Citations

Abstract Background:Erdheim-Chester Disease (ECD) is a rare, incurable histiocytic neoplasm. Since its recognition in 1930, our understanding of ECD's pathophysiology has evolved. The identification of its clonal nature after 2015 established ECD as a cancer, prompting increased disease awareness and treatment advances. Targeted therapies show promising responses, but changes in ECD mortality over time have not been extensively documented. Methods:A multi-institutional retrospective cohort study analyzed adults with ECD consecutively seen at Mayo Clinic MN, AZ, and FL and the University of Alabama at Birmingham between 2007 and 2024. Clinical and prognostic data were abstracted. Overall survival was estimated using the Kaplan-Meier method and compared to expected survival using U.S. Census data, based on age at diagnosis (by calendar year), date of diagnosis, and sex. Standardized mortality ratios (SMRs) were calculated by dividing the number of observed deaths in the study population by the expected number of deaths using U.S. population data. Risk of death was compared by date of diagnosis (pre- and post-2015) using Cox proportional hazards analysis. Statistical analysis was performed with R software. Results:A total of 159 ECD patients were included (median age 58 years [range 19-82], 65% male). Forty-nine patients were diagnosed between 1990-2014 and 110 between 2015-2024. Median follow-up for the entire cohort was 4.0 years (95% CI: 3.2-4.4). Median follow-up for those diagnosed between 1990-2014 was 10.4 years (CI: 3.2-16.8), compared to 3.5 years (CI: 3.0-4.2) for those diagnosed between 2015-2024. The 5-year overall survival rate was 80% (95% CI: 72-88). Patients with ECD had an increase in mortality over expected, with 28 deaths compared to an expected 11.2, an SMR of 2.5 (95% CI: 1.7-3.6, p<0.001). Of 17 patients with an identified cause of death, death was attributable to ECD in 11 (65%), secondary malignancy in 1 (7%), and unrelated causes in 5 (29%). Cause of death was unknown in 11 patients. Among deaths, 11 (39%) were treated with targeted therapy, 8 (29%) with chemotherapy, and 1 (4%) received both. One patient (4%) received steroids, 1 received immunomodulator and targeted therapy (4%), and 6 (21%) received no disease-directed therapy. Of the patients whose death was related to ECD, 10 (91%) had multisystem disease. For 49 patients diagnosed pre-2015, 14 deaths occurred during the follow-up, significantly higher than the expected 5.2 deaths based on U.S. population data (SMR of 2.7 [95% CI: 1.5-4.4, p=0.001]). Among those diagnosed between 2015 and 2024, 14 deaths occurred, compared to expected 6.1 (SMR of 2.3 [95% CI: 1.3-3.8, p=0.006]). In an age- and sex-adjusted Cox proportional hazards model, diagnosis after 2015 vs. diagnosis prior to 2015 yielded a hazard ratio of 0.59 (95% CI: 0.27-1.31, p=0.19). Conclusion:The mortality rate of ECD patients remains higher than the general population, despite advancements in disease recognition and development of targeted therapies. While our data suggest a possible trend toward improved survival among patients diagnosed after 2015, we did not find statistically significant evidence of decreased mortality compared to those diagnosed prior to 2015. Larger cohorts with longer follow-up periods are needed to draw definitive conclusions regarding mortality.

