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Pathogenesis of arthritis:
recent research progress

There are many forms of rheumatic disease and

Based on fundamental principles of immuno- sive arthritis. This arthritis is transferable by
few of us will escape from feeling the torments logy and association with major histocompati- serum antibodies, which led to the identificaof one or more types of arthritis. The most dis- bility complex class II, the concept that CD4+ T tion of the ubiquitous enzyme GPI as the target
abling is rheumatoid arthritis (RA). This cells are of major importance in driving disease of the autoimmune response3. Skeptics will
autoimmune disease of synovial joints, with its activity gained much currency in the 1980s and point out that this mouse model has as yet
chronic inflammation and ensuing destruction led to therapeutic trials of several antibodies to unknown relevance to RA, but it is nevertheless
of cartilage and bone, has a prevalence of 1%. CD4. These had limited success, which sug- interesting that a chronic immune response to
More common is osteoarthritis, which affects gested that perhaps the role of these cells in the nonjoint-specific antigens can yield arthritis
10% of the population, especially the elderly. chronic RA disease process is not the same as and a timely reminder that autoantibodies have
Other forms include a cluster of the HLA- in a normal immune response, or even that they a role in RA.
B27associated diseases, such as ankylosing are innocent bystanders. Subsequent research
Paradoxically, the T cell response in active
spondylitis. It is not possible to comprehen- has tended to support their relevance2. But, RA patients is abnormally reduced. Although
sively review the progress
the inflammatory process has
made in research on all forms
been implicated in this, the
of arthritis here, so I will conmechanism is not well underWhat is the role
centrate on RA, which has
stood. Nor is it understood
of shared epitopes?
Why is T cell function
attracted the most attention.
whether reduced T cell immuAPC
abnormal?
Recent research has lead to a
nity reflects adaptive mechaWhy do T cells persist
fuller understanding of the
nisms to ameliorate the disease
in the joints?
roles played by cytokines in
activity. Remission of disease
RA and significant improveactivity with, for example,
What are the T cell
ments in RA therapy; however,
antibodies to tumor necrosis
T
signals driving
What are the key
our understanding of the
factor- (F-) can restore T
macrophage activation?
arthritogenic antigens
immunology of the disease is
cell function. Thus normalizaand epitopes in man?
incomplete.
tion of T cell function might
In the 1970s Stasny desrestore normal homeostatic
Why is homeostsasis not
cribed the genetic association
mechanisms. Defective T cell
adequate e.g. IL-10 is
Macrophage
of RA with HLA. With their
function in RA may arise as a
produced, but not enough?
description of the shared epiresult of impaired thymic functopea sequence (QKRAA)
tion, as TCR exclusion circles
What are the non-HLA
in the DR of the HLA class II
are reduced in patients and
genes for susceptiblity?
How is tissue destruction
molecule that contributes to the
telomeres are shortened.
activated and upregulated?
What are the key
e.g. matrix metalloproteases,
angiogenic factors?
peptide-binding groove of
Several groups have identified
aggrecanases and osteoclasts.
HLA-DR allele subtypes assoTCR abnormalities, both in
ciated with RAthe genetics
calcium signaling and expreswere further refined by
sion of the chain. Chronic
Figure 1. Some of the unresolved key questions in rheumatology research,
Gregersen, Winchester and
TNF stimulation of T cells in
specifically for understanding RA.
Silver. However, it is still not
vitro leads to a similar phenoclear how this influences distype and may explain it4, as
ease. Many patients (2030%) lack it, so it is unlike some other autoimmune diseases, such TNF- is overexpressed in RA synovium.
not essential. Weyand, Goronczy, Wordsworth as multiple sclerosis and thyroiditis, the nature
The cells infiltrating the rheumatoid synoviand others have suggested that it affects disease of the T cell antigens driving the autoimmune um are 30% T cells. Chiefly, they are small
severity or may influence disease phenotype. response is not obvious. Although joint-specific noncycling CD4+ T cells, but most have markOther hypotheses include skewing of the T cell antigens such as collagen type II and chondro- ers of T cell activation. These cells may persist
repertoire or presentation of selected (cartilage) cyte gp39 are popular candidates, ubiquitous in the joints due to defective apoptosis5. Dayer
antigens. It is striking that the peptide-binding antigens such as BiP and the glucose-6-phos- and colleagues developed a T cellmacrophage
groove of HLA-DR4 selects similar collagen phate isomerase (GPI) have also been proposed coculture that enabled the study of chronically
peptides to that of I-Aqwhich is present in as candidates. It was serendipitously observed activated synovial T cells in order to analyze
mice susceptible to collagen type IIinduced that T cell receptor (TCR)-transgenic mice, the importance of T cell contact with other
arthritis, an animal model that resembles RA which recognize bovine ribonuclease peptide in cells in inflamed joints. Rheumatoid T cells
and DR4-transgenic mice present arthritogenic the context of I-Ak, crossed to nonobese diabet- are, indeed, activated and capable of inducing
antigens to murine CD4+ T cells1.
ic mice (I-Ag7) spontaneously develop an ero- interleukin 1 (IL-1), TNF- and metalloproBob Crimi

2001 Nature Publishing Group http://immunol.nature.com

MARC FELDMANN

Rheumatoid arthritis affects millions of

individuals worldwide. Luckily, it is the
autoimmune disease with the most
promising clinical results.

