The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (9 page)

Women with inflammatory arthritis, such as RA, often have reduced fertility (“reduced ovarian reserves”),
³¹
and studies find at least one-third may having trouble conceiving.

The medications you take to control your RA can also affect the menstrual cycle and your ability to become pregnant.

Recent studies show that higher doses of glucocorticoids can reduce the “pulses” of
luteinizing hormone (LH)
from the pituitary gland needed to trigger ovulation. Prednisone may also affect the function of the endometrium, where a fertilized egg is implanted.
³²

NSAIDs like celecoxib may also interfere with ovulation, implantation, and formation of the placenta by dampening prostaglandins.
³³

Cyclophosphamide may cause infertility, especially if taken for periods of greater than one year and if a woman is over age 35. Methotrexate is absolutely contraindicated in women trying to conceive. Contraception is advised for women taking this drug. Because of the potential for birth defects, some drugs may need a “washout” period before trying to conceive.

With Arava, contraception is required while taking the drug (for men who are taking the drug as well). If you want to become pregnant and have taken the drug within the past two years, you (and/or your partner) must undergo a specific drug elimination procedure. You’ll be given 8 grams of cholestyramine three times a day for 11 consecutive days, and then blood levels of Arava will be measured with two blood tests 14 days apart until they are below a specific level (0.02 milligrams per liter of blood).

“We stop drugs that are likely to cause trouble like methotrexate. How long the washout period should be can become a guess. For methotrexate, most people would say three to six months for a washout period,” remarks Dr. Pisetsky.

Women with RA are more likely to have had fertility treatments, but the effects of those drugs in women with RA have not been well studied. The high
doses of hormones needed to stimulate the production of multiple eggs by the ovary may make RA symptoms worse.

As we mentioned before, your symptoms will likely improve during pregnancy but could recur within the first eight weeks after delivery. After six to eight months, you’ll return to whatever level of disease severity you had before you became pregnant.

The major issue when you contemplate pregnancy is the effect of medications. The U.S. Food and Drug Administration (FDA) classifies drugs according to whether studies or case reports show risks to the fetus, such as birth defects, and whether those risks outweigh the benefits to the mother. Some drugs demonstrate no risks, while others cannot be used during pregnancy because they’ve been shown to cause harm. For many newer drugs, such as biological agents, animal studies have not shown harm to a fetus, but there are no data at all or no well-controlled studies of pregnant women—or animal studies have shown adverse effects, but well-done human studies have not.

Then there are medications that may have demonstrated adverse effects in animal studies, but there are no well-controlled studies in humans—or there have been neither animal nor human studies of the drug. Finally, there are drugs that have shown risks to the fetus in studies of pregnant women, but sometimes the benefits of a drug may outweigh the risks for a particular woman. As you can see, prescribing drugs in these categories during pregnancy must be individualized.

Drugs that you take during pregnancy, including those considered safe, may cross the placenta, and many pass into breast milk. According to rheumatologists, the most sensitive time during pregnancy for any drug effects is the first trimester, when the embryo is growing into a fetus. This is the period where birth defects are likely to occur. The third trimester, since it is closest to delivery, carries different risks.

In general, experts say NSAIDs appear safe during most of pregnancy, but physicians try to avoid their use too close to delivery since they inhibit hormones called prostaglandins, which affect uterine contractions and can prolong labor. Corticosteroids are generally considered safe at any time during pregnancy but carry a slight risk of infections.

Azathioprine can cause fetal harm and should not be given during pregnancy unless the benefits strongly outweigh the risks. However, it should be emphasized that women taking azathioprine after organ transplants who have become pregnant have had successful pregnancies. Still, its use is not recommended in nursing mothers. Methotrexate should never be used during pregnancy.

