ReviewPulmonary Adverse Events of Anti-Tumor Necrosis Factor-α Antibody Therapy
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)
- et al.
Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexatea randomised phase III trial
Lancet
(1999) - et al.
Tumor necrosis factorbiology and therapeutic inhibitors
Gastroenterology
(2000) - et al.
The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor
Cell
(1995) - et al.
Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection
Cell
(1993) - et al.
The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection
Cell
(1989) - et al.
Anti-tumour necrosis factor agents and tuberculosis riskmechanisms of action and clinical management
Lancet Infect Dis
(2003) - et al.
Role of TNF-alpha in the induction of fungicidal activity of mouse peritoneal exudate cells against Cryptococcus neoformans by IL-12 and IL-18
Cell Immunol
(1999) - et al.
Construction and initial characterization of a mouse-human chimeric anti-TNF antibody
Mol Immunol
(1993) - et al.
Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions
Cytokine
(1995) - et al.
Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway
Gastroenterology
(2001)
Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis
Chest
Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis factor-alpha inhibition
Chest
Tuberculosis and treatment with infliximab
N Engl J Med
Reactivation of histoplasmosis after treatment with infliximab
Am J Med
Pulmonary cryptococcosis after initiation of anti-tumor necrosis factor-alpha therapy
Chest
Treatment of active ankylosing spondylitis with infliximaba randomised controlled multicentre trial
Lancet
Lung injury linked to etanercept therapy
Chest
Exacerbation of Mycobacterium tuberculosis enteritis masquerading as Crohn’s disease after treatment with a tumor necrosis factor-alpha inhibitor
Am J Med
Infliximab and methotrexate in the treatment of rheumatoid arthritis
N Engl J Med
Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent
N Engl J Med
Cachectin and tumour necrosis factor as two sides of the same biological coin
Nature
Cytokine pathways and joint inflammation in rheumatoid arthritis
N Engl J Med
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
Recombinant human tumor necrosis factor-alpha. Regulation of N-formylmethionylleucylphenylalanine receptor affinity and function on human neutrophils
J Clin Invest
Stimulation of neutrophils by tumor necrosis factor
J Immunol
Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors
J Immunol
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
Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-alpha
J Immunol
Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages
J Immunol
Immunopathologic effects of tumor necrosis factor alpha in murine mycobacterial infection are dose dependent
Infect Immun
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
Damage to pseudohyphal forms of Candida albicans by neutrophils in the absence of serum in vitro
J Clin Invest
Role of TNF-alpha in pulmonary host defense in murine invasive aspergillosis
J Immunol
Interferon-gamma and tumor necrosis factor-alpha protect mice from invasive aspergillosis
J Infect Dis
Tumor necrosis factor alpha enhances antifungal activities of polymorphonuclear and mononuclear phagocytes against Aspergillus fumigatus
Infect Immun
Tumor necrosis factor alpha has a protective role in a murine model of systemic candidiasis
Infect Immun
TNF receptors in murine Candida albicans infectionevidence for an important role of TNF receptor p55 in antifungal defense
J Immunol
Role of tumor necrosis factor and gamma interferon in acquired resistance to Cryptococcus neoformans in the central nervous system of mice
Infect Immun
Binding and functional comparisons of two types of tumor necrosis factor antagonists
J Pharmacol Exp Ther
Cited by (51)
Autoantibodies
2021, Encyclopedia of Respiratory Medicine, Second EditionDrug-Induced Oral Complications
2017, Atlas of the Oral and Maxillofacial Surgery Clinics of North AmericaConnective Tissue Disease-related Thoracic Disease
2015, Clinics in Chest MedicineCitation Excerpt :Predisposition to infection in patients with CTD is both inherent, in the form of disease-related immune dysregulation, and acquired, caused by immunosuppressive treatment regimens. In particular, newer biologic agents, such as antitumor necrosis factor antibodies (etanercept, infliximab, and adalimumab), predispose to tuberculosis, nontuberculous mycobacteria, or fungal infection, including pneumocystis, and these should be strongly suspected when new parenchymal abnormalities are identified in these patients (Fig. 13).93–95 Screening for occult infection and careful follow-up with chest radiographs or CT are needed for patients with CTD throughout their treatment periods.
Connective Tissue Diseases
2015, Murray and Nadel's Textbook of Respiratory Medicine: Volume 1,2, Sixth EditionInvasive diagnostic strategies in immunosuppressed patients with acute respiratory distress syndrome
2014, Clinics in Chest Medicine
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.).