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Therapeutic strategies for Rheumatoid arthritis

Article in Nature Reviews Drug Discovery · July 2003

DOI: 10.1038/nrd1109 · Source: PubMed

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Referat I: Prothrombotische, antithrombotische und cardiovaskuläre Effekte von NSAIDs
und Coxiben
Salinas, G., Rangasetty, U. C., Uretsky, B. F., and Birnbaum, Y. (2007): The
cyclooxygenase 2 (COX-2) story; it´s time to explain, not inflame. J. Cardiovasc.
Pharmacol. Ther. 12: 98-111.
Grosser, T, Fries, S., and FitzGerald, G.A. (2006): Biological basis for the
cardiovascular consequences of COX-2 inhibition: therapeutic challenges and
opportunities. J. Clin. Invest. 116: 4-15.
Amer, M., Bead, V.R., Bathon, J., Blumenthal, R.S., and Edwards, D.N. (2010): Use
of nonsteroidal anti-inflammatory drugs in patients with cardiovascular disease.
Cardiol Rev. 18: 204-212.

Ihr Referat sollte folgende Punkte umfassen:

- Strukturelle Unterschiede und Physiologie der COX1- und COX2-Enzyme
- Vorstellung COX-2-selektiver Hemmer, Wirkungen und unerwünschten Wirkungen
- prothrombotische, antithrombotische und kardiovaskuläre Effekte von NSAIDs und Coxiben

Referat II: Unterschiede in der Pharmakotherapie der Rheumatoiden Arthritis und

Osteoarthritis
Smolen, J.S., and Steiner, G. (2003): Therapeutic Strategies for Rheumatoid
Arthritis. Nature Reviews 2: 473-488.
Wieland, H.A., Michaelis, M., Kirschbaum, B.J., and Rudolphi, K.A. (2005):
Osteoarthritis-an untreatable disease? Nat. Rev. Drug Discov. 4: 331-344.
Krüger, K. (2008): Quantensprünge in der Therapie der rheumatoiden Arthritis.
MMW Fortschr. Med. 150: 120-122.
Michael, J. W.-P., Schlüter-Brust, K.U., and Eysel, P. (2010): The epidemiology,
etiology, diagnosis, and treatment of osteoarthritis of the knee. Dtsch. Ärztebl. 107:
152-162.
Ihr Referat sollte folgende Punkte umfassen:
- Gegenüberstellung der Pharmakotherapie der Rheumatoiden Arthritis und Osteoarthritis
- Welche Rolle spielen NSAIDs? Nebenwirkungen von NSAIDs und Paracetamol.

Referat III: Neuropathischer Schmerz: therapeutische Ansätze

Galluzzi, K.E. (2005): Management of neuropathic pain. J. Am. Osteopath. Assoc.
105: S12-S19.
Baron, R. (2006): Diagnostik und Therapie neuropathischer Schmerzen. Dtsch.
Ärztebl. 41: A2720- A2730.
Jensen, T.S., Madsen, C.S., and Finnerup, N.B. (2009): Pharmacology and
treatment of neuropathic pains. Curr. Opin. Neurol. 22: 467-474.

Ihr Referat sollte folgende Punkte umfassen:

- Evidenzbasierte Therapie des neuropathischen Schmerzes
- Welche Rolle spielen NSAIDs?
 REVIEWS

THERAPEUTIC STRATEGIES FOR

RHEUMATOID ARTHRITIS
Josef S. Smolen and Günter Steiner
Recent years have seen considerable advances in our understanding of both the clinical and
basic-research aspects of rheumatoid arthritis. Clinical progress has come from a better
recognition of the natural history of the disease, the development and validation of outcome
measures for clinical trials and, consequently, innovative trial designs. In parallel, basic research
has provided clues to the pathogenic events underlying rheumatoid arthritis, and advances in
biotechnology have facilitated the development of new classes of therapeutics. Here, we
summarize the fruits of these advances: innovative approaches to the use of existing, traditional
disease-modifying antirheumatic drugs; novel agents approved very recently; and further
avenues that are presently under investigation or which are of more distant promise.

Rheumatoid arthritis (RA) is a chronic inflammatory
and destructive joint disease that affects 0.5–1% of the
population in the industrialized world and commonly
leads to significant disability and a consequent reduc-
tion in quality of life1,2. It is two to three times more
frequent in women than in men and can start at any
age, with a peak incidence between the fourth and sixth
decade of life. RA is associated with high costs and, if
not treated appropriately, with a reduction in life
expectancy3–5. In addition to the joint swelling and
pain caused by the inflammatory process, the ultimate
hallmark of RA is joint destruction (FIG. 1).
RA is a polyarthritis, that is, it involves many joints
(six or more), although in the early stages of the dis-
Division of Rheumatology, ease, only one or a few joints might be afflicted.
Department of Internal
Medicine III, University
Virtually all peripheral joints can be affected by the
of Vienna, and Center disease; however, the most commonly involved joints
of Molecular Medicine, are those of the hands, feet and knees 6, and distal
Austrian Academy of interphalangeal joints are usually spared. In addition,
Sciences, A-1090, Vienna, RA can affect the spine, and atlanto-axial joint
and 2nd Department
of Medicine, Center for involvement is common in longer-standing disease
Rheumatic Diseases, and constitutes a directly joint-related cause of mor-
Lainz Hospital, A-1130 tality. Extra-articular involvement is another hallmark
Vienna, Austria. of RA, and this can range from rheumatoid nodules
Correspondence to J. S. S.
e-mail:
to life-threatening vasculitis.
josef.smolen@wienkav.at Drug therapy for RA rests on two principal
doi:10.1038/nrd1109 approaches: symptomatic treatment with non-steroidal
anti-inflammatory drugs (NSAIDs) and disease-modi-
fying antirheumatic drugs (DMARDs). NSAIDs only
interfere with a small segment of the inflammatory cas-
cade, namely prostaglandin generation by cyclooxy-
genases (COXs), but do not interfere with the underlying
immuno-inflammatory events or retard joint destruc-
tion. By contrast, DMARDs ‘modify’ the disease process
in all these respects, and, once DMARDs are effective, no
further symptomatic therapies are needed. It is these lat-
ter forms of therapeutic intervention that will constitute
the focus of this review.
Pathogenesis of RA
RA is a disease in which the immune and inflamma-
tory systems are intimately linked to the destruction of
cartilage and bone. Although the penultimate link of
the two systems remains elusive, and the cause of RA
unknown, many pathways involved in the generation
of the disease have been recognized and some of these
have been unequivocally identified as important by
therapeutic proof-of-principle studies. It has long been
speculated that RA could be triggered by infectious
agents7–9, but proof of this is still lacking. Interestingly
in this respect, RA patients respond favourably to drugs
that have antibiotic activity or are derived from anti-
biotics10–12, although non-antibacterial mechanisms of
action are usually implicated in this effect.

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The reason for the joint-specific localization of the

ensuing immuno-inflammatory response is also
unknown. It could result from an arthrotropism of the
trigger, cross-reactivity of the trigger or its products with
structures primarily present in the joint tissues, or acti-
vation of other mechanisms that lead to homing of
involved cells to the joint. The products of such foreign
agent(s) could activate the innate immune system by
binding to Toll-like receptors (TLRs)13 or CD14 (REF. 14),
and subsequently triggering a T-cell response. T cells
undergo polarization into either TH1 or TH2 cells15,
which can be mutually inhibitory. TH2 cells are induced
by interleukin-4 (IL-4), whereas IL-12 is the strongest
TH1-inducing cytokine. TH1 cells mainly secrete inter-
feron-γ (IFN-γ) and tumour-necrosis factor-β (TNF-β);
TH2 cells produce IL-4, IL-5, IL-13 and IL-10. The polar-
ity of TH cells is decisive for the type of B-cell activation.
TH1 cells exert pro-inflammatory activities and promote
certain humoral responses, whereas TH2 cells have anti-
inflammatory potential and promote other types of
humoral responses, including immunoglobulin (Ig) E
production. In this context, it is important to bear in
mind that RA is regarded as an autoimmune disease16. In
particular, there is a strong association between RA and
several types of autoantibodies17; the longest known and
most important is rheumatoid factor (RF), which
is directed against the Fc fragment of IgG. Aside from
RF, responses to other autoantigens occur very com-
monly, both at the B- and T-cell level18,19. Whether such
autoantigens initiate the T-cell activation cascade and
the consequent inflammatory changes, or step in at a
later point in time to bolster and/or perpetuate the
process, is unknown. The potential role of autoimmune
responses in the chronicity and destructiveness of the
disease will be discussed later.
RA has a polygenic basis20, although the genes
involved have not yet been defined. So, it is assumed
Figure 1 | Schematic view of a normal joint and its changes in rheumatoid arthritis. that, in a genetically predisposed host, TH1 cells become
a | The synovial joint is composed of two adjacent bony ends each covered with a layer of cartilage, activated by arthritogenic antigen(s) in conjunction
separated by a joint space and surrounded by the synovial membrane and joint capsule. The with co-stimulatory signals and an appropriate cytokine
synovial membrane is normally <100 µm thick and the synovial lining (facing the cartilage and bone) environment (FIG. 2). The earliest event(s) might involve
consists of a thin (1–3 cells) layer of synoviocytes (type A are macrophage derived, and type B are
fibroblast derived); there is no basement membrane. Only a few, if any, mononuclear cells are
activation of the innate immune response, such as the
interspersed in the sublining connective tissue layer, which has considerable vascularity. The synovial triggering of dendritic cells (DCs) through TLRs (several
membrane covers all intra-articular structures except for cartilage and small areas of exposed bone of which are known to be expressed on synovial cells) by
(‘bare areas’) and inserts near the cartilage–bone junction. The ‘radiographic joint space’ (seen in c, exogenous material or by a combination of such foreign
which shows a radiograph of the second, third and fourth metacarpophalangeal joints in a normal stimuli together with autologous antigens, before or in
hand), in contrast to the usually minute ‘anatomic joint space’, consists of the latter, as well as of the
parallel to T-cell involvement.
two neighbouring, radiotranslucent portions of cartilage covering the non-translucent subchondral
bone. b | Like many other forms of arthritis, rheumatoid arthritis (RA) is initially characterized by an The T cells infiltrating the synovial membrane are
inflammatory response of the synovial membrane (‘synovitis’) that is conveyed by a transendothelial primarily CD4+ memory cells, which produce IL-2 and
influx and/or local activation of a variety of mononuclear cells, such as T cells, B cells, plasma IFN-γ to a similar extent as antigen-triggered T cells18,21
cells, dendritic cells, macrophages, mast cells, as well as by new vessel formation. The lymphoid and so clearly have a TH1 bias22–24. This polarity of the
infiltrate can be diffuse or, commonly, form lymphoid-follicle-like structures. The lining layer T-cell response in RA is further supported by a vast pre-
becomes hyperplastic (it can have a thickness of >20 cells) and the synovial membrane expands
and forms villi. However, in addition, the hallmark of RA is bone destruction (seen in d, which shows
ponderance of TH1 T-cell clones derived from RA
three metacarpophalangeal joints from a hand radiograph of a patient with established RA: the joint patients18,25,26 and by the presence of a milieu favouring
spaces have narrowed or disappeared as a sign of cartilage degradation and destructions of the the generation of myeloid DCs that preferentially activate
adjacent bone, also termed ‘erosions’, have occurred). The destructive portion of the synovial TH1 cells27. These T cells, by cell–cell contact — for
membrane is termed ‘pannus’, and the destructive cellular element is the osteoclast; destruction example, through CD11- and CD69-mediation28,29 —
mostly starts at the cartilage–bone–synovial membrane junction. Bone repair by osteoblasts
and activation by different cytokines, such as IFN-γ,
usually does not occur in active RA. Polymorphonuclear leukocytes are found in high numbers in
the joint fluid, but very rarely are seen in the synovial membrane, suggesting very rapid TNF-α and IL-17, activate monocytes, macrophages and
transgression from blood to the joint space. The neutrophils’ enzymes, together with enzymes synovial fibroblasts30–33 (FIG. 2). These latter cells then over-
secreted by synoviocytes and chondrocytes, lead to cartilage degradation. produce pro-inflammatory cytokines — mainly TNF-α,

