Bullous Pemphigoid-Associated Mortality Rate in a Canadian Tertiary Referral Centre.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disorder in adults. Most individuals with BP are over the age of 60. Its worldwide incidence has been increasing owing to population aging. Observational studies published over the last 2 decades highlight the non-negligible, albeit variable overall mortality of BP patients, with reported 12-month mortality rates of 10.8% to 40.8%, and 24-month mortality rates of 20.1% to 51.0%. Data in the Canadian population are lacking. OBJECTIVES: We aimed to estimate the 12- and 24-month overall mortality rate of Canadian patients diagnosed with BP, and to identify independent risk factors adversely impacting overall survival. METHODS: A retrospective cohort study of 166 patients with a diagnosis of BP between 2010 and 2020 was carried out at Centre hospitalier de l'Université de Montréal (CHUM), a tertiary referral center in Montréal, Québec, Canada. Cumulative mortality was calculated using the Kaplan-Meier estimator, and independent prognostic factors were identified using a Cox proportional hazards regression model. RESULTS: Eighty-five patients (51.2%) in our study were female. The median age was 79.1 years old, and 80 patients (48.2%) were 80 years old or older. Mortality at 12 and 24 months in our study cohort was 16.2% (CI95% = 10.5 - 21.8) and 27.6% (CI95% = 20.5 - 34.7), respectively. In a multivariate analysis, patients who were male, 80 years old or older, and/or had a diagnosis of a major neurocognitive disorder had a poorer overall survival. CONCLUSIONS: The all-cause mortality of patients with BP in our study population compared favorably with international data reported in the literature.

Mixed Individual-Aggregate Data on All-Cause Mortality in Bullous Pemphigoid: A Meta-analysis.

Importance: The 1-year standardized mortality ratio (SMR) of bullous pemphigoid (BP) has been reported as 2.15 to 7.56 and lower in the US than in Europe. Objective: To estimate the worldwide 1-year SMR of BP. Data Sources: PubMed, Embase, Cochrane Library, Google Scholar, Lissa, and gray literature (eg, medRxiv) were screened for studies of BP published from inception to June 10, 2020, with review of reference lists. Study Selection: Retrospective and prospective studies reporting 1-year all-cause mortality rate in patients with BP and providing age statistics (eg, mean [SD]). Data Extraction and Synthesis: Two reviewers independently extracted the data. The 1-year SMR was computed in studies reporting 1-year mortality by combining information on age obtained from studies with aggregate data and individual data. Risk of representativity, misclassification, and attrition bias were assessed by a custom tool. Main Outcomes and Measures: The primary end point was the worldwide 1-year SMR. Secondary analysis included comparison of 1-year SMRs between continents in a meta-regression. Results: Three studies were performed in the US (n = 260), 1 in South America (n = 45), 16 in Asia (n = 1903), and 36 in Europe (n = 10 132) for a total of 56 unique studies and 12 340 unique patients included in the meta-analysis (mean [SD] age, 77.3 [12.7] years; 55.9% women). The mean (SD) patient age in the United States was 75.6 (13.7) years; in Asia, 73.8 (13.6) years; and in Europe, 78.1 (12.3) years. The worldwide 1-year SMR was estimated at 2.93 (95% CI, 2.59-3.28; I2 = 85.6%) for all 56 studies. The 1-year SMR in the US was 2.40 (95% CI, 0.89-3.90; I2 = 86.3%) for 3 studies; in Asia, 3.53 (95% CI, 2.85-4.20; I2 = 86.3%) for 16 studies; and in Europe, 2.77 (95% CI, 2.35-3.19; I2 = 86.3%) for 36 studies. After adjustment on the expected 1-year mortality rate, the European 1-year SMR did not differ significantly from the 1-year SMR in the United States (-0.48 vs Europe; 95% CI, -2.09 to 1.14; P = .56) and Asia (0.51 vs Europe; 95% CI, -0.56 to 1.58; P = .35). Risk of attrition bias was high (>10% censorship) in 16 studies (28.6%), low in 16 (28.6%), and unclear in 24 (42.9%). Only 4 studies (7.1%) had a sampling method guaranteeing the representativity of BP cases in a population. Conclusions and Relevance: Although heterogeneity was high and overall quality of follow-up was poor, this meta-analysis confirms the high mortality rate among patients with BP.

