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Rheumatoid arthritis therapy after tumor necrosis factor and interleukin-1 blockade.

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ARTHRITIS & RHEUMATISM
Vol. 48, No. 12, December 2003, pp 3308–3319
DOI 10.1002/art.11358
© 2003, American College of Rheumatology
REVIEW
Rheumatoid Arthritis Therapy After
Tumor Necrosis Factor and Interleukin-1 Blockade
Kurt Redlich,1 Georg Schett,1 Günter Steiner,2 Silvia Hayer,1 Erwin F. Wagner,3
and Josef S. Smolen2
DMARD (2). In this trial, MTX showed a benefit that
was not dissimilar to that of the biologic agent, although
some subanalyses and extension trials favored the TNF
blocker (2,9). However, there are no head-to-head trials
comparing each biologic agent separately, and thus we
do not know if one of them may be better than another.
Importantly, 2 new trials have revealed that MTX ⫹
infliximab is superior to MTX alone in early RA, and
equally important, etanercept ⫹ MTX is superior to
either MTX or etanercept alone in established RA.
These data suggest that combination of a TNF blocker
with MTX may be the most efficacious therapeutic
approach at present. However, the results of these
studies have not yet been published.
Limitations. As much as these new targeted
therapies have expanded the therapeutic armamentarium and advanced the field of RA therapy, they nevertheless do have, in addition to their potential adverse
effects, limited efficacy (10). In fact, only a small proportion of patients achieve 70% improvement according
to the American College of Rheumatology (ACR70)
clinical response criteria, and remissions are exceedingly
rare. Moreover, the frequency of patients who do not
achieve even the weakest response, namely an ACR20
(20% improvement) response, amounts to 28–58% (Table 1). Taking into account that determination of the
ACR response, by virtue of its composite nature (14),
may over- or underestimate treatment effects, and considering that the determination of a European League
Against Rheumatism (EULAR) improvement response
as a continuous variable may better reflect therapeutic
responses (15,16), the frequency of unresponsiveness
according to the EULAR criteria is still high (17).
However, in this context it should be noted that patients
who are entered into clinical trials of biologic agents
have already shown nonresponsiveness to other
DMARDs alone, mostly in regimens including MTX
with one exception (2), and that the earlier DMARD
Introduction
The introduction of novel disease-modifying antirheumatic drugs (DMARDs), including biologic
agents, has set new standards in the treatment of rheumatoid arthritis (RA). These agents not only modify
disease (hence the name DMARDs) in terms of influencing its signs and symptoms, achieving high responder
rates, and retarding radiographic progression (1–6), but
also have made it possible to translate recent pathogenetic insights into clinical practice (7,8).
The success and limitations of the novel therapies
Efficacy. In clinical trial settings, the new agents
have been efficacious, particularly in patients whose
disease had failed to show improvement with prior
DMARDs. Although many rheumatologists believe that
the tumor necrosis factor (TNF) blockers are more
efficacious than traditional DMARDs, this is still unproven, since most trials have tested the new compounds
by comparing them with placebo alone or placebo ⫹
methotrexate (MTX) or using them in combination with
MTX in patients whose disease remains active despite
MTX therapy. There exists only one published head-tohead trial of a biologic agent versus a traditional
Supported in part by the ICP project of the Austrian Ministry
of Education and Research and the City of Vienna, and by the START
prize from the Austrian Research Council (Fonds zur Förderung der
wissenschaftlichen Forschung).
1
Kurt Redlich, MD, Georg Schett, MD, Silvia Hayer, MD:
University of Vienna, Vienna, Austria; 2Günter Steiner, PhD, Josef S.
Smolen, MD: University of Vienna and Center of Molecular Medicine,
Austrian Academy of Sciences, Vienna, Austria; 3Erwin F. Wagner,
PhD: Research Institute of Molecular Pathology, Vienna, Austria.
Address correspondence and reprint requests to Josef S.