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Figure 2 | Schematic representation of events occurring in rheumatoid arthritis. The T cells
invading the synovial membrane are primarily CD4+ memory cells, which produce interleukin-2 (IL-2)
and interferon-γ (IFN-γ) to a similar extent as antigen-triggered T cells21, and which are either already
pre-activated or become (further) activated by antigen-presenting cells (APCs) in conjunction with
arthritogenic (auto)antigen(s) and appropriate major histocompatibility complex (MHC) class II mole-
cules, co-stimulation (mainly through CD80/81 and CD28) and certain cytokines (IL-1, IL-15, IL-18).
Through cell–cell contact (for example, through CD11- and CD69-mediation28,29) and through
different cytokines, such as IFN-γ, tumour-necrosis factor (TNF)-α and IL-17, these T cells activate
monocytes, macrophages and synovial fibroblasts30–33. The latter then overproduce pro-inflammatory
cytokines, mainly TNF-α, IL-1 and IL-6, which seem to constitute the pivotal event leading to chronic
inflammation21,34–40. Through complex signal transduction cascades (FIG. 4), these cytokines
activate a variety of genes characteristic of inflammatory responses, including genes coding for
various cytokines and matrix metalloproteinases (MMPs) involved in tissue degradation. TNF-α and
IL-1 also induce RANK expression on macrophages which, when interfering with RANKL on stromal
cells or T cells, differentiate into osteoclasts that resorb and destroy bone. In addition, chondrocytes
also become activated, leading to the release of MMPs. Initial events might also involve activation of
APCs through Toll-like receptors (TLRs) before T-cell engagement. RANK, receptor activator of
nuclear factor-κB; RANKL, RANK ligand; RF, rheumatoid factor; TCR, T-cell receptor.
NATURE REVIEWS | DRUG DISCOVERY
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REVIEWS
IL-1 and IL-6 — which seem to constitute the pivotal
event leading to chronic inflammation21,34–40. Moreover,
several lines of evidence indicate that TNF-α might reside
at the apex of this particular pro-inflammatory cytokine
cascade and drive the production of IL-1 and IL-6
(REFS 41,42); however, IL-1 can also induce TNF-α42.
Moreover, aside from those mentioned, many other
cytokines and chemokines are involved in RA pathogene-
sis, including IL-15 and IL-18 (REF. 43) and angiogenic
factors44. These soluble molecules, once engaged to their
receptors, trigger various signal transduction cascades,
such as the MAPK, nuclear factor-κB (NF-κB) or
Jak/STAT pathways45–47, which lead to the activation of
transcription factors and the subsequent induction of
genes whose products mediate inflammation and tissue
degradation.Among these products are various cytokines,
chemokines and tissue-degrading enzymes, such as the
matrix metalloproteinases (MMPs), but also cell-surface
molecules that enhance cell activation and cell–cell inter-
actions, such as co-stimulatory and adhesion molecules.
The latter comprise selectins, integrins and their coun-
terparts, which mediate cell rolling, adhesion and migra-
tion into inflammatory sites via endothelial cells and
other important intercellular interactions48, and so are
pivotal in the generation of the inflammatory response.
Overall, many cell populations are involved in disease
pathogenesis: T cells, B cells, monocyte/macrophages,
mast cells, DCs and fibroblasts are found in highly
increased numbers in the synovial membrane in RA.
Aside from the inflammatory infiltrate in the perivascu-
lar and sublining regions, the lining layer consisting of
type A (macrophage-like) and type B (fibroblast-like)
synoviocytes becomes hyperplastic and, at the cartilage–
bone junction, transforms into an aggressive tissue, the
‘pannus’, which contains osteoclasts49,50 (FIGS 1 and 2). The
growth of the synovial membrane is accompanied by
neovascularization44. Neutrophils, although not demon-
strably present within the synovial membrane, accumu-
late within the synovial fluid and participate in the
degradative processes. Whereas the degradation of
cartilage is mainly mediated by the plethora of metallo-
proteinases present in the joint, bone destruction is
mediated by the generation and activation of osteo-
clasts50–52, an event that apparently does not occur in
non-destructive arthritides.
The role of B cells and autoantibodies, and/or
immune complexes, could lie in the propagation and
enhancement of the inflammatory process: it has long
been known that complement is activated in RA syn-
ovial fluids and complement components are even
locally produced53; moreover, immune complexes are
deposited in cartilage54, and, in experimental arthritis, a
lack of Fcγ-receptors abrogates the induction of disease55.
Endogeneous anti-inflammatory agents, such as
soluble cytokine receptors and receptor antagonists,
anti-inflammatory cytokines56, or regulatory T cells57,
are apparently insufficient to counterbalance the cas-
cade of pro-inflammatory events in chronic inflamma-
tion. Targeting these events by mimicking the action of
such natural inhibitors is one of the modern therapeutic
approaches, as discussed later.
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DMARDs
DMARDs are agents that impede both the inflammatory
and destructive processes of RA. Many such drugs only
start acting after several weeks (for example, methotrexate
(MTX)) or months (for example, gold salts), but once
they show effect, they reduce both pain and swelling, as
well as the progression of destruction. If efficacious,
patients often do not need other anti-inflammatory medi-
cations, such as NSAIDs or glucocorticoids. Remissions
occur in only 20–25% of the patients in clinical practice,
but continued DMARD therapy is warranted, as stop-
ping DMARDs is accompanied by a significant risk of
flares58.Aside from the direct implications for RA therapy,
these data, complemented by the finding of renewed effi-
cacy after re-institution of DMARDs59, also support the
idea that DMARDs confer significant benefit.
We will divide DMARDs into small molecules and
biological agents. The more well-established drugs will
only be reviewed briefly; more emphasis will be placed
on recent insights into mode of action, and possible
routes to novel therapies.
Small-molecule DMARDs presently used in RA
Small-molecule DMARDs have been used since the
1920s, and even in the days of biological therapies, one
such drug — MTX60,61 — is still the most commonly
used DMARD, and continues to be the gold standard of
DMARD therapy. MTX sets the level of efficacy that new
compounds have to match, and its efficacy has still not
been unequivocally surmounted in head-to-head trials.
The latest addition to the group of small chemical
DMARDs is leflunomide62, an active metabolite of which
inhibits dihydro-orotate-dehydrogenase, an enzyme that
is pivotally involved in de novo pyrimidine synthesis.
Inhibition of this enzyme affects various signal-trans-
duction mechanisms, the generation of cytokines, and
cell proliferation and migration63,64. However, all
presently used DMARDs (TABLE 1; see ONLINE TABLE 1 for
Table 1 | Small-molecule DMARDs in clinical use*
Agent First used Comments
Gold salts 1920s Relatively long period of administration before
clinical effects are seen; rarely used today
Sulphasalazine 1940s Second most common DMARD used in Europe
during the 1990s
Antimalarials‡ 1950s Less efficacious than other DMARDs, but also
less toxic
Methotrexate 1950s Gold-standard therapy
D-penicillamine 1960s One of the more toxic DMARDs; rarely used today
Azathioprine, 1960s Some clinical benefit
mycophenolic acid
Cyclosporine A, 1980s Efficacious, but relative toxicity has precluded
tacrolimus, sirolimus widespread use
Minocycline 1990s Mildly beneficial
Leflunomide 1990s Overall, has similar effects to sulphasalazine
and methotrexate
Glucocorticoids 1950s Rapid anti-inflammatory effects, but also qualities
of DMARDs; however, have long-term side effects
*See ONLINE TABLE 1 for a more detailed referenced version. ‡ Chloroquine, hydroxychloroquine.
DMARD, disease-modifying antirheumatic drug.
476 | JUNE 2003 | VOLUME 2
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a more detailed referenced version) have limited efficacy,
toxicity problems or both. Efficacies in clinical trials
range between ~40% and 70% for ACR20 responses, the
usual primary endpoint (BOX 1), compared with placebo
rates of between 15% and 30%. Drug retention rates in
clinical practice are relatively low, meaning that within
1–2 years, the majority of patients have to stop a given
DMARD course, with the exception of MTX, which has
a median retention rate of ~3–4 years65,66. Patients who
failed DMARDs previously can respond to subsequent
DMARD courses, but often to a lesser extent67. Only
recently has it been appreciated that aggressive DMARD
therapy early in the course of the disease is beneficial68,69
and that the therapeutic aim of RA therapy must be to
fully arrest the inflammatory and destructive process
rather than just alleviating it, as is suggested by even the
present clinical trial endpoints (BOX 1).
Combination therapy has also been advocated for
RA, and most combination therapy strategies include
MTX as one of the components. Some combinations
seemed to give better results than the monotherapies70–72,
whereas others did not73–75; however, toxicity was not
accelerated in the majority of the more recent trials.
Careful analyses of the doses employed in comparator
groups are necessary to fully appreciate potential differ-
ences, and it is probable that the improved efficacy in at
least one of the studies derived from high-dose glucocor-
ticoid therapy70,76. However, none of the combinations
tested so far have led to a clear-cut and reproducible
advantage in the achievement of higher rates of a
remission-like state77. Importantly, all the mentioned
trials were head-to-head comparisons of combinations
versus one of the drugs used as a single agent.
Another type of combination therapy involves the
addition of a second agent once an initial agent has
failed or demonstrated insufficient efficacy (step-up).
This was first introduced into clinical trials for insuffi-
cient responders to MTX by the addition of cyclosporin
A78, and has subsequently been used in trials of anti-
cytokine agents (see below). The most recent addition to
the list of compounds suitable for combination use with
MTX is leflunomide79. All of these trials allow important
information on efficacy and toxicity of the combina-
tions under study to be retrieved. However, none of
them provide an answer to the question of whether such
combinations are at all advantageous, as — with one
exception — they all involved only an MTX + new drug
arm, and an MTX + placebo arm, but not a new-drug-
only arm. The single exception was a relatively small
Phase II trial of MTX + infliximab (a monoclonal anti-
TNF antibody; see below) in which the addition of
infliximab to pre-existing MTX did not appear to be
superior to switching from MTX to infliximab80.
Biological DMARDs presently used in RA
The pro-inflammatory role of cytokines, and the
involvement of different cell types and their surface
molecules in the pathogenesis of RA, provides the ratio-
nale for the development of highly specific therapeutics
to target these molecules. Targeting of pro-inflamma-
tory cytokines can be achieved by several strategies.
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Box 1 | Development of outcome measures for RA clinical trials
When compared with other disorders in which a single, or a group, of objectively
assessable laboratory or clinical variables can be used as ‘activity’ or ‘outcome’ measures,
rheumatoid arthritis (RA) is difficult to study for a variety of reasons. First, there is a wide
variability between patients. Second, there are dozens of potential outcome measures
(ONLINE BOX 1), such as tender or swollen joint counts, global disease assessments by
patients or physicians, functional assessments and radiographic changes. And third,
patients with RA are amenable to a tremendous placebo response for most of these
variables (see ONLINE BOX 4 for details).
To improve the reliability of disease assessment, different groups of clinical researchers
have independently determined and validated core sets of clinical variables that were
sensitive to change, had long-term predictive value, had only little, if any, redundancy, and
were therefore reliable in determining disease activity and/or outcome in clinical
trials253–255. To distinguish therapeutic from placebo responses in clinical trials, the
American College of Rheumatology improvement criteria rely on relative changes of a
composite of these core set disease activity variables, whereas the European League Against
Rheumatism response criteria give absolute changes (see ONLINE BOX 1 for details)254.
First, monoclonal antibodies, soluble receptors, binding
proteins or receptor antagonists can bind to pro-
inflammatory molecules or their receptors and interfere
with receptor ligation and its consequences. Second,
anti-inflammatory cytokines, such as IL-4, IL-10 or IL-13,
can antagonize the production or action of the pro-
inflammatory cytokines. Third, monoclonal antibodies
targeted against differentiation- or function-associated
cell-surface antigens can lead to either elimination of
the targeted cells or interference with the cell’s function.
Agents that exploit each of these strategies have
entered clinical trials: some have failed, others are being
further evaluated in controlled trials (discussed below)
and a few have been approved. All of the approved ther-
apies, which are shown in TABLE 2 (see ONLINE TABLE 2
for a more detailed version), belong to the first group of
the previous paragraph: they prevent pro-inflamma-
tory cytokines — in particular TNF and IL-1 — from
interacting with their receptors.
Anti-TNF therapies. The key role of TNF in the patho-
genesis of RA was elucidated in detail during the late
1980s and throughout the 1990s by Feldmann, Maini and
others, in both experimental animals and in patients with
RA (reviewed in REF. 81). Key evidence for the importance
of TNF is also provided by the observation of the occur-
rence of a severe arthritis in TNF-overexpressing trans-
genic mice82, which, in common with other mouse
arthritis models, could be prevented by inhibiting TNF-α.
Three drugs that block the activity of TNF have been
approved (TABLE 2). Infliximab (which was the first TNF-
blocker to be clinically tested in RA) and adalimumab are
antibodies against TNF, and etanercept (which was the
first biological DMARD to be approved for treating RA)
is a fusion protein of the TNF receptor II. All of these
agents lead to clinical improvements in RA, and patients
typically achieve ~50–70% ACR20 and 30–50% ACR50
responses (FIG. 3). In addition, patients also experience a
significant improvement in function-related quality of
life, and, most importantly, radiographic progression is
very significantly retarded 61,80,83–89, and might even be
halted in a considerable fraction of the patients. As such,
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TNF blockade has been the major breakthrough in the
therapy of RA during the past ten years, both with respect
to transferring basic work to the bedside and regarding its
effects in otherwise often refractory patients. This, how-
ever, should not detract from the fact that more than half
of the patients in clinical trials do not achieve ACR50
responses, that remissions are rare, and that these drugs
do have side effects61,83–91(ONLINE TABLE 2).
IL-1 blockade. IL-1 is well established as another key pro-
inflammatory cytokine involved in RA. Binding of IL-1
to IL-1 receptor I (IL-1RI) allows the engagement of the
IL-1R accessory protein (IL-1RacP) and subsequent cell
signalling and activation. The natural inhibitor IL-1
receptor antagonist (IL-1ra), which belongs to the IL-1
family, competes with IL-1 for its receptor but does not
allow engagement of IL-1RacP, thereby blocking activa-
tion of signal transduction mechanisms92. The impor-
tance of the role of IL-1ra in regulating the inflammatory
response is exemplified by the occurrence of a destruc-
tive arthritis in IL-1ra-deficient animals93.
On the basis of several randomized double-blind con-
trolled clinical trials94–96, anakinra (TABLE 2) — a recombi-
nant form of IL-1ra — became the first, and so far the
only, IL-1-blocking drug to be approved for the treatment
of RA. Published results seem to indicate that the effects
of anakinra might be more modest than those seen with
other agents; however, head-to-head-trials of different
biological compounds have not yet been performed.
Summary of recently approved DMARDs
FIGURE 3 summarizes the principal results obtained with
adalimumab, etanercept, infliximab and anakinra, and
also with the recently introduced small-molecule com-
pound leflunomide. As the patient populations were
different in these studies, it is difficult to compare the
results of each trial with those of the others. However, as
most trials involved placebo groups, differences between
placebo and the agent studied can be extrapolated
between studies. Only leflunomide was studied against
an active comparator and placebo, and among the bio-
logicals, only etanercept was studied against an active
comparator. Such data for infliximab and adalimumab
are expected in the near future. The safety concerns
associated with the new biologicals mainly involve
application-specific issues, such as infusion- or injec-
tion-site reactions, and their potential to increase the
risk of infections, particularly tuberculosis and oppor-
tunistic infections with the TNF-blockers. Another issue
to be mentioned here is the high financial burden of the
new biological therapies, which is one of the reasons for
the increased interest in finding novel small-molecule
DMARDs that can be produced more cheaply.
Candidates for future small-molecule DMARDs
Most new candidate DMARDs are enzyme inhibitors,
which target either secreted enzymes involved in tissue
destruction, such as matrix metalloproteinases
(MMPs), enzymes that liberate active cytokines from
their precursor or membrane-associated forms, or
kinases of various signal-transduction cascades.
VOLUME 2 | JUNE 2003 | 4 7 7
REVIEWS

