Joint Bone Spine 77 (2010) 9698

Editorial

Targeting intracellular signaling pathways to treat rheumatoid arthritis:

Pandoras box?

Keywords:
Intracellular signaling peptides and proteins
Treatment
Rheumatoid arthritis

The introduction of targeted biotherapies based on insights

gained into the immunopathogenesis of rheumatoid arthritis (RA)
is a major breakthrough. Currently available targeted biotherapies
act on cytokines (IL-1, TNF, or IL-6) or cell populations (B cells or Tcell activation) via monoclonal antibodies or fusion proteins. Their
use is limited by a number of factors (e.g., immunogenic potential,
need for parenteral administration, and high production costs).
Intracellular signaling pathways have been implicated in the
various stages of the inammation and joint destruction process
that characterizes RA. They can be blocked by specic inhibitors,
which are already used to treat various malignancies. Treatments
targeting intracellular pathways may hold promise for the treatment of RA.
1. Intracellular signaling pathways relevant to rheumatoid
arthritis
Signals travel from the cell membrane to the nucleus via intracellular signaling pathways that also modulate the signals during
their transmission. Most signals are generated when a peptide (e.g.,
a cytokine) binds to a membrane receptor. The signal travels in the
cell via a sequence of kinase-induced activating phosphorylations
or phosphatase-induced inhibiting dephosphorylations [1,2]. The
phosphorylation cascade leads to the activation of a transcription
factor (e.g., NF-kB or AP-1), which modies the expression level
of the target genes (Fig. 1). Among the many signaling pathways
identied to date, some are selectively involved in inammation
(Table 1) [17]. These pathways are interconnected into a network
that shows substantial redundancy. They are also largely ubiquitous, being identical in most cells, although a few pathways are
more specialized and occur only in limited numbers of cell types
(e.g., spleen tyrosine kinases [SYK] are expressed chiey in B cells,
T cells, and macrophages).
Intracellular signaling pathways are composed of families of cell
proteins that recognize intracellular recognition molecules (e.g.,
suppressors of cytokine signaling [SOCS] inhibit JAK/STAT3). The
considerable complexity of the signaling system that results from
this cascade structure enables subtle regulation of cell activation,
with effects on a large number of potential targets. Furthermore,

activation of a given signaling pathway produces different effects

depending on the cell type. Signaling pathways can be activated
not only by cytokines, but also by other factors such as viral and
bacterial proteins, heat, ultraviolet radiation, and hormones [1].
Many studies have established that intracellular signaling pathways are involved in the pathogenesis of RA. These pathways are
central to the mechanisms underlying the inammatory process,
being both activated by cytokines and responsible for cytokine production. Thus, inhibition of signal transduction pathways might
abolish not only cell activation induced by cytokines or other stimuli, but also the production of new molecules of proinammatory
cytokines. In RA, overexpression of molecules involved in intracellular signal transduction has been found at sites of inammation,
most notably in the rheumatoid synovium [1], where NF-KB, MAPK,
and JAK/STAT are increased. A study of peripheral blood mononuclear cells from RA patients showed increased NF-kB activation that
was chiey mediated by TNF [8]. In a mouse model of arthritis,
direct NF-kB inhibition (via the administration of mutated I-kB)
inhibited the in vivo production of TNF and RANK-Ligand, abolished
the manifestations of arthritis, and halted the osteoclast activation
[9].
2. Inhibition of signaling pathways
Several approaches can be used. For instance, NF-kB activation
can be blocked by the administration of proteasome inhibitors (e.g.,
bortezomib) that prevent the destruction of the NF-kB inhibitor (IkB) or of antisense oligonucleotides or peptides that prevent NF-kB
from accessing its site of action in the nucleus [4].
Inhibiting the kinases that induce phosphorylation blocks intracellular signal transduction. Thus, kinase inhibitors may hold
promise as treatments targeting intracellular signaling pathways.
Several kinase inhibitors are already used in oncology.
3. Preliminary results of intracellular signaling pathway
inhibition used to treat rheumatoid arthritis
After preclinical studies in animal models, several randomized
controlled trials were conducted (Table 2) [1014]. The results
invite several comments. First, follow-up was only 12 weeks, which
limits the relevance of the ndings. Although the effect was rapid
in some studies, being detectable after one week [13,14], longer
follow-ups are clearly needed to determine whether the therapeutic effect is sustained over time (or whether the response rate
increases over time); to assess potential structural effects, whose

1297-319X/$ see front matter 2010 Socit francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.jbspin.2010.01.004

Editorial / Joint Bone Spine 77 (2010) 9698

Fig. 1. Highly simplied general diagram of intracellular signal transduction. Activation of the membrane receptors (R1, R2) generates a signal, with cascade activation
of several kinases (K1, K2, K3) that leads to activation of a transcription factor,
thereby modifying target gene expression and ultimately leading to the synthesis
of peptides (e.g., cytokines).

