Koster, Matthew J.

Abstract Objective To evaluate whether systemic hormone replacement therapy (HRT) influences recurrence outcomes in postmenopausal patients with idiopathic subglottic stenosis (iSGS). Study Design Retrospective cohort study. Setting Tertiary academic medical center. Methods Postmenopausal women (≥50 years) with iSGS who underwent laser‐wedge excision between 2002 and 2024 were included. Patients were categorized by systemic HRT exposure (oral estrogen, progesterone, combined estrogen‐progesterone, or transdermal estrogen) at or before their first surgery. Overdispersion was assessed for all Poisson models; given significant overdispersion, negative binomial regression with a log‐offset for follow‐up time was used as the primary model. Surgery‐free intervals were analyzed using linear mixed models, and time to first recurrence using Cox regression. Models were adjusted for age, body mass index (BMI), parity, oophorectomy, follow‐up length, surgery type, and serial intralesional steroid injections (SILSI) use. Results Among 125 patients, 96 had never used HRT (Never HRT) and 29 used HRT, including 19 actively using HRT at presentation (Current HRT), 5 past users, and 5 subsequent users. The HRT versus Never‐HRT recurrence rate comparison was not significant (adjusted incidence rate ratio [IRR] = 0.81, 95% CI: 0.48‐1.37, P = .422). However, Current HRT use was associated with a 53% lower adjusted recurrence rate versus Never‐HRT use (adjusted IRR = 0.47, 95% CI: 0.25, 0.89, P = .0203). Surgery‐free intervals and time to first recurrence trended longer in Current HRT users but were not statistically significant. Conclusion Current HRT use at presentation was associated with significantly fewer recurrences in postmenopausal iSGS patients. These findings may inform individualized, shared decision‐making regarding HRT use in this population. Level of Evidence 3.

Objective To evaluate the efficacy of cytokine‐directed therapies in VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory somatic) syndrome using previously proposed treatment response criteria. Methods All patients with genetically confirmed VEXAS syndrome who received targeted therapies with JAK inhibitors (JAKi), tumor necrosis factor α inhibitors (TNFαi), or interleukin‐1 (IL‐1) or IL‐6 inhibitors were identified. Clinical and biochemical data were recorded for patients at time of targeted therapy initiation, and at 3‐, 6‐, and 12‐month follow‐up time points. Treatment response was labeled as complete response (CR; normalization of C‐reactive protein [CRP], prednisone <10 mg/day, and resolution of disease activity), partial response (PR; >50% improvement in CRP, >50% prednisone dose reduction, improvement or resolution of disease features), treatment failure (TF; worsening CRP, increasing prednisone, worsening of disease features), or no response (not meeting criteria for CR, PR, or TF). Results Overall, 52 patients received an IL‐1i, IL‐6i, or JAKi therapy. At six‐month follow‐up, 3 of 19 IL‐6i patients experienced CR, 4 of 19 experienced PR, and 7 of 19 experienced TF. 2 of 17 patients receiving JAKi experienced CR, 3 of 17 experienced PR, and 6 of 17 experienced TF. No patients receiving IL‐1i or TNFαi experienced CR, and only 1 of 5 IL‐1i patients experienced PR. Among those still receiving biologic therapy at 12 months, only 1 of 11 receiving IL‐6i and 0 of 7 receiving JAKi experienced CR. Conclusion IL‐6i and JAKi therapies demonstrated limited, unsustained efficacy for management of VEXAS syndrome. IL‐1i and TNFαi therapies were not efficacious. Useful application of previously reported treatment response criteria was demonstrated, but future incorporation of hematologic parameters may be beneficial.

Objective Vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome (VEXAS) syndrome is characterized by a complex spectrum of inflammatory and hematologic manifestations. Clinical research to identify effective therapies is urgently needed but is hindered by the lack of validated outcome measures. A VEXAS‐specific disease activity index (DAI) is an essential tool for reliably capturing changes in disease activity over time, thereby supporting clinical research and informing patient care in this emerging disease. This study aimed to develop a comprehensive DAI to assess disease‐related inflammation across affected organ systems in patients with VEXAS syndrome. Methods Inflammatory manifestations of VEXAS were previously identified through a systematic literature review and expert input. A multinational expert advisory committee developed the VEXAS‐DAI using modified Delphi methodology until consensus (defined as ≥75% concurrence) was reached. Item grading was adapted from the Common Terminology Criteria for Adverse Events. Scoring criteria were developed based on 158 test cases using the Physician Global Assessment of Inflammation. Results Consensus on the VEXAS‐DAI was achieved after four Delphi rounds. The index assesses inflammatory activity at the time of evaluation across 12 domains: inflammatory rash, chondritis, periorbital, ophthalmologic, joint, pulmonary, cardiovascular, genitourinary, neurologic, oral and gastrointestinal, renal, and constitutional symptoms. The total score ranges from 0 to 40. Conclusion The VEXAS‐DAI is a novel instrument designed to quantify active inflammation over time in patients with VEXAS. Prospective validation within a clinical trial setting is ongoing. image

Abstract Background Takayasu arteritis (TA) is a rare large-vessel vasculitis that can involve pulmonary arteries, potentially leading to pulmonary hypertension (PH). Noninvasive evaluation by echocardiography is often used, but its reliability in confirming and characterizing PH in TA is unclear. We investigated the role of invasive hemodynamic testing in TA patients with suspected PH. Methods We retrospectively identified 10 patients with TA meeting 2022 ACR criteria and suspected PH based on symptoms and/or echocardiography; all underwent echocardiography followed by right heart catheterization (RHC).PH was defined as mean pulmonary artery pressure (mPAP) &gt;20 mmHg. PH was classified as pre-capillary (pulmonary artery wedge pressure [PAWP] ≤15 mmHg), post-capillary (PAWP &gt;15 mmHg), or combined (PAWP &gt;15 mmHg with elevated pulmonary vascular resistance). Echocardiographic parameters were collected where available, along with invasive hemodynamics, cardiac biomarkers (BNP/NT-proBNP), inflammatory markers (ESR, CRP), NYHA functional class, and outcomes. Results Median age was 44 years (range 18-58), and 90% were female. Based on invasive hemodynamics, pre-capillary PH was present in 5 patients, combined pre-/post-capillary PH in 3, and isolated post-capillary PH in 2. Median mPAP was 38 mmHg (IQR 30-55), median pulmonary vascular resistance 3.5 Wood units (IQR 2.3-8.7), and median PAWP 15 mmHg (IQR 8-24). Echocardiography frequently underestimated disease severity. Several patients with absent or low tricuspid regurgitation velocity (≤1.0 m/s), where measurable, demonstrated severe pre-capillary PH on RHC, including pulmonary vascular resistance &gt;6 Wood units. Among patients with available data, NT-proBNP levels ranged from 59 to 51,968 pg/mL, and inflammatory markers varied widely (CRP &lt;0.3 to 107.9 mg/L). Among patients with available NYHA data, most were class II-III. Conclusions In this TA cohort, RHC was essential to confirm and phenotype PH, which was present in the majority of those with suspected PH. Echocardiography alone often underestimated or misclassified PH in TA - in one case missing severe pre-capillary PH due to an absent TR signal, and in another failing to discern elevated left-heart filling pressure. Invasive assessment prevented missed diagnoses and misclassification, ensuring appropriate management of TA-associated PH This abstract is funded by: None

ABSTRACT Hypomethylating agents (HMA) and allogeneic hematopoietic stem cell transplantation (alloHSCT) have both demonstrated remissions in VEXAS; however, comparative data is lacking. We conducted a multicenter, retrospective analysis of 66 patients diagnosed with VEXAS syndrome treated with HMA ( n = 35) or alloHSCT ( n = 31). Baseline characteristics such as genetics, co‐morbidities, and performance status were balanced between the groups, except older age in the HMA group. Median follow‐up from therapy initiation was 18 months (95% CI: 11–26), and 14 (21%) deaths were reported (alloHSCT n = 3; HMA n = 11). Among all evaluable patients within the alloHSCT cohort, all patients achieved molecular remission, and a substantial proportion of patients discontinued glucocorticoids (58%). In contrast, HMA therapy was associated with lower but meaningful rates of molecular remission (22%) and glucocorticoid discontinuation (6%). In a real‐world setting, HMA therapy was associated with a high discontinuation rate related to toxicity or lack of response. On multivariable analysis adjusted for age and Charlson Comorbidity Index, alloHSCT was associated with improved overall survival (HR = 0.20, 95% CI: 0.05–0.81; p = 0.024). This association remained consistent across multiple ancillary sensitivity analyses, including restriction to transplant‐eligible patients, patients aged ≤ 75 years, 1:1 matching, and propensity score‐based weighted analyses. Although limited by retrospective design, these findings suggest that alloHSCT remains an attractive and potentially curative strategy in selected patients with VEXAS. Prospective validation of these findings is warranted.

