Rheumatoid Arthritis: Switzerland

Loetscher P, Moser B. · Theodor-Kocher Institute, University of Bern, Switzerland. · Arthritis Res. · Pubmed #12106492 links to  free full text

Abstract: In about 20% of patients with rheumatoid arthritis, B and T lymphocytes recruited into the inflamed synovium are organized into complex microstructures, which resemble secondary lymphoid organs. The development of such lymphoid aggregates with germinal centers appears to contribute to the pathogenesis of the disease. Growing evidence indicates that chemokines and their receptors control the recruitment and positioning of leukocytes as well as their organization into node-like lymphoid structures. Here, we comment on recent studies highlighting the importance of chemokines in rheumatoid arthritis, in particular of B-cell-activating chemokine-1 in lymphoid neogenesis in the inflamed synovium.

Karouzakis E, Gay RE, Gay S, Neidhart M. · Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland. · Nat Rev Rheumatol. · Pubmed #19412193 No free full text.

Abstract: Rheumatoid arthritis synovial fibroblasts (RASFs) are the effector cells of cartilage and bone destruction. These cells show an 'intrinsically' activated and aggressive phenotype that results in the increased production of matrix-degrading enzymes and adhesion molecules, and is conserved over long-term passage in vitro. The three main mechanisms of epigenetic control -- DNA methylation, histone modifications and microRNA activity -- interact in the development of the RASF phenotype. The extent of global DNA methylation is reduced in synoviocytes in situ and RASFs in vitro. In addition, histone hyperacetylation occurs and specific microRNAs are expressed in RASFs. Normal synovial fibroblasts cultured in a hypomethylating milieu acquire an activated phenotype similar to that of RASFs. These findings suggest that epigenetic control, in particular the control of DNA methylation, is deficient in RASFs. Genome-wide analyses of the epigenome will enable the detection of additional genes involved in the pathogenesis of rheumatoid arthritis, the identification of epigenetic biomarkers, and potentially the development of a therapeutic regimen that targets activated RASFs.

Villiger PM, Zellweger JP, Möller B. · Department of Rheumatology and Clinical Immunology/Allergology, University Hospital, University of Bern CH-3010, Switzerland. · Curr Opin Rheumatol. · Pubmed #19346950 No free full text.

Abstract: PURPOSE OF REVIEW: Therapeutic inhibition of tumour necrosis factor-alpha strongly increases the risk of reactivation in latent tuberculosis infection. Recent blood tests based on antigen-specific T cell response and measuring production of interferon-gamma, so called interferon-gamma release assays (IGRAs), are promising novel tools to identify infected patients. The performance of diagnostic testing for latent tuberculosis infection in patients with rheumatic diseases will be discussed. RECENT FINDINGS: In patients with rheumatoid arthritis, IGRAs are more sensitive and more specific than traditional tuberculin skin testing. They are unaffected by Bacillus-Calmette-Guérin vaccination and most nontuberculous mycobacteria. Most comparative studies show a better performance of the IGRAs than tuberculin skin testing in terms of a higher specificity. The rate of indeterminate results may be affected by glucocorticoids and the underlying disease but appears independent of disease-modifying antirheumatic drugs. Despite using identical Mycobacterium tuberculosis antigens, the two commercially available tests show differences in clinical performance. SUMMARY: The current information about the performance of the tuberculin skin testing and the IGRAs in the detection of latent tuberculosis infection in patients with rheumatic diseases strongly suggest a clinically relevant advantage of the IGRAs. Their use will help to reduce overuse and underuse of preventive treatment in tumour necrosis factor inhibition.

Finckh A. · Department of Internal Medicine, Geneva University Hospital, Switzerland. · Curr Opin Rheumatol. · Pubmed #19339921 No free full text.

Abstract: PURPOSE OF REVIEW: Rheumatoid arthritis (RA) has started to be perceived as a potentially curable condition with early, aggressive use of disease-modifying antirheumatic drugs. We review the pathophysiological concepts of RA development, the technological advances used to estimate the individual risk of progression to RA, and the impact of antirheumatic therapy for patients presenting with early inflammatory arthritis. RECENT FINDINGS: The finding of a strong gene-environment interaction has modified our concepts of RA pathogenesis and opened new opportunities for disease prevention and therapeutic interventions. Anticyclic citrullinated antibodies and prediction rules have improved our ability to estimate the risk of progression to RA in individual patients presenting with early inflammatory arthritis. In patients at high risk of developing RA, results from trials suggest that treating these patients with potent antirheumatic therapies may slow the progression from early inflammatory arthritis to definite RA and inhibit the progression of joint damage. SUMMARY: Early inflammatory arthritis is a critical period of the disease, during which therapy may have a durable effect and change the natural course of the condition. Physicians need to assess the individual risk of progression to RA in patients presenting with early inflammatory arthritis and consider initiating early disease-modifying antirheumatic drug therapy in patients at high risk of developing RA.

