Safety and efficacy of first-in-man intrathecal injection of human astrocytes (AstroRx®) in ALS patients: phase I/IIa clinical trial results.

BACKGROUND: Malfunction of astrocytes is implicated as one of the pathological factors of ALS. Thus, intrathecal injection of healthy astrocytes in ALS can potentially compensate for the diseased astrocytes. AstroRx® is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells. AstroRx® was shown to clear excessive glutamate, reduce oxidative stress, secrete various neuroprotective factors, and act as an immunomodulator. Intrathecal injection of AstroRx® to animal models of ALS slowed disease progression and extended survival. Here we report the result of a first-in-human clinical study evaluating intrathecal injection of AstroRx® in ALS patients. METHODS: We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of intrathecal injection of AstroRx® in patients with ALS. Five patients were injected intrathecally with a single dose of 100 × 106 AstroRx® cells and 5 patients with 250 × 106 cells (low and high dose, respectively). Safety and efficacy assessments were recorded for 3 months pre-treatment (run-in period) and 12 months post-treatment (follow-up period). RESULTS: A single administration of AstroRx® at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx® itself were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate. The study demonstrated a clinically meaningful effect that was maintained over the first 3 months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100 × 106 AstroRx® arm, the ALSFRS-R rate of deterioration was attenuated from - 0.88/month pre-treatment to - 0.30/month in the first 3 months post-treatment (p = 0.039). In the 250 × 106 AstroRx® arm, the ALSFRS-R slope decreased from - 1.43/month to - 0.78/month (p = 0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No statistically significant change was measured in muscle strength using hand-held dynamometry and slow vital capacity continued to deteriorate during the study. CONCLUSIONS: Overall, these findings suggest that a single IT administration of AstroRx® to ALS patients at a dose of 100 × 106 or 250 × 106 cells is safe. A signal of beneficial clinical effect was observed for the first 3 months following cell injection. These results support further investigation of repeated intrathecal administrations of AstroRx®, e.g., every 3 months. TRIAL REGISTRATION: NCT03482050.

Psoriasis and hidradenitis suppurativa: A large-scale population-based study.

BACKGROUND: The coexistence of psoriasis and hidradenitis suppurativa (HS) has been described, but the association between these conditions is yet to be firmly established. OBJECTIVE: To study the association between psoriasis and HS by using a large-scale real-life computerized database. METHODS: A cross-sectional study was conducted to compare the prevalence of HS among patients with psoriasis with that among age-, sex- and ethnicity-matched control subjects. RESULTS: A total of 68,836 patients with psoriasis and 68,836 controls were included in the study. The prevalence of HS was increased in patients with psoriasis versus in those in the control group (0.3% vs 0.2%, respectively; odds ratio, 1.8; 95% confidence interval, 1.5-2.3; P < .001). In a multivariate analysis adjusting for smoking, obesity, and other comorbidities, psoriasis was still associated with HS (odds ratio, 1.8; 95% confidence interval, 1.4-2.2; P < .001). Patients with coexistent psoriasis and HS were significantly younger (39.0 ± 15.7 vs 42.6 ± 21.2 years [P = .015]) and had a higher prevalence of obesity (35.1% vs 25.3% [P = .001]) and smoking (58.5% vs 37.3% [P < .001]) compared with patients with psoriasis alone. LIMITATIONS: Retrospective data collection. CONCLUSIONS: A positive association was observed between HS and psoriasis. Further longitudinal observational studies are necessary to establish these findings in other study populations.

Atopic Dermatitis and Infertility: A Nationwide Retrospective Cohort Study.

