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Current
Rheumatology Reviews
ISSN: 1573-3971
Current Rheumatology Reviews
Volume 4, Number 1, February 2008
Contents
Editorial
Pp. 1
Structure-Function Relationships in Anti-DNA and Anti
Phospholipid Antibodies and their Relevance to the Pathogenesis
of Disease Pp. 2-11
Anastasia Lambrianides, Ian Giles and Anisur Rahman
[Abstract]
Genetics of Spondyloarthropathies and Inflammatory
Bowel Disease: Searching for Common Susceptibility Factors
Pp. 12-22
Debby Laukens and Martine De Vos
[Abstract]
T-Cell Dysregulation in Systemic Lupus Erythematosus:
Pathophysiology and Opportunities for Biomarker Development
Pp. 23-33
Christine Bryson, Robert Busch and Frances C. Hall
[Abstract]
Clinical Presentation of Autoinflammatory Syndromes
in Childhood Pp. 34-45
Marco Gattorno, Maria Antonietta Pelagatti, Silvia Federici,
Giacomo Brisca and Alberto Martini
[Abstract]
Rheumatoid Arthritis Patients with Sjögren's
Syndrome are More Prone to Depression than Patients with Rheumatoid
Arthritis or Sjögren's Syndrome Alone Pp. 46-49
Yusuke Miwa, Michio Hosaka, Kunibobu Wakabayashi,Tsuyoshi
Odai, Takeo Isozaki, Mizuho Matsunawa, Nobuyuki Yajima, Fumitaka
Shiozawa, Ryosuke Hanaoka, Masao Negishi, HirotsuIde, Tsuyoshi
Kasama and Mitsuru Adachi
[Abstract]
Rheumatic Manifestations in Malignancy
Pp. 50-58
Mohannad A. Abu-Hilal and Eric L. Matteson
[Abstract]
Malignancy Risk in Systemic Lupus: Recent Research
and Ongoing Challenges Pp. 59-62
Sasha Bernatsky, Rosalind Ramsey-Goldman and Ann E. Clarke
[Abstract]
Use of Liposomal Drugs in the Treatment of Rheumatoid
Arthritis Pp. 63-70
Monica Gulati, Saranjit Singh, Dimple Chopra, Sanjiv Duggal
and Rajiv Kumar
[Abstract]
The Evaluation and Management of Adult-Onset
Henoch Schönlein Purpura Pp. 71-75
Faith Li-Ann Chia and Bernard Yu-Hor Thong
[Abstract]
Glucocorticoids and their Effects on Bone and
Joints in Rheumatoid Arthritis Pp. 76-79
Bouchra Lechkar, Jan F. Van Offel, Didier G. Ebo, Wim
J. Stevens and Luc S. De Clerck
[Abstract]
Abstracts
[Back to top]
Editorial
[Back to top]
Structure-Function Relationships in Anti-DNA and Anti Phospholipid
Antibodies and their Relevance to the Pathogenesis of Disease
Anastasia Lambrianides, Ian Giles and Anisur Rahman
Autoantibodies are pathogenic in systemic lupus erythematosus
(SLE) and the antiphospholipid syndrome (APS). These pathogenic
autoantibodies are generally characterized by IgG isotype
and high affinity binding to particular antigens. In SLE,
antibodies to double-stranded DNA (dsDNA), nucleosomes and
alpha-actinin are particularly important. In APS, pathogenic
antibodies that cause thrombosis or fetal loss are particularly
characterized by binding to anionic phospholipids (PL) and
beta-2-glycoprotein I.
Sequence analysis of human and murine monoclonal anti-dsDNA
and aPL antibodies shows that high affinity for these antigens
is associated with the presence of the residues arginine (Arg),
asparagine (Asn) and lysine (Lys) in the complementarity determining
regions (CDRs) of their heavy and light chains. In vitro
expression systems have been used to create variants of the
antibodies in which these amino acids have been altered. In
general, removal of arginine residues reduces affinity for
dsDNA, nucleosomes and anionic PL. Arginines at different
positions in the sequence have different effects on binding
affinity and effects on binding are not always mirrored by
effects on pathogenicity. These studies, together with molecular
models of antigen/antibody complexes, help us to understand
exactly how pathogenic antibodies interact with antigens.
Ultimately, this understanding may aid the design of therapeutic
agents to block the pathogenic effects of these antibodies.
[Back to top]
Genetics of Spondyloarthropathies and Inflammatory Bowel Disease:
Searching for Common Susceptibility Factors
Debby Laukens and Martine De Vos
Ileocolonoscopic evidence for subclinical gut inflammation
is found in a subpopulation of spondyloarthropathy (SpA) patients.
The prevalence of microscopic intestinal lesions is even higher
and can be classified as either an acute or a chronic type
of inflammation. The latter condition is associated with an
increased risk of developing overt inflammatory bowel disease
(IBD), especially Crohn’s disease (CD), over time. Evidence
for genetic predisposition in both SpA and IBD is strong,
and has resulted in the identification of several linked chromosomal
loci and putative candidate genes. The regular co-existence
of SpA and IBD within the same family suggests a common genetic
component. Interestingly, comparison of genome-wide linkage
and association data reveals thirteen disease-associated chromosomal
regions that are shared between SpA and IBD. This should convince
geneticists to examine genes within these regions as potential
susceptibility genes for the development of both SpA and IBD.
