Ignite Creation Date:
2024-05-05 @ 5:08 PM
Last Modification Date:
2024-10-26 @ 9:28 AM
Study NCT ID:
NCT00392093
Status:
COMPLETED
Last Update Posted:
2006-10-25
First Post:
2006-10-23
Brief Title:
Effect of Hormone Replacement Therapy on Lupus Activity
Sponsor:
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Organization:
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Study Overview
Official Title:
Effect Of Hormone Replacement Therapy On Disease Activity Menopausal Symptoms And Bone Mineral Density In PeriPostmenopausal Women With Systemic Lupus ErythematosusRandomized Clinical Trial
Status:
COMPLETED
Status Verified Date:
2006-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 profilecoagulation 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 IUL 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 20 mgdL or more
5 Hypertriglyceridemia 500 mgdL 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 0625 mgday plus 5 mgday of medroxyprogesterone acetate po for the first 10 days per-month or biologically inert placeboAll 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 baseline1236912151821 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 intervalsProbability of flares throughout the study using life-table analyses and log-rank test
Climacteric symptoms as the mean value of the Greens 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 Students t-test and categorical variables using chi-square or Fishers 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
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 profilecoagulation 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 IUL 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 20 mgdL or more
5 Hypertriglyceridemia 500 mgdL 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 0625 mgday plus 5 mgday of medroxyprogesterone acetate po for the first 10 days per-month or biologically inert placeboAll 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 baseline1236912151821 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 intervalsProbability of flares throughout the study using life-table analyses and log-rank test
Climacteric symptoms as the mean value of the Greens 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 Students t-test and categorical variables using chi-square or Fishers 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 910 An association between SLE and Klinefelters 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 NZBW F1 hybrid mouse support the role for female hormones in the modulation of autoantibody production development of renal disease and death 13 Female NZBW 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 NZBW F1 females 14 Prepubertal castration of NZBW 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 162
Menopause entails the risk of developing vasomotor and other symptoms as well as chronic conditions eg 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 319 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 2021 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 mildmoderate 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 peripostmenopausal 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 peripostmenopausal 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 US 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 US 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 2125
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 peripostmenopausal women with a diagnosis of SLE according to the American College of Rheumatology classification criteria 31 will be followed regularly baseline1236912151821 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 peripostmenopausal 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 peripostmenopausal women with systemic lupus erythematosus
3 Determine the effect of hormone replacement therapy on lipid profile mammographic parenchymal density in peripostmenopausal women with Systemic Lupus Erythematosus
4 Determine the incidence rate of major side effects of hormone replacement therapy in peripostmenopausal 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 Becks Depression Inventory 30 The Greene Climacteric Scale will be administered at baseline and the Becks 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 baseline1236 and 15 months lipid profile at baseline 9 and 21 months coagulation tests at baseline1 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 IUL 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 20 mgdL or more
