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Current
Rheumatology Reviews
ISSN: 1573-3971
Current Rheumatology Reviews
Volume 3, Number 4, November 2007
Contents
Editorial Pp. 242
Gene Expression Studies to Investigate Disease Mechanisms
in Rheumatoid Arthritis: Does Angiogenesis Play a Role?
Pp. 243-251
Helene Larsen, Mohammed Ali Akhavani, Yvonne Raatz and
Ewa M. Paleolog
[Abstract]
Pyridinoline, A Collagen Crosslink, As a Biochemical
Marker for Arthritis Pp. 252-260
Masaaki Takahashi
[Abstract]
The Significance of Oxidative Stress in Articular
Cartilage Ageing and Degradation Pp. 261-274
Yves Henrotin, Francisco J. Blanco, Thomas Aigner and
Bodo Kurz
[Abstract]
Therapeutic Strategies to Reverse Local Bone Loss
in Erosive Arthritis Pp. 275-279
Jochen Zwerina, Karin Polzer, Silvia Hayer, Kurt Redlich
and Georg Schett
[Abstract]
New Strategies in the Management of Children and Adolescents
with Proliferative Lupus Nephritis Pp. 280-286
Keith K. Lau, Maha N. Haddad and Lavjay Butani
[Abstract]
The Genetics and Genomics of Systemic Sclerosis: An
Update and Review Pp. 287-296
Firas Alkassab and Maureen D. Mayes
[Abstract]
Potential New Therapeutic Options for Involvement
of Central Nervous System in Behçet’s Disease
(Neuro-Behçet’s Syndrome) Pp. 297-303
Shunsei Hirohata
[Abstract]
Fibromyalgia and Related Syndromes Characterised by
Stress Intolerance and Pain Hypersensitivity: Do We Need a
New Nosology? Pp. 304-308
Boudewijn Van Houdenhove and Patrick Luyten
[Abstract]
Clinical Relevance of Cytokines and Inflammatory Molecules
in Rheumatoid Vasculitis Pp. 309-316
Tsuyoshi Kasama, Mizuho Matsunawa, Kuninobu Wakabayashi
and Yusuke Miwa
[Abstract]
Prevention of Ankylosis: A Specific Therapeutic Target in
Spondyloarthritis Pp. 317-321
Rik J.U. Lories and Kurt de Vlam
[Abstract]
Abstracts
[Back to top]
Editorial: Neuro-Behcet's Syndrome: Finally, New Insights
One of the most frustrating complications of Behcet's disease
is the 'Neuro-Behcet's Syndrome'. Manifested by a combination
of factors including headache, motor symptoms, cerebeller
dysfunction, dysarthria, sensory alterations, cognitive impairment,
seizures and peripheral neuropathy, its management has not
adequately been explored. Historically, neuro-Behcet's has
been managed with colchicine, corticosteroids, and immune
suppressive therapies. It is difficult for the treating doctor
to get a handle on the numerous anecdotal reports, case series
and reported experiences on how best to manage this aspect
of the disease. In this issue of Current Rheumatology
Reviews, Dr. Hirohata fills the void with a highly readable,
well referenced, critical review of the management of Neuro-Behcet's.
He distills the literature and focuses on what is important
and clinically relevant. Additionally, newer therapies, including
biologics are reviewed. Neuro-Behcet's is best managed by
dividing it into acutely active, recently active with emphasis
on prevention of relapse, and chronic progressive. Using this
classification, Dr. Hirohata guides the reader through various
options which are available, taking into consideration the
dearth of prospective, double-blind, placebo controlled studies
in this area. This provides the practitioner with all the
experience he would need in order to tailor management for
a specific Behcet's patient. The most interesting aspect of
the review details the author's experience with using cerebrospinal
fluid IL-6 to follow disease activity. We may finally have
a biomarker applicable to the bedside which may help us serially
follow patients.
Address correspondence to Editor-in-Chief at the David Geffen
School of Medicine at UCLA, Los Angeles, CA 90048, USA;
E-mail: dwallace@ucla.edu
[Back to top]
Gene Expression Studies to Investigate Disease Mechanisms
in Rheumatoid Arthritis: Does Angiogenesis Play a Role?
Helene Larsen, Mohammed Ali Akhavani, Yvonne Raatz and
Ewa M. Paleolog
Gene expression studies represent a new and challenging approach
that allows molecular dissection of complex diseases such
as rheumatoid arthritis (RA). Optimally, gene analysis should
be conducted in isolated populations of cells so that the
differential gene expression may be directly correlated with
transcription of genes. RA fibroblasts constitute the majority
of the expanding synovial cell mass in the RA joint, and alterations
in their phenotype are likely to be important in the pathogenic
process. However, RA involves many cell types from tissues
adjacent to the synovium and the important cell types are
not known. Analysis of gene expression profiles by processing
a complex tissue such as whole paws can provide useful information
about dysregulated genes, not only in the synoviocytes but
also in other, neighbouring cells (monocytes, osteocytes and
chondrocytes) that may contribute to disease pathology. This
review will focus on the use of gene expression studies, both
in isolated cells and in whole tissue, as a means of studying
the molecular mechanisms involved particularly in the angiogenic
process in RA. In particular, we will focus on synovial angiogenesis,
since the synovial vascular density is altered in RA. This
will provide an increased surface area for inflammatory cell
trafficking, as well as delivering nutrients and oxygen to
the proliferating synovial cells. Therapeutic approaches targeting
angiogenic factors such as vascular endothelial growth factor
(VEGF), which is increased in RA, have already shown some
clinical success in oncology, and in mouse models of arthritis.
