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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

To evaluate the effects of menopause hormonal therapy on disease activity in women with systemic lupus erythematosus (SLE).

Methods

We conducted a double-blind, randomized clinical trial involving 106 women with SLE who were in the menopausal transition or in early or late postmenopause. Patients received a continuous-sequential estrogen-progestogen regimen (n = 52) or placebo (n = 54). Disease activity was assessed at baseline and at 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months, according to the SLE Disease Activity Index (SLEDAI). The primary outcome measure was global disease activity, estimated by measuring the area under the SLEDAI curve. Secondary outcome measures included maximum SLEDAI score, change in SLEDAI score, incidence of lupus flares, median time to flare, medication use, and adverse events. Results were studied using intent-to-treat analysis.

Results

At baseline, demographic and disease characteristics were similar in both groups. Mean ± SD SLEDAI scores were 3.5 ± 3.3 and 3.1 ± 3.4 in the menopause hormonal therapy and placebo groups, respectively (P = 0.57). Disease activity remained mild and stable in both groups throughout the trial. There were no significant differences between the groups in global or maximum disease activity, incidence or probability of flares, or medication use. Median time to flare was 3 months in both groups. Thromboses occurred in 3 patients who received menopause hormonal therapy and in 1 patient who received placebo. One patient in each group died during the trial due to sepsis.

Conclusion

Menopause hormonal therapy did not alter disease activity during 2 years of treatment. However, an apparently increased risk of thrombosis seems to be a real threat in women with SLE who receive menopausal hormone therapy.

Systemic lupus erythematosus (SLE) is an autoimmune disease that primarily affects young women. Nonetheless, an increasing number of women with lupus now reach the postmenopausal stage because of their susceptibility to development of premature menopause, and because of the extraordinary improvement in the prognosis and survival rate (1, 2).

Menopause entails the risk of developing vasomotor and other symptoms, as well as chronic conditions, such as osteoporosis. Although menopause hormonal therapy is the most effective treatment for vasomotor and urogenital symptoms, the results of the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI) trials, which showed that the risks outweigh the benefits (3, 4), dramatically altered the medical practices of such therapy (5). Despite a striking decrease in the use of menopause hormonal therapy, many women remain eligible for it. Current guidelines recommend menopause hormonal therapy at the lowest effective dose and for the shortest time necessary (6).

Several studies have established the relevance of sex hormones in SLE. Overall, these data suggest that estrogens favor the development and/or exacerbation of the disease, while androgens seem to be protective (7–17).

Although a high rate of SLE flares in women taking combined oral contraceptives has been reported (18), recently we and the investigators in the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) group published the results of 2 randomized clinical trials, which showed that estrogen-containing oral contraceptives did not increase the risk of SLE disease activity exacerbation (19, 20). Menopause hormonal therapy was safe, well tolerated, and did not increase the risk of lupus flares in observational studies (21–23); however, the SELENA group detected a slight increase in the risk of developing mild or moderate, but not severe, flares (24).

We have sought to evaluate the effects of menopause hormonal therapy on disease activity, menopause symptoms, bone mineral density, lipid profile, and mammographic breast density in women with SLE who were in the menopausal transition or in early or late postmenopause. The results described herein focused on the question of whether there is a clinically significant difference in lupus activity (25), as measured by the SLE Disease Activity Index (SLEDAI) (26), in women receiving menopause hormonal therapy in comparison with women taking placebo. The study followup was completed prior to the publication of the WHI study, and data about other outcomes will be presented in future studies.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Study population.

We conducted a randomized, double-blind, placebo-controlled, 24-month clinical trial in women with SLE who attended the outpatient clinic at our hospital. From November 1997 through November 1999, 1,981 women with SLE as defined by the American College of Rheumatology 1982 criteria (27) were assessed for eligibility. Eligible women were those who met any 2 of the following criteria: amenorrhea of ≥6 months (except for women who had undergone a hysterectomy), serum follicle-stimulating hormone levels of ≥30 IU/liter, menopause symptoms (e.g., hot flashes, night sweats, or vaginal dryness), and age of ≥48 years. Exclusion criteria included an age of >65 years, severe lupus activity at baseline (SLEDAI score >30), use of estrogens within 3 months of the screening visit, serum creatinine level of ≥2.0 mg/dl, hypertriglyceridemia (≥500 mg/dl), metabolic bone diseases, liver disease, untreated hyperthyroidism, thrombosis within the past 6 months, malignancy, endometrial hyperplasia, undiagnosed uterine bleeding, or cervical dysplasia.

