Erdheim-Chester disease (ECD) is a rare disease characterized by the accumulation of neoplastic histiocytes in various extra-nodal tissues. Tissue biopsies involved by ECD are difficult to distinguish from reactive inflammatory infiltrates given the bland appearance of the neoplastic histiocytes. Confirmation of the ECD diagnosis often relies on molecular studies to confirm BRAF V600E mutation or other activating mutations involving MAPK pathway genes. In this study, we examined the diagnostic utility of cyclin D1 and pERK as immunohistochemical markers of MAPK pathway activation in ECD compared with its histopathologic mimics. The cohort included 41 clinically confirmed ECD patients, most with known genetic alterations in MAPK pathway genes (n=38). In 3 cases no mutation was identified. 37 of 41 (90%) of ECD cases showed cyclin D1 overexpression, with frequent staining in the cytoplasm as well as the nucleus. pERK expression was observed in 32 of 39 (82%) cases. Cyclin D1 staining was negative in histopathologic mimics of ECD, apart from weak patchy staining in fat necrosis and uniform staining in a subset of cases of juvenile/adult xanthogranuloma. While not entirely sensitive or specific, in the proper clinical and radiologic context strong nuclear and cytoplasmic cyclin D1 expression within histiocytic infiltrates helps to support a diagnosis of ECD.

OBJECTIVES:Reliable tools for monitoring disease activity in Takayasu arteritis (TAK) are lacking, and ultrasonography (US) may represent a valuable option. This study aimed to: 1) develop consensus-based definitions for key US lesions in TAK; 2) identify the relevant arterial segments to include in an US-based score; 3) assess inter- and intra-rater reliability of the definitions in a web-based image analysis and scoring exercise. METHODS:A Delphi survey was conducted among members of the OMERACT Ultrasound Working Group to agree upon the definitions of key elementary US lesions and arterial segments to be included. A subsequent web-based reliability exercise included US images from TAK patients and healthy controls depicting the consensual lesions. Experts scored each image in two separate rounds. Inter-rater and intra-rater reliability were assessed using Fleiss' and Cohen's kappa (κ), respectively. RESULTS:Three Delphi rounds were completed with 47, 46, and 43 experts respectively. Consensus was reached on three lesions ('macaroni sign', stenosis, occlusion) and seven arterial segments (bilateral common carotid, subclavian, axillary arteries, abdominal aorta). Forty-five experts completed the reliability exercise. Inter-rater reliability was moderate to good (κ = 0.47-0.64), with the highest agreement for the 'macaroni sign' in the carotid artery (κ = 0.73). Intra-rater reliability was good (κ = 0.72-0.79), with lower agreement for stenosis and occlusion in the abdominal aorta. CONCLUSIONS:This OMERACT initiative established consensus-based definitions for US lesions in TAK and identified key relevant arterial segments, providing a reliable basis for the development of a standardized US composite score.

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.

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).

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.

BACKGROUND:Imaging for giant cell arteritis (GCA) has traditionally relied on ultrasound, MRI, and, more recently, nuclear medicine. Computed tomographic angiography (CTA) has not been systematically evaluated, despite near-universal availability, rapid acquisition, and comprehensive neck vessel assessment. We evaluated the ability of CTA to discriminate between biopsy-proven GCA patients and age- and sex-matched controls by assessing cervical arterial abnormalities across multiple cervical arterial segments. METHODS:This retrospective single-center study included 20 biopsy-proven GCA cases (with CTA performed within 4 weeks before or 2 weeks after biopsy) and 20 age- and sex-matched controls. Two neuroradiologists independently assessed 21 predefined arterial segments for abnormalities (absent/present). Segment-level positivity was defined by circumferential wall thickening, >50% stenosis/occlusion, or perivascular inflammatory fat-stranding. Vessel-group-level involvement was through consensus positivity (both readers positive; either side). Per-patient total scores were evaluated with ROC (DeLong AUC), prespecified thresholds with secondary exploratory analysis through McNemar testing, and inter-reader agreement by percent agreement and Cohen's κ. RESULTS:Median age was 76 years (IQR, 70-84); 60% were female in both groups. Across 806 evaluable segments, involvement was most frequent along the maxillary (80%; 16/20), facial (75%; 15/20), and superficial temporal (70%; 14/20) arteries. Total-score discrimination was excellent (AUC 0.971 for both readers). At total score ≥3, sensitivity/specificity were 0.90/1.00 for both readers, with paired differences favoring cases (exact McNemar p<0.001). Pooled segment-level agreement was high (agreement 0.978; κ 0.924). CONCLUSION:Structured multi-segment CTA scoring of cranio-cervical arterial segments showed excellent discrimination of biopsy-proven GCA from matched controls, supporting CTA as a useful diagnostic tool in GCA patients.

