Randomized Study of Oral Contraceptives or Hormone Replacement Therapy in Women With Systemic Lupus Erythematosus

PROTOCOL OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to age/menopausal status (35 and under/premenopausal vs 50 and over/postmenopausal). Both strata are randomized to one of two treatment arms.

Stratum 1 (Premenopausal/Oral contraceptives): Patients receive either oral ethinyl estradiol and norethindrone or placebo daily for 28 days beginning on the Sunday following the first day of the menstrual cycle.

Stratum 2 (Postmenopausal/Hormone replacement therapy): Patients receive either oral estradiol and medroxyprogesterone or placebo on days 1-12 monthly.

Treatment continues in both arms of both strata for a total of 13 courses in the absence of a severe disease flare-up or other complication that would preclude further study participation.

All patients are followed at 1 year.

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

Established systemic lupus erythematosus meeting American College of Rheumatology criteria

Inactive disease Systemic Lupus Erythematosus Activity Index (SLEDAI) score no greater than 4

No increase in score of more than 2 from baseline over the past 3 months

Receiving the equivalent of 5 mg or less of prednisone per day OR Stable/active disease SLEDAI score 5-12

No increase in score of more than 2 from baseline over the past 3 months

Prednisone dose up to 0.5 mg/kg/day for control of underlying disease allowed if stable dose for at least 3 weeks

No concurrent severe disease activity as defined by any of the following:

• Acute renal disease (i.e., rising creatinine levels, cellular sediment, or increasing proteinuria)
• Involvement of 3 or more organ systems requiring more than the equivalent of 0.5 mg/kg/day of prednisone
• Necessity of immediate hospitalization for symptom control

No presence of a high titer IgG, IgM, or IgA antiphospholipid antibodies (aPL) GPL and MPL no more than 40 APL no more than 50

No features of primary antiphospholipid antibody syndrome

--Prior/Concurrent Therapy--

Biologic therapy: Not specified

Chemotherapy: Not specified

Endocrine therapy: See Disease Characteristics

Radiotherapy: Not specified

Surgery: Prior hysterectomy allowed

--Patient Characteristics--

Age: 35 and under for oral contraceptive stratum (premenopausal) 50 and over for hormone replacement therapy stratum (postmenopausal)

Menopausal status:

• Premenopausal for oral contraceptive stratum
• Postmenopausal for hormone replacement therapy stratum
• Follicle-stimulating hormone greater than 40 mIU/mL OR Amenorrhea for 6 months

Performance status: See Disease Characteristics

Hematopoietic: Not specified

Hepatic:

• No hepatic dysfunction
• No tumors of the liver

Renal: See Disease Characteristics

Cardiovascular:

• No uncontrolled high blood pressure requiring frequent change in medication
• Concurrent hypertension controlled with stable medication allowed
• No history of spontaneous superficial or deep venous thrombosis or arterial thrombosis
• No prior myocardial infarction
• Oral contraceptive stratum: No angina No diastolic blood pressure greater than 90 mm Hg or systolic blood pressure greater than 140 mm Hg on 3 separate determinations
• Hormone replacement therapy stratum: No diastolic blood pressure greater than 95 mm Hg or systolic blood pressure greater than 145 mm Hg on 3 separate determinations

Pulmonary: No history of pulmonary embolus

Other:

• Not pregnant
• Oral contraceptive stratum: Negative pregnancy test Fertile patients must use effective barrier contraception
• No prior gynecologic malignancy or breast malignancy
• No undiagnosed vaginal bleeding
• No diabetes (present prior to use of glucocorticoids) requiring oral hypoglycemic medications or insulin
• No congenital hyperlipidemia
• No complicated migraines (i.e., associated with neurological sequelae)