Authors: Rita Baron-Faust,Jill Buyon
The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (13 page)
Belimumab (Benlysta)
, the first new drug for treating lupus since 1955, was approved by the FDA in 2011. Approval was based on two large randomized clinical trials of approximately 800 patients each around the world, which showed that belimumab, a monoclonal antibody to circulating BLyS, is effective for managing SLE.
10
It’s thought that too much BLyS is produced in lupus and that this may accelerate autoimmune B cell proliferation and survival. While belimumab has shown benefits in SLE, it seems to work best in women with skin and joint problems and may help those who cannot lower their steroid dose without having a flare. It has also been shown to improve lupus-related fatigue.
Belimumab is very well tolerated and has an excellent safety profile. It does not cause infections to any greater degree than other currently used lupus medications. In rare cases, side effects include nausea, diarrhea, fever, hypersensitivity, and infusion-site reactions.
Belimumab is an intravenous drug given monthly to treat patients whose lupus is active and who are not doing well on conventional lupus medications. However, conventional lupus treatments are tried before belimumab is considered.
In general lupus treatments are aimed at reducing symptoms, decreasing the number and severity of flares, stopping progression of the disease, and minimizing permanent organ damage.
Pain medications
, most frequently
nonsteroidal anti-inflammatory drugs (NSAIDs)
, are given to reduce muscle and joint pain and inflammation. NSAIDs include aspirin,
ibuprofen (Motrin)
,
naproxen (Naprosyn)
, and
nabumetone (Relafen)
. However, these drugs can cause gastrointestinal problems, including bleeding. They can also affect kidney function and cause liver abnormalities, so they must be used with caution even though some can be purchased without a doctor’s prescription.
Some NSAIDs, called
COX-2 inhibitors
, are less likely to cause serious GI bleeding. They include
celecoxib (Celebrex)
and
meloxicam (Mobic)
, a partially selective COX-2 inhibitor. There’s a special precaution, however.
Selective COX-2 inhibitors
do not have the anticlotting properties of aspirin (and therefore don’t reduce the risk of a heart attack), so it’s important that women who take these drugs first be checked for antiphospholipid antibodies, which may add to the risk of clotting. Celecoxib also contains sulfa, and this may be a problem because lupus patients have a tendency to be allergic to sulfa.
Glucocorticoids (corticosteroids)
are used to reduce inflammation and suppress immune activity. Among the most commonly prescribed are
prednisone (Deltasone, Orasone)
and
methylprednisolone (Medrol)
.
Corticosteroids have a number of major side effects (see
pages 42
to
43
). The biggest risk for side effects occurs when higher doses of steroids are taken for long periods of time. Of particular concern, a large study from Johns Hopkins finds that the risk of developing cataracts more than doubles for SLE patients who have been on 10 mg/day of prednisone (or its equivalent) for 3 to 10 years.
11
While the risk of cataracts with prednisone is well known, this is the first indication of know how long it takes (and at what dose) for the problem to emerge. Adding to the risk: high blood pressure and elevated disease activity.
Corticosteroids are extremely effective in treating lupus and may be needed for weeks in cases of life-threatening complications. However, prolonged use can also lead to a shutdown of the adrenal glands. To get the adrenal glands working again, steroids must be slowly tapered.
Antimalarials
are drugs originally used to treat malaria that suppress the inflammation leading to skin rashes, joint pain, hair loss, and fatigue in lupus. They include
chloroquine (Aralen)
,
hydroxychloroquine (Plaquenil)
, and
quinacrine
(
Atabrine
, which must be ordered from a compounding pharmacy not your usual commercial drug store). Hydroxychloroquine is the most commonly prescribed. The side effects include rare nausea, diarrhea, and bad taste in the mouth, most of which can be avoided by taking the drug just before bedtime. In very rare cases a patient may have an allergic rash.
The most serious side effect of these drugs is eye damage (retinal deposit of the drug). This effect is rare and is related to long-term use of the drug and not even at all likely until after five years at the very least. Patients have taken this drug for over two decades with no eye toxicity. It is important to see an eye doctor once per year. Keep in mind that it may take months to see a benefit from antimalarials, so patience is important.
