Rituximab in the Treatment of Pemphigus Vulgaris

Labib R. Zakka 0 Shawn S. Shetty 0 A. Razzaque Ahmed 0 0 L. R. Zakka S. S. Shetty A. R. Ahmed (&) Center for Blistering Diseases , 697 Cambridge Street 302, Boston, MA 02135, USA Introduction: Rituximab is increasingly used in patients with pemphigus vulgaris (PV) who are nonresponders to conventional therapy. Methods: A PubMed search was conducted using the words pemphigus vulgaris and rituximab therapy from papers published between 2000 and 2012. Two protocols were used. In the lymphoma protocol, patients received four weekly infusions of rituximab (dose 375 mg/m2). The rheumatoid arthritis (RA) protocol consisted of two infusions of 1,000 mg each 15 days apart. The variables recorded from each study included clinical remission off or on therapy, relapse rate, incidence of serious adverse events, concomitant therapies, duration of follow-up, and when available, levels of B cells and autoantibodies. Results: Forty-two studies were found, which reported 272 patients; 180 were treated by the lymphoma protocol and 92 by the RA protocol. Both protocols were effective in treating recalcitrant PV. The lymphoma protocol had a lower response rate, relapse rate and serious infections, but higher mortality, and there were nonresponders. The RA protocol produced a higher response rate, relapse rate, number of infections, but lower mortality rate, and lacked nonresponders. The cumulative follow-up for patients treated with the lymphoma protocol was 15.44 months (range 1-41) and 21.04 months (range 8.35-29) for the RA protocol. A major concern in both protocols was the high infection rates, some of which were fatal. A different protocol using a combination of rituximab with intravenous immunoglobulin in a defined manner with a definitive endpoint, used in a limited cohort of patients, showed promising results. Conclusion: Neither protocol produced a sustained clinical remission and both required continued systemic therapy. Before initiation of treatment, physicians should have a specific - goal and endpoint and be aware of its potential side effects and lack of information on its longterm effects. Patients should be carefully monitored during and after therapy. INTRODUCTION Pemphigus vulgaris (PV) is a potentially fatal autoimmune mucocutaneous blistering disease that involves the skin and the mucous membranes [1]. PV is a rare disease with an incidence of approximately 0.13.2 cases per 100,000 individuals annually worldwide [2]. It is a disease of the middle-aged population, typically occurring after the age of 50 years, although some cases have been reported in younger adults and children [3]. PV is seen more frequently in people of Mediterranean decent and Ashkenazi Jews [4]. The incidence in men and women is equal [5]. The histology of PV is an intra-epidermal vesicle with acantholysis [6]. The described antigens are desmoglein 1 (Dsg 1) and desmoglein 3 (Dsg 3) [7]. The immunopathology demonstrates deposition of autoantibodies on keratinocyte cell surfaces and their presence in patients sera [8]. The mainstay of treatment of PV is systemic corticosteroids. Immunosuppressive agents (ISAs) are used for their steroid-sparing effect and possible ability to reduce autoantibody production [911]. Many patients do not respond to high dose long-term corticosteroids in combination with multiple ISAs. Newer methods of treatment, such as rituximab, have shown promise in such patients. Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule on B cells resulting in their lysis [12]. Pro-B cells, plasmablasts, and plasma cells do not express the CD20 molecule, and are unaffected by rituximab [12]. In 1997, the US Food and Drug Administration approved its use in lymphoma, in 2006 for rheumatoid arthritis (RA), in 2010 for chronic lymphocytic leukemia, and in 2011 for Wegeners granulomatosis [13]. Its use in PV is off label [14]. The rationale for the use of rituximab in patients with PV is based on its ability to deplete CD20? B cells that presumably produce pathogenic antibodies [12]. The purpose of this review is to provide a critical analysis of the use of rituximab in the treatment of patients with PV. A PubMed search was conducted using the following keywords: pemphigus vulgaris, rituximab, anti-CD20 monoclonal antibody. The patients included in this review were derived from studies published between 2000 and the present. The following inclusion criteria were used: (1) English language; (2) clinical profile consistent with PV; (3) routine histology demonstrating suprabasilar cleft with acantholysis; (4) demonstration of intra-epidermal deposition of immunoreactants on perilesional skin processed by direct immunofluorescence; (5) whenever possible, information on treatments used concomitantly as well as after rituximab therapy; (6) information on dose and frequency of rituximab therapy; (7) provision of clinical outcomes at the end of the study period; (8) occurrence of relapses if they occur, and management of the relapse; (9) reporting the length of follow-up; (10) documentation of serious adverse events, especially infections and mortality or lack thereof. The information retrieved was categorized as follows: patient number, dose of rituximab and number of cycles, concomitant therapies, follow-up duration, adverse effects, clinical outcomes, relapses with re-treatments, levels of B cells, and autoantibody levels. The data are divided into case reports and case series. Case series included a minimum of six patients. The patients were treated according to the lymphoma or RA protocol with rituximab. The lymphoma protocol consists of four weekly infusions of 375 mg/m2 [14]. The RA protocol consists of two infusions of 1,000 mg 2 weeks apart [14]. Clinical outcomes of rituximab therapy included were used as described by Murrell et al. [15]. Complete remission on or off therapy was recorded as reported. In this analysis, partial responders were those patients in whom, after the initiation of rituximab therapy, the dose of systemic corticosteroids and immunosuppressive agents could be reduced by less than 50% compared to the prerituximab dose. Furthermore, in those patients, clinical disease occurred at intermittent periods, but did not require additional systemic therapy. Nonresponders were those patients who showed no clinical improvement and were considered treatment failures. In 42 different publications, information on a total of 272 individual patients with PV treated with rituximab between 2000 and 2012 was available [1657]. These data were divided into patients treated by (1) the lymphoma protocol, (2) the RA protocol, and (3) modifications or different combinations of either protocol. The information in each of the protocols was divided into case reports and case series. In the lymphoma protocol, 22 case reports described 48 patients [1637] and seven case series described 88 patients [4349]. There are thus 136 patients who were treated by the lympho (...truncated)