Smolen, MD, Department of Internal Medicine III, Division of
Rheumatology, University of Vienna, Währinger Gürtel 18-20, A-1090
Vienna, Austria. E-mail: josef.smolen@wienkav.at.
Submitted for publication April 2, 2003; accepted in revised
form August 20, 2003.
3308
RA THERAPY AFTER TNF AND IL-1 BLOCKADE
3309
Table 1. Frequency of nonresponders according to the American College of Rheumatology 20% and
50% improvement criteria (ACR20 and ACR50, respectively) in clinical trials with tumor necrosis factor
or interleukin-1 blockers
Compound
Infliximab*
Etanercept*
Adalimumab*
PEG-TNFRI†
Anakinra*
Etanercept
ACR20
nonresponder, %
Placebo
nonresponder, %
ACR50
nonresponder, %
Duration of
treatment,
weeks
Reference
48
29
34
50
58
28
83
73
85
74
77
35‡
67
61
46
80
76
35
54
24
24
12
24
52
4
11
5
12
13
2
* With concomitant methotrexate.
† Pegylated recombinant methionyl human soluble tumor necrosis factor type I.
‡ Methotrexate used as comparator.
courses appear to be more effective than subsequent
ones (18).
With regard to retardation of radiographic progression, it is evident that the biologic agents, especially
in combination with MTX, may achieve results rarely
seen before. Nevertheless, both with etanercept and
anakinra, there is a mild slope of progression suggesting
that disease continues to progress, albeit at lower levels
(2,3). Even when considering the most impressive data
published to date on retardation of radiologic progression in RA, namely trials of infliximab (4), there are
many patients whose joint destruction still continues.
What do these results mean? 1) Do they mean
that we do not use the right doses of biologic agents in all
patients? This is unlikely, since no significant differences
in retardation of radiographic joint damage were seen
among several doses of infliximab, with the lowest dose
being as efficient as the highest one (⬎6-fold dose
difference) (4). 2) Do they mean that more than 1
proinflammatory cytokine is involved in driving the
rheumatoid process? This is a possibility, since inhibition of the activities of interleukin-1 (IL-1) also retards
joint destruction, and there may be TNF-independent
IL-1 activation (19). Furthermore, IL-6 may also be a
player in this respect (20). 3) Do they mean that other
mechanisms, upstream or downstream of the production
of proinflammatory cytokines, may be of importance?
This will be one of the focuses of this review.
It is evident from the data in the literature that
use of TNF blockers combined with MTX may be the
most powerful strategy currently available for treating
RA. However, the data shown in Table 1 reveal that
more needs to be done to attain full control of RA in all
patients. We need new therapies in order to achieve
better relief from the signs and symptoms of RA than is
currently possible, to fully revert RA from a destructive
to a nondestructive joint disease, to induce a complete
response or remission, which is currently only rarely
achieved with the biologic agents, and, ideally, to lead to
a cure.
To address the issue of potential new therapies,
we have divided the therapeutic targets into those
upstream of TNF and IL-1, those occurring downstream
of the proinflammatory cytokines, and events deemed to
be active in parallel with TNF and IL-1. The selection of
the targets is, by no means, comprehensive. Nevertheless, the selected targets ought to serve as examples for
future approaches. Moreover, in this context, we will
also discuss changes in therapeutic strategies.
Targets upstream of TNF and IL-1
Role of T cells. There is a continuing debate on
the involvement of T cells in the pathogenesis of RA.
