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Infliximab for Maintenance of Glucocorticosteroid-Induced Remission of Giant Cell Arteritis: A Randomized Trial

Gary S. Hoffman, MD; Maria C. Cid, MD; Karen E. Rendt-Zagar, MD; Peter A. Merkel, MD, MPH; Cornelia M. Weyand, MD; John H. Stone, MD, MPH; Carlo Salvarani, MD; Weichun Xu, PhD; Sudha Visvanathan, PhD; Mahboob U. Rahman, MD, PhD, Infliximab-GCA Study Group*
[+] Article and Author 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.


Ann Intern Med. 2007;146(9):621-630. doi:10.7326/0003-4819-146-9-200705010-00004
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To address the unmet need for a treatment that would allow patients with giant cell arteritis to reduce their dependence on glucocorticosteroids, we conducted the first double-blind, randomized, placebo-controlled trial in which a biological agent was used as an adjunct to glucocorticosteroid therapy for giant cell arteritis. Our results failed to demonstrate that infliximab improved the duration of remissions or decreased the glucocorticosteroid requirement in patients with newly diagnosed giant cell arteritis. These conclusions were based on a duration of follow-up of at least 22 weeks for all patients and a median of 7 infliximab infusions per patient. The results are consistent with a difference in the proportion of relapse-free patients ranging from a 38% advantage for placebo to a 23% advantage for infliximab. The results are also consistent with a difference in the proportion of relapse-free patients whose glucocorticosteroid dosages were tapered to 10 mg/d, ranging from a 42% advantage for placebo to a 14% advantage for infliximab. Thus, our study provides evidence that infliximab therapy is unlikely to greatly reduce the proportion of patients with relapse of giant cell arteritis.

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Figures

Grahic Jump Location
Figure 2.
Kaplan–Meier estimate of the proportion of patients who remained relapse-free through the end of the study.

The groups did not differ significantly in the time to first relapse, according to a log-rank test.

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Grahic Jump Location
Figure 3.
Box plots showing interleukin-6 level, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) at the time of first relapse.

Solid horizontal lines represent medians, boxes represent interquartile ranges, dashed horizontal lines represent means, and error bars represent SDs. Values were available for 13 placebo recipients and 21 infliximab recipients.

Grahic Jump Location

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Comments

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A Question of Harm
Posted on May 24, 2007
Daniel G. Arkfeld
USC Keck School of Medicine
Conflict of Interest: None Declared

In reading the article Infliximab for maintenance of glucocorticoid induced remission of giant cell arthritis by Hoffman et al I was surprised to see the conclusion statement of "...is of no benefit and may be harmful". I could find no evidence of "harm or injury" in the study patients and found it unfortunate that the sponsor ended the study prematurely. Of additional intrigue is the use of the exact same conclusion in the following article by Salvarani et al entitled Infliximab plus prednisone or placebo plus prednisone for the intitial treatment of polymyalgia rheumatica which similarly concluded in their abstract "...is of no benefit and may be harmful". Could the authors clarify this issue of "harm". As commented in the article, the treatment of refractory giant cell arteritis is an area where no proven options are available and one may be forced to use novel agents. Unfortunately trials of methotrexate,azathioprine, and other agents have not shown benefit. Since our first rule is to do no harm in the Hippocratic Oath, one may not use infliximab in giant cell arteritis which is not supported by the patient results presented in this article.

Conflict of Interest:

None declared

Dear Sir
Posted on May 26, 2007
Omer Karadag
Hacettepe University, Faculty of Medicine Departmrnt of Internal Medicine Rheumatology Unit, Ankara,
Conflict of Interest: None Declared

The study "˜Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial' was aimed to investigate infiliximab as a maintenance therapy for patients with glucocorticoid induced remission. There was not significiant difference between the treatment and plasebo groups. While taking patients to the study there was not a selection according to disease activity. Because of the substantial burden of corticosteroid-related side effects in giant cell arteritis (GCA), further investigations are needed with agents that directly target specific immunologic components to limit drug toxicity. There are several case reports describing that anti-TNF therapy might offer an approach to the treatment of GCA resistant to steroid and immunosuppressive drugs.(1,2) Despite the failure of this study, controlled studies might be warranted to formally address the effect of anti-TNF therapy for these selected patients.

Conflict of Interest:

None declared

The window of opportunity for infliximab therapy might have been closed
Posted on June 8, 2007
Allan C Gelber
Johns Hopkins University School of Medicine
Conflict of Interest: None Declared

The pair of articles in this issue of The Annals addresses a longstanding and critical therapeutic challenge in the related disorders of giant cell arteritis [GCA] and polymyalgia rheumatica [PMR] (1) (2). There is a compelling need to reduce patient exposure to high dose, long- term steroid therapy. In this context, the authors conclude that biologic therapy, in the form of infliximab, an inhibitor of tumor necrosis factor alpha [TNF], "is of no benefit" in these two conditions. Yet, we urge our fellow readers to exercise caution before arriving too quickly at the same conclusion.

One fundamental aspect of the study design in the GCA trial was to initiate infliximab only after clinical remission was achieved. In this manner, at the start of biologic therapy, the patients were uniformly asymptomatic and had normalized their sedimentation rate to levels <40 mm/hr. The study was conceptualized, as indicated in the title, to test the potential benefit of infliximab for "maintenance of glucocorticoid- induced remission of GCA." To this end, infliximab was of little to no benefit.

