Round 29: Menopause in Women with Systemic Lupus Erythematosus: A clinical perspective

Jorge Sánchez-Guerrero, MD, MS
Department of Immunology and Rheumatology
Instituto Nacional de Ciencias Médicas y Nutrición
Salvador Zubirán

Dr. Sánchez-Guerrero has no significant financial interest or relationships to disclose.

Release Date: May 20, 2010
Expiration Date: January 1, 2011

For CME credit,TAKE POST-TEST & EVALUATION

Objectives

After completing this activity, you’ll be able to:

  • Define the characteristics of menopause in women with systemic lupus erythematosus (SLE).
  • Outline the course of disease activity in peri- and postmenopausal women with SLE.
  • Evaluate the risk and benefit profile of menopause hormonal therapy in women with SLE.

Background

All over the world, the life expectancy for women has been increasing. However, the age of menopause all over the world remains almost the same, between 48 and 52 years.

Menopause and Age

The change in life expectancy presents a dilemma: women are spending more years in the postmenopausal period. Therefore, it is relevant to know how to deal with all of the problems that come with menopause.

Survival rate (%)
Reference

at 5yrs

at 10yrs

Merrill & Shulman 1955

Kellum & Hasericke1964

51
70

-
53

Estes & Christian 1971
Feinglass et al. 1976

77
94

60
82

Hochberg et al. 1981
Wallace et al. 1982

97
88

90
79

Ginzler et al. 1982
Rubin et al. 1985

88
88

71
-

Swaak et al. 1989
Johnsson et al. 1989

94
95

87
-

Key Points

  • Prevalence of menopause in SLE patients (in our center)
  • Age at menopause
  • Symptoms associated with menopause in SLE
  • SLE disease activity during menopausal transition and in the postmenopausal period
  • Hormone replacement therapy (HRT)–risks and benefits.

Prevalence of menopause in SLE patients

Methods: All women between 18 and 60 years of age were surveyed at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) from September 5, 2006 to September 4, 2007.
Survey tool included:

  • demographic information
  • gynecologic obstetric history
  • menopausal symptoms
  • current treatment and, if necessary, blood sample

Subjects were classified as having menopause if they were women aged 50 years or over with amenorrhea of at least one year.  Subjects were classified as postmenopausal if they were women aged 55 years or under, with amenorrhea for at least one year and an elevated follicle stimulating hormone (FSH) level. (In case of hysterectomy; an FSH level was sufficient for classification.) Women who were taking menopause hormone therapy were also considered postmenopausal.

Results: Eight hundred and seven patients were surveyed.  The mean age of the population was 35.5 years (35.5 ± 10.6) and 23% of those surveyed were postmenopausal (identified by status quo method).

Age at menopause

The age at menopause has been considered in four different studies, including one from INCMNSZ.

Age at menopause
(mean ± SD)
Urowitz M, et al. J Rheumatol. 2006;33:1–7. 45.9 ± 4.0
Lee C, et al. Rheumatology. 2006;45:53–60. 41.4 ± 7.5
Mok C, et al. Lupus. 2005;14:106–112. 47.8 ± 4.1
Cravioto MC, et al. Menopause. 1998;5:67 41.0 ± 8.0

In the studies in the above table, age at menopause onset was assessed by asking the patient what age they were when they had their last menstrual period. This is the wrong way to assess this issue because it has been shown to be very imprecise. In fact, in all these studies there are differences. Some considered that the age of menopausal onset is early 40’s, some in the mid 40’s and, in the study from Dr. Mok, menopausal onset reached an age of almost 48 years.

For the analysis at INCMNSZ all patients with hysterectomy were excluded, and the age at menopause was assessed by two methods. One method was similar to the classical method of self-recording and the other method was something that is considered the best method, which is the status quo method.

After excluding patients with hysterectomy, there were 764 patients. Almost 20% of these patients were less than 40 years of age. The mean age at menopause by the recording method was 40.5 years, similar to results from several years ago. However, the mean age at menopause is different when analyzed by the status quo method; 48 years—which is similar to the median age of menopause in the general population in Mexico.  Therefore, according to this study we cannot say that menopause in lupus patients occurs earlier than in the general population.

Something else that is interesting is the distribution of those patients who are postmenopausal according to different age groups:

Age, n (%) Post-menopausal
< 20 2 (5)
21-25 2 (2)
26-30 3 (2)
31-35 9 (7)
36-40 12 (10)
41-45 30 (29)
46-50 18 (35)
51-55 38 (93)
56-60 25 (100)
Total 139

Symptoms associated with menopause in SLE

Surprisingly, the symptoms associated with menopause in SLE, were identical to the symptoms associated with menopause in the general population. In the INCMNSZ study, the symptoms were highly prevalent (as suspected) in the postmenopausal women. All of the symptoms were also very common among the premenopausal women.  Some of them, which are strongly associated to menopause–for instance, vaginal dryness, hot flashes and night sweats–were present in at least one of every five females interviewed.