Several investigators have suggested that the major
pathogenetic events in RA involve the macrophage and
fibroblast-like cells (21). There is significant supporting
evidence for such an assumption, and the major inflammatory events, which include joint destruction, are
clearly mediated by these cells. Nevertheless, the major
histocompatibility complex (MHC) association with RA
(22), the production of significant amounts of T cell–
derived cytokines (23) when compared with active immunization with T cell–dependent antigens, and the
response to therapies directed or partly directed at T
cells, such as cyclosporin A (24) and leflunomide (6),
suggest that the involvement of T cells in the pathogenic
process could not be easily dismissed. Further support
for such involvement stems from data showing the
involvement of cell contact between T cells and macrophages as one mechanism for the secretion of proinflammatory cytokines (25). Finally, in situations of nonubiq-
3310
REDLICH ET AL
Figure 1. Illustration of rheumatoid arthritis synovial membrane, demonstrating differential localization of
stress- or mitogen-activated protein kinases. The upper right section of the sphere shows the different
compartments of the synovial membrane. EC ⫽ endothelial cells; PV ⫽ perivascular region; SSL ⫽ synovial
sublining layer; SLL ⫽ synovial lining layer. The upper left section and the 4 boxed images show the predominant
localizations of p38 MAPK, JNK, and ERK activation. Different cell types of the synovium are illustrated in the
lower section of the sphere.
uitous and even of ubiquitous autoantigen expression, an
arthritogenic or autoimmune response is initiated in the
local lymph nodes (26,27).
Recent observations in the course of early-phase
clinical trials tend to support the notion of a potential
role of T cells in the initiation and perpetuation of RA.
CTLA-4Ig, which binds to the costimulatory molecules
CD80 and CD86 and thus prevents their interaction with
and subsequent activation of the CD28 receptor on the
T cell (28), appears to be highly effective in RA. More
than 50% of RA patients treated with 10 mg/kg of
CTLA-4Ig achieved an ACR20 response, compared with
⬍20% of patients receiving placebo, and there was also
a dose-dependent decrease in the soluble IL-2 receptor,
a well-known measure of disease activity (29,30). Similar
clinical effects may be attributable to inhibition of
lymphocyte function–associated antigen 3–CD2 interaction, which also interferes with T cell costimulation, has
significant activities in psoriatic arthritis (31), and is
likely to have similar effects in RA.
Thus, not only do these data suggest that T cells
are involved in the pathogenesis of RA, but also they
reveal that therapies directed at interfering with T cell
activities may be as effective as other DMARDs. Nevertheless, these initial data will have to be confirmed in
future trials. Likewise, it has to be shown that radiographic progression is halted and functional impairment
significantly improved when this approach is used. A
variety of therapies targeting T cells have, however, been
hitherto unsuccessful (32), and the failure of T cell–
directed therapies to significantly benefit more than a
subset of patients suggests that perpetuation of chronic
disease is multifactorial and that T cells do not represent
the only responsible mechanism, at least not all of the
time in every patient. Moreover, initiation of the disease
process may occur prior to the first appearance of
RA THERAPY AFTER TNF AND IL-1 BLOCKADE
3311
Figure 2. Expression of matrix metalloproteinases (MMPs), but not tissue inhibitor of metalloproteinases
(TIMP), at the cartilage–pannus junction area of the joint from soluble human tumor necrosis factor–
transgenic mice. Deparaffined joint sections were stained with anti–MMP-3 (A), anti–MMP-9 (B), anti–
MMP-13 (C), or TIMP antibody (D). MMP- or TIMP-expressing cells are indicated by brown staining. JS ⫽
joint space; AC ⫽ articular cartilage; SB ⫽ subchondral bone. (Original magnification ⫻ 200.)
clinical symptoms, and pathways involving the innate
immune system, including dendritic cells (DCs) and
macrophages, and Toll-like receptors may be operative
therein (33,34).
Regulatory T cells. On a more speculative basis,
it is conceivable that activation of regulatory T cells,
shown to be deficient in nonarthritic experimental models of autoimmune diseases (35), may also exert beneficial effects in RA. These Treg cells have been only
recently described, and thus the importance of suppressor cells has been rediscovered (36). They appear to
exert their down-regulating effects not via CTLA-4, but
via cell–cell contact and transforming growth factor ␤
production. In experimental autoimmune models, activation of Treg cells leads to prevention and cure of
disease (37). This concept has also been taken forward
into human autoimmunity (38). Moreover, certain DC
subsets are involved in the induction of Treg cells (33).
