Rheumatoid Arthritis: Switzerland

Gobelet C, Luthi F, Al-Khodairy AT, Chamberlain MA. · Clinique romande de réadaptation SuvaCare, Sion, Switzerland. · Disabil Rehabil. · Pubmed #17729081 No free full text.

Abstract: This article focuses on work disability and sick leave and their cost; it also discusses the value of vocational rehabilitation programmes in rheumatic conditions such as rheumatoid arthritis, ankylosing spondylitis, hip and knee osteoarthritis. It acknowledges the importance of work not only for the worker who has one of these diseases but also for the public purse. Much can be done to improve the health of the persons and reduce their disability and its impact in the workplace which will have an important effect on their and their family's quality of life. It is important that neither rehabilitation nor vocational rehabilitation are regarded as bolt-on activities after drug treatment but are seen as an integral part of effective management. Publications dealing with return to work are relatively common in rheumatoid arthritis, less common in ankylosing spondylitis and relatively rare in osteoarthritis. Vocational rehabilitation programmes should aim to facilitate job retention or, failing that, to improve the ability to return to work. The process must be started with in the health arena and it has to be recognised that slow or poor practice in the health service can jeopardise the patient's work potential.

Zingg JM. · Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland. · Vitam Horm. · Pubmed #17628183 No free full text.

Abstract: Mast cells play an important role in the immune system by interacting with B and T cells and by releasing several mediators involved in activating other cells. Hyperreactivity of mast cells and their uncontrolled accumulation in tissues lead to increased release of inflammatory mediators contributing to the pathogenesis of several diseases such as rheumatoid arthritis, atherosclerosis, multiple sclerosis, and allergic disorders such as asthma and allergic rhinitis. Interference with mast cell proliferation, survival, degranulation, and migration by synthetic or natural compounds may represent a preventive strategy for the management of these diseases. Natural vitamin E covers a group of eight analogues-the alpha-, beta-, gamma-, and delta-tocopherols and the alpha-, beta-, gamma-, and delta-tocotrienols, but only alpha-tocopherol is efficiently retained by the liver and distributed to peripheral tissues. Mast cells preferentially locate in the proximity of tissues that interface with the external environment (the epithelial surface of the skin, the gastrointestinal mucosa, and the respiratory system), what may render them accessible to treatments with inefficiently retained natural vitamin E analogues and synthetic derivatives. In addition to scavenging free radicals, the natural vitamin E analogues differently modulate signal transduction and gene expression in several cell lines; in mast cells, protein kinase C, protein phosphatase 2A, and protein kinase B are affected by vitamin E, leading to the modulation of proliferation, apoptosis, secretion, and migration. In this chapter, the possibility that vitamin E can prevent diseases with mast cells involvement by modulating signal transduction and gene expression is evaluated.

Ostensen M, Villiger PM. · Clinic for Rheumatology and Clinical Immunology, University Hospital of Berne, CH-3010 Bern, Switzerland. · Semin Immunopathol. · Pubmed #17621703 No free full text.

Abstract: Rheumatoid arthritis (RA) is an autoimmune disease that is favorably influenced by pregnancy but relapses after delivery. A variety of circulating factors has been considered as candidates for inducing gestational improvement of RA; however, the factors/pathways responsible remain still elusive. This review discusses recent research on the effect of pregnancy on RA with a focus on immunregulation, cytokine secretion, HLA antigens, microchimerism, and innate immunity. The complex hormonal and immunological alterations of pregnancy may temporarily correct the disturbed immunregulation of RA.

Østensen M, Motta M. · Center for Women with Rheumatic Disease, Department of Rheumatology, University Hospital of Bern, Bern, Switzerland. · Nat Clin Pract Rheumatol. · Pubmed #17599074 No free full text.