5 Hypertriglyceridemia 500 mgdL 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 0625 mgday plus 5 mgday of medroxyprogesterone acetate po 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 baseline1236912151821 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 yesno 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 studys 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 patients 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 Greens 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 Students t-test and categorical variables using chi-square or Fishers 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 001 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 001 has been established or the presence of 3 thrombotic events in the hormone therapy group If a P value between 001 - 005 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 543504 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 005 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 studys 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- Studys 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 Studys analysis Manuscripts preparation End of study
34 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 NA
Main problems anticipated
1 Meet studys subjects number This is the main problem we face Although we follow regularly around 1900 SLE patients finding 106 peripostmenopausal women who would accept to participate in the study after reviewing inclusionexclusion 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 peripostmenopausal women with SLE
3 - We will be able to determine the incidence rate of secondary effect and the riskbenefit profile of hormone replacement therapy in peripostmenopausal women with SLE
4 We expect to publish our results in first line journals
38 References
1 - Alarcon-Segovia D The Pathogenesis of Immune Dysregulation in Systemic Lupus Erythematosus A Troika J Rheumatol 198411588-90
2 - Systemic Lupus Erythematosus In Silman AJ and Hochberg MC eds Epidemiology of the Rheumatic Diseases New York Oxford University Press Inc 1993163-91
3 - Sanchez-Guerrero J Liang MH Karlson EW Hunter DJ and Colditz GA Postmenopausal Estrogen Therapy and The Risk of Developing Systemic Lupus Erythematosus Ann Intern Med 1995122430-3
4 - Rose E Pillsbury DM Lupus Erythematosus and Ovarian Function Observations on a possible relationship with a report of 6 cases Ann Intern Med 1944211022-34
5 - Mund A Swison J Rothfield N Effect of pregnancy on the course of SLE JAMA 1963183917-20
6 - Jungers P Dougados M Pelissier C Kuttenn F Tron F Lesavre P y cols Influence of oral contraceptive therapy on the activity of Systemic Lupus Erythematosus Arthritis Rheum 198225618-23
7 - Barret C Neylon N Snaith ML Oestrogen-Induced Systemic Lupus Erythematosus Br J Rheumatol 198625300-1
8 - Lahita RG Bradlow HL Kunkel HG Fishman J Increased 16-alpha Hydroxylation of Estradiol in Systemic Lupus Erythematosus J Clin Endocrinol Metab 198153174-8
9 - Jungers P Nahoul K Pelissier C Dougados M Tron F Bach JF Low Plasma Androgens in Women with Active or Quiescent Systemic Lupus Erythematosus Arthritis Rheum 198225454-7
10 - Lahita RG Bradlow HL Ginzler E Pang S New M Low Plasma Androgens in Women with Systemic Lupus Erythematosus Arthritis Rheum 198730241-8
11 - Stern R Fishman J Brusman H Kunkel HG Systemic Lupus Erythematosus associated with Klinefelters syndrome Arthritis Rheum 19772018-22
12 - Cohen JHM Danel L Cordier G Saez S Revillard JP Sex Steroid Recptors in Peripheral T Cells Absence of Androgen Receptors and Restriction of Estrogen Receptors to OKT8-Positive Cells J Immunol 19831312767-71
13 - Kelley VE Winkelstein A Age- and Sex-related Glomerulonephritis in New Zealand White Mice Clin Immunol Immunopathol 1980 16142-50
14 - Roubinian JR Talal N Greenspan JS Goodman JR Siiteri PK Delayed Androgen Treatment Prolongs Survival in Murine Lupus J Clin Invest 197963902-11
15 - Roubinian JR Talal N Greenspan JS Goodman JR Siiteri PK Effect of castration and sex hormone treatment on survival anti-nucleic acid antibodies and glomerulonephritis in NZBNZW F1 mice J Exp Med 19781471568-83
16 Sánchez-Guerrero J Romero-Díaz J Mendoza-Fuentes A Mestanza-Peralta M Cravioto MC Menopause in Systemic Lupus Erythematosus Age at Presentation and Clinical Characteristics Arthritis Rheum 199841S67
17 The North American Menopause Society Recommendations for estrogens and progestogens use in peri- and postmenopausal women October 2004 Position Statement of the North American Menopause Society Menopause 200411589-600
18 Sánchez-Guerrero J Karlson EW Liang MH Hunter DJ Speizer FE Colditz GA Past use of oral contraceptives and the risk of developing systemic lupus erythematosus Arthritis Rheum 199740804-8
19 Meier CR Sturkenboom MC Cohen AS Jick H Postmenopausal estrogen replacement therapy and the risk of developing systemic lupus erythematosus or discoid lupus J Rheumatol 1998251515-9
20 Sánchez-Guerrero J Uribe AG Jiménez-Santana L et al A trial of contraceptive methods in women with systemic lupus erythematosus N Engl J Med 20053532539-49
21 Petri M Kim MY Kalunian KC et al Combined oral contraceptives in women with systemic lupus erythematosus N Engl J Med 20053532550-8
22 Arden NK Lloyd ME Spector TD Hughes GRV Safety of hormone replacement therapy HRT in systemic lupus erythematosus SLE Lupus 1994311-3
23 Kreidstein S Urowitz MB Gladman DD Gough J Hormone replacement therapy in systemic lupus erythematosus J Rheumatol 1997242149-52