Targets downstream of TNF and IL-1
Signal transduction cascades and the role of
matrix metalloproteinases (MMPs). Once TNF or IL-1
engages its cell surface receptor, a variety of signaling
pathways are triggered. Two of the most important are
the NF-␬B and the MAPK/SAPK pathways. Both
NF-␬B and MAPK have been shown to be activated in
the RA synovial membrane (39,40). Previous observations have already revealed that stress pathways are
activated in the synovium, since heat-shock protein 70
and heat-shock factor 1 are overexpressed in the lining
layer and other areas (39,41). Interestingly, although
TNF and IL-1 are overexpressed in the RA synovial
membrane (23,41–43), and although both cytokines appear to activate the 3 MAPKs ERK, JNK, and p38 to a
similar degree in vitro (40), they are differentially expressed in the synovial membrane (Figure 1). The p38
3312
REDLICH ET AL
Clearly, MAPK and their downstream transcription
factor, activator protein 1, are involved in the activation of
different cytokine and MMP genes (44–46), although
other transcription factors such as NF-␬B and Ets-1, involved in cytokine and MMP induction, are evidently
overexpressed in the RA, but not in the osteoarthritic,
synovium (39,47). In fact, an imbalance of MMPs and
tissue inhibitors of metalloproteinases (TIMPs) has been
Figure 3. Marked reduction of inflammation (A) and erosion (B) in the
proximal interphalangeal (PIP) and metatarsophalangeal (MTP) joints of
soluble human tumor necrosis factor–transgenic (hTNFtg) mice treated
with an adenoviral vector for tissue inhibitor of metalloproteinases
(TIMP), compared with untreated hTNFtg control (Co) mice. Bars show
the mean and SEM (n ⫽ 7 in each group). ⴱ ⫽ P ⬍ 0.01 versus controls.
kinase is mainly expressed in the lining layer and in
endothelial cells, ERK is mainly expressed in perivascular mononuclear cells, and JNK is mainly seen in the
sublining area. Since ingression of inflammatory cells
into the synovial membrane via the endothelium and
attachment of lining layer cells to cartilage and the
cartilage–bone junction appear to be important events in
the pathogenesis of RA, p38 MAPK may play a particularly important role. However, it is not clear at present
which subsequent events are differentially driven by the
3 MAPKs, nor do we know why they are distinctly
activated in specific regions of the synovial membrane.
Figure 4. Osteoclasts are found in inflamed joints at the site of
erosions in a soluble human tumor necrosis factor–transgenic (hTNFtg) mouse (A) and in a metatarsal joint of a patient with rheumatoid
arthritis (RA) (B). Osteoclasts are found in the tartrate-resistant acid
phosphatase (TRAP)–stained sections at the front of erosions (TRAPpositive multinucleated cells, indicated by arrows). SB ⫽ subchondral
bone. (Original magnification ⫻ 200 in A; ⫻ 100 in B.)
RA THERAPY AFTER TNF AND IL-1 BLOCKADE
3313
Figure 5. Evidence of severe joint inflammation in soluble human tumor necrosis factor–transgenic
(hTNFtg) and c-fos⫺/⫺ hTNFtg mice, but no signs of bone erosions in the c-fos⫺/⫺ hTNFtg mouse, as
demonstrated by hematoxylin and eosin–stained sections of tarsal areas of the hind paws of an hTNFtg
(A), c-fos⫺/⫺ hTNFtg (B), wild-type (WT) (C), and c-fos⫺/⫺ (D) mouse. Inflammatory tissue (indicated by
white arrows) and erosions (indicated by black arrows) are present in the hTNFtg mouse (A), whereas the
c-fos⫺/⫺ hTNFtg mouse only shows inflammatory tissue (white arrows) but no erosions (B). The WT (C)
and c-fos⫺/⫺ (D) mice lack any signs of inflammation, and therefore serve as controls. (Original
magnification ⫻ 50.)
observed in RA (48), and MMPs have been suggested to
play a pivotal role in the cartilage and bone destruction of
RA (32,49). On the basis of these findings, molecules
involved in the transduction of cytokine-induced signals,
such as the NF-␬B or p38 and JNK pathways, currently
constitute important targets of therapeutic efforts, both
experimentally and in early clinical trials (50,51). It will be
important to reveal their degree of efficacy as well as their
toxicity.