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.

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.

The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Renal lesions as the initial presentation of IgG4-related disease (IgG4-RD) and isolated IgG4-related kidney disease (IgG4-RKD) are rare.1,2A 65-year-old male with a history of high-grade urothelial cell carcinoma in remission was found to have multiple renal lesions on surveillance imaging (Figure 1A).

OBJECTIVES:To identify clinical and laboratory features associated with the presence of UBA1 mutation and develop predictive models to guide efficient diagnosis of VEXAS syndrome. METHODS:All patients who underwent UBA1 mutation testing were identified. Using a comprehensive list of VEXAS syndrome features, the presence or absence of each feature in each patient was determined for two timepoints: time of first VEXAS symptom onset and the time of UBA1 mutation testing. For each timepoint, the presence of each disease feature was compared between UBA1 positive and negative patients. The least absolute shrinkage and selection operator (LASSO) method was used to develop multi-feature models to predict the presence of pathogenic UBA1 mutations. RESULTS:Overall, 144 patients who underwent UBA1 mutation testing were included. Features including skin rash, chondritis, and monocytopenia were significantly associated with the presence of a UBA1 mutation at both timepoints. Macrocytosis, uveitis, and pulmonary disease had significant association at time of testing. 12-feature and 5-feature LASSO models at symptom onset demonstrated good discriminatory capacity with areas under receiver operating curves (AUCs) of 0.86 and 0.81, respectively. 16-variable and 5-feature models at time of testing had good-to-excellent performance with AUCs of 0.92 and 0.84, respectively. A single feature model utilizing absolute monocyte count also had fair discriminatory capacity with AUC of 0.78 at both timepoints. CONCLUSIONS:Multi-feature models that efficiently separate VEXAS cases from controls were successfully developed. These models have the potential to address existing diagnostic challenges including a lack of consensus regarding key features of VEXAS syndrome.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterised by multiorgan pathological histiocytic infiltration. Cardiac involvement occurs in 40-75% of patients and increases mortality. A 55-year-old woman with chest pain and dyspnoea was found to have an interatrial septal mass and aortitis suspicious for ECD without other organ involvement. After two inadequate transcatheter interatrial biopsies were obtained using ultrasound guidance alone, diagnostic samples were successfully obtained using intraprocedural frozen section examination. The patient started genotype-targeted treatment with good response. Biopsy confirmation of ECD is required to guide treatment; however, cardiac biopsies are uncommonly performed when other organs are affected. Our unique case of isolated cardiovascular involvement highlights how frozen sectioning with multimodal intraprocedural imaging guidance can improve diagnostic yield of endomyocardial biopsies. It also highlights how diagnosis of rare conditions requires careful multidisciplinary evaluation of affected organs, procedural risk and diagnostic yield. The use of frozen sectioning can improve diagnostic yield of endomyocardial biopsies.

OBJECTIVE:To evaluate concordance of symptoms between initial presentation, first relapse, and second relapse in patients with giant cell arteritis (GCA). METHODS:We analyzed three GCA cohorts: a 286-patient biopsy-proven cohort treated without tocilizumab (C1), a 110-patient biopsy-negative cohort treated without tocilizumab (C2), a 114-patient biopsy- or imaging-proven cohort that was treated with tocilizumab (C3), and an aggregate of these three cohorts (C4). We calculated odds ratios and conditional probabilities to evaluate concordance of symptoms from baseline presentation features to first relapse, baseline presentation to second relapse, and first relapse to second relapse. RESULTS:The study included a total of 510 patients (C4) diagnosed with GCA who were followed for a median of 5.3 (inter-quartile range: 3.1-8.7) years. Overall, 303 patients experienced at least 1 relapse (5-year first relapse rate 66%; 95% confidence interval [CI]: 60-70%) and 160 experiencing at least 2 relapses (5-year second relapse rate: 36%; 95% CI: 31-41%). Approximately 20% of patients relapsed with a symptom category that was absent at baseline. Baseline large vessel (LV) involvement provided higher risk of LV involvement on first and second relapse. Risk of visual symptoms on either first or second relapse was high if present at a previous stage, but low if either cranial or visual symptoms were absent at a previous stage. CONCLUSION:Patients and providers should be educated on the spectrum of GCA symptoms to be aware of, even beyond those present at a patient's initial presentation.

OBJECTIVE:This study aims to evaluate the impact of parity on the severity and recurrence rates of idiopathic subglottic stenosis (iSGS) in premenopausal females. STUDY DESIGN:A retrospective cohort study. SETTING:Two tertiary care centers from 2002 to 2024. METHODS:We 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. RESULTS:Forty-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. CONCLUSION:Parity 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 EVIDENCE: 3:

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: