In recent years, advances in our understanding of the regulation of the immune system have enabled the identification of cellular and molecular targets that could potentially affect the pathogenesis of many autoimmune diseases. In particular, the demonstration that B lymphocytes could play a central role in pathogenesis suggests that their elimination may be a highly beneficial therapeutic goal in a variety of diseases. Hybridoma antibody technology has been applied as a first step toward developing such specific agents. One of the initial applications of this technology was the characterization of the surface molecules on lymphocytes, to enable the discrimination of each type of lymphocyte. These early studies identified CD20 as a specific marker for B cells (1). CD20 has been found to be highly expressed on the surface of pre–B lymphocytes as well as on both resting and activated mature B lymphocytes, whereas it is not expressed by hematopoietic stem cells, pro–B cells, or other normal tissues (Figure 1). However, despite extensive investigation, the role of CD20 in B cell physiology has remained a mystery; there is no known natural ligand, and CD20-knockout mice are without a discernible immunologic phenotype (2). From the characterization of its encoding gene, CD20 has been predicted to be a 33–37-kd membraneassociated phosphoprotein, with a structure of 4 transmembrane regions, a 44–amino acid extracellular loop, and cytoplasmic Nand C-termini (3). Based on structural homologies, CD20 has been postulated to function as a calcium channel subunit (for review, see ref. 4), which may explain the finding that ligation of CD20 can affect B cell activation, differentiation, and cell cycle progression from the G1 to the S phase (5,6). Important for its use as a therapeutic target, binding of CD20 does not modulate its expression or result in substantial internalization. CD20 is also not shed, and there are no other known membrane or secreted analogs to interfere with its use for B cell targeting (7). In recent reports, the properties of different monoclonal antibodies against human CD20 have been investigated (8). The clinical potential of CD20-targeted therapy derives, in large part, from the unexpected finding that treatment with an antibody to CD20 induces the death of B lymphocytes, even without the need to conjugate the antibody to a toxin. The best-exploredmechanism has been the properties of rituximab (trade name Rituxan), a chimeric monoclonal antibody specific for human CD20, comprising the variable regions of a murine anti-human CD20 B cell hybridoma fused to human IgGand -constant regions (9) (see Figure 1). Rituximab has a binding affinity for human CD20 of 8 nM. The clearance of B cells is, in part, mediated through induction of complement-mediated activities and triggering of antibody-dependent cellular cytotoxicity. This latter activity is dependent on interactions with cellular receptors for the IgG1-constant regions (i.e., Fc receptors), especially Fc receptor type IIIa, which is expressed on a variety of cells including phagocytic cells (10). Rituximab has also been shown to directly trigger intracellular pathways for apoptotic B cell death that involve the activation of phospholipase C , interruption of the signal transducer and activator of transcription 3/interleukin-6 pathway, down-regulation of c-myc, and up-regulation of the proapoptosis molecule Bax, a member of the Bcl-2 family (11,12). This sequence of molecular events results in the activation of Supported by grants AI-40305, AR-47360, and AI-46637 from the NIH, and a grant from the Alliance for Lupus Research. Gregg J. Silverman, MD, Stuart Weisman, MD: University of California, San Diego. Address correspondence and reprint requests to Gregg J. Silverman, MD, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663. E-mail: gsilverman@ucsd.edu. Submitted for publication September 16, 2002; accepted in revised form January 28, 2003.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/art.10947

Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy

Rituximab for the treatment of refractory autoimmune hemolytic anemia in children

Autoimmune haemolytic anaemia (AIHA) is an immune disorder caused by antibodies directed against unmodified autologous red cells. The disorder may be a primary (idiopathic) or a secondary disease. The diagnosis is based on the presence of anaemia, signs of haemolysis with reticulocytosis, low haptoglobin, increased lactate dehydrogenase, elevated indirect bilirubin, and a positive direct antiglobulin test (Coombs test). Sometimes, not all of these typical features are present. Most AIHA are caused by warm antibodies, whereas cold antibodies are less commonly detected. While half of the warm antibody-based AIHA are idiopathic anaemias, almost all cold antibody AIHA are secondary anaemias. Underlying diseases are Non Hodgkin's lymphomas and systemic autoimmune disorders, and less frequently organ transplantation, infections, or solid tumors. Moreover, AIHA is an important complication of treatment with nucleoside analogs. Most patients with AIHA require therapy. In warm antibody AIHA, standard first line therapy are glucocorticosteroids with or without high dose immunoglobulins, whereas splenectomy is considered second-line therapy. Response rates of primary AIHA to corticosteroid therapy are high. After initial remission, the dose should be tapered down slowly and with caution, and in some cases, low-dose maintenance therapy is required. The efficacy of standard therapy is low in secondary AIHA that develops in lymphoma patients, posttransplant patients, or tumor patients. Among other immunosuppressive treatments, rituximab (anti-CD20) appears to be highly effective in patients with warm antibody AIHA refractory to standard therapy. Mycophenolate mofetil is quite effective in AIHA patients with an underlying autoimmune or lymphoproliferative disease. Patients with cold agglutinins are refractory to steroids and splenectomy. Half of these patients may respond to rituximab, although responses usually are short-lived. Sometimes, AIHA that is associated with malignant lymphomas or tumors, disappears after successful anti-lymphoma or anti-tumor therapy.