In an animal model in which overexpression of
TNF leads to severe destructive arthritis independent of
T and B cells (52), MMPs are also highly activated,
whereas TIMP is hardly found (Figure 2). Using a gene
therapeutic approach, TIMP was overexpressed, and
both inflammation and destruction were highly retarded
in these TNF-transgenic animals (Figure 3) (48). Thus,
targeting MMPs may also be of benefit in human RA.
Although several xenobiotic MMP inhibitors have been
tested with little success or with the occurrence of
significant adverse events (32), TIMP has not yet been
applied and could constitute a powerful therapy. Interestingly, the findings of the experiment demonstrated in
Figure 3 suggest that in addition to gross tissue destruction, MMPs are involved in the inflammatory process via
infiltration of inflammatory cells. Since, in RA, destruction correlates with the degree of joint inflammation, the
above data are compatible with such notions of some
linkage between inflammation and destruction in RA.
Mechanisms of joint destruction. In order to
pursue the question of whether or not inflammation and
3314
destruction are coupled, it is important to analyze which
cells and molecules are pivotally involved in the destructive process. In recent years, it had been assumed that
pannus invades cartilage and bone and that MMPs are
prominently involved in the destruction of the joint (49).
The synoviocytes or pannocytes, i.e., mainly the
fibroblast-like synovial lining cells, have been demonstrated to be of a particularly aggressive nature (49,53–
55). On the other hand, osteoclasts have been shown to
be present in RA synovial membrane near sites of
erosions (56), and the factors essential for osteoclast
differentiation and activation, namely receptor activator
of NF-␬B (RANK), RANK ligand (RANKL), and macrophage colony-stimulating factor (57), are all present in
the synovial membrane. Moreover, interference with the
RANK/RANKL system by osteoprotegerin (OPG) leads
to inhibition of destruction in adjuvant arthritis, a T
cell–mediated experimental arthritis (58), and because
RANK/RANKL are also important for T cell–DC interactions, it was suggested that these findings were due to
blockade of T cell activities in the context of osteoclast
maturation.
In order to pursue this issue further, we carried
out experiments utilizing the T cell– and B cell–
independent TNF-transgenic animal model (59). Indeed, in this model, as in RA, osteoclasts were found at
the pannus–bone junction (Figure 4). Administration of
OPG to these animals significantly reduced bone erosions but did not influence inflammation (59). However,
since this still did not rule out the possibility that
cell–cell interactions other than the differentiation of
osteoclasts were inhibited by OPG, other investigations
were necessary. This finding was further expanded in a
model utilizing c-Fos–deficient animals; these mice are
osteopetrotic, have no overt immunologic defects, and
lack osteoclasts, since c-Fos appears to be stringently
required for the transduction of RANK-mediated signals (60). Crossing c-Fos–deficient mice with TNFtransgenic mice led to a form of experimental arthritis in
which a high degree of inflammation and functional
impairment was seen, but bone destruction was prevented (61) (Figure 5). When serum from K/BxN mice
(a mouse strain with a transgenic T cell receptor that
develops severe, erosive arthritis due to antibodies
against glucose-6-phosphate isomerase [62]) was injected into osteoclast-deficient RANKL⫺/⫺ mice, similar
observations were reported (63). However, in both of
these animal models, cartilage matrix was degraded, as
evidenced by proteoglycan loss (Figure 6).
Thus, these data indicate that bone destruction in
arthritis is 1) dependent on the activation of osteoclasts,
REDLICH ET AL
and 2) an event which can be separated from inflammation, since mechanisms that lead to the differentiation
and/or activation of osteoclasts can be specifically targeted and blocked. Cartilage degradation is likely to
occur because of the production of proteinases by cells
within the pannus, synovial tissue, and chondrocytes, in
response to several stimuli resulting from the inflammatory process.
