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Current
Rheumatology Reviews
ISSN: 1573-3971
Current Rheumatology Reviews
Volume 4, Number 4, November 2008
Contents
Defining Novel Targets for Intervention in Rheumatoid
Arthritis
Guest Editor: Charles J. Malemud
Defining Novel Targets for Intervention in Rheumatoid Arthritis:
An Overview Pp. 214-218
Charles J. Malemud
[Abstract]
Targeting Cytokines, Chemokines and Adhesion
Molecules in Rheumatoid Arthritis Pp. 219-234
Charles J. Malemud and Sujana K.
Reddy
[Abstract]
Targeting Complement in Rheumatoid Arthritis
Pp. 235-245
Éva Biró, Paul P. Tak, Augueste
Sturk, C. Erik Hack and Rienk Nieuwland
[Abstract]
Update on Targets of Biologic Therapies
for Rheumatoid Arthritis Pp. 246-253
Zafar Rasheed and Tariq M. Haqqi
[Abstract]
Apoptotic Regulators and RA Pp.
254-258
Jack Hutcheson and Harris Perlman
[Abstract]
Measures of Disease Activity in Rheumatoid
Arthritis: A Clinician’s Guide Pp.
259-265
Sarah Ringold and Nora G. Singer
[Abstract]
Targeting Growth Factors in Arthritis:
A Rationale for Restoring the IGF-I Response in Chondrocytes
Pp. 266-276
Fons A. van de Loo, Sharon Veenbergen and
Wim B. van den Berg
[Abstract]
What Animal Models are Best to Test Novel
Rheumatoid Arthritis Therapies? Pp. 277-287
Paul H. Wooley
[Abstract]
Inhibition of Matrix Metalloproteinases
as a Feasible Therapeutic Target in Rheumatoid Arthritis
Pp. 288-297
Muhammad Zafarullah, Rasheed Ahmad, Mohammed
El Mabrouk, Abdelhamid Liacini and Hamid Yaqoob Qureshi
[Abstract]
Targeting Angiogenesis in Rheumatoid
Arthritis Pp. 298-313
Zoltán Szekanecz and Alisa
E. Koch
[Abstract]
Abstracts
[Back to top]
Defining Novel Targets for Intervention in Rheumatoid Arthritis:
An Overview
Charles J. Malemud
Many and sometimes disparate immune and non-immune-mediated
events contribute to the pathogenesis and progression of rheumatoid
arthritis (RA). Despite recent advances in the development
and implementation of disease-modifying anti-rheumatic drugs
and biological response modifiers for the treatment of RA,
it remains vital that additional RA targets suitable for RA
intervention be identified. Such novel targets for RA intervention
would include, non-interleukin-1 (non-IL-1)/non-tumor necrosis
factor-α/non-IL-6
pro-inflammatory cytokines, growth factors that regulate angiogenesis
as well as those required for synovial joint tissue repair.
Proteins that are integral to the modulation of T-lymphocyte,
B-lymphocyte, monocyte activity and synovial tissue apoptosis
as well as complement, chemokines, adhesion molecules must
also be considered. Because articular cartilage destruction
and subchondral bone erosions are hallmarks of RA pathology,
agents with the capability of modifying matrix metalloproteinases,
tissue inhibitor of metalloproteinases and the family of enzyme
proteins referred to as a disintegrin and metalloproteinases
(ADAMs) or ADAMs with a thrombospondin motif (ADAMTS) as well
as factors that regulate osteoclastogenesis and osteoclast
activity such as receptor activator of nuclear factor-κB
ligand (RANKL) should also be pursued.
[Back to top]
Targeting Cytokines, Chemokines and Adhesion Molecules in
Rheumatoid Arthritis
Charles J. Malemud and Sujana K.