Significant association of such shared genetic determinants
was established for NOD2 (16q), the major histocompatibility
complex I allele HLA-B27 (6p) and recently also the interleukin
23 receptor (1p). Transgenic animals in which tumor necrosis
factor alpha or HLA-B27 is overexpressed suffer both
joint and gut abnormalities resembling human SpA/CD pathology,
providing additional evidence for a common genetic predisposition
for the onset of joint and gut inflammation. In view of a
hypothetical pathway leading to intestinal and articular inflammation
in SpA and IBD, we review and compare genome-wide linkage
and genetic association data obtained for SpA and IBD.
[Back to top]
T-Cell Dysregulation in Systemic Lupus Erythematosus: Pathophysiology
and Opportunities for Biomarker Development
Christine Bryson, Robert Busch and Frances C. Hall
T cells in SLE patients are dysfunctional as a result
of altered signalling inputs and altered signal processing.
They contribute to pathogenesis through expansion of autoreactive
T cells, aberrant B-cell help and direct T cell-mediated tissue
damage. Tissue inflammation and damage, in turn, produce nuclear
autoantigens and perpetuate antigen presentation to T cells.
Improvements in T cell-targeted therapy will require biomarkers
of T-cell dysfunction that predict clinical response. Criteria
for defining such biomarkers in SLE are discussed here. Phenotypes
associated with T-cell activation, specific effector functions,
and/or altered proliferative and homeostatic dynamics are
promising candidates.
[Back to top]
Clinical Presentation of Autoinflammatory Syndromes in Childhood
Marco Gattorno, Maria Antonietta Pelagatti, Silvia Federici,
Giacomo Brisca and Alberto Martini
The autoinflammatory syndromes are group monogenic diseases
related to mutations of genes involved in the control and
in the regulation of the inflammatory response. All of them
display an early onset in childhood. Familial Mediterranean
Fever, Mevalonate-kinase deficiency and Tumour necrosis factor
(TNF) Receptor-Associated Syndrome are characterised by recurrent
episodes of systemic inflammation presenting as fever associated
with a number of clinical manifestations, such as rash, serositis,
lymphadenopathy, arthritis (also known as Periodic fevers).
The mutation of the gene Cryopyrin is responsible
of a spectrum of diseases (Familiary Cold Autoinflammatory
Syndrome, Muckle-Wells Syndrome, and Chronic Infantile Neurological
Cutaneous and Articular Syndrome) characterised by the dysregulation
of IL-1 production and secretion. These disorders are characterised
by a chronic or recurrent inflammatory condition variably
associated with a number of clinical features, such as urticarial-like
rash, arthritis, sensorineural deafness, central nervous system
and bone involvement. Other diseases, such as Blau syndrome
and Pyogenic Sterile Arthritis, Pyoderma Gangrenosum and Acne
syndrome (PAPA) are characterised by a prevalent localisation
of inflammation to specific organs and tissues, such as joints,
skin and eyes. In the present review we will focus on the
clinical presentation of these disorders in childhood and
report on the available therapeutic strategies.
[Back to top]
Rheumatoid Arthritis Patients with Sjögren's Syndrome
are More Prone to Depression than Patients with Rheumatoid
Arthritis or Sjögren's Syndrome Alone
Yusuke Miwa, Michio Hosaka, Kunibobu Wakabayashi, Tsuyoshi
Odai, Takeo Isozaki, Mizuho Matsunawa, Nobuyuk Yajima, Fumitaka
Shiozawa, Ryosuke Hanaoka, Masao Negishi, Hirotsu Ide, Tsuyoshi
Kasama and Mitsuru Adachi
Although depression is known to be an important complication
in patients with rheumatoid arthritis (RA) or Sjögren's
syndrome (SS), at present little is known about the mental
states of RA patients who also have SS. To address that issue,
we recently used a standardized questionnaire, the self-rating
depression scale (SDS), to compare the mental states of patients
with RA alone and those with RA complicated by SS. There were
no significant differences between the two groups with respect
to age, sex, arthralgia, patient global assessment or dosage
of steroid. On the other hand, the SDS scores of RA patients
with SS were significantly higher than those of RA patients
without SS. Among the twenty items on the SDS questionnaire,
RA patients with SS complained of “constipation”
significantly more often than RA patients without SS. Collectively,
our findings suggest SS exacerbates depression in RA patients.
In discussing our findings, we describe the features of the
depression seen in patients with RA, SS and RA with secondary
SS, and make comparisons among these three groups.
[Back to top]
Rheumatic Manifestations in Malignancy
Mohannad A. Abu-Hilal and Eric L. Matteson
The association between malignancy and rheumatic diseases
is complex and many factors contribute to it. Malignancies
may lead to rheumatic manifestations either directly by invasion
or metastases, or indirectly by remote paraneoplastic effects.
