Tumor Necrosis Factor and Anti-Tumor Necrosis

Factor Therapies
EDWARD C. KEYSTONE and CARL F. WARE

ABSTRACT. Tumor necrosis factor (TNF) plays a crucial role in the pathogenesis of immune-mediated inflammatory diseases (IMID). As a result, the inhibition of TNF is an important therapeutic avenue in the
treatment of these pathophysiologically diverse disease states. This section discusses TNF, its receptors, and its role in immunoregulation and inflammation, as well as the currently available
anti-TNF-based therapies. (J Rheumatol 2010;37 Suppl 85:2739; doi:10.3899/jrheum.091463)
Key Indexing Terms:
TUMOR NECROSIS FACTOR
BIOLOGIC THERAPIES
IMMUNE-MEDIATED INFLAMMATORY DISEASES

Tumor necrosis factor (TNF) plays a pivotal role in various

immune and inflammatory processes, including cellular
activation, survival and proliferation, as well as cell death
by necrosis and apoptosis. The cellular source of TNF
depends on the nature of the stimulus. TNF is produced primarily by cells of hematopoietic origin, including myeloid
lineage such as monocytes and macrophages, when stimulated by innate sensors, such as the Toll-like receptor (TLR)
system. T and B lymphocytes can also produce TNF in
response to antigenic stimulation.
Dysregulation of inflammatory pathways driven by
cytokines such as TNF is believed to be a common underlying mechanism leading to immune-mediated inflammatory diseases (IMID). This is supported by the finding that
TNF is upregulated in the majority of IMID (Table 1)1,
despite the very different clinical manifestations of these
disorders. It is also important to note that similar cytokine
dysregulation can cause an array of pathologies in different
organ systems, depending on when, where, why, and how
the dysregulation occurs. The development of TNF
inhibitors has clinically demonstrated the dominant role
played by TNF in IMID such as rheumatoid arthritis (RA),

psoriasis (Ps), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and Crohns disease (CD), and significantly
improved outcomes of patients affected by these disorders.
However, anti-TNF therapies are not without disadvantages. For example, there are considerable differences in the
response rates among different patients within a given
IMID. While some patients respond quickly, others may
take considerably longer, and some may not respond to the
initial anti-TNF agent at all. Further, some patients may lose
their response over time. In addition, there are considerable
differences in the efficacy of anti-TNF therapies in different
IMID. For example, in contrast to monoclonal antibodies
(adalimumab and infliximab), the decoy TNF receptor
(etanercept) has not proven effective in treating inflammatory bowel disease (IBD) or uveitis.
This article provides an overview of the biology of TNF
and related family members in the context of the potential
mechanisms of action of TNF inhibitors in a variety of
IMID. Differences between currently available agents are
addressed with regard to their therapeutic efficacy.

From the Rebecca MacDonald Centre for Arthritis and Autoimmune

Disease and Division of Advanced Therapeutics in Arthritis, University of
Toronto, Toronto, Ontario, Canada; and Division of Molecular
Immunology, La Jolla Institute for Allergy and Immunology, University of
California, San Diego, California, USA.
Dr. Keystone has acted as advertising board member and speaker for, and
research funding recipient from, Abbott, Schering Plough, UCB,
Hoffman-LaRoche, Amgen, Centocor, Celgene, Lux Biosciences, Allergan,
Wyeth, and Bristol-Myers Squibb; advertising board for Genentech and
UCB; and research funding recipient from Novartis. Dr. Ware has acted
as a speaker for Abbott and consultant for Amgen.
E.C. Keystone, MD, FRCPC, Professor of Medicine, University of
Toronto; Director, The Rebecca MacDonald Centre for Arthritis and
Autoimmune Disease; Director, Division of Advanced Therapeutics in
Arthritis; C.F. Ware, PhD, Professor and Head, Division of Molecular
Immunology, La Jolla Institute for Allergy and Immunology; Adjunct
Professor of Biology, University of California.
Address correspondence to Dr. Ware; E-mail: cware@liai.org

TNF Superfamily
TNF is a member of a family of structurally related
cytokines that signal through specific cell-surface receptors
that also form a structurally related family of proteins
(Figure 1)2. The TNF superfamily consists of more than 35
specific ligand-receptor pairs that play pivotal roles in many
biological processes in mammalian cells, such as host
defense, inflammation, apoptosis, autoimmunity, and development and organogenesis of the immune, ectodermal and
nervous systems3. The genes encoding lymphotoxin
(LT), LT, and TNF reside in tightly linked loci within the
major histocompatibility complex (MHC) on chromosome
(Chr) 6 in humans (Chr 17 in the mouse) (Figure 1). Their
receptors are linked on Chr 12 (mouse Chr 6). Three other

ROLE OF TNF AND ITS RECEPTORS IN

INFLAMMATION AND IMMUNOREGULATION

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Keystone and Ware: Anti-TNF in IMID

27

Table 1. Overexpression and underexpression of specific cytokines in

immune-mediated inflammatory diseases (IMID). From Williams and
Meyers, Am J Manag Care 2002;8 Suppl 21:S664S681; with permission1.
Condition

Crohns disease

Cytokines
Overexpressed

TNF, IL-1, IL-2, IL-6,

IL-8, IL-12, IFN-
Psoriatic arthritis
TNF, IL-1, IL-6, IL-8, IFN-
Psoriasis
TNF
Ankylosing spondylitis
TNF, IL-10
Rheumatoid arthritis
TNF, IL-1, IL-6
Ulcerative colitis
TNF, IL-1, IL-5, IL-6, IL-8

Cytokines
Underexpressed
IL-3

IFN-, IL-2

TNF: tumor necrosis factor; IL: interleukin; IFN: interferon.

