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The development of anticytokine therapeutics for rheumatic diseases.

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ARTHRITIS & RHEUMATISM
Vol. 58, No. 2, February 2008, pp S102–S109
DOI 10.1002/art.23053
© 2008, American College of Rheumatology
The Development of Anticytokine Therapeutics for
Rheumatic Diseases
William P. Arend,1 with Mary B. Goldring2
The 5-year period of July 1995
through June 2000 saw considerable advancement in knowledge about the mechanisms of
inflammation and tissue damage in many rheumatic diseases, particularly the important role of cytokines. Based
upon this knowledge, the principles of rational drug design
were applied to the development of new therapeutic
approaches intended to block cytokine effects (1–3).
Many of the most important articles that appeared in the
literature during this period reporting both advances in
basic science and the results of clinical trials in rheumatoid arthritis (RA) were published in Arthritis & Rheumatism (A&R).
A classic article on anticytokine therapy, appearing in the May 1996 issue, is the most frequently cited
basic research study published in A&R during this 5-year
period. We selected this study—“Anticytokine treatment of established type II collagen-induced arthritis in
DBA/1 mice: a comparative study using anti-TNF-␣,
anti-IL-1␣/␤, and IL-1Ra” by Joosten, Helsen, van de
Loo, and van den Berg (4)—as a focal point in a brief
review of the development of anticytokine therapeutics
for rheumatic diseases, including the scientific background, subsequent developments in this area since
publication of the article, and some comments on the
broader implications for science, education, and practice
in rheumatology.
The senior author (WPA) was not only the Editor
of A&R during this 5-year period, but was also a
participant in this field of research. This review will not
be comprehensive but will emphasize the evolution of
concepts and ideas, including some personal comments
on apparently serendipitous and paradoxical findings.
Tumor necrosis factor ␣ (TNF␣) and interleukin-1
(IL-1) in rheumatic diseases
The mechanisms whereby cells communicate with
each other remained a mystery until the 1950s when
studies began appearing that described biological activities in human or animal sera and in the supernatants of
cells that mediated cell–cell communication. These biological activities were given different names based on
their cellular sources or the functions they influenced,
either systemically or on adjacent cells in culture. Later,
it was discovered that many of these biological activities
were due to single molecules with pleiotropic functions
or that a specific biological activity could be attributed to
more than one molecule.
The first observation on TNF originated from
experimental work in oncology on the mechanisms of
“hemorrhagic necrosis” of transplanted tumors caused
by material from gram-negative bacteria. In 1975 Old
and colleagues reported that sera from BCG-infected
mice contained a substance that caused necrosis of
transplanted tumors in vivo or killed tumor cell lines in
vitro (5). The conclusion was that this material was
released from macrophages stimulated by bacterial
products, accounting for the ability of activated macrophages to suppress transformed cells. Many investigators
over the subsequent 30 years have described related
biological activities in the supernatants of cultured cells
called “cachectin” or other names. Finally in 1984, DNA
cloning permitted identification of the proteins responsible for these antitumor activities as two closely related
Supported by NIH grants AR-51749 to Dr. Arend and
AG-022021 to Dr. Goldring.
1
William P. Arend, MD: University of Colorado School of
Medicine, Denver (Editor, Arthritis & Rheumatism, 1995–2000);
2
Mary B. Goldring, PhD: Hospital for Special Surgery, Weill College
of Medicine of Cornell University, New York, New York.
Address correspondence to William P. Arend, MD,
UCDHSC, Division of Rheumatology B115, 1775 N. Ursula Street,
Aurora, CO 80045. E-mail: william.arend@uchsc.edu.
Submitted for publication August 22, 2007; accepted August
22, 2007.
S102
ANTICYTOKINE THERAPEUTICS
molecules: TNF␣ described by Goeddel and colleagues
(6) and TNF␤, or lymphotoxin, described by Gray et al
(7).
