Restoring immune tolerance in pemphigus vulgaris.

Intravenous immunoglobulin (IVIg), a preparation of polyclonal serum IgG pooled from numerous blood donors, has been used for nearly three decades and is proving to be an efficient treatment for many autoimmune blistering diseases, including pemphigus vulgaris (PV). Despite its widespread use and therapeutic success, its mechanisms of action are not completely understood. Some of its anti-inflammatory and immunomodulatory actions have been studied. In this study, the authors present a twenty-year follow-up of 21 patients with clinical and immunopathological confirmed PV, treated with IVIg as monotherapy, according to an established published protocol. IVIg therapy produced long-term sustained, clinical, serological, and immunopathological remission. For 20 y, these patients received no drugs and experienced no disease. This observation suggests that there was the establishment of immune balance or restoration of immune regulation in these PV patients. Twelve (57%) patients experienced no relapse during follow-up. Six (29%) patients experienced a relapse due to acute stress or post-coronavirus infection and/or vaccination. Reinstitution of IVIg resulted in prompt sustained recovery. Three (14.2%) patients, in clinical and serological remission, died due to unrelated causes. No severe adverse effects from IVIg were documented in all 21 patients. The simultaneous or sequential anti-inflammatory and immunomodulatory effects of IVIg may have influenced the long-term clinical remission observed. This study provides a human prototype to examine the pathophysiology of autoimmunity and a model to study immune regulation and mechanisms that can facilitate restoring immune tolerance.

Current biologics in treatment of pemphigus foliaceus: a systematic review.

Background: Pemphigus foliaceus (PF) differs from pemphigus vulgaris (PV) in that it affects only the skin and mucous membranes are not involved. Pemphigus is commonly treated with systemic corticosteroids and immunosuppressive agents (ISAs). More recently, biologics have been used. The current literature on biologic therapy often combines treatment of PF with PV, hence it is often difficult for clinicians to isolate the treatment of PF from PV. The purpose of this review was to provide information regarding the use of current biological therapy, specifically in PF. Materials and methods: A search of PubMed, Embase, and other databases was conducted using keywords pemphigus foliaceus (PF), rituximab (RTX), intravenous immunoglobulin (IVIg), and biologics. Forty-one studies were included in this review, which produced 105 patients with PF, treated with RTX, IVIg, or a combination of both. Eighty-five patients were treated with RTX, eight patients with IVIg, and 12 received both RTX and IVIg. Results: Most patients in this review had PF that was nonresponsive to conventional immunosuppressive therapies (CIST), and had significant side effects from their use. RTX treatment resulted in complete remission (CR) in 63.2%, a relapse rate of 39.5%, an infection rate of 19.7%, and a mortality rate of 3.9%. Relapse was greater in the lymphoma (LP) protocol than the rheumatoid arthritis (RA) protocol (p<0.0001). IVIg led to CR in 62.5% of patients, with no relapses or infections. Patients receiving both biologics experienced better outcomes when RTX was first administered, then followed by IVIg. Follow-up durations for patients receiving RTX, IVIg, and both were 22.1, 24.8, and 35.7 months, respectively. Discussion: In pemphigus foliaceus patients nonresponsive to conventional immunosuppressive therapy or in those with significant side effects from CIST, RTX and IVIg appear to be useful agents. Profile of clinical response, as well as relapse, infection, and mortality rates in PF patients treated with RTX were similar to those observed in PV patients. The data suggests that protocols specific for PF may produce better outcomes, less adverse effects, and improved quality of life.

Treatment of Pediatric Pemphigus Foliaceus.

