Koster, Matthew J.

AbstractBackgroundVEXAS syndrome is an autoinflammatory disease caused by somatic UBA1 mutations on the X chromosome, predominantly affecting men.ObjectiveTo characterize VEXAS syndrome in women and to compare the features of VEXAS syndrome between sexes.MethodsWe conducted an international, multicenter study, including 12 women and 301 men with genetically confirmed VEXAS syndrome. Data were collected using a standardized case report form. Bone marrow analyses and molecular investigations were performed locally.ResultsClinical features, age at onset, UBA1 mutation type, variant allele frequency, and mortality were comparable between sexes. Acquired X monosomy was found in 6/8 tested women. Additional clonal mutations were present in 3/5 tested women. Three additional UBA1‐mutated women without typical inflammation are described separately.ConclusionVEXAS syndrome affects women with clinical features similar to men, supporting the need for UBA1 testing in women with compatible presentations. X monosomy is common but not universal, suggesting alternative pathogenic mechanisms.

Abstract Erdheim-Chester disease (ECD) is a rare systemic histiocytic neoplasm, with cardiac morbidities, including cardiovascular (CV) risk factors and cardiac conditions, playing a significant yet poorly understood role in the disease burden. This study evaluated the prevalence, characteristics, and prognosis of ECD in patients with (ECD-C) and without cardiac involvement (ECD-noC) and compared the burden of cardiac morbidities with matched controls. Patients diagnosed with ECD between 1990 and 2021 at a tertiary center were included, with cardiac involvement centrally assessed using radiographic studies. Cardiac morbidities were compared with a control group without ECD, matched for age, sex, body mass index, and smoking history. Among 104 patients with ECD, 39 (37%) had cardiac involvement. Patients with ECD-C had higher rates of hypertension (67% vs 46%), hyperlipidemia (67% vs 40%), heart failure (36% vs 8%), and pericardial effusion (28% vs 2%) than those with ECD-noC. Compared with the matched non-ECD cohort, patients with ECD had higher prevalence of coronary artery disease (20% vs 7%), heart failure (18% vs 4%), and antihypertensive drug use (55% vs 40%). Notably, patients with ECD-C had inferior progression-free survival (PFS) from frontline therapy compared with patients with ECD-noC (5-year PFS, 28.3% vs 70.5%). These findings highlight the burden of CV risk factors and cardiac conditions in ECD, even without a clinical diagnosis of ECD-C. Importantly, this cardiac morbidity burden is substantial for patients with ECD-C compared with ECD-noC. Our findings highlight the need for comprehensive cardiac risk assessment and management strategies to improve patient outcomes.

ABSTRACT Background Idiopathic subglottic stenosis (iSGS) occasionally affects women of childbearing age. Surgical intervention is the primary treatment, yet limited research exists on factors influencing disease severity. This study explores the impact of hormonal contraception on iSGS recurrence rates and surgery‐free intervals. Methods This retrospective study was conducted at a tertiary academic care center. Patients using hormonal birth control (e.g., estrogen‐progesterone pills, progesterone implants) during their first procedure were classified in “Birth Control (BC)” group, while those not using contraceptives were placed in “No Birth Control (NBC)” group. Poisson regression evaluated recurrence rates, and Mann–Whitney tests assessed surgery‐free intervals. Kaplan–Meier analysis estimated time to first recurrence, adjusting for age and follow‐up duration. Results Twenty‐six patients were in the NBC group and 12 in the BC group (average ages 37 and 34, respectively). Patients in the NBC group were 2.6 times more likely to experience recurrence compared to those in the BC group ( p = 0.001). The expected number of recurrences for the BC group was 0.4 times that of the NBC group (95% CI: 0.2–0.7; p = 0.001). Furthermore, patients taking birth control were significantly less likely to have a first recurrence (HR: 0.4; 95% CI: 0.2–0.9; p = 0.025) and had longer times to first recurrence (Figure 1; p = 0.031). Conclusions Birth control appears to protect against iSGS severity, potentially through hormonal mechanisms. Hormonal contraception may serve as a non‐surgical alternative for managing iSGS. Future prospective studies may evaluate outcomes in newly diagnosed iSGS patients started on birth control compared to those not using hormonal contraceptives. Level of Evidence 3.

Objective Vacuoles E1 enzyme X‐linked autoinflammatory somatic syndrome (VEXAS) is a recently identified rare genetic disorder associated with somatic mutations in the UBA1 gene. VEXAS presents with a combination of inflammatory and hematologic manifestations, leading to increased morbidity and mortality. Methods Given the variability in disease presentation and the limited number of studies to date, no clinical documents currently exist to provide guidance to health care providers about the management of VEXAS. To address this gap, we formed an international multidisciplinary panel of VEXAS experts. Results Through formalized meetings and a voting process, the group developed consensus clinical guidance considerations for the management of VEXAS. These considerations offer practical advice on several key topics: (1) clinical features of VEXAS, (2) UBA1 screening methods, (3) the diagnosis of myelodysplastic syndromes (MDSs) in patients with VEXAS, and (4) prognosis and management. The aim is to provide expert guidance on which patients to test, how to test for VEXAS, how to approach MDS in the context of VEXAS, and considerations for management. Conclusion This work marks the first formal international consensus guidance for VEXAS and is intended to be used as a resource for clinicians seeking to understand the disease and its management.