Recent studies suggest that hydroxychloroquine may also have protective effects on bone mass, preventing bone loss at the hip and spine, areas vulnerable to fracture. They may even protect against blood clotting, high lipids, and diabetes. It is also thought that the drug may prevent worsening of lupus. It’s generally considered a drug to be taken by all patients with lupus and to be continued as long as there are no signs of eye problems. All other drugs can be added to hydroxychloroquine, and stopping the drug can result in lupus flares.
Immunomodulating drugs
belong to a class of drugs called
cytotoxic (cell-killing)
drugs that can help suppress the immune system by reducing populations of immune cells. These drugs include
azathioprine (Imuran)
,
cyclophosphamide (Cytoxan)
, and
mycophenolate mofetil (CellCept)
and are used when steroids are unable to be tapered and when there’s more serious kidney or other organ involvement. Methotrexate is often used to treat arthritic symptoms just as in RA.
Side effects include anemia, a low white blood cell count, and an increased risk of infection. There are suggestions these drugs may increase the risk of cancer (but this has not been proven). Cyclophosphamide can also cause sterility (premature menopause), especially in women who begin the drug after the age of 35.
The anticancer drug
rituximab (Rituxan)
, which targets a protein on the surface of B cells and helps deplete their numbers, is still being tested in SLE
and is sometimes used to treat low platelets and lupus nephritis that is not responsive to other immunosuppressive agents.
Anticoagulants
are prescribed for women with clotting abnormalities to prevent blood clots in leg veins (
deep vein thrombosis
) or in the lungs or coronary arteries. Low-dose aspirin (81 mg) prevents platelets from sticking together to form clots. The oldest of the anticoagulant drugs,
warfarin (Coumadin)
, interferes with some of the proteins that regulate clotting that depend on vitamin K.
Heparin
, usually used as low-molecular-weight heparins (
Lovenox
), affects another clotting mechanism. It’s important to remember that blood thinners must be monitored carefully to avoid bleeding episodes.
Intravenous immunoglobulin (IVIG)
may be used to raise platelet counts in women with thrombocytopenia (see
pages 370
to
373
).
Dehydroepiandrosterone (DHEA)
is an
androgen,
or male hormone, normally produced by the adrenal glands and converted by the body into estrogen and testosterone. Some scientists believe that women with lupus have low levels of androgens (which have anti-inflammatory properties). DHEA may be helpful if you have mild lupus, especially skin rashes, hair loss, and joint pain. It does not appear to be effective for more serious manifestations of lupus, such as kidney disease. DHEA is usually well tolerated with only minor side effects, including mild acne.
A pharmaceutical preparation of DHEA (
prasterone, Aslera
) has been tested in lupus patients and has yet to be approved by the FDA. But a systematic review of recent studies concludes that while some evidence suggests DHEA may improve disease activity and health-related quality of life in severe or active SLE, it has little or no effect in mild to moderate cases.
12
While DHEA is available in health food stores as a dietary supplement, these are not standardized or regulated, and some may be ineffective. Because of its anti-inflammatory properties, DHEA may allow you to reduce the amount of prednisone you’re taking. But don’t take it without a physician’s supervision.
Future treatments, including newer biologicals, are currently in clinical trials and are hoped to have a more specific effect on the immune abnormalities of lupus, not just global immunosuppression.
Another drug that blocks B cell activation and survival through BLyS,
blisibimod
, both in membrane and soluble forms, has produced mixed results in clinical trials, enabling some women to reduce corticosteroids, and seems to work best in severe lupus.
13
As this book went to press, blisibimod was still being tested.
Atacicept
, an agent that inhibits BLyS and another B cell activating factor dubbed APRIL, so far has been unsuccessful in dampening lupus flares.
14
Another B cell drug,
epratuzimab
, is also under investigation, along with
anifrolumab
, an experimental anti-interferon alpha receptor monoclonal antibody. Recent studies found that epratuzimab was disappointing because it did not meet its efficacy endpoints.