Chemotherapeutic agents and bone marrow stimulatory biologic
agents such as G-CSF and GM-CSF used in the treatment of malignant
diseases may also result in rheumatic symptoms. While many
of these rheumatic symptoms occur during the course of the
malignant disease, often these rheumatic manifestations are
the initial presenting features of a hidden malignancy or
sometimes occur as late complications of them.
Most of the cancer associated rheumatic disorders have no
distinguishing features. As well, it is generally held that
an extensive search for occult malignancy, beyond routine
age-appropriate cancer screening, is not cost efficient and
is not recommended unless accompanied by symptoms and signs
suggestive of cancer. In this review, we identify rheumatic
manifestations associated with malignancy and call attention
to possible features that may suggest the presence of an occult
malignancy. Awareness of these features may permit earlier
diagnosis of the malignancy or its relapse.
[Back to top]
Malignancy Risk in Systemic Lupus: Recent Research and Ongoing
Challenges
Sasha Bernatsky, Rosalind Ramsey-Goldman and Ann E. Clarke
What is the magnitude of cancer risk in systemic lupus
erythematosus (SLE) compared to the general population? Recent
data confirmed a slight increased risk in SLE for all cancers
combined, as well as a moderate increased risk of lung cancer,
and a strikingly increased risk for hematological malignancies.
The hematological cancer type most clearly elevated in SLE
is non-Hodgkin’s lymphoma (NHL); Hodgkin’s lymphoma
appears to be increased as well. In SLE, the most commonly
identified NHL subtype is diffuse large B-cell lymphoma. Recent
analyses suggest that lymphoma in autoimmune rheumatic diseases,
including SLE, often presents extra-nodally and/or in advanced
stages. Some data suggest that mortality risk in SLE patients
with NHL has a bimodal pattern, with a number of patients
succumbing early on, and the remainder experiencing fairly
good survival rates. Key issues remaining under study relate
to the links between cancer risk, clinical features, and medication
exposures. New data suggest that disease-related factors may
be as or more important, compared to other exposures such
as immunosuppressive therapy. The challenge of establishing
the independent influences of medication exposures versus
disease activity on the risk of malignancy in SLE remains.
Work in progress should shed light on these very important
issues.
[Back to top]
Use of Liposomal Drugs in the Treatment of Rheumatoid Arthritis
Monica Gulati, Saranjit Singh, Dimple Chopra, Sanjiv Duggal
and Rajiv Kumar
Rheumatoid arthritis is an autoimmune disease that results
in joint deformity and disability. Conventional nonsteroidal
anti-inflammatory drugs (NSAIDs), steroids and disease modifying
antirheumatic drugs (DMARD’s) are used for its treatment.
Unconventional therapies, like enzyme oligodeoxy nucleotides,
boron neutron capture therapy & radioisotopes are also
being tried. The use of all these drugs is limited by a number
of adverse effects. These side effects have been overcome
to a large extent by the use of liposomes as delivery systems.
This review presents rationale for the use of liposomes for
the treatment of arthritis. Systemic as well as intra-articular
delivery of liposome encapsulated anti-arthritic drugs is
discussed. Success and limitations of this approach are also
discussed by taking examples of different drug classes.
[Back to top]
The Evaluation and Management of Adult-Onset Henoch Schönlein
Purpura
Faith Li-Ann Chia and Bernard Yu-Hor Thong
Henoch-Schönlein Pupura (HSP) is a small vessel
vasculitis resulting from immunoglobulin A (IgA)-mediated
inflammation and characterized by leukocytoclastic angiitis
and predominant cutaneous involvement. It is more common in
children and characterized by a more benign, shorter and self-limiting
course, in contrast to adults where it is relatively rarer
but associated with a higher frequency of renal involvement
and morbidity. This review discusses the contrasting epidemiological
and clinical features between adult and childhood onset HSP,
pathogenesis, uncommon clinical manifestations and the evidence
for the use of corticosteroids and other immunosuppressive
therapies and their influence on long-term outcomes.
[Back to top]
Glucocorticoids and their Effects on Bone and Joints in Rheumatoid
Arthritis
Bouchra Lechkar, Jan F. Van Offel, Didier G. Ebo, Wim
J. Stevens and Luc S. De Clerck
In rheumatoid arthritis (RA) chronic inflammation results
in pain, swelling and ultimately destruction of joints. This
inflammation is also related to systemic bone loss and an
increased fracture risk. Glucocorticoids (GC) are widely used
to suppress the symptoms of inflammation in RA. There is increasing
evidence from clinical studies that GC are disease modifying,
in early disease and in combination with slow acting anti-rheumatic
drugs. The effects of GC on joint destruction remain a matter
of debate. However, some safety issues remain to be considered
for long-term treatment, related to high cumulative doses
such as the dose-related risk for glucocorticoid induced osteoporosis
(GIOP). Moreover, data from in vitro studies on chondrocyte
cultures question the cartilage-preserving function that has
been attributed to GC. Combination with bisphosphonates can
be advocated as these compounds protect against GIOP and chondrocyte
apoptosis. In conclusion, GC may have a disease modifying
role in RA, but they have to be used in combination with other
disease modifying anti-rheumatic drugs and a bisphosphonate.
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