Rheumatoid Arthritis: Israel

Day CS, Ramirez MA. · Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, E/CC2, Boston, MA 02215, USA. · Hand Clin. · Pubmed #16701135 No free full text.

Abstract: The human thumb assumes 50% of the workload of the human hand, and is therefore the most important digit. As such, the thumb has a propensity for the development of osteoarthritis. Moreover, the thumb is also often diseased, in anywhere from 68% to 80%of patients who have rheumatoid arthritis. Much attention over the years has been given to the carpalmetacarpal joint of the thumb, whereas the metacarpophalangeal (MP) joint of the thumb remains largely unstudied. The purpose of this article is to review the etiology of thumb MP joint arthritis, and discuss the different treatment options of this condition.

Steiman-Shimony A, Edelman H, Barak M, Shahaf G, Dunn-Walters D, Stott DI, Abraham RS, Mehr R. · Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel. · Autoimmun Rev. · Pubmed #16697964 No free full text.

Abstract: Lineage trees have frequently been drawn to illustrate diversification, via somatic hypermutation (SHM), of immunoglobulin variable-region (IGV) genes. In order to extract more information from IGV sequences, we developed a novel mathematical method for analyzing the graphical properties of IgV gene lineage trees, allowing quantification of the differences between the dynamics of SHM and antigen-driven selection in different lymphoid tissues, species, and disease situations. Here, we investigated trees generated from published IGV sequence data from B cell clones participating in autoimmune responses in patients with Myasthenia Gravis (MG), Rheumatoid Arthritis (RA), and Sjögren's Syndrome (SS). At present, as no standards exist for cell sampling and sequence extraction methods, data obtained by different research groups from two studies of the same disease often vary considerably. Nevertheless, based on comparisons of data groups within individual studies, we show here that lineage trees from different individual patients are often similar and can be grouped together, as can trees from two different tissues in the same patient, and even from IgG- and IgA-expressing B cell clones. Additionally, lineage trees from most studies reflect the chronic character of autoimmune diseases.

Ram M, Sherer Y, Shoenfeld Y. · Department of Medicine B & Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Jerusalem, Israel. · J Clin Immunol. · Pubmed #16652230 No free full text.

Abstract: Matrix metalloproteinases (also named matrixin or MMPs) are a major group of enzymes that regulate cell-matrix composition by using zinc for their proteolytic activities. They are essential for various normal biological processes such as embryonic development, morphogenesis, reproduction tissue resorption, and remodeling. Metalloproteinases also play a role in pathological processes including inflammation, arthritis, cardiovascular diseases, pulmonary diseases and cancer. Herein we review the involvement of MMP-9 in a variety of autoimmune diseases including systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, rheumatoid arthritis, multiple sclerosis, polymyositis and atherosclerosis. MMP-9 plays either a primary or secondary role in each one of those autoimmune diseases by its up or down-regulation. It is not expressed constantly but rather is induced or suppressed by many regulating molecules. This feature of MMP-9 along with its involvement in disease pathogenesis turns it into a target for therapy of autoimmune diseases.

Otero M, Lago R, Gómez R, Lago F, Gómez-Reino JJ, Gualillo O. · Beth Israel Deaconess Medical Center, New England Baptist Bone & Joint Institute, Harvard Institutes of Medicine, Boston, Massachusetts, USA. · Drug News Perspect. · Pubmed #16550253 No free full text.

Abstract: Initially described as a satiety factor with neuroendocrine properties, leptin has been shown to regulate immune and inflammatory processes. Mainly produced by white adipose tissue, this hormone was first known to regulate energy homeostasis by inhibiting food intake and by upregulating energy consumption. Leptin is a dual molecule: apart from its actions as a hormone involved in energy homeostasis, increasing evidence suggests that leptin is a novel proinflammatory adipocyte-derived factor that operates in the cytokine network by linking immune and inflammatory processes to the neuroendocrine system. In fact, recent findings have shown that leptin regulates and participates both in immune homeostasis and inflammatory processes not only by acting as a modulator of T-cell activity, but also by playing a key role in a host of autoimmune inflammatory conditions such as autoimmune encephalomyelitis, type 1 diabetes, bowel inflammation and articular degenerative diseases such as osteoarthritis and rheumatoid arthritis. This review will more closely address leptin's cytokine properties rather than its role as a metabolic hormone by focusing on its biological actions in inflammatory processes, specifically those related to degenerative inflammatory diseases of the joints.

