Effect of Hormone Replacement Therapy on Lupus Activity
Condition: Systemic Lupus Erythematosus
MeSH terms: Lupus Erythematosus, Systemic
Study type: Interventional
Phase: Phase 4

Summary: 
      Hypothesis, HRT does not increase the risk of lupus activity exacerbation, it is effective
      for the relief of menopausal symptoms and improves bone mineral density.

      Double-blind, randomized, placebo controlled clinical trial.

      Objectives

        1. Determine the effect of HRT on disease activity, menopausal symptoms, bone mineral
           density, lipid profile, and mammographic parenchymal density in menopausal women with
           SLE.

        2. Determine the incidence rate of major side effects of HRT in menopausal women with SLE.

      Outcome Measures

        1. Primary outcome will be global disease activity throughout the follow-up period.

        2. Incidence of lupus flares, time to the first flare, changes in SLEDAI values from
           baseline at each follow-up visit, maximum disease activity, lupus treatment,
           hospitalizations, thromboses, and deaths.

      Menopausal symptoms and depression will be assessed utilizing the Greene Climacteric Scale
      questionnaire and the Beck Depression Inventory.

      Bone mineral density of lumbar spine and hip will be performed with dual energy x-ray
      absorptiometry. In addition, blood and urine samples to measure biochemical markers of bone
      turnover.

      Estradiol levels, lipid profile,coagulation tests, cervical cytology examinations,
      mammography.

      Inclusion Criteria: (Any two of the following criteria)

        1. Amenorrhea of 6 months or more

        2. Serum FSH level of 30 IU/L or more

        3. Menopausal symptoms

        4. Age 48 years or older.

      Exclusion Criteria:

        1. Women older than 65 years

        2. Severe lupus activity at baseline

        3. Use of estrogens within 3 months of the screening visit

        4. Serum creatinine of 2.0 mg/dL or more

        5. Hypertriglyceridemia 500 mg/dL or more

        6. Metabolic bone diseases

        7. Liver disease

        8. Untreated hyperthyroidism

        9. Recent thrombosis

       10. Malignancy

       11. Endometrial hyperplasia

       12. Undiagnosed uterine bleeding

       13. Cervical dysplasia.

      Subject allocation Random assign, using a computer-generated randomization list to:
      Conjugated equine estrogens 0.625 mg/day plus 5 mg/day of medroxyprogesterone acetate p.o.
      for the first 10 days per-month, or biologically inert placebo.All women will receive 1200 mg
      of calcium carbonate and 800 IU of vitamin D, daily.

      Follow-up procedure All patients will be evaluated by a rheumatologist and a reproductive
      health specialist at baseline,1,2,3,6,9,12,15,18,21, and 24 months.

      Rheumatic evaluation:

        1. General information (baseline).

        2. Lupus activity (every visit).

        3. Medications: (every visit)

      Gynecological evaluation:

      Onset of symptoms since the previous visit using a standardized questionnaire. In addition, a
      gynecological examination will be performed.

      Criteria for early termination of the study:

      A patient will be discontinued from the study whenever any of the following criteria would be
      present:

        1. Development of severe lupus activity (SLEDAI > 30).

        2. Development of any putative complication to hormone therapy.

        3. Development of any other severe complications due neither to SLE nor hormone therapy.

        4. Need prolonged immobilization.

      Statistical analysis:

      Between-group comparisons of lupus activity, maximum SLEDAI, and change in SLEDAI score from
      baseline at each follow-up visit. Incidence-density rates of flares with relative risk and 95
      percent confidence intervals.Probability of flares throughout the study using life-table
      analyses and log-rank test.

      Climacteric symptoms as the mean value of the Green's scale score at baseline and at each
      follow-up visit, between-group and intra-group. Bone mineral density as the mean value at
      baseline, 12 and 24 months, between and intra-group.

      The proportion of patients in each group who develop secondary effects, as well as the number
      who quit the study during the follow-up period.

      Continuous variables will be compared using Student's t-test, and categorical variables using
      chi-square or Fisher's exact test. Within-group comparisons will be done using the Wilcoxon
      signed-rank test. P values will be two-sided. Analyses will be conducted by the
      intention-to-treat method.
    

