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Antiphospholipid antibodies are antibodies directed against phosphorus-fat components of your cell membranes called phospholipids, certain blood proteins that bind with phospholipids, and the complexes formed when proteins and phospholipids bind. Approximately 50% of people with lupus possesses these antibodies, and over a twenty-year period of time, one half of lupus patients with one of these antibodies—the lupus anticoagulant—will experience a blood clot. People without lupus can also have antiphospholipid antibodies.

The most commonly discussed antiphospholipid antibodies are the lupus anticoagulant (LA) and anticardiolipin antibody (aCL). These two antibodies are often found together, but can also be detected alone in an individual. Other antiphospholipid antibodies include anti-beta 2 glycoprotein 1 (anti-ß2 GPI), anti-prothrombin, and the “false-positive” test for syphilis. Like other antibodies involved in lupus that are directed against self (auto-antibodies), antiphospholipid antibodies can come and go or increase and decrease.

The presence of an antiphospholipid antibody such as the lupus anticoagulant and anticardiolipin antibody in an individual is associated with a predisposition for blood clots. Blood clots can form anywhere in the body and can lead to stroke, gangrene, heart attack, and other serious complications. In people with lupus, the risk of clotting does not necessarily correlate with disease activity, so the presence of these antibodies can cause problems even when a person’s lupus is in control. Complications of antiphospolipid antibodies in lupus include fetal loss and/or miscarriages, blood clots of the veins or arteries (thromboses), low platelet counts (autoimmune thrombocytopenia), strokes, transient ischemic attacks (stroke warnings), Libman-Sacks endocarditis (formation of a clot on a specific heart valve), pulmonary emboli, and pulmonary hypertension.

Many people with antiphospholipid antibodies have a purple or reddish lacy pattern just under their skin known as livedo. This pattern is especially apparent on the extremities (i.e., the arms and legs). It is important to realize, however, that having livedo does not necessarily mean one has antiphospholipid antibodies; rather, doctors acknowledge a correlation between the two conditions. Livedo can be associated with other diseases of the blood vessels, but in fact, many perfectly healthy women also experience the condition.

Antiphospholipid Antibody Syndrome (APS)

Individuals who experience complications from antiphospholipid antibodies are diagnosed with Antiphospholipid Antibody Syndrome (APS). This condition can occur both in people with lupus and those without lupus. Fifty percent of people with lupus have APS. The presence of one or more clinical episodes of thromboses (blood clots) and/or complications during pregnancy, such as miscarriage or premature birth, in conjunction with a significant level of anticardiolipin antibodies, antiphospholipid antibodies, and/or anti-ß2 GPI anti- antibodies usually indicates the presence of APS. When APS is the sole diagnosis, and no other connective tissue diseases are present, APS is often said to be the primary diagnosis; when APS is present in association with lupus or another connective tissue disease, APS is said to be “secondary.” This classification is controversial, however, because some people with primary APS (about 8%) later develop lupus, suggesting a connection between the two conditions.

Types of Antiphospholipid Antibodies

False-Positive Test for Syphilis

In the 1940s, when it was common for people to have premarital exams, doctors realized that some women with lupus tested positive for syphilis. Further studies indicated that 1 in 5 people with lupus had a false-positive syphilis test. The syphilis test of those days—the Wasserman test—was dependant on an antibody found in syphilis patients called reagin. The substance to which this antibody reacts is cardiolipin, so the individuals with a false-positive syphilis test actually had a form of anticardiolipin antibodies. The false-positive syphilis test was the first recognized test for antiphospholipid antibodies, but it is now known that people can have antiphospholipid antibodies without having a false-positive syphilis test and vice versa. The false-positive test is not associated with an increased risk of blood clots in all medical studies performed in the past, but certain studies, including the Johns Hopkins Lupus Cohort, suggest that there is a connection.

The false-positive syphilis test was one of the first three recognized indications of antiphospholipid antibodies. The other two were the lupus anticoagulant and anticardiolipin antibody.

