Am J Clin Dermatol DOI 10.1007/s40257-015-0121-0

REVIEW ARTICLE

The Emerging Role of Rituximab in Autoimmune Blistering Diseases A. Razzaque Ahmed • Shawn Shetty

Ó Springer International Publishing Switzerland 2015

Abstract Rituximab is a chimeric monoclonal antibody that selectively binds to the CD20 molecule on B cells, resulting in their lysis. In autoimmune blistering diseases, the auto-antibody-producing B cells are destroyed and auto-antibody levels are reduced or eliminated. In the majority of patients, rituximab produces rapid clinical response and early resolution. In part, this accounts for the increased use of rituximab. Rituximab does not distinguish normal from pathologic B cells. Hence, shortly after its use, B-cell levels are zero and remain so for several months. In most patients, the use of systemic corticosteroids and immunosuppressive agents are continued after rituximab therapy, while their dosages are significantly decreased. In the majority of patients rituximab is used according to the protocol used in treating lymphoma patients or patients with rheumatoid arthritis. Approximately 50 % of patients experience a relapse, requiring additional therapy. Serious adverse events and fatal outcomes have been reported, although their incidence is less than that observed with conventional therapy. Nonetheless, the causes, i.e. infections and septicemia, are similar. Several gaps exist in our understanding of how to optimally benefit from the use of this valuable biological agent. Future studies need to be targeted in designing and implanting protocols that maximize the benefit of rituximab and result in producing sustained prolonged remissions with minimal adverse events and a high quality of life.

A. R. Ahmed (&)
S. Shetty Center for Blistering Diseases, 697 Cambridge Street, Boston, MA 02135, USA e-mail: [email protected]

Key Points The majority of patients with autoimmune blistering diseases are being treated with rituximab using protocols that have been designed and implemented to treat non-Hodgkin’s lymphoma and rheumatoid arthritis. The use of these protocols does not produce a sustained long-term remission. On the contrary, the majority of patients suffer from one or more relapses and require additional therapy. Rituximab is a useful, viable and beneficial agent in the treatment of autoimmune blistering diseases. The emerging concept from the cumulative data is that the optimal goals are not being achieved because the appropriate protocols that are specifically tailored and based on the biology of blistering diseases have not been designed or used.

1 Introduction Rituximab is a chimeric, monoclonal antibody that binds to the molecule CD20 expressed on the cell surface of B cells but not plasma cells [1, 2]. Rituximab depletes B cells by many mechanisms, predominantly complement lysis [2, 3], and has been used to treat various diseases in which B cells have become pathogenic, such as in lymphomas and several autoimmune diseases [4–7]. In 1997, rituximab was approved by the US FDA for the treatment of nonHodgkin’s lymphoma [4]. The lymphoma protocol (LP) for rituximab in a single cycle consists of infusions of 375 mg/m2 for 4 consecutive weeks [4]. Rituximab has

A. R. Ahmed, S. Shetty

also been used to treat autoimmune diseases such as autoimmune blistering diseases, vasculitis, systemic lupus erythematosus, and rheumatoid arthritis [7, 8], and was approved by the FDA in 2006 for the treatment of rheumatoid arthritis [8]. The rheumatoid arthritis protocol (RAP) consists of one cycle of two infusions of 1000 mg administered on days 1 and 15 [8]. Systemic corticosteroids (CSs) have been the mainstay of treatment of autoimmune blistering diseases [9–12]. When the disease is not controlled with CSs or the dose of CSs needs to be decreased, immunosuppressive agents (ISAs) have been added [9–12]. However, some patients are non-responsive to either CSs or ISAs, or their combination, and the dosages of these therapies are increased to allow for remission of disease [9–12]. The increased dosage of CSs with or without ISAs over an extended period of time can lead to serious adverse events (SAEs) and mortality [9–12]. Hence, rituximab has been used off-label to treat various autoimmune blistering diseases, including pemphigus vulgaris (PV), bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), ocular cicatricial pemphigoid (OCP), and epidermolysis bullosa aquisita (EBA) [10]. Since the FDA approval of rituximab to treat lymphoma and rheumatoid arthritis, the LP and RAP have been the two most widely used protocols to treat autoimmune blistering diseases. The purpose of this review is to evaluate the current data on the use of rituximab in the treatment of autoimmune mucocutaneous blistering diseases (AMBD). The intent of the authors was that this information would provide the opportunity to determine the early results from the use of this agent and the emerging trend in clinical outcomes. Thus, a treating physician could evaluate current therapy and make adjustments or alterations to achieve optimal goals.

