The Journal of Rheumatology Volume 74, no. Differences between anti-tumor necrosis factor-alpha monoclonal antibodies and soluble TNF receptors in host defense impairment. Charles A Dinarello J Rheumatol 2005;74;40-47 http://www.jrheum.org/content/74/40 1. Sign up for TOCs and other alerts http://www.jrheum.org/alerts 2. Information on Subscriptions http://jrheum.com/faq 3. Information on permissions/orders of reprints http://jrheum.com/reprints_permissions The Journal of Rheumatology is a monthly international serial edited by Earl D. Silverman featuring research articles on clinical subjects from scientists working in rheumatology and related fields. Downloaded from www.jrheum.org on October 2, 2021 - Published by The Journal of Rheumatology Differences Between Anti-Tumor Necrosis Factor-α Monoclonal Antibodies and Soluble TNF Receptors in Host Defense Impairment CHARLES A. DINARELLO ABSTRACT. This review examines the differences in the incidence, spectrum, and mechanisms of activation of oppor- tunistic infections, such as Mycobacterium tuberculosis, in patients with rheumatic diseases treated with the soluble TNF p75 receptor etanercept compared to the 2 anti-TNF-α monoclonal antibodies, infliximab and adalimumab. (J Rheumatol 2005;32 Suppl 74:40-47) Key Indexing Terms: TUMOR NECROSIS FACTOR INFECTION MYCOBACTERIUM TUBERCULOSIS ETANERCEPT INFLIXIMAB RHEUMATIC DISEASES ADALIMUMAB INTRODUCTION receptors also can bind and neutralize TNF-β (lympho- Impairment in host defense against infection and can- toxin), which is produced by macrophages as well as T cer is a broad topic that includes various clinical and cells. Given the number of cytokines that are implicated in biological conditions that are either innate or acquired. host defense functions, the remarkable lesson from the use Both types of impairment, however, can result in simi- of TNF blockers in hundreds of thousands of patients lar clinical outcomes such as infection due to intracel- reinforces the importance of TNF in host defense. lular microorganisms and increased lymphoma, partic- However, of equal importance is the clinical finding that ularly Epstein-Barr virus. differences exist in the incidence and spectrum of infec- Similarities in the spectrum of infectious diseases in per- tions in patients treated with the soluble TNF p75 receptor sons born with defects in CD4+ T cell functions and those etanercept compared to either of the 2 anti-TNF-α mono- who lose CD4+ T cell numbers associated with infection clonal antibodies, infliximab or adalimumab. with HIV-1 are well documented. Although longterm In a recent review of the incidence of granulomatous immunosuppressive drug therapy in patients with organ infections reported to the US Food and Drug transplants is a source of epidemiologic data, in this Administration from 1998 to September, 2002, there review, there will be no discussion of impaired host defense were 239 per 100,000 infliximab-treated patients com- associated with immunosuppressive agents. The agents pared to 74 per 100,000 for etanercept-treated patients1. used to suppress the immune response in these patients are Mycobacterium tuberculosis infections occurred at rates 5 nonspecific, in that more than a single cytokine is affected. times greater for infliximab than for etanercept1.Of In patients receiving tumor necrosis factor (TNF) blocking these, the onset of M. tuberculosis reactivation occurred agents for chronic diseases such as rheumatoid arthritis in 72% of patients within 90 days of initiating infliximab (RA), ankylosing spondylitis (AS), psoriatic arthritis, or compared to 28% for etanercept1. In a correction to the psoriasis, the specificity of anti-TNF-α monoclonal anti- published analysis2, the number of patients in the USA body has important implications because only TNF-α or treated with infliximab was reduced from 233,000 to cytokines related to TNF-α activity are affected. 197,000, and the rate of M. tuberculosis infection associ- Although the soluble TNF receptors (etanercept, oner- ated with infliximab was 54 per 100,000 patients com- cept, pegsunercept, lenercept) share with anti-TNF-α mon- pared to 28 per 100,000 for etanercept. However, upon oclonal antibodies the ability to neutralize both extracellu- reanalysis of the reported cases, the rate of reactivation lar as well as membrane forms of TNF-α, these soluble of M. tuberculosis infections within the first 90 days of treatment was 95 per 100,000 patient-years for infliximab compared to 11 per 100,000 patient-years for etanercept2. From the Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA. Therefore, these data continue to reveal a difference Supported by US National Institutes of Health grants AI-15614 (CAD) between