These observations on the distinctions between
inflammation, cartilage degradation, and bone destruction are also indirectly supported by the finding that the
highest degree of cartilage matrix degradation occurs in
reactive arthritis, a disease rarely accompanied by bone
erosions (64,65). However, since the degree of radiographic joint destruction correlates with bad functional
outcome in RA in the long term (66), interference with
the destructive process in combination with specific or
nonspecific antiinflammatory measures might be an
interesting and necessary therapeutic avenue. Such interference could be brought about by OPG or antibodies
to RANKL (67).
Targets acting in parallel or some cross-dependence
with TNF and IL-1
Many cytokines other than TNF and IL-1 appear
to be involved in the pathogenesis of RA. They have
either an antigen-presenting cell, macrophage, or T cell
origin. For example, IL-6, IL-12, IL-15, IL-17, and IL-18
all appear to be involved in RA. In some instances, these
proinflammatory cytokines may be induced by TNF or
IL-1 (48,68–75). Although the hierarchy of the cellular
and cytokine pathways in the pathogenesis of RA is still
elusive, inhibition of each of these cytokines appears to
ameliorate experimental arthritis. In addition to IL-6,
for which data from phase II trials are available (76) and
phase III trials are ongoing, some targets, such as IL-15
and IL-18, have already been utilized in clinical trials
(77). Preliminary available information suggests the
efficacy of IL-15 and IL-18 blockade, but again, this
effect does not appear to supercede that known for
other types of interventions, further supporting the view
of a redundancy and multiplicity of cells and molecules
involved in the pathogenesis of RA.
Another area highly neglected in recent years is
autoimmunity (78). In many centers, research in RA has
drifted away from its previous major focus on autoimmunity (78–80). New autoantigens have been described in
recent years, and most of them have been characterized,
among them RA33, Sa, BiP, and citrullinated proteins
(78,81). T cell reactivity to some of these autoantigens has
RA THERAPY AFTER TNF AND IL-1 BLOCKADE
3315
Figure 6. Reduction in proteoglycan (PG) content in cartilage of c-fos⫺/⫺ soluble human tumor necrosis factor–transgenic (hTNFtg) mice and
receptor activator of NF-␬B ligand (RANKL)⫺/⫺ mice with serum transfer arthritis. Data from 2 different sets of experiments are shown. In one
set (A and B), c-fos⫺/⫺ mice, which lack osteoclasts, were crossed with hTNFtg mice, which develop severe erosive arthritis, generating animals with
severe inflammation but lack of osteoclasts (c-fos⫺/⫺ hTNFtg mice) (61). In another set of experiments (C–F), RANKL⫺/⫺ mice, which also lack
osteoclasts, received serum from K/BxN mice, which spontaneously develop severe, autoantibody-mediated erosive arthritis, generating an immune
complex–mediated arthritis model in the absence of osteoclasts (63). Toluidine blue staining of articular cartilage is shown for c-fos⫺/⫺ mice (A),
c-fos⫺/⫺ hTNFtg mice (B), littermate control mice with serum transfer arthritis (C and D), and RANKL⫺/⫺ mice with serum transfer arthritis (E and
F). A marked reduction in PG content, indicated by decreased staining intensity (black arrows), was found in c-fos⫺/⫺ hTNFtg mice as well as in
arthritic RANKL⫺/⫺ mice and arthritic control mice. Pannus formation with associated cartilage matrix destruction and PG loss was observed in the
serum transfer arthritis model (C and E). Red asterisks indicate full-thickness subchondral bone erosions with associated full-thickness cartilage
destruction in control mice with serum transfer arthritis (D), which were absent in arthritic RANKL⫺/⫺ mice. (Original magnification ⫻ 200 in A
and B; ⫻ 50 in C–F.) Figures 6C–F were kindly provided by Drs. Allison R. Pettit and Ellen M. Gravallese.
been demonstrated in RA patients (82,83). This T cell
reactivity, as well as observations on the IgG nature and the
somatic mutation of such autoantibodies, clearly suggest
the importance of T cell–B cell interactions in the course of
the autoimmune response. Furthermore, some indications
for a potential pathogenic role of autoantibodies in RA
come from clinical studies in which selective blocking of B
cells with anti-CD20 (rituximab) has led to a major improvement in disease activity (84,85). However, even
though rheumatoid factor (RF) levels decreased or even
3316
returned to normal levels in some of these patients, the
detailed mechanisms whereby anti-CD20 improves RA are
currently unknown and may involve pathways other than
interference with autoantibody production.