Table 2 | Approved biological DMARDs and related drugs in development*

Agent Status‡ Properties Comments
Anti-TNF therapies
Infliximab Approved Chimaeric monoclonal antibody First biological DMARD to be clinically
(RA: 1999) to TNF tested; trials showed that TNF blockade is
clinically effective short- and long-term
Etanercept Approved Construct of TNF-RII and the Fc Efficacy in RA comparable to infliximab used
(1998) portion of IgG1 as a monotherapy or combination therapy
Adalimumab Approved Human monoclonal antibody to TNF Efficacy in RA comparable to infliximab used
(2002) as a monotherapy or combination therapy
CDP870 In study PEGylated Fab fragment of CDP571,
a humanized antibody to TNF
PEG-TNF-RI In study PEGylated form of soluble TNF-RI
IL-1-blocking agents
Anakinra Approved IL-1R antagonist Clinically effective as a monotherapy and in
(2001) combination with MTX
IL-1 trap Phase I Construct of two IL-1R chains with
an IgG-Fc domain
*See ONLINE TABLE 2 for a more detailed version, including adverse events. ‡Years shown are those of the first approvals in a major
pharmaceutical market. Anti-TNF therapies are described in REFS 61,80–91; IL-1-blocking agents are described in REFS 92–96. DMARD,
disease-modifying anti-rheumatic drug; IgG1, immunoglobulin G1; IL-1, interleukin-1; IL-1R, interleukin-1 receptor; MTX, methotrexate;
RA, rheumatoid arthritis; TNF, tumour-necrosis factor; TNF-R, tumour-necrosis factor receptor.

Inhibitors of proteases. MMPs seem to be important in
RA, as they are present in increased amounts and in
active forms in the inflamed joint tissue97,98. This group
of molecules comprise more than 20 members that
include the collagenases (now termed MMP-1, MMP-8
and MMP-13), the gelatinases (now named MMP-2,
MMP-9), the stromelysins (MMP-3, MMP-10, MMP-11
and MMP-7) and the adamalysins99. TNF-α-converting
enzyme (TACE), which releases soluble TNF from its
membrane-bound form, is an adamalysin; indeed, the
adamalysins are involved in the shedding of many cell-
surface molecules. Therefore, MMP-inhibition consti-
tutes an interesting and important avenue to explore in
developing therapies.
Synthetic MMP inhibitors were originally developed
as anticancer agents, and were intended to inhibit the
invasive capacity of malignant cells and to interfere with
angiogenesis; however, results from cancer trials have
mostly been disappointing. MMP inhibitors include col-
lagen peptidomimetics and non-peptidomimetics100,101,
bisphosphonates and tetracyclines. The inhibition pro-
files of these compounds differ: for example, trocade
(Ro 32-3555) selectively inhibits the collagenases
(MMP-1, MMP-8 and MMP-13) and has low activity
against other MMPs, whereas Ro 113-0830 interferes
efficiently with MMP-2, MMP-9, MMP-8 and MMP-13,
but does not inhibit MMP-1 (REF. 102).
Several MMP inhibitors are efficacious in experi-
mental models of arthritis and have therefore consti-
tuted interesting compounds for the therapy of RA:
BAY12-9566 (which inhibits stromelysins and gelati-
nases), Ro 113-0830, GI 168, MDL 101, BB 1101, ONO
4817, and trocade. BAY 12-9566 was developed for
osteoarthritis (OA) and had reached Phase II trials, but
all trials were discontinued because of safety issues aris-
ing in the cancer trials102. Trocade was evaluated in
Phase III trials in RA, but its lack of clinical efficacy,
including failure to improve radiographic scores102,103,
led to discontinuation of this programme and, likewise,
to termination of Ro 113-0830 trials in OA.
There are potentially several reasons for the failure of
MMP inhibition for the treatment of arthritis. First,
MMPs could be less important in tissue destruction than
originally assumed. Second, the doses necessary to reach
sufficient MMP inhibition locally might be higher than
can be achieved given the safety profile of the drugs con-
cerned. Third, the MMPs targeted so far might not be the
most important ones in the process of joint destruction,
or it could be that the redundancy of MMP activities
allows tissue destruction to continue unless all or most of
them are inhibited sufficiently. So, at present, the only
compound in use that is also an MMP inhibitor is
minocycline; however, this drug seems to have limited
efficacy and probably exerts its effect mostly through
mechanisms other than MMP inhibition.
MMPs, however, are already naturally regulated by
different molecules, such as the tissue inhibitors of metal-
loproteinases (TIMPs)98,104. In fact, in experimental mod-
els of destructive arthritis, overexpression of TIMP-1 can
almost abrogate disease105. The short half-life of TIMPs
could be overcome by various molecular or biochemical
techniques that are already used for TNF-blocking
agents, although, as with the small-molecule MMP
inhibitors, safety issues might be a concern.
Yet another type of MMP inhibitor has entered
clinical trials in RA: drugs that interfere with TACE,
which cleaves TNF-α from its membrane-associated
form and thereby enables the cytokine to act in a
paracrine, endocrine and autocrine manner106. TACE is
overexpressed in RA107 and its inhibition by compounds
such as GW 3333, TMI-1, or Ro 32-7315 has shown effi-
cacy in experimental arthritis108–111. However, it has to be
considered that inhibition of TACE increases levels of
the membrane-associated TNF-α. The consequence of
this is unclear: on the one hand, the presence of mem-
brane TNF in the absence of secreted TNF might be

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 REVIEWS

insufficient to mount a full-blown inflammatory
response112; on the other hand, even such ‘suboptimal’
inflammation might be sufficient to lead to tissue
destruction. In fact, overexpression of membrane-bound
A Clinical response to new disease-modifying antirheumatic drugs
80
a b c d
% of patients achieving an ACR20 response
TNF was shown to be sufficient for the induction of
severe destructive arthritis in TNF transgenic mice113.
Moreover, an MMP inhibitor that blocked both the pro-
cessing of TNF receptors as well as TNF was unable to
inhibit further downstream generation of other pro-
inflammatory cytokines114. Phase I studies of TACE
e f
inhibitors have been performed and results from Phase
II trials in RA are awaited with great interest.

