Efficacy and safety of biosimilar rituximab in patients with pemphigus vulgaris: a prospective observational study.

Background: The optimal treatment for pemphigus vulgaris (PV) has not been clearly determined yet. Rituximab (RTX) was recently approved for the management of adults with moderate to severe PV. Objectives: This prospective observational study was designed to evaluate the efficacy and safety of biosimilar RTX in PV patients.Methods: The efficacy and safety were evaluated by assessing the pemphigus disease area index (PDAI) score, clinical response and any adverse events (AEs) during at least 12-month follow-up. We evaluated anti-desmoglein (Dsg) 1,3 level at baseline, 3 months and 12 months after RTX infusion.Results: A total of 110 patients treated with biosimilar RTX were enrolled between May 2016 and July 2017. The mean age was 43.58 ± 11.77 years and the mean follow-up time was 16.22 ± 3.45 months. A notable decrease in PDAI score, anti-Dsg 1,3 level and prednisolone dosage was observed. Median delay to achieve complete remission (CR), median duration of CR, and median time to relapse were 3, 9, and 12 months, respectively. Newly diagnosed patients (NDPs) experienced higher rate of CR, longer duration of remission and lower risk of relapse, compared to previously treated patients (PTPs). A total of 47 AEs were observed in 33 (30%) patients, which were mostly mild infusion-related reactions.Conclusion: Administration of biosimilar RTX in PV patients was associated with desirable outcomes in terms of efficacy and safety in both NDPs and PTPs.First-line use of RTX in NDPs was more effective and allowed a rapid tapering of corticosteroid doses compared to PTPs.

Risk factors for death and survival in paraneoplastic pemphigus associated with hematologic malignancies in adults.

BACKGROUND: Paraneoplastic pemphigus (PNP) occurs more often in patients with hematologic malignancies (HMs) than in patients with solid cancer. Lung bronchiolitis obliterans (BO) is a severe complication of PNP. OBJECTIVE: To determine the precise clinical and biologic features of HM-associated PNP and identify factors associated with mortality and survival. METHODS: Systematic review of previously described cases of PNP associated with HMs. RESULTS: A total of 144 patients were included. The HMs were non-Hodgkin lymphoma (52.78%), chronic lymphocytic leukemia (22.92%), Castleman disease (18.60%), and other underlying hematologic malignancy (5.70%). The mortality rate was 57%, and most deaths occurred within the first year after the diagnosis of PNP. Multivariate analysis showed that (1) the presence of antienvoplakin antibodies and BO were significantly associated with death, and (2) a toxic epidermal necrolysis-like clinical pattern, bullous pemphigoid-like clinical pattern, and BO were significantly associated with decreased survival. LIMITATION: Only case reports with sufficient mortality data were included. CONCLUSION: PNP associated with HM has a high mortality rate. The toxic epidermal necrolysis-like and BO-associated forms are independent survival factors in PNP associated with HMs.

Risk factors for lethal outcome in patients with pemphigus: a retrospective cohort study.

Although pemphigus is associated with increased mortality, little is known regarding factors that influence prognosis. To identify prognostic factors for mortality at five- and 10-year periods after an initial diagnosis of pemphigus. A retrospective cohort study was performed. Data were collected for all patients with a new diagnosis of pemphigus between 1990 and 2011, who were actively followed for at least five years at our centre. The endpoint was overall survival at five and 10 years after pemphigus diagnosis. Based on the test sample, associations between clinical variables and overall survival were assessed using univariate and multivariate analyses. A total of 184 patients were included in the study (mean age: 52.2 ± 16.1). The major risk factors for lethal outcome at both five and 10 years after diagnosis were age ≥65 years at diagnosis (with a multivariate hazard ratio [HR] of 5.9 and 4.2 at five and 10 years, respectively) and neurological disease at diagnosis (with a multivariate HR of 5.4 and 5.1 at 5 and 10 years, respectively). Diabetes mellitus was an independent risk factor for mortality at five years (multivariate HR: 3.8). Two risk factors were independently associated with lethal outcome at 10 years: serum albumin levels <3.5 g/dL (multivariate HR: 3.3) and lung disease at diagnosis (multivariate HR: 3.8). Mucosal involvement in patients with pemphigus vulgaris was not associated with increased mortality. Prognosis of patients with pemphigus is influenced by older age, hypoalbuminaemia, diabetes mellitus, and neurological and respiratory comorbidities at diagnosis.