Abstract: In 90% of cases, women with rheumatoid arthritis suffer a disease flare within 3 months of delivery of their baby. Drug treatment is, therefore, required; however, such therapies have implications for mothers who decide to nurse their infants. Unfortunately, because of a paucity of data, little is known about the transfer of antirheumatic drugs into breast milk, and even less is known about whether small amounts of these agents ingested during nursing could harm the infant. Our review of the literature indicates that paracetamol, prednisone, antimalarial agents, sulfasalazine and most NSAIDs can safely be used by lactating mothers. Expert opinions differ regarding the use of azathioprine, ciclosporin, and methotrexate during lactation because of varying views on the potential for short-term and long-term adverse effects. Evidence regarding the transfer of leflunomide and biologic drugs into breast milk is insufficient; therefore, until more studies are conducted, the use of these drugs in breastfeeding mothers should be restricted. At present, many patients feel they have to choose between postpartum disease control and lactation. Extended studies of the transfer of antirheumatic drugs into breast milk and the resulting consequences are, therefore, urgently needed.

Ospelt C, Gay S. · University Hospital Zürich, Center of Experimental Rheumatology, Gloriastrasse 23, Zürich, CH-8091, Switzerland. · Curr Opin Investig Drugs. · Pubmed #17520867 No free full text.

Abstract: Rheumatoid arthritis is a chronic autoimmune disease involving progressive destruction of the joints. Although a variety of antirheumatic drugs are in use, they usually only slow, and not halt, disease progression, or reverse the damage to cartilage and bone. Furthermore, treatment has to be discontinued in some cases due to toxicity and/or lack of response. By analyzing the whole transcriptome of a cell or tissue with microarray technology, a newo way of identifying treatments and discovering more about the mechanisms of known drugs has become available. This review discusses the strengths and weaknesses of microarray technology and gives an overview of gene expression studies currently performed in the field of antiheumatic therapies.

Gutcher I, Becher B. · Neuroimmunology Unit, Neurology Clinic, University of Zurich, Y44J7 Winterthurerstrasse 190, Zurich 8057, Switzerland. · J Clin Invest. · Pubmed #17476341 links to  free full text

Abstract: T cell-mediated autoimmune diseases such as multiple sclerosis and rheumatoid arthritis are driven by autoaggressive Th cells. The pathogenicity of such Th cells has, in the past, been considered to be dictated by their cytokine polarization profile. The polarization of such effector T cells relies critically upon the actions of cytokines secreted by APCs. While Th1 polarization has long been associated with the pathogenesis of autoimmune diseases, recent data obtained in gene-targeted mice and the discovery of Th17 cell involvement in autoimmunity conflict with this hypothesis. In light of these recent developments, we discuss in this review the actions of APC-derived cytokines and their emerging roles in T cell polarization in the context of autoimmune inflammatory responses.

Rommel C, Camps M, Ji H. · Merck Serono International S.A., 9 Chemin des Mines, 1211 Geneva, Switzerland. · Nat Rev Immunol. · Pubmed #17290298 No free full text.

Abstract: Dysregulated signal transduction in innate and adaptive immune cells is known to be associated with the development of various autoimmune and inflammatory diseases. Consequently, targeting intracellular signalling of the pro-inflammatory cytokine network heralds hope for the next generation of anti-inflammatory drugs. Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second messengers that control an array of intracellular signalling pathways that are known to have important roles in leukocytes. In light of the recent progress in the development of selective PI3K inhibitors, and the beneficial effects of these inhibitors in models of acute and chronic inflammatory disorders, we discuss the therapeutic potential of blocking PI3K isoforms for the treatment of rheumatoid arthritis and other immune-mediated diseases.

Tyndall A, Walker UA, Cope A, Dazzi F, De Bari C, Fibbe W, Guiducci S, Jones S, Jorgensen C, Le Blanc K, Luyten F, McGonagle D, Martin I, Bocelli-Tyndall C, Pennesi G, Pistoia V, Pitzalis C, Uccelli A, Wulffraat N, Feldmann M. · Rheumatology, University Hospital Basel, Felix Platter Spital, Burgfelderstrasse 101, Basel, CH-4012, Switzerland. · Arthritis Res Ther. · Pubmed #17284303 links to  free full text

Abstract: Multipotent mesenchymal stromal cells isolated from bone marrow and other sites are currently being studied to determine their potential role in the pathogenesis and/or management of autoimmune diseases. In vitro studies have shown that they exhibit a dose-dependent antiproliferative effect on T and B lymphocytes, dendritic cells, natural killer cells and various B cell tumour lines--an effect that is both cell contact and soluble factor dependent. Animal models of autoimmune disease treated with multipotent mesenchymal stromal cells have mostly exhibited a positive clinical response, as have a limited number of patients suffering from acute graft versus host disease. This review summarizes the findings of a 1-day meeting devoted to the subject with the aim of coordinating efforts.