Studies also suggest that low doses of
thalidomide (Thalomid)
may help improve rashes in women with cutaneous lupus who have failed other therapies. Thalidomide has some anti-inflammatory effects, but it has potentially severe side effects and has not been shown to produce remission in discoid lupus.
15
Side effects include a cessation of menstrual periods, weight gain, drowsiness, and blood clots in women who have risk factors for clots. The drug can also cause irreversible nerve damage, so nerve conduction tests must be done at baseline and periodically during treatment. It has not yet been approved for treating lupus, and because of its devastating effects on a developing fetus thalidomide cannot be used by women who wish to become pregnant.
Deanna’s story continues:
The high doses of steroids I was on made my muscles very weak, and I was in physical therapy to try to get my strength back. There was a period when I couldn’t even lift myself off the toilet. I was emotionally a mess from the
steroids. I would have temper tantrums. I had an inflamed esophagus, so I had difficulty swallowing food. But the joint pain got better. When my doctor told me I had lupus nephritis, he said I probably would not be able to go back to school. . . . That made me furious. . . . I was determined to get better. Eventually, they reduced the steroids. My face was going back to normal, my hair was growing in again, and my self-esteem was coming back.I had to go back to college that fall on crutches at first . . . but I worked even harder in school. I felt I had a lot to make up for. I graduated summa cum laude. Highest honors. I couldn’t control the lupus, but I could try to control everything else. I graduated from college, taught for a while, and eventually got my master’s degree.
Ninety percent of patients with lupus are women, and numerous studies suggest a role for estrogen in the disease. Unlike rheumatoid arthritis, which gets better during pregnancy when estrogen levels are high (but that’s not the whole story), lupus can sometimes flare during or after pregnancy. Some studies suggest that women with lupus may have an abnormality in the way their bodies process naturally occurring estrogens, while others find that women with SLE may metabolize testosterone at a faster rate than men, so high levels of estrogen may go unopposed by androgens. Male hormones may play a protective role in lupus; women with low levels of androgens may be more vulnerable to SLE. Genes have also been discovered that may interact with estrogen to heighten women’s responses to inflammation in SLE. These genes, called
toll-like receptors (TLRs)
, may stimulate greater immune system signaling.
16
Prolactin
(produced during lactation) is another hormone that may play a role. It not only stimulates the flow of mother’s milk, but it’s also produced by immune cells and can act as a cytokine. In this role, prolactin triggers the release of other cytokines and stimulates immune reactions. About 20 percent of lupus patients have higher prolactin levels than the body would normally produce.
There are also studies that suggest a role for microchimerism in lupus, where cells from the fetus get into the mother’s bloodstream and may trigger a reaction by the immune system (see
pages 13
to
15
). However, it may be
the maternal cells that get into the fetal circulation and persist into adult life that increase the risk of lupus and neonatal lupus, suggest researchers at the Fred Hutchinson Cancer Research Center and the University of Washington. These cells could travel to certain sites in the body and provoke immune reactions. The researchers noted that biopsies of heart muscle have found maternal cells in babies with neonatal lupus, and that studies also show that lupus can be created in mice by injecting parental cells. However, this area of research is still very much in its preliminary stages.
Lupus can affect women in many ways during their reproductive years, especially during and after pregnancy.
You may find that lupus symptoms flare during different times of the menstrual cycle. For some women, flares occur just prior to menses (when estrogens are lowest), while in others, flares occur just before the time of ovulation (when estrogens are highest). It may be the change in hormone levels that triggers a flare, not the absolute level itself. Birth control pills create steady levels of hormones and may help prevent these cyclic flares (although not proven).
Menstrual periods can stop during times of severe disease activity. One Brazilian study found that disease activity was a major factor associated with menstrual disturbances. The study, which included 36 SLE patients ages 18 to 39 years, determined half of the women had menstrual dysfunction, with increased menstrual flow being the most frequent.