guidelines [13]. The majority of the studies on the use of rituximab in PV used these guidelines which included clinical remission (CR) on or off systemic concomitant therapy, partial response (PR), or non-responder. In all other blistering diseases such guidelines have not been described, yet the majority of authors used similar language to describe the clinical outcomes in their patients. At the outset, the authors would like to clarify that this is not an evidence-based review. Such a review could not be written at this time because no randomized controlled trials (RCTs) have been published to date, for which there are several reasons. One important reason is that this is a rare disease and obtaining a statistically significant number of patients would be difficult. Second, it is a potentially fatal disease and therefore randomizing with a placebo would be unethical. There are several limitations of this review, including the use of different inclusion or exclusion criteria, the lack of a uniform system for scoring the extent and severity of disease, various treatment protocols [13], different lengths of follow-up, and differing concepts in determining outcomes. Nonetheless, the review has a very significant importance to the dermatology community. The use of rituximab is rapidly increasing. While a review that is based solely on RCTs cannot be carried out, treating dermatologists, confronted by a patient who they feel needs treatment with rituximab, will find the information beneficial and useful and will provide some insights that will facilitate the decision-making process. Equally important, the dermatologist can share with the patient what is concurrently known, although the information has limitations. A summary of the information collected from the published data on PV, BP, MMP, and EBA are presented in Tables 1 and 2.

3 Pemphigus Vulgaris 2 Methods A search of the PUBMED, EMBASE, and MEDLINE databases from 1997 to January 2015 was performed using the terms ‘rituximab’, ‘autoimmune blistering disease’, ‘pemphigus vulgaris’, ‘bullous pemphigoid’, ‘mucus membrane pemphigoid’, ‘ocular cicatricial pemphigoid’, ‘epidermolysis bullosa acquisita’, ‘linear IgA bullous disease’, ‘pemphigoid gestationis’, and ‘dermatitis herpetiformis’. The inclusion criteria encompassed patients in whom the diagnosis of AMBD was established by histology and confirmed by immunopathology, while the exclusion criteria encompassed the absence of such information. In 2008, the consensus guidelines for response to treatment in PV patients was published [13]; the majority of studies on the use of rituximab in PV used these

PV is an autoimmune blistering disease that affects the skin and mucous membranes. It is caused by pathogenic autoantibodies directed against desmoglein 1 and 3, which leads to acantholysis, causing blister formation and erosions. Treatment primarily consists of CSs and ISAs; however, patients with refractory disease require long-term use of CSs that can have severe and potentially fatal side effects [14]. In patients who are non-responsive to the use of conventional therapy that consists of systemic CSs with or without ISAs, in some patients as first-line therapy and in others where the disease is refractory and recalcitrant to multiple therapies, rituximab has been used [15–64]. A review of the literature on the use of rituximab to treat PV identified 475 patients [15–64], who were treated with either the LP or the RAP. Overall, 224 patients were treated with the LP [15–56] and 251 patients were treated with the

Rituximab in Blistering Diseases Table 1 Comparison of the parameters that influence clinical outcomes in the rituximab protocols used to treat pemphigus vulgaris Protocol (case series)

No. of patients

Lymphoma protocol

224

Disease distribution (%)

Prior therapy (%)

Concomitant therapy (%)

Clinical outcome (%)

Postrituximab therapy (%)

Relapse (%)

Time to relapse (months)

Patients who received additional infusions for relapse (%)

SAEs

Deaths

Mean followup (months)