Naumann UK, Käser L, Vetter W. · Medizinische Poliklinik Universitätsspital Zürich, Zürich. · Praxis (Bern 1994). · Pubmed #17136826 No free full text.

This publication has no abstract.

Genta MS, Genta RM, Gabay C. · Division of Rheumatology, Geneva University Hospitals, Geneva, Switzerland. · Semin Arthritis Rheum. · Pubmed #17023257 No free full text.

Abstract: OBJECTIVES: To review the most recent information on the incidence, clinical course, pathology, pathogenesis, diagnosis, and treatment of rheumatoid vasculitis (RV), including the still scanty data on the use of biologics. METHODS: PubMed and MEDLINE databases (1950-2006) were searched for the key words "vasculitis" and "rheumatoid arthritis"; and "rheumatoid arthritis" and "extra-articular manifestations." All relevant articles in English and French were reviewed. Additional words used in follow-up research include "anti-TNF," "rituximab," "IL-1 receptor antagonists," and "CTLA-4 Ig," all in conjunction with "vasculitis." Pertinent secondary references were also retrieved. RESULTS: RV is an inflammatory condition of the small- and medium-sized vessels that affects a subset of patients with established rheumatoid arthritis (RA) (approximately 1 to approximately 5%). It has a vast array of clinical manifestations with a predilection for the skin (peripheral gangrene, deep cutaneous ulcers) and the peripheral nervous system (mononeuritis multiplex). Because of the lack of specific signs and symptoms, the diagnosis relies on the exclusion of other causes of similar lesions (diabetes, atherosclerosis, drug reactions, infection, neoplasias) and, ideally, on the histopathological demonstration of necrotizing vasculitis. Despite the availability of a host of promising new drugs for the treatment of RA, no clinical trials have tested their efficacy in RV; therefore, its management remains largely empirical. CONCLUSIONS: Although RV has apparently been decreasing over the last 2 decades, possibly as a consequence of the more energetic approach to the management of RA currently used, it remains an important complication of RA that needs to be promptly recognized and treated.

Burger D, Dayer JM, Palmer G, Gabay C. · Clinical Immunology Unit, Division of Immunology and Allergy, Department of Internal Medicine, University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. · Best Pract Res Clin Rheumatol. · Pubmed #16980212 No free full text.

Abstract: Inflammation is an important homeostatic mechanism that limits the effects of infectious agents. However, inflammation might be self-damaging and therefore has to be tightly controlled or even abolished by the organism. Interleukin 1 (IL-1) is a crucial mediator of the inflammatory response, playing an important part in the body's natural responses and the development of pathological conditions leading to chronic inflammation. While IL-1 production may be decreased or its effects limited by so-called anti-inflammatory cytokines, in vitro IL-1 inflammatory effects are inhibited and can be abolished by one particularly powerful inhibitor, IL-1 receptor antagonist (IL-1Ra). Recent research has shown that in the processes of rheumatoid arthritis (RA) IL-1 is one of the pivotal cytokines in initiating disease, and IL-1Ra has been shown conclusively to block its effects. In laboratory and animal studies the inhibition of IL-1 by either antibodies to IL-1 or IL-1Ra proved beneficial to the outcome. Because of its beneficial effects in many animal disease models, IL-1Ra has been used as a therapeutic agent in human patients. The recombinant form of IL-1Ra, anakinra (Kineret, Amgen) failed to show beneficial effects in septic shock and displays weak effects in RA patients. However, IL-1 blockade by anakinra is dramatically effective in systemic-onset juvenile idiopathic arthritis, in adult Still's disease and in several autoinflammatory disorders, most of the latter being caused by mutations of proteins controlling IL-1beta secretion. Importantly, to be efficacious, anakinra required daily injections, suggesting that administered IL-1Ra displays very short-term effects. Better IL-1 antagonists are in the process of being developed.

Persson GR. · Department of Periodontology and Fixed Prosthodontics, School of Dental Medicine, Berne, Switzerland. · Int Dent J. · Pubmed #16972399 No free full text.