However, it seems biologically plausible that cytokine inhibition might have a favorable role, at diminishing the rate of relapse and the cumulative steroid exposure, were the biologic agent to be initiated at the outset of therapy, before a glucocorticosteroid-induced remission has been achieved (3) (4) (5). In contrast, the patients selected for inclusion in the GCA [but not in the PMR study] had already attained disease remission before ever seeing the first dose of a cytokine- inhibitor. The patients were eligible for enrollment after having received corticosteroids for up to 4 weeks. We are not specifically informed as to the average duration of steroid therapy among the studied patients at the start of infliximab or placebo? We also do not know how many were aggressively treated with pulse steroids (equivalent to 1000 mg intravenously methylprednisolone for 3 consecutive days) to achieve clinical remission?

This concern is germane in that the potential window of opportunity for infliximab therapy might have been closed at the time the trial was actually started! The notion that cytokine inhibition might be most advantageous when corticosteroids are first begun is seemingly of merit. Such a study design is worth considering and is perhaps analogous to trials outside rheumatology in which potent biologic agents, with a clear mechanism of action, are investigated during the acute phase of thrombotic events associated with myocardial infarction and stroke. It behooves renewed consideration of such a trial design when assessing the full potential benefit of potent inhibitors of inflammatory cytokines in the management of vasculitis.

REFERENCES

(1) Hoffman GS, Cid MC, Rendt-Zagar KE, Merkel PA, Weyand CM, Stone JH et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007; 146(9):621-630.

(2) Salvarani C, Macchioni P, Manzini C, Paolazzi G, Trotta A, Manganelli P et al. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial. Ann Intern Med 2007; 146(9):631-639.

(3) Hernandez-Rodriguez J, Segarra M, Vilardell C, Sanchez M, Garcia -Martinez A, Esteban MJ et al. Tissue production of pro-inflammatory cytokines (IL-1beta, TNFalpha and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell arteritis. Rheumatology (Oxford) 2004; 43(3):294-301.

(4) Jover JA, Hernandez-Garcia C, Morado IC, Vargas E, Banares A, Fernandez-Gutierrez B. Combined treatment of giant-cell arteritis with methotrexate and prednisone. a randomized, double-blind, placebo- controlled trial. Ann Intern Med 2001; 134(2):106-114.

(5) Weyand CM, Hicok KC, Hunder GG, Goronzy JJ. Tissue cytokine patterns in patients with polymyalgia rheumatica and giant cell arteritis. Ann Intern Med 1994; 121(7):484-491.

Conflict of Interest:

None declared

No benefit, possible harm
Posted on June 25, 2007
Gary S. Hoffman
Cleveland Clinic, Lerner College of Medicine
Conflict of Interest: None Declared

While we appreciate Dr. Arkfeld's thoughtful communication, the authors stand by original conclusion that the use of infliximab plus corticosteroids is of no benefit in the treatment of patients with newly diagnosed GCA and may be harmful. Clinical trials generally are too small for safety signals to be evaluated using statistical testing. This is especially true for a trial the size of the one in question and as a result a judgment regarding the benefit to risk must be based on clinical information. In our trial, 10 infusion reactions occurred in 6 patients in the infliximab group, whereas none occurred in the placebo group. While most reactions were of only mild to moderate intensity, one patient discontinued therapy because of dyspnea and flushing. While not of clinical consequence, antibodies to double-stranded DNA occurred in 16% of patients in the infliximab group and were not found in any patients in the control group. Although not noted in our study, it is known that infliximab and other anti-TNF agents have been infrequently, albeit significantly, associated with opportunistic infections, reactivation of tuberculosis, hepatitis B and either reactivation or occurrence of fungal infections. Rare cases of hepatosplenic T-cell lymphomas have been reported in adolescent and young adult patients with Crohn's disease treated with infliximab. Autoimmune events, including the appearance of anti-nuclear antibodies and antibodies to double-stranded DNA, lupus-like syndromes, immune-mediated hemocytopenias, optic neuritis, demyelinating disorders and heart failure may occur or be exacerbated by such therapy. Because of the unknown potential, but theoretical concerns over a role of anti-TNF therapy increasing the risk of malignancy, its' use is not advised in patients in whom there is a recent history of cancer, other than surgically cured skin cancers. While our study did not show any new or unusual adverse events in the elderly patient population studied, all the above mentioned adverse events have the potential to occur in this patient population. With these issues in mind, the absence of a signal to demonstrate efficacy for infliximab in new onset GCA and the skewed occurrence of infusion reactions among patients who received experimental therapy, we felt it prudent to stop infusions following the interim analysis. Thus, possible future harm and a low likelihood of benefit with continued use of infliximab supported our decision and conclusions. This study doesn¡¦t address the issue of anti-TNFƒÑ therapy in refractory GCA.

Gary S. Hoffman MD Maria C. Cid MD Mahboob U. Rahman MD, PhD

Conflict of Interest: None declared for Drs. Hoffman and Cid Dr. Rahman is employed by Centocor

Conflict of Interest:

Conflict of Interest: None declared for Drs. Hoffman and Cid Dr. Rahman is employed by Centocor

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Summary for Patients

Adding Infliximab to the Treatment Regimen for Giant Cell Arteritis

The summary below is from the full report titled “Infliximab for Maintenance of Glucocorticosteroid-Induced Remission of Giant Cell Arteritis. A Randomized Trial.” It is in the 1 May 2007 issue of Annals of Internal Medicine (volume 146, pages 621-630). The authors are 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, and M.U. Rahman, for the Infliximab-GCA Study Group.

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