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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
[+] Article and Author 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@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.


Ann Intern Med. 2005;142(12_Part_1):953-962. doi:10.7326/0003-4819-142-12_Part_1-200506210-00004
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Understanding the benefits and risks for exogenous estrogens is an important consideration in the care of women with SLE. The SELENA trial is the largest prospective study to provide evidence-based information. Moreover, this trial is likely to have a major impact on the success of future multicenter SLE trials by emphasizing the need for validation of site investigators in use of the instrument that defines flare. Validation is necessary to assure uniform agreement in the assignment of outcome measures, especially for diseases as heterogeneous as SLE. Our conclusions are relevant to physicians caring for patients, basic researchers considering biological effects of estrogens, and clinical trialists. First, the use of HRT (conjugated estrogen/cyclic medroxyprogesterone) does not result in a statistically significant increased risk for severe flares in women with SLE. Second, HRT is associated with a significantly increased rate and number of mild to moderate flares. Third, the mean change in SELENA–SLEDAI instrument score did not significantly differ between groups across all 12 months of analysis.

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Figures

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Figure 1. *Thirteen patients in the HRT group had a severe flare: Ten discontinued HRT because of severe flare, 1 had a flare after allocation but before taking the drug, 2 had a flare after discontinuing therapy with the drug (1 patient discontinued therapy because of medical reasons, and 1 discontinued voluntarily). †In consideration of the results of the Women's Health Initiative trial , the SELENA Data and Safety Monitoring Board ( ) mandated discontinuation of therapy with the study drug in September 2002. ‡Losses to follow-up are a subset of patients who discontinued therapy with the drug. §All patients were included in the intention-to-treat analysis according to the length of follow-up completed by each. A per protocol analysis to evaluate the primary end point (severe flare) was also performed; this analysis included only patients who completed 12 months of medication or who stopped taking medication because of severe flare and completed 12 months of follow-up (113 patients in the HRT group and 130 in the placebo group).
Flow diagram of the hormone replacement therapy (HRT) portion of the Safety of Estrogens in Lupus Erythematosus, National Assessment (SELENA) trial.(28)DSMB
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Figure 2. The difference between treatment groups in the 12-month severe flare rate is 0.033 (  = 0.23).
Kaplan–Meier estimates of the cumulative probability of severe flare for patients in the hormone replacement therapy (HRT) and placebo groups.P
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Summary for Patients

Hormone Replacement Therapy Does Not Increase Severe Lupus Flares

The summary below is from the full report titled “The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial.” It is in the 21 June 2005 issue of Annals of Internal Medicine (volume 142, pages 953-962). The authors are J.P. Buyon, M.A. Petri, M.Y. Kim, 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, L. Sigler, M.A. Dooley, J. Von Feldt, W.J. McCune, A. Friedman, J. Wachs, M. Cronin, M. Hearth-Holmes, M. Tan, and F. Licciardi.

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