Detailed description: 
      Background Systemic Lupus Erythematosus (SLE) is an autoimmune disease of unknown cause. Risk
      factors proposed as important in the pathogenesis of SLE include genetic, environmental, and
      hormonal factors (1). Strong evidence implicates sex steroid hormones in the pathogenesis of
      SLE and other autoimmune diseases in human beings. Female gender is considered the strongest
      risk factor for the development of SLE (2), which incidence is 8 times higher in females than
      in males during the reproductive years. This difference in the susceptibility for developing
      SLE strongly suggests the influence of sex hormones. We have shown a significantly increased
      risk to develop SLE among postmenopausal women under estrogen replacement therapy compared
      with postmenopausal women who did not take such hormones; this increased risk was directly
      related with the length of use of such therapy (3). Lupus flares have been reported during
      periods of major sex hormone changes such as puberty, menses, pregnancy and postpartum (4-7).
      Abnormal metabolism of estrogens yields an excess production of 16-alpha-hydroxyestrone in
      patients with SLE of both sexes (8), and low plasma androgens levels have been reported in
      women with active and quiescent disease (9,10). An association between SLE and Klinefelter's
      syndrome has been proposed (11). Estrogen receptors have been found on OKT8-positive
      lymphocytes (12).

      Studies in animal models of SLE have also shown the relevance of sex hormones for the
      development and course of SLE. Studies in the NZB/W F1 hybrid mouse support the role for
      female hormones in the modulation of autoantibody production, development of renal disease,
      and death (13). Female NZB/W F1 mice have higher autoantibodies titers and die several months
      earlier than males. Treatment with androgens improves the survival and reduces immune-complex
      deposits and development of renal disease in NZB/W F1 females (14). Prepubertal castration of
      NZB/W F1 males plus administration of exogenous estrogen causes a female pattern of lupus
      (15).

      In general, these studies consistently suggest an interaction between sex hormones and the
      immune system.

      In our Institute more than 1900 SLE patients are followed-up regularly; 95 percent are
      female, and around 20 percent of them are postmenopausal. These figures reflect the
      increasing number of women with lupus who reach the postmenopausal stage due to their
      susceptibility for developing either early or premature menopause, along with the
      extraordinary improvement in their prognosis and survival rate. (16,2).

      Menopause entails the risk of developing vasomotor and other symptoms, as well as chronic
      conditions, e.g. osteoporosis. Hormone therapy, with estrogens alone or in combination with
      progestins, constitutes the most effective treatment for vasomotor and urogenital symptoms.
      Current guidelines recommend hormone therapy, at the lowest effective dose and the shortest
      time necessary (17).

      The risk of exogenous estrogens for developing systemic lupus erythematosus and disease
      activity is controversial. Women users of oral contraceptives (18) or menopause hormonal
      therapy are at an increased risk of developing systemic lupus erythematosus than non-users
      (3,19). While a high rate of flares in women taking combined oral contraceptives has been
      reported (6), recently, we and the investigators of the Safety of Estrogens in Lupus
      Erythematosus National Assessment (SELENA) group have demonstrated that estrogen containing
      oral contraceptives did not increase the risk of activity exacerbation (20,21). Hormone
      therapy was safe, well tolerated, and did not increase the risk of lupus flares in
      observational studies (22-24); however, the SELENA group detected a slight increase in the
      risk of developing mild/moderate, but not severe flares (25).

      Considering the increasing number of women with systemic lupus erythematosus who become
      postmenopausal, the earlier age of menopause onset, and the co-morbidity appended; we aim to
      evaluate the effects of hormone therapy on disease activity, menopausal symptoms, bone
      mineral density, lipid profile, and mammographic breast density in peri/postmenopausal women
      with systemic lupus erythematosus.

      We consider this study will help to identify the benefits and major adverse effects,
      associated with the hormone replacement therapy in peri/postmenopausal women with SLE, and to
      determine their efficacy in this unknown field.