IL-3

MHC paralogous genomic regions contain the related family members (Chr 19 LIGHT, CD27L, 41BBL; Chr 1 FasL,
GITRL, Ox40L; Chr 9 CD30, TL1A). The receptors for
these ligands (except FasL) are linked on Chr 1p364.
Basic Structure of the TNF Molecule
The TNF-related ligands are type II (intracellular N-termi-

nus) transmembrane proteins containing a TNF homology

domain at the extracellular C terminus (Figure 2)5,6. TNF
is initially synthesized as a monomer that folds into a
-sheet sandwich and assembles into a functional trimer.
Thus, each TNF ligand has 3 receptor binding sites, formed
as a groove between adjacent subunits. The trimeric structure promotes efficient clustering of TNFs specific receptors, which in turn activate signaling pathways and cellular
responses. The trimeric protein is made as a 27-kDa
uncleaved, type 2 transmembrane form, which is processed
into a 17-kDa secreted form at the cell surface. The transmembrane form (tmTNF) is cleaved to the soluble form
(sTNF) by TNF- convertase (TACE), a member of the
ADAM disintegrin and metalloproteinase family7. Although
both soluble and membrane forms of the TNF ligands are
biologically active, the transmembrane form is about 1000
times more potent than a soluble form on a per-mole basis8.

Regulation of TNF Biosynthesis

Many different immune and nonimmune cell types can produce TNF, including macrophages, T cells, mast cells, granulocytes, natural killer (NK) cells, and nonhematopoietic

Figure 1. The TNF superfamily: MHC paralogs. TNF and related ligands encoded in the MHC (chromosome 6) and paralogous regions on chromosomes 1,
9, and 19, and their receptors. Arrows indicate interactions with receptor, where known. MHC: major histocompatibility complex; Ch: chromosome; LT: lymphotoxin; L: ligand; AITR: activation-inducible TNF receptor; TL1A: TNF-like cytokine; HVEM: herpes virus entry mediator; TRADD: TNF receptor-associated death domain; FADD: Fas-associated death domain; TRAF: TNF receptor-associated factor; NF-B: nuclear factor-B. From Ware CF, Cytokine
Growth Factor Rev 2003;14:181-4; with permission from Elsevier2.
28

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The Journal of Rheumatology 2010; 37: Suppl 85; doi:10.3899/jrheum.091463

Figure 2. Basic structure of the TNF molecule. The TNF-related ligands are type II (intracellular N-terminus) transmembrane proteins containing a TNF homology domain (THD) at the extracellular C terminus. TNF is initially
synthesized as a monomer that folds into a -sheet sandwich and assembles into a functional trimer. The membranebound form (tmTNF) is cleaved to the soluble form (sTNF) by TNF- convertase (TACE). From Ware CF,
TNF-related cytokines in immunity. In: Paul WE, editor. Fundamental immunology. 6th ed.; with permission from
Wolters Kluwer/Lippincott Williams & Wilkins6.

cells, such as fibroblasts, neurons, keratinocytes, and

smooth-muscle cells. The ability to produce TNF depends
on the nature of the stimulus. T cells produce TNF in
response to antigen stimulation, whereas activation of innate
sensors, such as the TLR, induces TNF production in
macrophages and many other cell types. TNF biosynthesis
and bioavailability are controlled at the transcriptional level
and by control of protein accessibility (Figure 3)6.
Regulation of TNF biosynthesis at the transcriptional level.
The first point of regulation of TNF is at the transcriptional
stage by adenosine and uridine (AU)-rich elements (ARE)
in the 3 mRNA. ARE were identified as determinants of
mRNA instability more than 2 decades ago9,10, and it is
presently clear that ARE are responsible for regulating the
decay of many mRNA11,12. The core sequence of ARE is a
nucleotide pentamer containing the AUUUA motif11. The
ARE interact with sequence-specific, RNA-binding proteins, which serve to coordinate instability or enhanced stability, depending on the circumstance13. A significant body
of evidence demonstrates the importance of mRNA stability

as a regulator of the inflammatory response. This is also

documented for the mRNA encoding TNF14. TNF mRNA
contains a clustered AUUUA pentamer motif that confers
instability, sensitivity to stimulus-driven stabilization, and
stimulus-sensitive control of translational efficiency. Mice
expressing a TNF gene in which the ARE motif has been
deleted exhibit a systemic inflammatory syndrome, which is
characterized by elevated TNF expression, widespread
inflammatory cell infiltrates, IBD, and polyarthritis14.
Regulation of TNF at the receptor level. The second point of
regulation of TNF bioavailability is at the receptor level.
TACE regulates TNF biosynthesis at the receptor level by
cleaving membrane-bound TNF receptor (TNFR) to form
soluble receptors capable of binding TNF15,16. This process
is referred to as receptor shedding. Soluble TNFR are constitutively released in the circulation17, and their levels
increase in the course of various disease states18 and after
TNF stimulation19,20. In cell culture systems, soluble receptors are rapidly produced in response to various stimuli such
as TNF21, lipopolysaccharide (LPS)22, phorbol myristate