Tissue eosinophil levels as a marker of disease severity in bullous pemphigoid.

BACKGROUND: Eosinophils play an important role in bullous pemphigoid (BP) pathogenesis. Although tissue infiltration with eosinophils has been known for a long time, there is a lack of knowledge about the relationship between tissue eosinophil levels and disease severity and clinical characteristics of the patients. METHODS: Fifty-nine patients diagnosed with BP between January 2008 and December 2018 were reviewed. Haematoxylin-Eosin (H&E)-stained preparations were re-evaluated in terms of tissue eosinophil levels. For disease severity, Bullous Pemphigoid Disease Area Index (BPDAI) was used. The relationship between tissue eosinophil levels and disease severity and clinical features were evaluated. RESULTS: Erosion/blister and urticaria/erythema BPDAI scores were higher in the group with high tissue eosinophil level than the group with low tissue eosinophil level. Tissue and peripheral blood eosinophil count were correlated with total urticaria/erythema BPDAI scores. There was no correlation between blood and tissue eosinophil count. The mortality rate was 64.7% vs 44.0% in the high vs low tissue eosinophil groups. Tissue eosinophil levels were high in patients with BP accompanying neurological disease. CONCLUSIONS: Tissue eosinophil count and peripheral blood eosinophil count were correlated with disease severity in BP. Tissue eosinophil levels were also high in patients with BP accompanying neurological disease.

Clinical characteristics, mortality, and prognostic factors for bullous pemphigoid in a Thai population.

Bullous pemphigoid is an uncommon, autoimmune, blistering disease. Clinical features, associated conditions, and outcomes differ according to country. We aimed to determine the mortality rate and clinical characteristics of Thai patients and to evaluate the risk factors associated with survival.A retrospective analysis was conducted on 119 patients, over a ten-year period, at Songklanagarind Hospital, the largest tertiary university hospital in Southern Thailand.The median age of onset was 82 years [interquartile range 72, 90], and 60 (50.4%) patients were men. The underlying diseases were hypertension (53.8%), neurological disease (42.8%), and diabetes mellitus (31.9%). Fifty-eight patients (48.7%) experienced pruritus, and 61.3% of patients had mild cutaneous lesions (less than 10% of the body surface area) on the day of diagnosis. Nine percent of patients presented with mucosal involvement. Complete blood counts showed anemia (32.8%), neutrophilia (30.3%), and eosinophilia (42.9%). The 1-, 3- and 5-year overall mortality rates were 28.1% [95% confidence interval (CI), 7.8-36.6], 55.7% (95% CI, 44.4-64.7) and 71.9% (95% CI 59.9-80.2), respectively. On multivariate analysis, high neutrophil/lymphocyte ratio [odds ratio (OR) 5.55, P < .001] and anemia (OR 2.93, P = .025) were found to be independently associated with mortality rate, whereas disease remission (OR 0.25, P = .003) was demonstrated to be a good prognostic factor.This is the first study to analyze the mortality rate of Bullous pemphigoid in Thailand. Mortality was associated with high neutrophil/lymphocyte ratio and anemia.

Mortality in Patients with Bullous Pemphigoid: A Retrospective Cohort Study, Systematic Review and Meta-analysis.

There is little consensus regarding mortality data in bullous pemphigoid (BP). The aim of this study was to evaluate mortality among a relatively large cohort of Israeli patients with BP and to perform a meta-analysis synthesizing existing data on 1-year mortality rates of patients with BP. This retrospective cohort study of 287 patients diagnosed with BP between 2000 and 2015 compared the mortality of patients with BP with age- and sex-matched control subjects in the general population. The results showed 1-, 5- and 10-year mortality rates of 26.9%, 56.9% and 69.5%, respectively, and a 3.4-fold higher risk of death. A systematic review and meta-analysis were then performed using a random effects model. Including the current study, 25 studies comprising 4,594 patients met the eligibility criteria. The pooled estimate of 1-year mortality rate was 23.5% (95% confidence interval 20.2-26.8; I2=81%; p < 0.001). The pooled 1-year mortality rate of European cohorts was prominently higher relative to the pooled rates of cohorts from the USA and Asia.

