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G Cambridge - One of the best experts on this subject based on the ideXlab platform.
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repeated B Lymphocyte depletion with rituximaB in rheumatoid arthritis over 7 yrs
Rheumatology, 2006Co-Authors: C Popa, M J Leandro, G Cambridge, Jcw EdwardsAbstract:OBjective To assess safety and efficacy of repeated B-cell depletion with rituximaB in patients with rheumatoid arthritis (RA). Methods Thirty-seven patients with refractory RA entered into a programme of repeated B-Lymphocyte depletion (up to 5 cycles, 89 cycles in total) with protocols Based on the anti-CD20 monoclonal antiBody, rituximaB, have Been oBserved over periods of >5 yrs (n = 22) or 3-5 yrs (n = 14). Results Twenty two suBjects have Been followed up for >5 yrs. Average duration of Benefit per cycle was 15 months (maximum 43 months), and time to re-treatment 20 months. Nineteen patients remain on the programme. Patients were withdrawn for lack of efficacy (n = 5), hypersensitivity infusion reaction (n = 1), Brevity of response (n = 8), or occurrence of adverse respiratory events (n = 1). Sixteen major lower respiratory events occurred during the 180 patient-yrs of follow-up. Of these only one had low IgG. In patients receiving rituximaB +/- cyclophosphamide (cy) carcinomata have developed as follows: Breast (3, +cy), ovary (1, +cy), transitional cell (1, +cy), and renal cell (1, -cy). Falls in total immunogloBulin levels to Below the normal range occurred in 12 patients for IgM (undetectaBle levels in three after repeated cycles), seven for IgG and one for IgA, not taking into account patients who started off with low immunogloBulin levels Before the first cycle. Conclusion Repeated B-Lymphocyte depletion over a 5-yr period appears to Be an acceptaBle and relatively well-tolerated therapy in RA with a relatively high rate of continuation. Long-term effects on immunogloBulin levels require surveillance.
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B Lymphocyte depletion in rheumatoid arthritis targeting of cd20
Current directions in autoimmunity, 2005Co-Authors: Jonathan C W Edwards, M J Leandro, G CambridgeAbstract:Background: During the 1990s evidence emerged to suggest that B Lymphocyte depletion in rheumatoid arthritis (RA) might Be of major Benefit. Methods and Results: In 1997 the B lympholytic monoclonal
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B Lymphocyte depletion therapy with rituximaB in rheumatoid arthritis
Rheumatic Diseases Clinics of North America, 2004Co-Authors: Jcw Edwards, M J Leandro, G CambridgeAbstract:B Lymphocyte depletion therapy in rheumatoid arthritis can provide major clinical Benefits. Widespread use in the future will depend on continued evidence of safety, particularly in the context of long term use. RituximaB is a highly effective agent, But it may Be Best used in comBination with other agents. SuBstantial improvement following a single course of therapy has Been found to last up to 42 months, and it is reasonaBle to hope that further development of strategies targeting B cells will extend this toward the original aim of truly long-term remission.