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Keystone and Ware: Anti-TNF in IMID

29

Figure 3. Regulation of TNF biosynthesis and bioavailability. The first point of regulation of TNF is at the transcriptional stage by adenosine and uridine (AU)-rich elements (ARE) in the 3 mRNA. The core sequence of
ARE is a nucleotide pentamer containing the AUUUA motif. TNF- mRNA contains a clustered AUUUA pentamer motif that confers instability, sensitivity to stimulus-driven stabilization, and stimulus-sensitive control
of translational efficiency. The ARE interact with sequence-specific, RNA-binding proteins, which serve to
coordinate instability or enhanced stability, depending on the circumstance. TNF- ARE allowed the identification of T cell intracellular antigen-1-related protein (TIAR), T cell intracellular antigen-1 (TIA-1), and tristetraprolin (TTP) as TNF- ARE-binding proteins. Whereas TIAR and TIA-1 bind the TNF- ARE independently of the activation state of macrophages, the TTP-ARE complex is detectable upon stimulation with
lipopolysaccharide (LPS). Moreover, treatment of LPS-induced macrophage extracts with phosphatase significantly abrogates TTP binding to the TNF- ARE, indicating that TTP phosphorylation is required for ARE
binding. The second point of regulation of TNF bioavailability is at the receptor level. TACE regulates TNF
biosynthesis at the receptor level by cleaving membrane-bound TNF receptor (TNFR) to form soluble receptors capable of binding TNF. This process is referred to as receptor shedding. From Ware CF, TNF-related
cytokines in immunity. In: Paul WE, editor. Fundamental immunology. 6th ed.; with permission from Wolters
Kluwer/Lippincott Williams & Wilkins6.

acetate, and interleukin 10, or after the activation of T cells23

and neutrophils24. Shedding results in an acute decrease in
the number of receptors on the cell surface and may transiently desensitize the cell to TNF action. The pool of soluble receptors competes with membrane-bound receptors for
free TNF. At relatively low concentrations of soluble receptors, the TNF trimer is actually stabilized, preserving activity; however, as soluble TNFR concentration increases, the
receptor binding sites on TNF become saturated, inhibiting
binding to the cellular receptors, and thereby attenuating
TNF activity19.
Synthesis of TNF is determined by inducing stimuli, cell
type involved, and activation status of cells; and amounts of
soluble TNF are also regulated by the level of active TACE
and the amounts of natural TACE inhibitors25. In organs
involved in immune reactions, such as lymph nodes, gut,
epithelium, and synovium, TNF is constantly transcribed at
low levels, and contributes to homeostasis of lymphoid
organs.

and Their Shared Receptors

TNF and Lymphotoxin-
TNF is closely related to LT (formerly known as TNF-;
Figure 4)26. LT can exist as a homotrimer (LT3) that is
exclusively secreted owing to cleavage of its traditional sig30

nal peptide, a unique feature in the TNF superfamily. LT

also forms heterotrimers with LT. LT, like TNF, binds 2
receptors, TNFR1 (also known as TNFRp55/60), which is
expressed on virtually all cell types, and TNFR2 (also
known as TNFRp75/80), which is more restricted in tissue
expression such as immune cells and endothelial cells. Both
TNFR1 and TNFR2 are membrane glycoproteins that
specifically bind TNF and LT. However, LT also binds
HVEM (TNFRSF14), and the LT heterotrimer binds the
LTR. TNFR1 and TNFR2 differ in their cellular expression
profiles, affinities for ligands, cytoplasmic tail structures,
and signaling mechanisms. Both receptors have structurally
similar extracellular domains, but signal through distinct
intracellular regions, with TNFR1 containing a death
domain that is absent from TNFR216. TNFR2 signaling is
mediated through TNFR-associated factors. Studies examining the individual roles of TNFR1 and TNFR2 have identified distinct and separate outcomes, with TNFR1 signaling
leading to inflammation and TNFR2 signaling leading to
immunoregulation.
TNF-TNFR1 Interaction Mediates Inflammation and
Cell Survival
Signaling through TNFR1 can initiate several cellular

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The Journal of Rheumatology 2010; 37: Suppl 85; doi:10.3899/jrheum.091463

become susceptible to tmTNF and undergo activationinduced cell death (AICD)29. The process of AICD is of particular importance in the regulation and destruction of
self-recognizing T cells. Without TNFR2 involvement,
AICD is not initiated and is believed to play a role in
autoimmune pathologies, including systemic lupus erythematosus (SLE)30 and RA31.

