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Importance: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined genetic disease with an estimated prevalence of 1 in 4269 men older than 50 years and is marked by systemic inflammation, progressive bone marrow failure, and inflammatory cutaneous manifestations., Objective: To define the spectrum of cutaneous manifestations in VEXAS syndrome and the association of these findings with clinical, genetic, and histological features., Design, Setting, and Participants: This observational cohort study included data from 112 patients who were diagnosed with VEXAS-defining genetic variants in UBA1 between 2019 and 2023. Data were collected from medical record review or from patients with VEXAS directly evaluated at the National Institutes of Health in Bethesda, Maryland., Main Outcomes and Measures: To define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histological, and other clinical findings. A secondary outcome was cutaneous response to treatment in VEXAS., Results: Among the 112 patients (median [range] age, 69 [39-79] years; 111 [99%] male), skin involvement was common (93 [83%]), and the most frequent presenting feature of disease (68 [61%]). Of 64 histopathologic reports available from 60 patients, predominant skin histopathologic findings were leukocytoclastic vasculitis (23 [36%]), neutrophilic dermatosis (22 [34%]), and perivascular dermatitis (19 [30%]). Distinct pathogenic genetic variants were associated with specific cutaneous manifestations. The p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates (14 of 17 patients [82%]), often resembling histiocytoid Sweet syndrome. In contrast, the p.Met41Val variant was associated with vasculitic lesions (11 of 20 patients [55%]) with a mixed leukocytic infiltrate (17 of 20 patients [85%]). Oral prednisone improved skin manifestations in 67 of 73 patients (92%). Patients with VEXAS treated with anakinra frequently developed severe injection-site reactions (12 of 16 [75%]), including ulceration (2 of 12 [17%]) and abscess formation (1 of 12 [8%])., Conclusions and Relevance: Results of this cohort study show that skin manifestations are a common and early manifestation of VEXAS syndrome. Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis. Awareness of VEXAS among dermatologists is critical to facilitate early diagnosis.

Background: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a genetic disorder characterized by bone marrow failure and systemic inflammation, putting patients at risk for infections. This study comprehensively examines the prevalence of opportunistic infections in patients with VEXAS, evaluating their impact on clinical outcomes and potential preventive measures., Methods: Patients with confirmed VEXAS were included. Survival analysis and logistic regression were used to identify associations between opportunistic infections and mortality. Infection rates (IRs) for Pneumocystis jirovecii pneumonia (PJP) and alphaherpesviruses were calculated over a prospective 8-month observation period in relationship to prophylaxis., Results: Of 94 patients with VEXAS, 6% developed PJP; 15% had alphaherpesvirus reactivation, with varicella zoster virus (VZV) being the most common herpesvirus; and 10% contracted a nontuberculous mycobacterial (NTM) infection. Risk of death was significantly increased per month following a diagnosis of PJP (hazard ratio [HR], 72.41 [95% confidence interval {CI}, 13.67-533.70]) or NTM (HR, 29.09 [95% CI, 9.51-88.79]). Increased odds for death were also observed in patients with a history of herpes simplex virus (HSV) reactivation (odds ratio [OR], 12.10 [95% CI, 1.29-114.80]) but not in patients with VZV (OR, 0.89 [95% CI, .30-2.59]). Prophylaxis for PJP (IR, 0.001 vs 0 per person-day, P < .01) and VZV (IR, 0.006 vs 0 per person-day, P = .04) markedly decreased infection rates with a number needed to treat of 4 and 7, respectively., Conclusions: Opportunistic infections are common in patients with VEXAS. Patients who develop PJP, HSV, or NTM are at increased risk for death. Prophylaxis against PJP and VZV is highly effective., Competing Interests: Potential conflicts of interest. The authors: Nothing to report., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Objective: We describe the demographics, clinical features, disease course, and survival of polyarteritis nodosa (PAN) through an international collaboration (GLOBAL-PAN)., Methods: Patients with PAN were recruited between 1990 and 2020 from observational cohorts of nine countries across Europe, Japan, and North America. Eligibility was retrospectively defined using the European Medicines Agency classification algorithm. Patients with PAN related to hepatitis B virus (n = 12) and two monogenic diseases mimicking PAN, deficiency of adenosine deaminase 2 enzyme (n = 16) or familial Mediterranean fever (n = 11), were excluded. Data regarding organ involvement, relapse, disease-related damage, and survival were analyzed., Results: Three hundred fifty-eight patients (female:male ratio 174:184), including those with systemic PAN (sPAN, n = 282) and cutaneous PAN (n = 76), were included. Twenty-five were pediatric onset. Mean ± SD age at diagnosis was 44.3 ± 18.1 years. Constitutional symptoms (71.5%), cutaneous involvement (70.5%), musculoskeletal findings (69.1%), and neurologic features (48.0%) were common manifestations. Among patients with sPAN, gastrointestinal involvement and proteinuria over 400 mg/day were reported in 52.2% and 11.2%, respectively. During a median (interquartile range) 59.6 (99.5) months of follow-up, relapse occurred in 48.5% of patients. One, 5- and 10-year survival rates for sPAN were 97.1%, 94.0%, and 89.0%, respectively. Predictors of death for sPAN included age ≥65 years at diagnosis, serum creatinine at diagnosis >140 μmol/L, gastrointestinal manifestations, and central nervous system (CNS) involvement., Conclusion: The spectrum of PAN remains a complex, multifaceted disease. Relapse is common. Age ≥65 years and serum creatinine >140 μmol/L at diagnosis, as well as gastrointestinal and CNS involvement, are independent predictors of death in sPAN., (© 2024 American College of Rheumatology.)