CRon: 57.6

CS: 43.4

40.7

16.9

24.4

9

3

28.9

58.6

13.1

83.9

4

2

20.3

32.2

13.3

72.2

2

1

29.5

MC: 86.9

CS: 7.6

CS: 38.0

MM: 7.0

ISA: 4.8

C: 5.5

CS ? ISA: 86.9

CS ? ISA: 59.2 None: 2.7

CRoff: 27.1

CS ? ISA: 48.3 Off: 7.6

PR: 14.6 Rheumatoid arthritis protocol

251

MC: 79.1

CS: 5.7

CS: 12.9

MM: 19.1

ISA: 0.4

C: 4.3

CS?ISA: 92.1

CS ? ISA: 74.7 None: 22.4

None: 3.8

CRon: 54.7

CS: 3.3

CRoff: 39.7

CS ? ISA: 26.3

PR: 9.1

Off: 59.8

ISA: 10.5

NR: 1.7 Modified protocol

58

MC: 66.1

CS: 3.2

CS: 8.0

MM: 24.1

ISA: 30.6

ISA: 9.6

CRon: 16.1

C: 11.2

CS ? ISA: 48.3

CS ? ISA: 27.4

CRoff: 58.0

None: 14.5

None: 43.5

PR: 19.35

CS: 24.1 CS ? ISA: 14.2 Off: 67.7

CS corticosteroids, CRon complete remission on therapy, CRoff complete remission off therapy, C cutaneous, ISA immunosuppressive agents, MC mucocutaneous, MM mucous membranes, NR non-responders, Off off therapy, PR partial remission, SAEs serious adverse events

RAP [56–64]. Analysis of the cumulative data highlighted certain interesting observations.

demonstrate resolution of lesions. The analysis of the clinical data would suggest that the response of the skin lesions is more rapid than the mucosal lesions [15–64].

3.1 Pre-Rituximab Therapy 3.3 Concomitant Therapy with Rituximab As mentioned earlier, a uniform system of describing the extent or severity of disease was not used by the authors because it has only recently been published and was therefore not used [13]. Approximately, 80 % of patients had mucocutaneous disease, indicating that the disease was relatively severe and widespread in clinical manifestation. This observation of the severity and extent of disease is further supported by the fact that approximately 90 % of patients reported were being treated, on a long-term basis, with high-dose systemic CSs and multiple ISAs. Some patients did not receive ISAs; however, the reasons for this were not always provided. In approximately 3 % of the reported patients, neither CSs or ISAs were administered, although reasons were not provided [15–64]. 3.2 Response to Initial Rituximab Therapy Regardless of the protocol used, patients with PV showed a dramatic and rapid response to infusions of rituximab. A majority of patients had significant clearing of lesions within 2–3 weeks, and a significant number of patients had complete resolution of clinical disease within 6–8 weeks after the initiation of rituximab. Hence, it is reasonable to infer that as a therapeutic agent the clinical response to rituximab is rather rapid and the majority of patients

Data on the use of various systemic agents, including CSs and ISAs, while administering rituximab infusions is not provided by the authors of every case report or case series. Nonetheless, it is clear that almost 90 % of patients were treated simultaneously with CSs or ISAs, CSs only, or ISAs only. The duration of these therapies, while referred to as ‘concomitant therapies’, is somewhat misleading, as these therapies were continued during the entire follow-up period in most reported cases [15–64]. Their continued use would indicate that they were of benefit in maintaining the remission, otherwise they would have been discontinued. 3.4 Clinical Outcomes The clinical outcomes were assessed from the literature based on the condition of the patient at the time of reporting or at the end of the duration of follow-up. Thus, this provides the reader with an overall assessment of the clinical effects of rituximab and its influence on the clinical course and treatment of PV. Based on this paradigm, the literature suggests that approximately 85 % of patients were in CR. Over half of these patients were still receiving systemic therapy which had been administered to them prior to and during rituximab therapy. Hence, it is clear that

A. R. Ahmed, S. Shetty Table 2 Characteristics of the treatment with rituximab in patients with autoimmune mucocutaneous blistering disease