Figure 4. TNF- and lymphotoxin 3 and their shared receptors. From

Ware CF, TNF-related cytokines in immunity. In: Paul WE, editor.
Fundamental immunology. 6th ed.; with permission from Wolters
Kluwer/Lippincott Williams & Wilkins6.

responses, including apoptosis, necrosis, cell survival, and

inflammation. However, TNFR1 rarely triggers apoptosis
unless the biosynthetic capacity of the cell is compromised,
typically during infection by pathogens27. The interaction
between TNF and TNFR1 is essential for the survival of
cells such as the macrophage. Without this interaction,
macrophages undergo disintegration and apoptosis. Cell survival is mediated through activation of the transcription factors nuclear factor-B (NF-B) and activator protein-1
(AP-1) that induce macrophage survival genes and genes
involved in the suppression of apoptosis28. Activation of
NF-B also induces genes such as IL-6, and chemokines,
like IL-8 and RANTES, and enzymes involved in generating acute inflammatory mediators, e.g., 12-lipoxygenase.
Therefore, cell survival and inflammation are closely connected and regulated.

TNF-TNFR2 Interaction Mediates Immunoregulation

The interaction between TNF and TNFR2 is crucial for several cellular processes, including proliferation, gene activation, and apoptosis. TNFR2 preferentially interacts with
tmTNF over sTNF, suggesting that tmTNF is the primary
activator of TNFR229. This identifies tmTNF and TNFR2
involvement in the local response pattern in the microenvironment of tissues. Indeed, TNFR2 has been observed to initiate a switch in the cellular response pattern to TNF such
that cells that are resistant to sTNF-induced apoptosis

TNF Orchestrates Immune Response and Inflammation

That Is Beneficial for Host Defense
Ligands and receptors in the TNF and LT systems have a
variety of roles in the development and function of the
immune system4,32,33. At low concentrations in tissues, TNF
is thought to have beneficial effects, such as the augmentation of host defense mechanisms against infections. At high
concentrations, TNF can lead to excess edema, erythema,
inflammation, pain, and organ injury. Acute release of very
large amounts of TNF during sepsis may result in septic
shock.
However, much of the evidence for the role of TNF in
immunity is based on studies with genetically deficient
mice; therefore, the relevance to human immune system
development and function is less clear. Although the mechanisms of resistance to bacterial and viral infections are
complex and still under investigation, some data implicate
TNF and LT as important components of host defense, particularly for intracellular bacteria such as Mycobacterium or
Listeria. Killing of the intracellular bacteria within activated
macrophages is primarily mediated by reactive oxygen
species, including nitric oxide. Mice deficient in TNF, LT,
TNFR1, or LTR are highly susceptible to experimental
Mycobacterium, Listeria, and Staphylococcus infections
compared with normal mice34-36.
Mechanisms of host defense against intracellular
pathogens, particularly Mycobacterium tuberculosis, in
humans have not been as well studied as those in mice, but
they have been extensively discussed in the context of the
clinical safety of TNF antagonists.
The rationale for the first clinical study of a TNF antagonist in RA was based on the role of TNF in a proinflammatory cytokine cascade37. That many of the hallmarks of
chronic inflammation, such as leukocyte recruitment, activation, and proliferation and production of inflammatory
mediators, are reduced by TNF antagonist therapy confirms
a mechanistic link to TNF. As more than 100 cytokines and
chemokines have been identified, many of them studied in
TNF antagonist-treated patients, the concept has emerged
that TNF is at the top of a proinflammatory cytokine
cascade38.
THE ROLE OF TNF and DEVELOPMENT OF IMID
Dysregulation of immune mechanisms may lead to dysregulated TNF production at a site of immunological tissue
injury, which in turn may sustain activation of innate

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Keystone and Ware: Anti-TNF in IMID

31

immune cells, leading to chronic inflammation. Depending

on the location, organ-specific inflammatory pathology and
tissue damage may ensue39. TNF, therefore, can play a significant role in the development of these pathologies and
may provide an alternative mechanism for disease initiation
or progression by altering cell differentiation, proliferation,
or death.
As previously mentioned, TNF has a particularly important role in the regulation of a cascade of pathogenic events

leading to RA, CD, Ps (Figure 5)40, and other autoimmune

diseases, illustrated by the rapid induction of production of
cytokines and acute-phase proteins38. However, numerous
studies have demonstrated that TNF acts within a complex
network of cells and mediators of inflammation41. It is postulated that TNF acts as the key upstream trigger and mediator of downstream mechanisms and that a variety of positive and negative feedback loops control the chronicity and
pathogenic outcomes of inflammation.