70 72
71 Like TNF-α, IL-1β (and likewise IL-18) has to be lib-
65 erated from a precursor form to become an active soluble
60
cytokine. This process is mediated by the interleukin-1
50 52 59 converting enzyme (ICE), which is identical to caspase-1
(REF. 115). Pro-IL-1β and pro-IL-18, although biologically
46
40 42 active molecules, reside in the cytosol and, in addition to
ICE, can also be cleaved by other proteases116,117.
30 Inhibiting IL-1β and IL-18 release by inhibiting ICE
27 could be a valuable avenue to investigate for RA therapy,
20 23 24 but it should be borne in mind that other enzymes can
20
17
also cleave the precursors of these cytokines. In addition,
10
ATP can lead to release of mature and precursor forms
0 of IL-1β through the P2X7 receptor118. One of several
bo ab bo ep
t
bo nra bo ide TX pt o ab ICE/caspase-1 inhibitors is pralnacasan119, which
ce ixim ce erc ce aki ce om rc
e eb
a a a a M
lac um reduced inflammation and joint destruction by ~60% in
p l f l p l
an p l n p l
lun ne p m
+) ) in +) et +) X+)
a
+) lef e ta +) d ali
TX TX+ TX X+) TX T TX +) TX )a experimental arthritis120. In a Phase II clinical trial,
( M ( M T ( M (M ( M X (M +
(M (M (M
T TX pralnacasan showed a dose-dependent increase in
(M
response which, however, did not reach statistical signifi-
B Radiographic progression cance compared with placebo121. Nevertheless, as only
8 mild adverse events were observed, further investigation
a e f g h
of higher doses might be warranted and could lead to
Increase in modified Sharp score (12 months)

7 7.2 better results. The P2X7 receptor, which, as mentioned

6
above, is involved in the release of IL-1 and IL-18, is like-
wise an attractive target. Indeed, inflammatory pain
5 resulting from the local inoculation of adjuvant was alle-
viated by injection of oxidized ATP, a selective inhibitor
4 of the P2X7 receptor, into rats’ paws122. In addition,
3.6 arthritis induced by monoclonal antibodies to collagen
3 was alleviated in P2X7-deficient mice123.
2.7
The novel small molecules discussed so far either
2 2.2
1.9 target enzymes secreted by cells into the extracellular
1.6
1
space or cellular enzymes that enable the secretion of
0.6
1.0
0.1 0.9 mature forms of pro-inflammatory cytokines, and so
0.5
0 interfere mainly with late effector phases of the
o b TX pt o b o n) o TX ide immuno-inflammatory events. However, the engage-
eb ma M rc
e eb ma eb ea eb M
lac flixi e lac imu Pl
ac (m Pl
ac o m
ment of cytokines with their receptors leads to a
+)
p
) in Et
an p
+) ada
l ra f lun
in Le
TX X+ TX ) ak plethora of redundant signal-transduction cascades and
(M (MT (M TX+ An
(M the consequent generation of activated transcription
Figure 3 | Data for recently approved antirheumatic agents. A | Clinical results of randomized factors that mediate the whole inflammatory process
controlled clinical trials. Only trials in which the newly approved agents (or placebo) were applied in through respective gene activation. This redundancy is
addition to methotrexate (MTX) to patients with insufficient response to MTX therapy or (in the case not only related to the instigation of several signal-
of etanercept) direct comparison between a new agent and high-dose MTX are shown. The transduction pathways in parallel, but also to the fact
anakinra + MTX, the etanercept + MTX and the leflunomide + MTX trial reflect six-month data,
that several cytokines can trigger the same cascades.
whereas all other trials reflect one-year data. In trials a, b, c, d and f, the differences between new
compound + MTX were statistically significantly different from placebo + MTX; at the 12-month
endpoint, the difference between the etanercept and the MTX group (e) was not significantly Inhibition of signal-transduction cascades. TNF-α and
different. Data from all trials are published as full papers61,79,84,85,87,95. B | Radiographic data of two IL-1 induce a variety of signal-transduction cascades
trials shown in A (a, e), a trial comparing anakinra with placebo96 (g) and a leflunomide 12-month that lead to the activation of a series of transcription
trial comparing leflunomide with intermediate-dose MTX and placebo256 (h); data from the 12- factors (FIG. 4), including the AP-1 complex and NF-κB
month adalimumab trial are published only in abstract form. The anakinra study used the Genant- (reviewed in REFS 45,46,124), and consequently to the
modified Sharp score, all others used the van der Heijde-modified Sharp score. It should be noted
that each trial can only stand on its own and that it is difficult to compare with other trials because
induction of a variety of genes, such as those coding for
of the non-comparative nature of the individual trials, as well as to significant differences in patient various cytokines, other inflammatory mediators
populations investigated. At best, an estimation of similarities or differences between trials is including prostaglandins, and MMPs125,126. The two
potentially possible where placebo arms exist. principal pathways activated by TNF-α and IL-1 are the

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REVIEWS
NF-κB PROTEINS
NF-κB consists of homo- or
heterodimers, and the most
important of its components are
the p50 and the p65 proteins.
TRANSCRIPTION FACTOR AP-1
The transcription factor AP-1 is
composed of homo- or
heterodimers of proteins that
primarily belong to the JUN and
FOS (but also other) families.
Whereas JUN proteins can
homodimerize, FOS proteins do
not form stable homodimers but
form heterodimers with JUN
proteins. Once phosphorylated
and dimerized, the AP-1
proteins gain enhanced DNA-
binding capacity and modify
transcriptional activity. AP-1
proteins are phosphorylated
(and thereby activated) by the
MAPK pathways.
480 | JUNE 2003 | VOLUME 2
MAPK- and the NF-κB pathways (FIG. 4), and molecules
of these signal-transduction cascades have been detected
in the RA synovial membrane127,128. As p38-MAPK is
predominant both in endothelial cells and in the lining
layer of the RA synovial membrane, the inhibition of
p38-MAPK could be of particular interest. A variety of
p38-MAPK inhibitors have been developed, such as SB
203580, SB 220025, RWJ 67657, VX-745, RPR 200765A,
RPR 203494 and BIRB 796 (REFS 129–140). These agents
usually inhibit two of the four isoforms of p38-MAPK
(α and β)137, and many have anti-arthritic activity in
experimental models129,132,133,138,139. RWJ 67657 also effec-
tively inhibited endotoxin-induced clinical effects and
cytokine release in Phase I studies140. Phase II clinical trials
of p38-MAPK inhibition in RA are in progress. Several of
these compounds have shown toxicities, many of which
do not seem to be related to the mode of action but to
the chemistry of the particular agents; these toxicities
involve the liver, heart and central nervous system.
Another important MAPK is c-JUN N-terminal
kinase (JNK), which has several isoforms that phosphory-
late specific sites on c-JUN. Specific JNK-inhibitors, such
as SP 600125, CEP 1347, or CEP 11004 (REFS 141,142),
might ameliorate experimental arthritis143. The JNK path-
way is particularly involved in the regulation of MMPs.
Finally, inhibitors of extracellular signal-regulated kinase
(ERK) or the upstream kinase MEK, such as PD 98059,
NAMI-A, or U0126 (REFS 144,145), have also been used, but
did not ameliorate experimental arthritis143.
The second major family of transcription factors acti-
vated in the course of the inflammatory response is the
NF-κB family. NF-κB exists as homo- or heterodimers of
five DNA-binding proteins, RelA/p65, Rel B, c-Rel, p52
and p50, which are usually bound to the inhibitory IκB
proteins. When IκB is phosphorylated by IκB kinases
(IKK), NF-κB is freed and can translocate to the
nucleus45. An adenovirus vector encoding IκBα can
inhibit the in vitro production of pro-inflammatory
cytokines and MMPs, and interfere with DC function;
the latter could also be achieved by a small-molecule
inhibitor146. Various compounds that are already used in
the therapy of RA act as NF-κB inhibitors, such as gluco-
corticoids, cyclosporin A and leflunomide; in addition,
flavonoids and proteasome inhibitors, such as gliotoxin,
PSI or parthenolide, interfere with the degradation of
IκB147–149. The potential of selective inhibitors of NF-κB
in the treatment of RA is also evidenced by the effects of
NF-κB inhibition in experimental animals: overexpres-
sion of IκBα, or the application of small-molecule agents
that target the NF-κB pathway at various points, inhibits
experimental inflammation and colitis147,148,150,151. At pre-
sent, the most promising target among the many mole-
cules composing the NF-κB pathway is IKK-β.
As T cells have a role in the pathogenesis of RA and
many forms of experimental arthritis, inhibiting T-cell
functions by interfering with pivotal kinases involved in
T- and/or B-cell activation is an attractive possibility. In
fact, leflunomide has been shown to also inhibit the tyro-
sine kinase LCK64, which is an essential protein for T-cell
activation. More specific LCK inhibitors have been char-
acterized152–155, and targeting LCK might be an attractive
© 2003 Nature Publishing Group
option; it will therefore be interesting to learn more about
the effects of LCK inhibitors in experimental arthritis156.
B cells are also likely to be important in RA, as evidenced
by the presence of autoantibodies in the vast majority of
RA patients and the relation of the severity of disease to
the presence of such autoantibodies, as discussed above.
In fact, in some experimental models, such as collagen-
induced arthritis and the K/BxN model, autoantibodies,
and hence B cells, are of significant importance157.
Moreover, mice with B-cell deficiency, such as mice with
the xid mutation, are resistant to developing collagen
arthritis and less susceptible to Staphylococcus-induced
arthritis158. The xid mouse carries a Bruton’s tyrosine
kinase (BTK) defect, and in humans BTK mutations are
associated with X-linked agammaglobulinaemia159. BTK
is essential for activation of NF-κB through the B-cell
receptor160 and also seems to be involved in the induction
of macrophage effector functions161. So, targeting BTK
might allow a combination of a B-cell-selective approach
by inhibiting (auto)antibody-mediated inflammation
and also interfering with inflammation-associated effec-
tor functions of macrophages162. Interestingly, BTK can be
phosphorylated by c-ABL, the tyrosine kinase responsible
for chronic myelogeneous leukaemia163, an observation
that opens new avenues to explore in the use of kinase
inhibitors in RA. Moreover, BTK has recently been
shown to be involved in the LPS-induced generation of
TNF-α164. In addition to BTK, other tyrosine kinases,
such as LYN and SYK, are involved in signalling through
B-cell receptors (and also other ones in other cells) and
it will be interesting to learn more about the effects of
specific inhibitors in arthritis165.
B-lymphocyte stimulator (BLys), also termed BAFF
(B-cell activating factor of the TNF family) leads to B-cell
activation and production of immunoglobulins, includ-
ing autoantibodies. BLys levels are, in fact, increased in
several autoimmune disorders, including RA. Targeting
Blys either with monoclonal antibodies or receptor con-
structs might be a further interesting targeted approach.
In summary, a plethora of kinases and transcription
factors might constitute promising therapeutic targets
for combating inflammatory disorders in general and
RA in particular. The reason why it is difficult to pin-
point a single or a few such molecules lies in the com-
plexity of the pathogenesis of RA and the redundancy of
the cellular and molecular pathways underlying the
inflammatory and arthritogenic response. In any case,
the use of kinase inhibitors will have to be watched
intensively for their tolerability. In particular, it will
have to be seen whether the inhibition of such essential
intracellular pathways is afflicted with an increased
propensity towards infections and/or malignancy, but
other safety issues could also arise.
Possible targets for new biological DMARDs
TNF, other pro-inflammatory cytokines and lymphokines.
Additional TNF blockers are being evaluated at present,
such as CDP 870, a pegylated Fab fragment of a human-
ized IgG monoclonal anti-TNF antibody166, and oner-
cept, a fusion protein of recombinant human TNF
receptor I (TNF-RI, also known as p55) with IgG1.
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 REVIEWS

