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The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial

Jill P. Buyon, MD; Michelle A. Petri, MD, MPH; Mimi Y. Kim, ScD; Kenneth C. Kalunian, MD; Jennifer Grossman, MD; Bevra H. Hahn, MD; Joan T. Merrill, MD; Lisa Sammaritano, MD; Michael Lockshin, MD; Graciela S. Alarcón, MD, MPH; Susan Manzi, MD, MPH; H. Michael Belmont, MD; Anca D. Askanase, MD, MPH; Lisa Sigler, MA; Mary Anne Dooley, MD, MPH; Joan Von Feldt, MD; W. Joseph McCune, MD; Alan Friedman, MD; Jane Wachs, MD; Mary Cronin, MD; Michelene Hearth-Holmes, MD; Mark Tan, MD; and Frederick Licciardi, MD

21 June 2005 | Volume 142 Issue 12 Part 1 | Pages 953-962

Background: There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE).

Objective: To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE.

Design: Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002.

Setting: 16 university-affiliated rheumatology clinics or practices in 11 U.S. states.

Patients: 351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE.

Interventions: 12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group.

Measurements: The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment–Systemic Lupus Erythematosus Disease Activity Index composite.

Results: Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis.

Limitations: Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis.

Conclusions: Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo.

Editors' Notes Context Clinicians sometimes avoid hormone replacement therapy (HRT) in women with systemic lupus erythematosus (SLE) because they think estrogens activate the disease. Contribution In this multicenter, double-blind trial, 351 menopausal patients with SLE were randomly assigned to HRT or placebo for 12 months. Severe flares were infrequent in both groups, and were not significantly increased in women taking HRT. Women taking HRT had more mild to moderate flares than did those taking placebo (1.14 flares vs. 0.86 flare/person-year). Four women taking HRT and 1 taking placebo had thromboembolic events. Implications Hormone replacement therapy given for 1 year does not significantly increase the risk for severe flare but does increase the risk for mild to moderate flares in menopausal women with SLE. –The Editors

 

Author and Article Information

From the Hospital for Joint Diseases of New York University School of Medicine, New York, New York; and Johns Hopkins University, Baltimore, Maryland.

This trial is registered as NCT00000419 on http://clinicaltrials.gov.

Note: Drs. Buyon and Petri contributed equally as first authors and principal investigators.

Acknowledgments: The authors thank Dr. Mary Louise Skovron for biostatistical expertise and intellectual contribution to the initial design of the study, Marcus Vogel and Jeanie Kantrowitz (Hospital for Joint Diseases pharmacists) for assistance in establishing and maintaining the system for blinded allocation and distribution of study medications, Michael Fillius for technical and administrative support in the collection and assembly of data, and Ann Rupel for administrative support and assistance in the preparation of the manuscript.

Grant Support: By National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases grant U01 AR42540. Wyeth-Ayerst Pharmaceuticals (St. David's, Pennsylvania) provided the study drug (Premarin/cyclic Provera) and matching placebo for free (Wyeth-Ayerst study 0713X1-962). The Hopkins Lupus Cohort is supported by NIH grant AR 43727. This study used the resources of the General Clinical Research Centers of Johns Hopkins University (NIH grant M01 RR00052) and the Hospital for Joint Diseases of New York University School of Medicine (NIH grant M01 RR00096).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Jill P. Buyon, MD, Department of Rheumatology, Room 1608, Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10003; e-mail, jill.buyon{at}nyumc.org.

Current Author Addresses: Drs. Buyon, Belmont, and Askanase: Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10003.

Dr. Petri and Ms. Sigler: Johns Hopkins University School of Medicine, 1830 East Monument Street, Baltimore, MD 21205.

Dr. Kim: Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.

Dr. Kalunian: Division of Rheumatology, Allergy and Immunology, University of California, San Diego, School of Medicine, 9350 Campus Point Drive, La Jolla, CA 92037.

Drs. Grossman and Hahn: University of California, Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90095.

Dr. Merrill: Oklahoma Medical Research Foundation, 825 Northeast 13th, Oklahoma City, OK 73104.

Drs. Sammaritano and Lockshin: Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021.

Dr. Alarcón: University of Alabama-Birmingham, 510 20th Street South, FOT 830, Birmingham, AL 35294.

Dr. Manzi: University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15261.

Dr. Dooley: University of North Carolina-Chapel Hill, 3330 Thurston Building, Chapel Hill, NC 27599.

Dr. Von Feldt: University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104.

Dr. McCune: University of Michigan Medical Center, Box 0358, Ann Arbor, MI 48109.

Dr. Friedman: University of Texas-Houston Health Science Center, 6410 Fannin Street, #1100, Houston, TX 77030.

Dr. Wachs: 3220 Fairfield Avenue, Riverdale, NY 10463.

Dr. Cronin: Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226.

Dr. Hearth-Holmes: Louisiana State University, 1501 Kings Highway, Shreveport, LA 71130.

Dr. Tan: 222 Middle Country Road, Suite 312, Smithtown, NY 11787.

Dr. Licciardi: New York University School of Medicine, 660 First Avenue, New York, NY 10016.

Author Contributions: Conception and design: J.P. Buyon, M.A. Petri, M.Y. Kim, K.C. Kalunian, B.H. Hahn, J.T. Merrill, L. Sammaritano, F. Licciardi.

Analysis and interpretation of the data: J.P. Buyon, M.A. Petri, M.Y. Kim, K.C. Kalunian, J.T. Merrill, A. Friedman, F. Licciardi.

Drafting of the article: J.P. Buyon, M.A. Petri, M.Y. Kim, J.T. Merrill, S. Manzi, F. Licciardi.

Critical revision of the article for important intellectual content: J.P. Buyon, M.A. Petri, M.Y. Kim, B.H. Hahn, J.T. Merrill, L. Sammaritano, G.S. Alarcón, A. Friedman, F. Licciardi.

Final approval of the article: J.P. Buyon, M.A. Petri, M.Y. Kim, K.C. Kalunian, J. Grossman, B.H. Hahn, J.T. Merrill, L. Sammaritano, M. Lockshin, S. Manzi, H.M. Belmont, A.D. Askanase, M.A. Dooley, J. Von Feldt, W.J. McCune, J. Wachs, M. Cronin, M. Hearth-Holmes, M. Tan, F. Licciardi.

Provision of study materials or patients: J.P. Buyon, M.A. Petri, K.C. Kalunian, J. Grossman, B.H. Hahn, J.T. Merrill, L. Sammaritano, M. Lockshin, G.S. Alarcón, S. Manzi, H.M. Belmont, A.D. Askanase, M.A. Dooley, J. Von Feldt, W.J. McCune, A. Friedman, J. Wachs, M. Cronin, M. Hearth-Holmes, M. Tan.

Statistical expertise: M.Y. Kim.

Obtaining of funding: J.P. Buyon.

Administrative, technical, or logistic support: J.P. Buyon, M.A. Petri, L. Sammaritano, A.D. Askanase, L. Sigler.

Collection and assembly of data: J.P. Buyon, M.A. Petri, J. Grossman, L. Sammaritano, M. Lockshin, A.D. Askanase, L. Sigler, A. Friedman.

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