Early work on fever laid the foundation for
characterizing the molecule now known as IL-1. The
concept that fever was due to products of tissue injury
acting on cerebral regulatory centers was proposed as
early as 1785 (discussed in ref. 8). Research in the 1940s
on the possible existence of an endogenous pyrogen was
plagued by the difficulty in separating the effects of
exogenous bacterial materials, used to induce fever in
experimental animals, from the release of a cellular
product acting as an endogenous pyrogen. In 1953
Bennett and Beeson described the isolation of a possible
endogenous pyrogen from rabbit polymorphonuclear
leukocytes (PMNLs) (8,9). Atkins and Wood subsequently proved in 1955 the existence of endogenous
pyrogen through serum transfer experiments in rabbits
(10,11). These workers all hypothesized that fever seen
in infection, inflammation, malignancy, and tissue injury
might be due to the release of endogenous products
from PMNLs and other cells.
Over the next 30 years, numerous investigators
described biological activities in serum and other body
compartments, and in the supernatants of cultured cells,
that induced seemingly unrelated responses in target
cells. Some of these proteins were purified and characterized, including lymphocyte activating factor (12,13),
endogenous pyrogen (14), and mononuclear cell factor
(15). The consensus that they were all IL-1 was published in 1979 (16). This work culminated in the cloning
in 1984 of two forms: IL-1␣ by Lomedico, Mizel, and
colleagues (17), and IL-1␤ by Auron et al (18).
Thus, the identification of TNF was based on
research in cancer, whereas the scientific foundation of
IL-1 was established by work in infectious diseases. The
potential roles of these cytokines in cartilage destruction
were first described by Fell and Jubb in this Journal in
1977, using the technique of organ culture developed
previously by the Fell laboratory (19). A major issue in
research on RA had been whether “the pannus destroys
and invades the cartilage or whether the cartilage first
undergoes some pathologic change that permits the
ingrowth of the synovial tissue . . .” (19). These investigators observed that living pig cartilage in contact with
synovium in a culture dish lost both collagen and proteoglycan; that dead cartilage lost some proteoglycan but
less collagen; and most importantly, separation of the
synovium from the cartilage in the same culture dish led
to destruction of living cartilage only (Figure 1). They
concluded that the synovium released a soluble material,
S103
Figure 1. Synovial factor (catabolin) mediates degradation of cartilage proteoglycans and collagen. Culture of living pig synovium with
dead cartilage produces little degradation of proteoglycans and no loss
of cartilage. Culture of living pig synovium with living cartilage leads to
significant degradation of both proteoglycans and collagen. This effect
is still seen after separation of the synovium from the cartilage in the
culture dish, suggesting the involvement of a soluble factor released
from the synovium, termed catabolin. IL-1 ⫽ interleukin-1. Adapted
from ref. 19.
called catabolin, which stimulated the chondrocytes to
release enzymes that destroyed the surrounding cartilage matrix. Catabolin was subsequently identified as pig
IL-1 (20). The roles of cytokines in inflammation and
tissue destruction in RA were first suggested by Dayer,
Krane, and coworkers showing that purified IL-1 and
TNF could stimulate the production of prostaglandins
and collagenase by rheumatoid synovial cells (21,22).
These observations and subsequent work by
many investigators performed in the 1980s and early
1990s, in both culture models and animal models of RA,
established the principle that TNF␣ and IL-1 originating
in the synovium from patients with RA could lead to the
production of inflammatory mediators and tissuedegrading enzymes (1–3). However, because of the
apparent redundancy in the cytokine network, many
prominent investigators remained skeptical that inhibition of any one cytokine would have a significant beneficial effect on human disease. As summarized in 1995,
five criteria were met for the involvement of IL-1 and
TNF␣ as mediators of joint tissue damage in RA (Table
S104
Table 1. Criteria for the involvement of IL-1 and TNF␣ as mediators
of joint tissue damage in rheumatoid arthritis*
1. These cytokines are present in the diseased tissue.
2. Synovial fluids containing these cytokines are injurious to normal
cartilage in vitro.
3. Cartilage damage can be prevented by specific cytokine inhibitors
or antagonists.
4. Recombinant IL-1 and TNF␣ produce damage to normal
cartilage in vitro or in vivo.
