Infliximab for Maintenance of Glucocorticosteroid-Induced Remission of Giant Cell Arteritis

A Randomized Trial

1 May 2007 | Volume 146 Issue 9 | Pages 621-630

Background: Tumor necrosis factor- is present in arteries in giant cell arteritis.

Objective: To evaluate the efficacy of infliximab, an anti–tumor necrosis factor- agent, in giant cell arteritis.

Design: Randomized, controlled trial.

Setting: 22 sites in the United States, the United Kingdom, Belgium, Italy, and Spain.

Patients: 44 patients with newly diagnosed giant cell arteritis that was in glucocorticosteroid-induced remission.

Intervention: Participants were randomly assigned in a 2:1 ratio to receive infliximab (5 mg/kg of body weight) or placebo. Sixteen patients were assigned to glucocorticosteroid plus placebo, and 28 patients to glucocorticosteroid plus infliximab.

Measurements: End points were measured through week 22, when an interim analysis resulted in early stopping of the planned 54-week trial. Primary end points were the number of patients who remained free of relapse through week 22 and adverse events. Secondary end points were time to first relapse, biomarkers, cumulative glucocorticosteroid dose, and the number of patients who remained relapse-free while the glucocorticosteroid dosage was tapered to 10 mg/d.

Results: Infliximab therapy did not increase the proportion of patients without relapse at week 22 compared with placebo (43% vs. 50%, respectively; difference, –7 percentage points [95% CI, –38 to 23 percentage points; P = 0.65), nor did it increase the proportion of patients whose glucocorticosteroid dosages were tapered to 10 mg/d without relapse (61% vs. 75%, respectively; difference, –14 percentage points [CI, –42 to 14 percentage points]; P = 0.31). The incidence of infection was 71% with infliximab and 56% with placebo (difference, 15 percentage points [CI, –14 to 45 percentage points]).

Limitations: The sample was too small to rule out modest effects of infliximab and included only patients with a new diagnosis. Only one dose of infliximab was evaluated, and the study was terminated early.

Conclusions: This trial is too small to draw definitive conclusions, but it provides evidence that using infliximab as maintenance therapy in patients in glucocorticoid-induced remission of newly diagnosed giant cell arteritis is of no benefit and may be harmful. If infliximab has benefit, it is unlikely to be great.

*For a list of the members of the Infliximab-GCA Study Group, see the Appendix.

ClinicalTrials.gov registration number: NCT00076726.

Editors' Notes Context Up to 80% of patients with giant cell arteritis (GCA) experience complications related to glucocorticoid therapy. Case reports suggest that patients with GCA who received infliximab achieved sustained disease remission and independence from glucocorticoids. Contribution Patients with glucocorticoid-induced GCA remission were randomly assigned to infusions of infliximab, 5 mg/kg, or placebo at 0, 2, and 6 weeks and every 8 weeks thereafter. The investigators found that infliximab did not reduce rates of relapse or any secondary end point. Caution The study was small and stopped early (after week 22 of the planned 54 weeks), so it could not definitively identify harms or small benefits. Implication Infliximab is unlikely to cause large reductions in rates of relapse of GCA. —The Editors

 

Author and Article Information

From The Cleveland Clinic Foundation, Cleveland, Ohio; Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomediques August Pi y Sunyer, Barcelona, Spain; Boston University School of Medicine, Boston, Massachusetts; Emory University School of Medicine, Atlanta, Georgia; Johns Hopkins University School of Medicine, Baltimore, Maryland; Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; and Centocor Research and Development, Inc., Malvern, Pennsylvania.

Acknowledgments: The authors thank Scott Newcomer, MS (Centocor Research and Development, Inc.), for assistance with the preparation of the manuscript; the patients, investigators, and study personnel; and the independent safety monitoring board who oversaw the study: Gene Hunder, MD (Mayo Clinic, Rochester, Minnesota); Stefano Bombardieri, MD (Università di Pisa, Pisa, Italy); and P.V. Rao, PhD (University of Florida, Miami, Florida).

Grant Support: By Centocor Research and Development, Inc., and the National Center for Research Resources General Clinical Research Centers program at Boston University (grant M01-RRO-00533). Dr. Merkel is supported in part by a Mid-Career Development Award in Clinical Investigation from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (K24 AR2224-01A1). Dr. Cid was supported in part by a grant from the Spanish Education and Science Ministry (SAF 05/06250).