Slovik Y, Putterman M, Nash M, Sion-Vardy N. · Department of Otolaryngology Head and Neck Surgery, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sieva, Israel. · Am J Rhinol. · Pubmed #16539302 No free full text.

Abstract: BACKGROUND: Eosinophilic angiocentric fibrosis (EAF) is an uncommon inflammatory fibrosing lesion involving the upper respiratory mucosa, occurring mainly in young to middle aged women (female/male ratio = 2:1). The etiology is unknown; however, severalfactors might play a role in the development of EAF. Among them are prior nasal trauma (in most of the reported cases nasal surgery had been performed afew years prior to diagnosis) and inflammatory or autoimmune etiology (suggested by the ratio and the fact that in many of the reported cases a history of nonspecific allergy was found). METHODS: We report the first case of EAF affecting a male patient who also suffered from chronic inflammatory bowel disease and rheumatic fever. RESULTS: The patient underwent a diagnostic biopsy of his nasal lesion via an open rhinoplasty approach, with the resulting diagnosis of EAF. Despite the fact that the literature does not show advantages to any specific therapy, the patient elected to remain under observation. During a two-year follow-up period, there is no evidence of progression of disease. CONCLUSION: The presence of concomitant rheumatoid arthritis and chronic inflammatory bowel disease in our patient, as well as the fact that nine previously reported cases of EAF had allergic/immune symptoms, raise the possibility that inflammatory or autoimmune factors may have a role in the development of this unusual pathological entity.

Walsh NC, Crotti TN, Goldring SR, Gravallese EM. · Beth Israel Deaconess Medical Center, New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, MA 02115, USA. · Immunol Rev. · Pubmed #16313352 No free full text.

Abstract: Rheumatoid arthritis, juvenile idiopathic arthritis, the seronegative spondyloarthropathies including psoriatic arthritis, and systemic lupus erythematosus are all examples of rheumatic diseases in which inflammation is associated with skeletal pathology. Although some of the mechanisms of skeletal remodeling are shared among these diseases, each disease has a unique impact on articular bone or on the axial or appendicular skeleton. Studies in human disease and in animal models of arthritis have identified the osteoclast as the predominant cell type mediating bone loss in arthritis. Many of the cytokines and growth factors implicated in the inflammatory processes in rheumatic diseases have also been demonstrated to impact osteoclast differentiation and function either directly, by acting on cells of the osteoclast-lineage, or indirectly, by acting on other cell types to modulate expression of the key osteoclastogenic factor receptor activator of nuclear factor (NF) kappaB ligand (RANKL) and/or its inhibitor osteoprotegerin (OPG). Further elucidation of the mechanisms responsible for inflammation-induced bone loss will potentially lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases. In this review, we provide an overview of the cell types, inflammatory mediators, and mechanisms that are implicated in bone loss and new bone formation in inflammatory joint diseases.

Zohar Y, Wildbaum G, Karin N. · Department of Immunology, Rappaport Faculty of Medicine, Rappaport Inst. for medical Sciences, Technion, Haifa, Israel. · Front Biosci. · Pubmed #16146738 No free full text.

Abstract: Antigen specific T cells and B cells recognize their target determinants by antigen specific receptors that are being rearranged in a random manner. These cells then undergo negative and positive selection processes that limit, albeit not eliminate, the escape of self-reactive T and B cells capable of eliciting autoimmune responses. The above processes are referred to as "central selection", and their outcome is the "central tolerance". Auto-reactive T and B cells escaping central tolerance are then subjected to peripheral mechanisms that restrain their auto-aggressive behavior. Different types of regulatory T cells are key players in maintaining actively induced peripheral tolerance. In patients suffering from various autoimmune disorders autoreactive T and/or B cells that escaped central tolerance also circumvented regulatory T cells that could, potentially, eradicate their pathogenicity in the periphery. We have found an additional regulatory mechanism that restrains the harmful activity of these cells at that time. It includes autoimmune B cells that produce neutralizing autoantibodies against numerous inflammatory mediators, mostly cytokines and chemokines, which participate in destructive autoimmunity. These autoantibodies restrain the harmful consequences of inflammatory autoimmune conditions such as in rheumatoid arthritis. Interestingly, this antibody production is elicited during autoimmune diseases, and to a much lesser extent during local inflammation. The specificity of this response is highly restricted to determinants with minimal cross reactivity to other known gene products. Thus, the immune system allows selective breakdown of tolerance in autoimmune conditions. The findings that this beneficial response is turned on by the autoimmune condition, and then regulated by its progression further imply for the existence of a programmed regulatory response of "beneficial autoimmunity". In the current review we describe how this mechanism was discovered in experimental models of rheumatoid arthritis and multiple sclerosis, demonstrate its importance in the natural regulation of these diseases, and finally explore its relevance to human diseases.