Abstract: Periodontitis is a multi-factorial disease and in most cases also a disease with a chronic progression. Exposure to factors which contribute to periodontitis occurs over a long period, so that at the time of diagnosis it may be difficult to identify and evaluate what co-factors have contributed to its development. These include exposure to bacteria and viruses, inflammation, genetic factors, health behaviours and a variety of social factors, socio-economic status, behavioural and nutritional habits, the ability to cope with stress and the ability of the immune system to fight infections. Many patients in their 50s also experience other conditions such as heart disease, diabetes mellitus, or rheumatoid arthritis and recent reports on the associations and potential biological mechanisms by which periodontitis can be linked to other systemic diseases suggest that the patient with periodontitis is a challenged individual. Neither individuals nor their oral health care providers are currently prepared for the challenges in oral health care as the expectation of successful ageing with remaining and aesthetically functional teeth is increasing. The scientific evidence is, however, growing, and while the opportunities to prepare for successful ageing exist they must be included in the educational process of both current and future oral health care providers and their patients.

Moritz F, Distler O, Ospelt C, Gay RE, Gay S. · Center of Experimental Rheumatology, Department of Rheumatology, University of Zurich, Switzerland. · Nat Clin Pract Rheumatol. · Pubmed #16932675 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by systemic inflammation and joint destruction. Novel therapies have emerged during the past decade, marking a new era in the treatment of RA. Meanwhile, in vivo and in vitro gene-transfer studies have provided valuable insights into mechanisms of disease pathogenesis. Advanced gene-delivery techniques and animal models promise further progress in RA research and the development of novel therapeutic strategies for this disease. In this article we provide an overview of the wide spectrum of potential targets that have been identified so far, discuss currently available gene-transfer methods, and outline the barriers that need to be overcome for these approaches to be successfully applied in daily practice.

Steffens S, Mach F. · Division of Cardiology, Department of Medicine, University Hospital, Foundation for Medical Research, Geneva, Switzerland. · Nat Clin Pract Nephrol. · Pubmed #16932466 No free full text.

Abstract: Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A reductase, an enzyme crucial to cholesterol synthesis. Drugs of this class reduce the risk of coronary heart disease and stroke, in large part through lipid modulation. Emerging evidence indicates that statins have additional modes of action. These actions, which encompass modification of endothelial function, plaque stability, thrombus formation and inflammatory pathways, are widely referred to as 'pleiotropic effects'. These pleiotropic effects indicate that the therapeutic potential of statins might extend beyond cholesterol lowering and cardiovascular disease to other inflammatory disorders or conditions such as transplantation, multiple sclerosis, rheumatoid arthritis and chronic kidney disease. Experimental and clinical data provide evidence to support these broader applications of statins; however, more large-scale trials are needed to clarify the therapeutic benefit.

Gabay C. · Division of Rheumatology, University Hospital of Geneva, Switzerland. · Arthritis Res Ther. · Pubmed #16899107 No free full text.

Abstract: Interleukin (IL)-6 is produced at the site of inflammation and plays a key role in the acute phase response as defined by a variety of clinical and biological features such as the production of acute phase proteins. IL-6 in combination with its soluble receptor sIL-6Ralpha, dictates the transition from acute to chonic inflammation by changing the nature of leucocyte infiltrate (from polymorphonuclear neutrophils to monocyte/macrophages). In addition, IL-6 exerts stimulatory effects on T- and B-cells, thus favoring chronic inflammatory responses. Strategies targeting IL-6 and IL-6 signaling led to effective prevention and treatment of models of rheumatoid arthritis and other chronic inflammatory diseases.

Østensen M, Förger F, Villiger PM. · Department of Rheumatology and Clinical Immunology and Allergy, University Hospital, CH-3010 Bern, Switzerland. · Ann N Y Acad Sci. · Pubmed #16855162 No free full text.

