Treatment of Bullous Pemphigoid With Rituximab: Critical Analysis of the Current Literature

June 2013 | Volume 12 | Issue 6 | Original Article | 672 | Copyright © June 2013

Shawn Shetty MD and A. Razzaque Ahmed MD DSc

Center for Blistering Diseases, Boston, MA

Abstract
The objective of this review was to critically analyze the currently available literature on the use of rituximab to treat patients with bullous pemphigoid (BP). The focus was to highlight clinical outcomes, treatment protocols, and adverse effects. A PubMed search from 2000 to the present day was conducted, using “bullous pemphigoid” and “rituximab” as keywords. Inclusion criteria were a description of the clinical disease, histology and immunopathology typical of BP, the use of at least 1 infusion of rituximab, and the availability of follow-up after rituximab treatment. Sixteen patients (12 adults and 4 children) were identified. Fourteen patients were treated according to the Lymphoma Protocol and 2 patients according to the Rheumatoid Arthritis Protocol. In the final clinical outcome after treatment with rituximab, 11 out of 16 (69%) had Complete Response, 1 (6%) had Partial Response, 1 (6%) had No Response, and 3 (19%) died. Two died of sepsis, including 1 child, and 1 died from cardiac effects. Three (20%) had serious infections. More than 1 cycle of rituximab was required in 38% of the patients who achieved Complete Response. The mean follow-up period was 15.6 months (range 1–36), which is a serious limitation of the available data. Rituximab is a useful option for BP patients who are recalcitrant to conventional therapy. A specific protocol for the use of rituximab to treat BP patients is not yet available. Since infection and mortality rates are of concern, careful and close monitoring may be necessary.

J Drugs Dermatol. 2013;12(6):672-677.

INTRODUCTION

Bullous pemphigoid (BP) is a potentially fatal autoimmune blistering disease that typically affects the elderly, but has also been reported in children.1,2 Bullous pemphigoid usually manifests as tense subepidermal blisters. Deposition of immunoglobulin G (IgG) with or without complement at the basement membrane zone (BMZ) of perilesional skin is pathognomonic.1 Antibodies to BMZ proteins are frequently detected in patients’ sera.1
Patients with limited disease involvement may respond to topical therapy. Patients with mild to moderate forms of the disease are often treated with systemic antibiotics with nicotinamide.3 Alternatively, those with more extensive forms of the disease often require systemic corticosteroids (CS) and immunosuppressive agents (ISA).3 The long-term use of such therapy can produce multiple side effects that can potentially reduce the quality of life and result in opportunistic infections, septicemia, and death.4,5
It appears that, besides other factors, anti-BMZ antibodies play an important role in the pathogenesis of BP.6 Rituximab selectively destroys CD-20+ B-cells that may be producing the pathogenic autoantibodies, which may be the basis for its use in treating BP.7 There is a growing tendency to use rituximab in treating other autoantibody mediated diseases.8
The purpose of this review is to analytically examine the currently available literature on the use of rituximab in the treatment of BP.

MATERIALS AND METHODS

A search on PubMed was conducted, using the keywords “bullous pemphigoid” and “rituximab.” Sixteen patients were identified in total.9-17 Publications with information on 5 or more patients were considered as case series, and only 1 case series with 5 patients was identified.9 Eight case reports with 11 patients were identified.10-17
The inclusion criteria were as follows: (1) clinical presentation,18 (2) the presence of a subepidermal vesicles on histology,18 (3) the deposition of immune-reactants at the BMZ on direct immunofluorescence,18 (4) the failure to respond to conventional therapy such as CS and ISA, (5) treated with at least 1 infusion of rituximab, and (6) childhood BP was classified as that of patients 18 years of age or younger.19
Patients who did not fulfill the inclusion criteria and those with other autoimmune diseases involving the basement membrane zone or dermo-epidermal junction were excluded.

Treatment Regimens

Ten out of 16 patients received rituximab based on the Lymphoma Protocol, which included 4 once-weekly infusions at a dose of 375 mg/m2 per infusion as a single cycle. This protocol was first used to treat lymphoma patients,20,21 but has also been recently approved by the Food and Drug Administration (FDA) for use in vascultitis.22,23 Four patients were treated with a modified Lymphoma Protocol. This included 2 patients treated with 4 once-weekly infusions of rituximab, followed by 1 infusion every 2 months for 3 years.10 One patient received only 2 infusions of rituximab.15 Another patient received 3 additional infusions on a monthly basis for 3 months after being treated with the Lymphoma Protocol.17 Two patients were treated with the Rheumatoid Arthritis Protocol13 that consists of a single cycle of 1gm rituximab, given on days 1 and 15.24