Shepshelovich D, Sherer Y, Shoenfeld Y. · Department of Medicine B & Center for Autoimmune Diseases, Sheba Medical Center Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Israel. · Harefuah. · Pubmed #16146154 No free full text.

Abstract: Cardiovascular manifestations are frequent in rheumatoid arthritis (RA) and significantly contribute to morbidity and mortality in this disorder. Premature atherosclerosis is responsible for these complications, as supported by autopsy studies. Moreover, a high prevalence of sub-clinical atherosclerosis--evaluated by imaging and instrumental parameters--has been reported. Traditional risk factors cannot completely account for accelerated atherosclerosis in RA. The presence of RA by itself and the immunosuppressive therapy (especially corticosteroids) represent non-traditional risk factors for premature atherosclerosis. Additional factors playing a synergistic role in the atherosclerotic process are systemic chronic inflammation frequently associated with RA and both humoral and cellular specific autoimmune responses. Herein we review and discuss atherosclerosis in rheumatoid arthritis, with special emphasis on clinical presentations, pathogenesis and therapy.

Shmerling RH. · Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA, USA. · South Med J. · Pubmed #16108239 No free full text.

Abstract: Establishing a diagnosis of systemic rheumatic disease requires an integration of a patient's symptoms, physical examination findings, and the results of diagnostic testing. There is often a temptation by clinicians to rely heavily on objective measures such as the presence or absence of an autoantibody. Medical textbooks and the medical literature may overestimate the diagnostic utility of many commonly ordered tests for rheumatic disease because the tests are usually analyzed among patients with established rheumatic disease rather than among patients with an uncertain cause of symptoms as is common in practice. Few diagnostic tests are highly sensitive, though the antinuclear antibody in systemic lupus erythematosus (SLE) and the erythrocyte sedimentation rate in temporal arteritis are notable exceptions. Conversely, few diagnostic tests are highly specific; anti-proteinase-3 and antimyeloperoxidase antibodies (types of antineutrophilic cytoplasmic antibodies) among patients with Wegener granulomatosis (and related vasculitides) and anti-double-stranded and anti-Smith antibodies among patients with SLE may be particularly helpful in the proper clinical settings due to their high specificity. Anticitrullinated cyclic protein (anti-CCP), a newly described autoantibody that may be highly specific for rheumatoid arthritis, requires additional study as its utility in clinical practice is uncertain.

Toubi E, Shoenfeld Y. · Divison of Allergy and Clinical Immunology, Bnai Zion Medical Center, Haifa, Israel. · Autoimmunity. · Pubmed #15621572 No free full text.

Abstract: Many tissue injuries and immune mediated pathologies such as graft allo-rejections were found to involve CD40-CD40 ligand (CD40L, CD154) signaling pathway. The disruption of this pathway in many animal models led to the improvement of graft survival in these models. CD40-CD154 interactions were also shown to play a significant role in the maintenance of autoimmunity, and the production of auto-antibodies in systemic lupus erythematosus (SLE). High-level expression of CD154 has been detected on T cells from patients with active SLE, rheumatoid arthritis (RA) and other autoimmune diseases, indicating that such cells could account for the high-level expression of immune accessory molecules on B cells of patients with active disease. An increased serum level of soluble CD154 was also reported in SLE, RA, and Sjogren's disease in correlation with the relevant auto-antibodies and with the clinical disease activity. Anti-CD154 antibody therapy prevents auto-antibody production and renal immune complex deposition in lupus nephritis, indicating that disruption of this pathway could be a beneficial treatment in SLE. However, the etiology of the higher than expected number of thromboembolic events in anti-CD154 treated SLE patients should be investigated and preventive measures should be considered.