Figure 5. A cascade and network of cellular responses mediated by tumor necrosis factor (TNF) in immune-mediated inflammatory diseases (IMID). TNF is
produced in high concentration by a number of cells in CD, RA, and Ps. Shown in the enclosed area are the cascade and network of cellular responses mediated by TNF and common to these 3 diseases. Mechanisms that are unique to each disease are shown outside the enclosed area. CD: Crohns disease; Chond:
chondrocyte; COX-2: cyclooxygenase-2; CRP: C-reactive protein; DC mat: mature dendritic cell; EC: endothelial cell; E-sel: E-selectin; GM-CSF: granulocyte-macrophage colony-stimulating factor; Hep: hepatocyte; ICAM-1: intercellular adhesion molecule 1; IL: interleukin; iNOS: inducible nitric oxide synthase; Mac: macrophage; Mast: mast cell; MCP-1: monocyte chemotactic protein-1; MMP: matrix metalloproteinases; NO: nitric oxide; OC: osteoclast; OPG:
osteoprotegerin; PGE2: prostaglandin E2; Ps: psoriasis; RA: rheumatoid arthritis; RANKL: receptor activator for nuclear factor-B ligand; RANTES: regulated upon activation, normal T cell expressed, and secreted; ROI: reactive oxygen intermediate; SOD: superoxide dismutase; (s/tm)TNF: (soluble/transmembrane); VCAM-1: vascular cell adhesion molecule-1; VEGF: vascular endothelial growth factor. From Tracey, et al, Pharmacol Ther 2008;117:244-79;
with permission from Elsevier40.
32

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The Journal of Rheumatology 2010; 37: Suppl 85; doi:10.3899/jrheum.091463

TNF-TNFR1 and IMID

It is widely accepted that TNF plays a critical role in RA by
activating synovial fibroblasts and stimulating their proliferation42. Further, bone-marrow grafting studies in mice have
demonstrated that the receptor TNFR1 is necessary for
development of chronic inflammatory joint and intestinal
diseases43 (Table 2). Without TNFR1, mice do not develop
arthritis, even when grafted into an ARE-deletion mutant
that would otherwise result in an arthritic phenotype.
Similar results are reported from crossbreeding studies
using ARE-deletion mice and TNFR1-deletion mice14. As
described, the TNF ARE-deletion mice in this study display
the chronic pathologies of inflammatory arthritis and
inflammatory bowel disease (IBD). When TNF ARE-deletion mice are bred into a TNFR1-deletion background, mice
develop normally and do not display any sign of macroscopic illness. Further, the use of transgenic mice expressing
Cre recombinase under the control of a collagen promoter
cassette demonstrates the role of TNFR1 in the development
of arthritis, CD-like IBD, and AS43. The findings identified
TNFR1-expressing mesenchymal cells as the common target for TNF in the onset of IMID and also indicated a common mechanism explaining the synovial-gut axis often
observed in human IMID. Taken together, these results point
to a dominant role for TNFR1 in IMID.
TNF-TNFR2 and IMID
Recent studies have suggested a critical role for TNFR2 in
the pathogenesis of CD. TNFR2 regulates immune homeostasis, therefore dysregulation of TNFR2 leads to disease
states characterized by multiorgan inflammation and
TNFR-associated factors (TRAF) activation. Studies carried
out in transgenic mice that express constitutive yet physiologically relevant levels of TNFR2 demonstrate a link
between TNFR2 upregulation and the development of a
severe multiinflammatory syndrome44. TNFR2 expression
is upregulated in colonic epithelial cells in murine colitis
models as well as in patients with colitis and CD45. The
upregulation of TNFR2, caused by key proinflammatory
cytokines, may cause colonic inflammation-associated alteration in the intestinal epithelium. TNFR2 signaling associated with TRAF activation is involved in the pathogenesis of
Table 2. Arthritis development following TnfARE bone marrow reconstitution of lethally irradiated recipients. From Armaka, et al, J Exp Med
2008;205:3317; with permission43.
Donor Genotype

WT
TnfARE/+
TnfARE/ARE TnfRI/
TnfARE/+

Recipient Genotype Arthritis Development

WT
WT
WT
TnfRI/

0/20
19/21
25/25
0/8

ARE: adenosine- and uridine-rich elements; WT: wild-type.

a murine model of CD46, and TRAF activation has also been

observed in human patients47.
TNFR2 also contributes to the pathogenesis of SLE, RA,
and AS. Circulating levels of soluble TNFR2 are elevated in
these patients48, and serum levels of soluble TNFR2 are
believed to provide useful information about disease activity in patients with SLE49. Mortality due to cardiovascular
disease in RA appears to be associated with elevated levels
of soluble TNFR2. Thus, serum levels of soluble TNFR2
may be a useful biomarker in identifying RA patients at
increased risk of premature death50.