24 Mok CC Lau CS Ho CT Lee KW Mok MY Wong RW Safety of hormonal replacement therapy in postmenopausal patients with systemic lupus erythematosus Scand J Rheumatol 199827342-6
25 Buyon JP Petri MA Kim MY et al The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus A randomized trial Ann Intern Med 2005142953-62
26 - Bombardier C Gladman DD Urowitz MB Caron D Chang CH and the Committee on Prognosis Studies in SLE Derivation of the SLEDAI Arthritis Rheum 199235630-40
27 - Petri M Genovese M Engle E Hochberg M Definition Incidence and Clinical Description of Flare in Systemic Lupus Erythematosus Arthritis Rheum 1991 34937-44
28 Gladman DD Ibañez D Urowitz MB Systemic lupus erythematosus disease activity index 2000 J Rheumatol 200229288-91
29 Greene JG Constructing a standard climacteric scale Maturitas 19982925-31
30 Beck AT Steer RA Brown GK Beck Depression Inventory -Second Edition Manual San Antonio TX The Psychological Corporation 2000
31 - Tan EM Cohen AS Fries JF Masi AT McShane DJ Rothfield NF et al The 1982 revised criteria for the classification of Systemic Lupus Erythematosus Arthritis Rheum 1982251271-7
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
Studies in animal models of SLE have also shown the relevance of sex hormones for the development and course of SLE Studies in the NZBW F1 hybrid mouse support the role for female hormones in the modulation of autoantibody production development of renal disease and death 13 Female NZBW 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 NZBW F1 females 14 Prepubertal castration of NZBW 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 162
Menopause entails the risk of developing vasomotor and other symptoms as well as chronic conditions eg 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 319 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 2021 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 mildmoderate 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 peripostmenopausal 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 peripostmenopausal 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 US 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 US 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 2125
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 peripostmenopausal women with a diagnosis of SLE according to the American College of Rheumatology classification criteria 31 will be followed regularly baseline1236912151821 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 peripostmenopausal 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 peripostmenopausal women with systemic lupus erythematosus
3 Determine the effect of hormone replacement therapy on lipid profile mammographic parenchymal density in peripostmenopausal women with Systemic Lupus Erythematosus
4 Determine the incidence rate of major side effects of hormone replacement therapy in peripostmenopausal 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 Becks Depression Inventory 30 The Greene Climacteric Scale will be administered at baseline and the Becks 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 baseline1236 and 15 months lipid profile at baseline 9 and 21 months coagulation tests at baseline1 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 IUL 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 20 mgdL or more
5 Hypertriglyceridemia 500 mgdL 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 0625 mgday plus 5 mgday of medroxyprogesterone acetate po 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 baseline1236912151821 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 yesno 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 studys 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 patients 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 Greens 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 Students t-test and categorical variables using chi-square or Fishers 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 001 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 001 has been established or the presence of 3 thrombotic events in the hormone therapy group If a P value between 001 - 005 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 543504 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 005 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 studys 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- Studys 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 Studys analysis Manuscripts preparation End of study
34 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 NA
Main problems anticipated
1 Meet studys subjects number This is the main problem we face Although we follow regularly around 1900 SLE patients finding 106 peripostmenopausal women who would accept to participate in the study after reviewing inclusionexclusion 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 peripostmenopausal women with SLE
3 - We will be able to determine the incidence rate of secondary effect and the riskbenefit profile of hormone replacement therapy in peripostmenopausal women with SLE
