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Rituximab in the Treatment of Pemphigus Vulgaris

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 long-term effects. Patients should be carefully monitored during and after therapy.

that involves the skin and the mucous membranes [1]. PV is a rare disease with an incidence of approximately 0.1-3.2 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 [9][10][11]. 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 Wegener's 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.

METHODS
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) [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.

RESULTS
In 42 different publications, information on a total of 272 individual patients with PV treated with rituximab between 2000 and 2012 was available . 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.
Varying and modified versions of the RA or the lymphoma protocols were used within the same group of patients. Ten patients in five case reports got modified versions of the lymphoma protocol [38][39][40][41][42]. There were 51 patients in four different case series [54][55][56][57]. Therefore, when the case series and case reports are grouped together, 61 patients received the modified protocols.
The data on these different categories have been summarized in Table 1.
Serious adverse events included one death from septicemia after 18 months [43], and one pyelonephritis 12 months after discontinuation of rituximab [43].

Depletion of B cells was reported in 35
patients and occurred between 1 and 4 weeks, and lasted up to 12 months [43][44][45]. Time for B cell repopulation occurred between 12 and 34 months (mean 18.93 months). The data suggest that the probability of relapse is higher in patients who take longer to repopulate.
IIF decreased in two patients studied [52]. In one patient, a relapse was accompanied by a rise in the titer [52]. ELISA levels decreased in some patients [50,51,53].

Case Reports
In ten patients, the modified lymphoma protocol was used [38][39][40][41][42]. Patients receiving modified lymphoma protocols received three or four additional monthly infusions and one received a complete second cycle of the protocol. Eight (80%) patients had complete remission, two (20%) had partial remission.

None of the patients had relapses. Patients received corticosteroids or corticosteroids and
ISAs as concomitant therapies. One patient experienced a bacterial pneumonia and pulmonary embolism [39].
B cell studies were not reported and antibody titers determined by IIF and ELISA decreased [38,39,41]. One study reported three patients treated with rituximab without details of the protocol [58]. They were not included in the analysis.

Case Series
Data on 51 patients were presented in four studies [54][55][56][57]. In the first study, six patients received eight weekly infusions of 375 mg/m 2 followed by a single dose once a month for 4 months [55]. All six had a complete remission off therapy. In 25 patients, two separate protocols were used [56]. One group received 375 mg/m 2 in two infusions in 2 weeks. Half of the patients had a complete remission and the other half had a partial remission. In the second group, patients got three or more weekly infusions of 375 mg/m 2 , and 90% had complete remission while 10% had partial remission. In the third study, 12 patients received the RA protocol at a dose of 500 mg at 2 week intervals [54]. Six of the 12 had complete remission off and on therapy, and six had partial remission. The fourth study concerned eight patients [57]. Of the four patients who got the RA protocol at a dose of 1,000 mg at 2 weeks, two had complete remission and two had partial remission. One patient received two infusions of 500 mg at 2 week intervals and had a complete remission.
The remaining three patients received the lymphoma protocol, two had complete remission and one had a partial remission.
Among the 51 patients in the modified protocol group, 18 (35.3%) patients had relapses after a mean of 18.75 months (range 11.5-24.25 months) [54,56,57]. Half were treated with a second cycle of rituximab and experienced a complete remission [54,57].

Depletion of B cells lasted up to 40 months
in studies that reported it [54,55]. In seven patients, repopulation was observed after 20-35 months. In five (71%) of these patients, repopulation was accompanied by relapses.
None of the studies reported IIF. ELISA for both Dsg 1 and Dsg 3 reported decreases [56,57].