A recent study from Italy suggests that TNFα inhibitors can be considered safe in the “peri-conception” period, making them a possible choice for women hoping to become pregnant. However, the Italian researchers caution that reports of anti-TNFα exposure during the second or third trimesters are “still limited” and they urge caution. Experience with abatacept, tocilizumab, anakinra and rituximab in pregnancy is insufficient, they add.
³⁴
A review of many hundreds of pregnancies in inflammatory arthritis suggest that exposure to anti-TNF therapies at the time of conception or during the first trimester do not result in an increased risk of adverse pregnancy or fetal outcomes.
³⁵

For Remicade, Azulfidine, penicillamine, and Enbrel, no harmful effects have been seen on a developing fetus, but since risk can’t be completely ruled out, the FDA advises that they should be given to pregnant women
only
if clearly needed. Remicade is usually not detectable in breast milk, but sulfa drugs like Azulfidine
are
excreted in breast milk and can cause liver toxicity in infants.

Data are extremely limited about pregnancy outcomes of women exposed to newer biologic DMARDs, including anakinra, abatacept, and tocilizumab. Manufacturers’ guidelines suggest abatacept be discontinued for at least 14 weeks prior to conception and between 3 months (tocilizumab) and 12 months (rituximab) prior to pregnancy for other biologics.

You’ll need to discuss the use of these drugs with your physician. Carefully read every package insert that comes with any medication, and always ask questions.

The peak years for a diagnosis of RA are those just before and after menopause, and opinions are divided over whether menopause itself affects the disease.

“The age of diagnosis seems to be creeping up,” remarks Dr. Bykerk, with many women now diagnosed around age 53. “Women in early menopause
are also more often seropositive” for rheumatoid factor and anti-CCPs, she adds.

While some studies find that RA diagnosed after menopause may progress at a faster rate, recent research suggests that earlier menopause may be linked to milder disease, such as rheumatoid-factor negative RA.
³⁶
“Hormonal changes may influence pathways that are distinct from those leading to severe, progressive disease,” Swedish researchers wrote in a study published in
Arthritis Research & Therapy
in 2012.

One study from Sweden found a strikingly decreased risk of more severe anti–cyclic citrullinated peptide antibody (ACPA) positive RA among current users of hormones ages 50 to 70, but not for ACPA-negative RA.
³⁷

Many rheumatologists focus on treating RA and leave the management of menopausal symptoms up to a woman and her gynecologist.

The ACR says hormone therapy (HT, or hormone replacement therapy, HRT) may be considered for postmenopausal women with severe hot flashes and other symptoms in whom there are no contraindications.

Estrogen therapy is generally considered safe for women with RA, and there have been some hints over the years that ET can even make RA a little better. However, given the increased risk of cardiovascular disease in RA, postmenopausal hormones should be approached cautiously.

Women, including those with RA, who are candidates for and wish to take postmenopausal hormones should take the lowest possible dose for the shortest possible period, advises the North American Menopause Society (NAMS).
³⁸

Hormone therapy needs to be individualized, depending on the drugs you’re taking. For example, it’s known that corticosteroids interact with estrogen. They may lessen the effectiveness of estrogen and often cause bleeding. This is because drugs like prednisone may interfere with estrogen receptors and can cause fluctuations in estrogen. So instead of the steady effects of your regular daily dose you get ups and downs that may cause you to bleed or spot.

Short-term estrogen replacement therapy (less than five years) has not been shown to increase the risk of breast cancer. Women with an intact uterus need to take progestin along with the estrogen to prevent precancerous overgrowth of the uterine lining (
endometrium
), such as
micronized progesterone (Prometrium)
.

