Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00011.x
Barbara L. Kroner
Two immune tolerance registries – the International Immune Tolerance Study Group (ITSG) and North American Immune Tolerance Study (NAITS) – are compared and findings from combined data reported. The registries differed with respect to data collection tools, location, host and environmental factors, start date distribution and treatment products. The success and failure rates were similar in the two studies. There was a highly significant association between maximum historical titre and immune tolerance success; the success rate decreased as the historical titre increased. There was a significant association between inhibitor titre immediately prior to treatment and the probability for treatment success, and between outcome and time from diagnosis to treatment in the ITSG (of borderline significance in the NAITS). There was a significant association between outcome and dose, though the direction of the associations was not the same. In the ITSG, success was associated with doses greater than or equal to 200 IU/kg/day, while in the NAITS, greater success was observed with doses of less than 50 IU/kg/day. There was no association between outcome and treatment product. Data from the two registries were combined to produce a table for calculating the chance of successful treatment by historical titre, pretreatment titre, and dose.
{"title":"Comparison of the International Immune Tolerance Registry and the North American Immune Tolerance Registry","authors":"Barbara L. Kroner","doi":"10.1111/j.1423-0410.1999.tb00011.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00011.x","url":null,"abstract":"Two immune tolerance registries – the International Immune Tolerance Study Group (ITSG) and North American Immune Tolerance Study (NAITS) – are compared and findings from combined data reported. The registries differed with respect to data collection tools, location, host and environmental factors, start date distribution and treatment products. The success and failure rates were similar in the two studies. There was a highly significant association between maximum historical titre and immune tolerance success; the success rate decreased as the historical titre increased. There was a significant association between inhibitor titre immediately prior to treatment and the probability for treatment success, and between outcome and time from diagnosis to treatment in the ITSG (of borderline significance in the NAITS). There was a significant association between outcome and dose, though the direction of the associations was not the same. In the ITSG, success was associated with doses greater than or equal to 200 IU/kg/day, while in the NAITS, greater success was observed with doses of less than 50 IU/kg/day. There was no association between outcome and treatment product. Data from the two registries were combined to produce a table for calculating the chance of successful treatment by historical titre, pretreatment titre, and dose.","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00012.x
Harold R. Roberts
{"title":"The Use of Agents that By‐Pass Factor VIII Inhibitors in Patients with Haemophilia","authors":"Harold R. Roberts","doi":"10.1111/j.1423-0410.1999.tb00012.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00012.x","url":null,"abstract":"","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00007.x
Jean‐Marie R. Saint‐Remy, Marc G. Jacquemin, Jean Guy Gilles
Evidence has recently accumulated showing that antiidiotype antibodies specific to anti‐FVIII antibodies are present in the plasma of healthy individuals and of haemophilia A patients with or without inhibitors, where they can neutralise the FVIII inhibitory activity. Additionally, patients successfully desensitised towards FVIII have an increased production of anti‐idiotypic antibodies with no significant reduction in anti‐FVIII antibodies. We review here possible strategies for modulating the anti‐FVIII immune response by idiotypic interactions.
{"title":"Anti‐ldiotypic Antibodies: From Regulation to Therapy of Factor VIII Inhibitors","authors":"Jean‐Marie R. Saint‐Remy, Marc G. Jacquemin, Jean Guy Gilles","doi":"10.1111/j.1423-0410.1999.tb00007.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00007.x","url":null,"abstract":"Evidence has recently accumulated showing that antiidiotype antibodies specific to anti‐FVIII antibodies are present in the plasma of healthy individuals and of haemophilia A patients with or without inhibitors, where they can neutralise the FVIII inhibitory activity. Additionally, patients successfully desensitised towards FVIII have an increased production of anti‐idiotypic antibodies with no significant reduction in anti‐FVIII antibodies. We review here possible strategies for modulating the anti‐FVIII immune response by idiotypic interactions.","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00005.x
E.G.D. Tuddenham
Mutation genotype studies have led to a number of interesting observations about the role of the different types of mutations in inhibitor development. Searchable information on mutations, phenotype data, models, etc., are available on the internet at http://europium.mrc.rpms.ac.uk. A relatively high incidence of inhibitors occurs in patients with deletion mutations. Stop mutations are also associated with a high incidence of inhibitors, although there is anomalous distribution of the inhibitors associated with different stop codons. Inhibitors have been associated with a small number of missense mutations. Missense mutations are of great interest from the structure/function viewpoint; in many instances, a missense mutation which results in reduced function of a circulating protein can be mapped onto a model structure and inferences can be made about the effects on the functionality of the protein. A model of the A domains of FVIII is available, but as yet, no structure is available on which to model the C domain of FVIII. Stop codons appear to have a different incidence of inhibitor formation compared to other types of mutations. It is concluded that while genotype mutation studies have led to a number of interesting observations about the role of the different types of mutations in inhibitor development, though more questions have been raised than answers provided to date.