Diagnosis and treatment of autoimmune haemolytic anaemias in adults: a clinical review.

In recent years, clinical studies have been undertaken with selected monoclonal antibodies (MoAbs) in the treatment of several hematological diseases, especially in malignant disorders. However, some clinical observations indicate that MoAbs may be an important alternative for the conventional therapy of some autoimmune disorders. Two MoAbs directed against CD20 antigen (rituximab, Rituxan, Mabthera) and CD52 antigen (alemtuzumab, Campath-1H) seem to be especially useful for this purpose. Autoimmune cytopenias have been investigated in the last few years with positive preliminary results. Rituximab seems to be an effective and safe agent for the treatment of immune thrombocytopenias, autoimmune hemolytic anemia, cold agglutinin disease and pure red cell aplasia. Although the case series are small, rituximab seems to be an effective and safe agent for the treatment of these diseases. Clinical experience with alemtuzumab in patients with autoimmune cytopenias is even more limited than with rituximab. However, preliminary results indicate that further studies with this MoAb are warranted. A longer follow-up and the studies on larger number of patients are needed to determine the real value of these new approaches in autoimmune cytopenias. Recent experiences with the use of MoAbs in treatment of these diseases are the subject of this review.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.0902-4441.2003.00196.x

Monoclonal antibodies in the treatment of autoimmune cytopenias.

Standard treatment for autoimmune hemolytic anemia (AIHA) due to warm antibodies includes combinations of glucocorticoids, immunosuppressive drugs (mainly azathioprine) and splenectomy. Patients who are refractory or intolerant to these therapies constitute an important therapeutic challenge. Rituximab, an anti-CD20 chimeric monoclonal antibody, can effectively deplete B-cells and is commonly used in B-cell non-Hodgkin lymphoma. In addition, it is being increasingly used in autoimmune disorders, such as idiopathic thrombocytopenic purpura, AIHA, systemic lupus erythematosus or vasculitis. We report a case of warm AIHA associated to primary antiphospholipid syndrome (APS). The patient was refractory to high-dose corticosteroids. Splenectomy was discarded in view of the high risk of thrombotic and/or hemorrhagic perioperative complications, due to the presence of APS. After treatment with four weekly doses of rituximab the patients had a rapid and sustained response which allowed progressive tapering of prednisone dose to 5 mg/d. In addition, IgM anticardiolipin titres decreased from > 600 MPL to < 100 MPL. Thirteen further cases of warm AIHA in adults treated with rituximab have been reviewed, showing excellent tolerance and high response rates. Rituximab may be considered prior to splenectomy in patients with refractory AIHA and high risk of complications following splenectomy.

Sustained response to rituximab of autoimmune hemolytic anemia associated with antiphospholipid syndrome

Mixed warm and cold autoimmune hemolytic anemia: complete recovery after 2 courses of rituximab treatment

The interferons are cytokines with a wide array of biological properties. In hematological malignancies the most used IFN class is -alpha; it has been used for thirty years but the mode of action is still not absolutely clear. Nevertheless, the benefits of IFN-alpha for the treatment of CMD have been described in particular for CML and less for PV, ET and MMM. IFN-alpha is presently considered the golden standard of therapy for CML patients not eligible for SCT; the antileukemic effect has been well documented by hematological and cytogenetic response. The survival advantage for IFN treated patients is remarkable in comparison with patients treated with conventional chemotherapy. Recently, the combination IFN-alpha plus Ara-C has demonstrated to increase the rate of major cytogenetic response and to prolong survival. To date, there is not a generally accepted treatment for ET, PV and MMM, which can reduce the risk of thromboembolism and/or hemorragic events. In several subsets of ET and PV patients, IFN-alpha can be considered as first line therapy. IFN-alpha is usually associated with the development of early and later side effects, that reduce the enthusiasm for its use. In the future PEG-IFN-alpha would improve the quality of life of IFN-treated CMD patients.

The role of interferon-alpha in the treatment of myeloproliferative disorders.

Persistent polyclonal B lymphocytosis: morphological, immunological, cytogenetic and molecular analysis of an Italian case

The role of interferon-alpha in the treatment of myeloproliferative disorders.Curr Pharm Des

"Gloves and socks" papular purpuric syndrome following primary infection with parvovirus B19: a link between dermatologists and haematologists.

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