primarily in Asians is called acute lupus hemophagocytic syndrome. It is generally of short duration and characterized by fever and a sudden drop in blood cells and platelets.
Lymphomas. Patients with SLE and other autoimmune disorders have a greater risk for developing lymph system cancers such as Hodgkins disease and non-Hodgkins lymphoma (NHL).
Heart and Circulation Complications
Heart disease is a primary cause of death in lupus patients. The immune response in SLE can cause chronic inflammation and other damaging effects that can cause significant injury to the arteries and tissues associated with the circulation and the heart. In addition, SLE treatments (particularly corticosteroids) affect cholesterol, weight, and other factors that can also affect the heart.
Patients with SLE, have a higher risk for developing the following conditions, which put them at risk for heart attack or stroke:
- Atherosclerosis, or plaque buildup in the arteries
- Increased stiffness in the arteries
- Unhealthy cholesterol and lipid (fatty molecules) levels
- High blood pressure, most likely because of kidney injury and corticosteroid treatments
- Heart failure
- Pericarditis, an inflammation of the tissue surrounding the heart
- Myocarditis, an inflammation of the heart muscle itself (rare)
- Abnormalities in the valves of the heart (rare)
- Blood clots
The risk for cardiovascular disease, heart attack, and stroke is much higher than average in younger women with SLE. The risks decline as such women age.
SLE affects the lungs in about 60% of patients:
- Inflammation of the membrane lining the lung (pleurisy) is the most common problem, which can cause shortness of breath and coughing.
- In some cases, fluid accumulates, a condition called pleural effusion.
- Inflammation of the lung tissue itself is called lupus pneumonitis. It can be caused by infections or by the SLE inflammatory process. Symptoms are the same in both cases: fever, chest pain, labored breathing, and coughing. Rarely, lupus pneumonitis becomes chronic and causes scarring in the lungs, which reduces their ability to deliver oxygen to the blood.
- A very serious and rare condition called pulmonary hypertension occurs when high pressure develops as a result of damage to the blood vessels of the lungs.
Kidney Complications (Lupus Nephritis)
The kidneys are a crucial battleground in SLE because it is here that the debris left over from the immune attacks is most likely to be deposited. Also, the immune response can also attack different parts of the kidney causing damage. About 50% of patients with SLE exhibit inflammation of the kidneys (called lupus nephritis).This condition occurs in different forms and can vary from mild to severe. Poor kidney function and kidney failure may result from this damage.
Serious complications occur eventually in about 30% of patients. If kidney injury develops, it almost always occurs within 10 years of the onset of SLE, rarely after that.
Central Nervous System Complications
Nearly all patients with SLE report some symptoms relating to problems that occur in the central nervous system (CNS), which includes the spinal cord and the brain. CNS involvement is more likely to occur in the first year, usually during flare-ups in other organs.
Symptoms vary widely and overlap with psychiatric or neurologic disorders. They may also be caused by of some medications used for SLE. Central nervous system symptoms are usually mild, but there is little effective treatment available for them. CNS symptoms get worse as the disease progresses.
The most serious CNS disorder is inflammation of the blood vessels in the brain (vasculitis), which occurs in 10% of patients with SLE. Fever, seizures, psychosis, and even coma can occur. Other CNS side effects include:
- Emotional disorders (anxiety, depression)
- Mild impairment of concentration and memory
- Migraine and tension headaches
- Problems with the reflex systems, sensation, vision, hearing, and motor control
Infections are a common complication and a major cause of death in all stages of SLE. The immune system is indeed overactive in SLE, but it is also abnormal and reduces the ability to fight infections. Patients are not only prone to the ordinary streptococcal and staphylococcal infections, but they are also susceptible to fungal and parasitic infections (called opportunistic infections), which are common in people with weakened immune systems. They also face an increased risk for urinary tract, herpes, salmonella, and yeast infections. Corticosteroid and immunosuppressants, treatments used for SLE, also increase the risk for infections, thereby compounding the problem.