Reddy
The therapy of rheumatoid arthritis (RA) was revolutionized
by basic research studies and biopharmaceutical development
of the first generation of anti-rheumatic biologic agents
(i.e. biological response modifiers), which targeted the pro-inflammatory
cytokines, tumor necrosis factor-α
(TNF-α),
interleukin-1 (IL-1) and interleukin-6 (IL-6). Further studies
resulted in biological response modifiers that have also targeted
activated T- and B-lymphocytes both of which play a prominent
role in RA pathogenesis and disease progression. Despite the
relatively impressive RA disease-modifying effects of these
biologic agents during the post-FDA approval period, there
are reports of moderate to severe adverse events associated
with their continuous use. Additionally, there is accumulating
evidence indicating that anti-rheumatic biologic agents, while
dampening RA disease activity as measured by the American
College of Rheumatology (ACR) criteria in clinical trials
or other arthritis disease activity instruments employed in
studies after approval of these anti-rheumatic medicines by
the FDA do not entirely halt the erosive joint cartilage and
bone destruction characteristic of RA. There is also still
some uncertainty as to how long the available anti-rheumatic
biologics can be continuously employed as RA therapies. Since
the development of TNF-α/IL-1/IL-6
anti-rheumatic biologics, several additional cytokines with
pro-inflammatory activity as well as their receptors, which
initiate upstream pathophysiologic effects, have been identified
and characterized. In several cases, these cytokines have
been cloned and sequenced. Thus, cytokines, such as IL-7,
IL12/IL-23, IL-15, IL-16, IL-17/IL-18, IL-19/IL-20/IL-22 and
IL-32, have been implicated in arthritis development in animal
models of RA and measurements in synovial tissue and synovial
fluid obtained from patients with RA also suggested a role
for them in RA disease progression, if not in its pathogenesis.
There has also been compelling evidence that cytokines with
chemokine-activity and adhesion molecules also play a crucial
role in RA via their capacity to recruit and retain leukocytes,
macrophages, monocytes and endothelial-cell complexes in RA
synovial joints. Taken together, non-TNF-α/non-IL-1/non-IL-6
cytokines, chemokines and their receptors as well as adhesion
molecules appear to be worthwhile targets for drug development
in RA.
[Back to top]
Targeting Complement in Rheumatoid Arthritis
Éva Biró, Paul P. Tak, Augueste
Sturk, C. Erik Hack and Rienk Nieuwland
Rheumatoid arthritis (RA) is a chronic inflammatory disease
characterized by polyarticular synovitis leading to cartilage,
tendon and bone destruction, and pain and dysfunction of the
joints. It is considered to be an immune-mediated inflammatory
disorder, in which the complement system also plays a fundamental
role. In the circulation of RA patients, increased levels
of complement activation products have been found, often correlating
with disease activity. In synovial fluid of the patients,
decreased levels of native complement components and increased
levels of activation products have been detected. Furthermore,
in synovial tissue and cartilage, deposition of activated
complement components has been demonstrated. As activators
of the complement system in RA, immune complexes, C-reactive
protein, and certain immunoglobulin G glycoforms have been
identified. A role for complement activation in the pathogenesis
of this disease is supported by studies showing an association
between complement activation and inflammatory responses in
the diseased joints or in individual cell types found in RA
joints, and by extensive studies on animal models of the disease,
utilizing for example animals deficient for certain complement
components. Finally, several agents are under development
to therapeutically influence the complement system, and some
have already been tested in clinical trials of RA.
[Back to top]
Update on Targets of Biologic Therapies for Rheumatoid Arthritis
Zafar Rasheed and Tariq M. Haqqi
With the advent of biological therapies, considerable
progress has been made in the treatment of rheumatoid arthritis
(RA). These revolutionary therapies owe their origin to the
role that cytokines play in the pathophysiology of the disease
and are best exemplified by the wide use of tumor necrosis
factor (TNF) blockade. The identification of additional pro-inflammatory
factors and an understanding of their effector function now
offer major possibilities for the generation of additional
novel biological therapeutics to address unmet clinical needs.