Yodfat Y. · Dr. Jullien Rozan, Family Medicine, Hebrew University--Hadassah Medical School, Jerusalem. · Harefuah. · Pubmed #15603272 No free full text.

Abstract: The two cyclooxygenase isoforms (COX-1 and COX-2--coxibs) have overlapping functions and both are involved in the regulation of homeostatic and inflammatory processes in the various tissues. Treatment with highly selective COX-2 inhibitors is associated with significantly fewer serious adverse gastrointestinal events than is treatment with the dual inhibitors--the non-selective NSAIDs. Of the two coxibs, rofecoxib was shown to be much more selective than celecoxib and with less interaction with other drugs. Various clinical studies have demonstrated that the coxibs are equivalent, in anti-inflammatory, analgesic and antipyretic efficacy to comparator non-selective NSAIDs in osteoarthritis, rheumatoid arthritis, post surgery pain and dysmenorrhea. Perioperative use of coxibs reduces pain, opioid consumption and the risk of bleeding caused by the non-selective NSAIDs. The coxibs show similar tolerability for renal, liver and cardiothrombotic events as compared to the non-selective NSAIDs. Coxibs are contraindicated in pregnancy, in nursing mothers and pediatric patients and should be used with caution in patients with asthma. The impact of the coxibs on the cardiovascular system is controversial. However, coxibs should be used in caution and at the lowest recommended dose in patients with hypertension, ischemic heart disease and heart failure. These drugs do not interfere with the aspirin anti-platelet aggregation activity. Emerging evidence suggest that the coxibs may also find potential use as supportive therapy in various malignant tumors and intestinal polyps where COX-2 is overly expressed.

Schattner A. · Department of Medicine, Kaplan Medical Center, Rehovot, Israel. · Arch Intern Med. · Pubmed #15534154 No free full text.

This publication has no abstract.

Reinstein E. · Department of Medicine B, Chaim Sheba Medical Center, Tel Hashomer. · Harefuah. · Pubmed #15523815 No free full text.

Abstract: The ubiquitin-proteasome pathway has a central role in selective degradation of intracellular proteins. Among the key proteins that are degraded by the system are those involved in the control of inflammation, cell cycle regulation, and gene expression. With so many important cellular pathways affected, derangements in the ubiquitin system have been shown to result in a variety of human diseases. Consequently, proteasome inhibition has a potential as a form of treatment for many human diseases such as cancer and inflammatory conditions. Two proteasome inhibitors, PS-341 and PS-519 are currently under clinical evaluation. PS-341 is currently being evaluated in phase III clinical trial for multiple myeloma, and PS-519 is now on a phase II trial for acute ischemic stroke. In addition, inhibition of the proteasome has been shown to be effective in several animal models for a variety of human diseases such as different malignancies, asthma, rheumatoid arthritis, and arterial restenosis. Future studies will be required to establish whether the promising animal studies could be successfully implicated in human disease states.

Slavin S, Aker M, Shapira MY, Resnick I, Bitan M, Or R. · Deptartment of Bone Marrow Transplantation & Cancer Immunotherapy, The Danny Cunniff Leukemia Research Laboratory, Jerusalem 91120, Israel. · Clin Transpl. · Pubmed #15387119 No free full text.