BACKGROUND: Given that common pathophysiological factors play a role in atopic dermatitis (AD) and infertility, we assumed that the 2 conditions might demonstrate an epidemiological association. Large-scale epidemiological data on this topic are lacking. OBJECTIVES: The aim of this work was to evaluate the potential association between AD and infertility in a broad community-based population. METHODS: A nationwide retrospective cohort study was conducted, analyzing the association between AD and infertility. We compared AD patients diagnosed by a dermatologist between 2002 and 2018 and a matched control group. The study population was subdivided according to age into adults (age ≥18 years) and children (age <18 years), and was further subdivided according to AD severity, classified as either mild or moderate-to-severe according to AD-related drug use and healthcare services utilization. RESULTS: The study included 127,150 patients with AD and 127,071 comparison enrollees. AD was associated with a higher prevalence of infertility than that of the control group (1.4 and 1.1%, respectively). The prevalence of infertility, per 1,000 patient-years, was increased in patients with AD compared to that of the control group (2.17 and 1.7, respectively). Multivariate analysis for infertility demonstrated that AD was a key risk factor for infertility in both males and females with mild AD and moderate-to-severe AD. CONCLUSION: A significant association between AD and infertility was observed. This association suggests that infertility may be an additional manifestation of AD. Further studies are warranted to evaluate the impact of AD management in the setting of infertility and vice versa.

Association Between Behçet's Disease and Depression.

BACKGROUND: Behçet's disease (BD) is a chronic vasculitic multi-systemic disease of unknown etiology. BD is characterized by recurrent attacks of oral aphthae, genital ulcers, and uveitis. BD is a multisystemic disorder and as such it may provoke various psychiatric manifestations, including depression. OBJECTIVES: To evaluate the association between BD and depression, adjusting for established risk factors for depression. METHODS: We executed a cross-sectional study based on the Clalit Health Services database, the largest healthcare organization in Israel, serving over 4.4 million members. For this study 873 BD patients were detected and matched with 4369 controls by age and sex. RESULTS: The rate of depression was higher among the BD patients compared with the control group (9.39% vs 5.49%, respectively, odds ratio [OR] 1.79, 95% confidence interval [95%CI] 1.37-2.31, P < 0.001). An association between BD and depression was also observed on multivariable analysis (OR 1.83, 95%CI 1.39-2.39, P < 0.001). When stratifying the data, according to established risk factors, the association between BD and depression was prominent in the youngest age group (18-39 years of age), low and high socioeconomical status, and non-smokers. CONCLUSIONS: Establishing the association between BD and depression should influence the attitude and the treatment of BD patients, as this relationship requires a more holistic approach and a multidisciplinary treatment regimen for all patient needs.

Psoriasis and Dementia: A Cross-sectional Study of 121,801 Patients.

Data regarding the association between psoriasis and dementia are inconclusive. The aim of this study was to evaluate this association in the database of Clalit Health Services, Israel. A comparative analysis for the association between psoriasis, dementia and its risk factors was performed for the entire study population and in the subgroup of patients with moderate-to-severe psoriasis. The study included 121,801 patients with psoriasis, of whom 16,947 were diagnosed with moderate-to-severe psoriasis, and 121,802 controls. Psoriasis was associated with a lower prevalence of dementia relative to control subjects (1.6% vs 1.8%; odds ratio (OR) 0.85; 95% confidence interval (95% CI) 0.80-0.91; p < 0.001). Multivariate analysis adjusting for demographic variables, cardiovascular-related risk factors, and healthcare utilization demonstrated a significant inverse association between psoriasis and dementia in the entire study population (adjusted OR 0.86; 95% CI 0.76-0.96; p = 0.009), but not in the subgroup of patients with moderate-to-severe psoriasis (adjusted OR 0.91; 95% CI 0.81-1.02; p = 0.113). In conclusion, these data support the hypothesis that psoriasis is inversely associated with dementia.

Healthcare Service Utilization by 116,816 Patients with Atopic Dermatitis in Israel.

Understanding of the epidemiology and healthcare service utilization related to atopic dermatitis is necessary to inform the use of new treatments. This cross-sectional study was based on a group of patients with atopic dermatitis and a matched control group comprised of age- and sex- matched enrolees without atopic dermatitis from a large medical database. Healthcare service utilization usage data were extracted and compared between groups. The study included 116,816 patients with atopic dermatitis and 116,812 controls. Atopic dermatitis was associated with an increased burden of healthcare utilization across the entire spectrum of healthcare services compared with controls. For patients severely affected by atopic dermatitis, the increased burden correlated with disease severity: a high-er frequency of emergency room visits (odd ratio (OR) 1.7; 95% confidence interval (CI) 1.6-1.9), dermatology wards hospitalizations (OR 315; 95% CI 0-7,342), and overall hospitalizations (OR 3.6; 95% CI 3.3-3.9). In conclusion, this study demonstrates an increased burden of healthcare utilization in atopic dermatitis.