MMP

Patients (N)

Treatment prior to rituximab (N)

Rituximab (dose) (N)

Concomitant therapy (N)

Response to rituximab (N)

Postrituximab therapy (N)

Patients who received additional rituximab infusions (N)

Mean duration of followup (months)

Serious adverse events (N)

Deaths (N)

40

CS, ISA, IVIg, gold: 39

LP: 29

CS, ISA, IVIg, PAIA: 38

CR: 24

CS, ISA: 37

LP: 22

23.3

2

1

CS, ISA: 14

LP: 4

CS, ISA: 13

LP: 14

RAP: 11

PR: 11

(infections)

RAP: 7

NR: 3 SD: 1 SD, Fail: 1a

BP

16

CS, ISA: 16

LP: 10

CS, ISA: 12

CR: 11

RAP: 2

None: 4

PR: 1

CS, ISA: 16

LP: 14

MLP: 4 EBA

16

RAP: 1 MLP: 1

15.6

3

3 (infections)

RAP: 3

NR: 1 CS, ISA: 16

CR: 11 PR: 4 NR: 1

16.5

1 (infection)

1

BP bullous pemphigoid, CR complete response, CS corticosteroids, EBA epidermolysis bullosa acquisita, IVIg intravenous immunoglobulin, ISA immunosuppressive agents, LP lymphoma protocol, MLP modified lymphoma protocol, MMP mucous membrane pemphigoid, NR no response, PAIA protein A immunoadsorption, PR partial response, RAP rheumatoid arthritis protocol, SD stabilization of disease a

The patient had stabilization of upper airway disease but the disease progressed, leading to blindness

the use of rituximab did not permit previous systemic therapy with CSs with or without ISAs to be discontinued. Interestingly, approximately 13 % of patients experienced only a partial remission and were receiving conventional systemic therapy after rituximab. At least 1.5 % of patients were non-responsive to rituximab therapy, and 1.3 % of patients died [14, 27, 34, 47, 59, 63]. During a mean follow-up period of 20.8 months, relapses occurred in approximately 50 % of patients, with approximately 52 % of these patients receiving additional infusions of rituximab [15–64]. 3.5 Post-Rituximab Therapy The data demonstrate that at least 68 % of patients continue to remain on either CSs and ISAs, CSs only, or ISAs only after rituximab therapy has been completed. Indeed, it is evident, and was documented, that the dosages of drugs used after completion of rituximab therapy were significantly reduced compared with those used prior to initiation [15–64]. Nonetheless, it needs to be emphasized that the side effects of CSs and ISAs are often dependent on the total dose of the drug used. Hence, the lower dosage, or even significantly smaller doses, does not eliminate the possibility of late-onset side effects. 3.6 Serious Adverse Events SAEs were reported in approximately 4.0 % of patients treated with rituximab. Approximately 79 % of the SAEs

were due to infections, most of which required hospitalization. Half of these infections resulted in septicemia [15, 21, 27, 29, 34, 35, 40, 42, 46, 59, 60, 63, 64]. Unfortunately, most authors did not measure B-cell (CD19?) levels; therefore, it is entirely plausible that these infections occurred while B-cell levels were still suppressed or below normal. This fact cannot be confirmed in every case. In two patients, thrombotic events were reported [64]. It should be noted that in one patient, late-onset neutropenia was documented [59]. The use of rituximab is invariably associated with low levels of serum immunoglobulin (Ig)M [8], and the long-term consequence of this is currently unknown. 3.7 Summary Since over 450 patients with PV have been treated with rituximab, certain preliminary observations can be made. It is of paramount importance that it be highlighted that the clinical outcomes are entirely driven by the protocols that have been used. In 80–85 % of patients, early clinical response or CR was observed. The rapidity of the response is remarkable and is one of the factors that make it an attractive choice. However, the majority of patients seem to require some form of immunosuppressive therapy to maintain the CR. In spite of the continuation of such therapies, a recurrence rate of almost 50 % is concerning. Since many of the studies lack levels of B cells in their follow-up, it cannot be ascertained that recurrence is related to the return of B cells to normal levels. The

Rituximab in Blistering Diseases

encouraging aspect of rituximab therapy is that it facilitates the reduction of the dose of CSs and ISAs compared with pre-rituximab dosages. While the mortality rate in PV patients treated with rituximab is lower than in those treated with conventional therapy, the cause of death remains the same. The majority of deaths have been attributed to septicemias [14, 27, 34, 47, 59].