Lupus Anticoagulant

In the late 1940s, it was found that an antibody present in some lupus patients prolonged a clotting test dependent on phospholipids. For this reason, it was thought that this antibody increased the tendency to bleed, and thus it was deemed the lupus anticoagulant. However, this name is now recognized as a misnomer for two reasons. First, the term “anticoagulant” is a false label, since lupus anticoagulant actually increases the ability of the blood to clot. Second, the term “lupus” in the name of the antibody is misleading, since more than half of all people who possess this antibody do not have lupus.

Tests called coagulation tests are used to detect the lupus anticoagulant (LA). Remember that even though the lupus anticoagulant causes the blood to clot more easily in vivo (i.e., in a person’s body), they actually cause prolonged clotting times in vitro (i.e., in a test tube). Therefore, if it takes more time than normal for the blood to clot, the lupus anticoagulant is usually suspected. The activated partial thromboplastin time (aPTT) is often used to test for LA. If this test is normal, more sensitive coagulation tests are performed, including the modified Russell viper venom time (RVVT), platelet neutralization procedure (PNP), and kaolin clotting time (KCT). Normally, two of these tests (the apt and the RVVT) are performed to detect whether lupus anticoagulant is present.

Anticardiolipin Antibody

Even though the false-positive syphilis test and the lupus anticoagulant were identified in the 1940s, the link between these entities was not investigated until the 1980s, when a researcher at the Graham Hughes laboratory in Britain named Nigel Harris began looking at antibodies to the phospholipid antigens. Harris realized that cardiolipin was a major element of the false-positive syphilis test, and he developed a more specific test for the antibody. He also determined that the presence of these anticardiolipin antibodies was associated with recurrent thromboses (blood clots) and pregnancy losses. Others in Hughes’ laboratory began to publish studies showing the link between anticardiolipin antibodies and stroke, deep vein thrombosis (DVT), recurrent pregnancy loss, livedo, seizures, and other conditions. In fact, what we now know as antiphospholipid syndrome was known as the anticardiolipin syndrome even though other antiphospholipids, namely the lupus anticoagulant, were known to produce similar effects.

There are different classes (isotypes) of anticardiolipin antibody, namely IgG, IgM, and IgA. IgG is the anticardiolipin antibody type most associated with complications. An enzyme-linked immunosorbent assay (ELISA) is used to test for anticardiolipin antibodies. One can test for all isotypes at once, or they can be detected separately. High levels of the IgM isotype are associated with autoimmune hemolytic anemia, a condition in which an individual’s immune system attacks their red blood cells.

Anti-beta2 glycoprotein 1

Beta2 glycoprotein 1 is the protein in the body to which anticardiolipin antibodies bind, and it is also possible to measure antibodies to beta2 glycoprotein 1. An individual can be positive for anticardiolipin antibodies and negative for anti-ß2 GPI and vice versa, and detection of anti-ß2 GPI is not yet part of routine testing done for patients with an increased likelihood of blood clots.

Sources

• “Antiphospholipid Antibodies.” Lab Tests Online. 3 June 2009.  American Association for Clinical Chemistry. 6 July 2009 <http://labtestsonline.org/understanding/analytes/antiphospholipids/test.html>.
• “Blood Tests.” The Lupus Site. 6 July 2009 <http://www.uklupus.co.uk/tests.html>.
• “Cardiolipin Antibodies.” Lab Tests Online. 3 June 2009.  American Association for Clinical Chemistry. 6 July 2009 <http://labtestsonline.org/understanding/analytes/cardiolipin/test.html>.

• “Laboratory Tests.” Lupus Foundation of America. 6 July 2009 <http://www.lupus.org/webmodules/webarticlesnet/templates/new_aboutdiagnosis.aspx?articleid=364&zoneid=15>.
• Laboratory Tests for Lupus.” Lupus Foundation of America. 12 July 2009 <http://www.lupus.org/webmodules/webarticlesnet/templates/new_learndiagnosing.aspx?articleid=2242&zoneid=524>.
• “Lupus Anticoagulant.” Lab Tests Online. 3 June 2009.  American Association for Clinical Chemistry. 6 July 2009 <http://labtestsonline.org/understanding/analytes/lupus_anticoagulant/test.html>.
• Wallace, Daniel J. The Lupus Book: A Guide for Patients and Their Families. 1st ed. New York: Oxford University Press, 1995.
• Wallace, Daniel J., and Bevra Hannahs Hahn, eds. Dubois’ Lupus Erythematosus. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2007.