Such interventions will ideally fulfill several of the following
criteria: control of inflammation, modulation of underlying
immune dysfunction by promoting the reestablishment of immune
tolerance, protection of targeted tissues such as bone and
cartilage, and preservation of host immune capability to avoid
profound immune suppression and amelioration of co-morbidity
associated with underlying RA. The identification and characterization
of the intracellular signaling pathways, in particular, the
mitogen-activated protein kinase pathway, the nuclear factor-κB
pathway and the cross-talk between these pathways offer several
potential therapeutic opportunities. This review will provide
an update on cytokine activities and signal transduction pathways
that represent, in our opinion, optimal utility as future
therapeutic targets.
[Back to top]
Apoptotic Regulators and RA
Jack Hutcheson and Harris Perlman
Although the etiology of rheumatoid arthritis (RA) is
currently unknown, the disease is mediated by chronic inflammation
within the joint, characterized by leukocyte recruitment and
the presence of pro-inflammatory cytokines such as TNFα,
IL-1, IL-8, and MCP-1. In this review, we discuss recent studies
suggesting that apoptosis plays an important role in preventing
the development of RA by reducing the number of leukocytes
in the joint. These studies provide the groundwork for a potentially
new therapeutic approach towards RA.
[Back to top]
Measures of Disease Activity in Rheumatoid Arthritis: A Clinician’s
Guide
Sarah Ringold and Nora G. Singer
Developments in the treatment of rheumatoid arthritis
(RA) have highlighted the need for objective disease activity
indices applicable to both research and clinical settings
and this area has become an important area of research. Previously,
the American College of Rheumatology (ACR) response criteria
were the most commonly used measures of response in clinical
trials, but because they were not developed to measure individual
responses to therapy in a clinical setting, the recent focus
has been on the, development of indices that provide continuous,
rather than relative, measures of improvement. Although the
Disease Activity Score (DAS) and DAS28 have been the most
commonly used of these continuous measures, these indices
are perceived by some to be difficult to perform in busy outpatient
settings. Therefore, indices based on simpler equations and/or
fewer elements, and indices based entirely on patient-reported
data have been proposed as alternatives. This review discusses
each of these major disease indices and focuses on the most
recent developments in their validation and application to
clinical care.
[Back to top]
Targeting Growth Factors in Arthritis: A Rationale for Restoring
the IGF-I Response in Chondrocytes
Fons A. van de Loo, Sharon Veenbergen and
Wim B. van den Berg
The role of growth factors in the pathogenesis of arthritis
has received considerably less attention as compared to proinflammatory
cytokines in recent years. This is understandable as it is
evident that current anti-tumor necrosis factor-α
(TNFα)
therapy is efficacious in at least in 60% of the rheumatoid
arthritis (RA) patients and when given in combination with
methotrexate stops radiological progression of bone erosion.
Other proinflammatory cytokines, such as interleukin-1 (IL-1)
and IL-17 have also been implicated in the dysregulation of
bone and cartilage remodelling characteristic of rheumatoid
arthritis (RA) and/or osteoarthritis (OA). The direct effects
of anti-cytokine treatment on cartilage pathology are not
that easy to determine in humans and it remains to be seen
if amelioration of cartilage destruction or better cartilage
repair has been accomplished with anti-TNF therapy. A complicating
factor is that chondrocytes in RA and OA become non-responsive
to insulin-like growth factor-I (IGF-I). IGF-I is the main
growth factor for stimulation of chondrocyte proteoglycan
and collagen type II synthesis in order to maintain the cartilage
matrix integrity. This article reviews our current understanding
of the role of IGF-I on cartilage extracellular matrix production
and the mechanisms underlying the cause of IGF-I non-responsiveness,
and in particular the inhibition of IGF-receptor signalling
by suppressor of cytokine signalling (SOCS) proteins. The
epigenetic and cytokine-dependent regulation of SOCS expression
may give an explanation for the loss of IGF-I signalling in
chondrocytes in ageing-related diseases such as OA and RA.
Whether IGF-1 is replaceable by other growth factors to maintain
the cartilage extracellular matrix will be discussed. It is
concluded that in addition to the current use of anti-cytokine
therapy in arthritis the IGF-I response of chondrocytes must
be restored in order to achieve cartilage matrix repair.