17
About 11 percent had elevations in follicle-stimulating hormone (FSH), with or without menstrual disturbances, suggesting there may have been subclinical ovarian damage. The study found no significant association of low-dose prednisone with menstrual changes. But other studies have shown that women being treated with high-dose steroids do have menstrual cycle irregularities, with a temporary loss of periods being most frequent. Unfortunately, treatment with cyclophosphamide (especially in women older than 35) can result in permanent sterility.
In general, recent studies show lupus patients can do well during pregnancy, with little or no permanent exacerbation of their disease.
Severe flares occur most often among women with prior kidney disease and low platelet counts, problems that can recur during pregnancy and must be carefully monitored for. Minor flares, with fatigue, joint pain, and rashes, may be uncomfortable but usually don’t pose a significant threat to mother or baby.
According to the largest study of pregnancy outcomes in SLE, rates of mild to moderate flares were just under 13 percent in the second trimester and less than 10 percent in the third trimester.
18
The eight-year multiethnic PROMISSE study (Predictors of Pregnancy Outcome: BioMarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus) looked at 385 patients with stable or mild/moderate SLE, and only 3 percent of women had severe flares.
Poor pregnancy outcomes—including preterm birth (before 36 weeks) due to low blood supply to the fetus (called placental insufficiency), maternal hypertension, preeclampsia (abnormally high blood pressure during pregnancy), low birthweight babies, and fetal death—occurred in only 19 percent of the women.
18
That means the vast majority of the women (89 percent) had uncomplicated pregnancies. Rates of poor pregnancy outcomes were higher among African American and Hispanic women.
Risk factors for poor outcomes include higher disease activity, platelet counts lower than 100K, the need for medications to control high blood pressure, and the presence of the lupus anticoagulant.
There’s no question that having SLE does increase your chances of complications. According to a recent analysis of almost 11,000 pregnancies, comparing women with and without SLE, those with lupus had almost double the risk of hypertension, preeclampsia (abnormally high blood pressure during pregnancy), preterm delivery, and stillbirths.
19
The study also found a more than sixteenfold occurrence of nephritis in SLE pregnancies, depending on disease activity.
However, fewer than half the women in this study with SLE received hydroxychloroquine,
19
although studies suggest that it prevents flares in pregnancy. One reason may be that the women in the study saw a rheumatologist
infrequently, comments Michelle A. Petri, MD, PhD, professor of medicine and director of the Johns Hopkins Lupus Center in Baltimore, the study’s lead author.
As for medical costs, Dr. Petri and her colleagues found that the costs of managing pregnancy in SLE could be as high as $20,000, about double that for a non-lupus pregnancy.
Most important, no matter how well you are doing, it’s critical that you be seen frequently by your rheumatologist, as well as by your obstetrician (who should be familiar with taking care of pregnant lupus patients). These doctors should be specialists in high-risk pregnancies (maternal fetal medicine specialists) and should be affiliated with a neonatal intensive care unit in case your baby needs special attention.
Women with SLE-related kidney disease are also more likely to have protein in the urine, or proteinuria, which may signal a lupus flare or preeclampsia. Experimental biomarkers that may predict preeclampsia (and flares) as early as 20 weeks are being researched, and clinical trials are underway in non-SLE patients of
ATryn
, an antithrombin recombinant drug, to treat preeclampsia during the twenty-fourth to twenty-eighth weeks of pregnancy.
20
Angiogenesis
is the process of growing new blood vessels, key to formation of the placenta in pregnancy, and dysregulation of this process may lead to preeclampsia and
placental insufficiency
(insufficient blood supply from the placenta) in SLE.
Recent studies led by Jane E. Salmon, MD, research professor at the Hospital for Joint Diseases in New York, found that levels of several angiogenic factors that interfere with placental development are elevated in women with lupus and antiphospholipid antibodies who go on to have preeclampsia, pregnancy complications, and poor outcomes.
21
According to Dr. Salmon, increases in angiogenic factors detected before 15 weeks of pregnancy could identify women at risk.
Regular monitoring for preeclampsia and other risky conditions in pregnancy is a must. As soon as you know you’re pregnant, a baseline measurement of protein in the urine over 24 hours should be done; after that, dipsticks should be done at each obstetrical visit, and 24-hour urine collections should be done each trimester.