Relapsing polychondritis is a rare inflammatory disease characterized by recurrent inflammation of cartilaginous structures, mainly of the ears, nose and respiratory tract, with a broad spectrum of accompanying systemic features. Despite its rarity, prompt recognition and accurate diagnosis of relapsing polychondritis is crucial for appropriate management and optimal outcomes. Our understanding of relapsing polychondritis has changed markedly in the past couple of years with the identification of three distinct patient clusters that have different clinical manifestations and prognostic outcomes. With the progress of pangenomic sequencing and the discovery of new somatic and monogenic autoinflammatory diseases, new differential diagnoses have emerged, notably the vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, autoinflammatory diseases and immune checkpoint inhibitor-related adverse events. In this Review, we present a detailed update of the newly identified clusters and highlight red flags that should raise suspicion of these alternative diagnoses. The identification of these different clusters and mimickers has a direct impact on the management, follow-up and prognosis of patients with relapsing polychondritis and autoinflammatory syndromes., (© 2024. Springer Nature Limited.)

Objective: Somatic variants in UBA1 cause VEXAS, a recently described, systemic autoinflammatory disease. Research on VEXAS has largely focused on highly symptomatic patients. We sought to determine the prevalence of canonical, VEXAS-associated somatic variants and their disease penetrance in a diverse, unselected population., Methods: We analyzed clinical-grade whole genome sequencing data from 245,368 participants in the All of Us Research Program. We compared persons carrying a canonical VEXAS-associated somatic variant to age, sex, and ancestry matched controls across the domains of diagnoses, medications, and laboratory values., Results: 74 participants were identified who carry one VEXAS-defining somatic variant, UBA1 c.121A>C, p.Met41Leu. The variant allele fraction ranged from 4.5% to 33%. No other canonical VEXAS-associated variants were identified. Of the 74 carriers, 62 (84%) were women, 20 (27%) were African American, and 14 (19%) were American Admixed/Latino. There was no statistically significant association between case/control status and any VEXAS-associated diagnosis code, medication prescription, or laboratory value., Conclusion: We report the largest cohort to date of persons with the VEXAS-associated p.Met41Leu somatic variant. This cohort differed substantially from reported cohorts of patients with clinical VEXAS, having a higher proportion of persons who were young, female, and of diverse ancestry. Variant allele fractions were lower than reported in clinical VEXAS cohorts, and bioinformatic analysis detected no clinical manifestations of VEXAS. Thus, the UBA1 p.Met41Leu somatic variant displayed incomplete penetrance for VEXAS. Further study is needed to determine the natural history of VEXAS-associated somatic variants in the predisease phase., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Abstract: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS syndrome. The risk factors and frequency of thrombosis in VEXAS syndrome are not well described, due to the disease's recent discovery and the paucity of large databases. We evaluated 119 patients with VEXAS syndrome for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two-thirds of VTEs were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism by univariate (odds ratio [OR]: 4.58, confidence interval [CI] 1.28-16.21, P = .02) and multivariate (OR: 16.94, CI 1.99-144.3, P = .01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival of the entire patient cohort at median follow-up time of 4.8 years was 88%, and there was no difference in survival between patients with or without thrombosis (P = .8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.

Objective: Accurate clinical assessment of disease activity in Takayasu arteritis (TAK) can be challenging. 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) can directly measure vascular inflammation. This study details the development of a new type of disease activity index called the Takayasu's Arteritis Integrated Disease Activity Index (TAIDAI)., Methods: Clinical symptoms for TAIDAI were identified from a literature review. Each symptom was paired with FDG-PET findings in corresponding arterial territories. Constitutional symptoms were paired with acute phase reactant levels. One point was given for each clinical symptom paired with supporting FDG-PET or laboratory abnormalities and summed into the TAIDAI score. A TAIDAI of ≥1 defined active disease. To assess performance of TAIDAI, face validity, content validity, and sensitivity to change were evaluated within a prospective observational cohort study of patients with TAK., Results: Seventeen clinical symptoms were paired with imaging or laboratory abnormalities. In a cohort of 96 patients contributing 204 study visits, TAIDAI showed excellent sensitivity (96.3%) and good specificity (79.2%) compared to physician's clinical assessment. TAIDAI significantly correlated with physician global assessment, PET Vascular Activity Score, patient global assessment, and acute phase reactant levels. In patients treated with either tumor necrosis factor inhibitors or tocilizumab, a TAIDAI of 0 was achieved in 21 (91%) of 23 patients who met a predefined definition of clinical response., Conclusion: TAIDAI is new type of disease activity index in TAK in which clinical symptoms are integrated with specific laboratory and imaging findings. TAIDAI should be validated in future randomized controlled trials in TAK., (© 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objectives: Ageing and inflammation are associated with clonal haematopoiesis (CH), the emergence of somatic mutations in haematopoietic cells. This study details CH in patients with systemic vasculitis in association with clinical, haematological and immunological parameters., Methods: Patients with three forms of vasculitis were screened for CH in peripheral blood by error-corrected sequencing. Relative contributions of age and vasculitis on CH prevalence were calculated using multivariable