Abstract: Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for the treatment of an otherwise incurable broad spectrum of malignant and non-malignant diseases. Until recently, BMT was used primarily to replace a malignant, genetically abnormal or deficient immunohematopoietic compartment and therefore, highly toxic myeloablative regimens were considered mandatory for more effective eradication of all undesirable host-derived hematopoietic cells, including stem cells and their progeny. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells can be mediated by donor lymphocytes in the process of adoptive allogeneic cell therapy following BMT. Thus, eradication of all malignant cells, especially in patients with CML and, to a lesser extent, in patients with other hematologic malignancies can be accomplished despite complete resistance of puch tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft-versus-malignancy effects might be used as a tool for eradication of otherwise resistant tumor cells of host origin. We speculated that the therapeutic benefit of BMT may be improved by using safer conditioning for engraftment of donor stem cells induce host-versus-graft unresponsiveness to enable engraftment of donor lymphocytes for subsequent induction of graft-versus-malignancy effects, or even graft-versus-autoimmunity and graft-versus-genetically abnormal cells. In other words, focusing on more selective and smarter rather than stronger modalities. Effective BMT procedures may be accomplished without lethal conditioning of the host, using a new, well-tolerated and user-friendly non-myeloablative regimen, thus eliminating or minimizing immediate and late procedure-related toxicity and mortality. It appears that initial induction of graft tolerance, mediated by engraftment of donor stem cells, leads to durable engraftment of immunocompetent donor lymphocytes, which may be necessary for induction of effective biologic warfare against host-type immunohematopoietic cells. Consequently, stem-cell therapy following induction of transplantation tolerance by selective elimination of alloreactive donor lymphocytes may represent the treatment of choice for a wide range of otherwise incurable diseases, including cancer (hematologic malignancies and certain metastatic solid tumors), genetic disorders (hemoglobinopathies and enzyme deficiency disorders), diseases caused by self-reactive lymphocytes (autoimmune diseases such as multiple sclerosis, rheumatoid arthritis) to mention just a few. Using reduced intensity conditioning, non-myeloablative stem cell transplantation (NST) can be accomplished with no major procedure-related toxicity or mortality. Thus, NST offers the feasibility of safe stem cell transplantation and cell-mediated procedures for a large and constantly growing spectrum of clinical indications for all patients in need without lower or upper age limit. Future strategies currently under investigation include developing new approaches for control of alloreactivity of host-versus-graft and graft-versus host reactivity reactions and developing better approaches for maximizing the capacity of donor lymphocytes to eliminate cancer cells more selectively, while avoiding or minimizing GVHD for safer and more effective treatment of patients in need of BMT.

Walsh NC, Gravallese EM. · Division of Rheumatology and Metabolic Bone Disease, Beth Israel Deaconess Medical Center and New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. · Curr Opin Rheumatol. · Pubmed #15201606 No free full text.

Abstract: PURPOSE OF REVIEW: Focal bone loss in inflammatory arthritis begins early in the disease process and can contribute to patient morbidity. Current treatment strategies primarily target suppression of the inflammatory cascade with varying success in limiting the progression of focal bone destruction. This review outlines the current understanding of the mechanisms mediating inflammation-induced focal bone loss in rheumatoid arthritis and other inflammatory arthritides and highlights recent studies in animal models of arthritis that have contributed to our knowledge of this process. RECENT FINDINGS: Bone-resorbing osteoclasts have been identified as important effector cells in inflammation-induced bone loss in both experimental animal models and human rheumatoid arthritis and psoriatic arthritis. The RANK/RANKL (receptor activator of nuclear factor-kappaB and RANK ligand) pathway has been shown to be essential for osteoclast differentiation in inflammatory arthritis. In addition, in vitro and in vivo studies have demonstrated that many cytokines and growth factors elaborated by inflamed synovial tissues may contribute to osteoclast differentiation and activation. SUMMARY: Elucidation of the mechanisms mediating osteoclast differentiation and function has identified new pathways for potential targeted therapeutic intervention for focal bone loss in inflammatory arthritis. Challenges in the application of this approach are that therapies targeting the osteoclast would need to be used in combination with effective anti-inflammatory agents, and that pathways mediating osteoclast differentiation and function would need to remain at least partially functional to allow for continued skeletal remodeling.

Rosner I, Rozenbaum M, Toubi E, Kessel A, Naschitz JE, Zuckerman E. · Department of Rheumatology, Bnai Zion Medical Center, Faculty of Medicine, Technion, Haifa, Israel. · Semin Arthritis Rheum. · Pubmed #15190523 No free full text.

