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Rapid Responses to:
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Electronic letters published:
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif){kind=icon}
No benefit, possible harm
The window of opportunity for infliximab therapy might have been closed
Dear Sir
A Question of Harm
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Gary S. Hoffman, M.D., M.S. Cleveland Clinic, Lerner College of Medicine, Maria C. Cid M.D., Mahboob Rahman M.D., Ph.D.
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hoffmag{at}ccf.org Gary S. Hoffman, et al.
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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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Allan C Gelber, MD, MPH, PhD Johns Hopkins University School of Medicine, Peter K. Wung
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agelber{at}jhmi.edu Allan C Gelber, et al.
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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 |
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Omer Karadag, MD Hacettepe University, Faculty of Medicine Departmrnt of Internal Medicine Rheumatology Unit, Ankara,, Omer Karadag, Bunyamin Kisacik, Sedat Kiraz
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omerk{at}hacettepe.edu.tr Omer Karadag, et al.
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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 |
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Daniel G. Arkfeld, MD USC Keck School of Medicine
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arkfeld{at}usc.edu Daniel G. Arkfeld
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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 |
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