Onercept (in contrast to etanercept) seems to have effi-

cacy in Crohn’s disease167 and constitutes another can-
didate TNF blocker for RA. Finally, pegsunercept, a
pegylated soluble TNF-RI, has shown anti-arthritic activ-
ity in experimental arthritis168. Like TNF, IL-1 constitutes
an important target in the pathogenic pathways under-
lying RA and, as mentioned above, anakinra (recombi-
nant IL-1ra) is approved for the treatment of the disease.
Other IL-1 blockers, such as soluble recombinant IL-1
receptors type I and II, are candidate agents169.
IL-6 is a pro-inflammatory cytokine that has been
consistently found in highly increased levels in RA and
linked to the acute-phase response. However, the role of
IL-6 in the pathogenesis of RA is not yet fully known. It
seems to be mainly induced by TNF-α and IL-1, and
TNF blockade leads to a significant decrease in IL-6
(REF. 170). Furthermore, IL-6 deficiency ameliorates some
forms of experimental arthritis171. Anti-IL-6 mono-
clonal antibodies were tested in RA patients in open
trials with minor success more than a decade ago172.
However, a recombinant human anti-IL-6 receptor
monoclonal antibody that inhibits the function of IL-6
has recently undergone Phase II clinical trials. In a small
Phase II trial, this anti-IL-6R antibody induced ACR20
responses in 56% of patients with established RA173.
This molecule is being further evaluated in RA and
might also be effective in multiple myeloma174.
IL-2 and its receptor were also targeted in experimen-
tal models by using monoclonal antibodies to the IL-2R
or recombinant human IL-2 coupled to diphtheria toxin
(DAB 389IL-2, DAB 486-IL-2)175,176. Although somewhat
effective in malignancies177 and psoriasis178, response rates
in RA were unremarkable179. However, the efficacy of
recombinant monoclonal anti-IL-2R antibodies, such as
daclizumab and basiliximab, in the treatment of trans-
plant rejection180, indicates that such intervention might
also be useful in RA, possibly in combination with other
Figure 4 | Simplified overview of pathways involved in TNF-α and IL-1 signalling. Two major agents, and particularly in the early stages of the disease.
pathways, the NF-κB (left) and the MAPK pathway (right) are activated by the pro-inflammatory As some of the functions of IL-2 can be substituted
cytokines TNF-α and IL-1. a | On the left of the figure, in the cytoplasm, NF-κB PROTEINS are usually for by IL-15, this cytokine is a focus of interest. IL-15 is
associated with inhibitors of NF-κB (IκBs). Various stimuli, including ligation of receptors of pro- produced by a variety of cell types, including mono-
inflammatory cytokines, activate the IκB kinase (IKK) complex, which consists of IKK1 (α), IKK2 (β),
and the regulatory subunit NEMO (also known as IKKγ). IKK phosphorylates IκBs, leading to their
cytes, DCs and fibroblasts. Its receptor comprises the
degradation, thereby allowing NF-κB to enter the nucleus and activate genes coding for various IL-2Rβ- and γ-chains and a unique IL-15R α-chain.
molecules, such as cytokines, chemokines, cyclooxygenase-2, anti-apoptotic and stress proteins. IL-15 is expressed in the synovial membrane and is also
NF-κB can be activated by a variety of engaged receptors and various other signalling pathways found in synovial fluids. TNF-α production by
than the one depicted here, which all involve activation of IKKs. b | On the right of the figure, MAPKs macrophages as induced by T-cells is partly dependent
are regulated by several (two or more) upstream phosphorylation cascades initialized after receptor
on the activity of IL-15 (REF. 181). IL-15 blockade by solu-
ligation and recruitment of adaptor proteins. The kinases immediately upstream of the MAPKs
belong to the MAPK or ERK kinase (MKK or MEK) family. The three major MAPK families are the ble mouse IL-15Rα inhibited experimental arthritis in
extracellular-signal-regulated kinases (ERKs), the c-JUN N-terminal kinases (JNKs) and the p38 mice182, and soluble human IL-15Rα has also shown
enzymes. The ERK subgroup of MAPKs is mainly activated by growth factors, whereas pro- efficacy against collagen-induced arthritis in a primate
inflammatory cytokines mostly induce the JNK and p38 MAPK cascades. After phosphorylation of model43. Results of a Phase I trial in RA have recently
its components (primarily members of the Fos and Jun families), the TRANSCRIPTION FACTOR AP-1 been publicized and further data are awaited.
induces activation of genes coding for various cytokines (including TNF-α and IL-1 themselves),
other inflammatory molecules, such as prostaglandins (PGs), and proteases, such as the matrix
Another potent pro-inflammatory cytokine is IL-12,
metalloproteinases (MMPs). In addition, AP-1 regulates cell proliferation, survival and apoptosis. which is the major inducer of TH1 cells. So, interference
As also shown, capture of TNF-α by TNF-blocking agents, or interaction of IL-1ra with the IL-1 with TH1 responses can be achieved by blocking IL-12,
receptor, prevents TNF-α and IL-1, respectively, from ligation to their receptors, induction of signal and anti-IL-12 antibodies suppress experimental
transduction cascades and activation of transcription factors AP-1 and NF-κB. Likewise, the arthritis both as monotherapy and even more effi-
different kinases, as well as the transcription factor activity itself, constitute therapeutic targets. AP-1,
ciently in synergy with anti-TNF therapy183. Clinical
activator protein-1; IL, interleukin; IRAK, IL-1 receptor-associated kinase; MAPK, mitogen-activated
protein kinase; MyD88, myeloid differentiation protein 88; NEMO, NF-κB essential modulator; trials of anti-IL-12 have been initiated in Crohn’s dis-
NF-κB, nuclear factor-κB; TNF, tumour-necrosis factor; TRADD, TNF receptor-associated death ease and RA, but results might not be impressive as
domain protein;TRAF, TNF receptor-associated factor. they have not yet been published.

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REVIEWS
CHEMOKINES
Chemokines are chemotactic
cytokines and play a pathogenic
role in various disorders,
including inflammatory
diseases. Many chemokine
receptors, such as CCRs and
CXCRs, have characteristic cell
or tissue expression profiles.
482 | JUNE 2003 | VOLUME 2
As discussed previously, IL-18 belongs to the IL-1
family and is derived from its precursor by ICE. IL-18
can be found in RA synovial membrane and joint fluid,
and it induces TNF-α, IFN-γ, IL-1 and other cytokines
through lymphocyte activation, as well as direct action
on macrophages. In addition, IL-18 increases the pro-
inflammatory activity of T-cell–macrophage interactions
in synergy with IL-15 and IL-12 (REF. 184), and has an
important effect on the induction of IFN-γ, which is why
it was originally described as IFN-γ-inducing factor185.
IL-18 signals through a receptor comprising an α- and
β-chain, with IL-18Rβ serving a similar function to the
IL-1RacP. In addition, there exists an IL-18-binding pro-
tein (IL-18BP) that has no sequence homology with the
IL-18Rα or β-chain and which serves as a decoy receptor.
A deficiency, or neutralization, of IL-18 ameliorates
experimental arthritis186,187. There are four ways to
block the actions of IL-18: anti-IL-18 antibodies, anti-
IL-18R antibodies, soluble IL-18Rα or their constructs,
and IL-18BP. As a molecule that induces IFN-γ, IL-1 and
TNF-α, IL-18 is an attractive therapeutic target for RA.
Finally, IL-17, a T-cell-derived cytokine present in
RA188, acts as a pro-inflammatory cytokine, particularly
in conjunction with IL-1 and TNF-α189. IL-17 induces
MMP production and downregulates TIMP190, and
blockade of IL-1 and IL-17 has a synergistic effect on
inflammation and bone destruction in vitro191. So, this
cytokine could also be an effective target, possibly in
conjunction with blockade of IL-1 and/or TNF in a
combination therapy approach.
Blocking chemokines and angiogenesis. CHEMOKINES and
chemokine receptors (CCRs) have attracted signifi-
cant interest in RA research192, and a CCR5 polymor-
phism seems to be related to the severity of RA 193.
Small-molecule inhibitors, as well as biological agents,
of this and other chemokine receptors194,195 could
become valuable compounds in anti-arthritic therapy,
although further investigations are needed.
Angiogenesis is an important event in the genera-
tion of RA44. A variety of molecules are engaged in the
process, among them chemokines and other angiogenic
cytokines. The most potent is vascular endothelial
growth factor (VEGF), and anti-VEGF antibody ther-
apy ameliorates experimental arthritis196. There are
various ways to block the action of VEGF or signal
transduction through VEGF receptors (VEGF-R), such
as humanized monoclonal anti-VEGF antibodies, solu-
ble VEGF-R, or tyrosine receptor kinase inhibitors197,
and early-phase trials are under way in several diseases
in which VEGF is implicated. The most potent VEGF
blocker seems to be VEGF-Trap, a construct of the first
three domains of the VEGF-R1 with a constant region
of IgG1 (REF. 198). This and other VEGF blockers are
candidate therapies for RA, and studies are ongoing.
Other anti-angiogenic compounds include angiostatin
and endostatin, both of which are endogeneous pro-
teins available in recombinant form that inhibit
endothelial cell proliferation44. Different kinase
inhibitors might act in a relatively specific manner on
endothelial cells and so inhibit angiogenesis.
© 2003 Nature Publishing Group
Anti-inflammatory cytokines. Several cytokines possess
anti-inflammatory activity, particularly in the context of
TH1-mediated diseases. The TH2 cytokines IL-4 and IL-10
have already been employed in clinical trials in RA.
Despite efficacy in experimental models199, a Phase I trial
of recombinant human (rh) IL-4 in RA, although well
tolerated, did not reveal significant clinical benefit200.
Daily subcutaneous injection of rhIL-10 initially seemed
to be beneficial201 and led to pronounced increases of
circulating TNF-R and IL-1ra202. However, thrombo-
cytopaenia occurred in some patients and efficacy was
not discerned in subsequent studies. So, it seems that
both these anti-inflammatory cytokines did not lead to
the expected shift to a TH2 phenotype or that the
assumption of a beneficial role of changes of the
TH1/TH2 balance in RA might be incorrect. The devel-
opment of both IL-4 and IL-10 for RA was discontin-
ued, but it is still possible that the combination of both
cytokines, or of other TH2-type cytokines, could lead to
a more marked improvement203.
IL-11, a member of the IL-6 superfamily, is a
haematopoietic growth factor for platelets204 that is
approved for use in chemotherapy-associated thrombo-
cytopaenia (as oprelvekin), but which is also an anti-
inflammatory cytokine. However, no significant clinical
benefit in RA was achieved205.
In experimental arthritis, IL-13 can also attenuate
disease206. IL-13 is an anti-inflammatory cytokine that
signals through a receptor that shares the IL-4Rα chain
with IL-4R and the common γ-chain with IL-2R, IL-4R
and IL-15R. IL-13 can markedly reduce IL-1, TNF-α
and IL-8 levels in synovial tissue explant cultures207.
Similarly to IL-4, it is hardly detectable in the RA syn-
ovial membrane and might therefore not be important
in the counter-regulatory mechanisms of the local
inflammatory response. Nevertheless, the beneficial
effects seen in experimental animals indicate that it
might become an attractive novel therapeutic candidate.
Some of the earliest therapeutic studies of cytokines
in RA were investigations on the effect of IFN-γ.
Although there were initial reports of beneficial effects
in controlled trials208,209, the overall efficacy of IFN-γ
therapy was relatively low, was not seen in subsequent
studies210, and significant adverse events, including the
induction of autoimmunity, were observed211. On the
other hand, no deterioration of RA was reported, which
is interesting to note given that RA is now considered an
autoimmune disease that might be initiated and driven
by a TH1 response.
Cell-surface antigens: T cells. T cells have been the most
frequently targeted cells in the history of the biological
therapy of RA. During the past decade, several attempts
to influence the disease by reducing cell number, or
interfering with the function of CD4+ cells in particular,
have been unsuccessful: several anti-CD4 monoclonal
antibodies, depleting or not-depleting circulating CD4
cells, have been tested and led to initially promising
results in open trials; however, controlled trials either
failed to show benefit or were too small to allow final
judgement103. Aside from prolonged lymphopenia,
www.nature.com/reviews/drugdisc

