TNFα blockade in human diseases: An overview of efficacy and safety

doi:10.1016/j.clim.2007.08.012

Clinical Immunology

Volume 126, Issue 1, January 2008, Pages 13-30

https://doi.org/10.1016/j.clim.2007.08.012 Get rights and content

Abstract

Tumor necrosis factor-alpha (TNFα) antagonists including antibodies and soluble receptors have shown remarkable efficacy in various immune-mediated inflammatory diseases (IMID). As experience with these agents has matured, there is an emerging need to integrate and critically assess the utility of these agents across disease states and clinical sub-specialties. Their remarkable efficacy in reducing chronic damage in Crohn’s disease and rheumatoid arthritis has led many investigators to propose a new, ‘top down’ paradigm for treating patients initially with aggressive regimens to quickly control disease. Intriguingly, in diseases such as rheumatoid arthritis and asthma, anti-TNFα agents appear to more profoundly benefit patients with more chronic stages of disease but have a relatively weaker or little effect in early disease. While the spectrum of therapeutic efficacy of TNFα antagonists widens to include diseases such as recalcitrant uveitis and vasculitis, these agents have failed or even exacerbated diseases such as heart failure and multiple sclerosis. Increasing use of these agents has also led to recognition of new toxicities as well as to understanding of their excellent long-term tolerability. Disconcertingly, new cases of active tuberculosis still occur in patients treated with all TNFα antagonists due to lack of compliance with recommendations to prevent reactivation of latent tuberculosis infection. These safety issues as well as guidelines to prevent treatment-associated complications are reviewed in detail in this article. New data on mechanisms of action and development of newer TNFα antagonists are discussed in a subsequent article in the Journal. It is hoped that these two review articles will stimulate a fresh assessment of the priorities for research and clinical innovation to improve and extend therapeutic use and safety of TNFα antagonism.

Introduction

Worldwide about a million patients have been treated with tumor necrosis factor-alpha (TNFα) antagonists for indications that include rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriatic arthritis (PsA), juvenile chronic arthritis (JCA), psoriasis (Ps), and ankylosing spondylitis (AS). Currently, there are three TNFα antagonists licensed for clinical use in the United States: two monoclonal antibodies [adalimumab (ADA) and infliximab (INF)] and a soluble receptor [etanercept (ETA)] (Table 1). Since the first license for clinical use in 1998, the three approved TNFα antagonists have shown clear benefits in a series of randomized, controlled trials enrolling over 8000 patients with these diseases. Here, we focus on the human therapeutic experience to examine the utility of these agents across disease states.

Section snippets

Rheumatoid arthritis (RA)

RA is a chronic, progressive, systemic inflammatory disease that targets primarily the synovial tissues, resulting in destruction of cartilage and ultimately bone. Delayed treatment often leads to substantial disability, functional declines, economic losses, work disability, and premature mortality [1]. Non-steroidal anti-inflammatory drugs (NSAIDs) were used to alleviate symptoms prior to realization in 1970s–80s that certain drugs [disease-modifying anti-rheumatoid drugs (DMARD)] can modify

Infections

Most infection data related to TNFα blockers come from postmarketing studies, which provide longer term risk estimates but are not well controlled for selection bias or bias by indication. Varying definitions of a “significant” or “serious” infection are a further complication. Of seven major reports on infections, increased frequency of “serious” infections with anti-TNF agents was reported in 3, while the other 4 showed no difference compared to other DMARDs [9], [79], [80], [81]. A recent

Acknowledgments

Drs. Braun, Reed, and Singh are recipients of grants from the National Institutes of Health. Dr. Lin is a recipient of a fellowship grant from the Southern California Chapter of the Scleroderma Foundation. Dr. Ziring is a recipient of a research fellowship award from the Crohns and Colitis Foundation of America.