Menopause status was assigned according to the Stages of Reproductive Aging Workshop definitions (28): women who had presented with endometrial bleeding within the 12 months prior to the study initiation were considered to be in the menopausal transition, whereas those with amenorrhea of at least 12 months' duration were postmenopausal. Early postmenopausal women included those with ≤5 years of amenorrhea, whereas late postmenopausal women were those with >5 years of amenorrhea. Premature menopause was diagnosed in those women who presented with natural or medically induced menopause at age 40 or younger (6).

Study protocol.

A computer-generated randomization list was used to assign the women to either menopause hormonal therapy (a continuous-sequential estrogen-progestogen regimen of conjugated equine estrogens 0.625 mg/day plus 5 mg/day of medroxyprogesterone acetate by mouth for the first 10 days per month) (Premarin and Cycrin, respectively; Wyeth Pharmaceuticals, Naucalpan, Mexico) or a biologically inert placebo identical in appearance and packaging size to the medications in the active treatment regimen. All women received a daily supplement of 1,200 mg of calcium carbonate and 400 IU of vitamin D. The study coordinator assigned the next available number to each patient upon her entry into the trial, and pharmacy personnel dispensed the study medications according to the randomization list. Only the study coordinator (PL-R) could access the allocation list.

To maintain blinding, the rheumatologists (JS-G, MG-P) were instructed not to provide care for gynecologic or menopause symptoms, and the women were asked to avoid discussing any related issue with them. All women were told during the first visit that they might experience uterine bleeding independently of the treatment assigned. The randomization code was broken at the end of the study.

Clinical assessments.

At baseline, data on sociodemographic and clinical characteristics were collected by the investigators. Information about the course of SLE, such as the date of diagnosis (i.e., the date on which 4 of the 11 criteria were met), duration of disease, number of criteria met, and damage accrual according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (29), was extracted from each patient's medical chart.

SLE activity was assessed at baseline and at 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months. Two rheumatologists (JS-G, MG-P) performed all assessments. To reduce the variability in these evaluations, a training session and a calibration exercise in the application of the SLEDAI were held before the study began and each rheumatologist examined the same patients. Treatment of the disease was administered according to the judgment of each participating provider and was recorded at each evaluation. An independent examination at each study visit was performed by the study gynecologists (MD-C, LJ-S), who were unblinded to treatment assignments. They were not allowed to either modify the treatment randomly assigned or prescribe additional treatments for osteoporosis or menopause symptoms. Adherence to treatment was assessed by self-reported medication intake, and by measurement of serum levels of estradiol at baseline and at 1, 2, 3, 6, and 15 months by specific radioimmunoassay, using reagents and protocols provided by the World Health Organization Matched Reagent Programme (Geneva, Switzerland). Study treatment was discontinued in women who had severe lupus activity, thrombosis, any other severe complications, or who needed prolonged immobilization.

The study was approved by the Institutional Committee of Biomedical Research at the Instituto de Ciencias Medicas. All patients provided written informed consent.

Outcome measures.

The primary outcome measure was global disease activity throughout the followup period, estimated as the area under the SLEDAI curve (AUC) (30). The secondary outcome measures were the incidence of lupus flares, the time to the first flare, changes in SLEDAI values from baseline noted at each followup visit, and maximum disease activity. Lupus flares and severe flares were defined as increases in the SLEDAI score of ≥3 points or ≥12 points, respectively, from the previous visit (31).

Data were also analyzed by SLEDAI score strata (0, 1–5, 6–11) among the patients with active disease (SLEDAI score of ≥1) at baseline, using the SLEDAI 2000 (SLEDAI-2K) (32) and a modified SLEDAI (M-SLEDAI) that excludes microhematuria and pyuria because they may be associated with the treatment. We also recorded data on SLE treatment, hospitalizations, thromboses, and deaths.

Statistical analysis.

Data were expressed as the mean ± SD. Between-group comparisons of lupus activity were measured by the SLEDAI AUC, maximum SLEDAI score, and change in SLEDAI score from baseline at each followup visit. Continuous variables were compared using Student's t-test, and categorical variables were examined using the chi-square test or Fisher's exact test. Within-group comparisons were calculated using Wilcoxon's signed rank test.

