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Anti-CCP Antibody Detection Facilitates Early Diagnosis and Prognosis of Rheumatoid Arthritis Pp.1-7
Ger J.M. Pruijn, Erik R. Vossenaar, Jan W. Drijfhout, Walther J. van Venrooij and Albert J.W. Zendman
[Abstract] [Full text article]

Recent Developments in Management of Psoriatic Arthritis Pp.9-19
Yasser El Miedany
[Abstract] [Full text article]

Circulating Osteoclast Precursors: A Mechanism and a Marker of Erosive Arthritis Pp.21-28
Lianping Xing and Edward M. Schwarz
[Abstract] [Full text article]

Assessment of Disease Activity and Progression of Osteoarthritis With Using Molecular Markers of Cartilage and Synovium Turnover Pp.29-32
Demet Ofluoglu and Onder Ofluoglu
[Abstract] [Full text article]

Rheumatoid Arthritis in Southern Europe: Epidemiological, Clinical, Radiological and Genetic Considerations Pp.33-36
Yannis Alamanos, Paraskevi V. Voulgari and Alexandros A. Drosos
[Abstract] [Full text article]

New Functions of Angiogenic Peptides in Osteoarthritic Cartilage Pp.37-43
Rolf Mentlein and Thomas Pufe
[Abstract] [Full text article]

Therapeutic Perspectives in Systemic Lupus Erythematosus Pp.45-47
Ricard Cervera and Josep Font
[Abstract] [Full text article]

Is there Any Interest in Combining Treatments in Osteoporosis? Pp.49-55
Veronique Rabenda, Linda Hanssens, Frederic De Ceulaer and Jean-Yves Reginster
[Abstract] [Full text article]

Osseotypes and Spondyloarthropathy Exposed Pp.57-63
Bruce M. Rothschild
[Abstract] [Full text article]

Chronic Active EBV Infection and Hypersensitivity to Mosquito Bites: Pathophysiology and Pharmacology Pp.65-70
Masaru Ishii, Shiro Ohshima and Yukihiko Saeki
[Abstract] [Full text article]

A Brief History of Stoll-Brodie-Fiessinger-Leroy Syndrome (Reiter’s Syndrome) and Reactive Arthritis with a Translation of Reiter's Original 1916 Article into English Pp.71-79
Antonio Iglesias-Gammara, Jose Felix Restrepo, Rafael Valle and Eric L. Matteson
[Abstract] [Full text article]

CRP and Anti-CRP Autoantibodies in Systemic Lupus Erythematosus Pp.81-89
Christopher Sjowall, Torbjorn Bengtsson and Thomas Skogh
[Abstract] [Full text article]

Pathophysiological Factors which Determine the Exercise Intolerance in Patients with Juvenile Dermatomyositis Pp.91-99
Tim Takken, Elisabeth F. Elst and Janjaap van der Net
[Abstract] [Full text article]

Characteristics of Animal Models for Scleroderma Pp.101-109
Toshiyuki Yamamoto
[Abstract] [Full text article]

Abstracts

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Anti-CCP Antibody Detection Facilitates Early Diagnosis and Prognosis of Rheumatoid Arthritis
Ger J.M. Pruijn, Erik R. Vossenaar, Jan W. Drijfhout, Walther J. van Venrooij and Albert J.W. Zendman
[Full text article]

Rheumatoid arthritis (RA) is a common systemic autoimmune disease with a prevalence of about 1% worldwide [1]. The American College of Rheumatology (ACR) criteria for the classification of RA [2] are not very well suited to diagnose RA at an early stage of the disease [3, 4], because these criteria rely heavily on the expression of clinical symptoms of RA. In early RA these clinical parameters are often not (yet) manifest. Therefore, a specific and sensitive (serological) marker, which is present very early in the disease, is needed. A good marker should ideally not only indicate the development of the disease, but also be able to predict its erosive or non-erosive progression. The serological parameter that meets these requirements for a good and useful marker for early RA is the anti-citrullinated protein antibody. The sensitivity of this antibody is comparable to that of the rheumatoid factor (RF) (approximately 80%), but its specificity is much higher, about 98%. Several assays have been developed to detect this class of autoantibodies, which are termed anti-CCP because the most sensitive test is based upon cyclic citrullinated peptides. This review will discuss the potential of this autoantibody system for the diagnosis and prognosis of RA.