COPD and lung cancer in patients with pemphigus- a population based study.

BACKGROUND: Recent evidence indicates that autoimmunity may contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD was observed at higher frequency in patients with several autoimmune diseases. The association between pemphigus and COPD has not been evaluated in the past. OBJECTIVES: To study the association between pemphigus and COPD using a large-scale real-life computerized database. METHODS: A cross-sectional study was conducted comparing pemphigus patients with age-, sex- and ethnicity-matched control subjects regarding the prevalence of COPD and lung cancer. Chi-square and t-tests were used for bivariate analysis, and logistic regression model was used for multivariate analysis. The study was performed utilizing the computerized database of Clalit Health Services ensuring 4.4 million subjects. RESULTS: A total of 1985 pemphigus patients and 9874 controls were included in the study. The prevalence of COPD was greater in patients with pemphigus as compared to the control group (13.4% vs. 10.1%, respectively; P < 0.001). In a multivariate analysis adjusting for smoking and other confounding factors, pemphigus was significantly associated with COPD (OR, 1.312-1. 5) but not with lung cancer. Study findings were robust to sensitivity analysis that included patients under pemphigus-specific treatments. CONCLUSIONS: A significant association was found between COPD and pemphigus. Physicians treating patients with pemphigus might be aware of this possible association. This observation may further support the hypothesis that COPD has an autoimmune component.

Pemphigus group: overview, epidemiology, mortality, and comorbidities.

Pemphigus forms a group of rare autoimmune bullous diseases that affect the skin and mucous membranes. This group has a chronic course leading to high morbidity and mortality. It is characterized by the production of pathogenic autoantibodies directed against different proteins of the desmosome, leading histologically to intraepidermal cleavage, and clinically to vesicles and erosions on the epithelium of the mucous membranes and/or the skin. The diagnosis of the subtype of pemphigus is based on clinical features, the level of histologic cleavage, and the identification of the antigens recognized by circulating autoantibodies by immunoserological analyses. The epidemiological features of pemphigus vary considerably in different regions of the world. Observational studies examining comorbidities and associations among patients with pemphigus are scarce and sometimes inconclusive. The prognosis, mortality, and clinical outcomes in pemphigus have undergone dramatic change throughout the years. This review provides a brief overview about the different subtypes of pemphigus: pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, pemphigus herpetiformis, and IgA pemphigus. In addition, it summarizes the most recent understanding of the epidemiology, mortality data, and comorbidities of this group of organ-specific autoimmune diseases.

Oral pemphigus treated with minipulse therapy

Pemphigus is a chronic potentially fatal autoimmune disorder that causes blisters and erosions of the skin and oral mucous membrane. most of the cases present oral manifestations as the first clinical sign along with dermal lesions. only 0.5 to 3.2 of cases are reported each year per 1,000,000 population with oral manifestations without dermal participation, and is at times difficult to diagnose. we report a case of oral pemphigus vulgaris in a 20 year old female patient without dermal manifestations treated with oral mini pulse therapy. pénfigo oral tratado con terapia minipulse. resumen: el pénfigo es un trastorno autoinmune crónico potencialmente fatal que causa ampollas y erosiones de la piel y la membrana mucosa oral. la mayoría de los casos presentan manifestaciones orales como el primer signo clínico junto con lesiones dérmicas. solo se reportan de 0.5 a 3.2 casos cada año por cada 1,000,000 de personas con manifestaciones orales sin afectación de la piel, y algunas veces es difícil de diagnosticar. presentamos un caso de pénfigo vulgar oral en un paciente de 20 años, sin manifestaciones cutáneas tratadas con mini terapia del pulso oral.