Pemphigus foliaceus (PF) is an autoimmune blistering disease limited to the superficial skin without mucosal involvement. It is clinically, histologically, and immunopathologically distinct from pemphigus vulgaris (PV). As data on pediatric PF is often merged with data on both pediatric and adult PV patients, isolating clinical outcomes in pediatric PF is not always possible. Therefore, the authors of this review analyzed clinical outcomes following therapy in pediatric PF patients only. A search of databases resulted in 33 pediatric patients with PF. In total, 19 (57.6%) patients were treated with conventional immunosuppressive therapies (CISTs), which consisted of systemic corticosteroids and multiple immunosuppressive agents (ISAs). Further, 14 (42.4%) patients were treated with biologic agents, predominantly rituximab (RTX). The mean age of those treated with biologics was 12.8 years (range = 0.88-18 years) compared to 8.9 years (range = 0.92-15 years) of those treated with CIST (p = 0.01). Treatment with biologics was initiated significantly longer after the diagnosis of PF when compared to patients treated with CIST (p = 0.003). RTX was used in all patients who received biologic therapy. Two (6%) patients also received intravenous immunoglobulin. When clinical outcomes were compared between CIST and biologic therapy, rates of clinical remission, partial remission, and relapse, were not statistically significantly different between groups. When RTX was used, rates of relapse and adverse events were higher in those treated with the lymphoma protocol (375 mg/m2 once weekly for four weeks) compared to those treated with the rheumatoid arthritis protocol (two doses of 1,000 mg two weeks apart) (p < 0.0001). The incidence of adverse events was statistically significantly higher in patients treated with CIST when compared to RTX (p = 0.003). These included both physical and psychological changes. The infection rate after treatment with RTX was 7.1%. These outcomes occurred during a follow-up of 12.5 months (range = 1-36 months) in the CIST group and 20.5 months (range = 6-67 months) in the biologic therapy group. The difference in the follow-up period was not statistically significant. The literature suggests that biologics are superior to CIST in treating pemphigus patients. The results of this review suggest similar responses to therapy in pediatric PF patients treated with biologics compared to CIST. This may have been due to a limited duration of follow-up and a lack of detailed treatment outcomes in pediatric PF patients. The data in this review strongly suggests that specific treatment protocols need to be developed and implemented for pediatric PF patients. These patients are at a critical phase in life where PF therapy can influence or affect physical growth, hormonal changes, psychosocial development, and essential education.

Paraneoplastic autoimmune Laminin-332 syndrome (PALS): Anti-Laminin-332 mucous membrane pemphigoid as a prototype.

IMPORTANCE: Laminin-332 is an important component of the basement membrane. Recently, autoantibodies to Laminin-332 have been described in several autoimmune diseases. Many of these autoimmune diseases have a high incidence of malignancy. The importance of Laminin-332 autoantibodies and its relationship to malignancy is highlighted by using Laminin-332 Pemphigoid (LM-332Pg) as a prototype. OBJECTIVE: To identify several autoimmune diseases that have autoantibodies to Laminin-332 present, and to determine the prevalence of malignancy in them. Using Laminin-332 Pemphigoid (LM-332Pg) as a prototype, to compare clinical profiles of LM-332Pg patients with and without cancer. By identifying the temporal detection of cancer, can the influence of autoantibodies to Laminin-332 on prognosis be determined. EVIDENCE REVIEW: A literature search was conducted to identify autoimmune and inflammatory diseases in which autoantibodies to Laminin-332 were present. Subsequently, the rate of malignancy in these autoimmune diseases was determined. A search for publications on LM-332Pg patients to determine cancer rates and clinical outcomes to examine if a relationship can be proposed, was performed. FINDINGS: Autoantibodies to Laminin-332 were detected in recent studies of systemic lupus erythematosus (SLE), psoriasis, bronchiolitis obliterans (BO), graft-vs-host disease (GVH), bullous pemphigoid (BP), lichen planus (LP), epidermolysis bullosa acquisita (EBA), and membranous glomerulonephropathy (MGN). A high incidence of cancer rate was reported in these autoimmune diseases including primary Sjögren's syndrome (pSS), systemic sclerosis (SS), dermatomyositis (DM), multiple sclerosis (MS), immune thrombocytopenia purpura (ITP), and rheumatoid arthritis (RA). Data analysis demonstrated that LM-332Pg patients had a higher risk of developing ovarian, uterine, lung, gastric cancers and leukemia. The incidence for breast cancer was lower, when compared with global cancer rates. Patients diagnosed with cancer after the presence of LM-332Pg had higher rates of mortality and lower rates of remission, compared to those diagnosed with cancer prior to the discovery/diagnosis of LM-332Pg. When studied, levels of Laminin-332 autoantibodies correlated with the presence or absence of malignancy. CONCLUSIONS AND RELEVANCE: Preliminary analysis suggests that autoantibodies to Laminin-332 are present in multiple autoimmune diseases, which also have a high incidence of malignancy. Detailed analysis of available data highlights that patients who developed LM-332Pg after cancer was diagnosed, had a more favorable prognosis, compared to patients who developed cancer when LM-332Pg was previously present. Preliminary data would suggest that autoantibodies to Laminin-332 could serve as an important biomarker in certain patients, for correlation with possible incidence of malignancy.