Use of postmenopausal hormones has declined since 2002, when results first emerged from the Women’s Health Initiative (WHI). The WHI, a major prevention trial of a combined estrogen/progestin drug (
Prempro
) among 16,608 healthy women aged 50 to 79, was stopped after five years because of an increased rate of heart attacks, strokes, deep vein clots, and invasive breast cancer among women taking this drug. There were fewer cases of colorectal cancer and bone fractures among women on HT, but the WHI Data Safety and Monitoring Board (DSMB) concluded that the health risks of HT outweighed the benefits and stopped the study. However, the actual risks were small. According to the WHI data, over one year, 10,000 women taking Prempro might experience seven more coronary heart disease events, eight more breast cancers, eight more strokes, and eight more pulmonary emboli (but six fewer colorectal cancers and five fewer hip fractures), compared to women not taking hormones.
³⁹

The estrogen-only arm of the WHI was continued, with no increased risk of breast cancer seen among that group (all of whom had had hysterectomies).

On the strength of the WHI and other recent studies, the U.S. Preventive Services Task Force recommends that estrogen or estrogen/progestin not be used to prevent heart disease and other chronic conditions, and women should explore other therapies to prevent bone loss.
⁴⁰
Experts stress that the main indication for hormone therapy is to ease menopausal symptoms.

Menopausal symptoms like hot flashes may get better, but there may be absolutely no difference in your RA. “Physicians do say that in their experience estrogen is helpful. But you can never be sure that it’s really doing something for the disease, or whether it’s improving a woman’s sense of well-being, helping her mood, or lessening her pain perception, and so on,” comments Duke University’s Dr. Pisetsky.

If you can’t (or don’t want to) take systemic oral estrogens, estrogen is available in patches (such as
Climara
) that are changed once or twice a week. Estrogen from transdermal patches is believed to have less cardiovascular risk. Local estrogen treatments include creams (
Estrace
) and tablet suppositories (
Vagifem
) that gradually release estrogen into vaginal tissues to prevent drying and thinning (atrophic vaginitis). Local estrogen therapy may also help with vaginal dryness in women who have Sjögren’s syndrome secondary to their RA (see
Chapter 6
).

According to NAMS, nonhormonal therapies for menopausal symptoms include the herbs black cohosh (
Cimicifuga racemosa
, sold in health food stores and under the brand name
Remifemin
) and red clover (sold as
Promensil
). Both have been tested in clinical trials, but not specifically in women with autoimmune disease. Red clover contains plant estrogens, or phytoestrogens, and some studies suggest that it can relieve hot flashes, night sweats, irritability, insomnia, vaginal dryness, and mood disturbances, without any estrogenic effects on the breasts or uterine lining. Do not use black cohosh if you’re also taking blood pressure medication. Red clover can interfere with blood thinners like aspirin, so do not use it if you have antiphospholipid antibodies or a bleeding disorder.

Soy protein contains phytoestrogens called isoflavones. Some short-term studies suggest that they can relieve hot flashes, but most studies find little or no effect. Soy advocates recommend 20 to 50 grams a day from soy milk, soybeans, meat substitutes, or tofu.

Some studies suggest that fish oil capsules may help hot flashes but, again, because of its blood-thinning effects, you need to talk to your doctor before using it.

B vitamins, especially vitamin B
₆
(200 mg a day), seem to help some women with the emotional symptoms of menopause, including mood swings and anxiety.

Wild yams grow on vines all over North America and contain
diosgenin
, a precursor to natural progesterone (used to make some prescription progestins). Creams containing progesterone made from diosgenin are said to help relieve hot flashes and other menopausal symptoms. According to the North American Menopause Society (NAMS), no adequate clinical trial data confirm these claims. If you want to try wild yam progesterone creams, do so only with your doctor’s supervision.

Evening primrose oil (EPO)
is made from the seeds of a North American wildflower that, true to its name, opens in the evening. EPO is rich in essential fatty acids, including linoleic acid. Some studies suggest that EPO may help lessen hot flashes and lower blood pressure and cholesterol, as well as relieve joint pain in RA. Side effects include inflammation, blood clots, nausea, and some immunosuppression, according to NAMS. EPO is best taken as capsules; the accepted dose is 2 to 3 grams a day (make sure it is “standardized to 8 percent gamma-linoleic acid”). Keep EPO refrigerated to prevent it from becoming rancid. It cannot be used with anticoagulants.