Abstract: OBJECTIVE: To present the data available supporting the existence of an arthropathy associated with hepatitis C infection. METHODS: The MEDLINE database was searched for "arthritis" intersecting with "hepatitis C" in addition to the authors' investigations and experience on this subject. RESULTS: Arthritis, not otherwise explained, has been noted in 2% to 20% of hepatitis C virus (HCV) patients. This arthritis is rheumatoid-like in two thirds of the cases and a waxing/waning oligoarthritis in the rest. Cryoglobulinemia alone does not explain the arthritis, and there is difficulty in differentiating it from rheumatoid arthritis. The arthropathy is nonerosive/nondeforming. Whereas nonsteroidal anti-inflammatory drugs, low-dose corticosteroids, and hydroxychloroquine may be helpful, conventional treatment of arthritis may be problematic in the context of viral hepatitic arthropathy. Antiviral therapy is most effective, even without viral clearance, but rheumatic complications may ensue. CONCLUSIONS: HCV arthropathy should be considered in the differential diagnosis of new-onset arthritis.

Karin N. · Technion-Israel Institute of Technology, Department of Immunology, Haifa 31096, Israel. · Curr Opin Mol Ther. · Pubmed #15011778 No free full text.

Abstract: T-cell-mediated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis or type 1 diabetes result from an aggressive attack of self-components by autoimmune T-cells. Pro-inflammatory mediators, particularly cytokines and chemokines, direct the homing and effectorfunction of these cells. It has recently been demonstrated that the immune system, which can attack self-components, also generates 'beneficial' autoimmunity against pro-inflammatory mediators. During the course of an autoimmune condition, and to a much lesser extent in response to microbial inflammation, the immune system produces auto-antibodies to pro-inflammatory mediators. This reduces the harm from these diseases. We also discovered that targeted DNA vaccines could effectively amplify these responses to provide protective immunity. The underlying mechanism is partially understood. At the site of immunization, the relevant gene product is produced and then presented by dendritic cells/macrophages, which undergo activation due to an interaction of plasmid CpG with toll-like receptor 9 on the dendritic cell. This then activates CD4+ T-cells, which help the production of T-cell-dependent antibodies against the gene product of the vaccines. These antibodies neutralize their target product and suppress inflammation. This review explores this interesting concept and its therapeutic implications.

Kupersmith MJ, Martin V, Heller G, Shah A, Mitnick HJ. · Institute of Neurology and Neurosurgery at Beth Israel Medical Center, New York Eye and Ear Infirmary, New York University School of Medicine, New York, NY, USA. · Neurology. · Pubmed #15007115 No free full text.

Abstract: BACKGROUND: Hypertrophic pachymeningitis is an uncommon disorder that causes a localized or diffuse thickening of the dura mater and has been associated with rheumatoid arthritis, syphilis, Wegener's granulomatosis, tuberculosis, and cancer. Few series of the idiopathic variety have been described, particularly with respect to MRI correlation to clinical outcome and treatment. OBJECTIVE: To investigate the clinical and laboratory evaluation, course, and treatment of patients with idiopathic hypertrophic pachymeningitis (IHP), to correlate the MRI findings with the clinical course, and to review the literature on IHP. METHODS: Retrospective case series of 12 patients (9 men, 3 women), with a mean age of 55 years (range 39 to 88 years), who had IHP by imaging studies, meningeal or orbital biopsy, or both. The clinical features, laboratory evaluation, contrast-enhanced MRI, treatment, and clinical outcome were documented for each case. The mean duration of follow-up was 3.5 years (range 3 months to 16 years). RESULTS: The main clinical features at presentation were headache (11 cases), loss of vision (7 cases), diplopia (4 cases), papilledema (2 cases), other cranial nerve involvement (3 cases), ataxia (2 cases), and seizures (1 case). On the initial MRI, the location of abnormal enhancement of the dura mater correlated with the clinical findings and the sphenoid wing area was affected in all patients. The sedimentation rate was elevated in five cases. The CSF had increased protein in six cases and lymphocytosis in four cases. Biopsy of the dura mater in five cases and the orbital soft tissue in one case showed infiltrates of small mature lymphocytes, plasma cells, and epithelioid histiocytes, but no neoplasia, vasculitis, or infectious agents. Cultures of the CSF and biopsy material remained sterile. Corticosteroid therapy improved the vision in 7 of 8 cases and controlled headache in 10 of 11 cases. Five cases had partial improvement of other neurologic symptoms and signs. Recurrence developed with steroid tapering in six cases. One case had progressive deterioration and died. In four cases methotrexate or azathioprine was added with reduction of the steroid dose. Follow-up MRI performed in 11 patients correlated 80% with the clinical state (p = 0.01). CONCLUSION: IHP can be suspected on MRI and defined pathologically on biopsy. Untreated, the clinical course is usually marked by severe headache and progressive neurologic deterioration and vision loss. Although initially steroid-responsive, clinical manifestations frequently recur with corticosteroid taper, requiring the addition of immunosuppressive agents in some cases.