Being in remission for six months is the best time to consider having a baby. This usually means being clinically well without major organ involvement such as active kidney, heart, lung, or brain disease, and taking less than 20 milligrams per day of prednisone. Taking greater than 20 milligrams of prednisone, despite feeling well, is not likely to represent a true state of remission. In fact, the definition of remission is quite individual. For example, blood tests may indicate a minor degree of disease activity (slightly low complement levels and slightly elevated anti-dsDNA antibodies), but a woman may have no other signs of a problem. So you needn’t always wait for a complete absence of evidence of lupus activity in your blood work before getting pregnant. If you’re planning a pregnancy, you also need to make sure that you’re not anemic and do not have a very low platelet count or over a gram of protein in your urine. Minor joint or skin involvement is usually not a reason to avoid pregnancy.
Fertility and sterility rates for women with SLE are comparable to those for women who don’t have SLE when the disease is in remission. However, your fertility may be depressed during times of severe disease activity.
If women experience problems becoming pregnant, they may need hormonal stimulation to produce multiple eggs for implantation during in vitro fertilization (IVF).
IVF can be successful in women with SLE and antiphospholipid syndrome (APS, see
Chapter 11
,
pages 347
to
362
), but hormonal stimulation may increase the risk of flares and complications.
One small study conducted at three lupus centers in New York City found that ovulation induction, ovarian hyperstimulation, and IVF resulted in increased disease activity in around a quarter of women with SLE.
22
The study, associated complications during pregnancy and postpartum, including toxemia, lupus flares, and diabetes; postpartum problems included a flare in kidney disease, cartilage inflammation (
costochondritis
), and depression.
If you make the decision to undergo IVF, it’s vital that adhere to your lupus treatments. A study of 34 women with SLE and/or APS who had undergone at least one cycle of IVF found that 92 percent had successful pregnancies. However, 10 percent did have hormone-related flares or clots, partly because of lack of adherence to SLE treatments, researchers told the 2013 ACR meeting.
23
Treatments included hydroxychloroquine, steroids, aspirin, and/or low-molecular-weight heparin.
Tests you’ll need if you’re pregnant.
Once you’re pregnant, you will need routine blood tests, such as a comprehensive chemistry to check kidney function, liver function, glucose, complete blood count, and urinalysis. The standard tests to assess lupus activity should also be done, such as measuring complement levels and anti-DNA antibodies.
During your first trimester you’ll need several other blood tests. The first set of tests assesses the risk of a spontaneous miscarriage and measures antibodies to phospholipids, which may cause blood clotting in the placenta. One of the tests you’ll need is the VDRL (a standard test for syphilis that can also detect anticardiolipin antibodies). A traditional ELISA for direct measurement of anticardiolipin antibodies and antibodies to B2GPI will also be done, along with special clotting tests. One type of clotting test is called a Dilute Russell Viper Venom Time (DRVVT), which checks for the presence of the so-called lupus anticoagulant (which actually promotes clotting, not bleeding).
A second set of antibody tests is done to assess the rare risk of permanent cardiac damage in the developing fetus and/or skin rash and liver disease in early infancy. These are antibodies to SSA/Ro and SSB/La proteins. Of course, a positive test for any of these antibodies does not mean you’ll have problems with the pregnancy, but your doctors need to know so they can be prepared.
Also, as a precaution, during each trimester you should be tested for anti-DNA antibodies and complement levels and also have a 24-hour urine collection to test for protein and creatinine. Protein in the urine means the kidneys are leaky—think of a colander in which the holes might be too big and spaghetti can leak out. The creatinine level tells you how well the kidneys are filtering waste products.
Each trimester, sonograms are done to check the baby’ growth and amniotic fluid. Later in pregnancy, fetal movements and breathing will be carefully measured. If there are signs of fetal distress, you may need to be hospitalized and may need to consider early delivery. There is a higher rate of premature births in women with lupus. Patients with lupus also have a higher risk of preeclampsia (toxemia of pregnancy, which includes high blood pressure and protein in the urine) than the general population.
Medications during pregnancy and breastfeeding.