• Hydroxychloroquine (Plaquenil)
• Chloroquine (Aralen)
• Quinacrine (Atabrine)

What are anti-malarial drugs, and why are they used to treat lupus?

Hydroxychloroquine (Plaquenil), chloroquine (Aralen), and quinacrine (Atabrine) are medications that were originally used to prevent or treat malaria. However, during World War II it was also found that these medications were effective in treating the symptoms of lupus. Specifically, anti-malarial medications have shown to improve muscle and joint pain, skin rashes, pericarditis (inflammation of the lining of the heart), pleuritis (inflammation of the lining of the lung), and other lupus symptoms such as fatigue and fever. These medications may also prevent lupus from spreading to certain organs, such as the kidney and central nervous system (your brain and spinal cord) and may help to reduce flares by as much as 50%. Plaquenil and other anti-malarials are the key to controlling lupus long term, and some lupus patients may be on Plaquenil for the rest of their lives. For this reason, you can think of anti-malarials as a sort of “lupus life insurance.”

Studies have shown lupus patients on anti-malarials actually live longer than those who are not, and these medications are usually prescribed when someone is first diagnosed with the disease. Anti-malarials are particularly useful in treating discoid lupus, subacute cutaneous lupus, and mouth sores associated with lupus; they are also effective in treating rheumatoid arthritis and Sjogren’s syndrome. However, anti-malarials are not a sufficient treatment for more severe lupus symptoms such as kidney disease and nervous system or blood vessel involvement. When lupus spreads to these organs, immunosuppressive medications are usually added to help minimize irreversible injury.

What anti-malarial drugs are commonly prescribed for lupus?

Three anti-malarial drugs are prescribed for lupus symptoms. Hydroxychloroquine (Plaquenil) is the most commonly prescribed because it is generally believed to cause fewer side effects; chloroquine (Aralen) has a reputation for more serious side effects, but it may be prescribed in situations where hydroxychloroquine cannot be used. Quinacrine (Atabrine) is another alternative, but it is prescribed less often because it can sometimes cause a yellow discoloration of the skin. It is sometimes given in addition to hydroxychloroquine if the patient does not respond to Plaquenil alone. Quinacrine tablets are no longer manufactured and can only be obtained through a compounding pharmacist. Your doctor will advise you on how to obtain quinacrine if this becomes your advised method of treatment.

How do anti-malarial drugs control lupus symptoms?

Anti-malarial medications help to control lupus in several ways by modulating the immune system without predisposing you to infection. Anti-malarials can protect against UV light and sometimes even improve skin lesions that do not respond to treatment with topical therapy (ointments). Anti-malarial medications may prevent activation of plasmacytoid dendritic cells, a component of the immune system that is responsible for making interferon.

Can anti-malarial drugs be taken with other lupus medications?

Yes, anti-malarials can be taken with other lupus medications, including corticosteroids (e.g., prednisone), immunosuppressives, cytotoxic drugs, and NSAIDs. Anti-malarial drugs may be given in combination with prednisone to reduce the amount of steroid needed to control lupus symptoms and thus to alleviate some of the side effects of the steroid. In addition, since it usually takes about 1-3 months for your anti-malarial medications to fully take effect, you may be given a steroid medication to act as a bridging medication and alleviate your symptoms during this interim.

Can anti-malarial drugs be taken during pregnancy?

Anti-malarials are safe to use during pregnancy, but you should speak to your doctor if you are pregnant or may become pregnant to decide the course of treatment that will be best for you. No fetal abnormalities are known to have occurred from taking hydroxychloroquine, and physicians at several major universities have used anti-malarial drugs for years to treat pregnant women with lupus without negative side effects on the fetus.

What should I keep in mind when taking anti-malarial drugs?

Damage to the retina, the light sensitive portion of the inner eye, can occur with long-term use of Plaquenil or chloroquine (Aralen). With Plaquenil, however, the most commonly prescribed anti-malarial, this sort of damage occurs only in 1 out of 5,000 people who take the drug for five years or more. For this reason though, it is important that you see an ophthalmologist for an exam before starting to take an anti-malarial medication for your lupus. Follow-up exams every 6 months (or, annually at the very least) are also advised. You can also monitor yourself between visits with a special grid called an Amsler grid, which can be obtained through your ophthalmologist.