logistic regression. Clonal hierarchies were assessed by proteogenomic single-cell DNA sequencing, and functional experiments were performed in association with CH status., Results: Patients with Takayasu's arteritis (TAK; n=70; mean age=33.2 years), antineutrophil cytoplasmic antibody-associated vasculitis (AAV; n=47; mean age=55.3 years) and giant cell arteritis (GCA; n=59; mean age=71.2 years) were studied. CH, most commonly in DNMT3A and TET2, was detected in 34% (60/176) of patients versus 18% (28/151) of age-matched controls (p<0.01). Prevalence of CH was independently associated with age (standardised B=0.96, p<0.01) and vasculitis (standardised B=0.46, p<0.01), occurring in 61%, 32% and 13% of patients with GCA, AAV and TAK, respectively. Both branched and linear clonal trajectories showed myeloid-lineage bias, and CH was associated with markers of cellular activation. In GCA, mutations were detected in temporal artery biopsies, and clinical relapse correlated with CH in a dose-dependent relationship with clone size., Conclusions: Age was more strongly associated with CH prevalence than inflammation in systemic vasculitis. Clonal profile was dominated by DNMT3A mutations which were associated with relapse in GCA. CH is not likely a primary causal factor in systemic vasculitis but may contribute to inflammation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Relapsing polychondritis (RP) is a systemic inflammatory disease of unknown aetiology. The objective of this study was to examine the contribution of rare genetic variations to RP., Methods: We performed a case-control exome-wide rare variant association analysis that included 66 unrelated European American cases with RP and 2923 healthy controls (HC). Gene-level collapsing analysis was performed using Firth's logistics regression. Exploratory pathway analysis was performed using three different methods: Gene Set Enrichment Analysis, sequence kernel association test and higher criticism test. Plasma DCBLD2 levels were measured in patients with RP and HC using ELISA., Results: In the collapsing analysis, RP was associated with a significantly higher burden of ultra-rare damaging variants in the DCBLD2 gene (7.6% vs 0.1%, unadjusted OR=79.8, p=2.93×10 -7 ). Plasma DCBLD2 protein levels were significantly higher in RP than in HC (median 4.06 ng/µL vs 0.05 ng/µL, p<0.001). The pathway analysis revealed a statistically significant enrichment of genes in the tumour necrosis factor signalling pathway driven by rare damaging variants in RELB , RELA and REL using higher criticism test weighted by eigenvector centrality., Conclusions: This study identified specific rare variants in the DCBLD2 gene as a putative genetic risk factor for RP. These findings should be validated in additional patients with RP and supported by future functional experiments., Competing Interests: Competing interests: MZ is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To develop treat-to-target (T2T) recommendations in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR)., Methods: A systematic literature review was conducted to retrieve data on treatment targets and outcomes in GCA/PMR as well as to identify the evidence for the effectiveness of a T2T-based management approach in these diseases. Based on evidence and expert opinion, the task force (29 participants from 10 countries consisting of physicians, a healthcare professional and a patient) developed recommendations, with consensus obtained through voting. The final level of agreement was provided anonymously., Results: Five overarching principles and six-specific recommendations were formulated. Management of GCA and PMR should be based on shared decisions between patient and physician recognising the need for urgent treatment of GCA to avoid ischaemic complications, and it should aim at maximising health-related quality of life in both diseases. The treatment targets are achievement and maintenance of remission, as well as prevention of tissue ischaemia and vascular damage. Comorbidities need to be considered when assessing disease activity and selecting treatment., Conclusion: These are the first T2T recommendations for GCA and PMR. Treatment targets, as well as strategies to assess, achieve and maintain these targets have been defined. The research agenda highlights the gaps in evidence and the need for future research., Competing Interests: Competing interests: CDe has received consulting/speaker’s fees from Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, Sparrow, Roche, Galapagos and Sanofi, all unrelated to this manuscript. He is an editorial board member of ARD. AK has received consultancy fees, honoraria and travel expenses from AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck Sharp and Dohme, Novartis, UCB and Pfizer, all unrelated to this manuscript. He is an editorial board member of ARD. DA received grants, speaker fees, and/or consultancy fees from Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz and Sanofi. He is an editorial board member of ARD. MB has received consulting fees from AbbVie. DC has received speaker fees from Abiogen, BMS and GSK. MCC received consultancy and/or speaker fees from GSK, Vifor, Abbvie, Astra Zeneca and Janssen and a research grant form Kiniksa Pharmaceuticals. BD has received consultancies from Novartis, Abbvie, Roche and speaker agreements from Chugai. CDu has received consultancy or speaker fees and travel expenses from Abbvie, AOP Orphan, Astra-Zeneca, Bristol-Myers-Squibb, Eli-Lilly, Janssen, Galapagos, Merck-Sharp-Dohme, Novartis, Pfizer, Roche, Sandoz, UCB, Vifor and research support by Eli-Lilly, Pfizer, UCB, all unrelated to this manuscript. BH received speaker fees and/or consultancies from Abbvie, Amgen, Astra-Zeneca, BMS, Boehringer, Chugai, GSK, InflaRx, Janssen, MSD, Pfizer, Novartis, Phadia, Roche and Vifor. ELM has received consulting fees from Boehringer-Ingelheim, Horizon Therapeutics, Alvotech Inc; speaker fees from Boehringer-Ingelheim; royalties from UpToDate. SPM has received consultancy fees (Invex Therapeutics); advisory board fees (Invex therapeutics; Gensight) and speaker fees (Heidelberg engineering; Chugai-Roche Ltd; Allergan; Santen; Teva UK; Chiesi; and Santhera). All unrelated to this manuscript. LN has received consulting fees