Rheumatoid Arthritis: Lipsky PE

Lipsky PE. · No affiliation provided · Nat Clin Pract Rheumatol. · Pubmed #18438424 No free full text.

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Lipsky PE. · No affiliation provided · Nat Clin Pract Rheumatol. · Pubmed #17968330 No free full text.

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Lipsky PE. · No affiliation provided · Nat Clin Pract Rheumatol. · Pubmed #16932714 No free full text.

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Goldbach-Mansky R, Woodburn J, Yao L, Lipsky PE. · No affiliation provided · Arthritis Rheum. · Pubmed #12632407 links to  free full text

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Lipsky PE, Abramson SB, Breedveld FC, Brook P, Burmester R, Buttgereit F, Cannon GW, Catella-Lawson F, Crofford LJ, Doherty M, Dougados M, DuBois RN, Froelich J, Garcia Rodriguez LA, Gibofsky A, Hernandez-Diaz S, Hochberg MC, Krause A, Liang MH, Machold K, Peloso PM, Raisz LG, Schayes B, Scheiman JM, Simon LS, Smolen J. · No affiliation provided · J Rheumatol. · Pubmed #10852251 No free full text.

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Ettinger R, Kuchen S, Lipsky PE. · Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. Bethesda, Maryland, USA. · Ann Rheum Dis. · Pubmed #19022821 No free full text.

Abstract: Interleukin 21 (IL21) belongs to a family of cytokines that bind to a composite receptor consisting of a private receptor (IL21R) and the common cytokine receptor gamma chain (gamma(C)). The IL21R is widely distributed on lympho-haematopoietic cells and IL21 impacts a number of cell types, including CD8+ memory T cells, NK cells and subsets of CD4 memory T cells. One essential role of IL21 is the promotion of B-cell activation and differentiation or death during humoral immune responses. Increased IL21 production is characteristic of certain autoimmune diseases and is likely to contribute to autoantibody production as well as pathological features of autoimmune disease. The critical role of IL21 in promoting humoral immune responses makes it an important focus of potential therapeutic interventions in conditions characterised by overproduction of pathogenic autoantibodies.

Hansen A, Lipsky PE, Dörner T. · Outpatients Department of Medicine, Charité University Hospital, Berlin, Germany. · Nat Clin Pract Rheumatol. · Pubmed #17906611 No free full text.

Abstract: Patients with chronic inflammatory rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and especially primary Sjögren's syndrome (SS), are at higher risk than the general population of developing B-cell non-Hodgkin lymphoma (NHL). Analyses of the association between various lymphoma subtypes and specific disease entities suggest that this association might be mediated by disease-specific mechanisms, as well as by mechanisms unique to lymphoma subtype. These specific associations can provide important information about abnormal B-cell stimulation in these conditions. Patients with primary SS, SLE and RA are at high risk of developing diffuse large B-cell lymphomas, a group of high-grade NHLs with remarkable heterogeneity. Patients with primary SS are at particularly high risk of developing marginal-zone B-cell lymphomas. The risk factors of lymphoma development in primary SS seem to be closely related to the underlying mechanisms of abnormal stimulation and/or impaired censoring mechanisms of B cells. In patients with RA and SLE, more intense disease activity and/or long-lasting disease might be indications of a higher risk of lymphoma development. This Review will focus on the risk of lymphoma, common and disease-specific mechanisms of B-cell lymphoma development, and on the clinical consequences of lymphoma in patients with inflammatory rheumatic diseases.

Dörner T, Lipsky PE. · Charite University Hospital Berlin and Deutsche Rheumaforschungszentrum, Chariteplatz 01, 10098 Berlin, Germany. · Expert Opin Biol Ther. · Pubmed #17727320 No free full text.

