Review
Pulmonary Adverse Events of Anti-Tumor Necrosis Factor-α Antibody Therapy

https://doi.org/10.1016/j.amjmed.2006.01.015Get rights and content

Abstract

It is well established that anti-tumor necrosis factor-α (TNFα) antibody is an efficacious disease-modifying drug for rheumatoid arthritis and Crohn’s disease. Unfortunately, its long-term use can be associated with ominous pulmonary adverse events, most notably mycobacterial and fungal lung infections. To this end, reactivation of latent tuberculosis infection represents a serious concern of anti-TNFα antibody therapy. Given the anticipated increase in the approved indications for these drugs, community-based physicians should be made aware of these events for implementation of better patient selection for anti-TNFα antibody therapy and initiation of appropriate measures once these adverse events are observed. This review will address this issue by outlining: 1) the role of TNFα in host inflammatory response to injury, particularly during mycobacterial and fungal infections; 2) the salutary effects of anti-TNFα antibody therapy in human diseases; and 3) the ominous pulmonary adverse events associated with these drugs.

Section snippets

Background

Tumor necrosis factor-α, a 17-kDa cytokine, plays a seminal role in host defense. It is predominantly elaborated from monocytes activated in response to noxious agents such as viruses and bacteria, as well as from activated T- and B-lymphocytes, natural killer cells and certain tumors.4, 5 It exists in soluble and transmembrane forms and exerts its effects through two specific receptors, TNF receptor 1 and receptor 2.4, 6 Soluble TNFα binds primarily to TNF receptor 1, whereas the

TNFα-mediated modulation of tuberculosis and fungal infections

Tumor necrosis factor-α is elaborated early in the course of an infection.5 It plays a pivotal role in host defense by increasing neutrophils’ adherence to endothelial cells, phagocytic activity, degranulation, and release of reactive oxygen species.10, 11 Additionally, TNFα modulates macrophage phagocytic activity and increases antibody-dependent cell cytotoxicity.12, 13

Tumor necrosis factor-α is paramount to the host’s immune response against M. tuberculosis.8 Production of TNFα is required

Anti-TNFα antibody drugs

Currently, there are three Food and Drug Administration-approved anti-TNFα antibodies in clinical use: etanercept, infliximab and adalimumab (Table 1). Etanercept is a dimeric human fusion protein that combines two extracellular binding domains of the p75 form of TNFα receptor with the Fc portion of a human immunoglobulin-G1 antibody. Although it binds significantly to the soluble form of TNFα, it forms less stable complexes with transmembrane forms.28 Infliximab is a chimeric monoclonal

Anti-TNFα antibody therapy in pulmonary disorders

Recently, anti-TNFα antibodies have been tested in treatment of inflammatory lung diseases, such as sarcoidosis. TNFα is important in the initiation and perpetuation of inflammation in sarcoidosis, contributing to the development of granulomas34 and progression of fibrosis.35, 36 Although two initial reports showed clinical37, 38 and physiological37 improvement after infliximab therapy, results of the prospective trial were disappointing.39 In a single-center prospective study, etanercept alone

Mycobacterium Tuberculosis

Because TNFα plays a central role in mycobacterial infections, it is not surprising that anti-TNFα antibody therapy is associated with progression of recently acquired tuberculosis or reactivation of latent tuberculosis infection. In 2001, the Food and Drug Administration reported 70 cases of tuberculosis in 147,000 patients treated with infliximab worldwide. This number increased to 117 within 2 months of the report47 (Table 2). Most patients were thought to have reactivation of latent

Screening for Latent Tuberculosis Infection

All candidates for anti-TNFα antibody therapy should undergo screening for latent tuberculosis infection before institution of these drugs (Figure). Screening includes a careful analysis regarding the history of exposure to tuberculosis and a tuberculin skin test, along with a baseline chest radiograph. QuantiFERON test (Cellestis Limited, Carnegie, Victoria, Australia) is an alternative to tuberculin test in screening for latent tuberculosis infection.73 It is a blood test that measures

Conclusions

Long-term treatment with anti-TNFα antibodies is associated with reactivation of latent tuberculosis infection. In view of anticipated increase in indications for anti-TNF-α antibody therapy, community-based physicians should be aware of this ominous adverse event so patient selection could be improved and close monitoring of treated individuals for active tuberculosis implemented.

Acknowledgement

The authors would like to acknowledge and thank Charles Fuller for help with editing the manuscript.

