Lupus & Hormone Therapy

A new study shows that in menopausal women with Lupus, HT does not increase blood clots. Good news! SG

In postmenopausal women with
lupus, no increase in vascular
thrombotic events with HT use

Fernandez M, Calvo-Alen J, Bertoli AM, et al, for the
LUMINA Study Group. Systemic lupus erythematosus in
a multiethnic US cohort (LUMINA L II): relationship
between vascular events and the use of hormone
replacement therapy in postmenopausal women. J Clin
Rheumatol 2007;13:261-265. Level of evidence: II-2.

Menopausal hormone therapy (HT) does not
predispose postmenopausal women with systemic
lupus erythematosus (SLE) to vascular throm-
botic events, found this substudy of LUMINA, a
longitudinal, observational, multiethnic cohort
study of outcome in SLE. The original cohort
included women with SLE, aged 16 years or
older, with disease duration of 5 years or greater.
For the current study, perimenopausal women
were drawn from the original cohort, excluding
those with positive IgG or IgM antiphospholipid
antibodies and/or the lupus anticoagulant, or
vascular arterial events occurring before the use
of HT. A total of 72 women were included (mean
age, 53.7 y), of whom 32 were HT users and 40
were nonusers. The occurrence of vascular
arterial and venous thrombotic events was
compared between the two groups.


available. Vascular arterial events considered in
the analysis were myocardial infarction, angina,
coronary artery bypass graft, stroke, inter-
mittent claudication, and peripheral arterial
thrombosis. Peripheral or visceral venous
events were also considered. Vascular arterial
events occurred more frequently in nonusers
than HT users (P = 0.029). No difference was
found for venous thrombotic events between
the two groups (P = 0.725). Although HT use
was negatively associated with vascular arterial
events (odds ratio, 0.156; P = 0.021), this
diminished to nonsignificance when a propen-
sity score, which adjusted for baseline
variables, was factored in. In women with SLE
who are antiphospholipid antibody negative,
with no previous thrombotic vascular events or
other risk factors for such events, HT may be
used in the immediate postmenopausal period,
the study authors suggest.

Comment. Contradictory findings exist re-
garding estrogen and SLE. The Nurses’ Health
Study1 demonstrated that the relative risk for
SLE was increased by events that increase
one’s lifetime exposure to estrogen, such as
early age at menarche, oral contraceptive (OC)
use, and the use of HT during perimenopause.

The same study also demonstrated an increased
risk for SLE with early age at menopause and
surgical menopause. Like other autoimmune
diseases, SLE has a varied disease course that
waxes and wanes irrespective of medical therapy.
Clearly there is a need for randomized controlled
trials (RCTs) to evaluate the effects and safety of
HT in patients with SLE. Prescribing HT to
women with SLE is of particular concern because
both SLE and HT have been associated with
vascular events.

To date, RCTs have found that neither the use of
OCs nor HT leads to significant flares.2 Sanchez-
Guerrero and colleagues3 performed a double-
blind RCT of 106 women with SLE either in the
menopause transition or in early or late
postmenopause who received a continuous-
sequential estrogen-progestogen regimen (n = 52)
or placebo (n = 54). Disease activity remained
mild and stable in both groups throughout the
trial. There were no significant differences
between the groups in global or maximum
disease activity, incidence or probability of
flares, or medication use. Thrombosis occurred in
three patients who received HT and in one patient
who received placebo. Thus, HT did not alter
disease activity during 2 years of treatment.
However, an increased risk of thrombosis was
found in women with SLE who received HT.

The largest RCT was conducted by Buyon and
colleagues4 who evaluated the risk of 12 months
of cyclic-combined HT in the Safety of Estrogens
in Lupus Erythematosis National Assessment
trial in 351 perimenopausal patients (mean age,
50 y) with inactive (81.5%) or stable-active
(18.5%) SLE. The addition of HT was associated
with a small risk for increasing the natural flare
rate of mild to moderate flares of SLE although
the risk for severe flare was not significantly
increased compared with placebo. During the
trial, they validated the Systemic Lupus
Erythematosis Disease Activity Index (SLEDAI)
of ongoing, recurrent, or new activity to capture
persistent activity/flares.

Neither Buyon nor Sanchez-Guerrero found an
increased occurrence of arterial thrombosis
with HT use in women with SLE. This lack of
increased risk of arterial thrombosis in selected
women with SLE was confirmed in this recent
study by Fernandez et al. The strengths of their
multiethnic, longitudinal, nonrandomized,
observational cohort trial included the use of
the SLEDAI and the process of pseudo-
randomization using a propensity scale to take
into account the fact that subjects using HT had
less severe and less active disease. The trial is
limited by the lack of information about precise
doses, formulations, and length of time of HT.
Their findings are not generalizable to women
with high-titer anticardiolipin antibodies, lupus
anticoagulant, or previous thrombosis as these
women were excluded from the trial.

The indications for HT in postmenopausal
women include the treatment of menopause-
related symptoms and the prevention of
osteoporosis. Women with SLE are more likely
to have premature menopause induced by
chemotherapy as well as increased risks of
osteoporosis and cardiovascular disease. Recent
studies2,3 have shown that HT can induce mild
to moderate SLE flares as well as
cardiovascular or venous thromboembolic
events. Therefore, at this time, we would not
recommend giving HT to women with active
SLE, lupus anticoagulant, antiphospholipid
antibodies, or previous thrombosis. Candidates
for HT might include young women with
premature ovarian failure from chemotherapy
for SLE or symptomatic women with SLE for
treatment of vasomotor symptoms and
prevention of osteoporosis. Nonoral admin-
istration may be preferable because of potential
decreased effect on coagulation. The increased
risk for mild to moderate flares needs to be
considered on an individual basis.

JoAnn V. Pinkerton, MD
Professor of Obstetrics and Gynecology
Vice Chair for Academic Affairs
University of Virginia
Charlottesville, VA
President-Elect, NAMS Board of Trustees
Credentialed NAMS Menopause Practitioner

Dale W. Stovall, MD
Professor of Obstetrics and Gynecology
Division Director, Reproductive Endocrinology
and Fertility
University of Virginia
Charlottesville, VA

References:
1. Costenbader KH, Feskanich D, Stampfer MJ, Karlson
EW. Reproductive and menopausal factors and risk of
systemic lupus erythematosus in women. Arthritis Rheum
2007;56:1251-1262.
2. Urowitz MB, Ibanez D, Jerome D, Gladman DD. The
effect of menopause on disease activity in systemic lupus
erythematosus. J Rheumatol 2006;33:2192-2198.
3. Sanchez-Guerrero J, Gonzalez-Perez M, Durand-
Carbajal M, et al. Menopause hormonal therapy in
women with systemic lupus erythematosus. Arthritis
Rheum 2007;56:3070-3079.
4. Buyon JP, Petri MA, Kim MY, et al The effect of
combined estrogen and progesterone hormone replace-
ment therapy on disease activity in systemic lupus
erythematosus: a randomized trial. Ann Intern Med
2005;142(12 Pt 1):953-962.