Abstract: B cells and their products, antibodies, play an important role in the diagnosis and, in some instances, in the pathogenesis of many autoimmune diseases. Specific B-cell directed therapies are of recent interest as their impact on B-cell activity can influence a variety of autoimmune diseases. The development and introduction of rituximab, a depleting antibody targeting CD20+ B cells, and previously CD52-directed treatment with Campath-1h for the treatment of B-cell malignancies as well as rheumatoid arthritis have pioneered this therapeutic field. Other non-depleting strategies employ CD22 or B-cell activating factor/B lymphocyte stimulator and apoptosis-inducing ligand as targets and are under clinical investigation at present. Abnormalities of B-cell subsets have been identified by a number of independent groups which often represent characteristic patterns of disturbances of the human B-cell repertoire. However, the clinical value of specific B-cell subset targeting/depletion has not been addressed extensively. As such an approach may afford the possibility to avoid unnecessary adverse events related to depletion of non-pathogenic B-cell populations, B-cell subset targeting may have the capacity to enhance the benefit/risk ratio of B-cell immune intervention.

Hansen A, Lipsky PE, Dörner T. · Charite Center (CC) 12, Department of Medicine, Charité-Universitätsmedizin Berlin, Charité-Platz 01, 10098 Berlin, Germany. · Arthritis Res Ther. · Pubmed #17697366 links to  free full text

Abstract: Primary Sjögren's syndrome (pSS) is an autoimmune disorder characterized by specific pathological features. A hallmark of pSS is B-cell hyperactivity as manifested by the production of autoantibodies, hypergammaglobulinemia, formation of ectopic lymphoid structures within the inflamed tissues, and enhanced risk of B-cell lymphoma. Changes in the distribution of peripheral B-cell subsets and differences in post-recombination processes of immunoglobulin variable region (IgV) gene usage are also characteristic features of pSS. Comparison of B cells from the peripheral blood and salivary glands of patients with pSS with regard to their expression of the chemokine receptors CXCR4 and CXCR5, and their migratory capacity towards the corresponding ligands, CXCL12 and CXCL13, provide a mechanism for the prominent accumulation of CXCR4+ CXCR5+ memory B cells in the inflamed glands. Glandular B cells expressing distinct features of IgV light and heavy chain rearrangements, (re)circulating B cells with increased mutations of cmu transcripts in both CD27- and CD27+ memory B-cell subsets, and enhanced frequencies of individual peripheral B cells containing IgV heavy chain transcripts of multiple isotypes indicate disordered selection and incomplete differentiation processes of B cells in the inflamed tissues in pSS. This may possibly be related to a lack of appropriate censoring mechanisms or different B-cell activation pathways within the ectopic lymphoid structures of the inflamed tissues. These findings add to our understanding of the pathogenesis of this autoimmune inflammatory disorder and may result in new therapeutic approaches.

Ochi T, Yoshikawa H, Toyosaki-Maeda T, Lipsky PE. · Sagamihara National Hospital, Sagamihara, Kanagawa, Japan. · Arthritis Res Ther. · Pubmed #17306036 links to  free full text

Abstract: A major question concerning the immunopathology of rheumatoid arthritis is why the disease is localized to particular joints. A possible explanation could be the presence within the synovium of cells that foster inflammation or easy accessibility of the synovium to migratory disease enhancing cells. Within both the bone marrow and the synovium, fibroblastic stromal cells play an important role in supporting the differentiation and survival of normal cells, and also contribute to the pathologic processes. Among fibroblastic stromal cells in synovial tissue and bone marrow, nurse-like cells are a unique population having the specific capacity to promote pseudoemperipolesis (adhesion and holding beneath) of lymphocytes, and also the ability to promote the growth and function of some populations of lymphocytes and monocytes. Nurse-like cells could therefore contribute to the immunopathogenesis of rheumatoid arthritis, and may contribute to the localization of inflammation within specific joints. The present review considers the evidence that supports these possibilities.

Skapenko A, Lipsky PE, Schulze-Koops H. · Nikolaus Fiebiger Center for Molecular Medicine, Clinical Research Group III, Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany. · Curr Top Microbiol Immunol. · Pubmed #16724807 No free full text.

Abstract: Rheumatic inflammation is driven by sustained specific immunity against self-antigens, resulting in local inflammation and cellular infiltration and, subsequently, in tissue damage. Although the specific autoantigen(s) eliciting the detrimental immune reactions in rheumatic diseases have rarely been defined, it has become clear that the mechanisms resulting in the destruction of tissue and the loss of organ function during the course of the diseases are essentially the same as in protective immunity against invasive microorganisms. Of fundamental importance in initiating, controlling, and driving these specific immune responses are CD4 T cells. Currently available data provide compelling evidence for a major role of CD4 T cells in the initiation and perpetuation of chronic rheumatic inflammation. Consequently, T cell-directed therapies have been employed with substantial clinical success in the treatment of rheumatic diseases. Here, we review current knowledge based on which CD4 T cells can be implicated as the motor of rheumatic inflammation.

