Rituximab treatment for chronic refractory idiopathic thrombocytopenic purpura
Introduction
Idiopathic thrombocytopenic purpura (ITP) is an organ-specific autoimmune disorder characterized by a low platelet count and mucocutaneous bleeding. The decrease of platelets is caused by increased autoantibodies against self-antigens, particularly IgG antibodies against GPIIb/IIIa and direct T-cell-mediated cytotoxicity [1], [2]. The incidence of ITP is approximately 100 cases/106 per year; of those affected, about half are adults [3], [4]. A prospective registry showed that the incidence of children ITP was 4.8/105 per year [5]. The adult ITP is usually chronic and affects women twice than men [3], [6], [7]. It is becoming clear that the pivotal process of the humoral immune response in the pathogenesis of the disorder is a complex interaction among antigen-presenting cells (APCs), T cells and B cells [8]. The autoantibodies are directed against the individual's own platelets, resulting in increased Fc-mediated platelet destruction by macrophages in the reticuloendothelial system [9]. T-cell-mediated cytotoxicity is an alternative mechanism for platelet destruction in ITP [1]. The treatment regimens for ITP include corticosteroids, intravenous immunoglobulin (IVIg), intravenous anti-D immunoglobulin, splenectomy, danazol and other immunosuppressive drugs [10], [11], [12]. The mechanisms of current therapies include decreasing the accelerated platelet destruction by FcR blockade/activating and immunosuppression and enhancing platelet production [13], [14], [15]. In generally, most patients with ITP have a good outcome and never experience serious bleeding even with severe thrombocytopenia. The frequency of death from complications of treatment is similar to the frequency of death from bleeding [16], [17]. However, about 10–30% patients with ITP cannot keep “safe” platelet counts through standard treatment with corticosteroids, IVIg, or splenectomy. Moreover, there is no consensus on the best treatment strategy for the refractory ITP [15], [17], [18]. Most of them will become refractory to corticosteroids and splenectomy, as well as other available agents such as IVIg, danazol, or chemotherapy. The treatment options for chronic ITP and refractory ITP were summarized in Table 1.
Different targeted immunotherapies have been explored in chronic refractory ITP, such as anti-CD20, anti-CD154 and anti-CD52 antibodies [19], [20], [21]. This review will summarize the therapeutic mechanisms and clinical results of rituximab, a chimeric anti-CD20 monoclonal antibody, in the treatment of chronic ITP.
Section snippets
Role of B cells in ITP
ITP is characterized by the presence of autoreactive immunoglobulins (Ig) on the platelet surface (platelet-associated Ig, PAIg) resulting in immune-mediated platelet destruction by the reticuloendothelial system. The sensitized platelet interacts with splenic macrophages via the Fc receptor (FcR), and is subsequently phagocytosed [22]. This explanation was further supported by studies where therapy with reticuloendothelial blockade was employed, such as high-dose IVIg and anti-D treatment [23].
The therapeutic mechanisms of rituximab
CD20 antigen is a nonglycosylated protein of 33–35 kDa. It appears on B cells at the pre-B stage and disappears during differentiation to plasma cells [46]. Both immature B cells and mature naïve and memory B cells express CD20. The B-cell restricted cell surface phosphoprotein CD20 is involved in many cellular signaling events including proliferation, activation, differentiation, and apoptosis upon cross-linking [47].
Rituximab, an agent commonly employed in the treatment of non-Hodgkin's
Clinical use of rituximab in ITP
The British Committee for Standards in Haematology (BCSH) defines patients who fail to respond to first line treatment or require unacceptably high doses of corticosteroids to maintain a safe platelet count as refractory ITP [74].
Refractory ITP represents a life-threatening condition, having failed to respond to a variety of therapeutic measures. The treatment regimens available for second line therapy in refractory ITP were shown in Table 1. However, the variety itself also reflects their
Conclusions
Rituximab still is expensive comparing with other first-line treatment measures for many patients with ITP. However, according to Perez-Calvo's data, for the reducing time of hospital admissions and visited the clinic, rituximab seems to be more cost-effective than standard therapy for refractory cases, as it allowed a reduction of 50% of direct costs [129].
Rituximab appears to be a promising immunotherapeutic agent for the treatment of ITP, especially severe and symptomatic ITP refractory to
Reviewers
Ellis J. Neufeld, MD, PhD, Division of Hematology/Oncology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, United States.
Nichola Cooper, MD, Institute of Child Health, Molecular Immunology Unit, 30 Guildford Street, London WC1N 1EH, United Kingdom.
Acknowledgements
This work was supported in part by grants of National Natural Science Foundation of China (30670900), Ministry of Education of China (20060023031), Ministry of Personnel of China (2006) and Tianjin Key Project for Basic Research (06YFJZJC01800). The authors thank Prof. Man-Chiu Poon (University of Calgary, Canada) for critical review of the manuscript.
Zeping Zhou received his medical master's degree in 2004 from Kunming Medical College, China. He is currently a M.D. fellow in the Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College. His research is focused on ITP. He has published several papers.
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Zeping Zhou received his medical master's degree in 2004 from Kunming Medical College, China. He is currently a M.D. fellow in the Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College. His research is focused on ITP. He has published several papers.
Renchi Yang graduated from Tongji Medical University in 1988 and from Peking Union Medical College with M.D. degree in 1995. He has engaged in clinical work in Department of Hematology, Institute of Hematology and Blood Diseases Hospital, CAMS and PUMC, China for 18 years and was at Institut des Vaisseaux et du Sang, Paris as visiting Scholar for 1 year. He is currently Professor of Hematology and Head of Department of Hemostasis and Thrombosis. Dr. Yang has published approximately 100 papers in peer-reviewed journals and several books.