TNF and TNFR in the Central Nervous System

TNF plays a central role in inflammation in the central nervous system (CNS) and has been implicated in the pathogenesis of several human inflammatory, infectious, and autoimmune CNS disorders. Studies using transgenic mice and
gene knockout mice have demonstrated that TNF dysregulation triggers a neurological disorder characterized by ataxia, seizures, and paresis, with histopathological features of
chronic CNS inflammation and white-matter degeneration51. When overexpressed by astrocytes, transmembrane
TNF is sufficient to trigger CNS inflammation and degeneration, demonstrating that TNF-producing cells localize in
the vicinity of astrocytes rather than neurons. Both soluble
and transmembrane forms of TNF play critical roles in the
pathogenesis of CNS inflammation and demyelination.
TNFR1 expression is necessary for TNF to trigger oligodendrocyte death and demyelination52. TNF released by glia
cells in the CNS potently and selectively induces local
oligodendrocyte apoptosis and inflammatory demyelination.
These effects are abrogated in mice genetically deficient for
TNFR1, demonstrating a dominant role for TNFR1-signaling pathways in TNF-mediated pathology. These results
demonstrate that TNFR1 signaling in the CNS can have a
potentially major role in demyelination observed in multiple
sclerosis (MS).
It is important to note, however, that both infliximab and
etanercept are contraindicated for patients with MS, based in
part on the unexpected symptoms of demyelinating disease
(paresthesia, optic neuritis, and confusion) developing in
people with quiescent MS and new-onset cases of demyelinating disease, which reversed upon drug removal53.
Further, that several inhibitors of TNF/LT are linked to
exacerbation of demyelinating disease in humans suggests
that their common mechanism of action, blockade of TNF,
is influencing pathogenesis. Failure of a TNF antagonist
therapy in MS may be due to pleiotropic aspects of TNF
actions. TNF may have important immunoregulatory functions, and be involved in tissue repair and regeneration, or
host defense.
TNF INHIBITORS
TNF inhibitors show remarkable efficacy in a variety of

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Keystone and Ware: Anti-TNF in IMID

33

IMID. In spite of their significant efficacy, little is known

about their mode of action in vivo and the factors that limit
their scope of therapeutic application. All TNF inhibitors are
antibodies with specificity for TNF, or in the case of etanercept, a chimera of the immunoglobulin molecule with
ectodomain of TNFR2, and thus is specific for both TNF
and LT. All the currently approved TNF inhibitors share a
common molecular mechanism of action, which is to competitively inhibit ligand-binding to their cognate receptors.
However, the inhibitors differ in their physical and functional properties, including valency, effector functions,
pharmacokinetics, and antigenicity (Figure 6 and Table 3).
The clinical differences in efficacy of these TNF inhibitors
in various IMID has led to discussions about how these
human therapeutics might work in vivo.
Infliximab is derived from a mouse anti-human TNF,
whereas adalimumab and golibumab are derived from
human IgG antibody gene sequences; both are complete
IgG1 molecules. Certolizumab is also an anti-TNF derived
from a human antibody, but is a monovalent Fab fragment
that has been chemically modified by addition of polyethyleneglycol to improve its pharmacokinetics, which are
notoriously poor for Fab.

Primary Mechanism of Action

The primary mechanism of action of TNF inhibitors is to act
as competitive antagonists to block soluble and membrane
TNF from binding their receptors. TNF inhibitors neutralize
TNF by recognizing antigenic epitopes on the ectodomain
of TNF near or at the receptor-binding region, thus sterically hindering the TNF molecule in engaging its receptors54.
Etanercept is a receptor-based therapeutic that binds directly to the receptor-binding region, which is formed by the
interaction of 2 adjacent subunits in the TNF trimer. Without
TNF binding to its receptor, the signaling cascade resulting
in inflammation is silenced, thereby blocking the inflammatory responses.

Binding Characteristics
Currently available TNF inhibitors exhibit the ability to neutralize both sTNF and tmTNF (Table 3)40. All the TNF
inhibitors bind membrane TNF with similar affinities,
although there is some debate over whether the monoclonal
antibodies infliximab and adalimumab bind with higher
affinity to TNF than the receptor-based inhibitor etanercept55. The bivalent etanercept has a higher avidity for TNF
compared to the monovalent, naturally shed TNFR.

Figure 6. Simplified diagrams of the molecular structures of 5 TNF antagonists. Infliximab is a mouse/human
chimeric monoclonal anti-TNF antibody of immunoglobulin (Ig) G1 isotype. Adalimumab and golimumab are
fully human IgG1 monoclonal anti-TNF antibodies. Etanercept is a fusion protein of TNFR2 (p75) and the Fc
region of human IgG1. Certolizumab is a PEGylated Fab fragment of a humanized IgG1 monoclonal anti-TNF
antibody. From Tracey, et al, Pharmacol Ther 2008;117:244-79; with permission from Elsevier40.
34

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The Journal of Rheumatology 2010; 37: Suppl 85; doi:10.3899/jrheum.091463

Table 3. Biochemical and mechanistic profile of TNF antagonists. Adapted from Tracey, et al, Pharmacol Ther 2008;117:24479, with permission from
Elsevier40.
Infliximab

Class
mAb
Structure
Mo/Hu chimeric IgG1
Molecular weight,
150
kDa
Specificity
TNF
TNF ligands
sTNF, tmTNF
LT ligands
None
Neutralization potency
sTNF (low conc)
Moderate
sTNF (high conc)
Strong
tmTNF binding
Strong

Etanercept

Adalimumab

TNF/LT
sTNF, tmTNF
LT3, LT21

TNF
sTNF, tmTNF
None

Fc fusion protein
Hu sTNFR2-Fcl
120 ?