      Previous similar studies Few studies have explored the influence of hormone replacement
      therapy on the activity of SLE. Arden et al. (22), conducted a retrospective study among 60
      postmenopausal women with SLE including 30 women users and 30 women non-users of HRT. The
      mean follow-up was 12 months. There was no significant difference in any parameter measured
      including lupus activity. They concluded that HRT appears to be well tolerated and safe.
      Kreidstein et al., in a case-control study (23), compared the incidence of lupus flares
      between 16 lupus patients receiving HRT and 32 controls. After 12 months of follow-up, the
      authors concluded that the use of HRT in postmenopausal females with SLE does not appear to
      increase the rate of lupus flares.

      Mok et al compared the frequency and severity of flares in 11 patients who received HRT with
      23 patients who did not. No significant increase in the rate or magnitude of flares couldbe
      demonstrated in patients who received HRT over a median follow-up period of 35 months (24).

      Although estrogens have been avoided in SLE patients, recently it has been considered that
      the safety of estrogens in lupus is unsolved. The U.S. National Institutes of Health have
      funded what is considered the first clinical trial on the safety of estrogens for women with
      SLE -SELENA (Safety of Estrogen in Lupus Erythematosus National Assessment). This clinical
      trial will be conducted in 5 U.S. rheumatology centers. It is considered that "the results of
      the trial will provide scientific evidence to support physicians' decisions about the safety
      of providing oral contraceptives and hormone replacement therapy (HRT) to women with SLE"
      (21,25).

      Hypothesis Hormone therapy does not increase the risk of lupus activity exacerbation, and it
      is effective for the relief of menopausal symptoms and improves bone mineral density.

      Design and methodology Design: Double-blind, randomized, placebo controlled clinical trial.

      Patients: One hundred and six peri/postmenopausal women with a diagnosis of SLE according to
      the American College of Rheumatology classification criteria (31), will be followed
      regularly, baseline,1,2,3,6,9,12,15,18,21 and 24 months, to assess SLE activity as well as
      efficacy, safety and acceptability of hormone replacement therapy.

      Objectives

        1. Determine the effect of hormone replacement therapy on disease activity in
           peri/postmenopausal women with Systemic Lupus Erythematosus.

        2. Determine the effect of hormone replacement therapy in the relief of menopausal
           symptoms, and on bone mineral density in peri/postmenopausal women with systemic lupus
           erythematosus.

        3. Determine the effect of hormone replacement therapy on lipid profile, mammographic
           parenchymal density in peri/postmenopausal women with Systemic Lupus Erythematosus.

        4. Determine the incidence rate of major side effects of hormone replacement therapy in
           peri/postmenopausal women with systemic lupus erythematosus.

      Outcome Measures.

      Lupus activity:

      In order to measure lupus activity, we will use a validated disease activity index, the
      Systemic Lupus Erythematosus disease activity index (SLEDAI) (26). The primary outcome will
      be global disease activity throughout the follow-up period, estimated as the area under the
      SLEDAI-curve (SLEDAI-AUC). Secondary outcomes will be the incidence of lupus flares, the time
      to the first flare, changes in SLEDAI values from baseline at each follow-up visit, and
      maximum disease activity. Lupus flares and severe flares are defined as an increase in the
      SLEDAI of 3 or more or 12 or more points, respectively, from the previous visit (27). The
      data will also be analyzed with the use of a new version of the SLEDAI (SLEDAI-2K) (28), and
      a modified SLEDAI (SLEDAIm) that excludes microhematuria and pyuria because they may be
      associated with the treatment. We will also record lupus treatment, hospitalizations,
      thromboses, and deaths.

      Menopausal symptoms:

      Menopausal symptoms and depression will be assessed through a face-to face interview,
      utilizing the Greene Climacteric Scale questionnaire (29) and the Beck's Depression Inventory
      (30). The Greene Climacteric Scale will be administered at baseline, and the Beck's
      Depression Inventory at baseline, 6, 12 and 24 months of treatment.

      Bone mineral density:

      Densitometry of lumbar spine and hip will be performed at baseline, 12 and 24 months with
      dual energy x-ray absorptiometry. In addition, blood and urine samples to measure biochemical
      markers of bone turnover will be taken at baseline, 6, 12 and 24 months.

      Other measurements:

      Blood samples will be collected for estradiol at baseline,1,2,3,6 and 15 months; lipid
      profile at baseline, 9 and 21 months; coagulation tests at baseline,1 and 3 months; cervical
      cytology examinations at baseline, 12 and 24 months; mammography at baseline and at the last
      study visit in all the patients who would complete > 12 months of follow-up.