Analysis of the incidence of flares was based on incidence-density rates, with patient-years of followup as the denominator, and with relative risk (RR) and 95% confidence interval (95% CI) as the measures of association. For each patient, we calculated the time from baseline until the first flare, withdrawal from the study, end of followup, or death (whichever came first). The probability of flares throughout the study was calculated using life-table analyses and the log rank test. All reported P values are 2-sided.

On the assumption of a mean ± SD baseline SLEDAI value of 5.43 ± 5.04 (31), we estimated that the planned sample size would provide an 80% chance of detecting a difference in the SLEDAI score of ≥3 points (on a scale of 0–105, with higher scores indicating greater severity), at a significance level of 0.05. With allowance for a 20% loss to followup, the planned sample size was 54 patients per group. All analyses were conducted by the intent-to-treat method using SPSS software, version 11.5 (SPSS, Chicago, IL).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Characteristics of the study population.

Of the 1,981 patients who underwent screening, 1,875 were excluded because they did not meet the inclusion criteria (n = 1,832) or declined to participate (n = 43), leaving 106 patients to be randomly assigned to either menopause hormonal therapy (n = 52) or placebo (n = 54) (Figure 1). Ninety-five menopausal women did not qualify according to the study participation criteria, but none was excluded from participation because of severe disease activity (SLEDAI score >30). The eligibility, enrollment, and recruitment fractions were 7.5%, 71%, and 5%, respectively, and the number of women who had to be screened in order to identify 1 patient to be enrolled in the study was 18.7. Women who declined to participate in the study and those who underwent randomization did not differ in most demographic characteristics, including previous use of menopause hormonal therapy (P = 0.64), and the features of their disease were similar. Nevertheless, those who underwent randomization were younger (mean ± SD 48.8 ± 7.6 years versus 52.7 ± 6.6 years; P = 0.004), developed menopause at an earlier age (mean ± SD 41.5 ± 7.7 years versus 44.2 ± 7.0 years; P = 0.04), had a higher body mass index (BMI) (mean ± SD 26.9 ± 5.2 kg/m2 versus 24.1 ± 3.8 kg/m2; P = 0.002), had a history of smoking (P = 0.01), and consumed alcohol (P = 0.06) more than women who declined to participate.

thumbnail image

Figure 1. Patients' progress from recruitment through the phases of the study.

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The baseline demographic features and manifestations of SLE were similar between the 2 treatment groups (Table 1). There were 2,053 patient-months of followup (81% of the possible 2,544 total patient-months of followup). The mean ± SD length of followup in the menopause hormonal therapy and placebo groups was 19.7 ± 7.9 and 19.1 ± 8.2 months, respectively (P = 0.70). Forty-four patients (85%) in the menopause hormonal therapy group finished the first year of the trial, while 45 patients (83%) in the placebo group finished the first year (P = 0.86). Thirty-seven patients (71%) in the menopause hormonal therapy group finished the second year of the trial, as did 38 patients (70%) in the placebo group (P = 0.91) (Figure 1).

Table 1. Selected baseline characteristics of the 106 women, by treatment group*
 Menopause hormonal therapy (n = 52)Placebo (n = 54)
  • *

    Except where indicated otherwise, values are the number (%) of patients. BMI = body mass index; SDI = Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; anti-β2GPI = anti–β2-glycoprotein I; NSAIDs = nonsteroidal antiinflammatory drugs. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores range from 0 to 105, with higher scores indicating more severe disease.

  • Estimated only for patients who were in early (n = 33) or late (n = 50) postmenopause.

  • Women who presented with endometrial bleeding in the 12 months prior to study initiation were considered to be in the menopausal transition. Women in early postmenopause included those with ≤5 years of amenorrhea, and women in late postmenopause were those with >5 years of amenorrhea.

  • §

    Follicle-stimulating hormone (FSH) levels were measured in 45 women in the menopause hormonal therapy group and in 40 women in the placebo group.

  • Low-titer antiphospholipid antibodies were considered positive.