About 45% of patients with SLE suffer gastrointestinal problems, including nausea, weight loss, mild abdominal pain, and diarrhea. Severe inflammation of the intestinal tract occurs in less than 5% of patients and causes acute cramping, vomiting, diarrhea, and, rarely, intestinal perforation, which can be life-threatening. Fluid retention and swelling can cause intestinal obstruction, which is much less serious but causes the same type of severe pain. Inflammation of the pancreas can be caused by the disease and by corticosteroid therapy.
Joint, Muscle, and Bone Complications
Arthritis caused by SLE almost never leads to destruction or deformity of joints. The inflammatory process can, however, damage muscles and cause weakness. Patients with SLE also commonly experience reductions in bone mass density (osteoporosis) and have a higher risk for fractures, whether or not they are taking corticosteroids (which can increase the risk for osteoporosis). Women who have SLE should have regular bone mineral density scans to monitor bone health.
Inflamed blood vessels in the eye can reduce blood supply to the retina, resulting in degeneration of nerve cells and a risk of hemorrhage in the retina. The most common symptoms are cotton-wool-like spots on the retina. In about 5% of patients sudden temporary blindness may occur.
In one study, 40% of patients with SLE quit work within 4 years of diagnosis, and many had to modify their work conditions. Significant factors that predicted job loss included high physical demands from the work itself, a more severe condition at the time of diagnosis, and lower educational levels. People with lower income jobs were at particular risk for leaving them.
Pregnancy and Systemic Lupus Erythematosus
Women with lupus who conceive face high-risk pregnancies that increase the risks for themselves and their babies. It is important for women to understand the potential complications and plan accordingly. The most important advice is to avoid becoming pregnant when lupus is active.
Research suggests that the following factors predict a successful pregnancy:
- Disease state at time of conception. Doctors strongly recommend that women wait to conceive until their disease state has been inactive for at least 6 months.
- Kidney (renal) function. Women should make sure that their kidney function is evaluated prior to conception. Poor kidney function can worsen high blood pressure and cause excess protein in the urine. These complications increase the risk for preeclampsia and miscarriage.
- Lupus-related antibodies. Antiphospholipid and anticardiolipin antibodies can increase the risks for preeclampsia, miscarriage, and stillbirths. Anti-SSA and anti-SSB antibodies can increase the risk for neonatal lupus erythematosus, a condition that can cause skin rash and liver and heart damage to the newborn baby. Levels of these antibodies should be tested at the start of pregnancy. Certain medications (aspirin, heparin) and tests (fetal heart monitoring) may be needed to ensure a safe pregnancy.
- Medication use during pregnancy. Women with active disease may need to take low-dose corticosteroids, but women with inactive disease should avoid these drugs. Steroids appear to pose a low risk for birth defects, but can increase a pregnant womans risks for gestational diabetes, high blood pressure, infection, and osteoporosis. For patients who need immunosuppressive therapy, azathioprine (Imuran) is an option. Methotrexate (Rheumatrex) and cyclophosphamide (Cytoxan) should not be taken during pregnancy.
Women with lupus are 20 times more likely to die during pregnancy than women without the disease. The risk for maternal death is due to the following serious conditions that can develop during pregnancy:
- Miscarriages. About 25% of lupus pregnancies result in miscarriage. The risk is highest for patients with antiphospholipid antibodies, active kidney disease, or high blood pressure.
- Blood clots. Women with lupus have a 6 times greater risk for developing deep vein thrombosis (blood clots) than women without the disease.
- Clotting complications. Low blood platelet count and anemia are also risks. Women with lupus are 3 times more likely to need a transfusion during pregnancy than women without lupus.
- Infections. Blood infections (sepsis), pneumonia, and urinary tract infections are more common in pregnant women with lupus.
- Preeclampsia. Women with lupus are three times more likely than healthy women to develop preeclampsia (pregnancy-related high blood pressure), which can be potentially life threatening.
- Birth Complications. Women with SLE have an increased risk of having a pre-term birth, stillbirth, or Caesarean section.
Despite these obstacles, many women with lupus have healthy pregnancies and deliver healthy babies. To increase the odds of a successful pregnancy, it is important for women to plan carefully before becoming pregnant. Be sure to find knowledgeable doctors with whom you can communicate and trust. Pregnant women with lupus should try to assemble an interdisciplinary health care team that includes a rheumatologist, high-risk obstetrician, and (for patients with kidney disease) a nephrologist.
