Current Rheumatology Reviews - Volume 3, Issue 4, 2007

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.

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.

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.

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.

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 overproduction 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 pathomechanisms leading to impaired bone turnover and potential mediators that could be targeted to reverse bone loss in RA.

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.

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.

Neuro-Behcet's syndrome consists of acute type and chronic progressive type (primary progressive and secondary progressive). Attacks of acute type neuro-Behcet's syndrome are sometimes self-limiting. However, when the neurological manifestations are progressive and severe, administration of corticosteroid is necessary. In addition, infliximab and interferon alpha might also be effective in acute type neuro-Behcet's disease. There are no drugs which have been demonstrated to be effective in preventing the occurrence of attacks of acute type neuro-Behcet's disease. Colchicine, low dose of steroids and various immunosuppressive drugs have been used anecdotally for this purpose. As to chronic progressive neuro-Behcet'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- Behcet'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 MTXresistant chronic progressive neuro-Behcet's syndrome.

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.

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.

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.