Demographic features
 Age, mean ± SD (range) years47.5 ± 7.4 (28–65)50.0 ± 7.7 (28–63)
 Education, mean ± SD years10.5 ± 4.910.3 ± 4.7
 BMI, mean ± SD kg/m227.4 ± 6.126.3 ± 4.3
 Current smoker10 (19.2)12 (22.2)
Menopause characteristics
 Age at menopause, mean ± SD years40.0 ± 7.542.9 ± 7.8
 Years since menopause, mean ± SD8.1 ± 5.78.3 ± 6.7
 Menopause-related stages
  Menopausal transition12 (23)11 (20)
  Early postmenopause13 (25)20 (37)
  Late postmenopause27 (52)23 (43)
 Premature menopause17 (33)13 (24)
 FSH level, IU/liter§83.7 ± 48.079.0 ± 51.6
 Previous use of hormone therapy18 (35)22 (41)
Disease characteristics
 Disease duration, mean ± SD years9.6 ± 8.98.9 ± 7.2
 No. of SLE criteria met, mean ± SD4.9 ± 1.25.2 ± 1.2
 SDI score, mean ± SD0.8 ± 1.20.9 ± 1.2
 SLEDAI score, mean ± SD (range)3.5 ± 3.3 (0–10)3.1 ± 3.4 (0–15)
 SLEDAI score distribution  
  020 (38)22 (41)
  1–516 (31)18 (33)
  6–1016 (31)13 (24)
  ≥1101 (2)
 Positive antiphospholipid antibody test result
  Anticardiolipin antibodies13 (25)18 (33)
  Anti-β2GPI8 (15)8 (15)
  Lupus anticoagulant6 (12)5 (9)
  Any antiphospholipid antibody20 (38)23 (43)
 Treatment at baseline
  Prednisone23 (44)27 (50)
  Azathioprine11 (21)14 (26)
  Antimalarial drugs22 (42)23 (43)
  NSAIDs18 (35)17 (31)

Mean ± SD serum estradiol levels (pg/ml) at baseline were 31.6 ± 35.3 and 36.6 ± 73.4 (P = 0.62), in the menopause hormonal therapy and placebo groups, respectively. During the followup, mean serum estradiol levels ranged between 55.7 and 80.9 in the menopause hormonal therapy group and 28.0 and 45.1 in the placebo group. Compared with baseline, estradiol levels at each followup assessment were higher in the menopause hormonal therapy group (P < 0.001) but not in the placebo group; between-group comparison also showed higher estradiol levels in the menopause hormonal therapy group than in the placebo group (P < 0.001) (data not shown).

Disease activity.

At baseline, the mean ± SD SLEDAI score was 3.5 ± 3.3 in the group receiving menopause hormonal therapy and 3.1 ± 3.4 in the group receiving placebo (P = 0.54) (Table 1). There were no significant differences in the SLEDAI AUC or in the maximum SLEDAI score between the groups throughout the study period (Table 2). No patient was withdrawn from the study because of severe disease activity. SLEDAI scores remained mild and stable during the trial, and there were no significant differences between the groups (Figure 2).

Table 2. Disease activity among the 106 treated women and the subgroup of 64 women who had active disease at baseline*
 Menopause hormonal therapyPlacebo
  • *

    Active disease at baseline was defined as a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of ≥1. AUC = area under the curve.

All treated patients
 No.5254
 SLEDAI AUC, mean ± SD
  1 month3.0 ± 2.42.9 ± 2.7
  2 months5.6 ± 4.55.6 ± 4.7
  3 months8.1 ± 6.88.2 ± 6.6
  6 months13.8 ± 10.815.8 ± 12.3
  9 months20.9 ± 15.523.9 ± 18.7
  12 months28.5 ± 20.431.9 ± 26.0
  15 months35.2 ± 24.538.5 ± 31.7
  18 months41.4 ± 29.344.4 ± 36.4
  21 months47.0 ± 34.550.3 ± 41.4
  24 months52.8 ± 38.956.7 ± 47.1
 Maximum SLEDAI score
  Mean ± SD6.7 ± 3.06.7 ± 3.1
  Range0–162–18
Treated patients with active disease at baseline
 No.3232
 Baseline SLEDAI score
  Mean ± SD5.6 ± 2.25.2 ± 3.0
  Range2–101–15
 SLEDAI AUC, mean ± SD
  1 month4.2 ± 2.24.1 ± 2.8
  2 months7.3 ± 4.87.3 ± 5.0
  3 months10.4 ± 7.510.7 ± 7.0
  6 months17.1 ± 11.819.9 ± 12.9
  9 months25.3 ± 16.230.2 ± 19.9
  12 months34.7 ± 19.541.3 ± 28.2
  15 months42.8 ± 22.849.3 ± 34.1
  18 months49.8 ± 27.656.2 ± 38.9
  21 months55.8 ± 33.763.7 ± 43.7
  24 months63.2 ± 38.472.8 ± 49.5
 Maximum SLEDAI score
  Mean ± SD10.2 ± 2.412.0 ± 3.0
  Range6–168–18
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Figure 2. Systemic lupus erythematosus (SLE) disease activity during 24 months in 106 women receiving menopause hormonal therapy or placebo. Disease activity was measured according to the SLE Disease Activity Index (SLEDAI). There were no significant differences between groups throughout the study period. Values are the mean ± SD.