Systemic lupus erythematosus (SLE) is one of the most serious rheumatic diseases. SLE can affect so many organs that a cause of death in some people with SLE may not be directly attributed to the condition. A primary cause of death among patients with lupus is atherosclerosis, a disease of the coronary blood vessels resulting from accelerated buildup of plaque.
SLE is unpredictable and varies greatly form one individual to the next.
Mild SLE. About 20 - 30% of cases are mild. The only symptoms may be the skin rashes of discoid lupus erythematosus (DLE) or subacute cutaneous lupus erythematosus (SCLE) with or without joint aches. The number and intensity of symptoms in mild cases often decrease over time, as does the likelihood of major organ involvement. Patients with mild SLE should still be tested for organ involvement.
Widespread SLE. More commonly, SLE is a chronic, life-long disease, alternating between periods of symptom relapse, (called flares), and remission. The disease may begin in any of the various systems of the body and progress unpredictably to others. The following are typical patterns:
- Symptom relapses, or flares, occur on the average of two or three times a year.
- Between flares, most patients with SLE function at about 90% of normal capacity.
The degree of severity depends on different factors:
- Severity of the inflammatory response
- Frequency of episodes
- The degree of organ or system involvement
Vital organs or systems, such as lungs, kidneys, nervous system, joints skin, and others are affected in over a half of patients with SLE. Infections followed by kidney failure are the chief causes of death in patients with SLE.
Because of more effective and aggressive treatment, the prognosis for SLE has improved markedly over the past two decades. Treatment early in the course of the illness improves long-term progress. About 85 - 95% of people with lupus survive 10 years, and many people have a normal life span. SLE that develops later in life is generally less serious than SLE that strikes in childhood or young adulthood.
No single test can confirm or rule out SLE. A number of tests are required before SLE can be diagnosed definitively. The first symptoms of SLE can resemble one of many syndromes or disorders, including rheumatoid arthritis, Still's disease, rheumatic fever, Lyme disease, multiple sclerosis, thrombotic thrombocytopenia purpura, cryoglobulinemia, Weber-Christian disease, viral infections, vasculitis, psychosis, and other conditions. Other autoimmune disorders, such as Sjgren syndrome or scleroderma, may even be present at the same time as SLE.
Criteria for Diagnosing System Lupus Erythematosus
1. Characteristic rash across the cheek
2. Discoid lesion rash
4. Oral ulcers
6. Inflammation of membranes in the lungs, the heart, or the abdomen
7. Evidence of kidney disease
8. Evidence of severe neurologic disease
9. Blood disorders, including low red and white blood cell and platelet counts
10. Immunologic abnormalities
11. Positive antinuclear antibody (ANA)
Note: A patient must experienced four of the criteria before a doctor can classify the condition as SLE. These criteria, proposed by the American College of Rheumatology, are not to be relied upon solely for diagnosis, however.
Tests for Autoantibodies
Methods for measuring the antibodies involved with SLE vary, and the range of results can be bewildering. Repeat tests may be needed.
Antinuclear Antibodies (ANAs). A primary test for SLE checks for antinuclear antibodies (ANA), which attack the cell nucleus.
High levels of ANA are found in more than 98% of patients with SLE. Other conditions, however, also cause high levels of ANA, so a positive test is not a definite diagnosis for SLE:
- Antinuclear antibodies may be strongly present in other autoimmune diseases (such as scleroderma, Sjgren syndrome, or rheumatoid arthritis).
- They also may be weakly present in about 20 - 40% of healthy women.
- Some drugs can also produce positive antibody tests, including hydralazine, procainamide, isoniazid, and chlorpromazine.
A negative ANA test makes a diagnosis of SLE unlikely but not impossible. High or low concentrations of ANA also do not necessarily indicate the severity of the disease, since antibodies tend to come and go in patients with SLE.
In general, the ANA test is considered a screening test:
- If SLE-like symptoms are present and the ANA test is positive, other tests for SLE will be administered.