Münz C, Lünemann JD, Getts MT, Miller SD. · Viral Immunobiology, Institute of Experimental Immunology, University Hospital Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. · Nat Rev Immunol. · Pubmed #19319143 No free full text.

Abstract: The predisposition of individuals to several common autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, is genetically linked to certain human MHC class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins, as well as the geographical distribution of disease risk, suggest the involvement of environmental factors in the development of these diseases. Among these environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. In this Review, we outline the mechanisms by which viral infection can trigger autoimmune disease and describe the pathways by which infection and immune control of infectious disease might be dysregulated during autoimmunity.

Crevoisier X, Assal M. · Service de chirurgie orthopedique et traumatologie, · Rev Med Suisse. · Pubmed #19160638 No free full text.

Abstract: Surgery of the rheumatoid foot and ankle Initial presentation of rheumatoid arthritis (RA) will be foot and ankle symptoms in 20% of cases. Eventually, 50-90% of patients will develop foot and ankle alterations. Typical deformities of the forefoot include hallux valgus and dorso-lateral dislocation of the lesser metatarso-phalangeal joints. RA involvement of the hindfoot frequently leads to plano-valgus deformity. Approximately 20% of surgery performed for RA is done at the foot and ankle. Early surgery is efficient against pain and deformity. Patient's satisfaction rate after surgery is high despite a slight higher complication rate compared to conventional foot and ankle surgery.

Doepfner KT, Boller D, De Laurentiis A, Guerreiro AS, Marinov M, Arcaro A. · Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland. · Recent Pat DNA Gene Seq. · Pubmed #19075915 No free full text.

Abstract: Phosphoinositide 3-kinases (PI3Ks) play an essential role in the signal transduction events initiated by the binding of extracellular signals to their cell surface receptors. There are eight known PI3Ks in humans, which have been subdivided into three classes (I-III). The class I(A) of PI3K comprises the p110alpha, p110beta and p110delta isoforms, which associate with receptor tyrosine kinases (RTKs). On the other hand, the class I(B) PI3K p110gamma is regulated by G-protein-coupled receptors (GPCRs). Gene targeting studies in mice have revealed specific biological functions for the class I(A) p110delta in lymphocyte activation, and the class I(B) p110gamma in inflammatory cell responses. In human cancer, recent reports have described activating mutations in the PIK3CA gene encoding p110alpha, and inactivating mutations in the PTEN gene, a tumor suppressor and antagonist of the PI3K pathway. Thus, individual PI3K isoforms are potential drug targets for a variety of human diseases, including allergies, cancer, rheumatoid arthritis and arterial thrombosis. In this review, we will discuss recent patents relating to class I PI3Ks, including patents on the cDNA sequences of p110gamma and p110delta. Moreover, we will review patents on novel pharmacological PI3K inhibitors and on methods of manipulating T cell responses through PI3K.

Sprott H. · Rheumaklinik und Institut für Physikalische Medizin, UniversitätsSpital Zürich, Gloriastr. 25, 8091, Zürich, Schweiz. · Z Rheumatol. · Pubmed #19002472 No free full text.

Abstract: Joint pain is one of the most common forms of pain and is experienced by almost a third of the population at some time. To date, it has not been possible to treat joint pain effectively and side effects of commonly prescribed drugs are often hazardous. Therefore, improvements in our understanding of causes and mechanisms associated with joint pain are required. Joints and their neighbouring structures are well endowed with nerve fibres which respond to mechanical stimuli. Following local inflammation, the activation threshold of these afferent nerve fibres is significantly decreased, such that even low level stimuli encode nociception.Currently, there is a lack about local mechanisms in synovial tissue. Various receptors, well known from the nervous system, are increasingly being detected in synovial fibroblasts. However, little is known about their function. Innovative new therapies are expected to emerge by targeting various receptors, e.g. the TRPV1- or the P(2)X(4) receptor system.