Pemphigoid of the pulmonary system (POPS): A review of a less recognized feature.

This review of Pemphigoid of the Pulmonary System (POPS) is a comprehensive description of pulmonary involvement in patients with mucous membrane pemphigoid (MMP), which is an orphan autoimmune blistering disease. The objective of the review was to analyze clinical features of pulmonary involvement in MMP. This POPS review is a case series in which multiple search engines were utilized from inception to June 2022 for cases of MMP with biopsy and immunopathology proven tracheal and bronchial pemphigoid. Clinical profiles prior to pulmonary involvement, bronchoscopy findings, clinical course and therapy were recorded and cause of death was analyzed. Patients with documented MMP who developed tracheal, bronchial and pulmonary involvement were included in the POPS review. Histology and immunopathology documentation were essential diagnostic criteria. Comparison groups were not possible. Patients were treated with immunosuppressive therapy. Some required surgical interventions. Six of the 11 patients attained complete or partial remission on or off therapy. Five patients died from pulmonary complications. The POPS review had six females and five males. The mean age at onset was 20 years (range 4-76), while 80% of the patients were under 40 years. All had severe widespread MMP involving three to five mucosal tissues. 100% had oral, 82% had ocular and cutaneous involvement. Pulmonary involvement occurred at 24 mo (range 2-372) after the onset of MMP. Bronchoscopy revealed acute inflammation during active disease and scarring of the trachea and bronchi in the later stages. Systemic infections occurred in 45%, while pulmonary infection occurred in 36%. Mortality due to respiratory failure, at the median age of 20 years (range 18-76), occurred in 45% of the patients, and was considered disease related. In spite of the young age, while there are some similarities in the clinical profile and response to systemic therapy, there are definitive differences from other patients with MMP. Early diagnosis with appropriate management could produce better clinical outcomes and prevent mortality in this orphan disease. Consequently, there is a critical need for early identification and diagnosis of POPS.

Use of rituximab in the treatment of mucous membrane pemphigoid: An analytic review.

Mucous Membrane Pemphigoid (MMP) is a potentially fatal mucocutaneous autoimmune blistering disease. Autoantibodies are produced against various components of the dermo-epidermal or mucosal-submucosal junction are referred to as basement membrane zone (BMZ). The hallmark is deposition of of Ig and C3 on the perilesional tissues and in some patients detection of anti-BMZ autoantibodies. A unique characteristic of MMP is that as the blisters or erosions heal, they leave irreversible scarring. This scarring results in serious and catastrophic sequelae that affect the quality of life. Conventional therapy consists of anti-inflammatory and immunosuppressive agents (ISA). In patients who fail conventional therapy or develop significant side effects to them, rituximab (RTX) has been used off label. In this review, the clinical outcomes of patients with MMP treated with RTX were studied. 124 patients were identified, 47.58% being male. 72 patients were treated by the Lymphoma Protocol and 51 by Rheumatoid Arthritis (RA) protocol. Follow up for the entire cohort was 36 months (range 0.5-72). On follow-up 64 patients (51.61%) achieved complete clinical remission (CR) off therapy, 25 patients (20.16%) were in CR on therapy, 5 patients (4.03%) were non-responders, and 9 patients (7.25%) were failures. 52 patients (41.93%) experienced a relapse, after 36 months follow-up. Duration between last RTX infusion and relapse was 10.5 months (range 1-30). Most patients with relapses were treated with additional RTX. A statistically significant better outcome was observed in patients treated with RTX as monotherapy compared to those who received RTX with ISA. Clinical outcomes in patients treated with Lymphoma protocol were better than RA protocol at a statistically significant level. Data on CD20+ B cell depletion and repopulation was limited. Interestingly relapses were seen in patients with CD20+ B cell depletion and after repopulation. In the final analysis, 89 patients (71.77%) were in complete remission. Data in this review indicated that RTX was a useful agent to treat MMP. While a randomized control trial may not be practically possible, better and disease specific protocols need to be developed. When publishing, authors should attempt to provide complete and detailed information. In doing so, they will benefit their colleagues and the patients with MMP they treat with RTX.