- If SLE-like symptoms are not present and the test is positive, the doctor will look for other causes, or the results will be ignored if the patient is feeling healthy.
ANA Subtypes. In some cases, doctors may test for specific ANA subtypes.
- Anti-double stranded DNA (Anti-ds DNA) is more likely to be found only in patients with SLE. It may play an important role in injury to blood vessels found in SLE, and high levels often indicate kidney involvement. Anti-ds DNA levels tend to fluctuate over time and may even disappear.
- Anti-Sm antibodies are also usually found only with SLE. Levels are more constant and are more likely to be detected in African-American patients. Although many lupus patients may not have this antibody, its presence almost always indicates SLE.
- When the ANA is negative but the diagnosis is still strongly suspected, a test for anti-Ro (also called anti-SSA) and anti-La (also called anti-SSB) antibodies may identify patients with a rare condition called ANA negative, Ro lupus. These autoantibodies may be involved in the sun-sensitive rashes experienced by patients with SLE and are also found in association with neonatal lupus syndrome, in which a pregnant mother's antibodies cross the placenta and cause inflammation in the developing child's skin or heart.
Antibodies to SR Proteins. An advance in diagnosing SLE has been the detection of antibodies to molecules called SR proteins, which are carried by most patients. The test accurately detects lupus in 50 - 70% of patients who test positive for these antibodies.
Antiphospholipid Antibodies. In patients with SLE in whom blood abnormalities are suspected, tests may be able to detect the presence of the two major antiphospholipid antibodies:
- A quarter to a half of patients with SLE may have these antibodies. Antiphospholipid antibodies increase the risks for blood clots and may be responsible for narrowing of (and irregularities in) blood vessels. Antiphospholipid antibodies are linked with miscarriages and other pregnancy complications, strokes, heart attacks and blood clots in almost any part of the body, including kidneys, legs, lungs, and eyes.
- The test for the lupus anticoagulant antibody measures the time it takes blood to clot. A longer than normal blood clotting time indicates a higher chance for clotting in the body and, therefore, the presence of lupus anticoagulant.
- An ELISA test (enzyme-linked immunosorbent assay) is performed to detect the anticardiolipin antibody.
As with the ANA, these antibodies also have a tendency to appear and disappear in a single patient. Patients who have these autoantibodies as well as blood clotting problems or frequent miscarriage are diagnosed with antiphospholipid syndrome (APS), which often occurs in SLE but can also develop independently.
Miscellaneous Blood Tests
Complement. Blood tests of patients with SLE often show low levels of serum complement, a protein in the blood that aids the body's infection fighters. Individual proteins are termed by the letter "C" followed by a number. Common complement tests measure C3, C4, C1q, and CH50. Complement levels are especially low if there is kidney involvement or other disease activity.
LE Cell Tests. The first blood test ever used for SLE called LE (lupus erythematosus) cell test is positive in only about half of patients with SLE and is no longer used that often.
Blood Count. White and red blood cell and platelet counts are usually lower than normal and, depending on severity, are used to determine complications, such as anemia or infection.
If a skin rash is present, the doctor may take a biopsy (a tissue sample) from the margin of a skin lesion. A test known as a lupus band detects antibodies known as immunoglobulin G (IgG), which are located just below the outer layer of the tissue sample. They are much more likely to be present with active SLE then with inactive disease. The biopsy will not differentiate between systemic and discoid lupus, but it can rule out other diseases. Tests for other antibodies will rule out or confirm discoid lupus and subacute cutaneous lupus.
Tests for Serious Complications of SLE
Kidney Damage and Lupus Nephritis. Kidney damage in patients already diagnosed with SLE may be detected from the following tests:
- Blood tests that measure creatinine, a protein metabolized in muscles and excreted in the urine. High levels suggest kidney damage, although kidney problems can also be present with normal creatinine levels.
- Tests for detecting anti-ds DNA antibodies and complements.
- A kidney biopsy. This may be performed to determine if lupus nephritis is present when less invasive tests indicate kidney involvement. It is not absolutely accurate but it helps determine treatment. Electron microscopy (very high-powered electronic microscopes) may be especially important in obtaining critical information on the degree of kidney damage.
