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Sigbjørn Berentsen - One of the best experts on this subject based on the ideXlab platform.
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How I Treat Cold Agglutinin Disease.
Blood, 2021Co-Authors: Sigbjørn BerentsenAbstract:The last decades have seen great progress in the treatment of Cold Agglutinin Disease (CAD). Comparative trials are lacking, and recommendations must be based mainly on nonrandomized trials and will be influenced by personal experience. Herein, current treatment options are reviewed and linked to 3 cases, each addressing specific aspects of therapy. Two major steps in CAD pathogenesis are identified - clonal B-cell lymphoproliferation and complement-mediated hemolysis - each of which constitutes a target of therapy. Although drug treatment is not always indicated, patients with symptomatic anemia or other bothersome symptoms should be treated. The importance of avoiding ineffective therapies is underscored. Corticosteroids should not be used to treat CAD. Studies on safety and efficacy of relevant drugs and combinations are briefly described. The author recommends that B-cell directed approaches should still be the first choice in most patients requiring treatment. The 4-cycle bendamustine plus rituximab combination is highly efficacious, sufficiently safe, and induces durable responses in most patients, but the time to response can be many months. Rituximab monotherapy should be preferred in frail patients. The complement C1s inhibitor sutimlimab is an emerging option in the second line and may also find its place in the first line in specific situations.
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Cold Agglutinin Disease: current challenges and future prospects
Journal of blood medicine, 2019Co-Authors: Sigbjørn Berentsen, Alexandra Roth, Ulla Randen, Bernd Jilma, Geir E. TjønnfjordAbstract:Cold Agglutinin Disease (CAD) is a complement-dependent, classical pathway-mediated immune hemolytic Disease, accounting for 15-25% of autoimmune hemolytic anemia, and at the same time, a distinct clonal B-cell lymphoproliferative disorder of the bone marrow. The Disease burden is often high, but not all patients require pharmacological treatment. Several therapies directed at the pathogenic B-cells are now available. Rituximab plus bendamustine or rituximab monotherapy should be considered first-line treatment, depending on individual patient characteristics. Novel treatment options that target the classical complement pathway are under development and appear very promising, and the C1s inhibitor sutimlimab is currently being investigated in two clinical Phase II and III trials. These achievements have raised new challenges and further prospects, which are discussed. Patients with CAD requiring therapy should be considered for clinical trials.
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how i manage patients with Cold Agglutinin Disease
British Journal of Haematology, 2018Co-Authors: Sigbjørn BerentsenAbstract:Cold Agglutinin Disease (CAD) is an uncommon autoimmune haemolytic anaemia in which a well-defined, clonal low-grade lymphoproliferative disorder of the bone marrow results in erythrocyte destruction mediated by the classical complement pathway. The pathogenesis, clinical features and diagnostic criteria are reviewed. Although anaemia is mild in some patients, approximately one-third of untreated patients have a haemoglobin level of ≤80 g/l, and about 50% have been considered transfusion dependent for shorter or longer periods. Therapy has improved greatly during the last 15 years. Mild Disease can be managed by avoidance of Cold and adequate precautions in specific situations, without drug therapy. Corticosteroids should not be used to treat CAD. Patients requiring pharmacological therapy should be considered for prospective trials. Outside clinical studies, the rituximab-bendamustine combination or rituximab monotherapy is recommended in the first line, depending on individual patient characteristics. Second-line options are rituximab-fludarabine in fit patients or, although less strongly documented, a bortezomib-based regimen. Therapies targeting the classical complement pathway are promising, and the complement C1s inhibitor, BIVV009, has shown favourable results in preliminary studies.
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Immunoglobulin heavy and light chain gene features are correlated with primary Cold Agglutinin Disease onset and activity.