The authors thank Drs. Daniel Furst and Harold Paulus (both UCLA) for helpful discussions, James Louie (Amgen Inc.) and John Rambharose (Centocor Inc.) for discussions on the risk of

References (125)

L. Klareskog et al.
Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial
Lancet
(2004)
P.J. Mease et al.
Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial
Lancet
(2000)
J. Braun et al.
Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial
Lancet
(2002)
H.M. van Dullemen et al.
Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2)
Gastroenterology
(1995)
G.R. Lichtenstein et al.
Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn’s disease
Gastroenterology
(2005)
W.J. Sandborn et al.
Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial
Gastroenterology
(2001)
W.J. Sandborn et al.
Infliximab in the treatment of Crohn’s disease: a user’s guide for clinicians
Am. J. Gastroenterol.
(2002)
K. Reich et al.
Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial
Lancet
(2005)
K.B. Gordon et al.
Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study
J. Am. Acad. Dermatol.
(2006)
F.N. Rouhani et al.
Effect of tumor necrosis factor antagonism on allergen-mediated asthmatic airway inflammation
Respir. Med.
(2005)

R.L. Chin et al.

Etanercept (Enbrel) therapy for chronic inflammatory demyelinating polyneuropathy

J. Neurol. Sci.

(2003)

A. Galor et al.

Differential effectiveness of Etanercept and Infliximab in the treatment of ocular inflammation

Ophthalmology

(2006)

J.P. Utz et al.

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

Chest

(2003)

D. Furst et al.

Tumor necrosis factor antagonists: different kinetics and/or mechanisms of action may explain differences in the risk for developing granulomatous infection

Semin. Arthritis Rheum.

(2006)

G. Ferrara et al.

Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study

Lancet

(2006)

T. Pincus et al.

Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years

Arthritis Rheum.

(1984)

D.E. Furst

Rational use of disease-modifying antirheumatic drugs

Drugs

(1990)

R.O. Williams et al.

Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis

Proc. Natl. Acad. Sci. U. S. A.

(1992)

C. Chu et al.

Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage–pannus junction in patients with rheumatoid arthritis

Arthritis Rheum.

(1991)

P. Charles et al.

Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis

J. Immunol.

(1999)

M. Weinblatt et al.

A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate

N. Engl. J. Med.

(1999)

P.E. Lipsky et al.

Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group

N. Engl. J. Med.

(2000)

M.E. Weinblatt et al.

Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial

Arthritis Rheum.

(2003)

E.C. Keystone et al.

Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial

Arthritis Rheum.

(2004)

R. Westhovens et al.

The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial

Arthritis Rheum.

(2006)

F.C. Breedveld et al.

The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment

Arthritis Rheum.

(2006)

L. Moreland et al.

Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial

Ann. Intern. Med.

(1999)

L.B. van de Putte et al.

Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed

Ann. Rheum. Dis.

(2004)

M.C. Genovese et al.

Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes

Arthritis Rheum.

(2002)

E.W. St Clair et al.

Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial

Arthritis Rheum.

(2004)

J.S. Smolen et al.

Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial

Arthritis Rheum.

(2006)

P.J. Mease et al.

Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression

Arthritis Rheum.

(2004)

P.J. Mease et al.

Psoriatic arthritis treatment: biological response modifiers

Ann Rheum Dis.

(2005)

E. Kruithof et al.

Repeated infusions of infliximab, a chimeric anti-TNFalpha monoclonal antibody, in patients with active spondyloarthropathy: one year follow up

Ann. Rheum. Dis.

(2002)

C. Antoni et al.

Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial

Ann. Rheum. Dis.

(2005)

P.J. Mease et al.

Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial

Arthritis Rheum.

(2005)

D.D. Gladman et al.

Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial

Arthritis Rheum.

(2007)

A. Anandarajah et al.

Treatment update on spondyloarthropathy

Curr. Opin. Rheumatol.

(2005)

J. Braun et al.

Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: an open, observational, extension study of a three-month, randomized, placebo-controlled trial

Arthritis Rheum.

(2003)

J. Braun et al.

Two year maintenance of efficacy and safety of infliximab in the treatment of ankylosing spondylitis

Ann. Rheum. Dis.

(2005)

J. Braun et al.

Persistent clinical response to the anti-TNF-alpha antibody infliximab in patients with ankylosing spondylitis over 3 years

Rheumatology (Oxford)

(2005)

H.D. van der et al.

Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT)

Arthritis Rheum.

(2005)

J.D. Gorman et al.

Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha

N. Engl. J. Med.

(2002)

J. Brandt et al.

Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis

Arthritis Rheum.

(2003)

J.C. Davis et al.

Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial

Arthritis Rheum.

(2003)

A. Calin et al.

Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis

Ann. Rheum. Dis.

(2004)

D. van der Heijde et al.

Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial

Arthritis Rheum.

(2006)

X. Baraliakos et al.

Clinical response to discontinuation of anti-TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with infliximab

Arthritis Res. Ther.

(2005)

X. Baraliakos et al.

Safety and efficacy of readministration of infliximab after longterm continuous therapy and withdrawal in patients with ankylosing spondylitis

J. Rheumatol.

(2007)

J. Braun et al.

Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept

Arthritis Rheum.

(2005)

Cited by (236)

Tackling TNF-α in autoinflammatory disorders and autoimmune diseases: From conventional to cutting edge in biologics and RNA- based nanomedicines
2023, Advanced Drug Delivery Reviews
Autoinflammatory disorders and autoimmune diseases result from abnormal deviations of innate and adaptive immunity that heterogeneously affect organs and clinical phenotypes. Despite having etiologic and phenotypic differences, these two conditions share the onset of an aberrant inflammatory process. Targeting the main drivers controlling inflammation is useful to treat both autoimmune and autoinflammatory syndromes. TNF-α is a major player in the inflammatory immune response, and anti-TNF-α antibodies have been a revolutionary treatment in many autoimmune disorders. However, production difficulties and high development costs hinder their implementation, and accessibility to their use is still limited. Innovative strategies aimed at overcoming the limitations associated with anti-TNF-α antibodies are being explored, including RNA-based therapies.
Here we summarize the central role of TNF-α in immune disorders and how anti-TNF-based immunotherapies changed the therapeutic landscape, albeit with important limitations related to side effects, tolerance, and resistance to therapies. We then outline how nanotechnology has provided the final momentum for the use of nucleic acids in the treatment of autoimmune and autoinflammatory diseases, with a focus on inflammatory bowel diseases (IBDs). The example of IBDs allows the evaluation and discussion of the nucleic acids-based treatments that have been developed, to identify the role that innovative approaches possess in view of the treatment of autoinflammatory disorders and autoimmune diseases.
Nanoparticles as a Novel Tool to Inhibit Inflammatory Cytokines in Human Lymphocytes and Macrophages of Coronary Artery Disease
2022, Journal of Pharmaceutical Sciences
TNFα and NF-kB contribute in activation of pro-inflammatory signaling pathways and complications of coronary artery diseases (CAD). Current study highlights novel properties of Au (15 ± 2 nm), ZnO (77 ± 45 nm) and MgO (11 ± 4 nm) nanoparticles (NPs) as possible anti-inflammatory agents with greater efficacy and lower toxicity. Decrease in TNFα and NF-kB levels in Single Vessel Disease (SVD), Double Vessel Disease (DVD) and Triple-Vessel coronary artery disease (TVD) macrophage and lymphocyte cultures at varying concentrations of NPs has been studied to find an effective therapeutic concentration (ETC). Au and MgO NPs exhibits 5 µg/ml ETC compared to 1 µg/ml ZnO in all three CAD categories with negligible toxicity. ZnO remains most statistically significant (p < 0.001) in SVD and TVD cultures whereas MgO shows efficacy in DVD and TVD cultures with more than 50% reduction in TNFα and NF-kB levels at their respective ETCs. Au NPs exhibit prominent effect in DVD cultures. The mRNA expression results support the down-regulation of TNFα and NF-kB after NPs exposure in respective cultures. Findings of this prospective observational cohort study suggest use of NPs as an alternate anti-inflammatory agent in coronary artery and other diseases.
Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation
2022, European Journal of Pharmacology
Neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, are characterized by the progressive loss of neuronal cells, resulting in different clinical symptoms according to the affected brain region. Although there are drugs available for the treatment of these diseases, they present relatively low efficacy and are not capable of modifying the course of the disease or stopping its progression. In the field of drug development, drug repurposing could be an interesting strategy to search new therapeutic options against neurodegenerative diseases, since it involves lower costs and time for development. In this review, we discuss the search of new treatments for Alzheimer's and Parkinson's disease through drug repurposing. A focus was given to drugs that modulate neuroinflammation, since it represents a common point among neurodegenerative diseases and has been explored as a target for drug action.
Viewing Legionella pneumophila Pathogenesis through an Immunological Lens
2019, Journal of Molecular Biology
Legionella pneumophila is the causative agent of the severe pneumonia Legionnaires' disease. L. pneumophila is ubiquitously found in freshwater environments, where it replicates within free-living protozoa. Aerosolization of contaminated water supplies allows the bacteria to be inhaled into the human lung, where L. pneumophila can be phagocytosed by alveolar macrophages and replicate intracellularly. The Dot/Icm type IV secretion system (T4SS) is one of the key virulence factors required for intracellular bacterial replication and subsequent disease. The Dot/Icm apparatus translocates more than 300 effector proteins into the host cell cytosol. These effectors interfere with a variety of cellular processes, thus enabling the bacterium to evade phagosome–lysosome fusion and establish an endoplasmic reticulum-derived Legionella-containing vacuole, which facilitates bacterial replication. In turn, the immune system has evolved numerous strategies to recognize intracellular bacteria such as L. pneumophila, leading to potent inflammatory responses that aid in eliminating infection. This review aims to provide an overview of L. pneumophila pathogenesis in the context of the host immune response.
Multiple Sclerosis Risk Among Anti-tumor Necrosis Factor Alpha Users: A Methodological Review of Observational Studies Based on Real-world Data
2024, Current Drug Safety
Potential Utilization of Phenolic Acid Compounds as Anti-Inflammatory Agents through TNF-α Convertase Inhibition Mechanisms: A Network Pharmacology, Docking, and Molecular Dynamics Approach
2023, ACS Omega