If your ophthalmologist does find some Plaquenil deposits, s/he will simply request that you stop taking the medication, and you may follow up with your rheumatologist about another advised method of treatment. Unfortunately, retinal damage caused by Aralen may be irreversible, but this medication is rarely prescribed anymore for lupus.

Do not smoke while taking anti-malarial medications, since smoking actually reduces the benefits of these drugs. In fact, people with lupus should not smoke at all due to their increased risk of cardiovascular disease.

You should always take your anti-malarial medications with food to prevent stomach upset. If a stomachache does occur, it is usually temporary. However, if you experience stomach upset while taking generic hydroxychloroquine, ask your doctor about trying name-brand Plaquenil instead. While these medications contain the same active ingredient, the preparation of generic hydroxychloroquine can sometimes cause stomach irritation. This sort of upset usually does not occur with commercial Plaquenil. Your doctor can ensure that you receive this version of the medication by writing “do not substitute” on your script.

Lastly, remember that even though you may feel the benefits of anti-malarial therapy after about a month of treatment, it may take up to three months for the full benefits of the drug to manifest. If you experience any serious adverse effects, notify your doctor.

Can I stop taking anti-malarials suddenly?

Long-term anti-malarial use is normally safe. However, if you stop taking your anti-malarial drugs, you may experience a lupus flare.

Potential added benefits of anti-malarial drugs

Anti-malarial drugs may have additional health benefits for some people. Potential benefits include greater protection from UV light and lower cholesterol and blood glucose levels. These benefits may be especially helpful for people taking steroids. In addition, individuals with antiphospholipid antibodies, such as the lupus anticoagulant and anticardiolipin antibodies, may experience a decreased likelihood of blood clots.

What are the possible side effects of anti-malarial drugs?

Most people (about 90%) who take anti-malarial medications experience no side effects. If side effects do occur, they are usually minor and last only for a short period of time.

Potential side effects of anti-malarial drugs include:

• Skin rashes and pigment change. Atabrine, specifically, can cause yellow pigmentation of skin. Sometimes Plaquenil can also deposit in the tissues of the body and cause the skin to take on a greenish tone.
• Dry skin
• Loss of appetite
• Abdominal bloating
• Upset stomach
• Stomach cramps
• Retinal damage – There is a small chance that retinal damage will occur while taking hydroxychloroquine (Plaquenil) or chloroquine (Aralen). For this reason, you should see your ophthalmologist at least once per year so that she/he may check for retinal deposits. Retinal damage caused by hydroxychloroquine is generally reversible, but damage caused by chloroquine may not be. More information on this effect can be found above.
• Less common side effects:
  • Headaches
  • Muscle aches
  • Weakness
  • Nervousness, irritability, dizziness (although these effects are uncommon)
  • Major neurological side effects: confusion, seizures – These are quite rare, but if you experience them, alert your doctor immediately.
  • Exacerbation of psoriasis – If you have psoriasis, Plaquenil may make your condition worse.     Talk to your doctor if you have this condition.

What causes lupus?

Lupus is caused by a complex interplay of genes, hormones, and environmental factors. When patients first present signs of lupus, they are often asked whether they have a family member—a mother, aunt, sister, or other relative—with lupus or another autoimmune condition.  Researchers were first drawn to the link between genes and lupus because of the clustering of lupus in families and the increased prevalence of the disease among certain ethnic groups. For example, the risk for development of lupus in siblings of individuals with the disease is about 20 times higher than that of the general population. In addition, even healthy family members of people with lupus are more likely to test positive in several lupus-related medical tests, including ANAs and the false-positive test for syphilis. However, the presence of genes predisposing a person to lupus does not necessarily mean that the individual will develop the disease. While researchers are confident that lupus is caused by both genes and environmental triggers, they cannot determine which factor sets the disease in motion or how precisely these two elements interact. Research into both areas seeks to draw light upon this subject.

Genes Associated with Lupus

Our knowledge of the genes associated with lupus and other autoimmune diseases is growing, but certain genes have been identified that provide insight into an individual’s chance of developing lupus.

