Citations

Objective Glucocorticoids (GCs) remain the primary treatment for polymyalgia rheumatica (PMR) but are associated with substantial long‐term toxicity. Although sex‐based differences in GC‐related adverse effects have been suggested, they have not been well studied in PMR. Methods We conducted a retrospective cohort study of patients with PMR treated between 2017 and 2024 within a multisite health system. Patients ≥50 years of age with at least two PMR International Classification of Diseases, Tenth Revision, codes and documented GC dosing for ≥75% of days during the first six months of treatment were included. Sex‐based differences in GC toxicity outcomes including incident or worsening hypertension, type 2 diabetes mellitus, and incidence of fragility fractures were evaluated using multivariable regression models adjusted for age, body mass index, treatment site, and baseline type 2 diabetes mellitus. Results A total of 1,899 patients met inclusion criteria (915 female patients and 984 male patients; mean age 72.5 years). At one year, the cumulative GC exposure and composite toxicity was not statistically different between sexes. At three years, cumulative GC exposure was higher in female patients (4,419.5 mg prednisone equivalents compared to 4,106.2 mg in male patients, P = 0.042) as well as daily GC dose ( P = 0.037). Female patients had a higher incidence of fractures at three years (8.5% vs 3.2%, P ≤ 0.001) and incidence of giant cell arteritis (GCA; 7.6% vs 3.4%, P < 0.001). Conclusion The median cumulative GC exposure in patients with PMR remains high, with higher exposure in female patients. Female patients were more likely to experience fracture and the development of GCA within the same time frame. image

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.

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 Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

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 Gain‐of‐function variants in IDH1 and IDH2 are enriched among individuals with coexisting myeloid neoplasms and autoimmune diseases. However, the association between IDH1 / IDH2 variants and rheumatic diseases independent of hematologic neoplasms remains unclear. We investigated the association between rare gain‐of‐function and loss‐of‐function genetic variants in IDH1 and IDH2 and immune‐mediated rheumatic diseases. Methods Individuals with gain‐of‐function and loss‐of‐function variants in IDH1/IDH2 were identified by whole genome sequencing in the UK Biobank and the All of Us Research Program. These individuals were matched 1:10 to controls without IDH1 or IDH2 variants by age, sex, and ancestry. The frequency of immune‐mediated rheumatic diseases in the presence and absence of IDH1/IDH2 variants was compared using chi‐square or Fisher exact tests. Results Fifty‐five individuals with IDH1 or IDH2 gain‐of‐function variants without pre‐existing hematologic neoplasms were identified in the UK Biobank. These individuals had a significantly higher frequency of incident immune‐mediated rheumatic diseases compared to matched controls (11 of 55 [20%] vs 20 of 550 [4%], odds ratio [OR] = 6.6, P = 2.7 × 10 −5 ), mainly polymyalgia rheumatica (6 of 11) and rheumatoid arthritis (5 of 11). Replication in the All of Us cohort identified 65 individuals with gain‐of‐function variants and confirmed an increased odds of incident immune‐mediated rheumatic diseases compared to controls (OR = 7.7, P < 5 × 10 −4 ), predominantly rheumatoid arthritis. There was no association between loss‐of‐function variants in IDH1/IDH2 and immune‐mediated rheumatic diseases in either cohort. Conclusion Rare gain‐of‐function variants in IDH1 / IDH2 are associated with increased risk of immune‐mediated rheumatic diseases, particularly rheumatoid arthritis and polymyalgia rheumatica. image