Mortality and Cause of Death in Patients with Pemphigus.

All-cause and cause-specific mortality among patients with pemphigus compared with the general population is yet to be established. This study investigated overall mortality and cause-specific mortality in a large immunopathologically validated cohort of patients with pemphigus. Mortality of patients with pemphigus was compared with age- and gender-matched control subjects in the general population. All-cause and cause-specific standardized mortality ratios (SMRs) were estimated. The study cohort included 245 patients newly-diagnosed with pemphigus between January 1990 and June 2016, contributing 2,679.4 person-years of follow-up. Overall, 48 deaths were observed during a mean follow-up period of 10.9 ± 8.1 years, which was more than twice the number expected (SMR 2.4; 95% confidence interval (95% CI) 1.82-3.20). The SMRs for death due to infections (22.6; 95% CI 13.6-35.3), namely pneumonia (25.7; 95% CI 11.7-48.8) and septicaemia (8.6; 95% CI 1.7-25.0), and due to cardiovascular diseases (2.8; 95% CI 1.0-6.0) were significantly higher than expected. Overall mortality among patients with pemphigus is 2.4-times greater than for the general population, mainly due to infections.

A 6-year treatment experience for pemphigus: retrospective study of 69 Chinese patients.

There is a lack of data on treatment and prognosis of pemphigus in China. The aim of this study was to evaluate long-term follow-up and prognosis of pemphigus. Forty-seven inpatients with pemphigus vulgaris (PV) and 22 with pemphigus foliaceus (PF) were recruited in this retrospective study. The average age at onset was 51.6 and 54.9 years in PV and PF, respectively. High-dose systemic steroids were administered in 47 PV and 21 PF, of which 18 PV and 8 PF with adjuvant therapies. CD4 lymphocytopenia was found in 5 PV and 2 PF patients at admission and successfully treated by intravenous thymopentin daily. During a mean follow-up of 37.1 months, 41 PV and 19 PF reached remission, 30 PV and 9 PF relapsed, 4 PV and 2 PF died. Major causes of death were relapse of pemphigus due to discontinuation of oral steroids by the patients themselves (four cases) and severe infections (two cases, one with severe CD4 lymphocytopenia). The 1-year mortality rate of PV and PF was 8.5% and 4.5%, respectively. Cox regression analysis indicated that age at onset of pemphigus was an independent risk factor related to the elevated mortality. Our report confirmed the high mortality rate of pemphigus in a Chinese population and stressed that patient education was urgently needed to prevent relapses and deaths.

Comorbidities and inpatient mortality for pemphigus in the U.S.A.

BACKGROUND: The morbidity and mortality associated with pemphigus and its treatments have not been fully described. Previous studies have found conflicting results about certain comorbidities and were limited by small sample sizes. OBJECTIVES: To determine the morbidity and mortality from pemphigus and its treatments in the U.S.A. METHODS: We examined a cross-sectional cohort of 87 039 711 hospitalized patients in the U.S.A. to determine the inpatient comorbidities and mortality of pemphigus. RESULTS: In multivariate survey logistic regression models adjusting for age, sex and race/ethnicity, pemphigus and its treatments were associated with 39 of 122 comorbidities examined. The disorders most strongly associated with pemphigus were Cushing syndrome [adjusted odds ratio (OR) 17·23, 95% confidence interval (CI) 2·41-122·90], adrenal insufficiency (4·08, 1·71-9·73), myasthenia gravis (6·92, 2·55-18·79), mucositis (17·19, 7·73-38·22), herpes infection (7·98, 3·62-17·62), fungal infections (4·03, 3·60-4·52), insomnia (18·02, 2·46-131·88) and hidradenitis (5·34, 1·33-21·43). Among malignancies, only leukaemia (OR 1·56, 95% CI 1·08-2·24) and non-Hodgkin lymphoma (1·52, 1·15-2·03) were associated with pemphigus, but not any solid organ malignancies. Patients with a secondary diagnosis of pemphigus had higher inpatient mortality (3·20%, 95% CI 2·71-3·69) than those with a primary (1·60%, 1·29-1·91) or no (1·78%, 1·78-1·78) diagnosis of pemphigus (P < 0·001). CONCLUSIONS: Pemphigus is associated with increased inpatient mortality, likely through its association with numerous comorbid health conditions. Patients with pemphigus require improved access to dermatological care and increased screening for the myriad of comorbidities.