Cohen Y, Nagler A. · Departments of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Ramat-Gan 52621, Israel. · Autoimmun Rev. · Pubmed #15003184 No free full text.

Abstract: Immunological manipulations are the basis of modern therapy for refractory autoimmune diseases (AID). Ablative chemotherapy with stem cell support (autotransplant) as well as targeted immunotherapy using specific monoclonal antibodies, such as rituximab and campath 1-H have become acceptable second line therapy for severe refractory AID. Until now, more than 500 autotransplants have been performed worldwide for various autoimmune disorders, including multiple sclerosis (MS), systemic sclerosis (SSc), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA) with encouraging results, although transplant related mortality (TRM) in the range between 2 and 17% still remains one of the major limitations of the procedure. Immunotherapy is a relatively safe approach associating with sustained remissions in a considerable proportion of treated patients. Better selection of patients and earlier immunotherapy, preceded an irreversible organ damage might further improve the clinical outcome of patients with AID.

Nagler RM, Nagler A. · Department of Oral and Maxillofacial Surgery, Oral Biochemistry Laboratory and Salivary Clinic, Rambam Medical Center, and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. · J Dent Res. · Pubmed #14742644 No free full text.

Abstract: During the past two decades, the involvement of salivary glands in graft vs. host disease (GVHD) had been intensively researched and published. GVHD occurs in 40-70% of patients treated with bone marrow and peripheral blood stem cell transplantation (PBSCT), and improved survival rates have led to a continuously increasing number of GVHD patients suffering from induced salivary insult. Limited studies suggest that a large percentage of GVHD patients is affected and that the induced salivary dysfunction occurs rapidly following the transplantation. It affects both major and minor salivary glands and reflects the severity of the disease. Moreover, profound sialochemical alterations may be diagnostic of GVHD. An additional reason for this vast research is that GVHD, as an autoimmune-like disease, seemed to be an appropriate model for studying a much more prevalent and well-known and well-studied autoimmune disease involving salivary glands: Sjögren's syndrome. The purpose of the current review-which is, to the best of our knowledge, the first of its kind-is to describe the GVHD-related sialometric and sialochemical data published in the past two decades for both major and minor salivary glands and to discuss the pathogenesis and molecular basis of the disease.

Goldring SR. · Beth Israel Deaconess Medical Center, Harvard Medical School, New England Baptist Bone and Joint Institute. Harvard Institutes of Medicine, Boston, MA, USA. · Calcif Tissue Int. · Pubmed #14565589 No free full text.

Abstract: Inflammatory disorders such as rheumatoid arthritis (RA), may have profound effects on skeletal homeostasis. In contrast to physiologic remodeling in which mechanical influences and/or systemic endocrine hormones initiate the remodeling process, in disorders such as RA the recruitment of macrophage lineage cells to sites of inflammation and the action of local osteoclastogenic cytokines associated with the inflammatory process initiate the remodeling process. In both physiologic and pathologic remodeling, osteoclasts appear to be the principal cell type responsible for the bone resorption. In addition, many of the same cytokines and mediators are involved in physiologic and pathologic bone remodeling. These observations have important implications with respect to the development of therapeutic strategies to prevent bone loss in inflammatory conditions.

Gravallese EM. · Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Room 241, 4 Blackfan Circle, Boston, Massachusetts 02115, USA. · J Clin Invest. · Pubmed #12865402 links to  free full text

Abstract: The molecular mechanisms underlying the putative role of osteopontin in the chronic inflammatory disease rheumatoid arthritis are unclear. A study in a murine model of arthritis now demonstrates that a specific antibody directed against the exposed osteopontin epitope SLAYGLR is capable of preventing inflammatory cell infiltration in arthritic joints.