from AbbVie. CP is or has been the principal investigator of studies by AbbVie, Sanofi and Novartis and has received consulting/speaker’s fees from Vifor, AstraZeneca, GlaxoSmithKline and Roche, all unrelated to this manuscript. CS has received consultancy fees from Abbvie, Boehringer-Ingelheim, Eli Lilly, Galapagos, Novartis, Pfizer and Roche and royalties from UpToDate. All unrelated to this manuscript. SES has received research support by Astra-Zeneca and has done provided unpaid consultancy for Sanofi. SES is supported by the Rheumatology Research Foundation RISE pilot award and Bristol Myers Squibb Foundation Robert A Winn Diversity in Clinical Trials Career Development Award, outside of the submitted work. WAS has received consultancy fees, honoraria and travel expenses from Abbvie, Amgen, Bristol-Myers Squibb, Chugai, GlaxoSmithKline, Johnson & Johnson, Medac, Novartis, Roche, and Sanofi and is principal investigator in trials sponsored by Abbvie, Amgen, GlaxoSmithKline, Novartis, Roche and Sanofi. PS has received consultancy fees from Amgen and Janssen and royalties from UpToDate, all unrelated to this manuscript. JSS received grants to his institution from Abbvie, AstraZeneca, Lilly, Novartis and Roche and provided expert advice for, or had symposia speaking engagements with, AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celltrion, Chugai, Gilead, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, R-Pharm, Roche, Samsung, Sanofi and UCB. He is the editor in chief of ARD. JT has received consultancy or speaker fees Bristol-Myers-Squibb, Novartis, Glaxo-Smith-Kline, Astra-Zeneca, Janssen, Abbvie, Eli-Lilly. All unrelated to this manuscript. CET-G has received consultancy fees, honoraria and travel expenses from Abbvie, BMS, Boehringer Ingelheim, Biopas, Janssen, Pfizer, Pharmalab, Roche, all unrelated to this manuscript. FB has received consultancy fees, honoraria and travel expenses from Abbvie, Novartis, Pfizer, Roche and Sanofi, all unrelated to this manuscript. He is an editorial board member of ARD. EH, LE, AA, SA, PCG, AH, TAK and MW declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Markers of extracellular mitochondria are present in giant cell arteritis (GCA) patients. However, their role in promoting inflammation and platelet activation is no known. To investigate this, isolated mitochondria were opsonized with plasma from GCA patients or healthy individuals and incubated with peripheral blood mononuclear cells (PBMCs) or platelets and assessed for inflammatory cytokine production and platelet activation. Plasma from GCA patients promoted increased mitochondrial-mediated cytokine production by PBMCs as compared to healthy controls (p < 0.05). Mitochondria opsonized with plasma factors from patients with GCA induced higher platelet activation as compared to mitochondria opsonized with plasma factors from healthy individuals (p = 0.0015). Platelet levels of P-selectin were associated with disease activity in GCA (r = 0.34, p = 0.01). GCA patients have impaired ability to regulate the clearance of extracellular mitochondria, possibly contributing to excessive inflammation and platelet activation. Targeting key drivers of mitochondrial extrusion and/or their clearance could lead to new therapeutic interventions in GCA., Competing Interests: Declaration of Competing Interest Dr. Michailidou received Advisory Board fees from ChemoCentryx. Dr. Khalidi received clinical trial support from BMS, Sanofi and Abbvie, travel support from Astra Zeneca, and Advisory Board fee from Roche. Dr. Koening served on the advisory board for Chemocentryx and Genentech. Dr. Sreih works at Bristol-Myers Squibb and owns Astra Zeneca and Alexion stock. Dr. Warrington received clinical trial support from Eli Lilly, BMS and Kiniksa, and consulting fees from Chemocentryx. Dr. Monach received consulting fees from Kiniksa, Celgene/BMC, and ChemoCentryx. Dr. Merkel reports receiving funds for the following activities: Consulting and Research Support: AbbVie, Amgen, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, InflaRx, Takeda. Consulting only: ArGenx, Cabaletta, CSL Behring, HiBio, Janssen, Jubilant, Kyverna, MiroBio, Novartis, NS Pharma, Q32, Regeneron, Sparrow, Vistera. Research Support only: Eicos, Electra, Forbius, Genentech/Roche, Genzyme/Sanofi, Neutrolis. Stock options: Kyverna. Royalties: UpToDate. Dr. Lood received research funding from Pfizer, Gilead Sciences, Boehringer Ingelheim, Redd Pharma, Amytryx, and Eli Lilly., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a pleiotropic, severe autoinflammatory disease caused by somatic mutations in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene. To elucidate VEXAS pathophysiology, we performed transcriptome sequencing of single bone marrow mononuclear cells and hematopoietic stem and progenitor cells (HSPCs) from VEXAS patients. HSPCs are biased toward myeloid (granulocytic) differentiation, and against lymphoid differentiation in VEXAS. Activation of multiple inflammatory pathways (interferons and tumor necrosis factor alpha) occurs ontogenically early in primitive hematopoietic cells and particularly in the myeloid lineage in VEXAS, and inflammation is prominent in UBA1-mutated cells. Dysregulation in protein degradation likely leads to higher stress response in VEXAS HSPCs, which positively correlates with inflammation. TCR usage is restricted and there are increased cytotoxicity and IFN-γ signaling in T cells. In VEXAS syndrome, both aberrant inflammation and myeloid predominance appear intrinsic to hematopoietic stem cells mutated in UBA1., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic autoinflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 patients with VEXAS for CH in their peripheral blood (PB) and correlated the findings with clinical outcomes in 77 of them. UBA1mut were most common at hot spot p.M41 (median variant allele frequency [VAF] = 75%). Typical CH mutations cooccurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mut was the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed 2 major patterns: with either typical CH preceding UBA1mut selection in a clone (pattern 1) or occurring as an UBA1mut subclone or in independent clones (pattern 2). VAF in the PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.

Objectives: The number of susceptibility loci currently associated with vasculitis is lower than in other immune-mediated diseases due in part to small cohort sizes, a consequence of the low prevalence of vasculitides. This study aimed to identify new genetic risk loci for the main systemic vasculitides through a comprehensive analysis of their genetic overlap., Methods: Genome-wide data from 8467 patients with any of the main forms of vasculitis and 29 795 healthy controls were meta-analysed using ASSET. Pleiotropic variants were functionally annotated and linked to their target genes. Prioritised genes were queried in DrugBank to identify potentially repositionable drugs for the treatment of vasculitis., Results: Sixteen variants were independently associated with two or more vasculitides, 15 of them representing new shared risk loci. Two of these pleiotropic signals, located close to CTLA4 and CPLX1 , emerged as novel genetic risk loci in vasculitis. Most of these polymorphisms appeared to affect vasculitis by regulating gene expression. In this regard, for some of these common signals, potential causal genes were prioritised based on functional annotation, including CTLA4 , RNF145 , IL12B , IL5 , IRF1 , IFNGR1 , PTK2B , TRIM35 , EGR2 and ETS2 , each of which has key roles in inflammation. In addition, drug repositioning analysis showed that several drugs, including abatacept and ustekinumab, could be potentially repurposed in the management of the analysed vasculitides., Conclusions: We identified new shared risk loci with functional impact in vasculitis and pinpointed potential causal genes, some of which could represent promising targets for the treatment of vasculitis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To examine and compare disease activity over time in giant cell arteritis (GCA) and Takayasu arteritis (TAK) using multimodal assessment combining clinical, laboratory, and imaging-based testing., Methods: Patients with GCA or TAK were enrolled into a single-center prospective, observational cohort at any point in the disease course. Patients underwent standardized assessment, including 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) at enrollment and follow-up visits. Each FDG-PET finding was subjectively interpreted as active or inactive vasculitis. Global arterial FDG uptake was quantified by the PET Vascular Activity Score (PETVAS). Patients were stratified by disease duration at enrollment (0-2 years; 2-5 years; >5 years). Fisher exact and Mann-Whitney U tests, Spearman's correlation, and linear regression were used for statistical analyses., Results: A total of 126 patients with large vessel vasculitis (GCA = 50; TAK = 76) were evaluated across 319 visits. Clinical disease activity was present in 33% of patients in the second to fifth year of disease and in 24% of patients evaluated >5 years after diagnosis. Active vasculitis by PET was observed in 66% of patients in years 2 to 5 after diagnosis and in 50% of patients enrolled >5 years into disease. PETVASs were consistently higher in GCA than TAK in the early and later phases of disease and significantly decreased over time in GCA but not TAK. Correlations between clinical, laboratory, and imaging findings were complex and varied with disease duration., Conclusion: Disease activity in GCA and TAK is common throughout the disease course. Patterns of vascular PET activity at diagnosis and later in disease differ between GCA and TAK., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To evaluate the feasibility of tocilizumab tapering and withdrawal in patients with giant cell arteritis (GCA)., Methods: GCA patients eligible for tocilizumab were prospectively enrolled. Tocilizumab was administered weekly for the first 12 months, every-other-week for an additional 12 months, then discontinued. Relapses on tocilizumab were managed with temporary increases in systemic glucocorticoids or addition of methotrexate. Primary outcome was relapse-free survival at month 6 after tocilizumab suspension. Relapse-free survival on tocilizumab, imaging response, and adverse events were evaluated., Results: 23 GCA patients were enrolled. Reasons for tocilizumab start were relapse (n = 14), persistence of activity (n = 5), or steroid-related adverse events (n = 4). At tocilizumab start, two patients were on methotrexate, which was maintained. Fourteen patients had extracranial vascular involvement on 18 FDG-PET/CT. During the first 12 months, four patients (17%) had clinical relapse. At every-other-week tocilizumab start, all patients were in clinical remission, two patients had active vasculitis on 18 FDG-PET/CT; two patients were on steroid therapy, and four patients were taking methotrexate. Two patients (9%) relapsed while on every-other-week tocilizumab. At tocilizumab suspension, no patient was on steroid therapy and no patient had signs of active vasculitis on 18 FDG-PET/CT. In the 6 months after tocilizumab discontinuation, six patients (26%) relapsed. No new or unexpected safety findings were identified., Conclusion: Tocilizumab tapered over a two-year period was effective to induce and maintain remission in GCA. Relapses on tocilizumab were minor and responded to incremental changes in therapy. A significant proportion of patients relapsed in the 6 months after therapy suspension., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Levels of neutrophil extracellular traps (NETs) were measured in plasma of healthy controls (HC, n = 30) and patients with granulomatosis