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Changes in SLEDAI scores from baseline at each followup visit were assessed in both groups. The mean change in SLEDAI score ranged between −0.31 (P = 0.42) and −1.02 (P = 0.07) in the group receiving menopause hormonal therapy and between −0.38 (P = 0.47) and 0.47 (P = 0.25) in the group receiving placebo.

When the data on patients with active disease (SLEDAI score ≥1) at baseline were analyzed separately, the baseline SLEDAI scores and the SLEDAI AUC and maximum SLEDAI scores during followup did not differ between treatment groups (Table 2). Disease activity did not differ either, when analyzed separately by SLEDAI strata (01–5, 6–11) at baseline, and the results obtained using the SLEDAI-2K and the M-SLEDAI were also similar to those of the primary analysis (data not shown).

Flares.

The number of patients who had flares and who had multiple flares during the trial was similar in both groups. Only 1 severe flare occurred during the trial, in a patient who received placebo; thus, the flares were analyzed altogether. The number of flares and the incidence-density rate of flares per patient-year were similar in both treatment groups. There were 79 flares, with an incidence-density rate of 0.93, in the group that received menopause hormonal therapy, and 83 flares, with an incidence-density rate of 0.97, in the group that received placebo. Compared with the placebo group, the group that received menopause hormonal therapy had a RR of flares of 0.96 (95% CI 0.70–1.32) (P = 0.80). The median time to the first flare was 3 months in both groups. The probability of flare at 1 and 2 years in the group receiving menopause hormonal therapy and the group receiving placebo was 0.91 and 0.75 (P = 0.29) and 0.94 and 0.79 (P = 0.25), respectively (Table 3).

Table 3. Flare characteristics and cumulative net probabilities of flares at 3, 6, 12, and 24 months in the 106 treated women and in the subgroup of 64 women who had active disease at baseline*
 Menopause hormonal therapyPlacebo
  • *

    Active disease was defined as a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of ≥1. A flare was defined as an increase in the SLEDAI score of ≥3 points from the previous visit. A severe flare was defined as an increase in the SLEDAI score of ≥12 points from the previous visit. RR = relative risk; 95% CI = 95% confidence interval.

All treated patients
No.5254
 Patients with flares, no. (%)44 (85)39 (72)
 Patients with multiple flares, no. (%)24 (46)26 (48)
  Severe flares01
  No. of flares7983
 Incidence-density rate per patient-year0.930.97
 RR (95% CI)0.96 (0.70–1.32) 
Probability of flare
 3 months0.470.54
 6 months0.640.60
 12 months0.910.75
 24 months0.940.79
Treated patients with active disease at baseline
 No.3232
 Patients with flares, no. (%)29 (91)24 (75)
 Patients with multiple flares, no. (%)18 (56)16 (50)
 No. of flares5454
 Incidence-density rate per patient-year1.050.99
 RR (95% CI)1.06 (0.71–1.58) 
Probability of flare
 3 months0.420.50
 6 months0.640.57
 12 months1.00.75
 24 months1.00.82

Among the patients with active disease at baseline, there were no differences according to treatment group in the probability of flares. The number and incidence rate of flare were also similar between the 2 groups (Table 3).

Other secondary outcome measures.

The rate of use and the dosage of prednisone, immunosuppressants, chloroquine, and nonsteroidal antiinflammatory drugs were similar between the groups during the study. Three patients in the menopause hormonal therapy group developed thromboses, 1 venous (lower limb) and 2 arterial (left middle cerebral and mesenteric arteries, respectively), for an incidence-density rate of 35.2 per 1,000 patient-years. Thromboses developed after 2, 15, and 18 months of treatment. One patient in the placebo group developed bilateral lacunar infarctions after 12 months of treatment (incidence-density rate of 11.6 per 1,000 patient-years; RR 3.0 [95% CI 0.24–158.9], P = 0.37). Only 1 patient in the menopause hormonal therapy group was both a smoker and had a history of thrombosis (transient ischemic attack 2 years before participating in the trial); only the patient receiving placebo had low titers of antiphospholipid antibodies (aPL). Nine patients in the menopause hormonal therapy group were hospitalized (ducto thrombosis in 3, elective surgery in 2, acute abdomen in 1, pneumonia in 1, pyelonephritis in 1, and vaginal carcinoma in 1), as were 6 patients in the placebo group (elective surgery in 2, dehydration in 1, thrombocytopenia in 1, acute abdomen in 1, and lacunar stroke in 1). Two patients died during the trial due to sepsis; the deaths occurred after 1 and 3 months of receiving placebo and menopause hormonal therapy, respectively.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

