Indications of Rituximab in autoimmune diseases

B cell targeted therapies are becoming widespread for the treatment of multiple autoimmune diseases including conditions such as Rheumatoid Arthritis, Multiple Sclerosis and Type ! diabetes typically considered as T cell mediated. This interest stems from the convergence of tremendous progress in understanding the multiple effector and regulatory roles played by B cells in regulating autoimmunity as well as in the promising results reported for B cell depletion in an ever expanding number of autoimmune diseases. This review will review current knowledge of Rituximab-induced B cell depletion in diseases where this therapy is either well established or represents a promising therapeutic avenue with potential to uncover important disease mechanisms.

Introduction

The past few years have witnessed an explosive growth of interest in the use of B cell targeted therapies for the treatment of a wide assortment of autoimmune diseases. As recently reviewed elsewhere, the use of this approach – initially pioneered for the therapy of non-Hodgkin's B cell lymphomas and later for Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) – has spread in both clinical studies and clinical practice to multiple rheumatic diseases such as Sjogren's syndrome, vasculitis and dermatomyositis; neurological diseases (multiple sclerosis, neuromyelitis optica, antibody-mediated paraneoplastic syndromes and IgM-mediated polyneuropathy); endocrinopathies (including Type 1 Diabetes and Graves disease), dermatological conditions (autoimmune blistering diseases); and hematological syndromes (ITP, autoimmune hemolytic anemia and TTP) among many other clinical entities [1, 2]. As it might be expected due to regulatory, ethical and financial considerations, and as formal, randomized, controlled prospective studies are completed, the main use of this therapeutic modality has centered on patients refractory to conventional therapy as dictated by current clinical practice for the disease in question. In this review, I shall summarize the status of knowledge regarding the rationale and evidence for the use of B cell depletion therapy (BCDT) in different autoimmune diseases. Diseases in which the use of BCDT has been most thoroughly tested or may otherwise provide useful information to guide current clinical utilization and/or future studies will represent the focus in this review.

This review will also focus on the use of B cell depletion induced by Rituximab as this drug is now commonly used in clinical practice and provides the vast majority of the information available. Rituximab is a chimeric mouse antihuman CD20 monoclonal antibody initially developed and FDA-approved for the treatment of follicular lymphoma. Owing to the pattern of expression of CD20 Rituximab targets a wide swath of the B cell compartment spanning from pre-B cell to activated memory cells and a fraction of preplasma cells while largely sparing pro-B cells as well as fully differentiated plasma cells (PC). Its pharmacokinetics and the multiple ways in which Rituximab mediates B cell depletion (including direct B cell apoptosis, complement-mediated cytotoxicity, antibody-dependent cell-mediated killing and immune complex decoy actions) have been extensively reviewed in multiple forums and will not be further discussed here [3]. Similarly, other agents that directly or indirectly target different B cell subsets will not be reviewed here.