Abstract Introduction Pulmonary artery masses have a broad differential. CT may offer initial characterization, but cardiac MRI and PET/CT provide more definitive information. Histopathologic evaluation is often required. We present a rare case of a pulmonary artery mass with an elevated IgG4 index, initially misclassified as more common benign and malignant entities. Case-Presentation: A 61-year-old never smoking female was referred to the pulmonary clinic for abnormal imaging. Her history was only for patent ductus arteriosus repair in infancy. She initially presented with pleuritic chest pain and was found to have near occlusive mass in the distal main pulmonary artery extending into the proximal left main pulmonary artery. This was presumed to be pulmonary embolism, and anticoagulation was started. At presentation, she reported mild dyspnea and improving chest pain, without constitutional symptoms. Cardiac MRI revealed restricted diffusion and enhancement consistent with pulmonary artery sarcoma. PET-CT revealed FDG avid pulmonary artery mass (SUV max 14.5) without other hypermetabolic lesions. She subsequently underwent resection of the main and proximal left PA mass resection with bovine pericardial reconstruction. Histopathology showed a dense lymphoplasmacytic infiltrate with prominent plasma cell infiltration, IgG4/IgG ratio of 40%, and &gt; 10 IgG4 positive plasma cells per high power field. No histiocytic proliferation or evidence of other atypia. Her serum IgG4 level, CRP, ANCA serology, and fungal serology were normal. Discussion Here we present the case of isolated pulmonary artery mass with elevated IgG4 index of greater than 40% without other organ manifestations of IgG4 related disease (IgG4-RD). Cases of IgG4-RD related infiltration with a pulmonary artery mass have been reported, yet these typically present with other systemic manifestations, vascular inflammation, luminal stenosis, and/or pulmonary hypertension. Based on ACR 2019 IgG4 related disease classification criteria, these patients would not strictly meet criteria for IgG4 related disease. After extensive multidisciplinary discussion, we have elected to hold systemic treatment for IgG4-RD. She will be followed closely, monitoring new evidence of organ infiltration that would warrant systemic treatment. Conclusion Pulmonary artery masses should raise suspicion for various benign etiologies, such as chronic thromboembolism, and malignant entities, including pulmonary artery sarcoma. Cardiac MRI, PET/CT, and histopathology were critical in this patient’s evaluation. IgG4-related disease can rarely present as an intimal pulmonary artery mass. However, this is typically accompanied by systemic findings suggestive of IgG4-RD, other vascular infiltration, and/or pulmonary hypertension, all of which were absent in this patient. This abstract is funded by: None

Objective Medium‐vessel vasculitis involving the visceral vasculature in adults is rare. Pancreatic ductal adenocarcinoma (PDAC) has been implicated in medium artery vascular thickening secondary to extravascular migratory metastasis with involvement of the celiac and superior mesenteric vessels. Methods Patients presenting to the rheumatology vasculitis subspecialty clinic were retrospectively identified using an electronic health record data exploration tool evaluating for diagnosis of pancreatic cancer, periaortitis, and vasculitis between January 2015 and December 2024. Results We retrospectively identified four patients with PDAC initially presenting with periarterial thickening of the celiac and superior celiac and superior mesenteric vessels (100% White, 50% male, median age 70.5 years). All four patients had abdominal pain with significant unintentional weight loss, with a median weight loss of 25 pounds (range 25–50 pounds). The median time to correct diagnosis was 221 days (range 162–340 days). All four patients had an elevated carbohydrate antigen 19‐9 level (range from 114 to 10,702, with a median of 341.5 U/mL). All four patients were diagnosed with endoscopic ultrasound–guided fine‐needle aspirations. The median number of biopsies required to make the diagnosis was three. Conclusion Isolated celiac and superior mesenteric periarterial thickening or “cuffing” is a vasculitis mimic that should prompt a comprehensive malignancy workup. Expedited referral to a tertiary center is essential given difficulty in tissue sampling with conventional methods and to avoid further delays in diagnosis.

VEXAS (Vacuoles, E1 ubiquitin-activating enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a systemic disorder characterized by an overlap of hematologic and inflammatory features. Most patients require chronic use of moderate-to-high doses of glucocorticoids (GCs) to maintain disease control. Data on GC-sparing therapies is limited, and there have been no prospective pharmacotherapeutic trials in VEXAS syndrome published to date. Pacritinib, an oral inhibitor of IRAK1, JAK2, and ACVR1, has emerged as a promising therapeutic option for VEXAS syndrome. The PAXIS trial is the first prospective, randomized pharmacotherapeutic study conducted in this rare and severe disease. Utilizing a novel study design and disease-specific endpoints, the trial will evaluate the efficacy and safety of two dose levels of pacritinib compared with placebo in patients with VEXAS syndrome (NCT06782373, EUCTR: 2024-516347-41-00).