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Current
Rheumatology Reviews
ISSN: 1573-3971
Current Rheumatology Reviews
Volume 3, Number 1, February 2007
Contents
Editorial Pp. 1
Mechanisms of Chondrocyte Survival and Matrix
Synthesis During Hypoxia Pp. 3-9
David Pfander, Claudia Grimmer, Lutz Müller, Thomas
Aigner and Thorsten Cramer
[Abstract] [Full
text article]
Possible Role of DNA Methylation in the Induction
of Systemic Lupus Erythematosus Pp. 11-16
Iwao Sekigawa, Mikiko Kawasaki, Hitoshi Ogasawara, Hiroshi
Kaneko, Yoshinari Takasaki, Hiroshi Hashimoto and Hideoki
Ogawa
[Abstract] [Full
text article]
Substance P in Rheumatic Diseases Pp. 17-30
Matthias F. Seidel, Julia Tsalik, Hans Vetter and Wolfgang
Müller
[Abstract] [Full
text article]
Somatostatin Involvement in Rheumatoid Arthritis
Pp. 31-36
Allan D. Blake, Frances Mae West, Sadia Ghafoor and Petros
Efthimiou
[Abstract] [Full
text article]
Rheumatoid Nodulosis in a Patient with Lupus Erythematosus:
Case Report and Review Pp. 37-40
Alain Bautista, José Felix Restrepo, Eric L. Matteson
and Antonio Iglesias
[Abstract] [Full
text article]
Catastrophic Antiphospholipid Syndrome: Lessons from
the “CAPS Registry” Pp. 41-46
Ricard Cervera, Josep Font and Ronald A. Asherson
[Abstract] [Full
text article]
Rheumatic Manifestations Associated With Inflammatory
Bowel Diseases Pp. 47-56
Marta Podswiadek, Renata D'Incà, Giacomo Carlo
Sturniolo, Francesca Oliviero and Leonardo Punzi
[Abstract] [Full
text article]
Healing of Radiologic Damage in Rheumatoid Arthritis
Pp. 57-65
Rolf Rau
[Abstract] [Full
text article]
Challenges and Controversies in Auto-antibodies Associated
with Systemic Rheumatic Diseases Pp. 67-78
Michael Mahler, Reinout Raijmakers and Marvin J. Fritzler
[Abstract] [Full
text article]
Vaccination and Rheumatic Diseases: Is There Still
a Dilemma? Pp. 79-91
Fabrizio Conti, Soheila Rezai and Guido Valesini
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial: To Immunize or Not?
The issue of immunization in patients with autoimmune disease
has plagued rheumatologists for over 50 years. This has been
confounded by a report from the World Health Organization
recommending that individuals with autoimmune diseases should
not receive allergy shots. Case reports have been published
demonstrating instances whereby the development of a vasculitic
or inflammatory process was temporally associated with a vaccine.
It is indeed possible that immune suppressed patients exposed
to a child who received a live vaccine are at an increased
risk of developing that infection (although no case reports
have ever been published in the rheumatic disease literature).
Further, many patients observe a flare of their inflammatory
process after receiving routine vaccinations. This could stem
from their hypervigilance, coincidence or a true reaction.
It is therefore a real pleasure to give the reader the opportunity
to review the article by Valesini et al. in this
issue of CRR, which addresses these important issues.
The authors distill the subject based on numbers of patients,
level of evidence based conclusions, study design, perception
and practicality.
In essence, the following guidelines apply:
1. Nearly all routine vaccinations are safe.
2. Rheumatic flares occur in less than 10% and are almost
always transient.
3. Increased diligence is mandated if a live vaccine is given
to a patient or family member, especially if one is immune
suppressed.
4. The effectiveness of any given vaccination is usually 100%
of what is seen in healthy controls, but may be less.
Hopefully, the mitigations and concerns articulated by rheumatologists
are mitigated by the thoughtful, thorough review in this issue.
Daniel J. Wallace
(Editor-in-Chief)
David Geffen School of Medicine at UCLA
Los Angeles
CA 90048
USA
E-mail: dwallace@ucla.edu
[Back to top]
Mechanisms of Chondrocyte Survival and Matrix Synthesis
During Hypoxia
David Pfander, Claudia Grimmer, Lutz Müller, Thomas
Aigner and Thorsten Cramer
[Full
text article]
Growth-plate cartilage and articular cartilage are virtually
avascular tissues. Thus, chondrocytes must exist in extreme
microenvironmental conditions, most prominently characterized
by low oxygen tension. Diffusion distances for oxygen and
nutrients between arteries and single chondrocytes range from
50μm
to 3mm. Therefore, chondrocytes need specific strategies to
adapt to these hostile conditions. Furthermore, they have
to synthesize ATP in order to fulfill their main function,
i.e. the synthesis of proteoglycans and type II collagen.
In recent years increasing evidence for a pivotal role of
the transcription factor hypoxia inducible factor-1α
(HIF-1α)
in cartilaginous tissues has been published. Murine growth-plates
with functionally inactivated HIF-1α
displayed great defects in their central areas caused by massive
cell death. This very important observation points out that
HIF-1α
is absolutely necessary for chondrocytes to survive developmental
hypoxia. Furthermore, it has been shown that HIF-1α
has important functions for the regulation of anaerobic energy
generation and matrix synthesis. Beside hypoxia, which seems
to be more pronounced during osteoarthritis, other factors
like pro-inflammatory mediators are able to activate HIF-1α
in chondrocytes. Thus, an increasing dependence of OA chondrocytes
on the adaptive functions of HIF-1 is reasonable to assume.
In this review we will summarize the knowledge about HIF-1α
for chondrocyte survival and matrix synthesis of growth-plate
and articular cartilage during development and disease.
[Back to top]
Possible Role of DNA Methylation in the Induction
of Systemic Lupus Erythematosus
Iwao Sekigawa, Mikiko Kawasaki, Hitoshi Ogasawara, Hiroshi
Kaneko, Yoshinari Takasaki, Hiroshi Hashimoto and Hideoki
Ogawa
[Full
text article]
Recent studies on epigenetics, including DNA methylation and
its regulatory enzymes, seem to contribute to elucidation
of the pathogenesis of autoimmune diseases such as systemic
lupus erythematosus (SLE), although the relationship between
DNA methylation and SLE has long been the subject of investigation.
To obtain a deeper understanding of the role of DNA methylation
in the induction of SLE, we reviewed the relationship between
DNA methylation and SLE based on findings reported in the
literature and our own data. Various studies, including ours,
have indicated the possible importance of DNA methylation,
especially hypomethylation, in the etiology of SLE. These
epigenetic studies may give us clues towards elucidation of
the pathogenesis of SLE and development of new therapeutic
strategies for this disease.
[Back to top]
Substance P in Rheumatic Diseases
Matthias F. Seidel, Julia Tsalik, Hans Vetter and Wolfgang
Müller
[Full
text article]
Inflammation in many autoimmune syndromes is modulated
by the nervous system. This paper reviews important principles
of neurogenic inflammation and findings of substance P overexpression
in rheumatic diseases. Substance P is a key molecule in activating
inflammation after antidromal axoplasmic transport and secretion
at the nociceptor. We summarize the results from studies with
rheumatoid arthritis, osteoarthritis, psoriatic arthritis,
systemic lupus erythematodes, systemic sclerosis, vasculitides,
Sjögren syndrome, vasculitides, reflex sympathetic dystrophy,
gouty arthritis, fibromyalgia syndrome, chronic fatigue syndrome
and degenerative vertebral spine disorders. Although substance
P is associated with many of these diseases, selective receptor
blockers have not been effective in therapy. In contrast,
the nonselective antagonist capsaicin is beneficial in some
conditions. We also discuss a novel therapeutic principle
with selective serotonin antagonists that may induce a powerful
downregulation of neurogenic inflammation.
[Back to top]
Somatostatin Involvement in Rheumatoid Arthritis
Allan D. Blake, Frances Mae West, Sadia Ghafoor and Petros
Efthimiou
[Full
text article]
Somatostatin (somatotropin release inhibitory factor; SRIF)
peptides are widely distributed in the mammalian body and,
acting through a family of genetically homologous cell surface
receptors (sst1-5), regulate cellular secretion
and proliferation. Compelling evidence implicates SRIF peptides
and peptidyl analogues in chronic inflammatory diseases such
as rheumatoid arthritis (RA). SRIF membrane receptors exist
on immune and synovial cells, thereby providing molecular
targets on the principal participants in the RA pro-inflammatory
cascade. Preclinical and clinical studies have shown that
SRIF peptides and analogues are anti-inflammatory, however
the cellular basis for this activity remains unclear. Since
RA inflammation is propagated through cell-mediated immune
responses which orchestrate the pro-inflammatory cytokine
production by monocytes, macrophages and synovial fibroblasts,
SRIF could provide a strategy for interrupting RA progression.
SRIF and SRIF analogues reduce synoviocyte proliferation and
suppress synovial cytokine production, thereby making SRIF
analogues a potentially novel approach to RA treatment. This
review summarizes our current knowledge of SRIF analogue therapies
in RA.
[Back to top]
Rheumatoid Nodulosis in a Patient with Lupus Erythematosus:
Case Report and Review
Alain Bautista, José Felix Restrepo, Eric L. Matteson
and Antonio Iglesias
[Full
text article]
Nodules are commonly found in patients with rheumatic diseases,
most often in rheumatoid arthritis, but also in other conditions
such as systemic lupus erythematosus (SLE). Rheumatoid nodulosis,
however, is less frequent and not an established feature of
SLE. We describe a patient with SLE and rheumatoid nodulosis,
reviewing the literature and suggest that this manifestation
falls into the spectrum of rhupus.
[Back to top]
Catastrophic Antiphospholipid Syndrome: Lessons from
the “CAPS Registry”
Ricard Cervera, Josep Font and Ronald A. Asherson
[Full
text article]
Although less than 1% of patients with the antiphospholipid
syndrome (APS) develop the catastrophic variant, its potentially
lethal outcome emphasizes its importance in clinical medicine
today. However, the rarity of this variant makes it extraordinarily
difficult to study in any systematic way. In order to put
together all the published case reports as well as the new
diagnosed cases from all over the world, an international
registry of patients with catastrophic APS ("CAPS Registry")
was created in 2000 by the European Forum on Antiphospholipid
Antibodies. Currently, it documents the entire clinical,
laboratory and therapeutic data of more than 300 patients
whose data has been fully registered. This registry can be
freely consulted at the Internet (www.med.ub.es/MIMMUN/FORUM/CAPS.HTM)
and it is expected that the periodical analysis of these data
will allow us to increase our knowledge of this condition.
[Back to top]
Rheumatic Manifestations Associated With Inflammatory
Bowel Diseases
Marta Podswiadek, Renata D'Incà, Giacomo Carlo
Sturniolo, Francesca Oliviero and Leonardo Punzi
[Full
text article]
Rheumatic manifestations, in particular joint complaints,
are frequent features in inflammatory bowel disease (IBD),
with a prevalence varying from 10 to 35%. Their spectrum is
almost wide, involving bone, tendons, entheses and joints.
Joint manifestations may be seen as arthralgia and/or inflammatory
arthropathies. These latter may in turn be found in three
principal forms: the peripheral, the axial or spondylitis
and that overlapping between these two varieties. Peripheral
arthritis may be classified in oligoarticular (type I) and
polyarticular (type II) forms. Oligoarthritis is the most
frequent. Usually asymmetric, involving large joints of lower
limbs, it is transient, commonly associated with IBD flares,
and may disappear after few weeks, although in 10% of cases
it may evolves to chronic arthritis. Type II arthritis is
polyarticular and symmetric, involving hands and feet but
also large joints. The prevalence is about 2-4% of IBD patients,
its course is independent from IBD flares and usually evolves
in chronic disease. Peripheral arthritis is classically non-deforming,
non erosive, and seronegative for the rheumatoid factor. Axial
involvement is equally frequent in both CD and UC and varies
in different studies from 10 to 30% for sacroiliitis and from
3 to 10% for ankylosing spondylitis. Its course is independent
from IBD state, the extension of IBD involvement and the occurrence
of flares. The treatment of rheumatic manifestations in IBD
is frequently problematic, due to the possibility of frequent
side effects. Among drugs used for IBD, corticosteroids, also
effective in joint complaints, may have osteopenic effects;
sulfasalazine, sometimes able to control peripheral arthritis,
is ineffective for the axial involvement. A potential gut
toxicity is associated with the use of NSAIDs, which in some
patients may induce asymptomatic lesions causing small gut
bleeding and loss of proteins. Local injections with steroid
may be used for tendonitis, monoarthritis or isolated sacroiliac
inflammation. In patients with peripheral arthritis, especially
when involving several joints and/or refractory to other therapies,
disease modifying drugs for rheumatoid arthritis (DMARDs)
should be used. Among these, methotrexate is also useful for
CD while it seems inefficacious in UC. Cyclosporin, administrated
alone or in association, may contain flares of steroid refractory
UC. Azathioprine is commonly used to induce and maintain remission
in refractory CD while its role on arthritis is marginal.
Amino-bisphosphonates seem effective for both axial and peripheral
involvements and probably, it may represent a good option
for the future in the management of enteropathic arthritis,
because of their anti-osteopenic effect. Finally, the most
promising opportunities derive from the recently introduced
biologic agents, in particular anti-tumour necrosis factor
(TNF) α.
Infliximab, a chimeric anti-TNFα
monoclonal IgGI antibody, has largely demonstrated its efficacy
in refractory CD and in all rheumatic manifestations. Other
biologic agents are proposed, including the human anti-TNF
monoclonal antibody adalimumab, antibodies to integrins (anti-α4β7),
anti-ICAM-1 (intracellular adhesion molecule 1) and IL-10.
Concerning the surgical options, the colectomy may be protective
on type I peripheral arthritis but is not influent on the
course of axial disease, while the surgery on small intestine
usually do not prevent the appearance of peripheral arthritis.
In the case of destructive arthritis, like coxitis, joint
prosthesis may be necessary.
[Back to top]
Healing of Radiologic Damage in Rheumatoid Arthritis
Rolf Rau
[Full
text article]
Until recently the possibility of healing of erosive changes
in RA has been neglected. When evaluating the radiographic
course within clinical studies, a reduction of the radiographic
score indicating improvement was not allowed since repair
of erosions was considered to be impossible. During the last
3 decades several case reports and case series have been published
demonstrating convincingly that healing of erosions of RA
patients really occurs. In addition, a subcommittee on healing
of the OMERACT imaging committee undertook to confirm the
existence of repair by performing several studies: different
experts had to evaluate erosions on radiographs of the same
patients taken at two different time points demonstrating
deterioration or improvement. Blinded to the sequence of the
films they agreed which film was better or worse and which
erosion was greater or smaller. Since 50% of the films showing
improvement were taken at the second time point, that study
confirmed that healing really exists. Owing to several special
features healing could be diagnosed without knowing the sequence
of the films in one study, not convincingly so in another
study. Among different features indicating healing on radiographs
the following can be distinguished with relative certainty:
“re-cortication”, meaning the re-appearance of
a cortical plate that had been destroyed; “filling-in”,
meaning filling of an erosion with new bone; “restoration”,
meaning complete normalisation of the shape of the joint and
the trabecular structure of the subchondral bone. The best
agreement between observers concerns erosion size. Radiographic
evaluation blinded to the sequence of the films in trials
with biologics resulted in negative scores exceeding the measurement
error of the scoring method in a certain percentage of patients,
again supporting the existence of healing. As healing only
occurs in an individual joint after the inflammatory process
has been quiet in that joint for several months, healing could
be utilized as an outcome measure in addition to the slowing
or arrest of progression. This article gives an overview over
the history and present knowledge of radiographic signs of
erosion healing.
[Back to top]
Challenges and Controversies in Auto-antibodies Associated
with Systemic Rheumatic Diseases
Michael Mahler, Reinout Raijmakers and Marvin J. Fritzler
[Full
text article]
Since the first identification of self-reactive antibodies
in systemic lupus erythematosus and other systemic autoimmune
rheumatic diseases, many autoantibodies have been identified
as useful probes in molecular and cell biology and as diagnostic
and prognostic biomarkers in clinical immunology. Among the
autoantigens, double-stranded desoxori-bonucleic acid (dsDNA),
the Smith antigen (Sm), ribonucleoproteins (RNP), Scl-70 (topoisomerase
I), proliferating cell nuclear antigen (PCNA), and others
were described as serologic hallmarks in the diagnosis of
systemic autoimmune rheumatic diseases. Despite these advances
in identifying autoantibody markers, a number of challenges
and controversies persist concerning their origin, clinical
usefulness and relevance. These include the association between
anti-ribosomal P antibodies and clinical features in systemic
lupus erythematosus, the disease specificity of several autoantibodies
(i.e. chromatin, Jo-1, alpha-fodrin, topo I and CENP), the
relationship between the SS-A/Ro52 and SS-A/Ro60 autoantibody
system(s) and the detection of anti-RNP/Sm and anti-fibrillarin
antibodies.
[Back to top]
Vaccination and Rheumatic Diseases: Is There Still
a Dilemma?
Fabrizio Conti, Soheila Rezai and Guido Valesini
[Full
text article]
The development of rheumatic diseases after immunization has
been reported in the medical literature but a causal relationship
has not been established. Infections remain an important cause
of morbidity and mortality in patients with rheumatic diseases
who may be immunodepressed for immunological dysfunctions
or immunosuppressed due to the pharmacologic therapy. Although
vaccines against infectious diseases are considered the standard
way in preventive medicine, it is still a controversial issue
among rheumatologists whether or not patients with rheumatic
disorders should undergo vaccination.
In recent decades increased numbers of studies on influenza
and pneumococcal vaccines administered to patients with systemic
lupus erythematosus have proven their safety. These vaccinations,
generally immunogenic (i.e. able to induce a protective level
of specific antibodies), may not induce an adequate response
in patients receiving immunosuppressive therapy. The safety
and the immunogenity of Tetanus toxoid, and HBV vaccinations
in SLE patients are not completely defined so far.
Considering the few available studies, influenza, pneumococcal,
and HBV vaccines seem to be safe and immunogenic in patients
with rheumatoid arthritis. The effect of TNFα
blocking therapies on human immune responses to vaccination
is discussed. We also review existing knowledge on vaccination
in patients with Sjogren’s syndrome and in children
with rheumatic disorders, discussing risks and benefits.
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