      Criteria for the selection of subjects Patients will be selected from the lupus clinic at the
      Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. Eligible patients will
      be identified by a research assistant when they attend their clinical appointments as
      outpatients, and will be invited to participate in the study.

      Inclusion Criteria: (Eligible women will be those having any two of the following criteria)

        1. Amenorrhea of 6 months or more.

        2. Serum follicle-stimulating hormone level of 30 IU/L or more.

        3. Menopausal symptoms.

        4. Age 48 years or older.

      Exclusion Criteria:

        1. Women older than 65 years.

        2. Severe lupus activity at baseline (SLEDAI score, more than 30).

        3. Use of estrogens within 3 months of the screening visit.

        4. Serum creatinine of 2.0 mg/dL or more.

        5. Hypertriglyceridemia 500 mg/dL or more.

        6. Metabolic bone diseases.

        7. Liver disease.

        8. Untreated hyperthyroidism.

        9. Recent thrombosis.

       10. Malignancy.

       11. Endometrial hyperplasia.

       12. Undiagnosed uterine bleeding or cervical dysplasia

      Use of hospital records:

      Hospital records will be needed in order to complete patients' information related to dates
      of entry to the hospital, first criteria, 4 criteria, chronic damage, sociodemographic
      information, etc., not for lupus activity or secondary effects from the hormone therapy,
      which will be collected prospectively. Medical records use has been authorized by the
      appropriate hospital authorities. This authorization is implicit in the approval form the
      ethics committee.

      Subject allocation Patients who fulfill the selection criteria will be randomly assign to
      hormone therapy or placebo, using a computer-generated randomization list. Patients will be
      allocated to the random numbers according to their entrance to the study, once they have been
      informed about the study and sign the acceptance form. The allocation will be done by a
      research assistant.

      Description of the medications to be studied

        1. Conjugated equine estrogens 0.625 mg/day plus 5 mg/day of medroxyprogesterone acetate
           p.o. for the first 10 days per-month (Premarin and Cycrin, respectively, Laboratorios
           Wyeth).

        2. Biologically inert placebo identical in appearance and packaging size to the active
           regimen.

        3. All women will receive a daily supplement of 1200 mg of calcium carbonate and 800 IU of
           vitamin D (Caltratate D, Laboratorios Whitehall-Robbins).

      Admission procedure

      Procedure for patients recruitment:

      All SLE patients will be identified from the lupus clinic. If the patient would accept to
      participate, she will be asked to sign the consent form and a study number will be assigned
      by the research assistant.

      Follow-up procedure All patients will be evaluated in a standardized way at the same dates (±
      7 days) by two independent specialists: a rheumatologist and a reproductive health
      specialist. Both evaluations will be done at baseline,1,2,3,6,9,12,15,18,21, and 24 months.

      Rheumatic evaluation:

      Each patient will be evaluated by a rheumatologist at entry and every follow-up visit. The
      following variables will be evaluated.

        1. - General information: (basal evaluation). A standardized entry form will be filled-out
           to every patient who enter the study.

        2. - Lupus activity: (every visit) This will be evaluated using the SLEDAI (26), a widely
           used and validated lupus activity index. A training session for the use of all indices
           will be conducted between both participating rheumatologists in order to reach agreement
           in their use and diminish inter-observer variability.

        3. - Medications: (every visit) Use of medications will be recorded, both as a continuous
           (dose) and binary (yes/no) scale. The following medications will be recorded: steroids,
           azathioprine, 6-mercaptopurine, cyclophosphamide, and chloroquine. Non-steroidal
           antiinflamatory drugs will be recorded only as binary scale.

      Study treatment evaluation:

      After completing the rheumatic evaluation, each patient will be interviewed about the onset
      of symptoms since the previous visit by an specialist in Biology of the Reproduction, who
      will be unblinded to the treatment assigned. A standardized questionnaire for this purpose
      will be used. In addition, the investigator will perform a gynecological physical
      examination, and will evaluate the compliance to the treatment.

      The pharmacy personnel will dispense the study medications according to the randomization
      list.