Lung and Heart Involvement. A chest x-ray may be performed to check lung and heart function. An electrocardiogram and an echocardiogram are administered if heart disease is suspected.
Central Nervous System Complications. SLE occurring in the central nervous system (CNS) can be difficult to diagnose because its symptoms are easily confused with other psychiatric and neurologic conditions.
- Tests of the cerebrospinal fluid (CSF) for elevated levels of autoantibodies are the most reliable ways to detect CNS complications caused by a faulty immune system.
- Additional tests, including electroencephalograms (EEGs), magnetic resonance imaging (MRI), computed tomography (CT), or x-rays may be useful when blood vessel blockage in the brain is suspected.
- If the doctor suspects that CNS symptoms are caused by infection, especially for patients who are receiving immunosuppressant therapy, a lumbar puncture should be performed.
Osteoporosis. To detect early osteoporosis in patients with SLE whose disease has lasted more than 3.5 years, doctors recommend an imaging test called dual energy x-ray absorptiometry (DEXA) to measure bone mineral density.
No treatment cures systemic lupus erythematosus, but many therapies can suppress symptoms and relieve discomfort. Treatment of SLE varies depending on the extent and severity of the disease.
Only three drugs are FDA-approved for the treatment of lupus:
However, none of these drugs are the current standard of care. In everyday practice, numerous other drugs are commonly used. Researchers are conducting numerous clinical studies and drug investigations. Genetic research in lupus is progressing very rapidly, and hopefully new drugs will be approved in the future. There are also different drugs available to treat some of the conditions associated with lupus.
Treating Mild Systemic Lupus Erythematosus
Less intensive treatments may be effective for symptoms of mild lupus. They include:
- Creams and sunblocks for rashes
- Nonsteroidal anti-inflammatory drugs for fever, arthritis, and headache
- Antimalarial drugs for pleurisy, mild kidney involvement, and inflammation of the tissue surrounding the heart
Treating Severe Systemic Lupus Erythematosus
More aggressive treatment is needed if there is serious disease progression, as evidenced by:
- Hemolytic anemia
- Low platelet count with an accompanying rash (thrombocytopenia purpura)
- Major involvement in the lungs or heart
- Significant kidney damage
- Acute inflammation of the small blood vessels in the extremities or gastrointestinal tract
- Severe central nervous system symptoms
The primary approach to treating severe SLE is to suppress the immune factors, most often first with corticosteroids and other immunosuppressant drugs. Investigational drugs and procedures are also showing promise.
Treating Specific Complications
The major complications of the disease must be treated as separate problems, keeping in mind the specific aspects of SLE. They are discussed elsewhere in this report.
Treatment for Cutaneous and Mild SLE
Creams. Steroid creams are often used for skin lesions. However, many patients with discoid lupus do not respond to steroids, particularly if they have eruptions that are caused by sun sensitivity. A cream derived from vitamin A (Tegison) may help some lesions that do not clear up with steroid creams.
Sun Protection. Sun protection is essential. Patients should always use sunblock creams (not just sunscreens) and always wear hats and clothing made of tightly woven fabrics.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Common NSAIDs. NSAIDs block prostaglandins, the substances that dilate blood vessels and cause inflammation and pain. There are dozens of NSAIDs.
- Over-the-counter NSAIDs include aspirin, ibuprofen (Motrin, Advil), naproxen (Aleve), ketoprofen (Actron, Orudis KT).
- Prescription NSAIDs include ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), diclofenac (Voltaren), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), dexibuprofen (Seractil).
For people with lupus, NSAIDs may help relieve:
- Joint pain and swelling
- Muscle pain
Side Effects. Regular, long-term use of NSAIDs can cause ulcers and gastrointestinal bleeding, which can lead to anemia. To avoid these problems, its best to take NSAIDs with food or immediately after a meal. Long-term use of NSAIDs (with the exception of aspirin) can also increase the risk for heart attack and stroke.
Other NSAID side effects may include:
- Upset stomach
- Dyspepsia (burning, bloated feeling in pit of stomach)
- Skin bruising
- High blood pressure
- Fluid retention
- Reduced kidney function
Patients who have kidney problems associated with lupus (lupus nephritis) should be especially cautious about using NSAIDs. Patients with lupus who take NSAIDs on a regular basis should have their liver and kidney function tested every 3 - 4 months.