Haematologica, 2016Co-Authors: Agnieszka Malecka, Sigbjørn Berentsen, Ulla Randen, Geir E. Tjønnfjord, Gunhild Trøen, Anne Tierens, Ingunn Østlie, Jędrzej Małecki, Jan DelabieAbstract:Immunoglobulin heavy chain ( IGH ) and light chain gene sequences of 27 patients with primary Cold Agglutinin Disease (CAD) were studied to find features explaining the heterogeneity of clinical presentation and Disease activity. CAD is a hemolytic anemia mediated by monoclonal IgM anti-I
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Cold Agglutinin Disease
Hematology, 2016Co-Authors: Sigbjørn BerentsenAbstract:Primary chronic Cold Agglutinin Disease (CAD) is a well-defined clinicopathologic entity in which a specific, clonal lymphoproliferative B-cell bone marrow disorder results in autoimmune hemolytic anemia. The immune hemolysis is entirely complement-dependent, predominantly mediated by activation of the classical pathway and phagocytosis of erythrocytes opsonized with complement protein C3b. Typical clinical features in CAD have diagnostic and therapeutic implications. Pharmacologic treatment should be offered to patients with symptom-producing anemia or disabling circulatory symptoms. CAD should not be treated with corticosteroids. Based on an individualized approach, rituximab monotherapy or rituximab-fludarabine in combination is recommended as first-line therapy. Rituximab-bendamustine is still an investigational therapy. Although complement-modulating agents are still to be considered experimental in CAD, therapy with the anti-C1s monoclonal antibody TNT009 seems promising.
Yukihiro Matsuno - One of the best experts on this subject based on the ideXlab platform.
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normothermic total arch replacement without hypothermic circulatory arrest to treat aortic distal arch aneurysm in a patient with Cold Agglutinin Disease
Interactive Cardiovascular and Thoracic Surgery, 2011Co-Authors: Narihiro Ishida, Hirofumi Takemura, Katsuya Shimabukuro, Yukihiro MatsunoAbstract:Cold Agglutinin Disease although rare, can lead to serious complications for patients undergoing cardio-thoracic surgery, especially when cardiopulmonary bypass is applied under hypothermic circulatory arrest. We describe normothermic total arch replacement without hypothermic circulatory arrest in a patient with Cold Agglutinin Disease. The patient tolerated all procedures well and did not develop cerebral ischemia due to surgical maneuvers or thrombotic or haemolytic complications due to Cold Agglutinin Disease. Although endovascular aortic repair is the first choice under such complex conditions, this method could also serve as an alternative strategy when endovascular aortic repair is precluded.
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Case report - Vascular thoracic Normothermic total arch replacement without hypothermic circulatory arrest to treat aortic distal arch aneurysm in a patient with Cold Agglutinin Disease
2011Co-Authors: Narihiro Ishida, Hirofumi Takemura, Katsuya Shimabukuro, Yukihiro MatsunoAbstract:Cold Agglutinin Disease although rare, can lead to serious complications for patients undergoing cardio-thoracic surgery, especially when cardiopulmonary bypass is applied under hypothermic circulatory arrest. We describe normothermic total arch replacement without hypo- thermic circulatory arrest in a patient with Cold Agglutinin Disease. The patient tolerated all procedures well and did not develop cerebral ischemia due to surgical maneuvers or thrombotic or haemolytic complications due to Cold Agglutinin Disease. Although endovascular aortic repair is the first choice under such complex conditions, this method could also serve as an alternative strategy when endovascular aortic repair is precluded. 2011 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.
Elling Ulvestad - One of the best experts on this subject based on the ideXlab platform.
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clinical immunology of chronic Cold Agglutinin Disease
European Journal of Haematology, 2009Co-Authors: Elling Ulvestad, Sigbjørn Berentsen, Fuad Victor ShammasAbstract:We studied clinical and immunological characteristics of 15 patients with chronic Cold Agglutinin Disease (CAD). Mean age at Disease debut was 68 years for female and 67 years for male patients. The patients had no signs of other autoimmune Diseases. All patients had V H 4-34 encoded IgM kappa Cold Agglutinins (CA) in high titre. In five patients IgM increased significantly with advancing Disease. Seven patients had reduced concentrations of lymphocytes, largely of CD4 and CD8 T cells. Percentages of NK cells (CD56) and B cells (CD19) were increased in seven and three patients, respectively. In six out of nine patients a clonal expansion of kappa positive B cells was found. Serum C3 was decreased in nine patients and C4 was decreased in 11 patients, six of whom had reduced CH50. Such data indicate that patients with CAD experience a continuous low-grade complement consumption. Five patients had experienced increased haemolysis during infections. After addition of active complement to patient sera in vitro, six sera showed increased haemolytic activity. Our results indicate that some patients with CAD have a relative deficit of complement in their serum and that an increase of complement production occurs during an acute phase reaction which enhances haemolysis. Our data also indicate that both CA titre and thermal amplitude are important characteristics when predicting complement activation and clinical course in CAD.