Hansen A, Lipsky PE, Dörner T. · Charité University Medicine Berlin, Germany. · Curr Opin Rheumatol. · Pubmed #16093833 No free full text.

Abstract: PURPOSE OF REVIEW: Recent studies have broadened our understanding of the etiopathogenesis and immunopathology of primary Sjögren's syndrome. This review highlights recent advances in understanding the underlying mechanisms of the disease as well as their implications for clinical handling and therapeutic options. RECENT FINDINGS: It becomes increasingly apparent that certain disturbances of the immune system (i.e. B-cell hyperreactivity and enhanced levels of B-cell-activating factor/B-lymphocyte stimulator) play a central role in this entity. Whether this is a primary abnormality or the result of predisposing factors or infectious, e.g. viral, agents remains uncertain. New insights into the pathogenesis also provide candidates for better diagnosis and classification of disease severity, such as flow cytometric analysis, measurement of soluble cell surface molecules, autoantibodies, cytokines, and ligands (B-cell-activating factor/B-lymphocyte stimulator). Whether B-cell-directed therapies (i.e. blocking B-cell-activating factor/B-lymphocyte stimulator, anti-CD20 therapy) will have an impact on primary Sjögren's syndrome needs to be shown in clinical trials. Alternative therapeutic approaches such as organ-targeted gene transfer are in development but must be carefully evaluated for safety and efficacy in preclinical models that resemble human primary Sjögren's syndrome. SUMMARY: The pathogenesis of primary Sjögren's syndrome is complex and the factors initiating and driving autoimmunity in this entity are largely unknown. Recent studies provide new insights into potential pathogenetic mechanisms of the disease and, thereby, the chance for improved strategies in disease management and therapy.

Leipe J, Skapenko A, Lipsky PE, Schulze-Koops H. · Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, Germany. · Arthritis Res Ther. · Pubmed #15899057 links to  free full text

Abstract: Apart from the deletion of autoreactive T cells in the thymus, various methods exist in the peripheral immune system to control specific human immune responses to self-antigens. One of these mechanisms involves regulatory T cells, of which CD4+CD25+ T cells are a major subset. Recent evidence suggests that CD4+CD25+ T cells have a role in controlling the development of autoimmune diseases in animals and in humans. The precise delineation of the function of CD4+CD25+ T cells in autoimmune inflammation is therefore of great importance for the understanding of the pathogenesis of autoimmune diseases. Moreover, the ability to control such regulatory mechanisms might provide novel therapeutic opportunities in autoimmune disorders such as rheumatoid arthritis. Here we review existing knowledge of CD4+CD25+ T cells and discuss their role in the pathogenesis of rheumatic diseases.

Skapenko A, Leipe J, Lipsky PE, Schulze-Koops H. · Nikolaus Fiebiger Center for Molecular Medicine, Clinical Research Group III, Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany. · Arthritis Res Ther. · Pubmed #15833146 No free full text.

Abstract: T cells, in particular CD4+ T cells, have been implicated in mediating many aspects of autoimmune inflammation. However, current evidence suggests that the role played by CD4+ T cells in the development of rheumatoid inflammation exceeds that of activated proinflammatory T-helper (Th)1 effector cells that drive the chronic autoimmune response. Subsets of CD4+ T cells with regulatory capacity, such as CD25+ regulatory T (Treg) cells and Th2 cells, have been identified, and recent observations suggest that in rheumatoid arthritis the function of these regulatory T cells is severely impaired. Thus, in rheumatoid arthritis, defective regulatory mechanisms might allow the breakdown of peripheral tolerance, after which the detrimental Th1-driven immune response evolves and proceeds to chronic inflammation. Here, we review the functional abnormalities and the contribution of different T cell subsets to rheumatoid inflammation.