Mortality and risk factors among Israeli bullous pemphigoid patients.

There are differences concerning reported mortality rates and prognostic factors of bullous pemphigoid (BP) patients in different studies. Our objectives were to evaluate the mortality rates and prognostic factors among Israeli BP patients compared to matched control subjects. Three age- and sex-matched patients without BP (n = 261) who were treated in our clinic were selected and compared to BP patients (n = 87). Mean survival period of the BP group was 4.1 years (95% CI: 3.3-4.8 years) and 5.9 years among the non-BP group (95% CI: 5.6-6.3 years). The 1-year mortality rate was 24.1% for the BP group and 6.5% for the control group. In multivariate analysis, age above 80 was a significant risk factor for mortality [HR 3.22 (95% CI, 1.15-8.96), p = 0.03], while statins intake had a protective role [HR 0.36 (95% CI, 0.15-0.88), p = 0.03]. In univariant analysis, dementia [HR 2.44 (95% CI, 1.02-5.99), p = 0.04] was a risk factor. In conclusion, BP patients' mortality is correlated to increasing age at diagnosis, dementia, and statins use. Statins' protective role is newly discussed in the literature.

Mortality in bullous pemphigoid: A systematic review and meta-analysis of standardized mortality ratios.

There are inconsistent data on mortality rates in patients with bullous pemphigoid (BP). Trends in mortality in BP throughout the years are yet to be established. The aim of the present study was to study the mortality in BP patients relative to the general population and to estimate trends in standardized mortality over the past 30 years. We performed a systematic review and meta-analysis of observational studies in Medline, Embase and Scopus (1823-2017). Reference lists of included studies were also searched for eligible studies. Quality of evidence was assessed using the Newcastle-Ottawa Scale (NOS). A meta-analysis was performed using random-effects models to estimate pooled standardized mortality ratios (SMR) with 95% confidence intervals (CI). Meta-regression models were used to investigate the secular trends in SMR. Ten studies were included covering the period 1960-2015 (1736 patients, 746 deaths). Pooled all-cause SMR was 3.6 (95% CI, 2.6-5.0). There was no trend in all-cause SMR across the last three decades (regression coefficient 0.02 [change in logSMR/year]; 95% CI, 0.04-0.08; P = 0.545). In conclusion, there is a 3.6-fold increased mortality among patients with BP as compared with the age-matched general population. The excess mortality in BP has not changed significantly over the past 30 years.

Prospective study in bullous pemphigoid: association of high serum anti-BP180 IgG levels with increased mortality and reduced Karnofsky score.

BACKGROUND: Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. The multicentre prospective BLISTER (Bullous Pemphigoid Steroids and Tetracyclines) trial randomized 253 patients with BP to compare the benefits and harms between initial treatment with doxycycline or prednisolone. OBJECTIVES: To analyse distinct autoantibody profiles for the prediction of the disease course in a well-characterized cohort of BP sera. METHODS: One hundred and forty-three patients of the BLISTER trial consented to participate in this serological study. Sera taken at baseline were analysed by (i) indirect immunofluorescence, (ii) anti-BP180 NC16A (16th noncollagenous domain) and anti-BP230 enzyme-linked immunosorbent assay and (iii) immunoblotting with various substrates. Results were then linked with clinical parameters including age, Karnofsky score, number of blisters, related adverse events and mortality. RESULTS: Disease activity correlated with immunoglobulin (Ig)G anti-BP180 levels but not with levels of anti-BP230 IgG and anti-BP180 IgE. High levels of both anti-BP180 IgG and anti-BP230 IgG were associated with a low Karnofsky score. The presence of anti-BP230 IgG was more frequent in older patients. Those with higher total IgE serum levels suffered from fewer adverse events. Higher IgG anti-BP180 levels were associated with an increased 1-year mortality rate. CONCLUSIONS: Analysis of the autoantibody profile is not only of diagnostic relevance but may also be helpful in predicting the course of the disease.

Relapse of bullous pemphigoid: an update on this stubborn clinical problem.