Abstract: Cytokines are important mediators involved in the successful outcome of pregnancy. The concept of pregnancy as biased toward a Th2 immune response states that Th1 type cytokines are associated with pregnancy failure and that Th2 cytokines are protective and counteract pregnancy-related disorders. Studies at the level of the maternal-fetal interface, in the maternal circulation and in cells of peripheral blood have shown that the Th2 concept of pregnancy is an oversimplification. Both Th1 and Th2 type cytokines play a role at different stages of pregnancy and are adapted to the localization and function of cells and tissues. The changes of local and systemic cytokine patterns during pregnancy correspond to neuroendocrine changes with hormones as powerful modulators of cytokine expression. Several autoimmune disorders show a modulation of disease activity during and after pregnancy. In rheumatic diseases with a predominance of a Th1 immune response, a shift to a Th2 type immune response during pregnancy has been regarded as beneficial. Studies of pregnant patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have shown a cytokine expression similar to that found in healthy pregnant women. Significant differences were present only for a few cytokines and seemed related to the activity of the underlying disease. Interestingly, a gestational increase of cytokine inhibitors interleukin 1 receptor antagonist (IL-1ra) and soluble tumor necrosis factor receptor (sTNFR) in the circulation corresponded to low disease activity in RA. The influence of hormones and cytokines on autoimmune disease is an issue for further study.

Karouzakis E, Neidhart M, Gay RE, Gay S. · Center of Experimental Rheumatology, University Hospital Zurich, Switzerland. · Immunol Lett. · Pubmed #16824621 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with joint destruction. Synovial fibroblasts are key players in this pathological process. They favorise a pro-inflammatory environment in the synovial tissue, interact with the immune system and regulate the differentiation of monocytes into osteoclasts. Synovial hyperplasia is another characteristic of RA, reflecting not only an imbalance between proliferation and apoptosis, but also the migration of cells into the synovial tissue. Gene transfer experiments have been used as important tools for the understanding of molecular and cellular changes that characterize the activated RA synovial fibroblasts. Activated synovial fibroblasts can invade cartilage and bone. Synovial activation is driven by cytokines, such as TNFalpha and IL-1, as well as IL-15, 16, 17, 18, 22, 23, but also by cytokine-independent mechanisms that involve the innate immune system (i.e. TLRs), a unique communication network of microparticles and epigenetic changes (e.g. L1 retroelements).

Hermann M. · Department of Cardiology, University Hospital Zürich, Zürich, Switzerland. · J Cardiovasc Pharmacol. · Pubmed #16785825 No free full text.

Abstract: Nitric oxide (NO) is a simple but pluripotent molecule that is mainly released from vascular endothelial cells where it is formed intracellularly by nitric oxide synthase from L-arginine in response to several stimuli, including shear stress or muscarinic receptor stimulation. NO stimulates guanylyl cyclase to form cyclic guanosine monophosphate, which results in relaxation and vasodilatation of vascular smooth muscle cells (VSMCs). In addition, NO prevents adhesion and aggregation of platelets, and it possesses anti-inflammatory, antiproliferative, and antimigratory effects on leukocytes, endothelial cells, and VSMCs, thus offering protection from atherosclerosis. Dysfunction of the vascular endothelium has been documented in most conditions that promote or are associated with atherosclerosis and is characterized by a reduced bioavailability of NO. The healthy endothelium prevents adhesion and migration of leukocytes, proliferation of VSMCs, and platelet adhesion and aggregation. Maintaining the balance of blood flow and thrombus formation is also a major task of the vascular endothelium. It has been shown that both NO and prostacyclin, a cyclooxygenase-derived relaxing factor, inhibit activation of platelets and regulate vasomotion. Reduced NO and prostacyclin levels can result in endothelial dysfunction, which is recognized as the first step in the atherogenic process. It is of note that chronic inflammation conditions, such as rheumatoid arthritis, are associated with endothelial dysfunction. The reduced NO bioavailability may therefore explain the increased risk for cardiovascular events in patients with chronic low-grade inflammation, such as rheumatoid arthritis and osteoarthritis. Thus, this article provides an overview of the impact of inflammation and anti-inflammatory treatment with cyclooxygenase inhibitors on endothelial function.

van Laar JM, Tyndall A. · Department of Rheumatology, University of Basel, Felix Platter Spital, Burgfelderstrasse 101, Basel 4012, Switzerland. · Rheumatology (Oxford). · Pubmed #16777856 links to  free full text