Demographic and health care service utilization by 4417 patients with hidradenitis suppurativa.

BACKGROUND: Data on the health care utilization of patients with hidradenitis suppurativa (HS) in primary care settings are scarce. OBJECTIVE: To investigate the health care service utilization of patients with HS. METHODS: In a cross-sectional study, patients with HS were compared with 2 age- and sex-matched control groups-general population enrollees of Clalit Health Services and a group of patients with psoriasis. Health care services data included inpatient and outpatient community clinic visits and pharmacy claims for topical and systemic treatments. Multivariate analysis of the data for patients with HS and controls was performed. RESULTS: The study included 4417 patients with HS, 22,085 general population enrollees, and 4417 patients with psoriasis. On the basis of multivariate analyses, patients with HS had more annual dermatology clinic visits compared with the general population enrollees (odds ratio [OR], 6.49; 95% confidence interval [CI], 7.06-5.97) and patients with psoriasis (OR, 1.32; 95% CI, 1.44-1.21), more annual surgical clinic visits (OR, 3.78; 95% CI 3.28-4.36 and OR, 1.65; 95% CI, 1.42-1.91, respectively), and more hospitalizations (OR, 2.21; 95% CI, 1.89-2.56 and OR, 1.51; 95% CI, 1.28-1.78, respectively). LIMITATIONS: Underestimation of HS frequency was possible. CONCLUSIONS: The burden on health care systems due to patients with HS is greater than that due to patients with psoriasis and the general population.

Biologic drug survival in Israeli psoriasis patients.

BACKGROUND: Drug survival is defined as the time period of treatment with a certain drug until its cessation. The role of previous exposure to traditional systemic treatments in biologic survival is still unknown. OBJECTIVE: To investigate the drug survival rates of biologic treatments in patients with psoriasis and to identify predictor factors. METHODS: Survival analysis was performed on patients with severe psoriasis who received adalimumab, infliximab, etanercept, and ustekinumab for treatment of psoriasis, drawn from the Clalit Health Services database. Multivariate analysis was performed adjusting for demographic variables; metabolic syndrome and its components; psoriatic arthritis; biologic naivety; coadministration of methotrexate, acitretin, or cyclosporine; and previous standard systemic treatment exposure. RESULTS: Among 907 patients treated with 1575 biologic treatments, ustekinumab had a significantly higher survival rate than tumor necrosis factor inhibitors. Biologic naivety and concomitant methotrexate intake were positive predictors for drug survival, whereas the female sex and the duration of previous systemic treatments were negative predictors. LIMITATIONS: Data regarding disease severity or duration could not be drawn from the Clalit Health Services database. CONCLUSION: Ustekinumab had better retention rates in comparison with other investigated biologics in patients with severe psoriasis, most of whom used it as a third line therapy.

Factors associated with drug survival of methotrexate and acitretin in patients with psoriasis.

Drug survival has recently become an important clinical issue in psoriasis. However, there has been little research into factors associated with drug survival of methotrexate and acitretin. The aim of this study was to investigate factors associated with drug survival of methotrexate and acitretin treatment for psoriasis. Survival analysis was performed in patients who received methotrexate or acitretin for the treatment of psoriasis, drawn from the Clalit Health Services database. Investigated factors included demographic variables, obesity, metabolic syndrome, psoriatic arthritis, administration route and folic acid supplementation. Among 6,256 patients, factors associated with treatment drop-out were: younger age (p <0.001) and psoriatic arthritis (acitretin p < 0.001). For methotrexate, metabolic syndrome (p = 0.033), intramuscular administration route of injection (p <0.001) and lack of folic acid supplementation (p <0.001) were associated with treatment drop-out. In patients with psoriasis, some ancillary factors may modify the drug survival of acitretin and methotrexate.

Astrocytes Downregulate Inflammation in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome: Applicability to COVID-19.