5. High levels of these cytokines, or their messenger RNA, are
present in the rheumatoid synovium at sites of active tissue
destruction.
6. Progression of tissue damage in patients with rheumatoid arthritis
should be prevented by treatment with inhibitors of IL-1 and TNF␣.
* IL-1 ⫽ interleukin-1; TNF␣ ⫽ tumor necrosis factor ␣. Reproduced
from ref. 2 and adapted, with permission, from Hollander AP. Criteria
for identifying mediators of tissue damage in human autoimmune
diseases. Autoimmunity 1991;9:171–6.
1) (2). The sixth criterion, the prevention of tissue
damage in patients with RA by treatment with inhibitors
of IL-1 and TNF␣, was being tested, based on parallel
developments in work on cytokine inhibitors.
Inhibitors of IL-1 and TNF␣
Given the ubiquitous presence of IL-1 and TNF␣
in inflammatory conditions and the pleiotropic nature of
their effects, many investigators in the early 1980s
hypothesized that natural regulators of their production
or action must exist. Inhibitory activities against IL-1 in
bioassays had been described by many investigators, who
found these activities primarily in urine or in the supernatants of cultured cells (23,24). However, these IL-1
inhibitory activities remained uncharacterized, and in
many cases they turned out to be due to substances
interfering with the bioassays.
At a symposium on IL-1 held in Ann Arbor in
June 1985, two different laboratories reported specific
inhibitory activities of IL-1 that were later determined to
be caused by the same molecule, now termed IL-1
receptor antagonist (IL-1Ra). Continuing earlier work
from many laboratories on excreted proteins, Dayer and
coworkers described a specific inhibitory activity against
IL-1 found in the urine of patients with fever or myelomonocytic leukemia (25). This laboratory subsequently described IL-1 inhibitory bioactivity in the serum and urine of patients with juvenile RA, suggesting
its relevance to inflammatory diseases (26).
Arend had previously spent a year (1980–1981) at
the Strangeways Laboratory in Cambridge where he
observed the continuing work on catabolin by Fell, who
was still working into her 80s. At that time, he met the
AREND AND GOLDRING
coauthor of this editorial, who was a member of a team
that identified IL-1–like activity in human synovial supernatants that stimulated plasminogen activator production by chondrocytes (27). Arend hypothesized that
monocytes encountered adherent immune complexes as
they entered an inflamed joint and may be stimulated to
produce catabolin or IL-1. The Arend laboratory subsequently observed that monocytes cultured on adherent
IgG released no detectable IL-1 bioactivity, but the
addition of IL-1 revealed inhibitory bioactivity toward
IL-1 in the supernatants (28). The ability of the semipurified material to specifically inhibit the binding of
IL-1 to its receptors on target cells was first shown by
Seckinger and Dayer for the IL-1 inhibitor in urine (29),
followed by Arend and colleagues for the IL-1 inhibitor
in the supernatants of monocytes cultured on adherent
IgG (30).
In the late 1980s, three different groups were
racing to be the first to purify, clone the cDNA, and
express recombinant IL-1Ra molecules (Figure 2). Earlier, Arend had given informal assistance to a team from
Upjohn in Kalamazoo on the monocyte production of
IL-1Ra and they proceeded independently. In 1987,
Arend entered into a scientific collaboration with the
biotechnology company Synergen in Boulder, with a
team led by Thompson. Dayer formed a similar collaboration with investigators at Biogen in Geneva. Three
different sources of IL-1Ra were employed: The Geneva
team used frozen urine from AIDS patients collected in
Boston and flown to Europe or urine from patients in
Geneva with high fever. The Colorado investigators used
supernatants from human monocytes cultured on a
substrate of IgG. The Upjohn team used the supernatants of the human myelomonocytic cell line U937
cultured on IgG (Figure 2). The Colorado investigators
were the first to be successful in this endeavor, followed
by the team from Upjohn (31–33). Subsequent development and preclinical evaluation of IL-1Ra has been
reviewed (34–36).