Abstract: During the past 10 yrs, over 700 patients suffering from severe autoimmune disease (AD) have received an autologous haematopoietic stem cell transplant as treatment of their disorder with durable remission being obtained in around one-third. The most commonly transplanted ADs have been systemic sclerosis (scleroderma), multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis and systemic lupus erythematosus. A fewer number of patients have received an allogeneic transplant. The initially reported overall treatment-related mortality of 7% has since fallen, with no further cases being reported in systemic sclerosis or multiple sclerosis in the past 3 yrs. This is thought to be due to more careful patient selection.The phase I/II data has led to currently running prospective randomised trials in systemic sclerosis, multiple sclerosis and systemic lupus erythematosus in Europe and North America. Immune reconstitution data suggests a 'resetting' of autoimmunity in those patients achieving stable remission, rather than simply prolonged immunosuppression. Recent results from in vitro experiments, animal models and early human experience in severe acute graft vs host disease suggest that multipotent mesenchymal stromal cells obtained from the bone marrow and expanded ex vivo, may exert a clinically useful immunomodulatory effect. Such cells are immune privileged and apparently of low toxicity. Further characterization of these cells and consideration of their possible clinical application in AD is underway.

Hasler P. · Rheumaklinik, Kantonsspital Aarau, Tellstrasse, 5001 Aarau, Switzerland. · Springer Semin Immunopathol. · Pubmed #16738955 No free full text.

Abstract: Among the cells of the immune system involved in the pathogenesis of autoimmune disease, T cells have received the most attention. The central role of these cells in several animal models of autoimmune diseases and in human disease counterparts has provided the rationale for specific therapeutic targeting of T cell subsets, especially CD4 T cells. So far, the applicability of this approach has not been clearly evident in clinical trials, which was also the case when nondepleting "coating" anti-CD4 monoclonal antibodies was used. In the past several years, experimental evidence supporting a major role of B cells in systemic autoimmune disease has grown. This includes the pathogenicity of certain autoantibodies, the potential of B cells to present antigen in the context of MHC Class II and to signal via costimulatory molecules, and to secrete proinflammatory cytokines. In some instances, engagement of the B cell receptor and other surface receptors is sufficient to stimulate B cells to produce antibodies. The depletion of B cells by targeting the surface marker CD20 has been shown to be effective in treating rheumatoid arthritis with a good side effect profile. Series of cases with other systemic autoimmune diseases indicate that this strategy may be effective in these conditions too. The clinical data add weight to the importance of B cells in the pathogenesis of autoimmune diseases.

Möller B, Villiger PM. · Inselspital Bern, Klinik für Rheumatologie und Klinische Immunologie/Allergologie, CH-3010 Bern, Switzerland. · Springer Semin Immunopathol. · Pubmed #16738952 No free full text.

Abstract: Blockade of cytokines, particularly of tumour necrosis factor alpha (TNF-alpha), in immuno-inflammatory diseases, has led to the greatest advances in medicine of recent years. We did a thorough review of the literature with a focus on inflammation models in rodents on modified gene expression or bioactivity for IL-1, IL-6, and TNF-alpha, and we summarized the results of randomized controlled clinical trials in human disease. What we have learned herewith is that important information can be achieved by the use of animal models in complex, immune-mediated diseases. However, a clear ranking for putative therapeutic targets appears difficult to obtain from an experimental approach alone. This is primarily due to the fact that none of the disease models has proven to cover more than one crucial pathogenetic aspect of the complex cascade of events leading to characteristic clinical disease signs and symptoms. This supports the notion that the addressed human immune-mediated diseases are polygenic and the summation of genetic, perhaps epigenetic, and environmental factors. Nevertheless, it has become apparent, so far, that TNF-alpha is of crucial importance in the development of antigen-dependent and antigen-independent models of inflammation, and that these results correlate well with clinical success. With some delay, clinical trials in conditions having some relationship with rheumatoid arthritis (RA) indicate new opportunities for blocking IL-1 or IL-6 therapeutically. It appears, therefore, that a translational approach with critical, mutual reflection of simultaneously performed experiments and clinical trials is important for rapid identification of new targets and development of novel treatment options in complex, immune-mediated, inflammatory diseases.

Chiavaroli C, Moore A. · Preclinical Development, OM PHARMA, Meyrin/Geneva, Switzerland. · BioDrugs. · Pubmed #16724862 No free full text.