4 Bullous Pemphigoid BP is an autoimmune disease that usually manifests as tense blisters in the elderly [66], although cases have been reported in young adults and children [53, 66–68] A review of the literature has identified 16 patients treated with rituximab [53, 56, 66–72]. The mean age of adults was 66 years (range 55–83). All patients were treated with CSs and ISAs before rituximab therapy. Ten patients were treated with the LP, two with the RAP, and four with a modified LP. Twelve patients continued CSs and ISAs as concomitant therapy while being treated with rituximab. After the initial infusion, 11 patients had a CR, one had a PR, and one died. Forty-four percent of patients required more than one cycle to achieve a CR. In the final clinical outcome, almost 70 % of patients had a CR. Three of the 16 patients died. Mortality was reported to be due to bacterial sepsis and cardiac complications [53, 67, 69]. Rituximab is an option for treating patients with BP who are non-responsive to conventional treatment with CSs and ISAs or in whom conventional immunosuppressive therapy is contraindicated. While rituximab provided CR to the majority of patients, relapses were reported and additional cycles of rituximab were needed to achieve a CR. Hence, it may be inferred that in some patients more than once cycle of rituximab may be required to keep the patient in a CR. In the literature, there is evidence that rituximab used as monotherapy, in which as many as 22 infusions were administered, produced a sustained CR for a 36-month period after rituximab therapy [73]. The majority of patients diagnosed with BP are elderly. The age of patients combined with the continued use and increased cumulative dosage of CSs and ISAs increases the likelihood for the occurrence of SAEs. Hence, when rituximab is used, several factors must be taken into account to prevent SAEs, including advanced age, immune status, the adverse effects of concomitant therapy, and existing co-morbidities. The use of an agent that depletes B cells for a variable and unpredictable period of time, which affects the immune system, may lead to decreased immune function [73]. This could lead to increased rates of infections, septicemia, and possibly death. It has also been reported that rituximab has cardiotoxic effects [74, 75];

therefore, careful pre-screening is required for patients who are at high risk for myocardial infarctions or other cardiac events.

5 Mucous Membrane Pemphigoid MMP is a rare and orphan disease, and the estimated incidence is one case per million individuals in the general population. MMP has the potential to be fatal, and involves multiple mucosae and the skin. The distinguishing feature and hallmark of MMP is that as the lesions heal they result in irreversible scar formation. Such scars have catastrophic and devastating effects on the eye, pharynx, larynx, esophagus, genitalia, and anal canal. Patients with severe disease do not respond to standard therapy and are placed on systemic CSs and ISAs. Rituximab has been used in patients who are non-responsive to conventional immunosuppressive therapies. However, the literature on the use of rituximab in MMP is limited [76]. In our review of the literature, 40 patients were treated with rituximab [53, 56, 69, 77–82]. Pre-rituximab therapy, 39 patients were treated with CSs and ISAs. The majority of patients were treated with the LP while on concomitant therapy, while 11 patients were treated with the RAP [82]. Twenty-nine patients required a second cycle of rituximab. The final clinical outcome was that approximately 60 % of patients had a CR while on systemic therapy at the time of reporting. It is noteworthy that some were non-responsive [77]. In one report, the scarring continued in spite of rituximab therapy [53]. Even though this observation was seen in a single patient, it may suggest the scarring process may not be decreased or eliminated by rituximab. One patient with MMP who was treated with rituximab died [77]. Two SAEs occurred—one patient on rituximab developed severe pyelonephritis and the other died from tuberculosis [77]. Both had hypogammaglobulinemia at the time of death. The mean follow-up was 19.5 months. Rituximab provided a CR in the majority of patients. However, several factors must be addressed. MMP is not a uniform disease as it affects the oral and ocular mucosa differently. There are different subsets of MMP that must be studied and individual factors analyzed with the use of rituximab. The early use of rituximab has been shown to affect the course of the disease in certain forms of MMP; however, rituximab cannot prevent disease progression if scarring is already present. In the case of OCP, rituximab cannot reverse blindness. While rituximab provides disease remission, an ideal protocol has yet to be identified. It is not clear how many infusions are needed to provide a sustained CR. Multiple infusions of rituximab have been shown to decrease serum IgM and IgG levels for extended periods of time [84, 85]. This could lead to increased rates of serious