MHC Genes

MHC class II and III represent two families of genes known to be associated with lupus. Major histocompatability complex (MHC) genes help to shape your immune response by coding for proteins that function in response to invaders (antigens). The strength of the association of MHC II genes with lupus varies by ethnicity. MHC III genes code for components of the complement system, a group of proteins that interact to clear immune complexes and affect your body’s inflammatory response. Specifically, lupus involves defects of the genes for complement proteins C4 and C2.

Other Genes

Other genes have also been associated with the development of lupus. Among these are genes that code for variants of opsonins, molecules that make it easier for cells in your immune response to initiate certain steps. [Specifically, opsonins are involved in the facilitation of phagocytosis, the process in which cells called macrophages swallow antibodies carrying invading particles (antigens).] The specific opsonins involved are two proteins called mannose binding protein and C-reactive protein.

Genes that code for complement receptors and antibody receptors are also known to be associated with lupus. These receptors are responsible for detecting and binding to pathogens in the body. In addition, genes for cytokines, molecules that function as signaling molecules in your immune system, have also been implicated in the association with lupus. Specifically, researchers have focused on cytokines called tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10).

Genes that code for molecules called Fcγ-receptors that function to “catch” antibodies carrying antigens also have been linked to lupus nephritis (lupus affecting the kidneys). Specifically, researchers have targeted variants of this gene that cause these receptors to function poorly, causing inefficient clearance of immune system cells from the body.

Hormones and Environmental Factors

Women are 9 times more likely than men to develop lupus. This phenomenon can be explained by sex hormones and the resulting relative strengths of the female and male immune systems. The female body generates and uses larger quantities of estrogen, while the male body relies on hormones called androgens. Estrogen is known to be an “immunoenhancing” hormone, which means that women have stronger immune systems than men. For this reason, the incidence of autoimmune diseases is generally higher in women than in men. Such an observation make sense in light of the evolutionary need for women to survive to nurture their children.

In addition, certain environmental factors have been linked to the development of lupus. These environmental contributors are difficult to isolate, but researchers have established links between lupus and a variety of toxins, such as cigarette smoke, silica, and mercury. Infectious disease agents such as the Epstein-Barr Virus (EBV, which causes mononucleosis or “mono”), herpes zoster virus (the virus that causes shingles), and cytomegalovirus have also been implicated. Certain drugs can cause lupus-like syndrome and exposure to ultraviolet light and stress are known to aggravate lupus symptoms, but none of these factors have been identified as direct causes of the disease.

Sources

• Miller, Frederick W., and Glinda S. Cooper. “Environmental Aspects of Lupus.” Dubois’ Lupus Erythematosus. Ed. Daniel J. Wallace and Bevra Hannahs Hahn. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2007. 21-33.
• Salmon, Jane E., and Robert P. Kimberly. “Systemic Lupus Erythematosus.” Hospital for Special Surgery Manual of Rheumatology and Outpatient Orthopedic Disorders: Diagnosis and Therapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2006. 221-38.
• Tsao, Betty P. and Hui Wu. “The Genetics of Human Lupus.” Dubois’ Lupus Erythematosus. Ed. Daniel J. Wallace and Bevra Hannahs Hahn. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2007. 54-81.
• Wallace, Daniel J. The Lupus Book: A Guide for Patients and Their Families. 1st ed. New York: Oxford UP, 1995. 37-45.

In people with lupus, the immune system begins to recognize and attack the body’s own tissues. This phenomenon is similar to “friendly fire” and causes inflammation in various parts of the body. It is important to realize, however, that lupus can affect different people in different ways and that signs and symptoms can come and go, producing periods of flares and remission. The following articles provide an introduction to how lupus may affect different parts of the body.