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serologic changes following B Lymphocyte depletion therapy for rheumatoid arthritis
Arthritis & Rheumatism, 2003Co-Authors: G Cambridge, Jonathan C W Edwards, M J Leandro, Michael R Ehrenstein, Martin Salden, M D Bodmansmith, Anthony D B WebsterAbstract:OBjective To explore the changes in serologic variaBles and clinical disease activity following B Lymphocyte depletion in 22 patients with rheumatoid arthritis (RA). Methods B Lymphocyte depletion was attained using comBination therapy Based on the monoclonal anti-CD20 antiBody rituximaB. Levels of a serologic indicator of inflammation, C-reactive protein (CRP), of antimicroBial antiBodies, of autoantiBodies including IgA-, IgM-, and IgG-class rheumatoid factors (RF), and of antiBodies to cyclic citrullinated peptide (anti-CCP) were assayed. Results The majority of patients showed a marked clinical improvement after treatment with rituximaB, with Benefit lasting up to 33 months. Levels of total serum immunogloBulins fell, although the mean values each remained within the normal range. Whereas the IgM-RF response paralleled the changes in total serum IgM levels, the levels of IgA-RF, IgG-RF, and IgG and anti-CCP antiBodies decreased significantly more than did those of their corresponding total serum immunogloBulin classes. The kinetics for the reduction in CRP levels also paralleled the decreases in autoantiBody levels. In contrast, levels of antimicroBial antiBodies did not change significantly. B Lymphocyte return occurred up to 21 months posttreatment. The time to relapse after B Lymphocyte return was often long and unpredictaBle (range 0–17 months). Relapse was, however, closely correlated with rises in the level of at least one autoantiBody. Increased autoantiBody levels were rarely oBserved in the aBsence of clinical change. Conclusion Following B Lymphocyte depletion in patients with RA, a positive clinical response occurred in correlation with a significant drop in the levels of CRP and autoantiBodies. AntiBacterial antiBody levels were relatively well maintained. B Lymphocyte return preceded relapse in all patients. There was also a temporal relationship Between clinical relapse and rises in autoantiBody levels. Although these oBservations are consistent with a role for B Lymphocytes in the pathogenesis of RA, the precise mechanisms involved remain unclear.
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an open study of B Lymphocyte depletion in systemic lupus erythematosus
Arthritis & Rheumatism, 2002Co-Authors: M J Leandro, G Cambridge, Jonatha C W Edwards, Michael R Ehrenstei, David A IsenbergAbstract:OBjective To gain preliminary evidence for the safety and efficacy of B Lymphocyte depletion therapy in refractory systemic lupus erythematosus (SLE). Methods Six female patients with active SLE, resistant to standard immunosuppressive therapy, were treated on an open-laBel Basis. During a 2-week period, each patient received two 500-mg infusions of rituximaB, two 750-mg infusions of cyclophosphamide, and high-dose oral corticosteroids. Results No significant adverse events were oBserved during followup. Patient 1 had not improved at 3 months But was then lost to followup. At 6 months, all 5 remaining patients had improved, as evidenced By improvement in British Isles Lupus Assessment Group gloBal scores, from a median of 14 (range 9–27) at Baseline to a median of 6 (range 3–8) at 6 months. Manifestations of SLE such as fatigue, arthralgia/arthritis, and serositis responded particularly well to this protocol. HemogloBulin levels increased in patients 2, 3, 5, and 6. The erythrocyte sedimentation rate decreased in patients 2, 3, 4, and 5 and was staBle in patient 1. In patients 4 and 5, the urinary protein–to-creatinine ratio decreased significantly. C3 serum levels increased in all 5 patients who had low levels at Baseline; in two of these patients, patients 2 and 5, C3 values were normal at 6 months. The variation in the level of anti–douBle-stranded DNA antiBody was different in individual patients. Conclusion This study provides sufficient evidence for the safety and possiBle efficacy of B Lymphocyte depletion therapy in SLE to justify a formal controlled trial.
M J Leandro - One of the best experts on this subject based on the ideXlab platform.