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Paradoxical haemolysis in a patient with Cold Agglutinin Disease
European journal of haematology, 2009Co-Authors: Elling UlvestadAbstract:A patient with classical Cold Agglutinin Disease initially experienced haemolytic episodes during Cold exposure. However, with advancing Disease Cold-induced haemolysis ceased and was substituted with a haemolytic disposition at elevated body temperatures. To investigate this paradoxical development of Disease manifestations, we performed a clinical and immunological study. Our results indicate that the patient's complement system became exhausted during the later phase of his Disease, probably due to continual consumption of complement components. Initially, the patient had slightly decreased C4 concentrations and moderately reduced total haemolytic activity (CH50). Later C4 fell to undetectable levels and CH50 declined to zero. The increased haemolytic activity experienced during febrile episodes is probably due to a Cold Agglutinin with a high thermal amplitude, combined with enhanced synthesis of complement molecules during the acute phase response. Although C4 concentrations never increased to detectable levels during infections or inflammations an acute phase reaction was determined each time, as evidenced by increased concentrations of CRP. By reconstituting the patient's serum with active complement from donor serum or plasma, increased haemolytic activity was observed. These results indicate that some patients with Cold Agglutinin Disease may experience deleterious haemolytic consequences if transfused with plasma-containing blood products.
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Favourable response to therapy with the anti-CD20 monoclonal antibody rituximab in primary chronic Cold Agglutinin Disease.
British journal of haematology, 2001Co-Authors: Sigbjørn Berentsen, Geir E. Tjønnfjord, Robert Brudevold, Bjørn Tore Gjertsen, Ruth Langholm, Erik Løkkevik, Jon Hjalmar Sørbø, Elling UlvestadAbstract:The ‘primary’ form of chronic Cold Agglutinin Disease is a clonal B-cell lymphoproliferative disorder that is notoriously difficult to treat with drugs, including corticosteroids, alkylating agents, alpha-interferon and purine analogues. We performed a small, open, uncontrolled, prospective study to evaluate the effect of therapy with the monoclonal anti-CD20 antibody rituximab. Six patients with clonal CD20+κ+ B-cell proliferation received seven courses of rituximab 375 mg/m2, d 1, 8, 15, and 22. One patient achieved a complete response. Four partial responses were observed, including a response to re-treatment in one patient. Two patients were categorized as non-responders. Haemoglobin levels increased by a median of 4·1 g/dl in the total group and 4·7 g/dl in the responders, who also experienced a substantial improvement of clinical symptoms. The treatment was well tolerated. We discuss the effect of rituximab therapy compared with other treatment options, and try to explain why two individual patients did not respond. Despite the small numbers, the results are very encouraging. Further studies of rituximab therapy for chronic Cold Agglutinin Disease are warranted.
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acute phase haemolysis in chronic Cold Agglutinin Disease
Scandinavian Journal of Immunology, 2001Co-Authors: Elling Ulvestad, Sigbjørn Berentsen, Tom Eirik MollnesAbstract:We previously described a paradoxical form of chronic Cold Agglutinin Disease (CAD) in which haemolysis occurred during episodes of fever but only marginally during exposure to Colds. In order to investigate the molecular basis for this response we performed a 12-month prospective study of a patient with CAD and paradoxical haemolysis. Blood samples were collected monthly during health, and daily following hospitalization owing to hip fracture. During health we observed decreased levels of C3, undetectable C4, a non-functional classical pathway and a normal alternative pathway. Increased concentrations of C1-INH/C1rs complexes indicated continuous formation of C1-antibody-antigen complexes. There was a low-grade temperature-dependent fluctuating haemolysis as evidenced from measurements of lactate dehydrogenase. Following the hip fracture, the haemolysis increased. Levels of interleukin (IL)-1beta, IL-6, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha increased as did C1-INH, C3, C4, CRP, and lactate dehydrogenase. The results support our hypothesis stating that paradoxical haemolysis in CAD is controlled by the availability of early classical pathway complement molecules and that haemolysis following acute phase responses occurs as a consequence of increased complement synthesis.