Montecucco F, Mach F. · Division of Cardiology, Department of Medicine, Geneva University Hospital, Foundation for Medical Researches, Geneva, Switzerland. · Rheumatology (Oxford). · Pubmed #18927189 No free full text.

Abstract: RA is characterized by a systemic inflammatory state, in which immune cells and soluble mediators play a crucial role. These inflammatory processes resemble those in other chronic inflammatory diseases, such as atherosclerosis. The chronic systemic inflammation in RA can be considered as an independent risk factor for the development of atherosclerosis, and represents an important field to investigate the reasons of the increase of acute cardiovascular events in RA. In the present review, we focused on several mediators of autoimmunity, inflammation and endothelial dysfunction, which can be considered the most promising targets to prevent atherogenesis in RA. Among several mediators, the pro-inflammatory cytokine TNF-alpha has been shown as a crucial factor to induce atherosclerosis in RA patients.

Finke D, Schmutz S. · Developmental Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. · Swiss Med Wkly. · Pubmed #18792823 links to  free full text

Abstract: Chronic inflammatory diseases such as rheumatoid arthritis (RA) are associated with the de novo formation of organised lymphoid tissue in a subpopulation of patients. The aberrant expression of cytokines and chemokines by stromal cells plays an important role in recruitment and survival of effector cells of the immune system and the development of ectopic tertiary lymphoid organs (TLOs). TLOs may promote the persistence of inflammation and the recognition of self antigens. Recent studies in man and mice now indicate that interleukin 7 (IL-7) is implicated in the formation of TLOs and progression of chronic inflammation.

van Laar JM, Tyndall A. · Department of Rheumatology, Felix-Platter Spital, University of Basel, Burgfelderstrasse 101, Basel 4012 Switzerland. · Curr Rheumatol Rep. · Pubmed #18638426 No free full text.

Abstract: Cell-based therapies bear promise as a means to dampen autoaggressive immune reactions and induce tolerance in patients with severe rheumatic autoimmune diseases. Of the various types of cell-based therapies, immunoablative treatment combined with autologous hematopoietic stem cell transplantation has been used in more than 1000 patients with severe autoimmune diseases worldwide, including patients with rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, and systemic sclerosis. Long-term improvements of disease activity have been documented, albeit at the expense of treatment-related toxicity and mortality. Based on the results of pilot studies, prospective randomized controlled trials have been initiated to compare safety and efficacy of hematopoietic stem cell transplantation versus conventional treatment. Therapies involving mesenchymal stromal cells are currently being explored in clinical settings because of their anti-inflammatory and tissue regenerative properties and their favorable risk/benefit ratio.

Ribi C. · Service d'immunologie et allergologie, Département de médecine interne, HUG, 1211 Geneve 14. · Rev Med Suisse. · Pubmed #18557533 No free full text.

Abstract: Adult onset Still's disease (AOSD) is a rare systemic inflammatory disorder affecting mainly young adults. AOSD is characterized clinically by spiking fever, arthritis, evanescent rash, sore throat, enlargement of lymph nodes and splenomegaly, and biologically by neutrophilic leukocytosis, high levels of ferritine and elevated liver enzymes. None of these features are specific, and although several classification criteria have been proposed, AOSD remains a diagnosis by exclusion. Its causes and pathomechanism are still unknown, although there is increasing evidence of dysregulated innate immune response. Treatment mainstays are systemic corticosteroids and methotrexate. Blockade of proinflammatory cytokines may be effective in the substantial proportion of patients with poor response to classical immunosuppressants.

Tyndall A, Dazzi F. · Department of Rheumatology, University of Basel, Felix Platter Spital, Burfelderstrasse 101, 4012 Basel, Switzerland. · Best Pract Res Clin Haematol. · Pubmed #18503993 No free full text.

Abstract: Many of the clinical, histological and serological manifestations of chronic graft-versus-host disease (GVHD) resemble autoimmune disease (AD), and although the differences are significant, they may be more semantic than biological. Indeed, studies suggest that some ADs may represent a fetal-versus-maternal chronic GVHD. Both conditions involve dysregulated immune responses resulting in tissue inflammation, damage, scarring and organ dysfunction, and both may be associated with a genetic predisposition. Epitope-specific autoaggressive phenomena such as immune thrombocytopenic purpura (ITP) are often seen following allogeneic hematopoietic stem-cell transplantation (HCT), implying a loss of specific tolerance to self structures. However, the more widespread manifestations of GVHD such as the well-known scleroderma-like symptoms differ in many fundamental respects from de-novo scleroderma, and other multisystem ADs such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA).

Revaz S, Dudler J. · Service de rhumatologie, médecine physique et réhabilitation, Département de l'appareil locomoteur, Hôpital orthopédique, CHUV, 1011 Lausanne. · Rev Med Suisse. · Pubmed #18472732 No free full text.

Abstract: Rheumatoid arthritis is a systemic disease that can potentially affect any organ. If the articular manifestations are central to the disease; skin, ophthalmic, neurological, cardiac, pulmonary as well as renal manifestations are well recognized, the latter particularly in the context of a secondary amyloidosis. Although incidence of extraarticular manifestations appears to decrease, likely a result from our more aggressive and early management of rheumatoid arthritis, their consequences remain severe in terms of morbidity and mortality, and their treatments complicated. The new biological therapies seem to be a promising alternative to current therapies, such as cyclophosphamide and high dose prednisone, even if evidences are still limited.

Dudler J, Revaz S. · Service de rhumatologie, médecine physique et réhabilitation, Departement de l'appareil locomoteur, Hôpital orthopédique, CHUV, 1011 Lausanne. · Rev Med Suisse. · Pubmed #18472730 No free full text.

Abstract: If the diagnosis of Adult-onset Still disease is often entertained, the disease remains difficult to diagnose in the absence of any specific clinical or laboratory anomaly. Diagnosis is still a diagnosis of exclusion, and the difficulty rests in the rational and appropriate use of those exclusion tests. Treatment is pragmatic, based on an analysis of the situation and a clear definition of the objectives. Finally, if biological treatments appear efficient, they should be reserved for patients resistant to conventional therapy or corticodependant.

Ospelt C, Gay S. · Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Gloriastrasse 23, CH-8091 Zürich, Switzerland. · Best Pract Res Clin Rheumatol. · Pubmed #18455682 No free full text.

Abstract: Infiltration by inflammatory cells, thickening of the lining layer, and destructive invasion into cartilage and bone are pathognomic features of the synovium in rheumatoid arthritis (RA). However, the most common cell types at the sites of invasion are resident cells of the joint, in particular synovial fibroblasts. These cells differ from healthy synovial fibroblasts in their morphology, their expression of proto-oncogenes and antiapoptotic molecules, and in their lack of certain tumor suppressor genes. Through their production of proinflammatory cytokines and chemokines mediated by signaling via Toll-like receptors, they are not only effector cells but also active parts of the innate immune system attracting inflammatory immune cells to the synovium. Most importantly, by producing matrix-degrading molecules they contribute strongly to the destructive mechanisms operative in RA.

Finckh A, Gabay C. · Division of Rheumatology, University Hospitals of Geneva and University of Geneva, Switzerland. · Curr Opin Rheumatol. · Pubmed #18388517 No free full text.

Abstract: PURPOSE OF REVIEW: To review the rational and the results regarding the use of novel biologic agents in inflammatory rheumatic diseases. RECENT FINDINGS: Recent findings show that excessive IL-1 processing and release contribute to different rheumatic conditions, including periodic fever syndromes, systemic-onset juvenile idiopathic arthritis, adult Still's disease, and crystal-induced arthritis. Preliminary results indicate that administration of IL-1 receptor antagonist and other IL-1 inhibitors improves these conditions. IL-6 also plays a major role in the control of inflammatory responses. Several clinical trials have shown that inhibition of IL-6 by a monoclonal antibody against its receptor is efficacious in rheumatoid arthritis and systemic-onset juvenile idiopathic arthritis patients. Accumulating evidence indicates that other cytokines, including IL-15, IL-18, and IL-21 may also play an important role in rheumatoid arthritis. Several signaling pathways involved in the immune and inflammatory responses may also constitute novel targets. Preliminary data on an agent targeting the Janus kinase/Signal transducer and activators of transcription pathway are encouraging. SUMMARY: Beyond tumor necrosis factor alpha targeting, the use of inhibitors against other cytokines and cytokine-induced intracellular responses is leading to a promising therapy in the future.

Stanczyk J, Ospelt C, Gay S. · Center of Experimental Rheumatology, University Hospital Zurich, Zurich Center of Integrative Human Physiology, University of Zurich, Switzerland. · Curr Opin Rheumatol. · Pubmed #18388515 No free full text.