Prevalence of myasthenia gravis and associated autoantibodies in paraneoplastic pemphigus and their correlations with symptoms and prognosis.

BACKGROUND: Paraneoplastic pemphigus (PNP) involves multiple organs, but little is known about its neurological involvement. OBJECTIVES: To investigate the symptoms, prognosis and profiles of associated autoantibodies in myasthenia gravis (MG), and their correlations in patients with PNP. METHODS: Fifty-eight patients with PNP were assessed for myasthenic symptoms and laboratory evidence. Serum autoantibodies against acetylcholine receptor (AChR), acetylcholinesterase (AChE), titin, ryanodine receptor (RyR) and muscle-specific kinase (MuSK) were measured by enzyme-linked immunosorbent assay. Patients with pemphigus vulgaris (PV), pemphigus foliaceus (PF), connective tissue disease (CTD) and non-PNP MG (NP-MG), and healthy donors, served as controls. These autoantibodies in PNP were also compared in the presence or absence of dyspnoea or muscle weakness. Cox regression and log-rank tests were used for survival analysis. RESULTS: Overall 39% of patients with PNP experienced muscle weakness, and 35% were diagnosed with MG. Moreover, 35% had positive anti-AChR and 28% had anti-AChE antibodies, similarly to NP-MG (33% and 17%, respectively, P > 0·05). However, both were negative in all patients with PV, PF and CTD and healthy donors (P < 0·005). No other antibodies showed significant differences among groups. Anti-AChR and anti-AChE antibody levels were significantly increased in patients with PNP with dyspnoea, while anti-AChR, anti-titin and anti-RyR were significantly increased in patients with PNP with muscle weakness (P < 0·05). Nevertheless, levels and positive rates of these autoantibodies showed no significant differences between PNP with Castleman disease and thymoma. Although anti-AChE levels impacted survival duration (P  =  0·027, odds ratio 3·14), MG complications did not affect the overall survival percentage in PNP. CONCLUSIONS: MG is a complication of PNP. Anti-AChR and anti-AChE antibodies are prominent in patients with PNP, especially those with dyspnoea.

Prognostic factors in pemphigus vulgaris and pemphigus foliaceus.

BACKGROUND: Pemphigus typically has a chronic course, although there is great variability in disease duration (DD) and time taken to disease remission (DR) between individuals with the disease. The reasons for this are unclear. OBJECTIVES: To explore the prognostic influence of epidemiological, clinical, immunological and genetic factors on disease course and remission in pemphigus vulgaris (PV) and pemphigus foliaceus (PF). METHODS: This was a retrospective study of patients with PV and PF, recruited from a single UK centre. Direct and indirect immunofluorescence and enzyme-linked immunosorbent assay studies for antidesmoglein (Dsg) antibodies were used to assess immunological factors. Polymerase chain reaction with sequence specific primers (PCR-SSP) was used to assess the Class II human leukocyte antigen status of patients. Prognostic endpoints investigated were time to initial first DR and total DD. RESULTS: Ninety-five patients were recruited (79 PV and 16 PF). Patients of Indo-Asian origin were significantly associated with longer DD than White-British patients (P = 0.029). In addition, younger age at onset was associated with a worse prognosis in terms of DD: the mean age at presentation of patients with DD of < 5 years was 49 years (SEM = 3.4) compared with 40 years (SEM = 1.9) in those with DD > 5 years (P = 0.039). A higher initial intercellular antibody titre on normal human skin substrate was associated with a greater time to initial DR (P = 0.007) and high anti-Dsg 3 levels at baseline were associated with a longer total DD (P = 0.03). CONCLUSIONS: Ethnic group, age at presentation, initial intercellular antibody titre and initial Dsg 3 antibody levels all had a significant impact on prognosis of pemphigus.