Keep in mind that all drugs taken during pregnancy could have potential harm to the growing
baby since they may cross the placenta. However, certain drugs are necessary even if there are risks, since they’re intended to either keep your lupus at bay or prevent a problem in the baby.
In general, low-dose aspirin (81 mg per day) is not likely to cause harm but may be helpful in preventing preeclampsia, and most doctors now recommend it. High-dose NSAIDs are not recommended during pregnancy because they may be associated with high pulmonary pressures in the fetus in some cases in lupus (for more on NSAIDs, see
pages 36
to
37
). NSAIDs can prolong labor and are generally avoided close to the time of delivery; because of the risk of bleeding, aspirin is also generally stopped when you’re close to term.
Prednisone at doses less than 20 milligrams daily is generally not a problem for the fetus, since the placenta inactivates the drug. At higher doses, slightly more active drug is available in fetal circulation, but it still may not be dangerous. Possible side effects of steroids to the fetus include decreased amniotic fluid, decreased growth, and suppression of the adrenal glands.
“The risks and benefits of treatment must be weighed carefully during pregnancy,” says Dr. Petri. “Prednisone in particular will increase the risk of both preeclampsia and gestational diabetes, but it is safe for the fetus.”
Hydroxychloroquine (Plaquenil)
does cross the placenta, although the available literature shows very few problems. Concerns about hydroxycloroquine have declined to such an extent that most rheumatologists with experience in treating pregnant lupus patients suggest staying on the drug. The reason is that there is a risk of a flare if it’s discontinued, and this may override any potential harm to the fetus.
Azathioprine (Imuran)
can be used during pregnancy. It is most often used when a patient has had previous kidney disease and was being treated with mycophenolate mofetil (MMF, CellCept). MMF is contraindicated in pregnancy. Cytoxan is also contraindicated during pregnancy, as is methotrexate. Low-molecular-weight heparin for treatment of clotting problems is often used to prevent recurrent fetal loss.
Certain antihypertensive drugs are unsafe during pregnancy. These include angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). If blood pressure control is needed, other medications such as Aldomet, beta-blockers, and calcium channel inhibitors may be used.
Drugs can be passed to your baby if you breastfeed. NSAIDs are generally safe, since they do not pass easily into breast milk. However, high doses of NSAIDs can pose a problem, since babies eliminate them more slowly than adults do and they can accumulate in an infant’s system. Hydroxychloroquine is excreted in small amounts in breast milk but seems to pose no risk. Lower doses of prednisone appear to be safe.
Using immunosuppressive agents is controversial. Small amounts of azathioprine have been found in breast milk, and some pediatricians advise against its use. Cyclophosphamide and cyclosporine cannot be used if you nurse because they are toxic to an infant.
Maternal autoantibodies can pass to the baby via breast milk but only during the first few days of life, so this is not likely to pose problems. Breastfeeding may increase fatigue, but don’t let that stop you. On the other hand, breastfeeding is not for everyone, and if you do not want to, don’t feel guilty as babies do quite well on formulas.
Neonatal lupus.
During pregnancy, antibodies in the mother s circulation travel across the placenta into the bloodstream of the developing fetus, starting at about 12 to 14 weeks of gestation. The fetus is unable to make antibodies on its own and is dependent on maternal antibodies to fight infection. Mothers with antibodies SSA/Ro and SSB/La can have children with neonatal lupus. Two concerns in neonatal lupus are heart problems and skin rash.
The most concerning heart problem is
congenital heart block
, in which there is a block in the middle of the heart (called the
atrioventricular AV node
) that interrupts the electrical signal coming from the sinus node located at the top of the heart to the bottom of the heart (ventricles). This electrical signal is responsible for normal cardiac rate and rhythm. Blockage of the signal causes the ventricles to contract more slowly, and the overall result is an abnormally slow heartbeat. In congenital heart block, the AV node is damaged by the maternal autoantibodies or other as yet unidentified associated factors. This cardiac dysfunction (slow heartbeat) is most often detected between 18 and 24 weeks of gestation, with the twentieth week probably being the most vulnerable.