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repeated B Lymphocyte depletion with rituximaB in rheumatoid arthritis over 7 yrs
Rheumatology, 2006Co-Authors: C Popa, M J Leandro, G Cambridge, Jcw EdwardsAbstract:OBjective To assess safety and efficacy of repeated B-cell depletion with rituximaB in patients with rheumatoid arthritis (RA). Methods Thirty-seven patients with refractory RA entered into a programme of repeated B-Lymphocyte depletion (up to 5 cycles, 89 cycles in total) with protocols Based on the anti-CD20 monoclonal antiBody, rituximaB, have Been oBserved over periods of >5 yrs (n = 22) or 3-5 yrs (n = 14). Results Twenty two suBjects have Been followed up for >5 yrs. Average duration of Benefit per cycle was 15 months (maximum 43 months), and time to re-treatment 20 months. Nineteen patients remain on the programme. Patients were withdrawn for lack of efficacy (n = 5), hypersensitivity infusion reaction (n = 1), Brevity of response (n = 8), or occurrence of adverse respiratory events (n = 1). Sixteen major lower respiratory events occurred during the 180 patient-yrs of follow-up. Of these only one had low IgG. In patients receiving rituximaB +/- cyclophosphamide (cy) carcinomata have developed as follows: Breast (3, +cy), ovary (1, +cy), transitional cell (1, +cy), and renal cell (1, -cy). Falls in total immunogloBulin levels to Below the normal range occurred in 12 patients for IgM (undetectaBle levels in three after repeated cycles), seven for IgG and one for IgA, not taking into account patients who started off with low immunogloBulin levels Before the first cycle. Conclusion Repeated B-Lymphocyte depletion over a 5-yr period appears to Be an acceptaBle and relatively well-tolerated therapy in RA with a relatively high rate of continuation. Long-term effects on immunogloBulin levels require surveillance.
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B Lymphocyte depletion in rheumatoid arthritis targeting of cd20
Current directions in autoimmunity, 2005Co-Authors: Jonathan C W Edwards, M J Leandro, G CambridgeAbstract:Background: During the 1990s evidence emerged to suggest that B Lymphocyte depletion in rheumatoid arthritis (RA) might Be of major Benefit. Methods and Results: In 1997 the B lympholytic monoclonal
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B Lymphocyte depletion therapy with rituximaB in rheumatoid arthritis
Rheumatic Diseases Clinics of North America, 2004Co-Authors: Jcw Edwards, M J Leandro, G CambridgeAbstract:B Lymphocyte depletion therapy in rheumatoid arthritis can provide major clinical Benefits. Widespread use in the future will depend on continued evidence of safety, particularly in the context of long term use. RituximaB is a highly effective agent, But it may Be Best used in comBination with other agents. SuBstantial improvement following a single course of therapy has Been found to last up to 42 months, and it is reasonaBle to hope that further development of strategies targeting B cells will extend this toward the original aim of truly long-term remission.
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serologic changes following B Lymphocyte depletion therapy for rheumatoid arthritis
Arthritis & Rheumatism, 2003Co-Authors: G Cambridge, Jonathan C W Edwards, M J Leandro, Michael R Ehrenstein, Martin Salden, M D Bodmansmith, Anthony D B WebsterAbstract:OBjective To explore the changes in serologic variaBles and clinical disease activity following B Lymphocyte depletion in 22 patients with rheumatoid arthritis (RA). Methods B Lymphocyte depletion was attained using comBination therapy Based on the monoclonal anti-CD20 antiBody rituximaB. Levels of a serologic indicator of inflammation, C-reactive protein (CRP), of antimicroBial antiBodies, of autoantiBodies including IgA-, IgM-, and IgG-class rheumatoid factors (RF), and of antiBodies to cyclic citrullinated peptide (anti-CCP) were assayed. Results The majority of patients showed a marked clinical improvement after treatment with rituximaB, with Benefit lasting up to 33 months. Levels of total serum immunogloBulins fell, although the mean values each remained within the normal range. Whereas the IgM-RF response paralleled the changes in total serum IgM levels, the levels of IgA-RF, IgG-RF, and IgG and anti-CCP antiBodies decreased significantly more than did those of their corresponding total serum immunogloBulin classes. The kinetics for the reduction in CRP levels also paralleled the decreases in autoantiBody levels. In contrast, levels of antimicroBial antiBodies did not change significantly. B Lymphocyte return occurred up to 21 months posttreatment. The time to relapse after B Lymphocyte return was often long and unpredictaBle (range 0–17 months). Relapse was, however, closely correlated with rises in the level of at least one autoantiBody. Increased autoantiBody levels were rarely oBserved in the aBsence of clinical change. Conclusion Following B Lymphocyte depletion in patients with RA, a positive clinical response occurred in correlation with a significant drop in the levels of CRP and autoantiBodies. AntiBacterial antiBody levels were relatively well maintained. B Lymphocyte return preceded relapse in all patients. There was also a temporal relationship Between clinical relapse and rises in autoantiBody levels. Although these oBservations are consistent with a role for B Lymphocytes in the pathogenesis of RA, the precise mechanisms involved remain unclear.