References (79)

  • J.P. Utz et al.

    Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis

    Chest

    (2003)
  • R. Vassallo et al.

    Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis factor-alpha inhibition

    Chest

    (2002)
  • Z. Zhang et al.

    Tuberculosis and treatment with infliximab

    N Engl J Med

    (2002)
  • M. Nakelchik et al.

    Reactivation of histoplasmosis after treatment with infliximab

    Am J Med

    (2002)
  • C.A. Hage et al.

    Pulmonary cryptococcosis after initiation of anti-tumor necrosis factor-alpha therapy

    Chest

    (2003)
  • J. Braun et al.

    Treatment of active ankylosing spondylitis with infliximaba randomised controlled multicentre trial

    Lancet

    (2002)
  • L. Peno-Green et al.

    Lung injury linked to etanercept therapy

    Chest

    (2002)
  • T.E. Wagner et al.

    Exacerbation of Mycobacterium tuberculosis enteritis masquerading as Crohn’s disease after treatment with a tumor necrosis factor-alpha inhibitor

    Am J Med

    (2002)
  • P.E. Lipsky et al.

    Infliximab and methotrexate in the treatment of rheumatoid arthritis

    N Engl J Med

    (2000)
  • J. Keane et al.

    Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent

    N Engl J Med

    (2001)
  • B. Beutler et al.

    Cachectin and tumour necrosis factor as two sides of the same biological coin

    Nature

    (1986)
  • E.H. Choy et al.

    Cytokine pathways and joint inflammation in rheumatoid arthritis

    N Engl J Med

    (2001)
  • A.G. Bean et al.

    Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin

    J Immunol

    (1999)
  • Y.H. Atkinson et al.

    Recombinant human tumor necrosis factor-alpha. Regulation of N-formylmethionylleucylphenylalanine receptor affinity and function on human neutrophils

    J Clin Invest

    (1988)
  • S.J. Klebanoff et al.

    Stimulation of neutrophils by tumor necrosis factor

    J Immunol

    (1986)
  • M.R. Shalaby et al.

    Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors

    J Immunol

    (1985)
  • B. Perussia et al.

    Immune interferon enhances functional properties of human granulocytesrole of Fc receptors and effect of lymphotoxin, tumor necrosis factor, and granulocyte-macrophage colony-stimulating factor

    J Immunol

    (1987)
  • M.K. Balcewicz-Sablinska et al.

    Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-alpha

    J Immunol

    (1998)
  • J. Keane et al.

    Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages

    J Immunol

    (2000)
  • L.G. Bekker et al.

    Immunopathologic effects of tumor necrosis factor alpha in murine mycobacterial infection are dose dependent

    Infect Immun

    (2000)
  • A. Schaffner et al.

    Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes

    J Clin Invest

    (1982)
  • R.D. Diamond et al.

    Damage to pseudohyphal forms of Candida albicans by neutrophils in the absence of serum in vitro

    J Clin Invest

    (1978)
  • B. Mehrad et al.

    Role of TNF-alpha in pulmonary host defense in murine invasive aspergillosis

    J Immunol

    (1999)
  • H. Nagai et al.

    Interferon-gamma and tumor necrosis factor-alpha protect mice from invasive aspergillosis

    J Infect Dis

    (1995)
  • E. Roilides et al.

    Tumor necrosis factor alpha enhances antifungal activities of polymorphonuclear and mononuclear phagocytes against Aspergillus fumigatus

    Infect Immun

    (1998)
  • A. Louie et al.

    Tumor necrosis factor alpha has a protective role in a murine model of systemic candidiasis

    Infect Immun

    (1994)
  • S. Steinshamn et al.

    TNF receptors in murine Candida albicans infectionevidence for an important role of TNF receptor p55 in antifungal defense

    J Immunol

    (1996)
  • K. Aguirre et al.

    Role of tumor necrosis factor and gamma interferon in acquired resistance to Cryptococcus neoformans in the central nervous system of mice

    Infect Immun

    (1995)
  • B. Scallon et al.

    Binding and functional comparisons of two types of tumor necrosis factor antagonists

    J Pharmacol Exp Ther

    (2002)
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    This work was supported in part by the American Lung Association, and the American Lung Association of Metropolitan Chicago (G.M.M.), National Institute of Diabetes & Digestive & Kidney Diseases (E.A.M.), National Institute on Aging and Veterans Administration (I.R.).

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