A doctor may prescribe antimalarial drugs for discoid lupus (skin sores) or mild lupus when skin problems and joint pains are the predominant symptoms:
- Hydroxychloroquine (Plaquenil) is the most common antimalarial drug used for lupus. This drug is effective as maintenance therapy to reduce flares in patients with mild or inactive disease. Hydroxychloroquine may help protect against blood clots in people with antiphospholipid syndrome, high cholesterol levels, and bone loss.
- Other antimalarial drugs include chloroquine (Aralen) or quinacrine (Atabrine).
Treatment may start initially with high doses in order to accumulate high levels of the drug in the bloodstream. It is not known exactly why antimalarials work. Some researchers believe they inhibit the immune response, and others think they interfere specifically with inflammation.
Side Effects. Side effects of antimalarials may include:
- Skin rash
- Change in skin color (yellow in the case of quinacrine)
- Gastrointestinal problems
- Hair loss
- Muscle aches
- Eye damage
The most serious is damage to the retina, although this is very uncommon at low doses. Eye damage after taking hydroxychloroquine is reversible when caught in time and treated, but it is not reversible if the damage develops after taking chloroquine. An eye exam is advisable about every 6 months.
Antimalarials may also be used in combination with other anti-SLE drugs, including immunosuppressants and corticosteroids. It should be noted that smoking significantly reduces the effectiveness of antimalarial drugs.
Treatment for Severe SLE
Severe SLE is treated with corticosteroids, also called steroids, which suppress the inflammatory process. Steroids can help relieve many of the complications and symptoms, including anemia and kidney involvement.
Oral prednisone (Deltasone, Orasone) is usually prescribed. Other drugs include methylprednisolone (Medrol, Solumedrol), hydrocortisone, and dexamethasone (Decadron).
Some people need to take oral prednisone for only a short time; others may require it for a long duration. An intravenous administration of methylprednisolone using "pulse" therapy for 3 days is proving useful for flare-ups in the joints. Combinations with other drugs, particularly immunosuppressants, may be beneficial.
Regimens vary widely, depending on the severity and location of the disease. Most patients with SLE can eventually function without prednisone, although some may have to choose between the long-term toxicity of corticosteroids and the complications of active disease.
Side Effects of Long-Term Oral Corticosteroids. Unfortunately, serious and even life-threatening complications have been associated with long-term steroid use. The bone-thinning condition osteoporosis is a common and particularly severe long-term side effect of prolonged steroid use. Medications that can prevent osteoporosis include calcium supplements, parathyroid hormone, alendronate risedronate, or hormone replacement therapy in post-menopausal women.
Other side effects associated with prolonged use of oral steroids include:
- Fluid retention
- Susceptibility to infections
- Weight gain
- High blood pressure
- Excess hair growth
- Wasting of the muscles
- Menstrual irregularities
Withdrawal from Long-Term Use of Oral Corticosteroids. Long-term use of oral steroid medications suppresses secretion of natural steroid hormones by the adrenal glands. After withdrawal from these drugs, this so-called adrenal suppression persists and it can take the body a while (sometimes up to a year) to regain its ability to produce natural steroids again. A few cases of severe adrenal insufficiency have occurred when patients switched from oral to inhaled steroids, which, in rare cases, has resulted in death.
No one should stop taking any steroids without consulting a doctor first, and if steroids are withdrawn, regular follow-up monitoring is necessary. Patients should discuss with their doctors measures for preventing adrenal insufficiency during withdrawal, particularly during stressful times, when the risk increases.
Drugs known as immunosuppressants are often used, either alone or with corticosteroids for very active SLE, particularly when kidney or neurologic involvement or acute blood vessel inflammation is present. These drugs suppress the immune system by damaging cells that grow rapidly, including those that produce antibodies. About a third of patients take immunosuppressants at some point in the course of the disease.