INDUCTION THERAPY
Therapeutic approach that
involves the initial application
of an ‘aggressive’ regimen to,
ideally, induce a remission-like
state, followed by maintenance
therapy with more traditional
agents, such as MTX.
NATURE REVIEWS | DRUG DISCOVERY
rashes and vasculitis complicated the application of
some of these antibodies212. Whether the use of higher
doses of non-depleting anti-CD4 antibodies still consti-
tutes a feasible option remains to be seen. Like the over-
all results of anti-CD4 therapy and the IL-2 diphtheria
toxin conjugate discussed above, an anti-CD5 ricin-
linked immunoconjugate failed to show efficacy213.
Anti-CD7 therapy is also no longer being pursued103.
By contrast, therapy directed at interfering with T-cell
co-stimulation proved quite effective. CD80/CD86 are
co-stimulatory molecules on antigen-presenting cells
that bind to the CD28 receptor of T cells. Once activated,
T cells can express CTLA4 (CD 152), another member of
the CD28 receptor family, which binds with higher affin-
ity to CD80/86 than CD28 and silences T-cell activity214.
A fusion protein, CTLA4Ig, which binds to CD80/86 and
prevents its interaction with CD28 and subsequent T-cell
activation, has meanwhile been successfully tested in
several Phase II trials. ACR20 responses were observed in
53% of patients receiving the highest dose (10 mg/kg),
compared with 31% on placebo215. When tested in com-
bination with MTX in patients with inadequate
response to MTX, ACR responses were observed in 60%
of the patients, compared with 35% on placebo216.
Furthermore, a combination of CTLA4Ig at suboptimal
doses (2 mg/kg) with etanercept in patients with inade-
quate response to this TNF blocker resulted in ACR20
responses in 48% of patients, compared with 28% on
placebo217. Phase III trials are in progress. Whether the
mode of action of CTLA4Ig in RA is merely an interrup-
tion of T-cell activation, or some other mechanism,
remains to be established.
Another important co-stimulatory ligand–receptor
pair are CD40 and CD40L (CD154), and monoclonal
anti-CD40L antibodies have been developed to inter-
fere with their interaction. Initial trials in another
rheumatic disease, systemic lupus erythematosus,
seemed to be successful with respect to reducing clini-
cal disease activity, but were complicated by throm-
boembolic events218. The importance of CD40L/CD40
interactions in T- and B-cell activation219 makes this
co-stimulatory pathway an attractive target in RA,
provided that safety issues can be resolved.
Co-stimulation is also provided by yet another
receptor–ligand pair, inducible T-cell co-stimulator
(ICOS)–ICOS-L. Interestingly, in contrast to CD40 and
CD28, ICOS seems to be solely expressed on T cells and
ICOS-deficiency is not accompanied by significant
immunodeficiency220. Moreover, inhibition of this co-
stimulatory pathway ameliorates experimental arthritis.
Cell-surface antigens: B cells and complement. As dis-
cussed previously, B cells, and particularly autoantibody
production, seem to be important in the pathogenesis of
RA. Pilot open trials indicated that anti-CD20 (rituxi-
mab), a monoclonal antibody licensed for the treatment
of B-cell lymphoma, might be effective as a monother-
apy in patients refractory to DMARDs including MTX
and TNF blockers221. In a double-blind, randomized
controlled trial, patients received intravenous infusions
of rituximab alone or in combination with other drugs:
© 2003 Nature Publishing Group
REVIEWS
58%, 80% and 33% ACR20 responses were observed in
patients receiving rituximab alone, rituximab and
MTX, and placebo and MTX in inadequate MTX
responders, respectively. Remarkably, 50% of the
patients receiving rituximab in combination with MTX,
compared with 32% on rituximab alone and 10% on
MTX and placebo, achieved an ACR50 response222.
When administered in combination with cyclophos-
phamide, rituximab had similar efficacy as when com-
bined with MTX. Adverse events were observed at
similar levels and types among all groups. The data
indicate that an INDUCTION THERAPY of rituximab might be
highly efficacious, although this, ultimately, will have to
be proven in Phase III trials. It will also be interesting to
learn more about the mode of action of this therapy.
Although not aiming at a B-cell surface antigen
directly, the efficacy of therapy targeting B cells and their
products is also supported by studies on immunoglob-
ulin elimination. In a controlled Phase II trial, an
ACR20 response was observed in 29% of the patients,
compared with 11% sham-treated individuals223.
In this context, mention should be made of Fc-γ
receptors (Fc-γR), which bind IgG though its Fc por-
tion. These exist as activating and inhibitory types, such
as Fc-γR IIb224. Interference with Fc-γR activity might
significantly modulate disease expression in experi-
mental inflammatory and autoimmune models55,225,
and the anti-inflammatory properties of intravenous
immunoglobulins might be mediated through
inhibitory Fc receptors.
The complement system, aside from its involvement
in innate immunity, can mediate immune-complex-
related cell and tissue injury, and is activated in, and so
probably pathogenically involved in, RA53. Eculizumab,
a humanized monoclonal antibody that prevents the
cleavage of human complement component C5 into its
pro-inflammatory components, has been investigated
in Phase II trials of RA after achieving ACR20 responses
in 50% of patients in early-phase studies, and results are
pending226. Other possibilities for inhibiting comple-
ment-mediated immune responses include interference
with complement receptors (CRs) and the application
of soluble CR1, which blocks complement activation227.
Adhesion molecules. Adhesion molecules play a pivotal
role in cell recruitment to inflammatory sites. Interfering
with the process of adhesion can, therefore, reduce cellu-
lar accumulation and thereby modify the process of
inflammation. An important adhesion molecule is
ICAM-1 (CD54)228. The efficacy and safety of a mouse
monoclonal anti-ICAM-1 antibody was evaluated in
several studies. Clinical improvement was observed in an
initial open-label dose-escalation study, in which adverse
events were minor and transient229. An open-label trial in
ten patients with early RA revealed a marked or moder-
ate clinical response in seven of the patients230. However,
when a second course was received by eight patients, no
significant clinical benefit was seen, but adverse effects
— immune complex reactions resulting from anti-
mouse Ig antibodies — were observed, which had not
been seen during the initial course231. Taken together,
VOLUME 2 | JUNE 2003 | 4 8 3
REVIEWS
MMPs
Chemokines
VEGF
IL-17
IL-6
IL-15
IL-18
TNF
IL-1
Figure 5 | The inflammatory house of cards. The findings that many cytokines are involved in
the generation of the inflammatory and destructive events characteristic of rheumatoid arthritis,
as well as observations in various clinical trials on the significant and similar efficacy of targeting
different cytokines, but the rare occurrence of remissions, suggest a multiplicity, redundancy and
even synergy of these events. This is depicted here as a house of cards: pulling one card —
that is, interference with one target — breaks part of this ‘inflammatory composite’. However,
no single card, when eliminated, seems to be sufficient to allow the collapse of the whole
inflammatory construct; rather, it might be necessary to interfere with more than one molecule to
fully block the events. The indicated cytokines can be replaced by other molecules, such as
co-stimulatory molecules or CD20, autoantibodies, and others, or by different types of cells,
including T cells, B cells, macrophages, mast cells and dendritic cells. IL, interleukin; MMPs, matrix
metalloproteinases; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor.
these data indicate that the use of mouse monoclonal
antibodies is precluded, but that ICAM-1 might con-
stitute an important therapeutic target.
Another adhesion molecule, integrin αvβ3 (CD51/
CD61), has been the focus of more recent research. This
molecule, also known as the vitronectin receptor, is
expressed at high levels on macrophages, osteoclasts and
angiogenic endothelial cells232. The principal ligands of
αvβ3 are extracellular matrix molecules such as
fibronectin and osteopontin. Interference with integrin
αvβ3 signalling leads to a defect in bone resorption233,
and antagonists of the vitronectin receptor, such as SB
273005, ameliorate experimental arthritis234. A human-
ized monoclonal IgG1 antibody to a conformational epi-
tope formed by the αv and the β3 subunit, MEDI-522
(Vitaxin) has been engineered, and clinical trials in RA
are in progress235.
Three further important adhesion molecules are
leukocyte-function-associated antigen (LFA)-1, which
consists of the subcomponents CD11a and CD18 (αLβ2
integrin), CD58 (also known as LFA-3), which is a mem-
ber of the immunoglobulin superfamily, and very late
antigen-4 (VLA-4), an α4β1 integrin (CD49d/CD29).
LFA-1 interacts with ICAMs, LFA-3 with CD2 and VLA-4
binds to VCAM-1 and fibronectin. Like other integrins,
484 | JUNE 2003 | VOLUME 2
© 2003 Nature Publishing Group
LFA-1 and VLA-4 can be targeted by small compounds
(including peptides) as well as biological agents. Recently,
the humanized anti-CD11a monoclonal antibody efali-
zumab has been shown to be efficacious in psoriasis, as
well as in initial studies in renal transplant patients236.
Likewise, natalizumab, a humanized monoclonal anti-
body against α4 integrin, has been proven to be highly
effective both in Crohn’s disease and multiple sclero-
sis237,238. Finally, alefacept, a recombinant LFA-3–IgG1
fusion protein that blocks LFA-3–CD2 interactions, has
been used successfully in psoriasis and in initial investiga-
tions on psoriatic arthritis239,240. Given that therapies that
are effective in RA are also effective in Crohn’s disease
and psoriasis, including the TNF blockers, it might be
assumed that this is also reciprocally true, a supposition
which will have to be proven in the near future.
Other potential targets among the adhesion mole-
cules obviously include the selectins and the cadherins241.
Moreover, it is of particular interest that a widely used
group of therapeutics, the statins, apparently inhibit
integrin function; this is unrelated to their inhibition
of HMG-CoA reductase and instead results from bind-
ing to a specific site on the integrin molecule. In fact,
statins inhibited the inflammatory reaction in an
experimental model242.
Toll-like receptors. Toll-like receptors (TLRs) have
attracted significant interest because of their capacity to
recognize pathogen-related molecular patterns and to
thereby subserve functions within the innate immune
system. In addition, their involvement as regulators of
the immune system and their bridging function between
the innate and the adaptive defence, as well as their inter-
action with several additional endogenous ligands, add
to their allure. These manifold activities make them
attractive candidates for therapeutic interventions in
many diseases, including chronic inflammation, and
possibilities in this area have been recently reviewed243. As
stated above, the activation of TLRs might be the earliest
event in the pathogenic cascade of RA, and several TLRs
are expressed in the rheumatoid synovial membrane244.
Osteoclasts. The hallmark of RA is the destruction of car-
tilage and bone. As has been detailed previously (FIG. 2),
this bone destruction is mediated predominantly, if not
solely, by osteoclasts50–52,245. Osteoclasts require signalling
through their receptor RANK, which engages its ligand
RANKL on other cells, such as osteoblasts, fibroblasts or
T cells, for their differentiation, maturation and activa-
tion. RANKL is induced by a variety of signals, among
them the pro-inflammatory cytokines TNF-α and IL-1.
A decoy receptor, osteoprotegerin (OPG), is able to bind
RANKL and to consequently prevent RANKL–RANK
interaction246. A fusion protein of recombinant OPG and
IgG-Fc ameliorates several types of experimental arthritis
in terms of bone destruction, but not inflammation246–249.
So, interfering with osteoclast activation in RA could pre-
vent joint damage, while the inflammatory process could
be targeted by other means (which would not necessarily
need to be DMARDs). Such approach could, therefore,
also work in patients in whom traditional DMARDs and
www.nature.com/reviews/drugdisc
 REVIEWS