Background: An acute respiratory distress syndrome (ARDS) is caused by the increased amounts of pro-inflammatory cytokines and neutrophil-mediated tissue injury. To date, there is no effective treatment for the ARDS available, while the need for one is growing due to the most severe complications of the current coronavirus disease-2019 (COVID-19) pandemic. The human astrocytes (AstroRx) have shown immunomodulatory properties in the central nervous system (CNS). This study aimed to evaluate the capacity of astrocytes to decrease lung inflammation and to be applied as a treatment therapy in ARDS. Methods: First, we assessed the ability of clinical-grade AstroRx to suppress T-cell proliferation in a mixed lymphocyte reaction test. Next, we tested the therapeutical potential of AstroRx cells in a lipopolysaccharide (LPS)-based ARDS mouse model by injecting AstroRx intravenously (i.v). We determined the degree of lung injury by using a severity scoring scale of 0-2, based on the American Thoracic Society. The scoring measured the presence of neutrophils, fibrin deposits, and the thickening of alveolar walls. The state of inflammation was further assessed by quantifying the immune-cell infiltration to the bronchoalveolar lavage fluid (BALF) and by the presence of proinflammatory cytokines and chemokines in the BALF and serum. Results: We detected that AstroRx cells were capable to suppress T-cell proliferation in vitro after exposure to the mitogen concanavalin A (ConA). In vivo, AstroRx cells were able to lower the degree of lung injury in LPS-treated animals compared with the sham injected animals (P = 0.039). In this study, 30% of AstroRx treated mice showed no lung lesions (responder mice), these mice presented a steady number of eosinophils, T cells, and neutrophils comparable with the level of naïve control mice. The inflammatory cytokines and chemokines, such as TNFα, IL1b, IL-6, and CXCL1, were also kept in check in responder AstroRx-treated mice and were not upregulated as in the sham-injected mice (P < 0.05). As a result, the LPS-treated ARDS mice had a higher survival rate when they were treated with AstroRx. Conclusions: Our results demonstrate that the immunosuppressive activity of AstroRx cells support the application of AstroRx cells as a cell therapy treatment for ARDS. The immunoregulatory activity may also be a part of the mechanism of action of AstroRx reported in the amyotrophic lateral sclerosis (ALS) neurodegenerative disease.

Primary Cutaneous Cryptococcosis: An Unusual Injection Site Infection.

Primary cutaneous cryptococcosis (PCC) is an uncommonly reported entity. We describe an unusual case of PCC in an injection site of an immunocompromised patient. The specific case demonstrates a challenging treating dilemma with different alternative treatment choices. In the presented clinical setting, each choice concealed its risks and benefits. We highlight the importance of patient education for taking the appropriate measures for the disinfection of subcutaneous injection sites.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Associated with Mycoplasma pneumoniae Infection.

Mycoplasma infection may lower the threshold for drug allergy in particular patients. We present a case of drug reaction with eosinophilia and systemic symptoms (DRESS), with drug etiology and non-drug etiology (Mycoplasma infection). Possible synergism between previously known drug allergy and the acute Mycoplasma infection may have led to DRESS eruption. Interferon-γ release test and TNF-α release test yielded different patterns in the present case, suggesting a different role for each in different drug eruption types.

Is there an association between alopecia areata and systemic lupus erythematosus? A population-based study.

The coexistence of alopecia areata (AA) and systemic lupus erythematosus (SLE) has been described, but the association between these conditions is yet to be firmly established. We aimed to evaluate the association between AA and SLE using a large-scale real-life computerized database. A cross-sectional study was conducted comparing the prevalence of SLE among patients with AA and among age-, sex-, and ethnicity-matched control subjects. Chi-square and t tests were used for univariate analysis, and a 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. A total of 51,561 patients with AA and 51,410 controls were included in the study. The prevalence of SLE was increased in patients with AA as compared to the control group (0.3% vs. 0.1%, respectively; OR, 2.1; 95% CI, 1.6-2.9; P < 0.001). The association increased consistently with age and was stronger among female and Jewish patients. In a multivariate analysis adjusting for sex, age, ethnicity, and other comorbidities, AA was still associated with SLE (OR, 2.1; 95% CI, 1.6-2.9; P < 0.001). To conclude, a significant positive association was observed between AA and SLE. Further longitudinal observational studies are necessary to establish these findings in other study populations. Physicians treating patients with AA may be aware of this possible association and may consider screening for SLE in patients with relevant symptoms.