Symptoms

Premenopausal
n=625

Postmenopausal
n=139

p

Depressed mood, n(%)

357 (57.1)

78(56.1)

0.84

Forgetfulness, n(%)

283 (45.3)

85 (61.2)

0.001

Insomnia, n(%)

255 (40.8)

73 (52.5)

0.011

Vaginal dryness, n(%)

150 (24)

65 (46.8)

<0.0001

Urinary incontinence, n(%)

167 (26.7)

46 (33.1)

0.089

Hot flashes, n(%)

143 (22.9)

60(43.2)

<0.0001

Night sweats, n(%)

136 (21.8)

56 (40.3)

<0.0001

Diminished sexual interest n(%)
from n with active sexual life

182(45)
404

58(78.4)
de 74

<0.0001

Corticosteroids use and menopausal symptoms.  In the premenopausal patients the ingestion of corticosteroids was associated with the presence of hot flashes and night sweats.  However the ingestion of corticosteroids was not associated with these symptoms in postmenopausal patients.

How does lupus activity behave during menopause?  Does menopause onset influence the course of SLE activity or not?

Ovarian failure and flares of SLE. In a study published in Arthritis and Rheumatism in 1999 (Mok et al.), 54 premenopausal women were analyzed and they received cyclophosphamide for less than a year.

  • Incidence rate of flares in the following 5 years after treatment, among women who developed ovarian failure (n = 14) and those who continued menstruating (n = 40).
  • Besides age (37.9 vs 25.5 years, P < 0.001), clinical manifestations, disease duration, treatment, and cumulative dose of cyclophosphamide were similar.
  • Patients who developed ovarian failure developed less severe flares (p = 0.01) and total flares (p = 0.03) than women who continued menstruating.

Disease activity during the pre- and postmenopausal periods in women with SLE. In another study conducted at INCMNSZ 30 women with lupus who developed natural menopause were analyzed.  We assessed the activity during a period of 4 years before and after menopause (results in table below).

Disease Activity Premenopausal period Postmenopausal period P
SLE disease activity index (SLEDAI) 2.3 ± 2.3 2.3 ± 2.9 0.36
Mex-SLEDAI 1.4 ± 1.4 1.2 ± 1.3 0.46
Total flares 55 40 0.20
- Incidence rate 0.56 0.43
Severe flares 17 11 0.33
- Incidence rate 0.17 0.12
Patients who flared, n (%) 22 (73) 17 (57) 0.18

The level of activity in the perimenopausal period and the postmenopausal period was very low. There was no difference between these two periods in the incidence of severe flares. However, there was a trend towards lower numbers during the postmenopausal period as compared to the premenopausal period although this was not statistically significant. Maximum disease activity was significantly lower during the postmenopausal period.

The Effect of Menopause on Disease Activity in SLE. In 2006, Urowitz published a study that compared many groups of patients.

  • Group A: Inception cohort 190 premenopausal women SLE.
  • Group B: Inception cohort 55 postmenopausal women SLE.
  • Group C: 49 women followed 3 years before/after menopause.
  • Group D: 193 patients followed 6 years premenopausal period.
  • Group E: 76 patients followed 6 years postmenopausal period.

The adjusted mean SLEDAI during the first three years of SLE was higher among premenopausal (group A) compared to the postmenopausal women (group B). When he analyzed those women who were followed during three years before and after the menopause (group C), the adjusted mean SLEDAI was also higher during the three years before menopause then after menopause. Although there was no difference in the incidence of flares, there was a trend toward higher incidence during the premenopausal period (group D). The Max-SLEDAI at the start of the study was significantly higher during the premenopausal period. However, the slope of disease activity during the pre- and postmenopausal period was similar.  This led to the conclusion that it is not the menopause onset that decreases the level of disease activity, but it is the length of the disease that influences the course of activity. Although premenopausal women with SLE have more disease activity than postmenopausal, there is a constant rate of improvement overtime independently of menopausal status. This conclusion is consistent with the hormone replacement arm of the SELENA trial (351 patients – SLEDAI = 2.5  (0-12), Buyon J, et al. Ann Intern Med 2005;142:953–62) and the INCMNSZ trial (106 patients – SLEDAI  3.3  (0-15), (Sánchez-Guerrero J, et al. Arthritis Rheum 2007;56:3070–9)