ABSTRACT Background Managing idiopathic subglottic stenosis (iSGS) during pregnancy presents distinct clinical challenges. As pregnancy is a naturally dyspneic state, the development of iSGS may exacerbate respiratory symptoms and compromise the airway—potentially impacting pregnancy and delivery decisions. This study characterizes surgical management strategies and outcomes in pregnant patients with symptomatic iSGS. Methods We conducted the largest known multi‐institutional retrospective review of pregnant patients who underwent endoscopic intervention for iSGS. Demographics, procedural details, anesthesia and medication use, and maternal and neonatal outcomes were analyzed. Results Twelve patients underwent 15 endoscopic procedures during pregnancy: 9 laser wedge excisions (8 CO 2 laser and 1 coblator) and 6 balloon dilations. Three additional procedures in different patients occurred postpartum (2–11 months after delivery). Higher‐risk pregnancies included two twin gestations, one patient with multiple surgeries during two different pregnancies, and two patients over age 35. Most interventions (87%) occurred in the second trimester. Fetal monitoring was performed preoperatively and postoperatively. Fentanyl and propofol were used in 88% and 94% of cases, respectively; rocuronium was the most common neuromuscular blocker (70%). One patient underwent balloon dilation via flexible bronchoscopy without anesthesia. Jet ventilation was used in 53% of cases, and Size C Kleinsasser laryngoscopes in 47%. Median procedure times were 75, 19, and 18 min for laser wedge excision, balloon dilation, and coblation, respectively. Most patients delivered full‐term with no surgical or postpartum complications. Conclusions Endoscopic intervention for iSGS during pregnancy appears safe and effective, even in high‐risk cases. These findings support individualized airway management and inform future practice. Level of Evidence 4.

ABSTRACTObjectiveThere is currently not a marker of disease severity in idiopathic subglottic stenosis (iSGS). Our objective was to characterize iSGS patients' disease severity using endoscopic surgery rates.MethodsThis was a two‐center retrospective analysis of iSGS patients with a minimum of 4 years of follow up following an initial endoscopic procedure (laser wedge excision (LWE) or endoscopic dilation (ED)). Disease severity was classified into Groups A–C, based on whether patients had fewer (Group A), the same number (Group B), or more surgeries (Group C) in years 3–5 compared to years 1 and 2. Disease severity proportions were compared across institutions using chi‐square analysis. Nonparametric testing compared clinical characteristics such as age, BMI, and GERD across severity groups.ResultsThere were 104 patients from institution 1 and 53 patients from institution 2 that were all female and predominantly Caucasian. Both institutions had clinically and statistically similar proportions of patients in Group A (64% vs. 62%), Group B (20% vs. 19%), and Group C (16% vs. 19%) disease (p > 0.05). No clinical characteristic (e.g., age, sex, race, BMI, GERD) was associated with disease severity.ConclusionAcross tertiary care institutions there is a consistent proportion of iSGS patients who either demonstrate nonrecurrent/decelerating (Group A), stable but persistent (Group B), or rapidly recurring disease (Group C). Two‐year surgery rates appear to be an important timepoint for providing expectations to patients on the likelihood of possessing severe disease.Level of Evidence4

ABSTRACTObjectiveWhile endoscopic laser wedge excision (LWE) for iSGS demonstrated lower surgical recurrence rates compared to endoscopic dilation (ED), ED remains the primary technique employed. Additionally, serial intralesional steroid injections (SILSIs) also demonstrate benefits in controlling disease. We aimed to compare surgical recurrence rates following ED, ED + SILSI, and LWE following a patient's first operation.MethodsThis was a two‐center retrospective analysis of iSGS patients who underwent either ED, ED + SILSI, or LWE. Patients were followed to their last follow‐up date or reoperation. Kaplan–Meier analysis and Cox proportional hazards were used to evaluate the recurrence times across the different surgical groups with additional stratification by age, compliance to medical adjuvant therapy, and percentage of stenosis rated at reoperation.ResultsA total of 126 patients from Institution 1 underwent LWE, while at Institution 2, ED and ED + SILSI were performed on 32 and 23 patients, respectively. One‐year recurrence estimates were 9%, 53%, and 0% for LWE, ED, and ED + SILSI, respectively, while 5‐year recurrence estimates were 45%, 90%, and 19%, respectively. Adjusted Cox‐proportional hazard ratios demonstrated a greater risk of surgical recurrence with ED compared to LWE (2.25; 95% confidence interval [CI]: 1.31–3.88) and no difference between ED + SILSI and LWE (0.84; 95% CI: 0.32–2.25).ConclusionLWE demonstrates reduced recurrence times compared to ED when controlling for surgery number, age, triple therapy compliance, and percentage of stenosis at reoperation. The application of postoperative SILSI appears to similarly reduce recurrence rates comparable to LWE and warrants further investigation.

AbstractObjectiveThis study aims to evaluate the impact of parity on the severity and recurrence rates of idiopathic subglottic stenosis (iSGS) in premenopausal females.Study DesignA retrospective cohort study.SettingTwo tertiary care centers from 2002 to 2024.MethodsWe analyzed premenopausal iSGS patients under 40 years who underwent balloon dilation or laser wedge excision. Clinical features, including demographics and pregnancy history, were examined. Recurrence rates between nulliparous and parous patients were compared using Poisson regression, adjusting for age and follow‐up duration. Linear regression assessed the relationship between pregnancy and iSGS recurrence.ResultsForty‐eight patients were included, with 36 parous and 12 nulliparous. Adjusting for age and follow‐up, the mean recurrence rate was 2.6 times higher in parous patients (95% confidence interval [CI]: [1.5, 4.8], P = .0008). Each additional pregnancy was associated with 0.81 additional recurrences (95% CI: [0.05, 1.57], P = .0375). No significant differences in surgery‐free time were observed between groups.ConclusionParity and pregnancy significantly increase the risk of iSGS recurrence, although they do not accelerate subsequent recurrences. Health care providers should counsel women of childbearing age about these risks in family planning discussions, emphasizing shared decision‐making regarding potential surgical interventions.Level of evidence3.