Strong
Strong
Moderate

Certolizumab

Golimumab

TNF
sTNF, tmTNF
None

TNF
sTNF, tmTNF
None

mAb
Hu IgG1
150

mAb fragment
PEG-Hu IgG1 Fab
~95

Moderate
Strong
Strong

ND
Strong
Strong

mAb
Hu IgG1
150

ND
ND
ND

ND: no data available; mAb: monoclonal antibody; Hu: human; Mo: mouse; LT: lymphotoxin; PEG: polyethyleneglycol; TNF: tumor necrosis factor; TNFR:
TNF receptor; tmTNF: transmembrane TNF; sTNF: soluble TNF; conc: concentration.

Infliximab is able to bind both the monomeric form as well

as the biologically active trimeric form of TNF. Etanercept
binds only the native trimeric form of TNF and LT55.
Adalimumab, infliximab, etanercept, and certolizumab have
similar affinities for soluble TNF, but with differing on- and
off-rates. Etanercept has a faster binding on-rate and a faster
dissociation off-rate to soluble TNF than does infliximab or
adalimumab. The difference in the specificity of etanercept,
which binds both TNF and LT, from the monoclonal antibodies, which bind only TNF, might also explain some differences in treatment outcomes using these agents4,56.

Pharmacokinetic Profile
The pharmacokinetic profiles of TNF inhibitors differ
(Table 4) and may contribute to the different efficacies of
these antagonists. Etanercept is rapidly cleared from serum
at 72 ml/h (compared to 11 ml/h for infliximab and 12 ml/h
for adalimumab), and has the shortest half-life at 45 days.
Intact IgG1 has a long half-life, which is reflected in the
longer half lives of infliximab (810 days) and adalimumab,
golimumab, and certolizumab (1020 days). Etanercept has
the lowest maximum steady-state concentration of 1.1
g/ml (compared to 118 g/ml for infliximab and 4.7 g/ml

for adalimumab). Taken together, these differences suggest

that the anti-TNF IgG may provide longer coverage than
etanercept.

Secondary Mechanisms of Action

Secondary mechanisms of action have been suggested to
account for some of the differences in efficacy of antibody
versus receptor-based inhibitors. For instance, TNF antibodies have been shown to mediate complement-dependent57,58
and antibody-dependent cell-mediated cytotoxicity (ADCC)
when incubated with cells expressing tmTNF, thus acting to
eliminate inflammatory cells59,60. Binding or cross-linking of
tmTNF by bivalent IgG has been suggested to induce a
reverse (outside to inside) intracellular signaling cascade41,54,
although such pathways by TNF-related ligands are undefined. These alternative mechanisms all depend on bivalent
IgG and an intact Fc domain. Although not a true controlled
experiment, a strong argument against these secondary mechanisms of action is that certolizumab, which is unable to
crosslink tmTNF or activate ADCC or complement, displays
very similar efficacy in IMID as bivalent IgG59.
Another unexplained feature of blocking TNF is that in
some patients the effects last longer than the drug is present

Table 4. Pharmacokinetics of TNF inhibitors. Adapted from Tracey, et al, Pharmacol Ther 2008;117:24479, with permission from Elsevier40.
Half-life, days
Volume of distribution, Vss
Clearance, CL
Cmax

Infliximab

810
4.3 2.5 la
11 ml/ha
118 g/mla

Etanercept

4
8.0 lb
72 5 ml/he
1.1 0.6 g/mle

Adalimumab

1020
4.76.0 lc
12 ml/hc
4.7 1.6 g/mlg

Certolizumab
~14
ND
ND
ND

Golimumab

720
6.9 ld
16.7 ml/hf
70.8 18.9 g/mlh

5 mg/kg intravenous (IV); b Vss (volume of distribution at steady state) estimated as sum of Vc + Vp for volumes of distribution in the central and peripheral compartments, respectively, from a 2-compartment population pharmacokinetic model based on 10 studies with 225 mg IV or subcutaneous (SC) single
dose or biw; c 0.2510 mg/kg IV; d Vss estimated as sum of Vc + Vp for volumes of distribution in the central and peripheral compartments, respectively,
from a 2-compartment population pharmacokinetic model based on data from 0.110 mg/kg IV; e based on data from 220 mg IV and 250 mg SC; f 0.110
mg IV; g 40 mg SC; h 3 mg/kg IV. ND: no data available.
a

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Keystone and Ware: Anti-TNF in IMID

35

in the circulation, although the beneficial effects are not permanent. The loss of TNF signaling may lead to fundamental
changes in the immune system, such as changes in lymphoid
tissue architecture or changes in T regulatory cells, which
may induce or help reestablish tolerance and homeostasis.