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an open study of B Lymphocyte depletion in systemic lupus erythematosus
Arthritis & Rheumatism, 2002Co-Authors: M J Leandro, G Cambridge, Jonatha C W Edwards, Michael R Ehrenstei, David A IsenbergAbstract:OBjective To gain preliminary evidence for the safety and efficacy of B Lymphocyte depletion therapy in refractory systemic lupus erythematosus (SLE). Methods Six female patients with active SLE, resistant to standard immunosuppressive therapy, were treated on an open-laBel Basis. During a 2-week period, each patient received two 500-mg infusions of rituximaB, two 750-mg infusions of cyclophosphamide, and high-dose oral corticosteroids. Results No significant adverse events were oBserved during followup. Patient 1 had not improved at 3 months But was then lost to followup. At 6 months, all 5 remaining patients had improved, as evidenced By improvement in British Isles Lupus Assessment Group gloBal scores, from a median of 14 (range 9–27) at Baseline to a median of 6 (range 3–8) at 6 months. Manifestations of SLE such as fatigue, arthralgia/arthritis, and serositis responded particularly well to this protocol. HemogloBulin levels increased in patients 2, 3, 5, and 6. The erythrocyte sedimentation rate decreased in patients 2, 3, 4, and 5 and was staBle in patient 1. In patients 4 and 5, the urinary protein–to-creatinine ratio decreased significantly. C3 serum levels increased in all 5 patients who had low levels at Baseline; in two of these patients, patients 2 and 5, C3 values were normal at 6 months. The variation in the level of anti–douBle-stranded DNA antiBody was different in individual patients. Conclusion This study provides sufficient evidence for the safety and possiBle efficacy of B Lymphocyte depletion therapy in SLE to justify a formal controlled trial.
Jcw Edwards - One of the best experts on this subject based on the ideXlab platform.
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repeated B Lymphocyte depletion with rituximaB in rheumatoid arthritis over 7 yrs
Rheumatology, 2006Co-Authors: C Popa, M J Leandro, G Cambridge, Jcw EdwardsAbstract:OBjective To assess safety and efficacy of repeated B-cell depletion with rituximaB in patients with rheumatoid arthritis (RA). Methods Thirty-seven patients with refractory RA entered into a programme of repeated B-Lymphocyte depletion (up to 5 cycles, 89 cycles in total) with protocols Based on the anti-CD20 monoclonal antiBody, rituximaB, have Been oBserved over periods of >5 yrs (n = 22) or 3-5 yrs (n = 14). Results Twenty two suBjects have Been followed up for >5 yrs. Average duration of Benefit per cycle was 15 months (maximum 43 months), and time to re-treatment 20 months. Nineteen patients remain on the programme. Patients were withdrawn for lack of efficacy (n = 5), hypersensitivity infusion reaction (n = 1), Brevity of response (n = 8), or occurrence of adverse respiratory events (n = 1). Sixteen major lower respiratory events occurred during the 180 patient-yrs of follow-up. Of these only one had low IgG. In patients receiving rituximaB +/- cyclophosphamide (cy) carcinomata have developed as follows: Breast (3, +cy), ovary (1, +cy), transitional cell (1, +cy), and renal cell (1, -cy). Falls in total immunogloBulin levels to Below the normal range occurred in 12 patients for IgM (undetectaBle levels in three after repeated cycles), seven for IgG and one for IgA, not taking into account patients who started off with low immunogloBulin levels Before the first cycle. Conclusion Repeated B-Lymphocyte depletion over a 5-yr period appears to Be an acceptaBle and relatively well-tolerated therapy in RA with a relatively high rate of continuation. Long-term effects on immunogloBulin levels require surveillance.