• Antiphospholipid Antibodies Antiphospholipis antibodies are antibodies directed against phosphorus-fat components of your cell membranes called phospholipids, certain blood proteins that bind with phospholipids, and the complexes formed when proteins and phospholipids bind. Approximately 50% of people with lupus possesses these antibodies, and over a twenty-year period of time, one half of lupus patients with one of these antibodies—the lupus anticoagulant—will experience a blood clot.
• Arthritis “Arthritis” is a broad term used to describe inflammation of the joints. There are many subsets of arthritis, but the arthritis seen in lupus closely resembles rheumatoid arthritis
• Cardiovascular System Lupus can affect the cardiovascular system, which includes your heart and blood vessels. In fact, cardiovascular disease, not lupus itself, is the number one cause of death in people with SLE. Therefore, it is very important that you take steps to maintain optimal cardiovascular health.
• Immune System in lupus and other autoimmune diseases, the immune system begins to recognize and attack “self.” In other words, the cells of the immune system begin to injure the body’s own tissues. This phenomenon is similar to “friendly fire” and can cause permanent scarring that ultimately jeopardizes the function of certain organs and systems in the body. Certain cells and processes of the immune system have been identified as playing a role in lupus.
• Kidneys About one half of people with lupus experience kidney involvement, and the kidney has become the most extensively studied organ affected by lupus.
• Lungs About 50% of people with SLE will experience lung involvement during the course of their disease. Five main lung problems occur in lupus: pleuritis, acute lupus pneumonitis, chronic (fibrotic) lupus pneumonitis, pulmonary hypertension, and “shrinking lung” syndrome.
• Nervous System Lupus can affect both the central nervous system (the brain and spinal cord) and the peripheral nervous system. Lupus may attack the nervous system via antibodies that bind to nerve cells or the blood vessels that feed them, or by interrupting the blood flow to nerves. Conditions associated with or sometimes seen in lupus include cognitive dysfunction, fibromyalgia, headaches, organic brain syndrome, and CNS vasculitis.
• Skin Most people with lupus experience some sort of skin involvement during the course of their disease. In fact, skin conditions comprise 4 of the 11 criteria used by the American College of Rheumatology for classifying lupus. There are three major types of skin disease specific to lupus and various other non-specific skin manifestautions associated with the disease.

by Michelle Petri, M.D., M.P.H

Introduction

Because lupus is a disease that strikes predominantly young women in the reproductive years, pregnancy is both a practical and a research issue. For most women with lupus, a successful pregnancy is possible. This is an immense change from the 1970’s, when most women with lupus were counseled not to become pregnant. Studies of the immune system in pregnancy are of interest for what they have taught us about the effect of hormones on lupus flares.

Risk of Miscarriage

First, the risks of pregnancy in lupus patients are real and involve both the mother and the fetus. About ten percent of pregnancies currently end in miscarriage. The first trimester losses appear either to have no known cause or to associate with signs of active lupus. Later losses occur primarily due to the antiphospholipid antibody syndrome, inspite of treatment with heparin and aspirin. All women with lupus, even if they do not have a previous history of miscarriage, should be screened for antiphospholipid antibodies, both the lupus anticoagulant (the RVVT and sensitive PTT are the best screening battery) and anticardiolipin antibody.

The classification criteria for the antiphospholipid antibody syndrome were revised last year. There are now two major criteria–vascular thrombosis and pregnancy morbidity. A woman who has had a past venous or arterial thrombosis should be therapeutically anticoagulated during the next pregnancy. A woman who has pregnancy morbidity–one or more late losses, three or more first trimester losses, or severe pre-eclampsia or placental insufficiency–should be treated with prophylactic doses of heparin and a baby aspirin during the next pregnancy. Several clinical trials have indicated that the combination of heparin and aspirin is likely preferable to aspirin alone, although some women do have successful pregnancies on aspirin alone. These pregnancies should be considered high risk, with appropriate fetal monitoring, including ultrasounds to monitor growth and placental development, and biophysical profiles, usually from the 26th week onwards. Many of these babies can be rescued by early C-section when there are signs of severe placental insufficiency. There is no consensus on whether treatment is indicated for the woman with lupus who has antiphospholipid antibodies in her first pregnancy. Many authorities in the field would use a baby aspirin in this situation.

Risk of Preterm Birth and Intrauterine Growth Retardation

An equal, if not more important risk is the risk of preterm birth. Preterm birth in lupus is usually not due to antiphospholipid antibodies, but due to pre-eclampsia and premature rupture of membranes. Risk factors for preterm birth in general include active lupus, high dose prednisone, and renal disease. Maternal hypertension in the second trimester is a good predictor. Overzealous treatment of maternal blood pressure could reduce placental blood flow, and is not recommended. We have not found any risk factors that predict premature rupture of membranes. In addition to being preterm, the baby is also at risk for intrauterine growth retardation (IUGR). We have not found a clinical variable that is predictive of IUGR. In fact, lupus activity, prednisone, and antiphospholipid antibodies are not predictive of IUGR. The best predictor using ultrasound monitoring is an abdominal circumference below the 10th percentile and an estimated fetal weight below the 50th percentile.