Abstract: PURPOSE OF REVIEW: In this review, we outline the landscape of recent developments regarding small molecule compounds for the treatment of inflammatory disorders by discussing drug candidates currently in the pipeline. We also stress the fact that novel techniques are available to evaluate the safety of new therapeutics at an early stage of development. RECENT FINDINGS: Regulation of signal transduction has evolved into an important field of drug research, and small molecule inhibitors of a number of pathways are tested as new anti-inflammatory agents. For rheumatic diseases, specific Jak3 and Syk inhibitors are, so far, the most successful compounds due to their good efficacy, representing a significant advantage over p38 mitogen-activated protein kinase inhibitors. Additional benefit in the treatment of inflammatory diseases may be provided by targeting CD80, IL-12/IL-23, AP-1 transcription factor and receptors modulating cellular activation like chemokine receptors, Toll-like receptors and adenosine A3 receptor. SUMMARY: There is a big hope that novel small molecule drugs, which are rationally designed, based on scientific advancements and biotechnological improvements, will achieve or even exceed efficacy of protein drugs. Thereby, new therapeutic alternatives would be given, and chances for improved outcomes in the care of rheumatic patients provided.

Simmen BR, Bogoch ER, Goldhahn J. · Upper Extremity Department, Schulthess Klinik in Zürich, Switzerland. · Nat Clin Pract Rheumatol. · Pubmed #18334981 No free full text.

Abstract: Longstanding rheumatoid arthritis (RA) leads to disability, caused mainly by joint destruction. The current goals of surgical intervention are to restore function and quality of life, prevent joint deterioration, relieve pain, and correct deformity. A number of different surgical treatment options are available to patients with RA, including synovectomy, arthrodesis, joint replacement, and soft tissue and special hand surgery; nonoperative management is also important. Decision-making and timing for orthopedic intervention are complex issues because of polyarticular involvement. Functional impairment, pain, and the subsequent loss of quality of life and inability to work have become the main considerations for surgical reconstruction. Early referral for orthopedic treatment can lead to improved functional benefit for patients with RA. The decision for orthopedic intervention should be established by an interdisciplinary team that includes rheumatologists and orthopedic surgeons experienced in the surgery of RA. Priority should be given to the joint that causes the greatest disability and pain. Disease progression and pharmaceutical treatment options should be taken into consideration when establishing an orthopedic intervention protocol.

Dudler J, Aubry-Rozier B. · Service de rhumatologie, médecine physique et réhabilitation, Hôpital Nestlé, CHUV, 1011 Lausanne. · Rev Med Suisse. · Pubmed #18251219 No free full text.

Abstract: The use of biological therapy is now firmly established in the management of inflammatory rheumatism. The anti-TNFalpha have rightly become agents of choice over the last 10 years, and the recent literature reminds us of their places and indications in ankylosing spondylitis. However, not all patients respond, and the availability of new treatments is certainly a welcome addition. Abatacept is a new treatment for rheumatoid arthritis with an innovative mode of action. It appears effective and safe, and some data as well as practical aspects on its use are presented. Nevertheless, we must still learn to integrate it into our therapeutic strategies, as we are presently doing with rituximab.

Rengel Y, Ospelt C, Gay S. · Center of Experimental Rheumatology, University Hospital Zürich, Gloriastrasse, CH-8091 Zurich, Switzerland. · Arthritis Res Ther. · Pubmed #18001502 links to  free full text

Abstract: Proteinases are involved in essential steps in cartilage and bone homeostasis. Consequently, efforts have been made to establish their potential role in the pathology of rheumatic conditions such as rheumatoid arthritis, osteoarthritis and spondyloarthritis. Matrix metalloproteinases (MMPs) are sensitive markers of disease severity and response to treatment, and therefore they have potential in the assessment of rheumatic diseases. Despite disappointing early results with synthetic inhibitors of MMPs, there is still much scope for developing effective and safe MMPs inhibitors, and consequently to deliver new options to inhibit joint destruction.

Grieshaber MC, Mozaffarieh M, Flammer J. · Department of Ophthalmology, University Hospital Basel, Basel, Switzerland. · Surv Ophthalmol. · Pubmed #17998040 No free full text.