biologicals fail to arrest bone destruction. OPG has been
investigated in several disorders of bone metabolism250
and is being studied in RA246; results from these trials are
eagerly awaited.
In this respect, another promising group of molecules
are the bisphosphonates251. Although initial clinical trials
in RA failed to show retardation of joint destruction252,
this could have resulted from the limitation of dosing
strategies by oral administration. Recent experimental
data from TNF-mediated destructive arthritis indicate
that high doses of bisphosphonates, although not inter-
fering with inflammation, could be highly effective in the
prevention of joint destruction247. With the availability of
parenteral bisphosphonates, these findings might war-
rant a renewed look at the efficacy of this class of drugs
in interfering with bone destruction.
Summary and prospects
During the past 10–15 years, rheumatologists have wit-
nessed a change in the fate of most RA patients that
would not have been predicted in earlier years: RA can
be relatively well controlled in many patients, extra-
articular manifestations, particularly vasculitis, have
become rare, and a consequence of the chronic inflam-
matory process — secondary amyloidosis — is also now
only rarely seen. This change was brought about, in part,
by the broad application of more efficient therapies,
such as MTX and sulphasalazine, at effective doses and,
more recently, with the newly approved agents. It also
resulted from the recognition that DMARD therapy
should be started immediately with the diagnosis of the
disease. In fact, there could even be a therapeutic win-
dow of opportunity for achieving remission or even
cure very early in the course of the disease, and future
studies will have to evaluate which agents, if any, can
induce full remission at the early stage of RA.
Many approved and investigational agents are
recombinant proteins whose large-scale production is
expensive. Given the prevalence and chronic nature of
RA, the cumulative costs of treatment are likely to
become a societal issue. The evolution of efficacious and
safe small-molecule compounds, especially if orally
available, could overcome this concern. Somatic gene
therapy is another approach being investigated, although
there are many challenges to be overcome (ONLINE BOX 2).
Even the best available therapies at present do not cure
RA and do not even sufficiently retard disease progres-
sion of this ailment in a majority of the patients. Potential
therapeutic targets (see ONLINE TABLE 4 for a summary of
novel targets) are as numerous as the still partly enigmatic
pathogenesis of RA is complex. Many therapeutic
approaches have failed, but many others are successful. In
a few patients, this success is permanent, whereas in
others it is complete but transient, indicating a break-
through of other pathological mechanisms. In yet others
it is incomplete or does not occur at all. Interestingly, if
effective, most of the newer therapeutic approaches to RA
furnish similar degrees of efficacy, both clinically and
with respect to inflammatory mediators and surrogates.
Regardless of the intervention, be it cytokine-, receptor-,
signal-transduction- or cell-type-directed, the inflamma-
tory process collapses at least partly, but rarely completely,
and never in all patients (FIG. 5), which reflects both the
pathogenetic complexity and redundancy. These findings
indicate that targeting individual molecules will not
suffice to stop the ongoing events to a sufficient degree in
a large number of patients. Consequently, until the
cause(s) of RA is known and causative therapy is avail-
able, the aim will be to interfere with several targets in a
combined way. Although the right mix has not yet been
determined, the multiplicity of the promising targets, and
the use of combinations of existing and/or future thera-
peutics, could pave the way to novel therapeutic regi-
mens. Although rheumatology, and particularly the
therapy of RA, seemed to be approaching a dead-end a
decade ago, the developments in basic and clinical
research (ONLINE BOX 3) during this period, both in acade-
mia and industry, have not only led to the new therapies
that now complement the traditional ones, but have also
made the outlook for the future of RA therapy bright.

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Online links
DATABASES
The following terms in this article are linked online to:
LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/
αlB2 | αvB3 | BTK | CD40 | CD40L | CD58 | CD80 | CD86 | CTLA4 |
ICAM-1 | ICE | IFN-γ | IL-1β | IL-1RI | IL-2 | IL-2R | IL-2Rβ | IL-4 |
IL-5 | IL-10 | IL-12 | IL-13 | IL-15 | IL-15R α-chain | IL-18 |
IκB | IKK-b | JNK | LCK | NF-κB | OPG | p38-MAPK | RANK |
RANKL | TACE | TIMP-1 | TNF-RI | VLA-4
Online Mendelian Inheritance in Man:
http://www.ncbi.nlm.nih.gov/Omim/
Agammaglobulinaemia | Crohn’s disease
FURTHER INFORMATION
Encyclopedia of Life Science: http://www.els.net
Rheumatoid arthritis
Access to this interactive links box is free online.
www.nature.com/reviews/drugdisc

Prof. Dr. med.
Klaus Krüger
MMW-Schriftleiter
Rheumatologie
Praxisgemeinschaft
München
– Die Behandlung chronischer Arthriti-
den in den letzten 25 Jahren kann in
zwei Phasen unterteilt werden: Nach eher
schleppenden und sporadischen Neuent-
wicklungen bis Anfang der 1990er-Jahre,
durch die der zerstörerische Krankheits-
verlauf der rheumatoiden Arthritis (RA)
nur zu verzögern war, haben wir in den
letzten 15 Jahren eine fast quantensprung­
artige Entwicklung erlebt, die in das heu-
tige Therapieziel einer kompletten Re-
mission mündete. Dagegen ist bei der
Arthrosebehandlung trotz kleinerer Fort-
schritte der Durchbruch hin zur nachhal-
tigen Verlaufsbeeinflussung bisher nicht
gelungen. Eine heilende Therapie fehlt,
wie für die meisten rheumatischen Er-
krankungen, für beide nach wie vor.
Rheumatoide Arthritis
Symptomatische Therapie mit nicht
steroidalen Antiphlogistika (NSAR),
Glukokortikoiden (GC) als „Feuerwehr“
und in hoher Dosis als Ultima Ratio so-
Dieter-Lothar Adam
Rheumatologie
Quantensprünge in der Therapie
der rheumatoiden Arthritis
Von K. Krüger
wie eine Handvoll Basistherapeutika –
dies war neben nicht medikamentösen
Behandlungsformen physikalischer
und operativer Art das therapeutische
Arsenal vor 25 Jahren.
NSAR
Im Bereich der NSAR waren die fol-
genden drei Jahrzehnte zunächst durch
diverse Neuentwicklungen gekennzeich-
net, die stets mit dem Anspruch besserer
Verträglichkeit auf den Markt gelangten.
Bei der praktischen Anwendung konn-
ten sie dem dann aber nicht oder kaum
gerecht werden. So entstand eine sehr
breite Palette ähnlicher Wirkstoffe, von
denen viele wieder verschwunden sind.
Einen deutlichen Fortschritt zumindest
in Bezug auf die gastrointestinale Ver-
träglichkeit stellte die Entwicklung der
selektiven Cyclooxygenase-2-Hemmer
(Coxibe) Ende der 1990er-Jahre dar. Aus
dieser Gruppe wurden mit Rofecoxib,
Valdecoxib und Lumiracoxib jedoch
drei Substanzen wegen vermeintlich ge-
fährlicher kardiovaskulärer, dermatolo-
gischer oder hepatischer Nebenwir-
kungen wieder vom Markt genommen.
Mit Celecoxib und Etoricoxib können
jedoch zwei Coxibe z. B. bei GI-Proble-
men eingesetzt werden. Insgesamt ha-
ben NSAR für die symptomatische Ar-
thritistherapie einen unverändert hohen
Stellenwert, werden aber wegen der
sonstigen Fortschritte heute vorwiegend
als Bedarfsmedikamente verwendet.
Glukokortikoide
GC werden seit rund 60 Jahren in der
Rheumatologie eingesetzt, sind jedoch
gleichwohl durch ständige Weiterent-
wicklung des Therapieprinzips charakte-
risiert. Hierzu zählt die feste Etablierung
der intraartikulären Verabreichungsform
in den letzten 20 Jahren, weiterhin die
Erkenntnis, dass GC in niedriger Dosie-
rung (≤ 7,5 mg) von Beginn an eine ba-
sistherapeutische Wirkung besitzen. Sie
 25 Jahre Fortschritte in der Rheumatologie –