Specific Immunosuppressants. The most common immunosuppressants are:
- Cyclophosphamide (Cytoxan) used to be considered the gold standard of treatment for lupus kidney disease (lupus nephritis). Cyclophosphamide is given intravenously and is sometimes used in combination with corticosteroids or other drugs. It has been used for lupus since the 1970s. Side effects are very severe and include nausea, vomiting, hair loss, infertility, and infections.
- Mycophenolate mofetil (CellCept, Myfortic) is now becoming the new standard. Many recent studies have shown that this drug works better than cyclophosphamide and causes far fewer severe side effects (diarrhea is the main side effect). Unlike cyclophosphamide, it is taken by mouth. Most doctors now recommend mycophenalate mofetil as a first-line treatment for newly diagnosed patients with mild or moderate lupus kidney disease. It may not be appropriate for patients with kidney failure or rapidly progressing kidney disease. Mycophenolate mofetil should not be used during pregnancy as it can cause miscarriage and birth defects.
- Azathioprine (Imuran) has the lowest toxicity, but is less effective than other immunosuppressants.
- Cyclosporine (Sandimmune) has been used for years, mostly for SLE associated with kidney involvement. High blood pressure is common, however, with this drug.
The most frequent side effects of immunosuppressants include:
- Stomach and intestinal problems
- Skin rash
- Mouth sores
- Hair loss
Serious side effects of immunosuppressants include:
- Low blood cell counts
- Menstrual irregularity
- Early menopause
- Ovarian failure
- Herpes zoster (shingles)
- Liver and bladder toxicity
- Increased risk of cancer
In general, immunosuppressants should not be used alone unless corticosteroids are ineffective or inappropriate. Grapefruit juice has an enzyme that may enhance the effects of some immunosuppressants.
Monoclonal Antibodies (MAbs). A MAb is a laboratory-made protein that targets specific immune cells, such as B cells. B cell over-activation has been identified as a key component of the lupus disease process. Promising MAbs in development for SLE treatment include epratuzumab and belimumab.
Intravenous Immunoglobulins. Intravenous immunoglobulins (IVIG) are sometimes used for patients who have not responded to other SLE treatments. Immunoglobulins are antibodies produced by immune system B-lymphocyte cells. IVIG is a blood product that contains these antibodies.
Dehydroepiandrosterone (DHEA). Dehydroepiandrosterone (DHEA) is a natural steroid hormone that is produced by the adrenal glands and converted into estrogen and androgen. The synthetic equivalent of DHEA, prasterone (Prestara), is being investigated as a potential treatment for SLE. Prasterone is still in the drug development stage and it is not clear when, or if, it will be commercially available.
Autologous Stem Cell Transplantation. Some patients with severe lupus have achieved at least short-term remission after undergoing autologous transplantation of stem cells and high-dose drug therapy to suppress the damaging immune factors. Stem cells are the early forms for all blood cells in the body. An autologous transplant is one in which marrow or blood cells used are the patient's own. (The advantage to an autologous transplant is that the patient's own cells are not at risk for rejection by the immune system.)
Phototherapy. A promising treatment uses ultraviolet A-1 (UVA-1) radiation, long UVA wave lengths that do not promote sunburn and may actually block inflammatory immune factors. Small studies have suggested that UVA-1 phototherapy may have some benefits for lowering disease activity in SLE.
Plasmapheresis. Plasmapheresis is a process in which the fluid part of the blood, called plasma, is removed from blood cells. The procedure involves first taking blood from the patient. The plasma, which contains the inflammatory antibodies and other immunologically active substances, is discarded and replaced with other fluids. The blood is then returned. Plasmapheresis is not useful for routine management of patients but may have some benefits for patients who do not respond to standard treatments or in specific cases, such as lupus patients with hemolytic anemia.
Treatments for Some Complications of Systemic Lupus Erythematosus
Infections, Inflammation, or Hypertension in the Lungs
Preventive Measures. Immunizations with inactive viruses and preventive antibiotics should be considered for patients with SLE who are at high risk for infection.
Treating Infections. Lung infections need to be treated aggressively with antibiotics. However, antibiotic drugs such as penicillin or the sulfa drugs may cause sensitivity rashes that can be confused with SLE rash.