Molecular Basis for Global Incidence of Pemphigoid Diseases and Differences in Phenotypes.

Pemphigoid (Pg) diseases are a group of potentially fatal autoimmune mucocutaneous diseases. They have different clinical phenotypes, involving only the skin or multiple mucous membranes. They occur globally and frequently affect the elderly. The common marker among all variants is the presence of autoantibodies targeting the dermal-epidermal or mucosal-submucosal junctions, or basement membrane zone (BMZ). Four target antigens in the BMZ were studied. These included BPAG1, BPAG2 and subunits of α6 and ß4 human integrins. Our objective was to find a molecular basis for the global incidence of Pg diseases and a mechanism that will explain the vast differences in clinical phenotypes and outcomes. All the variants of Pg that were analyzed had a statistically significant association with HLA-DQß1*03:01 in ten countries on four continents. This explains the reason for global incidence. Prediction models discovered multiple peptides in each of the four antigens that serve as T cell epitopes. These T cell epitopes were shown to bind to HLA-DQß1*03:01. In addition, structure modelling demonstrated the peptide-HLA complex bound to the T cell receptor. These autoreactive T cells would stimulate B cells to produce specific anti-BMZ autoantibodies. Anti-BMZ autoantibodies with different specificities will produce different phenotypes, which will account for involvement of different tissues and organs in different molecules. The contribution this study makes is that it provides a molecular basis of why a similar disease occurs in different racial groups. Furthermore, it provides the basis for the production of autoantibodies with different specificities, which resultantly produces different phenotypes.

IgM Deficiency in Autoimmune Blistering Mucocutaneous Diseases Following Various Treatments: Long Term Follow-Up and Relevant Observations.

IgM deficiency has been reported in patients with many autoimmune diseases treated with Rituximab (RTX). It has not been studied, in detail, in autoimmune mucocutaneous blistering diseases (AIMBD). Our objectives were: (i) Examine the dynamics of IgM levels in patients with and without RTX. (ii) Influence of reduced serum IgM levels on clinical and laboratory parameters. (iii) Explore the possible molecular and cellular basis for reduced serum IgM levels. This retrospective study that was conducted in a single-center from 2000 to 2020. Serial IgM levels were studied in 348 patients with five AIMBD (pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, and ocular cicatricial pemphigoid) and found decreased in 55 patients treated with RTX, IVIG, and conventional immunosuppressive therapy (CIST). Hence the incidence of decreased serum IgM is low. The incidence of decreased IgM in patients treated with RTX was 19.6%, in patients treated with IVIG and CIST, it was 52.8% amongst the 55 patients. IgM levels in the post-RTX group were statistically significantly different from the IVIG group (p<0.018) and CIST group (p<0.001). There were no statistically significant differences between the groups in other clinical and laboratory measures. Decreased serum IgM did not affect depletion or repopulation of CD19+ B cells. Patients in the three groups achieved clinical and serological remission, in spite of decreased IgM levels. Decrease in IgM was isolated, since IgG and IgA were normal throughout the study period. Decreased IgM persisted at the same level, while the patients were in clinical remission, for several years. In spite of persistent decreased IgM levels, the patients did not develop infections, tumors, other autoimmune diseases, or warrant hospitalization. Studies on IgM deficiency in knockout mice provided valuable insights. There is no universally accepted mechanism that defines decreased IgM levels in AIMBD. The data is complex, multifactorial, sometimes contradictory, and not well understood. Nonetheless, data in this study provides novel information that enhances our understanding of the biology of IgM in health and disease.

The evolving role of rituximab in the treatment of pemphigus vulgaris: a comprehensive state-of-the-art review.