Abstract: The need of blood flow to different organs varies rapidly over time which is why there is sophisticated local regulation of blood flow. The term dysregulation simply means that blood flow is not properly adapted to this need. Dysregulative mechanisms can lead to an over- or underperfusion. A steady overperfusion may be less critical for long-term damage. A constant underperfusion, however, can lead to some tissue atrophy or in extreme situations to infarction. Unstable perfusion (underperfusion followed by reperfusion) leads to oxidative stress. There are a number of causes that lead to local or systemic vascular dysregulation. Systemic dysregulation can be primary or secondary of nature. A secondary dysregulation is due to other autoimmune diseases such as rheumatoid arthritis, giant cell arteritis, systemic lupus erythematodes, multiple sclerosis, colitis ulcerosa, or Crohns disease. Patients with a secondary vascular dysregulation normally have a high level of circulating endothelin-1 (ET-1). This increased level of ET-1 leads to a reduction of blood flow both in the choroid and the optic nerve head but has little influence on autoregulation. In contrast, primary vascular dysregulation has little influence on baseline ocular blood flow but interferes with autoregulation. This, in turn, leads to unstable oxygen supply, which seems to be a relevant component in the pathogenesis of glaucomatous optic neuropathy.

Marone R, Cmiljanovic V, Giese B, Wymann MP. · Institute of Biochemistry and Genetics, Department of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058, Basel, Switzerland. · Biochim Biophys Acta. · Pubmed #17997386 No free full text.

Abstract: Phosphoinositide 3-kinases (PI3K) orchestrate cell responses including mitogenic signaling, cell survival and growth, metabolic control, vesicular trafficking, degranulation, cytoskeletal rearrangement and migration. Deregulation of the PI3K pathway occurs by activating mutations in growth factor receptors or the PIK3CA locus coding for PI3Kalpha, by loss of function of the lipid phosphatase and tensin homolog deleted in chromosome ten (PTEN/MMAC/TEP1), by the up-regulation of protein kinase B (PKB/Akt), or the impairment of the tuberous sclerosis complex (TSC1/2). All these events are linked to growth and proliferation, and have thus prompted a significant interest in the pharmaceutical targeting of the PI3K pathway in cancer. Genetic targeting of PI3Kgamma (p110gamma) and PI3Kdelta (p110delta) in mice has underlined a central role of these PI3K isoforms in inflammation and allergy, as they modulate chemotaxis of leukocytes and degranulation in mast cells. Proof-of-concept molecules selective for PI3Kgamma have already successfully alleviated disease progress in murine models of rheumatoid arthritis and lupus erythematosus. As targeting PI3K moves forward to therapy of chronic, non-fatal disease, safety concerns for PI3K inhibitors increase. Many of the present inhibitor series interfere with target of rapamycin (TOR), DNA-dependent protein kinase (DNA-PK(cs)) and activity of the ataxia telangiectasia mutated gene product (ATM). Here we review the current disease-relevant knowledge for isoform-specific PI3K function in the above mentioned diseases, and review the progress of >400 recent patents covering pharmaceutical targeting of PI3K. Currently, several drugs targeting the PI3K pathway have entered clinical trials (phase I) for solid tumors and suppression of tissue damage after myocardial infarction (phases I,II).

Huber LC, Stanczyk J, Jüngel A, Gay S. · University Hospital Zurich, Zurich Center for Integrative Human Physiology, Zurich, Switzerland. · Arthritis Rheum. · Pubmed #17968922 links to  free full text

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Passweg J, Tyndall A. · Division of Hematology, University Hospital Geneva, Geneva, Switzerland. · Semin Hematol. · Pubmed #17961728 No free full text.

Abstract: Since 1996, approximately 1,000 patients have received an autologous hematopoietic stem cell transplant (HSCT) as treatment for a severe autoimmune disease (AD). The European Group for Blood and Marrow Transplantation (EBMT)/European League Against Rheumatism (EULAR) Autoimmune Disease Working Party have registered more than 800 patients and works in close collaboration with networks in the United States where several hundred more AD patients have been similarly transplanted. The majority of ADs were multiple sclerosis (MS), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis, and immune cytopenias. Many patients have experienced long-term disease-free remissions and immune reconstitution studies have shown in some cases that a "resetting" of autoimmunity is possible. The initially high treatment-related mortality (TRM) is reduced significantly in the later years, and the phase I/II experience is now being verified in several international prospective randomized clinical trials. In addition, the past several years have seen a growing interest in the role and potential therapeutic application of mesenchymal stem cells (MSC) in the immunomodulation of AD, as in the early experience with acute-graft-versus host disease (GvHD).