A. R. Ahmed, S. Shetty

infections, some of which could result in death. This has been reported in various autoimmune diseases treated with rituximab [85]. The ideal time to use rituximab in MMP is before the onset of significant scarring. The best protocol would be one that produces and maintains CR over a prolonged period of time without additional scarring.

6 Ocular Cicatricial Pemphigoid OCP is a subset of MMP and may only involve the conjunctiva. In some patients it may involve other mucosal sites but the ocular involvement is predominant and/or most significantly involved. It is an insidious and progressive disease. Its importance lies in the fact that in 25 % of patients the clinical result is blindness in spite of aggressive therapy. Conventional therapy has been the administration of systemic ISAs and dapsone [86]; however, there are a group of patients, who may not respond to conventional therapy, in whom conventional therapy results in devastating side effects, or in whom conventional therapy is contraindicated. A recent report studied the effects of rituximab in patients who were blind in one eye and had continuous progression of disease in the second eye in spite of systemic ISA therapy. Six patients were treated with rituximab and intravenous Ig (IVIg) and six patients were treated with high-dose ISAs. Those treated with rituximab and IVIg had no further progression of disease and maintained vision during a follow-up of 55.5 months. Six patients who were blind in one eye were treated with ISAs only, to treat the second eye that was affected. Their treatment resulted in complete blindness during a follow-up of 57.5 months [87]. This preliminary observation suggested that rituximab and IVIg have the ability to preserve vision and prevent the progression of disease for a sustained period of time. In these six patients, remission has lasted 9 years [87].

7 Epidermolysis Bullosa Acquisita Epidermolysis bullosa acquisita is a rare and chronic bullous disease characterized by autoantibodies to type VII collagen [88]. A total of 16 patients with epidermolysis bullosa aquisita treated with rituximab have been identified in the literature [89–97], all of whom had mucocutaneous disease. All patients received CSs and ISAs prior to rituximab therapy and while receiving rituximab. Fourteen patients were treated with the LP. Approximately 70 % of patients had CR; however, approximately 90 % had a relapse and required a second cycle of rituximab. The future course of therapy could not be assessed because the mean

duration of the follow-up period was 16.5 months. Unfortunately, in spite of the small number of patients and limited follow-up, death was reported in one patient due to pneumocystis carinii pneumonia (PCP) [98]. Based on this limited data with a limited follow-up period, any preliminary or other conclusions cannot be made. Treatment of additional patients with longer followup periods will be required before a role for rituximab in the treatment of EBA can be ascertained.