M. tuberculosis infections associated with anti- and HL-68743 (CAD) and the Colorado Cancer Center. TNF-α monoclonal antibody and those associated with soluble TNF receptors. Dr. Dinarello serves on the speakers’ bureau for Amgen. Although there are no comparable studies of reactiva- C.A. Dinarello, MD. tion of M. tuberculosis infections in patients receiving adalimumab using comparable numbers of patient-years Address reprint requests to Dr. C.A. Dinarello, University of Colorado of treatment, there were 13 cases of tuberculosis in 2400 Health Sciences Center, 4200 East Ninth Ave., B168, Denver, CO 80262. treated patients in controlled studies of this antibody, Personal non-commercial use only. The Journal of Rheumatology Copyright © 2005. All rights reserved. 40 The Journal of Rheumatology 2005, Volume 32 Supplement 74 Downloaded from www.jrheum.org on October 2, 2021 - Published by The Journal of Rheumatology which resulted in a boxed warning added to the adali- cell is the phagocyte, most notably the neutrophil. These mumab label3. cells have the machinery to engulf the organism and kill Opportunistic infections associated with TNF blockers, it in the phagolysosome. Gram-positive bacteria such as particularly with anti-TNF-α monoclonal antibodies, are streptococci and staphylococci are examples of neu- often similar to infections observed in immunosuppressed trophil- and cell adhesion molecule-dependent host patients, particularly in HIV-1-infected patients. For exam- defense. In the case of macrophage intracellular microor- ple, about 50% of M. tuberculosis infections are extrapul- ganisms, the killing mechanisms of the infected monary in HIV-1 patients, and similar percentages have macrophage involves interferon-γ (IFN-γ) and nitric been reported for patients treated with TNF blockers3. oxide production. However, obligate intracellular organ- However, in the case of etanercept, the safety of this TNF isms such as M. tuberculosis, Listeria, Histoplasma, and blocker was evaluated in HIV-1 patients with known M. Salmonella can survive and replicate inside the tuberculosis infection being treated with anti-tuberculous macrophage by usurping killing. Most notably, cytokines therapy. Eight doses of etanercept were administered dur- such as TNF-α and IFN-γ increase the killing mecha- ing initiation of anti-tuberculous therapy, and improved nisms, and a balance is achieved whereby a microorgan- clinical responses were reported for patients receiving ism such as M. tuberculosis can survive inside a etanercept compared to those without etanercept4. macrophage. Further spread and overt disease is kept to Indeed, CD4+ T cell counts increased associated with a minimum by a competent immune system and the for- etanercept therapy. Other studies in patients with AS mation of granulomata. Reducing TNF-α activity being treated with infliximab or etanercept5,6 support the impairs the host’s mechanisms of killing intracellular concept that the mechanism of action of the monoclonal organisms by reducing the synergism of TNF-α plus antibody and the soluble TNF receptor are different and IFN-γ, which regulate nitric oxide production. In animal account for the differences in the clinical spectrum of dis- models of mycobacterial infections, anti-TNF-α prevents eases associated with impaired host defense. formation of granulomata. CYTOKINES DID NOT EVOLVE AS MEDIATORS LIMITED ACTION OF CYTOKINES DURING OF DISEASE INFECTION Prototypes of cytokines such as interleukin 1 (IL-1) or Cytokines act at several levels in combating infection. TNF-α and their respective signaling mechanisms can be First, cytokines such as TNF-α induce expression of found in insects; indeed, nuclear factor-κB and the signal- endothelial and cellular adhesion molecules to facilitate transducing domains of the mammalian IL-1 receptor are adherence of phagocytes to cell surfaces. This is an found in Drosophila7. With the use of anticytokine based important first step for emigration of phagocytes from therapies, there is little question that these and other the circulation into the site of infection. Next, increasing cytokines play an important role in disease. However, the production of local chemokines results in the move- proinflammatory cytokines did not evolve to harm, but ment of the phagocyte into infected tissue. By stimulating rather to benefit the host. Other cytokines such as IL-18 nitric oxide production by the phagocyte, cytokines pro- and IL-15, which also play a role in autoimmune diseases, vide the chemical agents for killing the microbe. similarly evolved as beneficial to the host, particularly in Cytokines such as IL-1 and TNF-α are expressed during terms of host defense to infection. Indeed, the use of this time