通过突变基因型研究，我们对不同类型的突变在抑制剂研发中的作用有了许多有趣的观察。有关突变、表型数据、模型等的可搜索信息可在互联网 http://europium.mrc.rpms.ac.uk 上获得。缺失突变患者的抑制剂发生率相对较高。终止突变也与抑制剂的高发病率有关，但不同终止密码子的抑制剂分布异常。抑制剂与少数错义突变有关。从结构/功能的角度来看，错义突变具有极大的意义；在许多情况下，导致循环蛋白功能降低的错义突变可以映射到模型结构上，从而推断出对蛋白功能的影响。目前已有 FVIII A 结构域的模型，但还没有 FVIII C 结构域的模型。与其他类型的突变相比，终止密码子形成抑制剂的几率似乎有所不同。结论是，虽然基因型突变研究对不同类型的突变在抑制剂形成中的作用提出了许多有趣的看法，但迄今为止提出的问题比给出的答案要多。
{"title":"Molecular Biological Aspects of Inhibitor Development","authors":"E.G.D. Tuddenham","doi":"10.1111/j.1423-0410.1999.tb00005.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00005.x","url":null,"abstract":"Mutation genotype studies have led to a number of interesting observations about the role of the different types of mutations in inhibitor development. Searchable information on mutations, phenotype data, models, etc., are available on the internet at <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"http://europium.mrc.rpms.ac.uk\">http://europium.mrc.rpms.ac.uk</jats:ext-link>. A relatively high incidence of inhibitors occurs in patients with deletion mutations. Stop mutations are also associated with a high incidence of inhibitors, although there is anomalous distribution of the inhibitors associated with different stop codons. Inhibitors have been associated with a small number of missense mutations. Missense mutations are of great interest from the structure/function viewpoint; in many instances, a missense mutation which results in reduced function of a circulating protein can be mapped onto a model structure and inferences can be made about the effects on the functionality of the protein. A model of the A domains of FVIII is available, but as yet, no structure is available on which to model the C domain of FVIII. Stop codons appear to have a different incidence of inhibitor formation compared to other types of mutations. It is concluded that while genotype mutation studies have led to a number of interesting observations about the role of the different types of mutations in inhibitor development, though more questions have been raised than answers provided to date.","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00003.x
Jeanne M. Lusher
{"title":"Inhibitor Development in Prospective Clinical Trials with Recombinant Factor VIII Preparations in Previously Untreated Patients","authors":"Jeanne M. Lusher","doi":"10.1111/j.1423-0410.1999.tb00003.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00003.x","url":null,"abstract":"","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00021.x
Jan Astermark, Erik Berntorp
Malmö International Brother Study (MIBS) was initiated in 1996 in order to set up an international registry of twins and non‐twin brothers with haemophilia and to search for genetic and compound factors predisposing for inhibitor development. As of July, 1997, 178 brother pairs are registered (143 haemophilia A and 35 haemophilia B patients). Sixteen of these pairs are twins. In 48 of the brother pairs (27%) there is a history of inhibitors, in 25 of them involving only one of the brothers. Immune tolerance induction has been attempted in 13 brother pairs (27%) and in four pairs the inhibitor has been eradicated. Additional demographic data need to be collected and, if possible plasma, IgG and DNA samples will be taken from inhibitor patients to serve as a tool for basic inhibitor experiments.
马尔默国际兄弟研究（Malmö International Brother Study，MIBS）于 1996 年启动，目的是建立一个血友病双胞胎和非双胞胎兄弟的国际登记册，并寻找导致抑制剂产生的遗传和复合因素。截至 1997 年 7 月，共有 178 对兄弟进行了登记（143 名 A 型血友病患者和 35 名 B 型血友病患者）。其中 16 对是双胞胎。在 48 对兄弟中（27%），有抑制剂病史，其中 25 对仅涉及兄弟中的一人。有 13 对兄弟（27%）尝试了免疫耐受诱导，有 4 对兄弟的抑制剂已被根除。需要收集更多的人口统计学数据，如有可能，还将从抑制剂患者身上采集血浆、IgG 和 DNA 样本，作为抑制剂基础实验的工具。
{"title":"Malmö International Brother Study (MIBS): An International Survey of Brother Pairs with Haemophilia","authors":"Jan Astermark, Erik Berntorp","doi":"10.1111/j.1423-0410.1999.tb00021.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00021.x","url":null,"abstract":"Malmö International Brother Study (MIBS) was initiated in 1996 in order to set up an international registry of twins and non‐twin brothers with haemophilia and to search for genetic and compound factors predisposing for inhibitor development. As of July, 1997, 178 brother pairs are registered (143 haemophilia A and 35 haemophilia B patients). Sixteen of these pairs are twins. In 48 of the brother pairs (27%) there is a history of inhibitors, in 25 of them involving only one of the brothers. Immune tolerance induction has been attempted in 13 brother pairs (27%) and in four pairs the inhibitor has been eradicated. Additional demographic data need to be collected and, if possible plasma, IgG and DNA samples will be taken from inhibitor patients to serve as a tool for basic inhibitor experiments.","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00017.x
Paul Knöbl, Kurt Derfler
Background and Objectives: This article reviews the relevance of immunoadsorption in the treatment of haemophilic patients with inhibitors. Materials and Methods: Immunosorba (sepharose‐bound staphylococcal protein A) and Ig‐Therasorb (sepharose‐bound polycional sheep antibodies to human immunoglobulin) columns are suitable for the clinical use of immunoadsorption. They allow the processing of large plasma volumes (>7,000 ml) without relevant side‐effects. Results: A haemophilic patient was treated with the Malmö protocol, another was admitted with intracerebral bleeding. Immunoadsorption reduced the inhibitor titer by 70–90%. Conclusions: Immunoadsorption can be used in cases of acute bleeding, before surgery, acquired factor VIII (FVIII) antibodies, and before the start of immune tolerance therapy. We suggest the inclusion of this method in immune tolerance protocols in order to improve levels, recovery, and half‐life of FVIII and to save concentrates.