EFFICACY OF TNF INHIBITORS

The efficacy of TNF inhibitors varies: some inhibitors show
clear benefit in certain IMID, while others have little or no
effect (Table 5). However, about one-third of patients with
IMID do not respond to any anti-TNF treatment and in some
diseases TNF inhibitors are contraindicated. The reasons for
these differences remain unknown, but contributions from
genetic makeup of the patients to underlying mechanisms of
pathogenesis are undoubtedly important.
All currently available anti-TNF inhibitors are effective
in treating RA. Of particular importance is their ability to
improve symptoms and physical function, and to slow radiographic progression61-63. Etanercept, infliximab, and adalimumab are efficacious in treating moderate to severe Ps,
showing improvement in severity [Psoriasis Area and
Severity Index (PASI) score], remission and relapse rates,
and health-related quality of life64,65. Adalimumab has also
proven to be effective in patients with moderate to severe Ps
who fail to respond to etanercept66. Etanercept, infliximab,
and golimumab show efficacy for the treatment of active
and progressive PsA, exhibiting beneficial effects on both
joint and Ps symptoms and on functional status67,68.
Adalimumab is efficacious in patients with severe plaque Ps
and PsA and mediates a decisive regression of joint/skin
involvement69. Adalimumab, etanercept, and infliximab are
clinically effective in AS in relation to ASAS (Assessment
in Ankylosing Spondylitis), BASDAI (Bath Ankylosing
Spondylitis Disease Activity Index), and BASFI (Bath
Ankylosing Spondylitis Functional Index)70. Indirect comparisons of treatments for AS are limited and do not show a
significant difference in efficacy between the presently
available agents. Infliximab is effective in closing fistulas
and significantly reducing hospitalizations, surgeries, and

procedures in patients with fistulizing CD90. Certolizumab

has been shown to be effective in patients with moderate to
severe CD91. Although infliximab is highly effective in
treating CD, some patients develop an attenuated response
over time. Adalimumab offers good efficacy in infliximabresistant or intolerant patients and is well tolerated without
signs of immunogenicity92. Adalimumab is also well tolerated in pediatric CD patients, mediating a complete or partial response without serious adverse events93. In contrast,
etanercept shows no efficacy in the treatment of CD79. As
mentioned, etanercept is also not efficacious in treating sarcoidosis, Wegeners granulomatosis, or uveitis. It has been
postulated that the different disease mechanisms might
account for varying efficacy, that the role of TNF might
change from one stage of disease to another, or that the varying genetic makeup of patients contributes to differences.

Patient Genetic Makeup

The genetic makeup of patients may influence their
response to biological treatments. For example, RA patients
with a TNF-308 G/G genotype respond better to infliximab
treatment than patients with A/A or A/G genotypes94. This
observation holds true for patients with PsA or AS95.
Therefore, TNF-308 genotyping may be a useful tool for
predicting response to infliximab treatment. RA patients
with a TNF-308 G/G genotype also respond better to etanercept and adalimumab than patients with a TNF-308 A/G
genotype96,97. Genome-wide association studies of IMID in
progress will be important new sources of information for
helping to predict patient responses to TNF inhibitors98,99.

CONCLUSION
TNF-related ligands and their receptors act as key communication systems between cells of the immune system that
mediate inflammation and tissue destruction. These
cytokines have evolved as part of a complex system of
innate immunity and host defense, particularly against
microbial infections, and can either enhance or suppress
adaptive immunity.

Table 5. Efficacy of tumor necrosis factor antagonists in different IMID.

Efficacy in

RA71-76
PsA71-73,75-77
AS71-73,75,76,78
CD74,79,80
UC81
Psoriasis82-84
JIA85,86
WG87,88
Sarcoidosis89

Infliximab
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

Etanercept
Yes
Yes
Yes
No
ND
Yes
Yes
No
No

Adalimumab
Yes
Yes
Yes
Yes
ND
Yes
ND
ND
ND

Certolizumab
Yes
ND
ND
Yes
ND
ND
ND
ND
ND

Golimumab
Yes
ND
ND
ND
ND
ND
ND
ND
ND

PsA: psoriatic arthritis; AS: ankylosing spondylitis; UC: ulcerative colitis; JIA: juvenile idiopathic arthritis; WG:
Wegeners granulomatosis; ND: no data. Adapted from Tracey D, Pharmacol Ther 2008;117:244-79; with permission from Elsevier40.

36

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The Journal of Rheumatology 2010; 37: Suppl 85; doi:10.3899/jrheum.091463

Studies in humans with TNF inhibitors have demonstrated that TNF plays a pivotal role in the pathogenesis of
several IMID including RA, PsA, Ps, AS, and IBD. The
biosynthesis and bioavailability of TNF are tightly regulated at both transcription and receptor-binding levels.
TNF-binding to TNFRI is typically associated with inflammation and cell survival, whereas binding to TNFR2 is usually associated with immunoregulation and apoptosis.
Although all currently available TNF inhibitors show
remarkable efficacy in joint-related IMID, their efficacy in
other IMID-related conditions (i.e., IBD, uveitis) varies.
This may be due to differences in their molecular actions
and pharmacokinetic properties. Better understanding of
mechanisms of action of TNF antagonists, and related distinctions between the agents, will continue to emerge with
the discoveries of other TNF-based therapies and with
broader use of these agents in clinical practice.

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Keystone and Ware: Anti-TNF in IMID

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