INTRODUCTION: Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease. Systemic corticosteroids (CS), while life-saving, have several serious side effects. To improve treatment and prognosis, recently rituximab (RTX), a chimeric monoclonal antibody against CD20 molecule on B cells, has become popular. This Expert Opinion discusses clinical and scientifically relevant aspects of RTX treating PV. AREA COVERED: This presentation describes the mechanism of action, clinical efficacy, safety, adverse events, protocols used, and clinical outcomes. Concerns for infection, reactivation of latent or previous infections, and high relapse rate are discussed. EXPERT OPINION: Use of RTX in PV is still a work in progress. There are many unanswered questions. FDA did not provide a protocol or guidelines. Whenever RTX is used, systemic corticosteroids are simultaneously used, albeit for a shorter duration and lower dose. Used in these doses for these durations they can cause immunosuppression. Would it be more appropriate if instead of 'First Line Therapy' it would be more advisable to use the term 'First Adjunctive Immunosuppressive Agent'?

Post-rituximab immunoglobulin M (IgM) hypogammaglobulinemia.

Rituximab is a B cell depleting monoclonal antibody that targets the B cell-specific cell surface antigen CD20 and is currently used to treat several autoimmune diseases. The elimination of mature CD20-positive B lymphocytes committed to differentiate into autoantibody-producing plasma cells is considered to be the major effect of rituximab, that makes it a beneficial biological agent in treating autoimmune diseases. Hypogammaglobulinemia has been reported after rituximab therapy in patients with lymphoma and rheumatoid arthritis. Similar data are scarce for other autoimmune diseases. Low immunoglobulin G (IgG) or hypogammaglobulinemia has attracted the most attention because of its significant role in protective immunity. However, the incidence and clinical implications of low immunoglobulin M (IgM) or hypogammaglobulinemia have not been studied in detail. This review will focus on the frequency and the clinical concerns of low IgM levels that result as a consequence of the administration of rituximab. The etiopathogenic mechanisms underlying post-rituximab IgM hypogammaglobulinemia and its implications are presented. The long-term consequences, if any, are not known or documented. Multiple factors may be involved in whether IgG or IgM decreases secondary to rituximab therapy. It is possible that the autoimmune disease itself may be one of the important factors. The dose, frequency and number of infusions appear to be important variables. Post-rituximab therapy immunoglobulin levels return to normal. During this process. IgM levels take a longer time to return to normal levels when compared to IgG or other immunoglobulins. IgM deficiency persists after B cell repopulation to normal levels has occurred. Laboratory animals and humans deficient in IgM can have multiple infections. Specific pharmacologic agents or biologic therapy that address and resolve IgM deficiency are currently unavailable. If the clinical situation so warrants, then prophylactic antibiotics may be indicated and perhaps helpful. Research in this iatrogenic phenomenon will provide a better understanding of not only the biology of IgM, but also the factor(s) that control its production and regulation, besides its influence if any, on rituximab therapy.

Anti-p200 Pemphigoid: A Systematic Review.

The many clinical aspects of anti-p200 pemphigoid are not well-characterized. We aimed to analyze and correlate known existing data on the epidemiological, clinical, histological, and immunological features of anti-p200 pemphigoid. We performed a review using Medline, Embase, and Web of Science databases (1900-2018). Case reports and series of patients were included. A total of 68 eligible studies that comprised 113 anti-p200 pemphigoid patients were included in the qualitative analysis, where there was a mean age of onset of 65.5 years. All patients presented with bullae/vesicles, and 54.3% had urticarial plaques. A similarity to bullous pemphigoid was reported in 66.1% of cases, but palmoplantar (51.4%), cephalic (40.3%), and mucosal (38.5%) involvement, besides frequent development of scars/milia (15.7%), were reported. Autoantibodies against recombinant laminin γ1 were detected in the sera of 73.1% of patients. Psoriasis was present in 28.3% of anti-p200 pemphigoid patients, particularly among Japanese patients (56.4%). The incidence of pustular psoriasis in this subgroup, was significantly greater than in the normal population. In conclusion, the diagnosis of anti-p200 pemphigoid may be suspected when a subepidermal autoimmune blistering disease develops in a younger age group, along with significant acral and cephalic distribution and mucosal involvement.