背景与目的：本文回顾了免疫吸附在治疗嗜血患者抑制剂中的相关性。材料与方法：Immunosorba（sepharose-bound staphylococcal protein A）和 Ig-Therasorb（sepharose-bound polycional sheep antibodies to human immunoglobulin）色谱柱适用于免疫吸附的临床应用。它们可处理大容量血浆（7000 毫升），且无相关副作用。结果一名血友病患者接受了马尔默方案治疗，另一名患者因脑内出血入院。免疫吸附使抑制剂滴度降低了 70-90%。结论免疫吸附可用于急性出血、手术前、获得性因子 VIII (FVIII) 抗体和开始免疫耐受治疗前。我们建议将这种方法纳入免疫耐受方案，以提高 FVIII 的水平、恢复和半衰期，并节省浓缩液。
{"title":"Extracorporeal Immunoadsorption for the Treatment of Haemophilia Patients with Inhibitors to Factor VIII or IX","authors":"Paul Knöbl, Kurt Derfler","doi":"10.1111/j.1423-0410.1999.tb00017.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00017.x","url":null,"abstract":"<jats:italic>Background and Objectives:</jats:italic> This article reviews the relevance of immunoadsorption in the treatment of haemophilic patients with inhibitors. <jats:italic>Materials and Methods:</jats:italic> Immunosorba (sepharose‐bound staphylococcal protein A) and Ig‐Therasorb (sepharose‐bound polycional sheep antibodies to human immunoglobulin) columns are suitable for the clinical use of immunoadsorption. They allow the processing of large plasma volumes (>7,000 ml) without relevant side‐effects. <jats:italic>Results:</jats:italic> A haemophilic patient was treated with the Malmö protocol, another was admitted with intracerebral bleeding. Immunoadsorption reduced the inhibitor titer by 70–90%. <jats:italic>Conclusions:</jats:italic> Immunoadsorption can be used in cases of acute bleeding, before surgery, acquired factor VIII (FVIII) antibodies, and before the start of immune tolerance therapy. We suggest the inclusion of this method in immune tolerance protocols in order to improve levels, recovery, and half‐life of FVIII and to save concentrates.","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00016.x
Y. Sultan
Low‐dose immune tolerance protocols use doses of factor VIII of less than 50 IU/kg/day to induce immune tolerance. Such protocols are chosen for a variety of reasons including cost, patient acceptability and ease of administration. Early published reports of low‐dose protocols appeared in 1981, described small numbers of patients and moderate success. It was proposed that such protocols might modify inhibitor responses from high to low. Later reports are sparse and clinical success is again moderate. Useful treatment and expectation guidelines have emerged from experience with these protocols, and improvements for patients with inhibitors can be achieved. Consideration of immunological success, however, raises doubts about whether real immune tolerance is achieved with such protocols.
{"title":"Immune Tolerance Protocols Using Low‐Dose Factor VIII: A Review of the Literature","authors":"Y. Sultan","doi":"10.1111/j.1423-0410.1999.tb00016.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00016.x","url":null,"abstract":"Low‐dose immune tolerance protocols use doses of factor VIII of less than 50 IU/kg/day to induce immune tolerance. Such protocols are chosen for a variety of reasons including cost, patient acceptability and ease of administration. Early published reports of low‐dose protocols appeared in 1981, described small numbers of patients and moderate success. It was proposed that such protocols might modify inhibitor responses from high to low. Later reports are sparse and clinical success is again moderate. Useful treatment and expectation guidelines have emerged from experience with these protocols, and improvements for patients with inhibitors can be achieved. Consideration of immunological success, however, raises doubts about whether real immune tolerance is achieved with such protocols.","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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