Rising Stars: Astrocytes as a Therapeutic Target for ALS Disease.

Amyotrophic lateral sclerosis (ALS) is a multifactorial disease, characterized by a progressive loss of motor neurons that eventually leads to paralysis and death. The current ALS-approved drugs modestly change the clinical course of the disease. The mechanism by which motor neurons progressively degenerate remains unclear but entails a non-cell autonomous process. Astrocytes impaired biological functionality were implicated in multiple neurodegenerative diseases, including ALS, frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer disease (AD). In ALS disease patients, A1 reactive astrocytes were found to play a key role in the pathology of ALS disease and death of motor neurons, via loss or gain of function or acquired toxicity. The contribution of astrocytes to the maintenance of motor neurons by diverse mechanisms makes them a promising therapeutic candidate for the treatment of ALS. Therapeutic approaches targeting at modulating the function of endogenous astrocytes or replacing lost functionality by transplantation of healthy astrocytes, may contribute to the development of therapies which might slow down or even halt the progression ALS diseases. The proposed mechanisms by which astrocytes can potentially ameliorate ALS progression and the status of ALS clinical studies involving astrocytes are discussed.

Atopic Dermatitis and Celiac Disease: A Cross-Sectional Study of 116,816 Patients.

BACKGROUND: Both atopic dermatitis and celiac disease are often accompanied by other immune-mediated disorders. OBJECTIVE: The objective of this study was to evaluate the potential association between atopic dermatitis and celiac disease in a broad community-based population. METHODS: A cross-sectional observational design was used. Demographic and clinical data were collected for patients enrolled in a large health management organization who were diagnosed with atopic dermatitis by a dermatologist in 2002-17. The presence of celiac disease/celiac disease-related morbidities was recorded for the whole group, for adults (age > 18 years), and for adults with moderate-to-severe atopic dermatitis. Findings were compared with a matched control group without atopic dermatitis. RESULTS: The study group included 116,816 patients of whom 45,157 were adults; 1909 adult patients had moderate-to-severe atopic dermatitis. Compared to the respective control subjects, the prevalence rate of celiac disease in the whole group was 0.6% vs. 0.4%; in the adults, 0.6% vs. 0.3%; and in the adults with moderate-to-severe atopic dermatitis, 0.8% vs. 0.3% (p < 0.001 for all). On multivariate analysis, atopic dermatitis was associated with a significantly higher prevalence of celiac disease (odds ratio = 1.609, 95% confidence interval 1.42-1.82, p < 0.001) in the entire study population and each subgroup. CONCLUSIONS: We observed a significant association between atopic dermatitis and celiac disease. This association emphasizes the need for timely screening of gastrointestinal morbidities in individuals with atopic dermatitis to prevent long-term complications.

Melkersson-Rosenthal Syndrome: the possible role of comorbidities in the etiopathogenesis.

BACKGROUND: Melkersson-Rosenthal Syndrome (MRS) is a rare syndrome. Recently, possible association between MRS and psoriasis was reported. Our objective is to evaluate the presence of comorbidities in MRS with a focus on psoriasis-related morbidities. METHODS: We conducted a case-control study consisting of a series of 12 patients with MRS and two groups of age- and gender-matched controls: 30 patients with psoriasis vulgaris and 28 patients with acute contact dermatitis. A comparative analysis for the prevalence of comorbidities, with a focus on psoriasis-related morbidities, was done. RESULTS: Psoriasis-related morbidities including smoking, obesity, dyslipidemia, hypertension, and diabetes mellitus were recorded in 5 (42%) patients with MRS, compared to 15 (50%) patients with psoriasis and 2 (7%) patients with acute contact dermatitis. The prevalence of psoriasis-related morbidities did not differ significantly between the group of patients with MRS and the group of patients with psoriasis. On the other hand, the difference between the group of patients with MRS and the group of patients with contact dermatitis was statistically significant (P=0.01). CONCLUSIONS: The similar prevalence of psoriasis-related morbidities in MRS and in psoriasis may further support an association between MRS and psoriasis.

The coexistence of pemphigus and psoriasis: a systematic review and meta-analysis.