Treatment of pemphigus vulgaris: part 2 - emerging therapies.

Introduction: Corticosteroids and immunosuppressive agents have been the mainstay for the treatment of pemphigus vulgaris (PV). While they have benefited patients, they have been associated with the risks of prolonged immune suppression and a high incidence of significant and catastrophic side effects. Relapses are common. Novel agents promising targeted therapies, that may provide better outcomes, are being studied. Areas covered: Recently rituximab with corticosteroids has been recommended as the first-line treatment for PV. A number of known and new therapeutic agents currently investigated are BAFF, P13K, BTK inhibitors along with the use of IVIg and CAR-T therapy. The possible role of these therapeutic targets in the pathophysiology appears to be the rationale for the treatment of this potentially fatal disease. Expert opinion: While there is significant enthusiasm for these therapies, certain concerns and consequences are being under-discussed. None of the current clinical trials in progress are specific for PV, except possibly CAR-T therapy. The major issue(s) that are unclear is whether these therapies would be successful in providing long-term clinical remissions. Will these therapies require additional agents to be effective? Will the benefits be limited in duration? The answers to many questions will determine their final place in the algorithm for the treatment of PV.

Treatment of pemphigus vulgaris: part 1 - current therapies.

Introduction: While biologic agents that can be used for treating pemphigus vulgaris (PV) are increasing, themajority of the world's PV patients can afford only corticosteroids (CS) and some immunosuppressive agents (ISA). Areas covered: The spectrum of side effects encountered when PV patients receive high-dose, long-term CS and ISA are presented based on total dose and duration of therapy. The steroid-sparing effect of individual ISA as documented in published studies and their clinical outcomes, in terms of duration of remissions, frequency of relapses and time to relapse, are presented, so that comparisons are possible. Thus, rational choices can be made for the individual patient. Expert opinion: In 2019, the majority of PV patients globally will continue to be treated with CS and ISA. This review will help clinicians and patients become aware of when to anticipate which side effects and if possible, to prevent or avoid them. It provides guidelines to maximize the clinical benefits of ISA in inducing and maintaining remission and minimizing side effects by monitoring them.

Reversing Autoimmunity Combination of Rituximab and Intravenous Immunoglobulin.

In this concept paper, the authors present a unique and novel protocol to treat autoimmune diseases that may have the potential to reverse autoimmunity. It uses a combination of B cell depletion therapy (BDT), specifically rituximab (RTX) and intravenous immunoglobulin (IVIg), based on a specifically designed protocol (Ahmed Protocol). Twelve infusions of RTX are given in 6-14 months. Once the CD20+ B cells are depleted from the peripheral blood, IVIg is given monthly until B cells repopulation occurs. Six additional cycles are given to end the protocol. During the stages of B cell depletion, repopulation and after clinical recovery, IVIg is continued. Along with clinical recovery, significant reduction and eventual disappearance of pathogenic autoantibody occurs. Administration of IVIg in the post-clinical period is a crucial part of this protocol. This combination reduces and may eventually significantly eliminates inflammation in the microenvironment and facilitates restoring immune balance. Consequently, the process of autoimmunity and the phenomenon that lead to autoimmune disease are arrested, and a sustained and prolonged disease and drug-free remission is achieved. Data from seven published studies, in which this combination protocol was used, are presented. It is known that BDT does not affect check points. IVIg has functions that mimic checkpoints. Hence, when inflammation is reduced and the microenvironment is favorable, IVIg may restore tolerance. The authors provide relevant information, molecular mechanism of action of BDT, IVIg, autoimmunity, and autoimmune diseases. The focus of the manuscript is providing an explanation, using the current literature, to demonstrate possible pathways, used by the combination of BDT and IVIg in providing sustained, long-term, drug-free remissions of autoimmune diseases, and thus reversing autoimmunity, albeit for the duration of the observation.

Monopathogenic vs multipathogenic explanations of pemphigus pathophysiology.