Abstract Introduction: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an aggressive auto-inflammatory disorder defined by somatic UBA1 mutations. UBA1 mutations arise in hematopoietic stem cells and bias differentiation toward myeloid lineages. Clonal involvement of monocytes and neutrophils in VEXAS is frequent. Recently, natural killer (NK) cells have been recognized within the UBA1 mutant clone; mutated NK cells have an exhausted phenotype and impaired cytotoxicity (Ganesan BioRxiv 2025; Breillat et al, Blood 2025). A unique NK-like T cell type (CD3+CD16+[CD56-] T cells) has a role in the immunopathogenesis of severe COVID-19, resulting in heightened cytotoxicity and tissue damage (Georg et all, Cell 2022). As NK cells do not typically express CD3, and as the activation of inflammatory pathways is not restricted to myeloid cells in VEXAS, (Mizumaki et al, Nat Comm 2025) we sought to assess the CD3+ cell populations for co-expression of CD16 using single-cell (sc) multiomic data from VEXAS patients. Methods: After IRB approval, we performed sc-proteogenomic sequencing using a custom-made gene panel (Tapestri, MissionBio) in 2 VEXAS patients. Libraries were sequenced on an Illumina NovaSeq instrument. In one case, we performed in parallel CITE-Seq in parallel and used canonical correlation analysis (CCA) to integrate these immunophenotypic and transcriptomic data with matching cell populations identified from proteogenomic sequencing. We used pathway analysis (IPA) and gene ontology enrichment (gProfiler), as well as differential gene expression (RNA-seq) to identify significant gene signatures. T-tests with Welch's correction were performed for statistical significance on surface markers from proteogenomic data which were transformed by center log ratio. Our observations were then validated in sc-proteogenomic data from two additional VEXAS patients profiled at the NIH. Results: We used a sc-multiomic strategy to study CD3+ T cell subsets in VEXAS patients. In the first UBA1 mutant (mt) sample, using clusters defined by UMAP overlay of CITE-Seq/proteogenomic data, we defined positive expression of CD3 expression in the non-UBA1mt T cell cluster. We then examined the proteogenomic data (n=700 cells) to identify CD3+ cells (n=89 UBA1mt, n=42 UBA1wt). We then divided the CD3+ fraction into CD56+ vs CD56- to obtain CD3+CD56+ (n=25 UBA1mt, n=12 UBA1wt) and CD3+CD56- (n=64 UBA1mt, n=0 UBA1wt) cells. The CD3+CD56- cells were not only entirely UBA1mt, but also co-expressed CD16, significantly elevated from CD3+CD56+ UBA1wt cells (p<0.0001; and no significance from granulocyte populations): 10% of UBA1mt cells were CD3+CD16+CD56-. This cell subset was detected in an additional 3 VEXAS samples, and, in each case, there was no significant difference between UBA1mt/UBA1wt CD3 expression (both were T cell subsets) and no significant difference in CD56 expression. There was a significant increase in CD16+ expression in UBA1mt over UBA1wt (p<0.0001) cells, but not between UBA1mt cells and other granulocytes. Finally, we assessed the CITEseq data from the first UBA1mt case and focussed on gene expression and pathway differences between CD3+ and CD3+CD16+(CD56-) cell populations. Using IPA, we found top differentially expressed pathways included neutrophil degranulation, inflammation, cell killing, and IL-8 activity. Differentially expressed genes included FCGR3B, TLR2, IL1R2, FCGR2A, CCR1, CXCL8, and CXCR1, some of these overlapping with what was reported in similar cells (CD3+CD16+) detected in COVID-19 (Georg et all, Cell 2022). Conclusion: We identify a unique NK-T cell like [CD3+CD16+(CD56] subset of cells within UBA1mt cells in patients with VEXAS. This cell type has been reported in patients with severe COVID-19 as having increased cytotoxic functions and associated with fatal outcomes. Rare or aberrant cell clusters defined by standard clustering analysis may mis-identify some cell types, especially if they aberrantly express CD3+CD16+, as either marker could be used to pre-gate cells into larger clusters of lymphoid or myeloid cells. Prospective and functional profiling of this cell type in VEXAS patients is ongoing.

Abstract Objective VEXAS syndrome is a severe systemic haemato-inflammatory disease with heterogeneous clinical presentations. Most patients experience recurrent inflammatory flares despite anti-inflammatory therapy. The lack of accepted definitions of flare in these patients is preventing development of disease activity tools that are essential for conducting clinical trials. We aimed to develop a consensus definition of a VEXAS flare for use in clinical trials. Methods A nine-member international expert advisory committee established a consensus definition of VEXAS flare using modified Delphi methodology. Clinical inflammatory manifestations of VEXAS syndrome were identified through a systematic literature review. Committee members developed a conceptual framework for flare definition, proposed revisions and voted on changes until consensus (≥75% concurrence) was reached. Results Consensus defined VEXAS flare as active inflammatory manifestation(s) of VEXAS syndrome requiring escalation in glucocorticoid therapy. Three flare categories were established: (i) recurrence of a prior documented VEXAS manifestation; (ii) development of a new VEXAS-defining inflammatory manifestation; or (iii) emergence of a new inflammatory manifestation not meeting criteria for A or B. The panel endorsed an independent adjudication committee to assess Category C flares in clinical trials. Conclusions This study proposes a standardized definition of VEXAS flare, providing uniform criteria for identifying VEXAS disease activity. Future research will evaluate its performance in clinical trials.

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.