Bullous pemphigoid (BP) is a chronic autoimmune blistering disorder that has a predilection for the elderly. It is characterized by a poor prognosis due to its high mortality rate and the tendency to relapse. The relapse rate of BP ranges from 27.87% to 53% after disease remission, while the majority of relapses occur early (within 6 months) during remission. Clinical interventions aimed to prevent early relapses could reduce potential complications from first-line treatment and make follow-up care easier for clinicians in practice, thus improving the prognosis of BP and the quality of patients' lives. In this article, we attempt to review previous studies from the medical literature concerning relapse and risk factors related to relapse in BP patients. Treatments found to be able to reduce or increase relapse rate were also discussed. We propose that clinicians be aware of these risk factors and manage proper treatment accordingly. Key Messages • The relapse rate of bullous pemphigoid ranges from 27.87% to 53% after disease remission, while the majority of relapses occur early (within 6 months) during remission. • Ageing, disease severity, neurological disorder, serum ECP, BAFF, IL-17, IL-23, CXCL10 and anti-BP180 antibody levels have been shown to be related to relapse, while confirmation studies are needed before using them for guidance for relapse prevention. • Longer usage of corticosteroid with a low dose, combination of immunosuppressants and intravenous immunoglobulin are helpful in lowering relapse rate.

Mortality in bullous pemphigoid and prognostic factors in 1st and 3rd year of follow-up in specialized centre in Poland.

Bullous pemphigoid (BP) is associated with higher mortality and coexisting comorbidities, some of them affecting poor prognosis. The aim of the study was to identify prognostic factors causing greater mortality both in the 1st and 3rd year of follow-up and to determine the 1-, 2-, 3-year mortality rates, standardized mortality ratio (SMR) in Polish BP patients. All patients with BP (a cohort of 205 patients, mean age 76.2 years) diagnosed between 5 January 2000 and 10 December 2013 in a referral unit for autoimmune bullous diseases at the university hospital in Poland were included retrospectively. Mortality data were obtained from the Centre for Document Personalization at the Minister of Interior and Administration. Our original observation was that prednisone in moderate dose (0.5 mg kg-1) in monotherapy was an independent risk factor of fatal prognosis in the 1st year of follow-up, assessed using multivariate analysis. We confirmed the strong correlation between neurological diseases and greater mortality. Both in the 1st and 3rd year of follow-up, dementia and Parkinson disease resulted in increased mortality. We also found that arrhythmias significantly increased mortality in the 1st and 3rd year of follow-up. The prognostic factors in BP changed over time of follow-up. In the 3rd year of observation, the age above 77, longer hospitalization and BP severity were associated with greater mortality. We observed poorer prognosis in BP patients than age-matched general Polish population. The 1-, 2-, 3-year mortality rates were 22.4, 31.2, 39.5% and SMR was 3.8 (95% CI 3.4-3.7).

The association between bullous pemphigoid and neurological disorders: a systematic review.

Studies suggest an association between neurological disorders and bullous pemphigoid. The goal of this systematic review was to characterize the occurrence of neurological disorders in patients with bullous pemphigoid. We performed a systematic review of the current English literature from 1984 to June 1st, 2015 for documented cases of coexistent BP and neurological disorders. The literature search resulted in 53 articles meeting the inclusion criteria. Patients with bullous pemphigoid had an increased risk of stroke (OR: 4.43 [95% CI: 2.69-7.28]; p<0.001), dementia (OR: 5.48 [95% CI: 3.26-9.23]; p<0.001), Parkinson's (OR: 3.06 [95% CI: 1.97-4.77]; p< 0.001), and epilepsy/seizures (OR: 22.88 [95% CI: 2.64-198.21]; p = 0.0045). Neurological disorders preceded bullous pemphigoid in the majority of cases with a mean time interval of 6.7 years. The one-year mortality was increased in bullous pemphigoid patients who had concomitant stroke (OR: 2.87 [95% CI: 1.67-4.96]; p<0.001). Bullous pemphigoid patients have an increased association with neurological disorders which may increase mortality.

Increased Risk of Bullous Pemphigoid after First-Ever Stroke: A Population-Based Study.