There is little consensus regarding the association between pemphigus and psoriasis. The aim of the current study is to synthesize existing data on the prevalence of psoriasis in patients with pemphigus and on the association between the two conditions. We performed a systematic review and meta-analysis of observational studies in Medline, Embase, and Web of Science (1900-2018). Reference lists of included studies were also searched for eligible studies. Quality of evidence was assessed using Newcastle-Ottawa scale (NOS). A meta-analysis was performed using random-effects models to estimate pooled prevalence rates and odds ratios (ORs) with 95% confidence intervals (CI). Subgroup and sensitivity analyses were also conducted. Twelve eligible studies comprising 12,238 patients with pemphigus were included in the quantitative synthesis. The overall random-effects pooled prevalence of psoriasis among patients with pemphigus was 2.4% (95% CI, 1.0-4.4) across all studies. The overall pooled multivariate OR for psoriasis in patients with pemphigus was significantly increased and estimated at 3.5 (95% CI, 1.6-7.6). In conclusion, a significant association was found between pemphigus and psoriasis. Physicians managing patients with pemphigus may be aware of this comorbidity. Further studies are warranted to establish the precise mechanisms underlying this relationship.

Acute generalized exanthematous pustulosis and psoriasis: what can be learned from comorbidities.

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a rare pustular severe cutaneous adverse reaction. Differentiating between AGEP and pustular psoriasis may represent a diagnostic challenge. We sought to evaluate the prevalence of comorbidities in a series of patients with AGEP compared to a series of patients with psoriasis vulgaris and to a series of patients with drug-related psoriasis. METHODS: Medical records of 14 patients with AGEP, 33 patients with psoriasis vulgaris, and 18 patients with drug-related psoriasis were reviewed. The presence of comorbidities was recorded, and a comparative analysis was performed. RESULTS: A personal history of psoriasis was present in 4 (28%) patients with AGEP compared to 12 (66%) patients with drug-related psoriasis (Pv=0.03). The prevalence of psoriasis-related morbidities was significantly lower in the AGEP group compared to the psoriasis group and to the drug-related psoriasis group (Pv<0.01, 0.05, respectively). Each of the psoriasis-related morbidities had significantly lower prevalence in the AGEP group compared to the psoriasis group and to the drug-related psoriasis group (Pv<0.01). CONCLUSIONS: In conclusion, differences between AGEP, psoriasis vulgaris, and drug-related psoriasis regarding the prevalence of psoriasis-related morbidities may assist differentiation in borderline cases.

The Risk of Pulmonary Embolism in Patients With Pemphigus: A Population-Based Large-Scale Longitudinal Study.

Growing evidence suggests that inflammation may pose an atypical risk factor for pulmonary embolism (PE), as it drives venous thrombosis via several pathways. The increased risk of PE in several autoimmune diseases has lent weight to this concept. However, the relative risk of PE among patients with pemphigus has not yet been established. We aimed to examine the risk of PE in patients with pemphigus. A large-scale population-based longitudinal cohort study was conducted to evaluate the relative risk (RR) of PE among 1,985 patients with pemphigus relative to 9,874 age-, sex-, and ethnicity-matched control subjects. A multivariate Cox regression model was utilized. The incidence of PE was 3.0 (95% CI, 2.2-4.0) and 1.2 (95% CI, 1.0-1.5) per 1,000 person-years among patients with pemphigus and controls, respectively. The period prevalence of PE corresponding to the study period was 2.2% (95% CI, 1.6-2.9%) among cases and 0.9% (95% CI, 0.7-1.1%) among controls. Patients with pemphigus were twice as likely to develop PE as compared to control subjects (adjusted RR, 1.98; 95% confidence interval [CI], 1.29-3.04). The highest PE risk was observed during the 1st year following the diagnosis of pemphigus (adjusted RR, 3.55; 95% CI, 1.78-7.09) and decreased over time. The increased risk was robust to a sensitivity analysis that included only cases managed by pemphigus-related systemic medications (adjusted RR, 1.82; 95% CI, 1.11-2.98). In conclusion, pemphigus is associated with an increased risk of PE, particularly during the 1st year of the disease. An awareness of this risk should be increased, additional precipitating factors for PE should be avoided, and thromboprophylaxis may be evaluated in high-risk patients. Further research is required to establish this risk.