Trial Information

Effect Of Hormone Replacement Therapy On Disease Activity, Menopausal Symptoms And Bone Mineral Density In Peri/Postmenopausal Women With Systemic Lupus Erythematosus.Randomized Clinical Trial

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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8. - Lahita RG, Bradlow HL, Kunkel HG, Fishman J. Increased 16-alpha Hydroxylation of
Estradiol in Systemic Lupus Erythematosus. J Clin Endocrinol Metab 1981;53:174-8.

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Treatment Prolongs Survival in Murine Lupus. J Clin Invest 1979;63:902-11.

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
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16. Sánchez-Guerrero J, Romero-Díaz J, Mendoza-Fuentes A, Mestanza-Peralta M, Cravioto MC.
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17. The North American Menopause Society. Recommendations for estrogens and progestogens
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of oral contraceptives and the risk of developing systemic lupus erythematosus.
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20. Sánchez-Guerrero J, Uribe AG, Jiménez-Santana L, et al. A trial of contraceptive
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21. Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with
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22. Arden NK, Lloyd ME, Spector TD, Hughes GRV. Safety of hormone replacement therapy (HRT)
in systemic lupus erythematosus (SLE). Lupus 1994;3:11-3.

23. Kreidstein S, Urowitz MB, Gladman DD, Gough J. Hormone replacement therapy in systemic
lupus erythematosus. J Rheumatol 1997;24:2149-52.

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
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25. Buyon JP, Petri MA, Kim MY, et al. The effect of combined estrogen and progesterone
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Prognosis Studies in SLE. Derivation of the SLEDAI. Arthritis Rheum 1992;35:630-40.

27. - Petri M, Genovese M, Engle E, Hochberg M. Definition, Incidence, and Clinical
Description of Flare in Systemic Lupus Erythematosus. Arthritis Rheum 1991; 34:937-44.

28. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index
2000. J Rheumatol 2002;29:288-91.

29. Greene JG. Constructing a standard climacteric scale. Maturitas 1998;29:25-31.

30. Beck AT, Steer RA, Brown GK. Beck Depression Inventory –Second Edition Manual. San
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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.