BACKGROUND: We hypothesize that autoantibodies are induced after the blood-brain barrier is damaged by stroke and the risk of bullous pemphigoid (BP) is increased after stroke. We assess the risk of BP after first-ever stroke in a nationwide population-based cohort of first-ever stroke patients. METHODS: We extracted data from the Longitudinal Health Insurance Database 2005 and identified patients with first-ever stroke as well as control patients matched for age, gender, and year of enrollment. The risk of BP in first-ever stroke patients in comparison with that in control patients was analyzed using Cox regression. RESULTS: Of 12,607 patients with first-ever stroke, 38 (0.3%) patients developed BP in a median of 3.5 years. In the control patients, 8 persons (0.06%) had BP in a median of 3.7 years. The crude hazard ratio (HR) of BP in first-ever stroke patients was 4.83 (95% CI 2.25-10.34, p < 0.001) compared to the control group. The adjusted HR was 4.20 (95% CI 1.94-9.08, p < 0.001) after adjustments for age, gender, hypertension, diabetes, dementia, epilepsy, Parkinson disease, furosemide, and neuroleptics for stroke patients. CONCLUSIONS: The risk of BP is increased in first-ever stroke patients in a nationwide population-based cohort and this association is independent of well-known confounders of BP.

Prognostic factors for mortality in patients with bullous pemphigoid: a meta-analysis.

Bullous pemphigoid (BP) is a chronic debilitating autoimmune blistering disease that frequently occurs in the elderly population. Previous studies have suggested a high morbidity and mortality associated with BP. However, relatively few studies have investigated prognostic factors of BP mortality, and they showed considerably various results. This meta-analysis aimed to quantitatively assess the association between several potential prognostic factors and risk of mortality in bullous pemphigoid. A comprehensive search was performed using Pubmed, Embase, and Cochrane Library. Cohort studies that assessed prognostic factors of BP mortality were included. Random-effects model was utilized to calculate the pooled hazard ratio (HR). Publication bias was evaluated qualitatively by constructing a funnel plot and quantitatively by conducting Egger's test. 14 studies were included comprising 2499 patients. Combined HRs suggested that advanced age (HR 1.63, 95% CI 1.34-1.97), presence of circulating antibodies (HR 1.77, 95% CI 1.20-2.62), concomitant dementia (HR 2.01, 95% CI 1.22-3.33), and concomitant stroke (HR 1.86, 95% CI 1.29-2.67) have an unfavorable impact on patient survival. Gender, disease extent, mucosal involvement, and indirect immunofluorescence result were not shown to be linked to mortality by our analysis. This study indicated that BP patients with older age, circulating antibodies, dementia, and stroke are at greater risk of mortality. Clinicians should be aware of this association and utilize this information in patient education and treatment process.

Increased frequency of multiple sclerosis among patients with bullous pemphigoid: a population-based cohort study on comorbidities anchored around the diagnosis of bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is a disease of the elderly and may be associated with neurological and cardiovascular diseases and diabetes. Mortality rates strongly exceed those of the background population. OBJECTIVES: To investigate the frequency of comorbidities and their temporal relation to BP. METHODS: A register-based matched-cohort study on all Danish patients with a hospital-based diagnosis of BP (n = 3281). The main outcomes were multiple sclerosis (MS), Parkinson disease (PD), Alzheimer disease (AD), stroke, diabetes types 1 and 2, malignancies, ischaemic heart disease (IHD), hypertension and eventually death. RESULTS: At baseline, patients with BP had increased prevalences of MS [odds ratio (OR) 9·7, 95% confidence interval (CI) 6·0-15·6], PD (OR 4·2, 95% CI 3·1-5·8), AD (OR 2·6, 95% CI 1·8-3·5) and stroke (OR 2·7, 95% CI 2·4-2·9). Furthermore, malignancies, cardiovascular disease and diabetes were over-represented among patients with BP: type 1 diabetes (OR 3·1, 95% CI 2·5-3·8), type 2 diabetes (OR 2·3, 95% CI 2·0-2·6), malignancies (OR 1·3, 95% CI 1·1-1·4), IHD (OR 1·7, 95% CI 1·5-1·9) and hypertension (OR 2·0, 95% CI 1·8-2·2). During follow-up, the risk of MS was significantly higher among patients with BP [hazard ratio (HR) 9·4, 95% CI 4·9-18·0], even if events during the first year after diagnosis of BP were excluded (HR 5·1, 95% CI 2·3-11·3). Patients with BP had an average increased mortality rate of 2·04 (95% CI 1·96-2·13). CONCLUSIONS: We discovered a significantly increased frequency of MS among patients with BP. At the time of diagnosis, patients with BP had an excessive number of comorbidities and an increased mortality rate over the following years.