8 Discussion While many patients with autoimmune blistering diseases have been treated with rituximab, the results are variable and do not show a pattern in which a definitive conclusion or recommendations can be made. There is little doubt that there is an initial positive response and resolution of active disease in a short period of time. The downside of that benefit is that the B cells that are depleted may not return to normal levels for 12–36 months in most patients [83]. Since the majority of patients in the literature have continued to receive CSs with our without ISAs for extended periods of time after rituximab therapy, the level of immune suppression is high. Furthermore, one cannot discount the fact that if a CR is observed after rituximab therapy is completed and immunosuppressive therapy is continued, that this immunosuppressive therapy is not contributing to the continued remission. There is evidence that the dosages of CSs and ISAs used post-rituximab therapy are significantly lower than those used pre-rituximab [14–97]. The ability to discontinue CSs and ISAs has been reported in a minority of patients, and the recurrence rates of 50 % or more are very concerning. Furthermore, while some patients were treated with additional rituximab, it is not known if the others were treated with increased doses of CSs and ISAs. In those cases, the true benefit of rituximab would be of significant concern. The rates of serious infections and deaths in patients with rituximab are lower than those treated with CSs plus ISAs [99]. However, the causes of SAEs and mortality seem to be identical [99]. The duration of follow-up in patients receiving conventional therapy with CSs with or without ISAs has been long and has continued over decades [100]. The duration of follow-up of PV patients treated with rituximab is one of the most important issues in determining its role and its benefits in therapy. In several studies and reports, the duration of follow-up is 2 years or less [14–59], but longer in other studies and reports [28, 61]. Hence, it becomes a matter of conjecture whether with longer follow-ups there will be a larger incidence of recurrences and, similarly, an increased incidence of SAEs and mortality. One would wonder whether repeated infusions of rituximab may be

Rituximab in Blistering Diseases

necessary in order to maintain patients in CR. Such a requirement seems to be emerging in patients with rheumatoid arthritis [101]. A careful and unbiased examination of the literature would indicate that high doses of systemic CSs (prednisone) also produce a rapid clearance of clinical disease [100]. However, in a significant majority of patients there is a recurrence of disease when the doses are reduced. Very often, disease recurrence requires an increase in the dose of prednisone and the addition of an ISA [100]. In many patients, lower doses of prednisone and/or ISAs are required to keep patients in CRs. Based on the protocols that have been used thus far, a similar pattern of clinical response is observed in patients treated with rituximab; however, the wide and enormous spectrum of the dangerous side effects of prednisone and ISAs have not yet been reported with rituximab. Prednisone or other systemic CSs do not have a specific mode of action in treating blistering diseases but have a generalized anti-inflammatory or generalized immunosuppressive effect which, in the end, benefit the treatment of the blistering diseases. Rituximab kills B cells that carry the CD20 molecule on their surface [2, 3]. It does not discriminate between normal and healthy B cells and those that produce pathogenic autoantibody [2, 3]. Hence, its effects are also generalized and not specific for blistering diseases. In autoimmune blistering diseases, it is not uncommon to use the same protocols that are used in treating rheumatologic disorders. The apparent and obvious rationale would be that blistering diseases are also autoimmune in their pathobiology; however, B cells in patients with hematological malignancies and autoimmune diseases are different [102–104]. Quite possibly, the biology and pathophysiology of autoimmune B cells may differ from one autoimmune disease to the other [105]. The investigators who proposed the use of the LP and RAP in treating AMBD did not provide the rationale for the dose or dosing schedule. The results that were expected in lymphoma patients were a 3-year period during which a lack of progression of disease would occur [4]. Furthermore, rituximab was not used as monotherapy in the treatment of lymphoma patients but was part of a chemotherapeutic regimen. Long-term or lifetime remission was never to be expected. In rheumatoid arthritis patients, initially there was no specific or objective criteria used to assess benefits of therapy. Based on a subsequent consensus statement, the current target is to have a disease activity score (DAS) in 28 joints of 2.6 or less [8]. Such criteria do not exist in blistering diseases. Another vital issue regarding the use of rituximab in RA is that the majority, if not all, of patients receive methotrexate before, concomitantly, and after rituximab therapy. This is not the case with blistering diseases. Thus, evaluating the true benefit of using