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N EWS & V IEWS

teinase production. T cellmacrophage interactions may be important in RA tissue, as serum

contains inhibitors of this interaction, namely
apolipoprotein AI6. This culture system showed
that T cells activated by a cocktail of cytokines,
rather than just by antigen, may be of importance in the rheumatoid process. Brennan and
colleagues have found that T cells isolated
from late-stage synovium in RA behave very
much like cytokine-activated T cells, as judged
by analysis of the signaling pathways they
induce in monocytes. It is noteworthy that
these RA synovial T cells induce TNF- in
macrophages with signaling pathways other
than those used by antigen-activated T cells,
which suggests that it will eventually be possible to block rheumatoid TNF- without interfering with immune TNF-.
Tissue damage and destruction are important
underlying mechanisms in the progressive
course of severe RA and osteoarthritis. A major
recent advance has been the definition of some
of the key enzymes involved in initiating the
destruction of cartilage. Although matrix metalloproteinases are involved, the classically
described enzymes did not explain the specificity of cleavages. Cartilage is a complex,
hypocellular tissue whose physical properties,
such as compressibility and resilience, are due
to the matrix of a dense network of collagen
type II and a hydrophilic macromolecular complex of proteoglycan termed aggrecan.
Aggrecan cleavage is the first step in cartilage
destruction and two enzymes, termed aggrecanases, were cloned in 19997. These are
members of the ADAMTS (a disintegrin and
metalloproteinase with thrombospondin type I
motif) family. Inhibitors of their activity are
being actively sought to protect cartilage from
degredation, especially in the more prevalent
disease osteoarthritis. Tissue inhibitor of metalloproteinase 3 (TIMP-3) is an endogenous
inhibitor of aggrecanases, and it may provide
major clues to designing more effective and
specific inhibitors.
Bone destruction is mediated by osteoclasts.
Osteoclast biology has recently been transformed by the ability to grow these cells in
vitro. This allows researchers to differentiate
them from monocytic precursors under the
influence of the TNF-like factor known as
receptor-activator of NF-B (RANK) ligand
(RANKL, also known as OPGL, ODF and
TRANCE)8. RANKL is produced by a variety
of cell types, including osteoclasts, T cells and
fibroblasts, and interacts with its cognate signaling receptor, RANK, on osteoclastic precursors. Osteoclastogenesis is promoted by the
cells found in inflammatory bone lesions and
can be enhanced by pro-inflammatory
772

cytokines such as TNF- and IL-1. A soluble

decoy receptor, osteoprotegerin (OPG), can
bind to RANK, inhibiting RANKL-RANK signal transduction. OPG-deficient mice develop
osteoporosis, which is effectively rescued by
administration of recombinant OPG. OPG
recently entered clinical trials to evaluate its
potential for preventing bone loss in osteoporosis and, if successful, may be useful in the
treatment of other bone-destructive diseases,
including RA and cancer.
The most unambiguously successful aspect
of RA research in the past decades has been in
the field of cytokine expression and regulation,
as it has led to new rational therapies. In the
early 1980s, when cytokine cDNAs were
cloned, the tools became available to evaluate
cytokine expression in rheumatoid synovia.
This led to a better understanding of their role
in the pathogenesis of RA and their value as
potential therapeutic targets.
The RA synovium expresses most of the
known pro-inflammatory cytokines9, which led
many groups to abandon the idea of antiinflammatory anticytokine therapy, on the
assumption that blocking a single one was
unlikely to be effective and blocking many
unrealistic. However, in vitro studies found that
TNF- regulates the expression of other proinflammatory cytokines and, thus, may be an
attractive target. This hypothesis was confirmed
in animal models of RA and led to the initiation
of clinical trials of antiTNF- therapy in 1992.
These have been very successful: 6080%
patients resistant to existing therapy, including
the gold standard low-dose methotrexate
therapy, nevertheless respond to anti-TNF biological agents. Two anti-TNF drugs have been
approved for use in the US and Europe for
severe RA: an antibody to TNF- (infliximab,
Remicade) and TNF receptorimmunoglobulin fusion protein (etanercept, Enbrel)10 and
by mid 2001, over 150,000 rheumatoid patients
have been treated wth anti-TNF biologicals.
More biological agents are likely in the future
(for example, D2E7, another antibody that is in
phase III clinical trials). These TNF inhibitors
relieve symptoms (pain, morning stiffness),
signs (joint swelling, joint tenderness) and normalize production of cytokines and inflammatory proteins (for example, IL-6 and C-reactive
protein). Most importantly, they inhibit and, in
a proportion, halt joint destruction, based on
clinical trials extending now for 2 years11.
Successful clinical trials of antiTNF- in RA
have led to advances in the treatment of other
chronic inflammatory diseases, with Crohns
disease being the first follow-on, but now also
juvenile arthritis, psoriatic arthritis, ankylosing
spondylitis and psoriasis.