4 We expect to publish our results in first line journals
38 References
1 - Alarcon-Segovia D The Pathogenesis of Immune Dysregulation in Systemic Lupus Erythematosus A Troika J Rheumatol 198411588-90
2 - Systemic Lupus Erythematosus In Silman AJ and Hochberg MC eds Epidemiology of the Rheumatic Diseases New York Oxford University Press Inc 1993163-91
3 - Sanchez-Guerrero J Liang MH Karlson EW Hunter DJ and Colditz GA Postmenopausal Estrogen Therapy and The Risk of Developing Systemic Lupus Erythematosus Ann Intern Med 1995122430-3
4 - Rose E Pillsbury DM Lupus Erythematosus and Ovarian Function Observations on a possible relationship with a report of 6 cases Ann Intern Med 1944211022-34
5 - Mund A Swison J Rothfield N Effect of pregnancy on the course of SLE JAMA 1963183917-20
6 - Jungers P Dougados M Pelissier C Kuttenn F Tron F Lesavre P y cols Influence of oral contraceptive therapy on the activity of Systemic Lupus Erythematosus Arthritis Rheum 198225618-23
7 - Barret C Neylon N Snaith ML Oestrogen-Induced Systemic Lupus Erythematosus Br J Rheumatol 198625300-1
8 - Lahita RG Bradlow HL Kunkel HG Fishman J Increased 16-alpha Hydroxylation of Estradiol in Systemic Lupus Erythematosus J Clin Endocrinol Metab 198153174-8
9 - Jungers P Nahoul K Pelissier C Dougados M Tron F Bach JF Low Plasma Androgens in Women with Active or Quiescent Systemic Lupus Erythematosus Arthritis Rheum 198225454-7
10 - Lahita RG Bradlow HL Ginzler E Pang S New M Low Plasma Androgens in Women with Systemic Lupus Erythematosus Arthritis Rheum 198730241-8
11 - Stern R Fishman J Brusman H Kunkel HG Systemic Lupus Erythematosus associated with Klinefelters syndrome Arthritis Rheum 19772018-22
12 - Cohen JHM Danel L Cordier G Saez S Revillard JP Sex Steroid Recptors in Peripheral T Cells Absence of Androgen Receptors and Restriction of Estrogen Receptors to OKT8-Positive Cells J Immunol 19831312767-71
13 - Kelley VE Winkelstein A Age- and Sex-related Glomerulonephritis in New Zealand White Mice Clin Immunol Immunopathol 1980 16142-50
14 - Roubinian JR Talal N Greenspan JS Goodman JR Siiteri PK Delayed Androgen Treatment Prolongs Survival in Murine Lupus J Clin Invest 197963902-11
15 - Roubinian JR Talal N Greenspan JS Goodman JR Siiteri PK Effect of castration and sex hormone treatment on survival anti-nucleic acid antibodies and glomerulonephritis in NZBNZW F1 mice J Exp Med 19781471568-83
16 Sánchez-Guerrero J Romero-Díaz J Mendoza-Fuentes A Mestanza-Peralta M Cravioto MC Menopause in Systemic Lupus Erythematosus Age at Presentation and Clinical Characteristics Arthritis Rheum 199841S67
17 The North American Menopause Society Recommendations for estrogens and progestogens use in peri- and postmenopausal women October 2004 Position Statement of the North American Menopause Society Menopause 200411589-600
18 Sánchez-Guerrero J Karlson EW Liang MH Hunter DJ Speizer FE Colditz GA Past use of oral contraceptives and the risk of developing systemic lupus erythematosus Arthritis Rheum 199740804-8
19 Meier CR Sturkenboom MC Cohen AS Jick H Postmenopausal estrogen replacement therapy and the risk of developing systemic lupus erythematosus or discoid lupus J Rheumatol 1998251515-9
20 Sánchez-Guerrero J Uribe AG Jiménez-Santana L et al A trial of contraceptive methods in women with systemic lupus erythematosus N Engl J Med 20053532539-49
21 Petri M Kim MY Kalunian KC et al Combined oral contraceptives in women with systemic lupus erythematosus N Engl J Med 20053532550-8
22 Arden NK Lloyd ME Spector TD Hughes GRV Safety of hormone replacement therapy HRT in systemic lupus erythematosus SLE Lupus 1994311-3
23 Kreidstein S Urowitz MB Gladman DD Gough J Hormone replacement therapy in systemic lupus erythematosus J Rheumatol 1997242149-52
24 Mok CC Lau CS Ho CT Lee KW Mok MY Wong RW Safety of hormonal replacement therapy in postmenopausal patients with systemic lupus erythematosus Scand J Rheumatol 199827342-6
25 Buyon JP Petri MA Kim MY et al The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus A randomized trial Ann Intern Med 2005142953-62
26 - Bombardier C Gladman DD Urowitz MB Caron D Chang CH and the Committee on Prognosis Studies in SLE Derivation of the SLEDAI Arthritis Rheum 199235630-40
27 - Petri M Genovese M Engle E Hochberg M Definition Incidence and Clinical Description of Flare in Systemic Lupus Erythematosus Arthritis Rheum 1991 34937-44
28 Gladman DD Ibañez D Urowitz MB Systemic lupus erythematosus disease activity index 2000 J Rheumatol 200229288-91
29 Greene JG Constructing a standard climacteric scale Maturitas 19982925-31
30 Beck AT Steer RA Brown GK Beck Depression Inventory -Second Edition Manual San Antonio TX The Psychological Corporation 2000
31 - Tan EM Cohen AS Fries JF Masi AT McShane DJ Rothfield NF et al The 1982 revised criteria for the classification of Systemic Lupus Erythematosus Arthritis Rheum 1982251271-7
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None