[Back to top]
What Animal Models are Best to Test Novel Rheumatoid Arthritis
Therapies?
Paul H. Wooley
The relevance of animal models of rheumatoid arthritis
and their relationship to the development of anti-arthritic
therapies is reviewed in depth. Different mechanisms for the
induction of experimental arthritis, including infectious
processes, non-specific inflammation, autoimmune responses
to cartilage components, and genetic manipulation are discussed
in context of pathological pathways relevant to rheumatoid
arthritis. A variety of species, including rats, mice, dogs,
pigs, and monkey are examined for advantages and drawbacks
in preclinical development of anti-arthritic agents, and their
capacity to mimic critical aspects of arthritis pathology.
The history of anti-arthritic therapy from non-steroidal anti-inflammatory
agents to biological response modifiers is placed in context
with the evolution of animal models of arthritis. The potential
of novel models based upon targeted gene manipulations and
corresponding pathway-specific drugs is examined as a new
approach to identifying therapies relevant to rheumatoid disease.
[Back to top]
Inhibition of Matrix Metalloproteinases as a Feasible Therapeutic
Target in Rheumatoid Arthritis
Muhammad Zafarullah, Rasheed Ahmad, Mohammed
El Mabrouk, Abdelhamid Liacini and Hamid Yaqoob Qureshi
Rheumatoid arthritis (RA) is a systemic inflammatory
disease affecting several joints. Proinflammatory cytokines
(IL-1, IL-17, TNF-α
and oncostatin M) activate multiple signalling pathways and
transcription factors that augment matrix metalloproteinases
(MMPs) and aggrecanases (ADAMTSs) expression. These events
promote invasion of cartilage by proliferating pannus and
ultimate loss of cartilage and bone. MMPs/ADAMTSs can be blocked
at the levels of cytokines, signal transduction, transcription
factors, mRNA translation and enzyme activity by the small-molecule
synthetic and natural inhibitors including tissue inhibitors
of metalloproteinases (TIMPs), specific ribozymes and by RNA
interference. Overexpression of TIMP-1, TIMP-3 and TIMP-4
inhibits inflammation in RA-like animal models. TIMP-3 uniquely
blocks aggrecanases and TNF-α
converting enzyme (TACE/ADAM17) in vitro and could
diminish synovial proliferation, its invasion of cartilage
and inflammation in vivo. TIMP-3 knockout mice display
enhanced inflammation and cartilage destruction. TIMPs are
being engineered for therapeutic use to reduce RA synovial
inflammation, pannus invasion of cartilage and tissue destruction.
Because MMPs and aggrecanases inhibition may also interfere
with their physiological functions of cytokine and growth
factor processing, skeletal development, normal tissue remodelling
and repair, extensive research on possible side effects of
inhibitors is needed before their therapeutic use for RA.
Nevertheless, multiple inhibitory strategies appear promising.
[Back to top]
Targeting Angiogenesis in Rheumatoid Arthritis
Zoltán Szekanecz and Alisa
E. Koch
Angiogenesis, the development of new capillaries, is
a crucial process in health and disease. The perpetuation
of neovascularization in rheumatoid arthritis is highly involved
in leukocyte extravasation into the synovium and pannus formation.
Numerous soluble and cell surface-bound angiogenic mediators,
including growth factors, cytokines, proteases, matrix macromolecules,
cell adhesion receptors, chemokines and chemokine receptors,
have been implicated in the process of neovascularization.
Endogenous angiostatic factors, primarily angiostatin, endostatin,
IL-4, IL-13, some angiostatic chemokines may be used to downregulate
neovascularization. In addition, angiogenesis might be targeted
by several specific approaches against VEGF, angiopoietin,
αvβ3
integrin or by exogenously administered compounds including
DMARDs, anti-TNF agents, fumagillin analogues or thalidomide.
Potentially all anti-angiogenic could be tried in order to
control synovitis.
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