A somewhat different endeavor was underway in
the late 1980s to develop inhibitors of TNF␣. Based on
observations that IL-1 inhibitory bioactivities were
present in human urine, three different laboratories
examined this source and found inhibitory activities
against TNF␣: Seckinger et al (37), Olsson et al (38),
and Engelmann et al (39). These TNF␣ inhibitory
activities in urine were found to be due to the soluble
extracellular portions of TNF receptors. Subsequently,
investigators at Immunex developed a therapeutic agent
containing the extracellular portions of two p75 TNF␣
receptors coupled to the Fc portion of human IgG1 (40).
ANTICYTOKINE THERAPEUTICS
S105
Classic article from A&R, 1996
Figure 2. Race to purify the protein, clone the cDNA, and express
recombinant interleukin-1 receptor antagonist. Three different laboratory groups in Colorado, Kalamazoo, and Geneva were simultaneously working on this project in the late 1980s. The Colorado group
was the first to be successful.
The development of monoclonal antibodies
against TNF␣ began in the laboratory of Vilcek in 1984, in
collaboration with Centocor. In 1989, a murine anti-TNF␣
monoclonal antibody, termed A2, was developed (41). In
the same year, a strong rationale for the inhibition of
TNF␣ in RA was established through the studies of
Brennan, Maini, and Feldman et al (42). They suggested
that TNF␣ may be the main inducer of IL-1, since antibodies to TNF␣ reduced the production of IL-1 in cultured
rheumatoid synovial cells. Based on the initial development of the monoclonal antibody A2, the construction and
characterization of a mouse/human chimeric anti-TNF␣
antibody, termed cA2, was described in 1993 (43). This
eventual therapeutic agent was capable of neutralizing
TNF␣ in vitro, blocking TNF␣ binding to both types of
receptors in vitro, and protecting against cachexia and
lethality in TNF␣-transgenic mice (44). The subsequent
development and preclinical evaluation of therapeutic
agents inhibitory to TNF␣ has been reviewed (3,45).
With the efficacy of blockade of TNF␣ or IL-1 in
experimental animal models of RA, which was described
in the early 1990s, questions were raised about the
relative effects of these two therapeutic approaches on
inflammation vs. tissue destruction. Early studies suggested that inhibition of TNF␣ was more antiinflammatory, whereas IL-1 blockade was more effective in
preventing tissue destruction. The selected article from
the van den Berg laboratory provides a complete analysis of various inhibitors of TNF␣ and IL-1 in collageninduced arthritis (CIA) in mice (4). Five important
conclusions can be drawn from these studies: 1) Antibodies against TNF␣ prevented the onset of CIA, were
mildly efficacious early in disease, and exhibited only
weak effects in established CIA. 2) Antibodies to IL1␣/␤ or IL-1Ra completely prevented the onset of CIA
and markedly suppressed established disease. 3) Blockade of TNF␣ did not necessarily eliminate the production of IL-1. 4) IL-1 inhibition in established CIA
prevented destruction of cartilage more effectively than
did blockade of TNF␣. 5) High continuous doses of
IL-1Ra were necessary to prevent CIA and to treat
established disease.
The role of IL-1 and TNF␣ in inflammation and
tissue destruction in CIA has been clarified in recent
studies. Mice transgenic for human TNF␣ but lacking
the genes for IL-1␣ and IL-1␤ developed inflammation
but no destruction of cartilage or bone, whereas the
opposite phenotype was found with mice lacking TNF␣
production but possessing intact genes for IL-1 (46).
These results clearly establish that in this animal model
of arthritis TNF␣ is primarily responsible for inflammation with cartilage and bone destruction mediated solely
by IL-1.
However, caution should be exercised in applying
these findings to human disease. IL-1 inhibition is more
beneficial in CIA than in other animal models such as
antigen-induced arthritis. The doses, half-lives, and neutralizing capacities of the experimental therapeutic approaches may not have been comparable in the studies
of Joosten et al (4). It is clear that no animal model of
inflammatory arthritis is totally equivalent to the human
disease of RA, in which disease mechanisms may be
more complex than those operative in any animal model.