97

presence is a dening characteristic of disease-modifying agents;

and to evaluate the safety prole, particularly as these treatments
are likely to be used for long periods (several years). Second, treatment efcacy varied across studies, being signicant in about half
the cases. This variability seems related to the target. Various MAPkinase inhibitors produced ACR response rates that were either
not signicantly different from those in the placebo groups [11] or
lower than those obtained using methotrexate [12]. Thus, despite
promising results from animal studies [15,16], proof of concept has
not been obtained for inhibitors of the MAP kinases (most notably
p38). The lack of efcacy of MAP kinase inhibition illustrates the
complexity of the signal transduction systems, whose redundancy
ensures the correction of many deciencies. For instance, the production of proinammatory cytokines such as TNF depends both
on MAP kinase activation and on NF-kB [17,18]. Third, the results of
the few trials conducted to date raise a number of safety concerns.
Adverse events that were more common in the active-treatment
groups than in the placebo groups included gastrointestinal symptoms, headaches, neutropenia, and serum creatinine elevation.
Treatments that interfere with intracellular signaling also affect
the physiological regulation mechanisms of many cell types. The
objective in RA is to modulate a complex set of systems (inammation, cytokines, and proteases); whereas the objective in oncology

Table 1
The main intracellular signaling pathways.
Signaling pathway

Role

Activated by

JAK-STAT (Janus Activated Kinase)

Transmission of cytokine signals (IL-6, IL-23), Th17

polarization
Production of interferon

gp 130 (IL-6, IFN gamma)

SYK (Spleen tYrosin Kinase)

Expressed by B and T cells and macrophages

Immunoreceptor signal transduction
Synthesis of cytokines (IL-6) and MMP induced by TNF
Osteoclast differentiation

Fcgamma receptor

MAP kinases (p38, ERK, JNK)

Cell proliferation, apoptosis

Production of TNF and of IL-1, IL-6, IL-8
Results in activation of the transcription factor AP-1

Mitogenic factors and growth factors (ERK),

cytokines, and cell stress factors (JNK, p38)

NF-KB

Production of cytokines, most notably proinammatory

cytokines (IL-1, IL-6, TNF-), MMP, collagenases, adhesion
molecules, chemokines (RANTES)
Activates genes involved in cell growth, inhibition of
apoptosis, oncogenesis, and negative NF-kB (IkB)
regulation
Cell growth, inhibition of apoptosis, oncogenesis
Adhesion, angiogenesis

Cytokines, bacterial and viral proteins, UV

Phosphatidylinositol-3 protein kinase

(PI3K)/AKT

Activated by growth factors, cytokines, hormones,

viral proteins, co-stimulation of T-cells

Table 2
The main controlled studies of signaling pathway inhibition in patients with rheumatoid arthritis.
Author (ref)

Target (agent)

No. of patients Study design

Duration
(weeks)

ACR 20
response rate

Weisman et
al. [10]

p38 MAPK
(vx-745)

44

12

43% active
17% placebo

Damjanov et
al. [11]

p38 MAPK
(vx-702)

313
2 doses/d vs. placebo

12

4036% active
28% placebo
(NS)
4044% active
22% placebo
(NS)

Cohen et al.
[12]

p38 MAPK
(pamapimod)

Kremer et al.
[13]

JAK
(CP-690,550)

Weinblatt et
al. [14]

Syk kinase
(R 788)

117
1 dose/d + MTX vs. 2
doses/week + MTX (mean
13.5 mg/week)
204
3 doses vs. MTX (up to
20 mg/week at W8)
264
3 doses vs. placebo
189, active RA with MTX
(mean 15 mg/week) 3 doses
vs. placebo

12

23%, 18%, 31%

45% (MTX)

70%, 81%, 76%,

29% placebo

12

38%, 65%, 72%,

32% placebo

Other results

Safety
14/44 withdrawals for lack of efcacy or
intolerance (gastrointestinal symptoms)

Decreases in
CRP, SAA, and
sTNFR p55 at
W1, return to
baseline
levels at W4

Serious infections
2.4% vs. 0%
2.% vs. 4.9%

Headaches, nausea
Elevations in serum creatinine and HDL
Decrease in
IL-6
MMP-3

Diarrhea, hypertension
Neutropenia, hepatic cytolysis

MTX: methotrexate; W: week; CRP: C-reactive protein; SAA: serum amyloid A; sTNFR p55: soluble tumor necrosis factor receptor p55.