Hospitalization, inpatient burden and comorbidities associated with bullous pemphigoid in the U.S.A.

BACKGROUND: Bullous pemphigoid (BP) is associated with significant disability and comorbid health disorders that may lead to or result from hospitalization. However, little is known about the inpatient burden and comorbidities of BP. OBJECTIVES: To obtain data on the inpatient burden and comorbidities of BP in the U.S.A. METHODS: We analysed data from the 2002 to 2012 National Inpatient Sample, including a representative 20% sample of all hospitalizations in the U.S.A. (72 108 077 adults). RESULTS: The prevalence of hospitalization for BP increased from 25·84 to 32·60 cases per million inpatients from 2002 to 2012. In multivariate logistic regression models with stepwise selection, increasing age, nonwhite ethnicity, higher median household income, being insured with Medicare or Medicaid, and increasing number of chronic conditions were all associated with hospitalization for BP (P < 0·05 for all). The top three primary discharge diagnoses for patients with a secondary diagnosis of BP were septicaemia (prevalence 5·51%, 95% confidence interval 5·03-5·99), pneumonia (4·60%, 4·19-5·01) and urinary tract infection (3·52%, 3·15-3·89). Patients with BP also had numerous autoimmune, infectious, cardiovascular and other comorbidities. Interestingly, BP was associated with multiple neuropsychiatric disorders, including demyelinating disorders, dementias (presenile, senile, vascular and other), paralysis, neuropathy (diabetic, other polyneuropathy), Parkinson disease, epilepsy, psychoses and depression. The mean annual age- and sex-adjusted in-hospital mortality rate was significantly higher in patients with a secondary diagnosis of BP compared with no BP (2·9%, range 2·8-3·9% vs. 2·1%, range 1·9-2·2%). Significant predictors of mortality in patients with BP included increasing age, nonwhite ethnicity and insurance with Medicaid or other payment status (P < 0·05 for all). CONCLUSIONS: Hospitalization for BP increased significantly between 2002 and 2012. Moreover, there were significant ethnic and healthcare disparities with respect to hospitalization and inpatient mortality from BP.

[Impact of neurological diseases on the prognosis of bullous pemphigoid: A retrospective study of 178 patients]. / Impact pronostique des maladies neurologiques au cours de la pemphigoïde bulleuse : étude rétrospective de 178 cas.

BACKGROUND: Bullous pemphigoid (BP) mainly affects elderly patients. It is often associated with neurological disorders, which constitute a major risk factor of the disease. The aim of our study was to determine whether neurological disorders, particularly dementia, influence outcome and mortality in BP patients. PATIENTS AND METHODS: We conducted a retrospective study of all patients with BP seen in our dermatology department consecutively between 1997 and 2011. Clinical, immunological and therapeutic data, number of relapses and survival status were compared according to the presence at diagnosis of neurological disorders, particularly dementia. RESULTS: Among the 178 patients included, an associated neurological disease was present in 84 (47.2%) and dementia in 43 (24.2%) at the time of diagnosis of BP. Patients with associated dementia were older and had a lower Karnofsky index. Sixty-four patients (37.8%) had had at least one clinical relapse of BP, chiefly within the first 18 months after starting therapy. Coexistent neurological disease was not associated with BP relapse (P=0.55) contrary to an extensive BP phenotype at diagnosis (P=0.008). Coexistent neurological disease and/or dementia were associated with higher mortality (P=0.03 and P<0.001, respectively), but did not modify the type or the total duration of BP treatment. CONCLUSION: A coexistent neurological disease or dementia at the time of diagnosis of BP significantly increase the risk of mortality and shortens the duration of clinical follow-up of patients with BP, thus limiting the analysis of their influence on the outcome of BP itself.

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.