This viewpoint highlights major, partly controversial concepts about the pathogenesis of pemphigus. The monopathogenic theory explains intra-epidermal blistering through the "desmoglein (Dsg) compensation" hypothesis, according to which an antibody-dependent disabling of Dsg 1- and/or Dsg 3-mediated cell-cell attachments of keratinocytes (KCs) is sufficient to disrupt epidermal integrity and cause blistering. The multipathogenic theory explains intra-epidermal blistering through the "multiple hit" hypothesis stating that a simultaneous and synchronized inactivation of the physiological mechanisms regulating and/or mediating intercellular adhesion of KCs is necessary to disrupt epidermal integrity. The major premise for a multipathogenic theory is that a single type of autoantibody induces only reversible changes, so that affected KCs can recover due to a self-repair. The damage, however, becomes irreversible when the salvage pathway and/or other cell functions are altered by a partnering autoantibody and/or other pathogenic factors. Future studies are needed to (i) corroborate these findings, (ii) characterize in detail patient populations with non-Dsg-specific autoantibodies, and (iii) determine the extent of the contribution of non-Dsg antibodies in disease pathophysiology.

First line treatment of pemphigus vulgaris with a novel protocol in patients with contraindications to systemic corticosteroids and immunosuppressive agents: Preliminary retrospective study with a seven year follow-up.

BACKGROUND: Conventional therapy for pemphigus vulgaris (PV) consists of high-dose systemic corticosteroids (CS) and immunosuppressive agents (ISA). This combination may be ineffective, cause serious adverse events or relapses in some patients. OBJECTIVE: To determine if the combination of intravenous immunoglobulin (IVIg) therapy and rituximab (RTX) can be used as first-line therapy in PV patients in whom systemic CS and ISA are contraindicated and evaluate its ability to produce long-term sustained remissions. METHOD: This a retrospective study of five male and five female patients (mean age 47.87 years). RTX was administered once weekly for eight consecutive weeks, followed by once monthly for four months (dose 375 mg/m(2)). Since CD20(+) B cells were undetectable, IVIg was infused until they reached normal levels (dose 2 g/kg/cycle). IVIg was then continued according to published protocol. RESULTS: Initial clinical response and complete disease resolution occurred in a mean of 3.2 weeks and 7.4 weeks, respectively. Mean duration of rituximab therapy was 6.09 months and 33.7 months for IVIg therapy. Mean duration of follow-up after the last dose of rituximab was 86.08 months, during which all patients remained in complete remission. Mean length of total follow-up was 103.99 months. No relapses, infections, or hospitalizations were reported. CONCLUSIONS: When systemic CS and ISA are contraindicated in PV patients, combination RTX and IVIg therapy can produce a prolonged, sustained remission without additional systemic therapy. This positive clinical outcome could be the consequence of pathogenic B cell depletion and restoration of immune regulation.

Treatment of recalcitrant bullous pemphigoid (BP) with a novel protocol: A retrospective study with a 6-year follow-up.

BACKGROUND: Bullous pemphigoid is an autoimmune blistering skin disease that predominantly affects the elderly. Conventional therapy using high-dose systemic corticosteroids and immunosuppressive agents can be ineffective in some patients and produce adverse events and relapses. Hence, alternate therapies are required. OBJECTIVE: The clinical outcomes of patients with extensive, recalcitrant bullous pemphigoid treated with a combination therapy of rituximab (RTX) and intravenous immunoglobulin were evaluated. METHODS: In this retrospective study, 12 patients (mean age of 68.25 years) unresponsive to previous conventional immunosuppressive therapy, intravenous immunoglobulin, and/or RTX were treated with this combination therapy. RESULTS: Complete clinical resolution occurred in a mean of 4.6 months and previous systemic therapy was discontinued in 6.2 months. Two patients had a recurrence posttherapy and responded to additional RTX infusions. The remaining 10 patients had no recurrences. Patients were followed up for a mean of 73.8 months after discontinuation of all systemic therapy. All have remained in remission without adverse events for 6 years. LIMITATIONS: This was a retrospective study with a small sample size. CONCLUSION: The combination of RTX and intravenous immunoglobulin produced a sustained clinical remission without adverse events, infections, and hospitalizations. This specific combination protocol offers a promising therapy for patients with recalcitrant bullous pemphigoid.

The emerging role of rituximab in autoimmune blistering diseases.

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.