Lipsky PE. · Intramural Research Program, The National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA. · J Rheumatol Suppl. · Pubmed #15660470 No free full text.

Abstract: The advent of biologic therapy has not only provided the opportunity for better care of patients with rheumatoid arthritis (RA), but also has permitted a better understanding of the pathogenesis of this autoimmune/inflammatory disease. The capacity of these agents to suppress signs and symptoms as well as radiographic progression of RA strongly indicates that they can alter the course of the disease. Appropriate analysis of the effect of biologics should provide new insight into the role of the specific targeted molecules in rheumatoid inflammation, and provide information about means to optimize therapy with these highly potent therapeutics.

Goldbach-Mansky R, Mahadevan V, Yao L, Lipsky PE. · National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA. · Clin Exp Rheumatol. · Pubmed #14969050 No free full text.

Abstract: Magnetic resonance imaging (MRA) greatly improves the early detection and visualization of osseous and non-osseous joint changes over conventional x-rays of involved joints in patients with rheumatoid arthritis (RA). However, the "pathophysiological correlate" of these MR imaging changes remains poorly defined. Careful validation of MRI findings and the evaluation of MRI as a tool to follow the effect of therapy remain to be performed before MRI may be used as a clinical tool to follow therapy or as a surrogate for evaluating osseous changes over time.

Hansen A, Lipsky PE, Dörner T. · Charité University Hospital, Berlin, Germany. · Curr Opin Rheumatol. · Pubmed #12960481 No free full text.

Abstract: Although a modified European-American consensus classification of Sjögren syndrome has been introduced during the last year, the etiopathogenesis of this disease characterized by chronic lymphocytic inflammation, impaired function, and, finally, destruction of the salivary and lacrimal glands as well as systemic manifestations remains to be elucidated. Recent insights into the pathogenesis of Sjögren syndrome resulting from immunogenetic, hormonal, and epidemiologic evaluations as well as animal and in vitro studies are highlighted by this review. Evidence confirms that lymphocytic disturbances, including ectopic germinal center formation and aberrations of cellular signaling play a significant role in Sjögren syndrome. Although some of these features are unique to Sjögren syndrome, others are also found in a number of systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. The underlying cause of Sjögren syndrome remains largely enigmatic. However, distinct characteristics may provide the basis for the classification of the disease entities. Finally, an enhanced risk of lymphomagenesis is a well-known hallmark of primary Sjögren syndrome, indicating the central role of derangement of lymphocyte regulation. As demonstrated by the introduction of the new targeted therapeutic approaches in rheumatoid arthritis, solid insights into the pathogenesis of Sjögren syndrome may pave the way toward new therapeutic approaches.

Dörner T, Hansen A, Jacobi A, Lipsky PE. · Department of Medicine, Rheumatology and Clinical Immunology, University Hospital Charité, Schumannstrasse 20/21, 10098 Berlin, Germany. · Autoimmun Rev. · Pubmed #12849004 No free full text.

Abstract: This review focuses on the use of immunglobulin (Ig) variable region genes by B cells from patients with primary Sjögren's syndrome (pSS) and the biologic insights that this provides. Comparison of the Ig repertoire from the blood and parotid gland of pSS patients with that of normal donors suggests that there are typical disturbances of B cell homeostasis with depletion of memory B cells from the peripheral blood and accumulation/retention of these antigen-experienced B cells in the inflamed tissue. Although there are clonally expanded B cells in the parotid gland, generalized abnormalities in the B cell repertoire are also found in pSS patients. The vast majority of the current data indicate that there is no major molecular abnormality in generating the IgV chain repertoire in patients with pSS. In contrast, disordered selection leads to considerable differences in the V(L) gene usage and V(H) CDR3 length of the B cell Ig repertoire in pSS patients. The nature of the influences that lead to disordered selection in pSS remains to be determined, but should provide important clues to the etiology of this autoimmune inflammatory disorder.

