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.

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.

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.

Relationship between radiation therapy and bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. OBJECTIVE: To review the literature on radiation therapy (RT)-associated BP. METHODS: A review of the English language literature on patients who developed BP during and up to 10 years post RT was performed. RESULTS: 29 patients were reported. 25 (86.2%) were women, 84% of whom had received RT for breast cancer. Three patients were male (10.3%). Gender was not mentioned in 1 (3.4%). 72% developed BP post RT; 28% developed BP while undergoing RT. BP was initially localized to irradiated sites in 25 patients and to non-irradiated sites in 2 patients. Two patients presented with generalized disease. Disease control was reported in 12 patients, partial remission in 7 and complete remission in 5. CONCLUSION: The clinical profile, response to therapy and clinical outcome may indicate that RT-associated BP may be a specific subset of BP with a relatively benign course.

Critical analysis of the use of rituximab in mucous membrane pemphigoid: a review of the literature.

BACKGROUND: Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease. In patients who do not respond to conventional therapy, rituximab (RTX) may be an option. The current literature on the treatment of MMP with RTX is limited. OBJECTIVE: In this review, the data on 28 patients with MMP treated with RTX are critically analyzed. The goal is to provide objective information useful in decision making and treatment. METHODS: A PubMed search using the key words "rituximab" and "mucous membrane pemphigoid" was made in the English language only. The studies were divided into case reports and case series. RESULTS: In the final analysis, 20 of 28 patients had a complete response, 3 had a partial response, 2 were nonresponders, and 1 had stabilization of disease. In 1 patient, stabilization of upper airway disease was observed but the patient developed bilateral blindness as a result of progression of disease. Hence, the patient was considered a treatment failure. One died from infection. At least half of the patients were treated with a second cycle because of relapse or lack of response. LIMITATIONS: Long-term follow-up after RTX therapy is lacking. Hence, the clinical benefit of inducing long-term remissions cannot be assessed. Responses of individual mucosal sites cannot be differentiated. Studies on B-cell levels and antibody responses are lacking. CONCLUSION: Using the protocol described, RTX benefits patients with recalcitrant MMP. Some patients fail treatment or experience a relapse. The ability of RTX to influence the clinical course of MMP remains to be determined.

Review on the influence of protocol design on clinical outcomes in rheumatoid arthritis treated with rituximab.

OBJECTIVE: To critically analyze the influence of protocol design on clinical outcome in patients with rheumatoid arthritis (RA) treated with rituximab. DATA SOURCES: A PubMed and EMBASE search (January 2000-January 2012) using the key words rheumatoid arthritis and rituximab was performed. STUDY SELECTION AND DATA EXTRACTION: A search of English-language studies from the data sources was conducted for randomized, double-blind, placebo-controlled studies with 100 patients or more assessing the efficacy and safety of rituximab in the treatment of RA. From these studies, 2 authors independently extracted, compiled, and aggregated the data. DATA SYNTHESIS: Eight studies met the inclusion criteria. In these studies, some patients had not been treated with tumor necrosis factor-alfa (TNF-α) inhibitors, while most did not respond to it. The variables compared included dose (500 vs 1000 mg), duration of study (24 vs 48 weeks), and number of cycles (1 vs 2). They were statistically analyzed using the χ(2) test. There was a statistically significant difference in the response to rituximab compared to the control (methotrexate) (p < 0.001). In patients who were studied for only 24 weeks, given 500 or 1000 mg for 1 or 2 cycles, a 90% or greater response rate was reported in those who achieved an ACR 20, but no statistically significant differences were observed (p = 0.75). In patients studied for 48 weeks who received 2 cycles of either 500 mg or 1000 mg of rituximab and achieved an ACR 20, a statistically significant difference (p < 0.001) was observed in those who received a dose of 1000 mg for 2 cycles (42.77% vs 67.49%). CONCLUSIONS: In patients who are nonresponsive to disease-modifying antirheumatic drugs and TNF-α inhibitors, rituximab may be a promising and well-tolerated biologic agent. The capacity of rituximab to produce long-term, sustained remissions could not be evaluated because the duration of the studies was limited to 24 weeks or 48 weeks. Studies with longer periods of observation are warranted.

Treatment of bullous pemphigoid with rituximab: critical analysis of the current literature.

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

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.

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.

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.

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.

Analysis of current therapy and clinical outcome in childhood pemphigus vulgaris.

Pemphigus vulgaris (PV) is a rare, potentially fatal chronic autoimmune disease of the skin and mucous membrane. The objective of this study was to analyze the clinical outcomes and side effects associated with treatment of childhood PV (CPV). A retrospective review of the English language literature was conducted through PUBMED using the words childhood pemphigus vulgaris, and treatment or clinical outcome. Only patients under 12 years of age were included. Thirty-three cases were found in 29 reports. Mean age at onset was 8.3 years (range 1.5-12 yrs). Mucosal involvement (97.0%) was more common than cutaneous involvement (84.8%). Oral mucosa was the most common site of mucosal involvement (93.9%), followed by genital (20.6%), ocular (11.8%), and nasal mucosa (2.9%). Mean duration of therapy was 4.5 years (range 0.6-14.5 yrs), and mean duration of follow-up was 5.2 years (range 0.6-16 yrs). Complete recovery with no further therapy was achieved in 18.2% and partial recovery with minor relapses while on maintenance therapy in 78.8%. One patient died due to infection (3.0%). Serious side effects were present in 60.6%. The most common were cushingoid features (65.0%), growth retardation (50.0%), and infection (50.0%). Two patients who were refractory to systemic corticosteroids and immunosuppressive agents (ISA) had a favorable clinical response to Rituximab. Current therapy for CPV involving the use of long-term systemic corticosteroids in conjunction with ISA results in prolonged immunosuppression, causing systemic infections and growth retardation. Safer and more effective therapies need to be explored.