      Women who do not attend their scheduled visits will be contacted by the social worker, and
      visited at home when it was required.

      Criteria for early termination of the study:

      A patient will be discontinued from the study whenever any of the following criteria would be
      present:

        1. Development of severe lupus activity (SLEDAI > 30).

        2. Development of any putative complication to hormone therapy (thrombosis, cholestasis,
           etc.).

        3. Development of any other severe complications due neither to SLE nor hormone therapy.

        4. Need prolonged immobilization. The decision will be taken after an special meeting held
           by the study's physicians. It is required an agreement between at least one physician
           from each of the participating departments (Rheumatology and Reproduction Biology).

      Data management An entry form for each patient (original and copy) will be filled-out at both
      reproductive health clinic and lupus clinic. On follow-up visits, standardized forms
      (original and copy) will be filled for each patient at both clinics. The information of these
      forms will be entered (double entry) on a master processing file which will be updated once a
      week. All paper forms will be kept in special locked cabinets. Study investigators will be
      the only persons having access to this information in order to maintain absolute
      confidentiality.

      Data analysis Final analysis will be undertaken after 24 months follow-up is completed in all
      subjects.

      Population for analysis:

      All those patients who enter the study will be included in the analysis. The analysis period
      will be from the basal evaluation until the last patient's visit or the study ending.

      Statistical analysis:

      Lupus disease activity will be analyzed by between-group comparisons of lupus activity as
      measured by the SLEDAI-AUC, maximum SLEDAI, and change in SLEDAI score from baseline at each
      follow-up visit. nalysis of the incidence of flares will be based on incidence-density rates,
      with patient-years of follow-up as the denominator and with relative risk and 95 percent
      confidence intervals as the measure of association. For each patient, time will be calculated
      from baseline until the first flare, withdrawal from the study, end of follow-up, or death,
      whichever is first. The probability of flares throughout the study will be calculated with
      use of life-table analyses and the log-rank test.

      Climacteric symptoms will be analyzed as the mean value of the Green's scale score at
      baseline and at each follow-up visit, between-group and intra-group. Bone mineral density
      will be analyzed as the mean value at baseline, 12 and 24 months, between-group and
      intra-group.

      The safety and acceptability of hormone therapy will be analyzed as the proportion of
      patients in each group who develop secondary effects, as well as the number who quit the
      study during the follow-up period.

      Continuous variables will be compared using Student's t-test, and categorical variables using
      chi-square or Fisher's exact test. Within-group comparisons were made with use of the
      Wilcoxon signed-rank test. P values will be two-sided. All analyses will be conducted by the
      intention-to-treat method.

      Safety Monitoring Committee: An independent Safety Monitoring Committee consisting of 2
      rheumatologists, 1 epidemiologist/ biostatistician, and 2 endocrinologists, not participating
      as investigators will be established. The committee will meet every 12 months, or at any time
      if an unusual problem occurs, to review all unacceptable events as defined by the
      investigators during the planning phase, and determine whether they may be attributable to
      the treatment studied. The study will be stopped by the Safety Monitoring Committee if the
      number of unacceptable events reaches the stopping criterion. The committee will also review
      the interim analysis, with authority to stop the study if a significant difference (P < 0.01)
      was detected.

      Missing observations: We will try not to miss any data, however, because this study involves
      several variables it is expected that some of them will be missing. We consider the
      percentage of missing observations will be small and at random, due to the prospective nature
      of the study. Anyway, we will seek advice from a statistician on the best way to handle the
      problem

      Preliminary (Interim) analysis:

      Since we consider we will not have enough patients to detect any significant treatment
      difference earlier, a mid-term preliminary analysis will be done at 18 months. The objective
      of this analysis is to evaluate if there is an important difference between the two groups
      related to disease activity or adverse effects. If there was a satisfactory answer to the
      main study hypothesis or an unexpectedly higher number of thrombotic events would be present
      in the hormone therapy group, the study will be finished. As a stopping rule, a two-tailed
      significance level for SLE activity P < 0.01 has been established, or the presence of >3
      thrombotic events in the hormone therapy group. If a P value between 0.01 - 0.05 was detected
      in the interim analysis, a second analysis will be undertaken 9 months later with an
      identical stopping rule for both SLE activity and thrombosis.

