AutoimmunityIndications of Rituximab in autoimmune diseases
Section editors:
Michel Goldman – Innovative Medicines Initiative, COV2, Brussels, Belgium
Lucienne Chatenoud – Inserm U1013, Paris, France
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.
Section snippets
Rationale and working models to understand B cell depletion in autoimmune diseases
Autoantibodies are considered crucial contributors to the pathogenesis of most, if not all, autoimmune diseases whether through the generation of proinflammatory circulating immune complexes (conventional type 3 hypersensitivity reaction), antibody-mediated cytotoxicity (type 2 hypersensitivity) or as inducers of type IFN production [4, 5]. Of note however, the actual contribution of autoantibodies to disease is far from clear in many conditions, may differ between diseases, within disease
Rituximab in Rheumatoid Arthritis
RA remains the only non-malignant conditions for which Rituximab has received FDA approval. On the basis of strong clinical benefit in controlled studies, current practice centers on the use of Rituximab together with methotrexate for the treatment of cases refractory to anti-TNF agents [15]. Such approach has a beneficial impact on radiological progression [16]. Although the duration of clinical benefit may vary and include long-standing responses in a small fraction of patients, most patients
Rituximab in multiple sclerosis
Rituximab-induced BCDT has shown highly promising results in the relapsing-remitting form of multiple sclerosis (RRMS) in a phase II double-blind study in which a very significant decrease in total and new gadolinium enhancing lesions was observed as early as week 12 after treatment [14]. This benefit was sustained over the 48 weeks of follow-up after a single cycle of Rituximab was administered. In this study, the rapid clinical benefit observed in the absence of significant decreases in
Rituximab in ANCA-mediated vasculitis
Early open label studies of Rituximab suggested a striking benefit of this intervention in refractory ANCA-mediated vasculitis (AMV). One striking feature of at least some of the initial studies was a steep decline in ANCA titers [27, 28]. The interpretation of these changes is complicated by the concomitant use of high dose corticosteroids in one study [27] and the observation in another study that clinical response often preceded significant decline in autoantibody titers [29]. Nevertheless,
Rituximab in Type 1 Diabetes
While most immunological and therapeutic studies of Type 1 Diabetes (T1D) have concentrated on T cells, autoantibodies are almost universal markers of this disease and when appropriately used represent a major risk factor for disease development. This fact, together with numerous animal studies indicating a major role for B cells in the pathogenesis of T1D led to the design and implementation of a clinical trial of Rituximab in patients with new onset T1D whose initial results were recently
Rituximab in SLE
The actual benefit of Rituximab in SLE continues to baffle physicians and scientists alike. From a pathophysiological standpoint, this disease characterized by high levels of multiple autoantibodies and florid abnormalities of B cell homeostasis and activation would appear to be an ideal target for BCDT. Indeed, and in keeping with this notion, early open label studies indicted substantial benefit in SLE including induction of long-term remissions with a single course of Rituximab in the
Clinical use and monitorization
In most clinical situations Rituximab is now used as two 1 g IV infusions two weeks apart. There is no evidence that the original ‘lymphoma’ regimen of four infusions of 375 mg/m2 provides significant advantages and has the drawback of inconvenience to the patient. As discussed in multiple reviews, concurrent medication with corticosteroids and antihistamines is typically used to minimize infusion reactions which may be more frequent in SLE. When measured by conventional flow cytometry and
Acknowledgement
This work was supported in part by NIH U19 AI56390, Rochester Autoimmunity Center of Excellence.
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Rituximab and its Use in Autoimmune Bullous Disorders
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