Hormone replacement therapy

Background: In the mid-1990s, trials for HRT and contraception began. At that time, HRT was being considered as an answer to late morbidity in SLE patients. Since then, the North American Menopause Society has published four different position statements about the use of HRT in postmenopausal women. In March 2007, a new statement was issued:

  • Data from the WHI and HERS studies should not be extrapolated to symptomatic postmenopausal women younger than 50 years of age
  • Current evidence supports the use of Estrogen Therapy or Estrogen Progestogen Therapy for menopause-related symptoms and disease prevention in appropriate populations of peri- and postmenopausal women

Studies that focus on SLE patients involve young patients that are prone to develop premature menopause, osteoporotic fractures, cognitive dysfunction and very often they have poor quality of life.  On the other side they tend to develop premature arterial sclerosis, thrombosis and cardiovascular events. This leads to the question: Are women with SLE an accurate population for menopause hormonal therapy use?

Studies

During the 90’s there were three studies published by different groups:

Author

Design

Patients Follow-up
Arden NK, et al. Case-control

30 users
30 never users

12 months

Kreidstein SH, et al. Case-control

16 users
32 never users

12 months

Mok CC, et al. Retrospective Cohort

11 users
23 never users

35 months

Because of the design and number of patients who were included in this study it is difficult to make a conclusion about the use of hormone therapy in this population.  However something that is interesting is that all these studies conclude that HRT is safe and does not increase the incidence rate of flares. This was validated in postmenopausal patients with SLE.

A 2005 randomized trial of HRT in postmenopausal woman (Buyon JP, et al. Ann Intern Med 2005;142:953–62)

  • 351 postmenopausal patients with inactive or mild and stable lupus activity
  • 12 months of treatment, 0.625 mg conjugated estrogens daily + 5 mg/d medroxyprogesterone (12 days), n = 174 or placebo, n = 177
  • Primary outcome: severe flare/person-year, SELENA/SLEDAI
  • Severe flares rate: HRT 0.081, Placebo 0.049 (p = 0.23)
  • Mild/moderate flares: HRT 1.14, Placebo 0.86 (p = 0.01)
  • Adverse events:
    – HRT 1 death, 1 stroke, 2 deep venous thrombosis and 1 arteriovenous graft thrombosis.
    – Placebo 1 deep venous thrombosis

The main adverse events in this trial are related with the development of thrombosis.

INCMNSZ trial published in 2007 (Sánchez-Guerrero J, et al. Arthritis Rheum 2007;56:3070–9).

  • Double blind placebo controlled clinical trial
  • 52 patients were randomized to receive estrogens plus medroxyprogesterone
  • 54 patients were assigned to receive placebo
  • Two-year followup study

Results of the INCMSZ trial

HRT

n 52

Placebo

n 54

p

Age (years)

47.5 ± 7 .4
(28 – 65)

50.0 ± 7.7
(28 – 63)

0.08

Education (years)

10.5 ± 4.9

10.3 ± 4.7

0.83

BMI (Kg/m2)

27.4 ± 6.1

26.3 ± 4.3

0.26

Menopause <40 years [n (%)]

17 (33)

13 (24)

0.33

SLE Criteria

4.9 ± 1.2

5.2 ± 1.2

0.18

SLE duration  (years)

9.6 ± 8.9

8.9 ± 7.2

0.62

SLICC

0.8 ± 1.2

0.9 ± 1.2

0.66

APLA (+) [n (%)]

13 (25)

18 (33)

0.35

LAC (+) [n (%)]

6 (12)

5 (9)

0.76

B2GPI (+) [n (%)]

8 (15)

8 (15)

0.94

SLEDAI

3.5 ± 3.3

3.1 ± 3.4

0.58

Prednisone [n (%)]

23 (44)

27 (50)

0.55

Prednisone dose (mg)

7.9 ± 9.9

9.2 ± 6.8

0.59

Azathioprine [n (%)]

11 (21)

14 (26)

0.56

Chloroquine [n (%)]

22 (42)

23 (43)

0.98

NSAIDS [n (%)]

18 (35)

17 (32)

0.73

The probability of flares was not different between the groups, the proportion of groups who flare and the maximum SLEDAI score in each group was identical.

Adverse effects.  Three thrombotic events developed in the HRT group and one thrombosis event occurred in the placebo group.  Exogenous estrogens are considered an independent risk factor for developing thrombosis and comparing a population who receives estrogen versus with one that does not, the relative risk is between 2 and 4.  This is consistent with the proportion of thrombosis observed in both studies.

Conclusions of 2 trials.