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Recent Developments in Management of Psoriatic Arthritis
Yasser El Miedany
[Full text article]

Until recently, little attention has been paid to psoriatic arthritis, perhaps because the disease was thought to be mild and infrequent. However, it has become clear that the disease may be severe in a significant proportion of the patients and may be more prevalent than initially considered. Recent studies supported the increasing clinical evidence that disruption of specific immune interactions can improve psoriasis and its musculoskeletal manifestations. Agents being evaluated for the treatment of psoriasis and psoriatic arthritis include, TNF-α antagonists: infliximab and etanercept, an anti-CD11a monoclonal antibody, efalizumab, and a soluble LFA-3-IgG fusion protein, alefacept. However, in concordance with the advent of new and emerging therapies, similar development in the measures of the disease activity and severity is highly required. This article gives an overview of the new developments in clinical assessment and management of psoriasis and its associated musculoskeletal manifestation. With the understanding of the disease immunopathogenesis, this review will outline a new suggested algorithm for management of psoriasis in its different clinical forms incorporating the new biologic agents with the conventional modalities.

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Circulating Osteoclast Precursors: A Mechanism and a Marker of Erosive Arthritis
Lianping Xing and Edward M. Schwarz
[Full text article]

Genetic studies have demonstrated that osteoclasts are essential for focal erosion of bone and cartilage as a consequence of chronic pro-inflammatory cytokine production (TNF, IL-1) in inflammatory arthritis. In these inflamed joints, mature osteoclasts differentiate from circulating osteoclast precursors (OCPs) in response to local increased production of RANKL and pro-inflammatory cytokines. Once activated to resorb calcified matrix, these osteoclasts have a short lifespan (days), and must be continually replaced by bone marrow derived OCPs to achieve focal erosions. Therefore, the peripheral blood OCP frequency may directly determine the severity of bone erosion around inflamed joints. Based on the remarkable advances in our knowledge of osteoclast biology, investigators have been able to model the molecular events that control temporal and spatial regulation of osteoclastogenesis in vivo. Here we review the results of these pre-clinical and clinical studies and provide model of pathogenesis in which pro-inflammatory cytokines produced in the joint feedback on the bone marrow to produce and release elevated numbers of OCP into the circulation, which then home to the inflamed joint. Understanding the regulation of OCP generation and mobilization will provide a new strategy for development of drug targets in the treatment of inflammatory arthritis and other disorders associated with elevated peripheral OCP/myeloid progenitors.

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Assessment of Disease Activity and Progression of Osteoarthritis With Using Molecular Markers of Cartilage and Synovium Turnover
Demet Ofluoglu and Onder Ofluoglu
[Full text article]

Osteoarthritis (OA) is the most common joint disease, which is characterized by cartilage loss and concomitant alteration of synovium and subchondral bone metabolism. Pain and stiffness in the affected joints are the main complains. It also causes physical functional impairment. The measurement of joint space width by plain radiography is currently established method for assessing the progression of the disease. This method however has some limitations. The most important issue is to determine early OA before significant joint damage has occurred. When there is radiological evidence of OA, significant joint damage has often already occurred. Therefore, there is need for noninvasive methods that can be repeated and have better sensitivity than plain radiography to identify patients at high risk for destructive OA and monitoring drug efficacy.

Molecular markers are released into biological fluids during tissue biosynthesis and turnover. They can be measured by immunoassay. Several molecular markers of bone, cartilage and synovium have been described such as crosslinking telopeptide of collagen type II (CTX II), Glc-Gal-PYD, hyaluronic acid, type I collagen.

In conclusion, using a newly developed molecular marker, early OA can be properly detected before significant joint destruction has occurred.