      Preliminary analysis will be done by personnel from the Clinic Epidemiology Unit at our
      Institute, whom will be blinded to groups' coding. Results will be reviewed by members of the
      Safety Monitoring Committee. The result will not be informed to the research group, unless an
      indication for termination of the study would be present.

      Final analysis will be undertaken after 12 months follow-up is completed on all subjects.

      Number of subjects and statistical power

      Sample Size:

      On the assumption of a mean (+SD) baseline SLEDAI value of 5.43±5.04 (27), we estimate that
      the planned sample size would provide an 80 percent chance of detecting a difference in
      SLEDAI of 3 points or more (on a scale of 0 to 105, with higher scores indicating greater
      severity), at a significance level 0.05. With allowance for a 20 percent loss to follow-up,
      the planned sample size was 54 patients per group.

      Monitoring study progress:

      A monthly meeting will be held among all study participants in order to evaluate the study's
      flow, solving problems, evaluate intermediate outcomes, and reach agreements. Decisions not
      foreseen at the beginning of the study will be taken in those meetings. Minutes will be
      written in each of those meetings which will be filed in the research book.

      Duration of project (table 1)

      Table 1.- Study's timetable

      Activities Months 1-4 5-8 9-12 13-16 17-18 19-22 23-26 27-30 31- 36 Study forms ** Training
      phase ** Lab Organization ** Monthly meetings **** **** **** **** **** **** **** **** ***
      Patient enrollment 1-14 15-42 43-70 71-98 99-106 Patient follow-up 1-14 1-42 15-70 43-98
      71-106 99-106 Patient study ending 1-14 15-42 43-70 71-98 99-106 Study's analysis ***
      Manuscript's preparation *** End of study ***

      3.4 Project management

      General coordination, supervision and analysis of the study will be under the principal
      investigators responsibility. Funds administration will be at the Institute administrative
      office for research projects. All publications derived from the present investigation will be
      done according to established regulations, giving recognition to the support received.

      Links with other projects N.A.

      Main problems anticipated

        1. Meet study's subjects number. This is the main problem we face. Although we follow
           regularly around 1900 SLE patients, finding 106 peri/postmenopausal women who would
           accept to participate in the study after reviewing inclusion/exclusion criteria remains
           a hard number to reach. However, every year about 200 new SLE patients come to our
           Institute. We expect to meet the necessary number to conduct the study. If we noticed we
           had a low number, we will invite lupus patients from other institutions to participate.

        2. We do not consider we may have problems neither with the evaluation from rheumatology
           nor reproductive health clinic.

      Expected outcomes of the study

      The results expected from this study will provide light about several unanswered questions:

        1. - We will be able to determine whether postmenopausal hormone therapy affects SLE
           activity.

        2. - We will be able to determine the effect of hormone replacement therapy on climacteric
           symptoms and bone mineral density in peri/postmenopausal women with SLE.

        3. - We will be able to determine the incidence rate of secondary effect and the
           risk/benefit profile of hormone replacement therapy in peri/postmenopausal women with
           SLE.

        4. We expect to publish our results in first line journals.

      3.8 References.

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      Supported by the Consejo Nacional de Ciencia y Tecnología de México (CONACYT) (Grant
      3367P-M).

      The hormone therapy and calcium will be provided by Wyeth México and Whitehall-Robbins,
      respectively; neither company will participate in the trial design, gathering and analysis of
      the data, or writing of the manuscript.

      Computer facilities of the Department of Reproductive Biology will serve to undertake the
      study.

      Administrative clerks, health auxiliaries and nurses at the Rheumatology and Reproductive
      Health Clinics will give overall support to the study, without additional payment.

      Compensations or overtime payment to principal investigators and research assistants are not
      available.

      Medical costs of side effects appeared within the study will be covered by the Institute.
    

Intervention name(s): Conjugated equine estrogens 0.625 mg/d + MPA 5 mg/d/10d
Intervention type(s): Drug
Intervention MeSH terms: Estrogens; Estrogens, Conjugated (USP)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Systemic lupus erythematosus; Menopause hormonal therapy; Menopausal symptoms; Bone mineral density