Paran D, Paran H. · Department of Rheumatology, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, Tel-Aviv 64239, Israel. · Curr Opin Investig Drugs. · Pubmed #12833652 No free full text.

Abstract: Somatostatin (SST) is a naturally occurring neuropeptide that has multiple modulatory effects on the immune system and the function of synovial cells, as well as anti-angiogenic, antiproliferative and analgesic properties. These unique and diverse properties make this naturally occurring peptide an attractive candidate for use as a therapeutic agent in immune-mediated diseases, particularly in rheumatoid arthritis (RA). In this disease, proliferation of the synovial membrane, angiogenesis and dysregulated immunological activity lead to joint erosion and destruction. Here we review the postulated modes of action of SST in animal models of inflammation, autoimmunity and RA, as well as in humans. We also discuss the wide distribution of SST and its specific receptors, and the various SST analogs available. Results of a pilot study to evaluate the effect of SST analog treatment in refractory RA is discussed, and future directions for treatment and investigation are suggested.

Abu-Shakra M, Buskila D, Shoenfeld Y. · Autoimmune Rheumatic Diseases Unit and Departments of Medicine B & D, Soroka Medical Center, Beer-Sheva, Israel. · Clin Rev Allergy Immunol. · Pubmed #12794257 No free full text.

Abstract: Osteonecrosis is a clinical entity characterized by death of bone marrow and trabecular bone as a result of disruption of blood supply to the bone (1,2). Other aspects of this condition include avascular necrosis, aseptic necrosis, and osseous ischemic necrosis of bones. Osteonecrosis is classified into two main forms; post-traumatic and nontraumatic. The post-traumatic form of osteonecrosis usually develops as a result of traumatic displacement of bone fragments, which leads to impaired blood supply and ischemia to the affected bone. Osteonecrosis of the femoral head is common following fracture of the femoral neck. A variety of systemic diseases and clinical conditions are associated with nontraumatic osteonecrosis. These include autoimmune rheumatic diseases, alcoholism, pregnancy, Gaucher's disease, thrombophilia, corticosteroid therapy, Sickle-cell anemia, pancreatitis, inflammatory bowel diseases, and use of cytotoxic drugs and others. Idiopathic forms of osteonecrosis have also been reported (2-4). Among the rheumatic diseases, osteonecrosis is strongly associated with systemic lupus erythematosus (SLE) (5). However, osteonecrosis has been diagnosed in patients with primary antiphospholipid syndrome (APS) (6), rheumatoid arthritis (7), and systemic vasculitis (8). This article reviews the causes, clinical and epidemiological features, diagnosis, and treatment options for osteonecrosis among patients with SLE.

Naor D, Nedvetzki S. · Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel. · Arthritis Res Ther. · Pubmed #12723975 links to  free full text

Abstract: CD44 is a multistructural cell-surface glycoprotein that can theoretically generate close to 800 isoforms by differential alternative splicing. At present, several dozen isoforms are known. The polymorphic nature of CD44 might explain its multifunctionality and its ability to interact with many cell-surface and extracellular ligands, the principal one being hyaluronic acid (HA). Of the many CD44 functions, our review focuses on its involvement in cell-cell and cell-matrix interactions, as well as on its implication in the support of cell migration and the presentation of growth factors to their cognate receptors. Cells involved in pathological activities such as cancer cells and destructive inflammatory cells, and also normal cells engaged in physiological functions, use cell-surface CD44 for their localization and expansion at extravascular sites. This article reviews the evidence that the joint synovium of patients with rheumatoid arthritis (RA) contains considerable amounts of various CD44 isoforms as well as the HA ligand. The review also shows that anti-CD44 monoclonal antibody (mAb) directed against constant epitopes, shared by all CD44 isoforms, can markedly reduce the inflammatory activity of arthritis induced by collagen or proteoglycans in mice. Anti-CD44 mAb also interferes with the migration of RA synovial-like fibroblasts in vitro and is able to disturb the destructive interaction between RA synovial-like fibroblasts and the cartilaginous matrix. However, the transition from the experimental model to the patient's bedside is dependent on the ability to target the CD44 of cells engaged in RA pathology, while skipping the CD44 of normal cells.