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The success of these clinical trials has

focused the spotlight on pro-inflammatory
cytokine signaling, as inhibition of receptors is
a classic target for the development of orally
available drugs. A popular approach targets the
p38 mitogen-activated protein kinase (MAPK),
part of a signaling pathway involved in both
IL-1 and TNF function. Despite the fact that
drugs blocking p38 are effective in animal
models, human studies so far have been hindered by drug toxicity. This has prompted studies to investigate how p38 MAPK acts to mediate its inflammatory effect. Stabilization of
mRNAs (such as IL-1, TNF- and cyclooxygenase 2), which contain clusters of the motif
AUUUA in their 3 region, also appears to be
important12. The importance of this region was
also highlighted in knockout mice: mice in
which this motif in the gene encoding TNF-
had been deleted spontaneously developed
arthritis and colitis, and mice that lacked tristetraprolin, a protein that binds to this region,
also developed arthritis. In both instances, elevated TNF- was detected.
Other approaches to blocking TNF- signaling are being researched, particularly the
development of safe and effective inhibitors of
the NF-B pathway. The molecular dissection
of the induction of NF-B by the IB kinase
complex discovered by Karin and colleagues
has provided a number of molecular targets.
NF-B is likely to be a good target for the
treatment of RA13. Specifically blocking NFB in human rheumatoid synovial cultures by
using an adenovirus over expressing IB (an
endogenous inhibitor of NF-B) reduced
rheumatoid synovial production of TNF- by
70%14. It also reduced other pro-inflammatory
cytokines and destructive metalloproteinases,
without altering the production of anti-inflammatory cytokines such as IL-10 or IL-1 receptor- antagonist (IL-1ra)15. The use of adenoviruses to effectively deliver inhibitory
cDNAs to appropriate human cells in the diseased tissue aids our understanding of pathogenesis and is useful for target validation14,15.
The role of IL-1 in the pathogenesis of RA,
long suspected, has not yet been adequately
tested. Clinical trials of inhibition of IL-1 by
IL-1ra are only modestly effective compared to
antiTNF-16. However, IL-1R has a much
briefer serum half-life than antibodies, so it is
not yet clear whether the lesser efficacy is due
to the different biological roles of TNF- and
IL-1 or to the incapacity of IL-1ra at the doses
used to maintain a sufficient degree of IL-1R
blockade. These issues will not be resolved
until other tools become available, such as soluble IL-1R or antibodies to IL-1 or IL-1R
type I. IL-1 receptorassociated kinase (IRAK

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inhibitors) will block IL-1, but also IL-18 and

Toll-like receptor function, so these results will
be more difficult to interpret. Whether a combination of IL-1 and TNF inhibitors17 will be
more protective of joints seems questionable in
view of the marked joint protection and some
initiation of repair seen in antiTNF- trials11,
but is a hypothesis worth evaluating.
There are many other aspects of arthritis
research that show progress worthy of mention.
Gene therapy of arthritis has been contemplated, and multiple successful experiments in animal models have led to one trial, in humans, to
monitor gene expression (of the gene encoding
IL-1ra) in joints that are soon to be replaced18.
If the problems of gene delivery can be solved,
the capacity of gene therapy to deliver multiple

therapeutic proteins locally, which could, like

other genes, be regulated, offers exciting
prospects for the future. Another research area
that is likely to eventually blossom into therapeutics is the interactions of stem cells and their
growth factors to engineer tissue repair. That
prospect is as bright in joints as in other tissues,
with the added bonus that joints are more accessible. Further work on mesenchymal stem
cellswhich are found in bone marrow and
blood, and can differentiate into connective tissueswill surely be rewarding.
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3. Matsumoto, I., Staub, A., Benoist, C. & Mathis, D. Science 286,
17321735 (1999).
4. Isomaki, P. et al. J. Immunol. 166, 54955507 (2001).

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6.
9.
10.
11.

Kennedy Institute of Rheumatology Division, Imperial

College School of Medicine, 1 Aspenlea Road,
Hammersmith, London W6 8LH, UK.
(m.feldmann@ic.ac.uk)

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