98

Editorial / Joint Bone Spine 77 (2010) 9698

is to limit the growth of, or to destroy, a cell population. The

long-term safety requirements are more stringent in patients with
chronic and generally non-life-threatening diseases such as RA.
Furthermore, prolonged signaling pathway inhibition may induce
paradoxical effects. For instance, inhibition of NF-kB activation
may exacerbate the inammatory process by allowing uncontrolled
TNF production by macrophages [3]. Beware of opening Pandoras
box.
Signaling pathway inhibitors exhibit a number of favorable
properties that are generating considerable interest. Most of these
inhibitors are small biochemical compounds that can cross the cell
membrane. Compared to biotherapies, they cost less to produce
and are less likely to induce immunization. Finally, they can be
administered orally.
Signaling pathways are diverse and induce reaction cascades
upon activation. As a result, the number of potential treatment
targets is high, and many different inhibition modalities may be
available, including local treatments [19]. We are witnessing the
birth of a new class of potential treatments. However, extensive
evaluation and validation studies are needed to determine whether
signal pathway inhibition deserves consideration as a treatment
tool for everyday clinical practice.
Conict of interest statement
The authors have no conict of interest to declare.
References
[1] Morel J, Berenbaum F. Signal transduction pathways: new targets for treating
rheumatoid arthritis. Joint Bone Spine 2004;71:50310.
[2] Sweeney SE, Firestein GS. Signal transduction in rheumatoid arthritis. Curr Opin
Rheumatol 2004;16:2317.
[3] Simmonds RE, Foxwell BM. NF-kB and its relevance to arthritis and inammation. Rheumatology 2008;47:58490.
[4] Roman-Blas JA, Jimenez SA. NF-kB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage
2006;14:83948.
[5] Schett G, Zwerina J, Firestein G. The p38 mitogen-activated protein
kinase (MAPK) pathway in rheumatoid arthritis. Ann Rheum Dis 2008;67:
90916.
[6] OShea JJ, Murray PJ. Cytokine signaling modules in inammatory responses.
Immunity 2008;28:47787.
[7] Berton G, Mocsai A, Lowell CA. Src and Syk kinases: key regulators of phagocytic
cell activation. Trends Immunol 2005;26:20814.
[8] Dichamp I, Bourgeois A, Dirand C, et al. Increased nuclear factor-kB activation in peripheral blood monocytes of patients with rheumatoid arthritis
is mediated primarily by tumor necrosis factor-. J Rheumatol 2007;34:
197683.
[9] Clohisy JC, Roy BC, Biondo C, et al. Direct inhibition of NF-kB blocks
bone erosion associated with inammatory arthritis. J Immunol 2003;171:
554753.

[10] Weisman M, Furst D, Schiff M, et al. A double-blind, placebo-controlled trial

of VX-745, an oral p38 mitogen-activated protein kinase (MAPK) inhibitor in
patients with rheumatoid arthritis. Ann Rheum Dis 2002;61:166.
[11] Damjanov N, Kauffman RS, Spencer-Green GT. Efcacy, pharmacodynamics,
and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis
Results of two randomized, double-blind, placebo-controlled clinical studies.
Arthritis Rheum 2009;60:123241.
[12] Cohen SB, Cheng TT, Chindalore V, et al. Evaluation of the efcacy and safety
of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexatecontrolled study of patients with active rheumatoid arthritis. Arthritis Rheum
2009;60:33544.
[13] Kremer J, Bloom BJ, Breedveld FC, et al. The safety and efcacy of a JAK inhibitor
in patients with active rheumatoid arthritis. Results of a double-blind, placebocontrolled phase IIa trial of three dosage levels of CP-690,550 versus placebo.
Arthritis Rheum 2009;60:1895905.
[14] Weinblatt ME, Kavanaugh A, Burgos-Vargas R, et al. Treatment of rheumatoid
arthritis with a Syk kinase inhibitor. A twelve-week, randomized, placebocontrolled trial. Arthritis Rheum 2008;58:330918.
[15] Kaminska B. MAPK signaling pathways as molecular targets for antiinammatory therapy. From molecular mechanisms to therapeutic benets.
Biochim Biophys Acta 2005;1754:25362.
[16] Sweeney SE, Firestein GS. Mitogen activated protein kinase inhibitors: where
are we now and where are we going? Ann Rheum Dis 2006;65(Suppl. 3):838
[iii].
[17] Mahlknecht U, Will J, Varin A, et al. Histone deacetylase 3, a class I histone
deacetylase, suppresses MAPK11-mediated activating transcription factor-2
activation and represses TNF gene expression. J Immunol 2004;173:397990.
[18] Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription
factors in the immune system. Annu Rev Immunol 2009;27:693733.
[19] Tas SW, Vervoordeldonk MJ, Hajji N, et al. Local treatment with the selective
IkB kinase inhibitor NEMO-binding domain peptide ameliorates synovial
inammation. Arthritis Res Ther 2006;8:R86.

Daniel Wendling a,
Clment Prati b
ric Toussirot c
Georges Herbein d
a EA 3186, Service de Rhumatologie, CHU Minjoz,
Universit de Franche-Comt, Boulevard Fleming,
25030 Besancon, France
b Service de Rhumatologie, CHU Minjoz, Universit de
Franche-Comt, Besancon, France
c EA 3186, Service de Rhumatologie, CHU Minjoz,
Universit de Franche-Comt, Besancon, France
d EA 3186, Service de Virologie, CHU, Universit de
Franche-Comt, Besancon, France
Corresponding author.
E-mail address: dwendling@chu-besancon.fr
(D. Wendling).

13 October 2009
Available online19 February 2010