Geir E. Tjønnfjord - One of the best experts on this subject based on the ideXlab platform.
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Cold Agglutinin Disease: current challenges and future prospects
Journal of blood medicine, 2019Co-Authors: Sigbjørn Berentsen, Alexandra Roth, Ulla Randen, Bernd Jilma, Geir E. TjønnfjordAbstract:Cold Agglutinin Disease (CAD) is a complement-dependent, classical pathway-mediated immune hemolytic Disease, accounting for 15-25% of autoimmune hemolytic anemia, and at the same time, a distinct clonal B-cell lymphoproliferative disorder of the bone marrow. The Disease burden is often high, but not all patients require pharmacological treatment. Several therapies directed at the pathogenic B-cells are now available. Rituximab plus bendamustine or rituximab monotherapy should be considered first-line treatment, depending on individual patient characteristics. Novel treatment options that target the classical complement pathway are under development and appear very promising, and the C1s inhibitor sutimlimab is currently being investigated in two clinical Phase II and III trials. These achievements have raised new challenges and further prospects, which are discussed. Patients with CAD requiring therapy should be considered for clinical trials.
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Immunoglobulin heavy and light chain gene features are correlated with primary Cold Agglutinin Disease onset and activity.
Haematologica, 2016Co-Authors: Agnieszka Malecka, Sigbjørn Berentsen, Ulla Randen, Geir E. Tjønnfjord, Gunhild Trøen, Anne Tierens, Ingunn Østlie, Jędrzej Małecki, Jan DelabieAbstract:Immunoglobulin heavy chain ( IGH ) and light chain gene sequences of 27 patients with primary Cold Agglutinin Disease (CAD) were studied to find features explaining the heterogeneity of clinical presentation and Disease activity. CAD is a hemolytic anemia mediated by monoclonal IgM anti-I
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Favourable response to therapy with the anti-CD20 monoclonal antibody rituximab in primary chronic Cold Agglutinin Disease.
British journal of haematology, 2001Co-Authors: Sigbjørn Berentsen, Geir E. Tjønnfjord, Robert Brudevold, Bjørn Tore Gjertsen, Ruth Langholm, Erik Løkkevik, Jon Hjalmar Sørbø, Elling UlvestadAbstract:The ‘primary’ form of chronic Cold Agglutinin Disease is a clonal B-cell lymphoproliferative disorder that is notoriously difficult to treat with drugs, including corticosteroids, alkylating agents, alpha-interferon and purine analogues. We performed a small, open, uncontrolled, prospective study to evaluate the effect of therapy with the monoclonal anti-CD20 antibody rituximab. Six patients with clonal CD20+κ+ B-cell proliferation received seven courses of rituximab 375 mg/m2, d 1, 8, 15, and 22. One patient achieved a complete response. Four partial responses were observed, including a response to re-treatment in one patient. Two patients were categorized as non-responders. Haemoglobin levels increased by a median of 4·1 g/dl in the total group and 4·7 g/dl in the responders, who also experienced a substantial improvement of clinical symptoms. The treatment was well tolerated. We discuss the effect of rituximab therapy compared with other treatment options, and try to explain why two individual patients did not respond. Despite the small numbers, the results are very encouraging. Further studies of rituximab therapy for chronic Cold Agglutinin Disease are warranted.
Hitoshi Ogino - One of the best experts on this subject based on the ideXlab platform.
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Type A aortic dissection with Cold Agglutinin Disease.
The Annals of thoracic surgery, 2011Co-Authors: Hiroaki Osada, Hiroyuki Nakajima, Atsushi Shimizu, Atsushi Nagasawa, Hitoshi OginoAbstract:Cold Agglutinin Disease is an uncommon condition characterized by hemagglutination and microvascular thrombosis of red blood cells at low temperatures during cardiopulmonary bypass. We report the rare case of an ambulatory 74-year-old woman with a relatively high thermal amplitude for antibody activation. We performed aortic arch repair for type A aortic dissection using moderately hypothermic cardiopulmonary bypass and warm blood cardioplegia in a retrograde manner. This case report provides evidence that these are safe and suitable techniques for selected aortic arch repair patients with Cold Agglutinin Disease.