TLALPAN, Mexico—Women with systemic lupus erythematosus (SLE) are at increased risk for premature menopause, with its attendant risks of osteoporotic fracture, however, hormone therapy (HT) is a possible treatment. Jorge Sanchez-Guerrero, MD, MS, and colleagues have conducted a double-blind, randomized, clinical trial allaying concerns that HT might worsen SLE activity but reinforcing fears that HT might add to an already elevated risk of thrombosis in women with SLE. The study is reported in Arthritis & Rheumatism.¹

"[W]e consider the real threat of menopause hormonal therapy in women with SLE to be the risk of developing thrombosis, not the effect of menopause hormonal therapy on disease activity. Whether this hazard can be diminished by alternative routes of estrogen administration or preparations of lower dosages needs to be explored," says Dr. Sanchez Guerrero, with the department of immunology and rheumatology at the Instituto Nacional de Ciencias Madicas y Nutricion Salvador Zubiran, in Tlalpan, Mexico.

This trial involved 106 women with SLE who were in the menopausal transition or in early or late postmenopause. Patients were randomized to a continuous-sequential estrogen-progestogen regimen of conjugated equine estrogens (Premarin^® and Cycrin^®) or to a biologically inert placebo identical in appearance and packaging size. SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI) at baseline, 1 through 3 months, then every third month from 6 to 24 months. Primary outcome measure was the area under the curve (AUC), as an estimate of global disease activity.

The primary outcome was not significantly different for the HT (n = 52) versus the placebo (n = 54) patients. Baseline SLEDAI scores were 3.5 versus 3.1 (P = .54). "There were no significant differences in the SLEDAI AUC or in the maximum SLEDAI score between the groups throughout the study period," the investigators report. "SLEDAI scores remained mild and stable during the trial, and there were no significant differences between the groups." [Table 1]

Table 1.

Month	HRT	Placebo
1	3	2.9
2	5.6	5.6
3	8.1	8.2
6	13.8	15.8
9	20.9	23.9
12	28.5	31.9
15	35.2	38.5
18	41.4	44.4
21	47	50.3
24	52.8	56.7

 

There were 79 flares in the HT group versus 83 in the placebo group over the 2-year period. Compared with the placebo group, the HT group had a relative risk of flare of 0.96 (P = .80), and the median time to flare was 3 months in both groups.

Dr. Sánchez-Guerrero reports, "Three patients in the menopause hormonal therapy group developed thromboses, one venous (lower limb) and two arterial (left middle cerebral and mesenteric arteries, respectively), for an incidence-density rate of 35.2 per 1000 patient-years. Thromboses developed after 2, 15, and 18 months of treatment." [Table 2]

 

Figure 2. HRT and Lupus – Adverse Events

Event	HRT (n=52)	Placebo (n=54)	Significance
Flares	79	83	RR=0.96
Probability of flare at 1 yr	0.91	0.75	P=0.29
Probability of flare at 2 yrs	0.75	0.79	P=0.25
Thromboses	3	1	Incidence density rate = 35.2/1,000 pt-yrs

According to Dr. Sanchez-Guerrero, similar problems with thrombotic events and estrogen-containing oral contraceptives are suspected. "[I]n our trial of contraceptive methods in women with SLE, thrombosis occurred only among women assigned to hormonal methods," he notes.

Thrombosis is rare among women under 30 but occurs in an estimated 10% to 20% of lupus patients. "Considering that the use of exogenous estrogens is associated with a thrombosis RR of 2.1 to 3.6, the absolute risk imposed by menopause hormonal therapy in women with SLE seems to be unacceptable. In our study, one episode of thrombosis was observed among every 28 women who received menopause hormonal therapy," the investigators report, while also noting that the study was not sufficiently powered to assess the risk for cardiovascular events.

Lupus experts are cautious about interpreting these results. "I think the numbers are small. There seems to be a trend that might be significant with more patients," Betty Diamond, MD, told CIAOMed. Dr.

Diamond heads the center for autoimmune diseases at the Feinstein Institute for Medical Research, in New York.

Reference

1. Sanchez-Guerrero J, Gonzalez-Parez M, Durand-Carbajal M, et al. Menopause hormonal therapy in women with systemic lupus erythematosus. Arthritis Rheum. 2007;56:3070-3079.