Assessment of the rate of long-term complete remission off therapy in patients with pemphigus treated with different regimens including medium- and high-dose corticosteroids.

BACKGROUND: Few studies have evaluated pemphigus treatments according to the definitions of the consensus statement. Prognostic factors for complete remission off therapy (CRoffT) remain unknown. OBJECTIVE: We sought to assess the rate of CRoffT in patients with pemphigus treated with different regimens. METHODS: In all, 134 patients with pemphigus were included in a retrospective, multicenter study. Primary end point was the rate of CRoffT. Prognostic factors for CRoffT were determined using univariate and multivariate analyses. RESULTS: Eighty patients with pemphigus vulgaris, 47 with pemphigus foliaceus, and 7 with paraneoplastic pemphigus were included. Mean age was 60 ± 18 years. Patients were treated either with medium (≤0.5 mg/kg/d) (n = 32) or high (≥1 mg/kg/d) (n = 59) doses of prednisone, or without systemic corticosteroids (n = 43). Mean follow-up was 77 ± 64 months. In all, 68 patients (50.7%) achieved CRoffT (95% confidence interval 42.3%-59.2%) after a mean treatment duration of 36 ± 39 months, including 47 of 80 patients with pemphigus vulgaris (58.7%) and 21 of 47 with pemphigus foliaceus (44.7%). Main prognostic factors for CRoffT were initial mucosal involvement (hazard ratio 2.2; 95% confidence interval 1.05-4.58; P = .036) and younger age (<61 years) (hazard ratio 2.5; 95% confidence interval 1.18-5.12; P = .0167). The rate of long-lasting CRoffT was 44%, with a mean follow-up after treatment withdrawal of 59 ± 50 months. LIMITATIONS: This was a retrospective study. CONCLUSION: The rate of CRoffT was 51%. Patients with pemphigus vulgaris were more likely to achieve CRoffT than those with pemphigus foliaceus.

Mortality from acquired bullous diseases of skin in Canadian adults 2000-2007.

BACKGROUND: Bullous skin diseases are known to be associated with significant morbidity and mortality. There have been no studies on mortality from severe bullous skin diseases in Canada. METHODS: We used mortality data from the Statistics Canada website from 2000 to 2007 for three major bullous skin diseases: bullous pemphigoid; pemphigus; and toxic epidermal necrolysis (TEN). Crude and age-standardized mortality rates were calculated and compared with the corresponding US mortality rates. Linear regression was used to assess time trend and effect of gender and age on mortality rates. RESULTS: During the period of eight years, there were 115 deaths attributed to pemphigoid, 84 to pemphigus, and 44 to TEN. The crude annual mortality rate was the highest for pemphigoid (0.045 per 100,000), followed by pemphigus (0.033), and TEN (0.017). None of these conditions demonstrated significant time trends in mortality rates over the eight-year period, although a trend towards decreasing pemphigus mortality was observed (P = 0.07). No gender difference in mortality was observed, but advanced age was associated with mortality in all three conditions. CONCLUSION: Among bullous skin diseases, pemphigoid is the leading cause of mortality in Canada. This is in contrast to the USA, where TEN is the leading cause of mortality from bullous skin diseases. It is not clear whether differences in healthcare systems explain these findings.

Urban legends: pemphigus vulgaris.