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Rheumatoid Arthritis in Southern Europe: Epidemiological, Clinical, Radiological and Genetic Considerations
Yannis Alamanos, Paraskevi V. Voulgari and Alexandros A. Drosos
[Full text article]

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovium, leading to joint damage and bone destruction and causing severe disability and increased mortality. Several prevalence and incidence studies for RA during the last decades have suggested considerable variations of the disease occurrence among different populations. The majority of the prevalence studies carried out in Northern European and North American countries estimate a prevalence of 0.5 to 1.1%, while the annual incidence varies between about 20 and 50 cases per 100.000 inhabitants. In the last decade studies from Southern Europe and especially from the Mediterranean area showed a different clinical, serological and radiological phenotype for RA as compared to Northern European countries. In subsequent studies it is reported that the majority of RA patients in this area, lack the putative HLA-DRb motif, which suggest that considerable immunogenetic heterogeneity underlies disease susceptibility in these populations. In addition, studies from Southern European countries report a relatively lower occurrence of the disease. The prevalence rates vary between 0.3 to 0.7%, while the annual incidence is estimated between about 10 to 20 new cases per 100.000 inhabitants. The available data suggest that RA in Southern Europe present a particular genetic, epidemiological and clinical profile. It seems that RA in this area is less frequent, and milder, with less extraarticular and radiological manifestations. Environmental and life-style factors may contribute to this different profile. Dietary factors such as olive oil and fish consumption and even the Mediterranean diet, could offer a protective effect for disease development and disease severity.

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New Functions of Angiogenic Peptides in Osteoarthritic Cartilage
Rolf Mentlein and Thomas Pufe
[Full text article]

Inflammation is often associated with angiogenesis and angiogenic peptides might also be involved in inflammatory diseases like osteoarthritis (OA). This review summarizes recent findings about the occurrence and function of vascular endothelial growth factor (VEGF) and another angiogenic / growth factor, pleiotrophin (PTN) in osteoarthritic cartilage. Both peptides are produced in OA chondrocytes, but not in normal adult chondrocytes. Beside their well known effects on the infiltration of blood vessels that are sometimes observed in OA, they have additional, auto-/paracrine effects on chondrocytes and osteoblasts of the subchondral bone. PTN is found in early stages of OA, and appears to be a protective factor inducing remodelling and chondrogenesis. VEGF is induced by mechanical overload and appears to increase OA progression. VEGF promotes cartilage remodelling by inducing matrix metalloproteinases and reducing their inhibitors. Under chronic inflammatory conditions, this should result in subsequent destructive processes in OA cartilage. Chemotactic effects of VEGF and PTN on osteoblasts and endothelial cells may contribute to additional pathologic features such as osteophyte formation and blood vessel invasion. Overall, angiogenic peptides are new autocrine factors in OA initiating cartilage remodelling. VEGF appears to contribute to destructive processes in late OA stages whereas PTN may play protective roles in earlier OA stages.

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Therapeutic Perspectives in Systemic Lupus Erythematosus
Ricard Cervera and Josep Font
[Full text article]

Prognosis in systemic lupus erythematosus (SLE) has improved markedly in the last 40 years. From mortality rate which was higher than 50% after 5 years of SLE diagnosis in the 60´s to a more than 90% survival after 10 years in the more recent prospective studies [1]. This is probably due to a number of reasons, including a better knowledge of the disease (earlier and easier diagnosis, assessment of new subsets) and an improved general healthcare (new antibiotics or better drugs to treat hypertension or hyperlipidemia, development of intensive therapy units), but also to the introduction of non-specific anti-inflammatory drugs, immunosuppressors and immunomodulators (steroids, cytostatics, intravenous gammaglobulins). Future challenges are to improve the quality of life of these patients and to reduce even more the mortality – the current mortality is still 3-4 times higher then expected for the similar age and gender population. In order to achieve these objectives, three main goals should be addressed: 1) to improve the use of some drugs already available; 2) to introduce some drugs in the clinical practice that are currently in phase I-III trials; and 3) to increase the basic research in order to discover targets for new selective immunomodulators.