Maternal Risks

The most important maternal risk, that of a lupus flare, is actually the most controversial. In prospective studies at both Hopkins and in London, the risk of flare is greater in a pregnant than a non-pregnant woman. However, other centers have not confirmed this. There may be differences in patient selection that account for the different findings. We have found that the hormone prolactin, which rises during pregnancy, is associated with lupus activity during pregnancy. Likely other hormonal influences, especially estrogen, changes in cytokines are involved as well, although these have not been studied. We have found that the type of organ system involvement is different in pregnant vs. non-pregnant patients. In pregnancy we have found an excess of renal and hematologic flares, and fewer arthritis flares.

Some of the risk to the mother is not directly due to lupus. In a case-control study we found that women with lupus were more likely to have multiple complications of pregnancy, including diabetes, urinary tract infections, and pre-eclampsia. For this reason, referral to a high-risk obstetrician is always appropriate. Women on prednisone were more likely to have hypertension and diabetes, as would be expected. The physician caring for a woman with lupus who wishes to become pregnant must review her medications. Prednisone is largely metabolized by the placenta, and is unlikely to cause any fetal malformations, but will increase the risk of diabetes and hypertension in the mother. Some immunosuppressives, such as imuran (azathioprine) have been continued during lupus pregnancy when necessary to control maternal lupus. Cyclophosphamide should never be used during pregnancy because of the high risk of important birth defects. Because of potential teratogenicity, Coumadin should be switched to heparin as soon as the woman knows she is pregnant. ACE-inhibitors, because of effects on fetal kidney development, should be stopped as soon as the woman knows she is pregnant. NSAIDs are usually allowed during the first trimester only, because of potential adverse effects on the fetal ductus arteriosus. Plaquenil (hydroxychloroquine) has a good safety record in lupus pregnancy, and is usually continued if needed to control maternal lupus.

Management and Monitoring

Lupus pregnancy should be timed to coincide with a period of good disease control if at all possible. It does not make sense to taper medication simply because a woman desires pregnancy, because of the likelihood of inducing a flare if medications are reduced too low. General screening tests should include the antiphospholipid antibodies, and also anti-Ro and anti-La. A woman who is positive for these antibodies is at increased risk of congenital heart block in the baby, and monitoring of the fetal cardiac conduction system by 4-chamber fetal cardiac echo should be instituted. We generally monitor the mother monthly during pregnancy and obviously more often if disease activity warrants it. Laboratory monitoring done monthly includes the complete blood count, creatinine, liver function tests, urinalysis, and a 24 hour urine for creatinine clearance and total protein. It is controversial whether serologic tests are helpful during pregnancy. In normal pregnancy the C3 and C4 should rise.

Summary

We are lucky to have a long-term collaboration between our high-risk obstetricians and the Lupus Center at Hopkins that has allowed not only for superb clinical care of the mothers and babies, but also for the prospective database that has led to the studies summarized above. For nearly all mothers, a happy outcome is possible, but we must not forget that we have had one maternal death in our 150 pregnancies and that 7% of the pregnancies are characterized by a severe maternal complication. This is our impetus to continue our research into lupus and its interactions with pregnancy.

Selected Reference

Petri M. Systemic lupus erythematosus and pregnancy. Rheum Dis Clin North America 20:87117, 1994.

Fine LG, Barnett EV, Danovitch GM, et al. Systemic lupus erythematosus in pregnancy. Ann Intern Med 94:667-677, 1981.

Cowchock FS, Reece EA, Balaban D, et al. Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low dose heparin treatment. Am J Obstet Gynecon 166:1318-23, 1992.