We evaluated the effects of menopause hormonal therapy as compared with placebo on disease activity in women with SLE who were in the menopausal transition or in early or late postmenopause. Over 24 months of followup, disease activity remained mild and stable, and no clinically significant difference was seen between treatment groups.

Disease activity was assessed by a validated measure that was sensitive to change over time (26), and the incidence of flares was estimated using a validated definition (31). We also analyzed disease activity according to the SLEDAI-2K (32) and M-SLEDAI, and in the subgroup of patients with active disease at entry. The results of these analyses were similar to those of the primary analyses. We believe that the assessments of disease activity were adequate and that menopause hormonal therapy does not increase lupus activity to a clinically significant degree. Our results are consistent with those of observational studies of menopause hormonal therapy (21–23), our clinical trial of contraceptive methods in women with SLE (19), and the contraception trial conducted by the SELENA group (20), in which no increase in disease activity was observed.

Recently, the SELENA group, using the same hormone regimen in postmenopausal women, found that the rate of severe flares and the mean change in the activity index score were not different between women who received menopause hormonal therapy and those who received placebo; nevertheless, women receiving menopause hormonal therapy experienced an increased rate of mild or moderate flares (24). In our study, although the number of patients with flares and the probability of flares tended to be higher among women receiving menopause hormonal therapy, especially when the lupus was active at baseline, the incidence rate of flares was similar in both groups. The difference in these results might be explained by the more sensitive definition of flare, the larger number of patients, or the higher rates of stopping the study medication and loss to followup (35% for the menopause hormonal therapy group and 27% for the placebo group) in the SELENA trial in comparison with our study. Nevertheless, this statistical difference is not clinically relevant and overall, these studies show that the use of menopause hormonal therapy by women with SLE does not elicit disease exacerbation.

Disease activity in the study population was mild/moderate at entry; since we did not restrict study participation unless the SLEDAI score was >30, and no patient was rejected for this reason, this result reflects the mildness of lupus activity at various postreproductive stages (33, 34). So, we consider that the population studied represents most women with SLE in the menopausal transition or in early or late postmenopause, in terms of disease activity.

Although the risk–benefit profile of menopause hormonal therapy has been established by the results of the HERS and the WHI trials (3, 4), the population included in those studies does not exactly correspond with that included in this study. Our population was composed of younger women, half of whom were in the menopausal transition or in early postmenopause (28), when menopause symptoms are most severe and bone loss is accelerated.

No differences in adverse events were observed between treatment groups in this study. However, the study was not adequately powered to detect differences in the incidence rates of most adverse events between the groups.

A result from our study and the SELENA trial (24) that is worth discussion is that thrombotic events occurred more often and at an identical ratio (3:1) in women receiving menopause hormonal therapy than in those receiving placebo. This result is consistent with results of observational studies (35–37) and clinical trials (4) of the use of menopause hormonal therapy among healthy women. Also, in our trial of contraceptive methods in women with SLE, thrombosis occurred only among women assigned to hormonal methods (2 patients in the combined oral contraceptives group and 2 in the progestin-only pill group); none occurred in the copper intrauterine device group (19).

Thrombosis is unusual in the general population. The incidence rate among women ≤30 years of age is 0.05 per 1,000 person-years (38), and in postmenopausal women, it is 0.08–0.11 per 1,000 person-years (35–37). In stark contrast, thrombosis has been reported in 10–20% of lupus patients (39–41), and the incidence rate among patients in whom the disease is prevalent is 5.1 per 1,000 patient-years (39) and up to 51.9 per 1,000 patient-years in an inception cohort of lupus patients (40). Considering that the use of exogenous estrogens is associated with a thrombosis RR of 2.1–3.6 (35–37), the absolute risk imposed by menopause hormonal therapy in women with SLE seems to be unacceptable. In our study, 1 episode of thrombosis was observed among every 28 women who received menopause hormonal therapy.