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Is there Any Interest in Combining Treatments in Osteoporosis?
Veronique Rabenda, Linda Hanssens, Frederic De Ceulaer and Jean-Yves Reginster
[Full text article]

Combination therapy includes the concomitant or sequential use of compounds sharing the same mode of action (e.g. two or more inhibitors of bone resorption) or with distinct pathways of activity (e.g. an inhibitor of resorption plus an anabolic agent). Combinatorial use of anti-resorptive agents may generate concerns, due to the risk of inducing oversuppression of bone turnover. However, if low doses of estrogen, used for the management of climacteric symptoms, are insufficient to normalize bone turnover, an addition of a bisphosphonate to HRT can prove to be useful to achieve this objective. Patients pre-treated with inhibitors of resorption, who have no full therapeutic response, are good candidates for the treatment with anabolic agents. The increase in bone turnover that follows the introduction of parathyroid hormone in patients treated with an anti-resorptive agent is similar to that observed in treatment-naïve patients and the pattern of bone mineral density (BMD) increase is also identical, with the exception of a 6-month delay in the spine and hip BMD changes observed in prior alendronate-treated subjects. Current data discourage the concomitant use of alendronate and parathyroid hormone since the bisphosphonate appears to blunt, in men and women, the anabolic action of parathyroid hormone. Whether this also applies to other bisphosphonates or inhibitors of resorption remains unknown. The use of an inhibitor of bone resorption after completion of parathyroid hormone treatment seems an appropriate way to maintain the skeletal benefits gained during therapy. Longterm clinical studies, using fractures as an end-point should be initiated to better understand the clinical and pharmaco-economic interest of combination therapies in the management of osteoporosis.

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Osseotypes and Spondyloarthropathy Exposed
Bruce M. Rothschild
[Full text article]

Tendency to afflict one part of the skeleton, rather than another, could be referred to as the osseotropism of the disease. That term would also include which part of the particular bone was affected. That, in addition to characteristics of erosions facilitates distinguishing spondyloarthropathy from rheumatoid arthritis, calcium pyrophosphate deposition disease and gout. Spondyloarthropathy, however, is not limited to humans. Initially recognized in 20% of gorillas and rhesus macaques, it was subsequently identified in 25% of bears and 35% of rhinoceros. It is truly a pan-mammalian phenomenon, extending from marsupials and rodents to whales and as ancient as dinosaurs.

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Chronic Active EBV Infection and Hypersensitivity to Mosquito Bites: Pathophysiology and Pharmacology
Masaru Ishii, Shiro Ohshima and Yukihiko Saeki
[Full text article]

Hypersensitivity to mosquito bites (HMB) is characterized clinically by intense skin reactions at mosquito bite sites with severe systemic symptoms. Another important feature is the high mortality rate due to complications, such as malignant NK cell-lineage granular lymphoproliferative disorder (NK-GLPD) and hemophagocytic syndrome (HPS). Previous studies have indicated that chronic active Epstein-Barr virus infection (CAEBV) is closely associated with HMB and its malignant complications. We and other groups have recently shown the abnormal oligoclonal expansion of EBV-infected NK cells in the periphery of HMB patients, which contributes to the pathogenesis of pleiotropic symptoms in HMB. To explore the therapeutic possibility, we have examined the anti-viral drugs on the symptoms, and some drugs have been emerging as the candidates for the treatment for HMB. In this brief review, we show the recent progresses in the studies elucidating the intricate web among CAEBV, NK-GLPD and HMB. The pathophysiology and pharmacology regarding CAEBV and HMB should also be generally important in viral-associated rheumatic diseases and their therapeutics.