[Back to top]
Pyridinoline, A Collagen Crosslink, As a Biochemical
Marker for Arthritis
Masaaki Takahashi
Pyridinoline is a crosslink synthesized in collagen that has
generally been used as a biochemical marker for bone metabolism.
In addition, as pyridinoline is more abundant in cartilage
and synovium than in the other tissues, there is extensive
literature describing pyridinoline as a biochemical marker
for cartilage destruction and metabolism, or arthritis. This
paper will review the use of pyridinoline as a biochemical
marker for arthritis.
[Back to top]
The Significance of Oxidative Stress in Articular
Cartilage Ageing and Degradation
Yves Henrotin, Francisco J. Blanco, Thomas Aigner and
Bodo Kurz
It is well recognised that age is a primary risk factor for
the development of osteoarthritis (OA), but the mechanisms
by which ageing contributes to an increased susceptibility
to OA are poorly understood. Reactive oxygen species seem
to play a key role in this process by acting on cellular and
extracellular levels. According to the redox status of the
biological medium, they can be regulators or dysregulators
of the mitochondrial and cell signalling machinery. Further,
ROS induce structural and functional alteration of the extracellular
matrix, leading to matrix stiffness and brittleness. This
paper is an extensive review of the literature about the oxidative-related
cartilage changes during the ageing process. It highlights
the possible relationships between ageing, chronic inflammation
and cartilage degradation in OA.
[Back to top]
Therapeutic Strategies to Reverse Local Bone Loss
in Erosive Arthritis
Jochen Zwerina, Karin Polzer, Silvia Hayer, Kurt Redlich
and Georg Schett
In rheumatoid arthritis (RA), the chronically inflamed joint
undergoes profound phenotypical changes. Aside synovial inflammation
and cartilage degeneration, subchondral bone erosions emerge
early in the course of disease and are associated with functional
impairment in RA patients.
Chronic joint inflammation injures the bone as consequence
of two key pathophysiological mechanisms: On the one hand,
the proliferative synovial tissue (“pannus”) attracts
monocytes/macrophages to migrate into the joint and provides
specific signals for these cells to differentiate into bone-resorbing
osteoclasts. These cells are activated by pro-inflammatory
cytokines and resorb mineralized tissue. Second, the injured
bone attempts to counteract bone resorption by attracting
osteoblasts at the site of erosion. However, the inflammatory
local environment prevents significant repair by over-production
of osteoblast-inhibitory mediators and facilitation of osteoblast
apoptosis.
Until now, osteoimmunology research in arthritis primarily
focused on the mechanism of joint destruction and the effects
of inhibiting osteoclasts. However, recent experimental studies
imply that fostering bone formation in chronic erosive arthritis
could potentially reverse joint destruction with induction
of repair phenomena. This review discusses the pathome-chanisms
leading to impaired bone turnover and potential mediators
that could be targeted to reverse bone loss in RA.
[Back to top]
New Strategies in the Management of Children and Adolescents
with Proliferative Lupus Nephritis
Keith K. Lau, Maha N. Haddad and Lavjay Butani
Systemic lupus erythematosus (SLE) is a serious medical illness
with frequent renal involvement at disease onset. Although
predominantly affecting young women, SLE often first presents
during childhood. Previous studies have suggested that patients
with disease onset in childhood have a worse prognosis. Renal
involvement in SLE is the major determinant of long-term outcome;
the ten-year survival in children with lupus nephritis was
only around 20% in late 60s, but outcomes have improved dramatically
in recent years to around 94%. This article will review recent
data on new approaches in the treatment of pediatric lupus
nephritis by referencing the major studies over the last few
years. We will also examine the validity of various factors
that have been suggested by previous studies to have prognostic
value in determining outcomes.
[Back to top]
The Genetics and Genomics of Systemic Sclerosis: An
Update and Review
Firas Alkassab and Maureen D. Mayes
Systemic sclerosis (SSc) has a genetic component as demonstrated
by familial clustering, by twin studies (showing higher concordance
for antinuclear antibody positivity among monozygotic versus
dizygotic pairs), and by HLA associations. Identification
of the specific genes involved and their mechanism of conferring
disease susceptibility or influencing disease expression is
under intense study. Several polymorphisms in multiple genes
have been put forward as potential candidates but there are
discrepancies among some studies. It now appears that the
strongest genetic associations are determined by subsetting
cases according to autoantibodies.