The following medications are often used by doctors to treat other conditions that commonly occur in people with lupus. Although these drugs do not specifically address the underlying cause of lupus, they are used to treat other conditions that may be compounded or indirectly caused by lupus. Since lupus affects different people in different ways, treatment courses are highly individualized. Please remember to take your medications exactly as directed by your physician and notify him/her of any concerns upon your next visit. Never take any medications until they are approved by your doctor – in other words, do not self-medicate!

• Aspirin Low doses of aspirin are often recommended for lupus patients who have antiphospholipid antibodies and may reduce the risk of heart attack and stroke.
• Antidepressents Anti-depressant medications are used to treat depression and anxiety, present in almost half of all people who have lupus. It is important that you speak with your doctor if you feel you are experiencing clinical depression, because many people who are physically ill respond well to anti-depressant medications. In addition, your doctor may treat your depression in different ways depending on the cause.
• Antiplatelet Medications (Platelet Antagonists) Some lupus patients are at an increased risk for blood clots due to the prevalence of a condition known as antiphospholipid antibody syndrome (APS). Platelet antagonists help prevent these clots and in doing so, also help to prevent heart attack, stroke, and other complications.
• Osteoporosis Medications (Bisphosphonates) Bisphosponates are medications used to treat and prevent osteoporosis. People with lupus are at an increased risk for this condition due to the inflammation they experience with the disease. Certain medications taken by lupus patients also increase the risk of osteoporosis, especially corticosteroids such as prednisone.
• Blood Pressure Medications (Anti-hypertensives) 25-30% of people with lupus experience hypertension (high blood pressure). The most common causes of high blood pressure in people with lupus are kidney disease and long-term steroid use. Other medications, such as cyclosporine (Neoral, Sandimmune, Gengraf) can also cause elevations in blood pressure. It is important to remember that while diet and exercise are extremely important for optimal cardiovascular health, these elements alone may be insufficient in controlling your blood pressure; in this case, your doctor will prescribe a medication.
• Anticoagulants Anticoagulants (“blood thinners”) are medications that decrease the ability of the blood to clot and are used in lupus patients with antiphospholipid antibodies to reduce the risk of deep venous thrombosis (DVT), stroke, and heart attack.
• Gastrointestinal Medications Many people with lupus suffer from gastrointestinal problems, especially heartburn caused by gastroesophageal reflux disease (GERD). Peptic ulcers can also occur, often due to certain medications used in lupus treatment, including NSAIDs and steroids. Certain medications may be prescribed or recommended by your doctor to control these conditions.
• Cholesterol Medications (Statins) Statins are medications that lower the level of cholesterol in your blood by reducing the production of cholesterol in the liver. People with high levels of cholesterol in their blood face an increased risk of cardiovascular disease, which can lead to chest pain, heart attack, stroke, and peripheral vascular disease. Studies have shown that people with lupus are more likely to have clogged arteries that can lead to heart attack and stroke at a younger age. This increased risk is caused by elevated cholesterol levels, high blood pressure, diabetes, and inflammation, conditions that occur often in people with lupus. Certain medications, such as corticosteroids (e.g., prednisone) can provoke or compound these symptoms. For this reason, the cholesterol-lowering properties of statins are commonly called upon for lupus patients.
• Thyroid Medications Autoimmune thyroid disease is common in lupus. It is believed that about 6% of people with lupus have hypothyroidism (underactive thyroid) and about 2% have hyperthyroidism (overactive thyroid). A thyroid gland that is functioning improperly can affect the function of organs such as the brain, heart, kidneys, liver, and skin. Hypothyroidism can cause weight gain, fatigue, depression, moodiness, and dry hair and skin. Hyperthyroidism can cause weight loss, heart palpitations, tremors, heat intolerance, and eventually lead to osteoporosis. Treatment for both underactive and overactive thyroid involves getting your body’s metabolism back to normal.
• Fibromyalgia Medications Fibromyalgia is a chronic disorder characterized by widespread pain and tenderness, general fatigue, and non-restful sleep. Many people with lupus have fibromyalgia; in fact, much of the pain that people with lupus feel is due to this condition. Three medications are used to reduce some of the physical and emotional symptoms of fibromyalgia.
• Restasis (Dry Eye Medication) Restasis is an immunosuppressive medication used to treat eye symptoms related to Sjogren’s syndrome, a chronic autoimmune disorder in which the glands that produce tears and saliva do not function correctly.