Rituximab is an IgG antibody that targets the CD20 antigen of B lymphocytes, the precursor cell to antibody producing plasma cells. It depletes the pathogenic desmoglein antibodies in PV for 6–12 months [2]. Rituximab is FDA approved for various leukemias and lymphomas, rheumatoid arthritis, and some vasculitides. It is used off-label for PV.

The optimal dosing protocol of rituximab for PV treatment is unclear. Initial PV treatment with rituximab used the lymphoma dosing protocol of four weekly 375 mg/m² infusions. More recent studies examined the use of the rheumatoid arthritis dosing of 1,000 mg twice, 2 weeks apart. In a meta-analysis of 42 case reports and case series from 2000 to 2012 of rituximab therapy in PV patients recalcitrant to standard therapies, complete remission was achieved in 67 % (32/48) of patients from case reports and in 67 % (56/84) of patients from case series using the lymphoma protocol compared to 79 % (n = 59/75) of patients from case series following the RA protocol [3]. Both dosing protocols required the concurrent use of prednisone and/or other systemic therapies. Seven patients following the lymphoma protocol did not respond to treatment, while no patients on the RA protocol were non-responders. Relapse occurred in 23 % (30/132) of patients on the lymphoma protocol and in 36 % (27/75) on the RA protocol. Overall, this meta-analysis found that patients in the RA protocol had a higher response rate, a higher relapse rate, a higher number of infections, and a lower mortality rate compared to the lymphoma protocol. A recent, prospective, randomized, observer blinded study of 22 patients with PV or pemphigus foliaceus (PF) found no difference in time to disease control between patients treated with low dose rituximab (two 500 mg doses, 15 days apart) compared to the higher dose RA protocol, although relapse was more common and more adjuvant immunosuppressive therapy was needed in the low dose group [4].

A multicenter, prospective study of 14 PV patients with refractory disease treated with a single cycle of rituximab using the lymphoma protocol suggests that a second cycle of rituximab may be required only in relapse that cannot be controlled with first-line therapies. This study reported that 86 % (12/14) of subjects had complete remission of disease (defined as the epithelization of all skin and mucosal lesions) 3 months after the last infusion [5]. Of the remaining two subjects, one had complete remission by 180 days and the other by 360 days. All patients that were concurrently treated with steroids were able to significantly reduce their baseline prednisone dose. At the 34 month follow-up, 57 % (8/14) of subjects remained free of disease.

In a later study, Lunardon et al. found that 100 % (24/24) of severe and/or refractory PV patients treated with rituximab had clinical disease activity improvement [6]. Patients were treated with either the lymphoma or RA dosing protocol for up to four cycles if needed to improve the clinical outcome or to treat relapses. 58 % (14/24) of patients reached the study endpoint: complete remission on no or minimal systemic therapy. There was no significant difference between the two protocols in achieving this end point. In addition, 46 % of patients (11/24) attained complete remission on no systemic therapy. Of note, the study examined an additional seven patients with PF and found similar results. The median relapse-free remission time of the combined PV and PF patients was 19 months. This study also found a significant decrease in the serum desmoglein index value (median change of −80 %) in ten paired serum samples of patients before and after therapy. Finally, the study found that treatment with rituximab earlier in the disease course yielded better outcomes. The median duration of disease prior to rituximab therapy was 19 months for patients who achieved complete remission on no or minimal systemic therapy compared to 86 months for patients who did not. The mechanism of incomplete remission and/or relapse in some PV patients treated with rituximab is unclear, but may be attributed to persistent B cells in the spleen or lymph nodes, or new bone marrow-derived B cells with novel immunoglobulin rearrangements [7].