In this review, we will summarize recent studies of candidate
gene polymorphisms (including HLA) associated with SSc, which
are thought to influence disease susceptibility. In addition,
we will review gene expression studies of SSc cultured fibroblasts,
intact skin, and peripheral blood to identify common themes
among this work. Finally we will highlight future areas of
study that will best address deficiencies in our knowledge.
[Back to top]
Potential New Therapeutic Options for Involvement
of Central Nervous System in Behçet’s Disease
(Neuro-Behçet’s Syndrome)
Shunsei Hirohata
Neuro-Behçet’s syndrome consists of acute type
and chronic progressive type (primary progressive and secondary
progressive). Attacks of acute type neuro-Behçet’s
syndrome are sometimes self-limiting. However, when the neuro-logical
manifestations are progressive and severe, administration
of corticosteroid is necessary. In addition, infliximab and
interferon alpha might also be effective in acute type neuro-Behçet’s
disease. There are no drugs which have been demonstrated to
be effective in preventing the occurrence of attacks of acute
type neuro-Behçet’s disease. Colchicine, low
dose of steroids and various immunosuppressive drugs have
been used anecdotally for this purpose. As to chronic progressive
neuro-Behçet’s syndrome, one should realize that
corticosteroids are not effective. Cyclophosphamide is not
effective, either. Low dose methotrexate (MTX) has been shown
to be beneficial for the treatment of chronic progressive
neuro-Behçet’s syndrome by an open clinical trial.
Thus, low dose MTX has been shown to decrease cerebrospinal
fluid IL-6 levels without progression of neuropsychological
manifestations, although there are a fraction of patients
who do not adequately respond to MTX. Preliminary results
indicate that infliximab has a beneficial effect in such patients
with MTX-resistant chronic progressive neuro-Behçet’s
syndrome.
[Back to top]
Fibromyalgia and Related Syndromes Characterised by
Stress Intolerance and Pain Hypersensitivity: Do We Need a
New Nosology?
Boudewijn Van Houdenhove and Patrick Luyten
Patients with functional somatic syndromes such as fibromyalgia
(FM) and chronic fatigue syndrome (CFS) are frequently seen
in primary care as well as in various medical specialties.
Despite a controversy between ‘lumpers' and ‘splitters'
regarding these syndromes, many authors assume that FM and
CFS patients show more communalities than differences. Stress
system dysfunctioning and associated abnormal pain processing
seem to link these syndromes from a pathophysiological point
of view. Consequently, we propose to rename FM and CFS as
‘stress intolerance and pain hypersensitivity (SIPH)
syndromes’. Furthermore, we make a plea for developing
specific treatment settings for SIPH patients. Finally, we
outline future research perspectives on the interaction between
life stress, personality/lifestyle factors, and stress system/pain
processing disturbances in the aetio-pathogenesis of SIPH
and other functional somatic syndromes.
[Back to top]
Clinical Relevance of Cytokines and Inflammatory Molecules
in Rheumatoid Vasculitis
Tsuyoshi Kasama, Mizuho Matsunawa, Kuninobu Wakabayashi
and Yusuke Miwa
Rheumatoid vasculitis (RV) is an uncommon but severe complication
of rheumatoid arthritis (RA) that can cause skin disorders,
such as rash, cutaneous ulcerations and gangrene, neuropathy,
eye symptoms, and systemic inflammation. Although the molecular
mechanisms underlying RV in RA are unclear, it is well known
that a chronic imbalance in the expression of chemokines and
proinflammatory cytokines is important for orchestrating inflammatory
responses in RA patients, and similar dysregulation of cytokines
and other inflammatory molecules, such as adhesion molecules,
has been suggested to occur in patients with RV. Recently,
we reported elevated levels of the soluble form of CX3CL1,
which is a newly described membrane-bound CX3C chemokine,
in the serum of patients with RV. In the present review, we
discuss the involvement of cytokines and inflammatory molecules
in the pathogenesis of RV and evaluate their significance
as useful laboratory parameters of active vasculitis disease.
[Back to top]
Prevention of Ankylosis: A Specific Therapeutic Target in
Spondyloarthritis
Rik J.U. Lories and Kurt de Vlam
New cartilage and bone formation potentially leading to joint
and spine ankylosis is an important feature of the human spondyloarthritides.
Increasing evidence suggests that inflammation and remodeling
of the joint are at least partially independent processes.
Patient cohort data have not demonstrated an effect of the
current therapeutic strategies, including anti-tumor necrosis
factor on these important aspects of spondyloarthritis. In
this article, we review the evidence that inflammation and
new tissue formation are uncoupled and indicate potential
new therapeutic targets to inhibit disease progression. Both
bone morphogenetic protein and wingless-like signaling have
been demonstrated to control the process of joint ankylosis
in mouse models. However, translation of these concepts to
human pathology remains a challenge.
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