Avoiding menopause hormonal therapy in women who are positive for aPL would not be enough, since other factors, such as smoking, older age, disease activity over time, and glucocorticoid dose, are also associated with the occurrence of venous thrombosis in lupus patients (42). Therefore, we consider the real threat of menopause hormonal therapy in women with SLE to be the risk of developing thrombosis, not the effect of menopause hormonal therapy on disease activity. Whether this hazard can be diminished by alternative routes of estrogen administration or preparations of lower dosages needs to be explored.

Our study has several limitations. Since women who had previously received menopause hormonal therapy were allowed to participate, a selection bias toward women in whom this therapy was safe and well tolerated may exist. Nevertheless, the percentage of women who received menopause hormonal therapy in the past was similar between those who declined to participate and those who enrolled in the study; thus, we do not consider that this situation influenced our results.

We used a continuous-sequential estrogen-progestogen regimen, in which medroxyprogesterone acetate may attenuate estrogen's proinflammatory effects (43); therefore, our results should not be extrapolable to regimens containing only estrogens. The present trial evaluated the effect of a continuous-sequential estrogen-progestogen regimen on lupus activity during most of the recommended period of treatment for menopause symptoms; however, the risks and benefits of long-term use in SLE patients still need to be addressed. Treatment of SLE was administered at the discretion of the rheumatologist, and no differences in the treatment administered between the patient groups were evident at entry or throughout the followup period. Because this study was conducted at a single center with limited ethnic variation among the patients, one must be circumspect about extrapolating the results to all women with SLE. However, our results are consistent with those of studies conducted in populations of other ethnicities (21–24).

Our study was a nonequivalence trial; however, considering the actual level of disease activity in the study population at baseline, the sample size we achieved provided a 90% chance of detecting a difference in the SLEDAI score of ≥2.10, instead of the originally planned 3.0. Therefore, although we did not detect any clinically significant differences in disease activity (25) between treatment groups, the study had limited power to detect a smaller difference. The study was underpowered to assess the risk for cardiovascular events, cancer, and other disorders associated with menopause hormonal therapy. Also, in this report we do not describe the effects of this therapy on menopause symptoms, bone mineral density, lipid profile, and mammographic breast density in women with lupus. Such analysis is under way.

Some strengths of our study also need to be considered. The participation rate throughout the trial was high, and the adherence to treatment was assessed by estradiol measurements. We offered participation in the study to all women with SLE at different postreproductive stages, including the menopausal transition and early or late postmenopause (28), who attended our center, including those with variable disease activity and those who tested positive for aPL, provided they had no history of recent thrombosis. Twenty-seven percent of the patients had undergone premature menopause, and the mean BMI was <27 kg/m2. Our patients were all Mexican women, and we think the results can be generalized to most Hispanic women with SLE at different menopause-related stages.

In conclusion, since women with SLE are at an increased risk of developing premature menopause (2), osteoporotic fractures (44), cognitive dysfunction (45), premature atherosclerosis (46), thrombosis (40), and cardiovascular events (47), and their quality of life often is poorer than that of the general population (48), the effects of menopause in addition to these conditions, and the risk–benefit profile of menopause hormonal therapy in these women and those with other chronic diseases, need to be explored in depth. Menopause hormonal therapy did not affect the course of disease activity, at a clinically significant level, in women with SLE who were in the menopausal transition or in early or late postmenopause. Nonetheless, the potential increase in the risk of developing thrombosis may outweigh any benefits.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Dr. Sánchez-Guerrero had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Sánchez-Guerrero, González-Pérez, Cravioto.

Acquisition of data. Sánchez-Guerrero, González-Pérez, Durand-Carbajal, Lara-Reyes, Jiménez-Santana, Cravioto.

Analysis and interpretation of data. Sánchez-Guerrero, González-Pérez, Durand-Carbajal, Lara-Reyes, Jiménez-Santana, Romero-Díaz, Cravioto.

Manuscript preparation. Sánchez-Guerrero, González-Pérez, Durand-Carbajal, Lara-Reyes, Jiménez-Santana, Romero-Díaz, Cravioto.

Statistical analysis. Sánchez-Guerrero, Romero-Díaz, Cravioto.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

The menopause hormonal therapy and calcium were kindly provided by Wyeth Mexico and Whitehall-Robbins, respectively.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
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