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'?

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.

Combination of rituximab and intravenous immunoglobulin for recalcitrant ocular cicatricial pemphigoid: a preliminary report.

PURPOSE: To compare the effectiveness and safety of the combination therapy of rituximab (RTX) and intravenous immunoglobulin (IVIg) to other immunosuppressive regimens in the treatment of ocular cicatricial pemphigoid (OCP). DESIGN: Retrospective, comparative, interventional case series. PARTICIPANTS: Twelve patients with OCP. METHODS: We reviewed medical records of 12 patients with OCP. Ten of the 12 patients were blind in 1 eye after initial systemic immunosuppressive therapies (phase 1 treatment). The patients were then divided into 2 groups based on treatments received during phase 2. The study group consisted of 6 patients who received the combination of RTX and IVIg during phase 2 of their treatment. For comparison purposes, the control group consisted of 6 patients who during phase 2 of their treatment received more aggressive immunosuppressive therapies, but not RTX and IVIg, because the insurance carriers refused to pay for the combination therapy. MAIN OUTCOME MEASURES: Blindness (best-corrected visual acuity [BCVA] < or =20/200) and OCP staging (Foster). RESULTS: The median total follow-up periods were 57.5 and 55.5 months in the control group and the study group, respectively. After phase 1 treatment, all 6 patients in the control group were blind in 1 eye. Similarly, 4 of the patients in the study group were blind in 1 eye, whereas 2 had good BCVA bilaterally but experienced persistent conjunctival inflammation despite phase 1 treatment. After phase 2 treatment, all 6 patients in the control group had OCP progression and became blind in both eyes. In contrast, BCVA was stable and no further progression of OCP staging was observed in all 6 patients in the study group. In the study group, the median follow-up from completion of the RTX and IVIg treatment protocol was 11 months. No adverse events, immediate or delayed, were reported in any of the patients who received the combination therapy of RTX and IVIg. CONCLUSIONS: In this preliminary study, the combination therapy of RTX and IVIg arrested disease progression and prevented total blindness in patients with recalcitrant OCP.

A current review of juvenile pemphigus vulgaris: analysis of data on clinical outcomes.

Forty-seven cases of juvenile pemphigus vulgaris have been reported in the English literature. Histology of lesional skin and direct immunofluorescence of perilesional skin are both necessary for a complete diagnosis. The autoimmune bullous condition can affect the skin and mucous membranes individually, but typically affects both concurrently. Disease characteristics in juvenile patients are similar to those in adults; however, a disruption of biologic and social development is of particular concern during adolescence. Although systemic corticosteroids have been used to successfully treat the disease in most cases, long-term use is often necessary for adequate control. Adverse effects from therapy can have devastating effects during this critical period of hormonal changes, physical and mental growth, and social and cultural development that occurs during adolescence. Newer therapies must be designed to adequately treat juvenile patients while also limiting serious adverse effects.

Association between cancer and immunosuppressive therapy--analysis of selected studies in pemphigus and pemphigoid.

OBJECTIVE: To determine whether there is an association between the use of immunosuppressive agents (ISAs) and cancer in patients with pemphigus and pemphigoid-rare, potentially fatal diseases of the skin and mucous membranes, often requiring long-term use of ISAs. DATA SOURCE: Literature was accessed through PubMed (all years available), using the search terms cancer, immunosuppressive agents, pemphigoid, and pemphigus. STUDY SELECTION AND DATA EXTRACTION: A retrospective review of the literature was conducted. Inclusion criteria for studies were: (1) English language, (2) diagnosis of pemphigus and/or pemphigoid based on histology and immunopathology, (3) more than 10 patients evaluated, (4) investigators had a high index of suspicion of cancer and patients were monitored for it, (5) follow-up information was provided for at least 1 year after initiation of therapy, and (6) absence of diagnosis of cancer before initiation of an ISA. Case reports were not included in the analysis. DATA SYNTHESIS: A total of 929 patients diagnosed with either pemphigus or pemphigoid in 17 studies were identified. Patients were divided into 2 groups. Group A comprised patients treated with azathioprine, cyclophosphamide, cyclosporine, or mycophenolate mofetil in combination with prednisone. In Group A, 22 cases of cancer were reported in 21 of the 218 patients (9.6%). Group B comprised patients treated with systemic corticosteroids only. In this group, cancer was reported in 11 of the 711 patients (1.5%). In this study there was no control group (untreated patients) and the sample sizes were small. CONCLUSIONS: Preliminary data suggest a possible association between the use of azathioprine, cyclophosphamide, and cyclosporine and increased susceptibility to cancer in patients with pemphigus and pemphigoid.