Potential Financial Conflicts of Interest: Employment: W. Xu (Centocor Research and Development, Inc.), S. Visvanathan (Centocor Research and Development, Inc.), M.U. Rahman (Centocor Research and Development, Inc.); Consultancies: G.S. Hoffman (Centocor Research and Development, Inc.), M.C. Cid (Centocor Research and Development, Inc.), C.M. Weyand (Centocor Research and Development, Inc., Genentech), K.E. Rendt-Zagar (Centocor Research and Development, Inc.); Honoraria: G.S. Hoffman (Centocor Research and Development, Inc.), M.C. Cid (Centocor Research and Development, Inc.), J.H. Stone (steering committee for the trial); Stock ownership or options (other than mutual funds): S. Visvanathan (Johnson & Johnson), M.U. Rahman; Grants received: G.S. Hoffman, K.E. Rendt-Zagar (Centocor Research and Development, Inc.), P.A. Merkel (Centocor Research and Development, Inc., Amgen).

Requests for Single Reprints: Gary S. Hoffman, MD, Center for Vasculitis Care and Research, Cleveland Clinic Foundation (A50), Lerner College of Medicine, Cleveland, OH 44195.

Current Author Addresses: Dr. Hoffman: Center for Vasculitis Care and Research, Cleveland Clinic Foundation (A50), Lerner College of Medicine, Cleveland, OH 44195.

Dr. Cid: Department of Internal Medicine, Hospital Clinic, Institut d'Investigacions Biomediques August Pi y Sunyer, Villarroel, 170, 08036 Barcelona, Spain.

Dr. Rendt-Zagar: The Arthritis Center, 32615 U.S. Highway 19N, Suite 2, Palm Harbor, FL 34684.

Dr. Merkel: Boston University School of Medicine, Vasculitis Center, E-5, 715 Albany Street, Boston, MA 02118.

Dr. Weyand: Department of Medicine, Emory School of Medicine, Atlanta, GA 30322.

Dr. Stone: UpToDate, 95 Sawyer Road, Waltham, MA 02453-3471.

Dr. Salvarani: Arcispedale Santa Maria Nuova, Viale Umberto I° No 50, 42100 Reggio Emilia, Italy.

Drs. Xu, Visvanathan, and Rahman: Centocor Research and Development, Inc., 200 Great Valley Parkway, Malvern, PA 19355.

Author Contributions: Conception and design: G.S. Hoffman, M.C. Cid, K.E. Rendt-Zagar, P.A. Merkel, C.M. Weyand, J.H. Stone, C. Salvarani, W. Xu, S. Visvanathan, M.U. Rahman.

Analysis and interpretation of the data: G.S. Hoffman, M.C. Cid, P.A. Merkel, J.H. Stone, W. Xu, S. Visvanathan, M.U. Rahman.

Drafting of the article: G.S. Hoffman.

Critical revision of the article for important intellectual content: G.S. Hoffman, M.C. Cid, P.A. Merkel, C.M. Weyand, C. Salvarani, W. Xu, S. Visvanathan, M.U. Rahman.

Final approval of the article: G.S. Hoffman, M.C. Cid, P.A. Merkel, C.M. Weyand, J.H. Stone, C. Salvarani, W. Xu, M.U. Rahman.

Provision of study materials or patients: G.S. Hoffman, M.C. Cid, K.E. Rendt-Zagar, P.A. Merkel, J.H. Stone.

Statistical expertise: G.S. Hoffman, W. Xu.

Obtaining of funding: G.S. Hoffman, M.U. Rahman.

Administrative, technical, or logistic support: G.S. Hoffman, S. Visvanathan, M.U. Rahman.

Collection and assembly of data: G.S. Hoffman, M.C. Cid, C. Salvarani.

Read all Rapid Responses

A Question of Harm

Daniel G. Arkfeld

Annals Online, 25 May 2007 [Full text]

Dear Sir

Omer Karadag, et al.

Annals Online, 29 May 2007 [Full text]

The window of opportunity for infliximab therapy might have been closed

Allan C Gelber, et al.

Annals Online, 11 Jun 2007 [Full text]

No benefit, possible harm

Gary S. Hoffman, et al.

Annals Online, 26 Jun 2007 [Full text]