Abbildung 1 wiegend mit Mtx kombiniert. Bei früh-

Exemplarischer Therapieablauf bei hochaktiver RA
Sofortiger Beginn einer Basistherapie mit Mtx nach Diagnosesicherung, vorzugs-
weise parenteraler Beginn, schrittweise Ausdosierung + Low-dose-Kortikoid
innerhalb von 3 Monaten
Kombination Mtx + SSZ + Hcl
(alternativ: Mtx + Leflunomid, Mtx + Cyclosporin A) + LDC
innerhalb von 3 Monaten
Etanercept + Mtx, Adalimumab + Mtx,
Infliximab + Mtx (+ LDC)
innerhalb von 3–6 Monaten
Rituximab + Mtx, Abatacept + Mtx (+ LDC)
Mtx = Methotrexat, SSZ = Sulfasalazin, Hcl = Hydroxychloroquin, LDC = Low-dose-Corticoid
bremsen die radiologisch sichtbaren De- DMARDs erweitert, so Cyclosporin A
struktionen und gehören deshalb min- und Leflunomid, welches heute nach
destens im ersten Halbjahr fest zur Kom- Mtx als zweitwichtigstes DMARD gilt.
binationstherapie der RA. Parenterales Gold, vor Mtx der DMARD-
Goldstandard, ist heute ebenso wie Aza-
Basistherapeutika thioprin eher als Reservepräparat zu se­
In der heterogenen Gruppe der Basis- hen. Die Antimalariamittel Chloroquin
therapeutika (Disease-modifying Anti- und Hydroxychloroquin finden nur
rheumatic Drugs = DMARDs) kam es noch bei sehr gering aktiver RA und in
in den späten 1970er- und 80er-Jahren der Kombinationstherapie Verwendung.
sporadisch zu Neueinführungen wie Der kombinierte Einsatz mehrerer
D-Penicillamin oder Auranofin (orales DMARDs wurde seit den frühen 1990er-
Gold), die sich mittelfristig nicht wirk- Jahren vermehrt erprobt und hat heute
lich als Bereicherungen erwiesen. Zwei einen festen Stellenwert, wenn sich die
Wiederentdeckungen war später ein Monotherapie mit Mtx als unzureichend
besserer Erfolg beschieden: Sulfasala- erweist. Zu den meist verwendeten Kom-
zin (SSZ) und Methotrexat (Mtx). binationen zählen heute Mtx + SSZ +
SSZ war bereits zu Beginn der 1940er- Hydroxychloroquin, Mtx + Leflunomid
Jahre bei RA erprobt worden und dann und Mtx + Cyclosporin A. Kombina­
bei dieser Indikation in Vergessenheit tionstherapien sind i. d. R. nicht schlech-
geraten. Es erwies sich jetzt als gut wirk- ter verträglich als Monotherapien.
sames Basistherapeutikum für leichte
Formen der RA und anderer chro- Biologika
nischer Arthritiden. Die bessere Aufklärung der Pathogene-
Die Wiedereinführung von Mtx ent- se chronischer Arthritiden im Lauf der
wickelte sich sowohl bei der RA wie auch letzten 20 Jahre war Voraussetzung für
bei der Psoriasis-Arthritis als Erfolgsge- die Entdeckung neuer hochwirksamer
schichte. Die Substanz stellt heute unter Sustanzen mit gut definiertem Wirkan-
allen DMARDs den Goldstandard für satz, der Biologika. So wurden Hemm-
aktive chronische Arthritiden dar und stoffe der proinflammatorischen Zyto­
ist der wichtigste Partner in der Kombi­ kine Tumornekrosefaktor a sowie Inter-
na­tionstherapie sowohl mit anderen leukin 1 und 6 entwickelt, weiterhin
DMARDs als auch mit Biologika (s. u.). Substanzen, die B-Lymphozyten bzw.
Einige Neueinführungen in den die Aktivierung der T-Lymphozyten
1990er-Jahren haben die Palette der hemmen (Tab. 1). Biologika werden vor-
zeitigem Einsatz ist diese Kombination
in der Lage, bei ca. 50 % der RA-Pati-
enten eine Remission zu erzeugen. Ins-
besondere für die Kombination TNF-
Blocker + Mtx ist nachgewiesen, dass sie
in den meisten Fällen zu einem kom-
pletten Stillstand der Progression von
Destruktionen führt. Neue Daten zeigen
zudem substanzielle Verbesserungen der
Lebensqualität und Arbeitsfähigkeit der
Patienten sowie eine drastische Reduzie-
rung der krankheitsimmanent gesteiger-
ten Mortalität. Ähnlich gut wirken die
TNF-Blocker bei Psoriasis, Psoriasis-Ar-
thritis und ankylosierender Spondylitis.
Gemessen an ihrer Wirkstärke ist die
Verträglichkeit der Biologika exzellent,
allerdings ist auf eine verminderte Infekt­
abwehr bei den behandelten Patienten
zu achten. Limitierend auf den Einsatz
der Biologika wirken die hohen Thera-
piekosten, die ein Vielfaches der meisten
DMARDs betragen. Gemessen an ihrer
ausgezeichneten Wirksamkeit werden
Biologika in Deutschland jedoch zu zu-
rückhaltend eingesetzt: Nur 3,8 % der
RA-Patienten erhalten diese Therapie,
eine der niedrigsten Raten in ganz Euro-
pa. Bei Einhaltung der nationalen The-
rapieempfehlungen (Einsatz nach zwei
unwirksamen DMARDs möglich) müsste
diese Rate deutlich höher liegen.
Qualitätsmanagement
Neben der Entwicklung vielverspre-
chender neuer Substanzen haben auch
neue Anwendungsstrategien zu den
großen Fortschritten bei der Behand-
lung chronischer Arthritiden beigetra-
gen. So beinhaltet heute das Qualitäts-
management der RA-Therapie schnellst-
mögliche Diagnosestellung und Einlei-
tung einer Basistherapie (im Idealfall
innerhalb von zwölf Wochen). Im wei-
teren Verlauf sollte die Therapie zumin-
dest alle drei Monate mittels standar­
disierter Verlaufsparameter wie DAS
(Disease Activity Score) überprüft und
ggf. modifiziert bzw. eskaliert werden,
bis eine Remission oder zumindest eine
gute Response erreicht ist. Zusätzlich
werden bildgebende Kontrollen zur Ver-
hinderung von Destruktionen durchge-
führt (Abb. 1).

MMW-Fortschr. Med. Nr. 48 / 2008 (150. Jg.) 121

 – 25 Jahre Fortschritte in der Rheumatologie

– Tabelle 1
Für die RA aktuell oder demnächst zugelassene Biologika

Name Wirkprinzip Verabreichung/Dosierung Bemerkungen Weitere Indikationen

Infliximab Chimärer monoklonaler I.v. Inf. – Startdosis 3 mg/kg Bei RA nur in Kombination Ank. Spondylitis, Psoriasis/Psoriasis-
Antikörper gegen TNF Woche 0, 2, 6, 14, dann alle 8 Wo. mit Mtx zugelassen Arthritis, M. Crohn, Colitis ulcerosa
Adalimumab Humaner monoklonaler S.c. 40 mg alle zwei Monotherapie und Kombin. Ank. Spondylitis, Psoriasis/juven. RA
Antikörper gegen TNF Wochen mit Mtx zugelassen Psoriasis-Arthritis, M. Crohn
Etanercept Löslicher TNF-Rezeptor S.c. 25 mg 2 x wöch. Monotherapie und Kombin. Ank. Spondylitis, Psoriasis/
oder 50 mg 1 x wöch. mit Mtx zugelassen Psoriasis-Arthritis, juvenile RA
Anakinra Interleukin-1-Rezeptor S.c. 100 mg 1 x tgl. Bei RA nur noch
wenig verwendet
Rituximab Chimärer monoklonaler I.v. Infusionen mit Zulassung nach Versagen Auch in der Lymphom-
Antikörper gegen 1000 mg, Tag 0/14, dann von TNF-Blocker-Therapie Therapie verwendet
B-Lymphozyten (Anti-CD20) wieder nach frühest. 6 Mon. in Kombination mit Mtx
Abatacept Hemmstoff der I.v. Infusion – 10 mg/kg Zulassung nach Versagen
T-Zell-Aktiv. (Hemmung Tag 0, 14, 28 von TNF-Blocker-Therapie
des kostimul. Signals) dann alle 4 Wochen in Kombination mit Mtx
Tocilizumab Interleukin-6-Rezeptor- 8 mg/kg als Infusion Zulassung vermutlich
Antagonist alle vier Wochen Anfang 2009
Certolizumab Pegylierter monoklonaler 200 mg als Infusion Zulassung vermutlich
Antikörper gegen TNF alle 2–4 Wochen Mitte 2009
Golimumab Humaner monoklonaler 50–100 mg s.c. Zulassung vermutlich
Antikörper gegen TNF alle 4 Wochen Mitte 2009

Arthrose
Mehr noch als die RA ist die Arthrose
durch eine breite Palette von therapeu-
tischen Ansätzen charakterisiert: Neben
medikamentöser und operativer Interven-
tion sowie Krankengymnastik beinhalten
diese u.a. so heterogene Maßnahmen wie
Akupunktur, Röntgenbestrahlung, Radio-
synoviorthese (unter bestimmten Bedin-
gungen) oder Elektrotherapie. Doch mit
keiner dieser Maßnahmen gelingt bisher
ein grundlegendes und nachhaltiges Ein-
greifen in den Krankheitsablauf, abgese-
hen von operativen Eingriffen im Endsta-
dium (Endoprothese, Arthrodese).
Therapie gegen Schmerz und Entzündung
Die symptomatische Therapie der Ar-
throse wird im gering symptomatischen
Stadium heute durch reine Analgetika
und im fortgeschritteneren Stadium,
bei dem Entzündungsmechanismen ei-
ne zunehmende Rolle spielen, durch
NSAR sowie bei GI-Risiken durch Coxi-
be bestimmt. Bei geringer Symptomatik
hat sich auch die topische NSAR-Gabe
als wirksam erwiesen. Die systemische
Gabe von GC ist hier generell nicht in-
diziert, eine intraartikuläre Verabrei-
chung gehört im Stadium der akti-
vierten Arthrose hingegen zum festen
Behandlungs-Repertoire. Auch Substan-
zen wie Oxazeprol und Glucosamin ha-
ben in Studien bei guter Verträglichkeit
einen symptomatischen Effekt gezeigt,
der etwa mit NSAR in niedriger Dosie-
rung vergleichbar ist, bei ausgeprägter
Symptomatik jedoch nicht ausreicht.
In den letzten zehn Jahren wurde die
Suche nach strukturell wirksamen
(„chondro­protektiven“) Substanzen, so-
genannten DMOADs (Disease-modifying
Osteoarthritic Drugs) intensiviert, bisher
aber nicht zu einem eindeutig Erfolg ver-
sprechenden Abschluss gebracht.
Verschleißbremse – Ersatzknorpel
Gentechnologisch entwickelte Inter-
ventionen mit dem Ziel, im Gelenk
protektive oder die Knorpeldestruktion
bremsende Mechanismen zu induzie-
ren oder mittels Gentransfer Knorpel-
zellen und -vorläuferzellen zu generie-
ren, werden seit fast zehn Jahren in
vitro intensiv beforscht. Keines dieser
Verfahren ist jedoch bis jetzt in vivo in
das Stadium einer Erfolg verspre-
chenden Anwendung gelangt.
Eine im weiteren Sinne auf diesem
Prinzip beruhende Intervention, das aus
Eigenblut gewonnene Orthokin, wird
seit Jahren intensiv mittels Pressemittei-
lungen und über das Internet beworben
und sehr kostenintensiv bei Arthrose­
patienten angewendet, ohne dass im ge-
samten Zeitraum ein eindeutiger Wirk-
samkeitsnachweis in Form einer aussa-
gekräftigen Publikation erfolgte.
Ein weiterer innovativer Ansatz ist
die sogenannte Knorpelersatztherapie
mit Implantation von im Labor gezüch-
teten Knorpelzellen. Über eine erfolg-
reiche Anwendung wurde bisher aber
nur für kleine Knorpeldefekte berichtet.
Korrespondenz:
Prof. Dr. med. Klaus Krüger
St.-Bonifatius-Str. 5, D-81541 München
Tel.: 089/6914222
E-Mail: klaus.krueger@med.uni-muenchen.de
– Ausblick
Da auch auf dem Gebiet der medika-
mentösen Arthrosetherapie intensiv
und vielversprechend geforscht wird,
ist in den kommenden Jahren mit In-
novationen zu rechnen, die mittelfristig
die rasante Entwicklung der Behand-
lungsmöglichkeiten bei RA einholen
könnten. Spannende Neuentwicklun-
gen innerhalb der Glukokortikoide zur
Therapie der RA sind demnächst durch
ein Modified-Release-Präparat, liposo-
male GC und selektive Glukokortikoid-
Rezeptor-Agonisten zu erwarten.
– Keywords
25 Years of Progress in Rheumatology:
Quantum Jumps in the Treatment of
Rheumatoid Arthritis
Rheumatoid arthritis – Osteoarthritis–
NSAID – Glucocorticoid – Biologicals

122 MMW-Fortschr. Med. Nr. 48 / 2008 (150. Jg.)

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