Pemphigus vulgaris (PV) is the most common type of pemphigus. PV pathogenesis is still debated, and treatment remains challenging. We investigated five controversial topics: (1) What are the target antigens in PV? (2) Do desmogleins adequately address PV pathophysiology? (3) How does acantholysis occur in PV? (4) Is PV still a lethal disease? (5) What is the role of rituximab (RTX) in PV treatment? Results from extensive literature searches suggested the following: (1) Target antigens of PV include a variety of molecules and receptors that are not physically compartmentalized within the epidermis. (2) PV is caused by a variety of autoantibodies to keratinocyte self-antigens, which concur to cause blistering by acting synergistically. (3) The concept of apoptolysis distinguishes the unique mechanism of autoantibody-induced keratinocyte damage in PV from other known forms of cell death. (4) PV remains potentially life-threatening largely because of treatment side effects, but it is uncertain which therapies carry the highest likelihood of lethal risk. (5) RTX is a very promising treatment option in patients with widespread recalcitrant or life-threatening PV. RTX's cost is an issue, its long-term side effects are still unknown, and randomized controlled trials are needed to establish the optimal dosing regimen.

Incidence, mortality, and causes of death of patients with pemphigus in Taiwan: a nationwide population-based study.

Pemphigus is a potentially life-threatening autoimmune blistering disease. However, little is known about the all-cause and cause-specific mortality among patients with pemphigus compared with the general population. The incidence of pemphigus in Taiwan has not been described previously. The objective of this study was to estimate the incidence of pemphigus in Taiwan and to investigate the overall mortality, causes of death, and cause-specific mortality in a nationwide population-based cohort of pemphigus patients. The study cohort included 853 patients newly diagnosed with pemphigus between 2002 and 2009 in the National Health Insurance Research Database. Survival status, date of death, and cause of death were ascertained by linking the study cohort with the National Register of Deaths Database of Taiwan. All-cause and cause-specific standardized mortality ratios (SMRs) were estimated. The incidence of pemphigus in Taiwan was 4.7 (95% confidence interval (CI), 3.2-6.2) per million per year. Overall, 88 deaths were observed during a mean follow-up period of 3.8 years, which was more than two times the number expected (SMR, 2.36; 95% confidence interval, 1.92-2.91). In the analysis of causes of death, the SMRs for death due to pneumonia (3.64; 95% CI, 1.30-10.21), septicemia (11.57; 95% CI, 2.95-45.34), cardiovascular disease (2.69; 95% CI, 1.18-6.12), and peptic ulcer disease (8.44; 95% CI, 1.22-58.21) were significantly higher than expected. We concluded that the incidence of pemphigus is not low in Taiwan, and the overall mortality among pemphigus patients is two times greater than that of the general population. In particular, patients with pemphigus have higher risk of mortality from systemic and respiratory tract infections, cardiovascular disease, and peptic ulcer disease.

Cardiac autoantibodies from patients affected by a new variant of endemic pemphigus foliaceus in Colombia, South America.

Several patients affected by a new variant of endemic pemphigus foliaceus in El Bagre, Colombia (El Bagre-EPF) have experienced a sudden death syndrome, including persons below the age of 50. El Bagre-EPF patients share several autoantigens with paraneoplastic pemphigus patients, such as reactivity to plakins. Further, paraneoplastic pemphigus patients have autoantibodies to the heart. Therefore, we tested 15 El Bagre-EPF patients and 15 controls from the endemic area for autoreactivity to heart tissue using direct and indirect immunofluorescence, confocal microscopy, immunohistochemistry, immunoblotting, and immunoelectron microscopy utilizing heart extracts as antigens. We found that 7 of 15 El Bagre patients exhibited a polyclonal immune response to several cell junctions of the heart, often colocalizing with known markers. These colocalizing markers included those for the area composita of the heart, such as anti-desmoplakins I and II; markers for gap junctions, such as connexin 43; markers for tight junctions, such as ezrin and junctional adhesion molecule A; and adherens junctions, such pan-cadherin. We also detected colocalization of the patient antibodies within blood vessels, Purkinje fibers, and cardiac sarcomeres. We conclude that El Bagre-EPF patients display autoreactivity to multiple cardiac epitopes, that this disease may resemble what is found in patients with rheumatic carditis, and further, that the cardiac pathophysiology of this disorder warrants further evaluation.