Although anticytokine therapies in animal models have
been useful to establish proof-of-principle, it is not a
substitute for clinical trials in RA.
S106
Development of IL-1 and TNF␣ inhibitory
therapeutics since 1996
Treatment of sepsis syndrome was the primary
interest of biotechnology companies supporting clinical
trials with recombinant IL-1Ra or chimeric monoclonal
antibodies to TNF␣. Sepsis syndrome is an acute disease
that often leads to a rapid decline and death within 30
days. A not insignificant impetus for placing a high
priority on targeting this disease was the financial incentive, since a successful new treatment for this lethal
disease would return potentially early and vast profits.
Despite extensive preclinical evidence that IL-1 and
TNF␣ were important targets, clinical trials on treatment of sepsis syndrome with inhibitors of IL-1 or TNF␣
failed, forcing more than one biotechnology company
out of business.
Despite this setback, the development of anticytokine treatments for RA, other chronic rheumatic
diseases, and inflammatory diseases of other organs was
continued with considerable success. The clinical trials
on TNF␣ blockade, using either chimeric or humanized
monoclonal antibodies or using soluble receptors, gave
positive results in one-half or more of RA patients, as
summarized by Feldmann and colleagues (3,45). TNF␣
blockade with both approaches has also proven efficacious in spondylarthropathies and psoriatic arthritis,
while treatment of inflammatory bowel disease with
monoclonal antibodies to TNF␣ has been successful.
Most importantly, blockade of TNF␣ prevents cartilage
and bone damage, possibly even in patients who do not
show a dramatic clinical response. Treatment of RA with
IL-1Ra was only modestly beneficial, possibly due to its
poor pharmacokinetics and the inability to achieve consistently high levels in the circulation even with daily
injections (47). However, IL-1Ra results in a rapid and
dramatic response in childhood or adult-onset Still’s
disease and in a variety of autoinflammatory disorders
characterized by over-production of IL-1 (48,49).
Other cytokines in the pathogenesis of RA
Considerable knowledge has been amassed over
the past 10 years on pathogenic mechanisms in RA and
the possible importance of additional cytokines beyond
IL-1 and TNF␣. The chondrocyte is a complex cell that
produces and responds to a variety of cytokines in its
primary role in remodeling the cartilage matrix (50). All
cells in the rheumatoid joint—including T and B lymphocytes, dendritic cells, macrophages, fibroblasts, and
AREND AND GOLDRING
Table 2. Some broader implications of the development of inhibitors
of IL-1 and TNF␣*
1. Provided unique tools for basic, translational, and clinical
research.
2. Permitted an elucidation of mechanisms of disease.
3. Used successfully for diseases outside of rheumatology.
4. Stimulated the development of new and novel anticytokine
agents.
5. Changed the nature of postgraduate education and practice in
rheumatology.
* IL-1 ⫽ interleukin-1; TNF␣ ⫽ tumor necrosis factor ␣.
mast cells in the synovial tissue as well as chondrocytes
in the cartilage—are under the influence of a complex
network of cytokines (51). A number of these molecules
may promote inflammation including GM-CSF, IL-6,
IL-12, IL-15, IL-17, IL-18, IL-23, IL-32, and IL-33.
However, it remains unclear whether cytokines in the
rheumatoid joint are organized in any hierarchical pattern and which molecules might be the best targets for
clinical intervention (51).
Broader implications for science and rheumatology
The development of TNF␣ and IL-1 inhibitors
has provided new therapeutic options for diseases where
traditional approaches have often failed. This is the most
important point for patients and physicians; we can now
better relieve suffering and prevent disability from some
severe diseases. In addition, the emergence of this new
field has broader implications for science and for the
practice of rheumatology (Table 2).