Treating Lung Inflammation. While inflammation of the lung (pneumonitis) resembles pneumonia, it is not an infection but is a result of the autoimmune process. This condition needs to be treated with corticosteroids or immunosuppressants, but only if the doctor is sure infection is not present.
Treating Pulmonary Hypertension. Pulmonary hypertension is very serious. Drugs known as prostacylins -- which include epoprostenol, iloprost, and treprostinil -- are standard drugs. Bosentan (Tracleer) is the first oral drug approved for pulmonary hypertension. An inhaled iloprost formulation (Ventavis) was approved in 2004. Sildenafil (Viagra, Revatio) may also be used for this condition. Lung transplantation may be required.
Bleeding and Clotting Disorders
Antiphospholipid Syndrome and Clotting Disorders. Hydroxychloroquine or aspirin may help prevent blood clots in women with antiphospholipid syndrome (APS). (Aspirin does not appear to be protective in men who carry the autoantibodies responsible for APS.) In patients who have experienced blood clots, treatment with the anticoagulant warfarin (Coumadin) is advisable. This blood-thinning drug may be needed lifelong. Scientists are investigating other treatment options, including autologous stem cell transplantation. The procedure has shown promise in studies for treating lupus-associated APS, but it is still experimental.
Excess Bleeding from Thrombocytopenia (Drop in Blood Platelets). Treatments that may be effective for thrombocytopenia include combinations of a corticosteroid and either danazol (a male hormone) or the antimalarial hydroxychloroquine. Immunosuppressants or intravenous immunoglobulin IgG may be helpful in some patients. Surgical removal of the spleen may be advisable if bleeding disorders are a serious problem, but this option should be considered carefully, because the spleen provides one line of defense against infection. (Abnormal spleen function, in any case, appears to be fairly common in SLE.)
Drugs. Mycophenolate mofetil (CellCept, Myfortic) and intravenous cyclophosphamide, as well as steroids are used to treat lupus kidney disease.
Procedures. Kidney transplant or dialysis should be considered for patients with SLE with severe kidney damage. For unknown reasons, SLE does not generally recur in the transplanted kidneys. Studies are conflicting, however, over whether SLE transplant patients have higher organ-rejection rates than other kidney-transplant recipients. Both transplantation and dialysis have potentially serious complications.
Plasmapheresis. It is not clear if plasmapheresis is beneficial for SLE kidney disease.
Treatments for osteoporosis include calcium, vitamin D, bisphosphonates, parathyroid hormone, and selective estrogen-receptor modulators (SERMs). [For more information, see In-Depth Report #18: Osteoporosis.]
The need for aggressive treatment of high blood pressure often accompanies kidney disease. SLE is also accompanied by high cholesterol levels, which requires diet changes and drug therapies. [For more information, see In-Depth Reports #3: Coronary artery disease; #14: High blood pressure; #23: Cholesterol; and #43: Heart healthy diet.]
People with SLE should try to maintain a healthy and active lifestyle. Light-to-moderate exercise, interspersed with rest periods, is good for the heart, helps fight depression and fatigue, and can help keep joints flexible.
Patients should be sure they are fully immunized and should minimize their exposure to crowds or people with contagious illnesses. Careful hygiene, including dental hygiene, is also important.
Avoiding SLE Triggers
It is very important that patients with SLE avoid excessive exposure to sunlight. Simple preventive measures include avoiding overexposure to ultraviolet rays and wearing protective clothing and sunblocks. There is some concern that allergy shots may cause flare ups in certain cases. Patients who may benefit from them should discuss risks and benefits with an SLE specialist. In general, patients with SLE should use only hypoallergenic cosmetics or hair products.
Chronic stress has profound physical effects and influences the progression of SLE. Getting adequate rest of at least 8 hours and possibly napping during the day may be helpful. Maintaining social relationships and healthy activities may also help prevent the depression and anxiety associated with the disease.
- www.lupus.org -- Lupus Foundation of America
- www.lupusny.org -- SLE Lupus Foundation
- www.niams.nih.gov -- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- www.rheumatology.org -- American College of Rheumatology
- www.lupusresearchinstitute.org -- Lupus Research Institute
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Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.