with polyangiitis (GPA, n = 123), microscopic polyangiitis (MPA, n = 61), Takayasu's arteritis (TAK, n = 58), and giant cell arteritis (GCA, n = 68), at times of remission or activity and correlated with levels of the platelet-derived thrombospondin-1 (TSP-1). Levels of NETs were elevated during active disease in patients with GPA (p < 0.0001), MPA (p = 0.0038), TAK (p < 0.0001), and GCA (p < 0.0001), and in remission for GPA, p < 0.0001, MPA, p = 0.005, TAK, p = 0.03, and GCA, p = 0.0009. All cohorts demonstrated impaired NET degradation. Patients with GPA (p = 0.0045) and MPA (p = 0.005) had anti-NET IgG antibodies. Patients with TAK had anti-histone antibodies (p < 0.01), correlating with presence of NETs. Levels of TSP-1 were increased in all patients with vasculitis, and associated with NET formation. NET formation is a common process in vasculitides. Targeting NET formation or degradation could be potential therapeutic approaches for vasculitides., Competing Interests: Declaration of Competing Interest Dr. Michailidou received Advisory Board fees from ChemoCentryx. Dr. Khalidi received clinical trial support from BMS, Sanofi and Abbvie, travel support from Astra Zeneca, and Advisory Board fee from Roche. Dr. Koening served on the advisory board for Chemocentryx and Genentech. Dr. Specks reports receiving funds for the following activities: Consulting: AstraZeneca, ChemoCentryx. Research Support: AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Genentech/Roche, InflaRx. Dr. Sreih works at Bristol-Myers Squibb and owns Astra Zeneca and Alexion Stocks. Dr. Warrington received clinical trial support from Eli Lilly and Kiniksa. Dr. Monach received consulting fees from Kiniksa, Celgene/BMC, and ChemoCentryx. Dr. Merkel reports receiving funds for the following activities: Consulting and Research Support: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Takeda. Consulting only: CSL Behring, Dynacure, EMDSerono, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, Pfizer, Sparrow, Talaris. Royalties: UpToDate. Dr. Lood received research funding from Pfizer, Gilead Sciences, Boehringer Ingelheim, Redd Pharma, Amytryx, and Eli Lilly., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The use of fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging to detect vascular inflammation is increasingly common in the clinical management of patients with large-vessel vasculitis (LVV). In this review, the role of FDG-PET imaging to diagnose and monitor vascular disease activity will be detailed. Suggestions on incorporation of FDG-PET imaging into a clinical workflow will be provided with emphasis on patient preparation, image acquisition, and image interpretation. If FDG-PET imaging is obtained, multimodal imaging assessment, whereby FDG-PET imaging and non-invasive angiography are obtained concurrently, and correlation of imaging findings with clinical assessment is generally advisable. Considering the clinical scenario and treatment status of the patient is important when interpreting vascular FDG-PET image findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: The frequency of proteinase 3 gene (PRTN3) polymorphisms in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is not fully characterised. We hypothesise that the presence of a PRTN3 gene polymorphism (single nucleotide polymorphism (SNP) rs351111) is relevant for clinical outcomes., Methods: DNA variant calling for SNP rs351111 (chr.19:844020, c.355G>A) in PRTN3 gene assessed the allelic frequency in patients with PR3-AAV included in the Rituximab in ANCA-Associated Vasculitis trial. This was followed by RNA-seq variant calling to characterise the mRNA expression. We compared clinical outcomes between patients homozygous for PRTN3-Ile 119 or PRTN3-Val 119 ., Results: Whole blood samples for DNA calling were available in 188 patients. 75 patients with PR3-AAV had the allelic variant: 62 heterozygous PRTN3-Val 119 Ile and 13 homozygous for PRTN3-Ile 119 . RNA-seq was available for 89 patients and mRNA corresponding to the allelic variant was found in 32 patients with PR3-AAV: 25 heterozygous PRTN3-Val 119 Ile and 7 homozygous for PRTN3-Ile 119 . The agreement between the DNA calling results and mRNA expression of the 86 patients analysed by both methods was 100%. We compared the clinical outcomes of 64 patients with PR3-AAV: 51 homozygous for PRTN3-Val 119 and 13 homozygous for PRTN3-Ile 119 . The frequency of severe flares at 18 months in homozygous PRTN3-Ile 119 was significantly higher when compared with homozygous PRTN3-Val 119 (46.2% vs 19.6%, p=0.048). Multivariate analysis identified homozygous PR3-Ile 119 as main predictor of severe relapse (HR 4.67, 95% CI 1.16 to 18.86, p=0.030)., Conclusion: In patients with PR3-AAV, homozygosity for PRTN3-Val 119 Ile polymorphism appears associated with higher frequency of severe relapse. Further studies are necessary to better understand the association of this observation with the risk of severe relapse., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes., Objective: To determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach., Design, Setting, and Participants: This retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022., Exposures: Exome sequencing was performed., Main Outcomes and Measures: Outcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays., Results: In 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669)., Conclusions and Relevance: This study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.