Nevertheless, when trying to differentiate the
characteristics of highly erosive RA from those of less
erosive diseases, such as psoriatic arthritis and postinfectious arthritis, one does not find major differences in
either the synovial histology or qualitative cytokine
profile (86,87), but rather, a disparity is evident in the
MHC associations (HLA–DR4 in RA versus class I
antigens in non-RA diseases) and in the autoantibody
response (RF and a variety of other autoantibodies in
RA versus none in the other disorders). In fact, these
other arthritides are subsumed as “seronegative” arthritides. Moreover, RF has been shown to be associated
with more aggressive RA (88). Although this has also
been suggested for the shared epitope of the HLA–DR
cluster, that association is possibly due to an association
of HLA–DR4 with RF (89).
Thus, the presence of autoantibodies appears to
sustain arthritic destruction. This has also been seen in
experimental models of arthritis in which autoantibodies
were found when destruction occurred, including the
model of TNF-transgenic mice bearing a primary non–
immune-mediated arthritic disease (48). On the other
hand, autoantibodies could be a consequence of inflammation and destruction, and this is suggested by the
occurrence of RF in the course of infections and chronic
diseases as well as by observations in TNF-transgenic
mice in which inhibition of inflammation and/or destruction prevented the generation of autoantibodies (48).
This is further supported by clinical studies in which,
following successful therapy, RF titers decreased (6,90).
How could autoantibodies be related to joint
destruction? It is conceivable that Fc receptor and/or
complement or complement receptor–mediated events
play an important role in this respect. In fact, it has long
been known that complement is activated in RA synovial
fluid, but not in most other diseases (91). Moreover,
mice deficient in either Fc␥ receptors or complement
receptors are protected from at least some forms of
experimental arthritis (92–94). Taken together, these
data suggest that immune complexes, presumably consisting of autoantibodies and autoantigens, may promote
inflammation and tissue destruction in RA. The ability
of immune complexes to induce TNF production by
macrophages has previously been determined (95).
Thus, since autoimmune phenomena are clearly associated with the destructiveness of arthritis, one could
REDLICH ET AL
hypothesize that Fc-receptor– and/or complementreceptor–mediated signaling could be operative in the
differentiation and activation of osteoclasts in conjunction with or via enhanced induction of TNF and/or
RANKL or RANK. All of these observations suggest
that targeting Fc-receptor function and complement
components may constitute interesting therapeutic avenues for RA.
Conclusion
Current therapies for RA are highly efficacious
but fail to induce remission in most patients (2–6,11,13).
On the basis of the known linkage of multiple pathogenetic pathways to arthritis, it must be assumed that
targeting of individual cells or molecules is insufficient.
This is suggested in even apparently straightforward
mouse models, as in the TNF-transgenic mouse model in
which TNF blockade is insufficient to abrogate inflammation or destruction and combination therapy is much
more efficacious (96). Obviously, this notion should not
impede our search for individual novel targets and
individual novel agents (97), which are still much needed
for the treatment of RA. However, drawing conclusions
from the above observations is necessary for the design
of new combination strategies, such as inhibition of TNF
plus at least 1 additional target. In this context, it must
be our aim to interfere with both the pathways that lead
to inflammation and those that ultimately activate the
destruction cascade, although it is possible that complete
inhibition of the inflammatory response will also prevent
bone and cartilage destruction. It is this aim that we
must keep in mind when designing new strategies and
new clinical trials in the era after TNF and IL-1
blockade.
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