rituximab in autoimmune blistering diseases will only be possible when a panel of experts decides on objective criteria for short- and long-term benefit. The ideal scenario would be one in which the use of rituximab results in a sustained and prolonged CR without the need for any additional systemic therapy, whether such therapy is additional rituximab or CSs or ISAs. Limited and preliminary evidence for such results are present in two small studies in which rituximab was used with IVIg. In these preliminary studies, patients did not have any infections, hospitalizations, or deaths, and had sustained remissions without additional rituximab, CS, or ISA treatments [67, 106]. In patients with other autoimmune diseases who were treated with rituximab, the use of IVIg helped prevent infections and hospitalization [107]. The obvious question that emerges is what lies in the future. Future research will need to focus on why some patients respond to rituximab in a favorable manner, while others do not. The answers may be complex and multifactorial. Preliminary studies on this issue were recently conducted by a group of French investigators [28]. Their study showed that some of the factors that contributed to long-lasting effectiveness of rituximab in the treatment of PV patients were blockage of B-cell maturation, prolongation of repopulation of naı¨ve B cells, and delayed reappearance of memory cells. This phenomenon resulted in the disappearance of desmoglein-specific IgG? bearing B cells from circulation. Additional, more detailed, and confirmatory studies on the many aspects of the immune and inflammatory systems will help better understand the complex network between tissues, cells, inflammatory mediators, chemokines, cytokines, and other molecules in the pathogenesis of autoimmune blistering diseases. Once these processes are better understood, it will become possible to determine the site(s) at which an appropriate and timely intervention can result in long-term, sustained remission without recurrence of disease. One would hope that this is a goal that future investigators will pursue. The current trend in the treatment of blistering diseases has been an increased use of rituximab. This may be due to the evidence that rituximab is able to clear the majority of patients of disease for a relatively short period of time. Thus, there has been a ‘rush to rituximab’. However, there is an absence of understanding the pathophysiology of blistering diseases. It appears that most clinicians consider B cells the cause of the disease; hence, removing them would cause remission of disease. At least 50 % or more of patients treated with rituximab have a relapse. It could be speculated that with longer periods of follow-up, the percentage of relapses could be even higher. There are no clear answers to these dilemmas. However, three issues emerge that need to be considered. First, that rituximab is still an excellent drug and its use should not be dismissed

A. R. Ahmed, S. Shetty

or discarded [108]. However, it is possible that the obstacle may lie in the current LP and RAP that are being used. Instead of imitating oncologists or rheumatologists, a novel approach that addresses the biology and immunology of blistering disease is required. Newer, innovative, and more relevant protocols need to be designed and implemented. The second issue is that blistering diseases as a clinical entity are complex. They involve not only B cells but other cells of the immune and inflammatory pathways and their multiple mediators. Third, autoimmune blistering diseases represent a dysfunction of immune regulation. Restoring immune regulation to non-diseased levels or homeostasis, after eliminating pathogenic auto-antibodies and their products, may help maintain normal immune regulation for sustained periods. In autoimmune blistering diseases, IVIg has shown preliminary promising results in restoring immune regulation [109].

9 Conclusions The message that is evident in the literature highlights the fact that rituximab has demonstrated the capacity to produce rapid CR and a complete resolution of clinical symptoms in a very short time in the majority of patients. This major advance in the treatment of blistering diseases is similar to that made by Walter Lever, 5 decades ago, by the introduction of systemic CSs. However, his regimen of doubling the dose of prednisone when the desired clinical results were not obtained ultimately resulted in significant morbidity and mortality. While CSs were not abandoned, the protocols with which they were used were changed. A new class of immunosuppressive drugs such as methotrexate and azathioprine were added so that lower dosages of CSs could be used. In studies in which follow-up is present for 3 years or more regarding the use of rituximab in treating blistering diseases, the high rates of relapses are documented. However, rituximab reduces the dose of CSs and ISAs posttherapy compared with pre-therapy levels. The essence of the problems is that the optimal outcome of rituximab, by preventing the production of autoantibodies and thus producing a long-term and perhaps lifetime remission, have not been studied or understood. Perhaps rituximab, like CSs, may be more effective and produce less adverse events if it was used in combination with other agents or drugs. Treating more patients with protocols that address these issues has the potential to be useful and may provide insight into the pathogenesis of these diseases. Alternatively, new protocols need to be designed and implemented so that such an outcome can be obtained. This will further enhance the value and use of rituximab in the treatment of AMBD.

Acknowledgments No sources of funding were used to prepare this review. A. Razzaque Ahmed and Shawn Shetty have no conflicts of interest that are directly relevant to the content of this review.

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