Dörner T, Lipsky PE. · Department of Medicine, Rheumatology and Clinical Immunology, University Hospital Charité, Berlin, Germany. · Arthritis Res. · Pubmed #12453312 links to  free full text

Abstract: Primary Sjögren's syndrome (pSS) is an autoimmune disorder characterized by specific pathologic features and the production of typical autoantibodies. In addition, characteristic changes in the distribution of peripheral B cell subsets and differences in use of immunoglobulin variable-region genes are also features of pSS. Comparison of B cells from the blood and parotid gland of patients with pSS with those of normal donors suggests that there is a depletion of memory B cells from the peripheral blood and an accumulation or retention of these antigen-experienced B cells in the parotids. Because disordered selection leads to considerable differences in the B cell repertoire in these patients, the delineation of its nature should provide important further clues to the pathogenesis of this autoimmune inflammatory disorder.

Goldbach-Mansky R, Lipsky PE. · National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. · Annu Rev Med. · Pubmed #12359827 No free full text.

Abstract: Recent advances have made rheumatoid arthritis (RA) amenable to treatment. Clinical studies in patients with early and established RA have broadened understanding of its pathogenesis and have fundamentally changed the therapeutic approach to this disease. Quantum leaps in therapy-including the use of early, aggressive therapy, combination therapy, and the introduction of anti-cytokine agents-have improved patients' quality of life, eased clinical symptoms, retarded the progression of joint destruction, and delayed disability. We review clinical evidence supporting these therapeutic approaches. Diagnostic and therapeutic challenges are highlighted, and a decision tree to guide treatment in patients with early or established RA is provided.

Cravens PD, Lipsky PE. · Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, USA. · Immunol Cell Biol. · Pubmed #12225387 No free full text.

Abstract: Dendritic cells (DC) have been implicated in the induction of autoimmune diseases and have been identified in lesions associated with several autoimmune inflammatory diseases. Since DC are regarded as the professional antigen-presenting cell (APC) of the immune system and the only APC capable of activating naïve T cells, they are likely to play a significant role in breaking tolerance of self-reactive lymphocytes and in supporting autoimmune responses in these diseases. A number of studies have revealed that small molecular weight chemotactic proteins known as chemokines are present within the autoimmune lesions and may contribute to the recruitment not only of DC populations, but also of immune cells such as T cells, B cells, neutrophils and monocytes into the site, and to the formation of organized lymphoid tissue structures within the target organ. The focus of this review will be a discussion of the role of chemokines in the recruitment of DC in human autoimmune inflammatory disorders, specifically the trafficking of DC into the inflammatory sites and the subsequent migration of differentiated DC from the inflammatory sites into the draining lymph nodes. Once DC are properly positioned within the lymph nodes, circulating antigen specific naïve T cells can interact with DC and become activated, clonally expanded and stimulated to undergo differentiation into antigen-experienced memory T cells. Subsequent reactivation of memory T cells that enter the autoimmune lesions by DC present in the inflammatory lesion is thought to play a central role in tissue inflammation.

Huizinga TW, Machold KP, Breedveld FC, Lipsky PE, Smolen JS. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #12115216 links to  free full text

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El-Gabalawy HD, Lipsky PE. · Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA. · Arthritis Res. · Pubmed #12110149 No free full text.

Abstract: There are currently unprecedented opportunities to treat rheumatoid arthritis using well-designed, highly effective, targeted therapies. This will result in a substantial improvement in the outcome of this disorder for most affected individuals, if they can afford these therapies. Yet our lack of understanding of the basic mechanisms that initiate and sustain this disease remains a major obstacle in the search for a definitive cure. It is possible, if not likely, that our best approach will be to identify individuals at risk and devise reliable, safe methods of preventing the disease before it occurs. The means to do this are currently unknown but should serve as a major focus of research.

Schulze-Koops H, Lipsky PE. · Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany. · Curr Dir Autoimmun. · Pubmed #11791458 No free full text.

This publication has no abstract.

Illei GG, Lipsky PE. · National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Building 10, Bethesda, MD 20892, USA. · Curr Opin Immunol. · Pubmed #11102777 No free full text.

Abstract: Anti-TNF therapy has made a major impact on the treatment of inflammatory arthritides and Crohn's disease. It leads to prompt and prolonged clinical response, even in patients refractory to conventional therapy. Moreover, the progression of joint damage noted in patients with rheumatoid arthritis treated with methotrexate was prevented by an anti-TNF-alpha antibody, suggesting a genuine disease-modifying potential of TNF-alpha blockade.