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B Lymphocyte depletion therapy with rituximaB in rheumatoid arthritis
Rheumatic Diseases Clinics of North America, 2004Co-Authors: Jcw Edwards, M J Leandro, G CambridgeAbstract:B Lymphocyte depletion therapy in rheumatoid arthritis can provide major clinical Benefits. Widespread use in the future will depend on continued evidence of safety, particularly in the context of long term use. RituximaB is a highly effective agent, But it may Be Best used in comBination with other agents. SuBstantial improvement following a single course of therapy has Been found to last up to 42 months, and it is reasonaBle to hope that further development of strategies targeting B cells will extend this toward the original aim of truly long-term remission.
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clinical outcome in 22 patients with rheumatoid arthritis treated with B Lymphocyte depletion
Annals of the Rheumatic Diseases, 2002Co-Authors: M J Leandro, Jcw Edwards, G CambridgeAbstract:OBjectives: To oBtain evidence for dose response and to extend evidence of safety and efficacy for B Lymphocyte depletion in rheumatoid arthritis. Methods: Twenty two patients with rheumatoid arthritis received a total of 29 treatments with five different comBinations of rituximaB (RTX), cyclophosphamide (CP), and/or high dose prednisolone (PR) on an open Basis as follows; cohort I: RTX 1400 mg/m2, CP 750x2+PR; cohort II: RTX 300–700 mg/m2, -CP±PR); cohort III: RTX 600–700 mg/m2, CP 750x2+PR; cohort IV: RTX 1200 mg/m2, CP 750x2-PR; cohort V: RTX 500 mg/m2, CP 750x2+PR. American College of Rheumatology (ACR) criteria of improvement at six months were chosen as the primary outcome measure. Disease activity scores and total duration of improvement and of B cytopenia were also recorded. Results: No major adverse events attriButaBle to treatment were seen. ACR grades of improvement at six months were as follows: cohort I: ACR70x3, ACR50x2; cohort II: ACR20x1, ACR0x3; cohort III: ACR70x6, ACR50x2, ACR20x2; cohort IV: ACR70x2, ACR50x2, ACR20x1, ACR0x1; cohort V: ACR0x4. Conclusions: B Lymphocyte depletion in rheumatoid arthritis has so far proved to Be safe and associated with major improvement with protocols including RTX 600 mg/m2 or more and CP, But not with more limited protocols. These oBservations provide an initial Basis for the design of formal trials of B cell depletion and other B cell directed treatments, including a phase II controlled trial now in progress.
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B Lymphocyte depletion therapy in rheumatoid arthritis and other autoimmune disorders
Biochemical Society Transactions, 2001Co-Authors: Jcw Edwards, M J Leandro, G CambridgeAbstract:B-Lymphocyte depletion therapy is Being explored in a wide range of autoimmune disorders. In many, there is early evidence for efficacy, and immunosuppression has not Been a major proBlem. The mechanism of action is unclear, But appears to Be consistent with the lowering of autoantiBody levels, where relevant antiBodies are quantifiaBle. An interesting finding is the persistence of clinical improvement for periods of 1 year or more after B-Lymphocyte return, which supports the concept that stochastic generation of rare pathogenic B-Lymphocyte suBsets may Be a rate-limiting step in pathogenesis.
