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Oral Contraceptives in Systemic Lupus Erythematosus — A Tough Pill to Swallow?
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     Oral contraceptives were introduced into clinical practice in the 1960s. The "pill," as this method of contraception was quickly dubbed, was touted for its ease of administration and effectiveness. The subsequent wide use of oral contraceptives provided women with invaluable reproductive choices and social opportunities.1 As a result, the pill has been called one of the most socially important advances of the modern medical era.2 Yet for patients with systemic lupus erythematosus, there has been an implicit moratorium on prescribing these medications because of concerns that exogenous estrogens could potentially exacerbate disease symptoms.

    The large ratio of women to men (9:1) among patients with systemic lupus erythematosus during the childbearing years as well as the finding of altered levels of both the 16- and 2-hydroxylated metabolites of estrogens in these patients have led many investigators to conclude that systemic lupus erythematosus might be hormonally mediated.3 Experimental data lend some support to this hypothesis: in lupus-prone mice, the administration of exogenous estrogens worsens disease4; conversely, treating lupus-prone mice with androgens has a beneficial effect.5

    In this issue of the Journal, Petri et al.6 report on the Oral Contraceptives–Safety of Estrogens in Lupus Erythematosus National Assessment (OC-SELENA) trial and in another report, Sánchez-Guerrero et al.7 address the safety of oral contraceptives in women with systemic lupus erythematosus.6,7 An earlier retrospective, uncontrolled study showed a high flare rate (43 percent) among patients with lupus receiving oral contraceptives.8 However, that study enrolled patients with active nephritis, and the findings may not apply to all patients with lupus. Although a later case series did not demonstrate an increased flare rate among patients with lupus taking combined oral contraceptives,9 established medical practice has been to avoid prescribing oral-contraceptive agents and exogenous estrogens for women with systemic lupus erythematosus.

    In the past decade, the attitude toward the prohibition of the use of estrogen in patients with lupus has changed. Although Sánchez-Guerrero and colleagues previously reported10 that among women in the Nurses' Health Study who had ever used oral contraceptives there was an increased incidence of systemic lupus erythematosus, a retrospective survey indicated that systemic lupus erythematosus was not exacerbated by oral-contraceptive use.11 More recently, the SELENA trial showed that in postmenopausal women in the group receiving hormone-replacement therapy, there was a slight increase in the number of mild-to-moderate flares, but there was no increase in the number of severe flares.12

    There are several sound clinical reasons for prescribing oral contraceptives for women with lupus. First, among these women, planned pregnancies and conception during remission have better outcomes.13 Second, patients with very active disease or those receiving potentially teratogenic medications should use an extremely reliable form of birth control. Third, oral contraceptives may preserve ovarian function and therefore could mitigate the infertility that can result from cyclophosphamide therapy in systemic lupus erythematosus.14 Finally, oral contraceptives may reduce bone loss and the attendant osteoporosis that can be seen in patients treated with glucocorticoids.15 For these reasons, there has been a renewal of interest in more clearly establishing the effects of oral contraceptives on disease activity in systemic lupus erythematosus.

    Petri et al. and Sánchez-Guerrero et al. report on large prospective studies addressing the safety of oral contraceptives in systemic lupus erythematosus. The OC-SELENA study reported on by Petri et al.6 was a double-blind, noninferiority trial involving 183 premenopausal women with systemic lupus erythematosus at 15 centers in the United States. The women were randomly assigned to receive either combined oral contraceptives or placebo, and all of them were asked to use an additional method of birth control during the trial. Seventy-six percent of the patients had inactive disease and 24 percent had stable active disease. Patients were excluded if they had moderate-to-high titers of anticardiolipin antibodies (>40 units), were taking a lupus anticoagulant, had a history of thrombosis, or were smokers over the age of 35 years. Rates of severe flare were similar in the two study groups — 7.7 percent in the group assigned to combined oral contraceptives and 7.6 percent in the placebo group. The rates for mild or moderate flares were 1.40 flares per person-year in the oral-contraceptive group and 1.44 flares per person-year in the placebo group. There were two thrombotic events in the group assigned to combined oral contraceptives and three thrombotic events and one death in the placebo group. Investigators in the OC-SELENA study concluded that oral contraceptives did not increase the expected rate of lupus flare in a group of patients of diverse ethnic backgrounds with mild or moderate lupus. At entry into the trial, the mean (±SD) score in the two study groups, according to the SELENA Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), a modified index developed for this study (range, 0 to 105, with 0 indicating inactive disease), was 3.01 in the oral-contraceptive group and 3.39 in the placebo group, and the mean prednisone dose was 5.2 mg per day and 5.4 mg per day, respectively. Thus, the patients in the OC-SELENA trial had mild disease.

    Sánchez-Guerrero et al.7 report on a single-blind, uncontrolled clinical trial involving 162 women with lupus who were randomly assigned to combined oral contraceptives, a progestin-only pill, or a copper intrauterine device (IUD). At baseline, the mean SLEDAI score was in the range of 5.0 to 6.4 in each of the three groups, representing a patient population with more active disease at entry into the study than that in the OC-SELENA trial. The incident-density rates of flares (flare rate per patient-year) were similar in the three groups: 0.86 in the group assigned to combined oral contraceptives, 1.14 in the group assigned to the progestin-only pill, and 0.91 in the IUD group. Severe flares were rare and occurred at a similar rate in the three groups. There were four thrombotic events, two in the group assigned to combined oral contraceptives and two in the group assigned to the progestin-only pill; each of the four patients who had a thrombotic event had low titers of antiphospholipid antibodies.

    The study by Sánchez-Guerrero et al. was limited by its single-blind design — the clinical assessors were unaware of the treatment assignment but the patients were aware of the assignment. Nonetheless, the SLEDAI scale that was used to measure flares is objective and requires examination by a physician and laboratory testing. The study population was an ethnically homogeneous group, and it is possible that the results may not be generalizable to other groups. These limitations notwithstanding, the findings of the study, like those of the SELENA trial, support the use of oral contraceptives in patients with systemic lupus erythematosus.

    One cautionary note: Neither of these reports addresses the issue of the use of combined oral contraceptives in women with severe active systemic lupus erythematosus. Whether combined oral contraceptives can be used safely in this subgroup has yet to be determined. Furthermore, thrombotic events occurred in both trials. In the trial reported on by Sánchez-Guerrero et al., these events occurred only among patients receiving exogenous hormones who had low titers of antiphospholipid antibodies (anticardiolipin or anti–2-glycoprotein I antibodies). These findings suggest that patients with lupus should be tested for the presence of antiphospholipid antibodies before oral contraceptives are started and that oral contraceptives should probably be avoided among those with these antibodies or other hypercoagulable states.

    These two studies of the use of oral contraceptives in women with systemic lupus erythematosus provide prospective data that support the use of combined oral contraceptives by those with inactive or moderately active, stable disease. Although decisions on the type of contraceptive to use should ultimately be based on patients' preferences and should reflect the patients' values, the option to use combined oral contraceptives in antiphospholipid antibody–negative patients with mild disease appears to be worth consideration in the appropriate clinical setting.

    Source Information

    From the Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston.

    References

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