DISCUSSION
The analysis of the available literature on the use of rituximab in treating patients with PV is not only difficult but restrictive, as a direct consequence of the significant limitations of the data. Therefore, interpretation of the data analysis must be done in the light and perspective of these limitations. An obvious inference would be that such an analysis could be of limited value. On the contrary, these limitations are of significant benefit, because they will help in the design of future studies, and focus on elements of the pharmacodynamics of rituximab therapy.
Some of these limitations are as follows: the data come from multiple sources; there is a significant lack of uniformity in the selection of the patients, in defining their severity or extent of disease, and in identifying failed treatment before rituximab; the lack of an objective scoring system makes changes or responses difficult to evaluate numerically; the more concerning aspect is the limited follow-up provided by most authors, this becomes an important issue because significant side effects and relapses can occur several months after the discontinuation of rituximab therapy.
As rituximab is a B cell depletion therapy, many authors have not provided any data on B cell levels and the changes in autoantibody levels. None of the studies provide any rationale or scientific basis for the use of the lymphoma or RA protocols in treating patients with PV.
The response of patients to rituximab using the lymphoma protocol or RA protocol has been described in the results section. The total The data analysis did not provide clear indications for specific reasons that may account for these differences.
Preliminary observations would suggest that while the use of the lymphoma protocol produces a lower response rate, there is a lower rate of recurrences and serious infections but a higher mortality rate. Patients treated by the RA protocol had higher response rates, a larger number of infections, but a lower mortality rate. This could be partly due to the fact that more patients were on corticosteroids and immunosuppressive agents as concomitant therapy in the lymphoma protocol, thus adding to the degree and duration of prolonged immune suppression.
To serve the best interests of the patient, it is useful and relevant to determine what purpose the lymphoma and RA protocols serve in their respective diseases. The use of rituximab in lymphoma patients has a duration of response of a median of 12 months (range 11-13.4 months) after which relapses frequently occur [59]. A median progression-free survival of 18 months and a 5-year relapse free survival of 28% was reported [59]. The most relevant use of rituximab comes from a 3-year progression-free survival study in which patients were given cyclophosphamide, doxorubicin, vincristine, and prednisone-like chemotherapy with or without rituximab and the 3-year survival rates were 93% and 84%, respectively [60]. Therefore, to obtain the benefit of rituximab in lymphoma patients, the addition of other chemotherapeutic agents is required, and can be best measured in 3-year survival rates. rituximab is given on an as-needed basis [70]. Some patients need five cycles or more to maintain clinical remission [71][72][73]. However, at the present time, there is no protocol that provides prolonged and sustained remission in RA. Therefore, it is unclear how many cycles are required to keep patients symptom free, prevent joint destruction, or can be safely given in any defined period. Furthermore, RA patients usually receive rituximab with methotrexate concomitantly and often additional prednisone [61][62][63][64][65][66][67][68]. PV treated by the RA protocol needed multiple infusions to treat recurrent relapses [52,53].
The objectives of treating patients with PV are different from those with lymphoma or RA. The optimal treatment for PV is one in which the disease is controlled, relapses are prevented, and the long-term sustained clinical remission without continued treatment can be achieved.
In patients with PV and ocular cicatricial pemphigoid, a defined protocol with a definitive endpoint was used [74,75]. This combination of rituximab and intravenous immunoglobulin allowed for the discontinuation of previous systemic corticosteroids and ISAs and produced sustained clinical remissions. There were no infections or deaths. There is a growing trend among dermatologists to use rituximab. Many variables have yet to be determined or defined. Providing guidelines or indications for therapy is preliminary and may change in the future. Presently, the indications for using rituximab could be as follows.
• Failure of conventional therapy for minimally 6 months.
• When conventional therapy has failed, or produced significant and catastrophic side effects, or is contraindicated, then intravenous immunoglobulin may be used [76].
• Active or latent infections are a definitive contraindication.
• Before initiating rituximab therapy, the goals and the endpoint should be discussed. The long-term side effects of rituximab in patients with PV are not yet known. Rituximab can result in cardiac side effects [77,78]. Patients and their families should be advised of these facts.
• As clinical response may be faster with rituximab compared to conventional therapy, patients should be advised to return at frequent intervals for the early detection of possible recurrences and also for monitoring of late-onset side effects.

CONCLUSION
The use of rituximab in PV is an evolving work in progress. Although the data have limitations, the drug is effective in controlling recalcitrant disease. Whether this control is long term, life long, or of limited duration is not yet known. The data suggest that following either the lymphoma or RA protocols is not optimal or particularly advantageous, and modifications of both are warranted. Both carry a risk of severe and possibly fatal infections. Presently, it should be the treatment of last resort. Monitoring the levels of B cells (CD19?/CD20?) in the peripheral blood and immunoglobulin levels during and after therapy is advisable. A protocol that is unique for autoimmune mucocutaneous blistering disease is needed. Preliminary studies using such a protocol show promising results [74,75]. Rituximab is the new frontier for the treatment of PV.