Objective: To assess whether vascular activity seen on 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan is associated with angiographic change in large vessel vasculitis (LVV)., Methods: Patients with LVV were recruited into a prospective cohort. All patients underwent magnetic resonance angiography or computed tomography angiography and FDG-PET imaging. Follow-up imaging using the same imaging modalities was obtained ≥6 months later per a standardized imaging protocol. Arterial damage, defined as stenosis, occlusion, or aneurysm, and corresponding FDG uptake were evaluated in 17 arterial territories. On follow-up, development of new lesions was recorded, and existing lesions were characterized as improved, worsened, or unchanged., Results: A total of 1,091 arterial territories from 70 patients with LVV (38 patients with Takayasu arteritis, 32 patients with giant cell arteritis) were evaluated. Over a median 1.6 years of follow-up, new lesions developed only in 8 arterial territories in 5 patients with Takayasu arteritis. Arterial lesions improved in 16 territories and worsened in 6 territories. Most arterial territories that did not have vascular activity on FDG-PET scan at baseline had no angiographic change over the follow-up period (787 [99%] of 793). Few territories with baseline FDG-PET activity had angiographic change over time (24 [8%] of 298), but of the territories that developed angiographic change, 80% had FDG-PET activity at baseline. Within the same patient, an arterial territory with baseline FDG-PET activity had significantly increased risk for angiographic change compared to a paired arterial territory without FDG-PET activity (odds ratio 19.49 [95% confidence interval 2.44-156.02]; P < 0.01). Concomitant edema and wall thickening further increased risk for angiographic change., Conclusion: Development of angiographic change was infrequent in this cohort of patients with LVV. A lack of baseline FDG-PET activity was strongly associated with stable angiographic disease. In cases of angiographic progression, change was preceded by the presence of FDG-PET activity., (© 2022 American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: To develop and validate updated classification criteria for giant cell arteritis (GCA)., Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in six phases: (1) identification of candidate items, (2) prospective collection of candidate items present at the time of diagnosis, (3) expert panel review of cases, (4) data-driven reduction of candidate items, (5) derivation of a points-based risk classification score in a development data set and (6) validation in an independent data set., Results: The development data set consisted of 518 cases of GCA and 536 comparators. The validation data set consisted of 238 cases of GCA and 213 comparators. Age ≥50 years at diagnosis was an absolute requirement for classification. The final criteria items and weights were as follows: positive temporal artery biopsy or temporal artery halo sign on ultrasound (+5); erythrocyte sedimentation rate ≥50 mm/hour or C reactive protein ≥10 mg/L (+3); sudden visual loss (+3); morning stiffness in shoulders or neck, jaw or tongue claudication, new temporal headache, scalp tenderness, temporal artery abnormality on vascular examination, bilateral axillary involvement on imaging and fluorodeoxyglucose-positron emission tomography activity throughout the aorta (+2 each). A patient could be classified as having GCA with a cumulative score of ≥6 points. When these criteria were tested in the validation data set, the model area under the curve was 0.91 (95% CI 0.88 to 0.94) with a sensitivity of 87.0% (95% CI 82.0% to 91.0%) and specificity of 94.8% (95% CI 91.0% to 97.4%)., Conclusion: The 2022 American College of Rheumatology/EULAR GCA classification criteria are now validated for use in clinical research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop and validate new classification criteria for Takayasu arteritis (TAK)., Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in six phases: (1) identification of candidate criteria items, (2) collection of candidate items present at diagnosis, (3) expert panel review of cases, (4) data-driven reduction of candidate items, (5) derivation of a points-based classification score in a development data set and (6) validation in an independent data set., Results: The development data set consisted of 316 cases of TAK and 323 comparators. The validation data set consisted of an additional 146 cases of TAK and 127 comparators. Age ≤60 years at diagnosis and imaging evidence of large-vessel vasculitis were absolute requirements to classify a patient as having TAK. The final criteria items and weights were as follows: female sex (+1), angina (+2), limb claudication (+2), arterial bruit (+2), reduced upper extremity pulse (+2), reduced pulse or tenderness of a carotid artery (+2), blood pressure difference between arms of ≥20 mm Hg (+1), number of affected arterial territories (+1 to +3), paired artery involvement (+1) and abdominal aorta plus renal or mesenteric involvement (+3). A patient could be classified as having TAK with a cumulative score of ≥5 points. When these criteria were tested in the validation data set, the model area under the curve was 0.97 (95% CI 0.94 to 0.99) with a sensitivity of 93.8% (95% CI 88.6% to 97.1%) and specificity of 99.2% (95% CI 96.7% to 100.0%)., Conclusion: The 2022 American College of Rheumatology/EULAR classification criteria for TAK are now validated for use in research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop and validate updated classification criteria for giant cell arteritis (GCA)., Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 6 phases: 1) identification of candidate items, 2) prospective collection of candidate items present at the time of diagnosis, 3) expert panel review of cases, 4) data-driven reduction of candidate items, 5) derivation of a points-based risk classification score in a development data set, and 6) validation in an independent data set., Results: The development data set consisted of 518 cases of GCA and 536 comparators. The validation data set consisted of 238 cases of GCA and 213 comparators. Age ≥50 years at diagnosis was an absolute requirement for classification. The final criteria items and weights were as follows: positive temporal artery biopsy or temporal artery halo sign on ultrasound (+5); erythrocyte sedimentation rate ≥50 mm/hour or C-reactive protein ≥10 mg/liter (+3); sudden visual loss (+3); morning stiffness in shoulders or neck, jaw or tongue claudication, new temporal headache, scalp tenderness, temporal artery abnormality on vascular examination, bilateral axillary involvement on imaging, and fluorodeoxyglucose-positron emission tomography activity throughout the aorta (+2 each). A patient could be classified as having GCA with a cumulative score of ≥6 points. When these criteria were tested in the validation data set, the model area under the curve was 0.91 (95% confidence interval [95% CI] 0.88-0.94) with a sensitivity of 87.0% (95% CI 82.0-91.0%) and specificity of 94.8% (95% CI 91.0-97.4%)., Conclusion: The 2022 American College of Rheumatology/EULAR GCA classification criteria are now validated for use in clinical research., (© 2022 American College of Rheumatology.)