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expression of molecules involved in B Lymphocyte survival and differentiation By synovial fiBroBlasts
Clinical and Experimental Immunology, 1997Co-Authors: Jcw Edwards, Richard Leigh, G CambridgeAbstract:The synovitis of rheumatoid arthritis (RA) is one of few pathological lesions in which B Lymphocyte accumulation progresses to the extent of germinal centre formation. The present study was designed to assess the aBility of synovial fiBroBlasts to express molecules implicated in B Lymphocyte survival and differentiation, Both in vivo, and in response to cytokines in vitro. Normal and diseased synovia were examined By indirect immunofluorescence. In all tissues synovial intimal fiBroBlasts showed co-expression of vascular cell adhesion molecule-1 (VCAM-1) and complement decay-accelerating factor (DAF) comparaBle to that of follicular dendritic cells (FDC), But not complement receptor 2 (CR2). In rheumatoid synovia, suBintimal cells showed variaBle expression of VCAM-1 and DAF, with Bright co-expression of VCAM-1, DAF and CR2 in lymphoid follicle centres. B Lymphocytes, some of which were proliferating cell nuclear antigen-positive, were present in contact with suBintimal cells expressing VCAM-1 with or without DAF or CR2. B Lymphocytes were rarely present in the intimal layer, and, where present, showed fragmentation. In vitro, synovial fiBroBlasts exposed to tumour necrosis factor-alpha (TNF-alpha) in comBination with interferon-gamma (IFN-gamma) showed enhanced expression of VCAM-1, in comparison with fiBroBlasts from skin and lung and, unlike skin and lung fiBroBlasts, also expressed DAF and CR2. These findings support the hypothesis that synovial targeting in RA involves an enhanced aBility of synovial fiBroBlasts to support B Lymphocyte survival. This appears to Be dependent, not on the constitutive expression of VCAM-1 and DAF on intimal cells, But on the increased aBility of suBintimal cells to respond to proinflammatory cytokines, perhaps critically in the expression of VCAM-1.
David A Isenberg - One of the best experts on this subject based on the ideXlab platform.
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an open study of B Lymphocyte depletion in systemic lupus erythematosus
Arthritis & Rheumatism, 2002Co-Authors: M J Leandro, G Cambridge, Jonatha C W Edwards, Michael R Ehrenstei, David A IsenbergAbstract:OBjective To gain preliminary evidence for the safety and efficacy of B Lymphocyte depletion therapy in refractory systemic lupus erythematosus (SLE). Methods Six female patients with active SLE, resistant to standard immunosuppressive therapy, were treated on an open-laBel Basis. During a 2-week period, each patient received two 500-mg infusions of rituximaB, two 750-mg infusions of cyclophosphamide, and high-dose oral corticosteroids. Results No significant adverse events were oBserved during followup. Patient 1 had not improved at 3 months But was then lost to followup. At 6 months, all 5 remaining patients had improved, as evidenced By improvement in British Isles Lupus Assessment Group gloBal scores, from a median of 14 (range 9–27) at Baseline to a median of 6 (range 3–8) at 6 months. Manifestations of SLE such as fatigue, arthralgia/arthritis, and serositis responded particularly well to this protocol. HemogloBulin levels increased in patients 2, 3, 5, and 6. The erythrocyte sedimentation rate decreased in patients 2, 3, 4, and 5 and was staBle in patient 1. In patients 4 and 5, the urinary protein–to-creatinine ratio decreased significantly. C3 serum levels increased in all 5 patients who had low levels at Baseline; in two of these patients, patients 2 and 5, C3 values were normal at 6 months. The variation in the level of anti–douBle-stranded DNA antiBody was different in individual patients. Conclusion This study provides sufficient evidence for the safety and possiBle efficacy of B Lymphocyte depletion therapy in SLE to justify a formal controlled trial.
Motonari Kondo - One of the best experts on this subject based on the ideXlab platform.
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T and B Lymphocyte differentiation from hematopoietic stem cell
Seminars in immunology, 2008Co-Authors: Anne Y. Lai, Motonari KondoAbstract:Until the past few years, it has Been thought that lymphoid and myeloid lineage segregation represents the first step of lineage restriction during hematopoiesis from hematopoietic stem cell. Recent investigation of the cell populations within multipotent progenitors in the Bone marrow has led to new understanding of how hematopoietic stem cells diversify into different hematopoietic cell types. This review focuses on the recent advances in understanding the developmental events that occur during hematopoietic stem cell specification into the T and B Lymphocyte lineages in adult mice.