  • Hormone replacement therapy increases slightly the risk of mild/moderate flares, but not severe flares (Buyon JP et al. Ann Intern Med 2005; 142:953–62)
  • Hormone therapy did not alter disease activity during two years of treatment (Sánchez-Guerrero J et al. Arthritis Rheum 2007;56:3070–9)

Effect of oral contraceptives on lupus disease activity. Estrogen-containing oral-contraceptives do not appear to increase the risk of disease exacerbation in women with SLE. Also, oral contraceptives do not increase the risk of flare among women with SLE (stable).

Benefits

INCMSZ trial densitometry

HRT

n = 34

Placebo
n = 34

p

Femoral neck

BASAL - BMD (g/cm2)

– t-score

0.789 + 0.113

- 1.88 + 0.91

0.766 + 0.15

- 2.04 + 1.16

0.43

0.53

12 months - BMD (g/cm2)

– t-score

0.798 + 0.112

- 1.8 + 0.92

0.773 + 0.136

- 2.02 + 1.13

0.33

0.38

24 months - BMD (g/cm2)

– t-score

0.805 + 0.109

- 1.69 + 0.92

0.762 + 0.133

- 2.02 + 1.12

0.09

0.19

Lumbar spine

BASAL- BMD (g/cm2)

– t-score

0.889 + 0.131

- 1.04 + 0.82

0.862 + 0.135

- 1.21 + 0.85

0.41

0.40

12 months- BMD (g/cm2)

– t-score

0.917 + 0.119

- 0.87 + 0.743

0.885 + 0.139

- 1.26 + 0.869

0.03

0.054

24 month- BMD (g/cm2)

– t-score

0.926 + 0.118

- 0.76 + 0.75

0.852 + 0.136

- 1.27 + 0.85

0.013

0.01

There seems to be a mild increase in the density along the two years of follow-up, and the group who received placebo remained stable or tended to decrease.

The effect of HRT in the climacteric syndrome.  At each assessment performed the Greene scale was applied, which is on the scale for menopausal symptoms and at baseline 6, 12 and 24 months we applied the Beck depression inventory.

Greene Scale

As soon as therapy is started in both groups, there is an improvement in the Greene scale.  This improvement is escalated during the first 12 months of treatment. After that period the group assigned to placebo tends to return to the baseline levels.  However, the group assigned to HRT remains improved. When the vasomotor symptoms are analyzed, the group that was more symptomatic has sustained improvement and is better than the group assigned to the placebo.

Beck Depression Inventory

In the Beck depression inventory, patients assigned to the placebo group had no score difference at any of the follow-up periods.  However, the group that was assigned to HRT had improvement at each of these assessments and this was statistically significant. This seemed to be good news, however we need to consider the risk of thrombosis in SLE and the risk of thrombosis of the prescription of estrogens.  Thrombosis is a very unusual event in the general population.

Incidence rates of cardiovascular events per 1,000 person-years in the 498 women with SLE

Age (years)

SLE

Framingham

Rate ratio

CI 95%

Rate

CI 95%

Rate

CI 95%

15 – 24
25 – 34

6.33
3.66

0.2 – 35.3
0.8 – 10.7

0.0
0.0

0.0 – 11.8
0.0 – 1.2

¥
¥

35 – 44
45 – 54

8.39
4.82

4.2 – 15.0
1.0 – 14.1

0.16
1.95

0.0 – 0.9
0.9 – 3.6

52.43
2.47

21.6 – 98.5
0.8 – 6.0

55 – 64
65 – 74

8.38
7.94

1.7 – 24.5
1.0- – 28.7

1.99
0.0

0.6 – 4.6
0.0 – 17.1

4.21
¥

1.7 – 7.9

In the first study, the incidence of thrombosis among postmenopausal women with coronary artery disease increases to more than 400 patients. SLE is a very, very strong risk factor for developing thrombosis. This risk of thrombosis develops especially during the early years of the disease—the first five years of the disease.  After that period, the risk of developing the disease remains stable.  Also it seems like the risk for developing venous and arterial thrombosis is the same in lupus patients. It has also been shown that women who are premenopausal are more at risk for developing myocardial infarction than the general population.

Conclusions

  • In the INCMNSZ:
    • One out of five SLE women are postmenopausal
    • The median age at menopause is 48 years, not different from the general population
    • One out of five postmenopausal SLE women is younger than 40 years of age
  • Disease activity is mild during the peri- and postmenopausal periods
  • The real threat of menopause hormonal therapy in women with SLE is the risk of developing thrombosis, not the effect on disease activity
  • In selected patients, menopause hormonal therapy may be of great benefit in women with SLE
  • Use of menopause hormonal therapy should be consistent with treatment goals, benefits, and risks for the individual woman

For CME credit,TAKE POST-TEST & EVALUATION

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Updated: August 16, 2012

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