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A Brief History of Stoll-Brodie-Fiessinger-Leroy Syndrome (Reiter’s Syndrome) and Reactive Arthritis with a Translation of Reiter's Original 1916 Article into English
Antonio Iglesias-Gammara, Jose Felix Restrepo, Rafael Valle and Eric L. Matteson
[Full text article]

While not the only form of reactive arthrits, Reiter’s syndrome is the eponym given to a form of reactive arthritis associated with with the classice triad of conjuntivitis, urethritis, and inflammatory arthritis. Although in popular use, the term Reiter’s syndrome has become clouded, not only because of the variable pathophysiology of reactive arthritis, but also because of Reiter’s own past as an early member of the Nazi party and his prominent role in the German health system during the Thrid Reich, including involvement with involuntary medical procedures and experiments in Nazi concentration camps. As is often the case, the eponym attached to the syndrome does not honor the original describers of the disease, although doubtless Reiter’s account remains the classic description. We offer a brief historical review of the disease, and complete it with a translation into English of Reiter’s original publication.

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CRP and Anti-CRP Autoantibodies in Systemic Lupus Erythematosus
Christopher Sjowall, Torbjorn Bengtsson and Thomas Skogh
[Full text article]

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement, production of a wide range of autoantibodies and by formation and tissue deposition of immune complexes in the inflamed organs. In contrast to most systemic inflammatory conditions, and despite raised levels of pro-inflammatory cytokines, SLE flares are rarely reflected by elevated C-reactive protein (CRP), an important acute-phase reactant in man with homologues in vertebrates and several invertebrates. Normally, the circulating concentration of liver-derived CRP rises rapidly in response to infections and tissue injury, and CRP measurement is widely employed as a marker of ongoing inflammation. With sensitive methods, detection of small elevations of CRP is also valuable as a prognostic marker in cardiovascular disease. As a part of the innate immune system, CRP binds certain molecules exposed on the surface of dying cells/apoptotic bodies and on the surface of pathogens and mediates their elimination by uptake in the reticuloendothelial system. CRP also interacts with IgG-containing immune complexes, binds Fc-receptors and activates the complement system via C1q. In murine lupus, CRP has been found to decrease autoantibody levels and increase the survival rates. In this review we discuss possible explanations for, and consequences of, the relative CRP failure in SLE, as well as pathogenetic implications of anti-CRP autoantibodies.

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Pathophysiological Factors which Determine the Exercise Intolerance in Patients with Juvenile Dermatomyositis
Tim Takken, Elisabeth F. Elst and Janjaap van der Net
[Full text article]

Juvenile Dermatomyositis (JDM) is one of the idiopathic inflammatory myopathies in childhood. In this disease the immune system targets the microvasculature of the skeletal muscle and skin, leading to myopathy and a typical skin rash. During episodes of active disease patients experience a significant reduction in exercise tolerance which is not only related to loss in muscle mass. In this chapter we propose a model consisting of 5 pathways that could explain the reduced exercise tolerance in children with JDM. The five pathways are 1) the increased concentration of intramuscular cytokines, 2) the systemic inflammation process 3) the inflammation of the capillaries in the muscle 4) the result of hypo-activity and 5) the effect of glucocorticoid treatment on body mass gain and protein breakdown.

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Characteristics of Animal Models for Scleroderma
Toshiyuki Yamamoto
[Full text article]

Scleroderma is a fibrotic condition characterized by immunologic abnormalities, vascular injury and increased accumulation of matrix proteins in the affected dermis. Although the etiology of scleroderma is not fully elucidated, numerous studies suggest that extracellular matrix overproduction by activated fibroblasts and myofibroblasts results from a complex interactions among endothelial cells, lymphocytes, macrophages, and fibroblasts, via a number of mediators. Animal models which exhibit all the aspects of human scleroderma are not currently available, however, several spontaneous or experimental animal models, such as tight skin (Tsk) mouse, Tsk2 mouse, bleomycin-induced scleroderma, sclerodermatous graft-versus-host disease (Scl GvHD) model, UCD chicken, and fibrosis model by exogenous injections of TGF-β/CTGF have been investigated. This review describes different animal models for scleroderma, paying the most attention to the recent progress in bleomycin-induced experimental murine scleroderma. Each model exhibits unique characteristics of dermal fibrosis/sclerosis which can be of great help in exploring the pathogenesis as well as therapeutic strategies of scleroderma.