Rituximab Use in Pediatric Dermatology

July 2016 | Volume 15 | Issue 7 | Original Article | 821 | Copyright © 2016

Melissa B. Hoffman MD,a Rachna A. Bhandari MD,b and Animesh A. Sinha MD PhDc

aUniversity at Buffalo School of Medicine, Buffalo, NY
bDepartment of Dermatology; University of North Carolina, Chapel Hill, NC
cDepartment of Dermatology; University at Buffalo, Buffalo, N

Abstract

Rituximab, an anti CD20 monoclonal antibody leading to transitory B cell depletion, is used to treat a wide variety of immune system tumors and immune mediated diseases. While most of data supporting the efficacy and safety of rituximab in treating autoimmune patients is focused on the adult population, the utilization of rituximab (RTX) for a wide range of pediatric conditions is also increasing. While there are a number of published case reports, a comprehensive review of the various uses for rituximab in pediatric dermatology is lacking. To better assess the therapeutic role of rituximab in the management of skin disease in children, here we comprehensively document reported cases of use including details regarding specific treatment regimens, efficacy and safety profile. Evaluation of the data supports consideration for the initiation of rituximab at early time points in the treatment ladder, before certain diseases become refractory to conventional treatment.

J Drugs Dermatol. 2016;15(7):821-829.

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INTRODUCTION

Rituximab (RTX), first developed for clinical use in 1997, is a monoclonal antibody constructed from human/mouse chimeric IgG1/kappa constant region fused to murine variable regions. It binds with high affinity to cells expressing CD20, an antigen present on all pre-B and mature antibody-producing B cells except for plasma cells. The human region of this chimeric antibody allows it to bind to the Fc receptor on effector cells. Once bound to CD20, RTX causes B lymphocyte death by a variety of mechanisms, which include apoptosis, cell mediated cytotoxicity, and complement mediated cytotoxicity.

Rituximab is currently FDA approved for use in adults with CD20 positive non-Hodgkin’s lymphomas and active rheumatoid arthritis failing anti-tumor necrosis factor (TNF) therapy.1 In children, RTX has been safely and successfully used off-label to treat a wide variety of diseases including chronic immune thrombocytopenic purpura, nephrotic syndrome, and post-transplant lymphoproliferative disease.2,3 Various case reports have demonstrated the growing use of rituximab for a wide variety of pediatric diseases. RTX is now being used to treat several conditions ranging from the autoimmune blistering disorders and other primary dermatologic diseases, dermatologic malignancies, as well as systemic inflammatory diseases with cutaneous manifestations. While there have been numerous reports individually demonstrating success with this monoclonal antibody, there has not yet been a comprehensive review of the various uses for rituximab in pediatric dermatology.

To better assess the therapeutic role of rituximab in pediatric dermatology we have comprehensively documented reported cases in the literature, and further discuss treatment regimens, efficacy, and safety profile. Thus far, rituximab has been used typically only after first-line treatment with systemic corticosteroid therapy has failed. An analysis of the literature suggests consideration of incorporating rituximab at earlier stages of the therapeutic ladder before certain diseases become refractory to conventional treatment, and to avoid the significant side effects that can be associated with many systemic therapies.

Mechanism of Action

RTX binds to all B lymphocyte populations expressing CD20, including immature B cells in the bone marrow, autoantigen-activated follicular and marginal B cells, and memory B cells.4 Hematopoietic stem cells, pro-B cells, plasma cells, and other normal tissue all lack CD20, and are therefore not targeted by rituximab.

Three major mechanisms of action are used to describe how rituximab causes CD20+ B lymphocyte death in vitro: 1) antibody-dependent cellular cytotoxicity, 2) complement-dependent cytotoxicity, and 3) direct induction of apoptosis (Figure 1).5 Antibody-dependent cytotoxicity, which is thought to be the most important mechanism of action of rituximab in vivo, involves the binding of the Fc portion of rituximab to Fc and gamma receptors on natural killer (NK) cells. Thus, when rituximab targets the CD20 antigen on B lymphocytes, this pathway directs B cell death via NK cells. Complement-dependent cytotoxicity occurs because subsequent to rituximab binding to the B cell CD20 receptor, there is binding of human complement C1q, initiating complement mediated lysis of circulating B cells. The third mechanism of action, in which RTX causes

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