Abstract: Extracts of lysed pathogenic bacteria were developed approximately 4 decades ago as oral vaccines in order to stimulate efficient specific immune and proinflammatory responses in patients experiencing recurrent infections, the ultimate aim being to rid the patient of the pathogen responsible for the infections. OM-89, a lysate of Escherichia coli, is clinically effective in patients who experience recurrent urinary tract infections by activating both innate and adaptive immunity. If immune activation is necessary to combat infectious pathogens, it may appear at first sight to be detrimental in patients with autoimmune diseases. However, OM-89 has also shown clear efficacy in patients with rheumatoid arthritis or with undifferentiated spondyloarthropathies, probably through oral tolerance and the long-term activation of regulatory cells. These phenomena may be explained by a hypothesis that immune exclusion and oral tolerance, both key functions of the gut, may be boosted by adjuvant-like molecules within orally administered OM-89.

Melchers F, Rolink AR. · Department of Cell Biology, Biozentrum, University of Basel, Switzerland. · Curr Top Microbiol Immunol. · Pubmed #16724798 No free full text.

Abstract: A series of checkpoints for antigen receptor fitness and specificity during B cell development ensures the elimination or anergy of primary, high-avidity-autoantigen-reactive B cells. Defects in genes encoding molecules with which this purging of the original B cell repertoires is achieved may break this B cell tolerance, allowing the development of B cell- and autoantibody-mediated immune diseases. Furthermore, whenever tolerance of helper T cells to a part of an autoantigen is broken, a T cell-dependent germinal center-type response of the remaining low--or no--autoreactive B cells is activated. It induces longevity of these B cells, and expression of AiD, which effects Ig class switching and IgV-region hypermutation. The development of V-region-mutant B cells and the selections of high-avidity-autoantigen-reactive antibodies producing B cells by autoantigens from them, again, can lead to the development and propagation of autoimmune diseases such as lupus erythematosus or chronic inflammatory rheumatoid arthritis by the autoantibody BcR-expressing B cells and their secreted autoantibodies.

Rutishauser J. · Innere Medizin B, Universitätsspital, Basel, Switzerland. · Swiss Med Wkly. · Pubmed #16633945 links to  free full text

Abstract: In the past years, statins have emerged as the most important class of lipid lowering agents. Through inhibition of HMG-CoA reductase, they restrict the rate-limiting step of cholesterol synthesis, which leads to upregulation of LDL receptors on the cell membrane and thus reduction of atherogenic LDLs. This effect translates into clinical benefit by reducing cardiovascular events both in primary and secondary prevention settings. As an approximate rule, statin therapy leads to a relative risk reduction of 25-30% in most of the large randomised controlled trials. Stroke risk is reduced to a similar degree. Despite initial concerns, the currently available statins have a favourable safety profile; however, potential interactions with other drugs must be considered. Recently, characteristics unrelated to LDL lowering have been intensively studied. These pleiotropic statin effects result from decreased levels of isoprenoid intermediates of cholesterol synthesis. They include--among others--anti-inflammatory, anti-proliferative, and immunomodulatory actions. Pleiotropic effects favourably influence pathomechanisms of plaque formation. Furthermore, they may prove beneficial in the prevention or treatment of diseases unrelated to atherosclerosis, eg rheumatoid arthritis, multiple sclerosis, or cancer.

Van Delden C. · Service des maladies infectieuses, Département de médecine, HUG, 1211 Genève 14. · Rev Med Suisse. · Pubmed #16604876 No free full text.

Abstract: Corticosteroids and cytotoxic drugs form the conventional immunomodulators in rheumatology. This therapeutic arsenal has recently been widened by TNF-alpha antagonists and other anti-cytokines. If rheumatoid arthritis is itself associated with infections, immunomodulating therapies further increase the risk of infection, especially when used in combination therapies. Among conventional therapies, corticosteroids are associated with the highest risk for both common bacterial and opportunistic infections. Infliximab is the TNF-alpha antagonist associated with the highest risk of infection. Its use has been particularly associated with cases of severe tuberculosis. All patients at risk for tuberculosis, treated with corticosteroids or TNF-alpha antagonists, should therefore receive an adequate prophylaxis.