Tools of basic and translational science. The
development of specific inhibitors of IL-1 and TNF␣ has
allowed scientists to explore more precisely the roles of
these cytokines in systems in vitro, in normal physiology
in vivo, and in animal models of disease. IL-1Ra is the
first described naturally occurring molecule that functions as a specific competitor of receptor binding of a
hormone-like molecule. Maintaining a local tissue balance between IL-1 and IL-1Ra is important in prevention of disease. Particular inbred strains of mice rendered genetically deficient in production of IL-1Ra
spontaneously develop a chronic inflammatory arthritis
resembling RA or inflammation of the arterial wall
resembling vasculitis (52,53). An allelic polymorphism in
the IL-1Ra gene is associated with a variety of human
diseases, primarily of epithelial or endothelial cells,
possibly through decreasing the production of an intracellular isoform of IL-1Ra and interrupting the balance
with IL-1 (54).
ANTICYTOKINE THERAPEUTICS
Abnormalities in disease. The mechanism
whereby TNF␣ may predispose to a disease process
remains unclear. The results of initial studies indicated
that the major action of TNF␣ blockers in vivo included
down-regulation of the cytokine cascade, decreased trafficking of leukocytes into the joint, a reduction in local
angiogenesis, and induced apoptosis in synovial fibroblasts (45). However, the results of recent studies indicate that anti-TNF␣ therapy restores deficient regulatory T cell function in RA (55,56). How excess TNF␣
may lead to abnormalities in regulatory T cell function in
RA is under current study, although both IL-1 and TNF␣
may directly inhibit regulatory T cell function (57).
Applications to other diseases. The availability of
inhibitors of IL-1 and TNF␣ has led to a greater
understanding of disease mechanisms in other organs
including the brain, lungs, heart, kidneys, reproductive
system, and endocrine system. For example, IL-1Ra is
efficacious in treatment of type 2 diabetes mellitus and
studies on type 1 diabetes are in progress (58).
New anticytokine treatments. The success of antiIL-1 and TNF␣ agents in the treatment of rheumatic and
other diseases has given considerable impetus to a
search for better treatment approaches. Recent reviews
have established some lessons learned over the past 10
years and possible directions in the development of new
biologic therapies for RA (59,60). Among them are: 1)
mechanisms of action of biologic therapies may differ
from those derived from in vitro/ex vivo assays or
preclinical studies; 2) Fc regions of monoclonal antibodies or Ig fusion proteins confer multiple functions on
biologic agents, not all beneficial; 3) immunogenicity is a
feature of all biologic agents; and 4) observed adverse
effects of biologic therapies might not be entirely predictable. Recommendations for development of future
biologic therapies are summarized in a recent review (60).
Despite this complexity and uncertainty, several
new approaches are being developed to block IL-1
including other biologics, inhibitors of IL-1 processing,
and small molecule inhibitors (61). Based on the success
of blocking IL-1 or TNF␣ in the treatment of disease,
there is interest in the potential efficacy of inhibiting
more upstream cytokines, including IL-15, IL-17, IL-18,
IL-21, and IL-32 (59,62,63). Treatment of disease is also
being explored through the use of inhibitors of signal
transduction pathways induced by IL-1 or TNF␣.
Postgraduate education and practice in rheumatology. The successful development of anticytokine therapies has not only benefited our patients but has been
accompanied by changes in postgraduate education and
practice. Physicians and trainees now routinely experi-
S107
ence drug marketing masquerading as postgraduate
education. The ACR faces ethical issues with regard to
the potential financial influences of large companies,
and the opportunity has emerged to enhance practice
income through altering prescription patterns. In a
sense, we have witnessed a “loss of innocence” in the
field of rheumatology, joining other subspecialties such
as oncology and cardiology, where such changes in
education and practice are also occurring.
Summary
We have briefly reviewed the history of IL-1 and
TNF␣ and the development of therapeutic agents that
block these cytokines. This line of investigation started
with observations by astute investigators in the fields of
oncology and infectious diseases who were using relatively simple experimental approaches. A variety of
sometimes serendipitous and paradoxical findings have
characterized progress to our present state of knowledge. Our patients have benefited and our professional
life has changed, perhaps not always for the better.
Although anticytokine agents represent an important
advance in treatment, development of the next level of
new therapeutic agents will follow after further knowledge emerges on the causes of rheumatic diseases.
ACKNOWLEDGMENT
Review of this manuscript by Dr. V. Michael Holers is
gratefully acknowledged.
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