View all citing articles on Scopus

¹: These authors contributed equally to the work.

View full text

Short Analytical ReviewTNFα blockade in human diseases: An overview of efficacy and safety

Abstract

Introduction

Section snippets

Rheumatoid arthritis (RA)

Infections

Acknowledgments

Lancet

Lancet

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Am. J. Gastroenterol.

Lancet

J. Am. Acad. Dermatol.

Respir. Med.

J. Neurol. Sci.

Ophthalmology

Chest

Semin. Arthritis Rheum.

Lancet

Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years

Arthritis Rheum.

Rational use of disease-modifying antirheumatic drugs

Drugs

Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis

Proc. Natl. Acad. Sci. U. S. A.

Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage–pannus junction in patients with rheumatoid arthritis

Arthritis Rheum.

Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis

J. Immunol.

A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate

N. Engl. J. Med.

Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group

N. Engl. J. Med.

Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial

Arthritis Rheum.

Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial

Arthritis Rheum.

The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial

Arthritis Rheum.

The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment

Arthritis Rheum.

Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial

Ann. Intern. Med.

Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed

Ann. Rheum. Dis.

Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes

Arthritis Rheum.

Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial

Arthritis Rheum.

Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial

Arthritis Rheum.

Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression

Arthritis Rheum.

Psoriatic arthritis treatment: biological response modifiers

Ann Rheum Dis.

Repeated infusions of infliximab, a chimeric anti-TNFalpha monoclonal antibody, in patients with active spondyloarthropathy: one year follow up

Ann. Rheum. Dis.

Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial

Ann. Rheum. Dis.

Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial

Arthritis Rheum.

Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial

Arthritis Rheum.

Treatment update on spondyloarthropathy

Curr. Opin. Rheumatol.

Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: an open, observational, extension study of a three-month, randomized, placebo-controlled trial

Arthritis Rheum.

Two year maintenance of efficacy and safety of infliximab in the treatment of ankylosing spondylitis

Ann. Rheum. Dis.

Persistent clinical response to the anti-TNF-alpha antibody infliximab in patients with ankylosing spondylitis over 3 years

Rheumatology (Oxford)

Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT)

Arthritis Rheum.

Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha

N. Engl. J. Med.

Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis

Arthritis Rheum.

Short Analytical Review
TNFα blockade in human diseases: An overview of efficacy and safety