Objective: To develop and validate new classification criteria for Takayasu arteritis (TAK)., Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 6 phases: 1) identification of candidate criteria items, 2) collection of candidate items present at diagnosis, 3) expert panel review of cases, 4) data-driven reduction of candidate items, 5) derivation of a points-based classification score in a development data set, and 6) validation in an independent data set., Results: The development data set consisted of 316 cases of TAK and 323 comparators. The validation data set consisted of an additional 146 cases of TAK and 127 comparators. Age ≤60 years at diagnosis and imaging evidence of large-vessel vasculitis were absolute requirements to classify a patient as having TAK. The final criteria items and weights were as follows: female sex (+1), angina (+2), limb claudication (+2), arterial bruit (+2), reduced upper extremity pulse (+2), reduced pulse or tenderness of a carotid artery (+2), blood pressure difference between arms of ≥20 mm Hg (+1), number of affected arterial territories (+1 to +3), paired artery involvement (+1), and abdominal aorta plus renal or mesenteric involvement (+3). A patient could be classified as having TAK with a cumulative score of ≥5 points. When these criteria were tested in the validation data set, the model area under the curve was 0.97 (95% confidence interval [95% CI] 0.94-0.99) with a sensitivity of 93.8% (95% CI 88.6-97.1%) and specificity of 99.2% (95% CI 96.7-100.0%)., Conclusion: The 2022 American College of Rheumatology/EULAR classification criteria for TAK are now validated for use in research., (© 2022 American College of Rheumatology.)

Objectives: To assess whether data from 18F-fluorodeoxyglucose (FDG) PET should be incorporated into eligibility criteria for clinical trials in Takayasu's arteritis (TAK)., Methods: The study was conducted in two parts. Part one was an international online survey among physicians with experience managing TAK to determine, using clinical vignettes, whether FDG-PET data influence decisions about enrolment in trials. Part two used patient data from an observational cohort study in TAK to assess agreement regarding decisions about enrolment into trials, based on clinical assessment with and without incorporation of FDG-PET data., Results: In part one, 68 physicians responded to the survey. Most physicians had used FDG-PET to diagnose TAK (82%) or monitor disease activity (66%). In vignettes representing active clinical disease, FDG-PET findings increased physician confidence in disease assessment and reduced outlier assessments. The greatest variability in decisions regarding enrolment into trials was observed in vignettes representing constitutional symptoms alone and elevated acute-phase reactants. In these cases, FDG-PET findings influenced decisions about enrolment and improved physician confidence. In multivariable models, FDG-PET findings were 1.29 times more strongly associated with enrolment decisions compared with levels of acute-phase reactants. In part two, incorporation of FDG-PET data significantly improved agreement about enrolment decisions between raters [inter-rater reliability (IRR) = 0.68 (95% CI 0.67, 0.69) to IRR = 0.88 (95% CI 0.87, 0.89); P < 0.01]., Conclusions: Incorporation of FDG-PET data into assessment of TAK influences decisions about enrolment of patients into trials, improves physician confidence about clinical assessment and could help reduce variability in study populations. Future trials in TAK should consider incorporating FDG-PET data into eligibility criteria., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2022. This work is written by US Government employees and is in the public domain in the US.)

Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but coexpression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis., (© 2022 by The American Society of Hematology.)

Discovery of the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome demonstrates that somatic mutations in haematological precursor cells can cause adult-onset, complex inflammatory disease. Unlike germline mutations, somatic mutations occur throughout the lifespan, are restricted to specific tissue types, and may play a causal role in non-heritable rheumatological diseases, especially conditions that start in later life. Improvements in sequencing technology have enabled researchers and clinicians to detect somatic mutations in various tissue types, especially blood. Understanding the relationships between cell-specific acquired mutations and inflammation is likely to yield key insights into causal factors that underlie many rheumatological diseases. The objective of this review is to detail how somatic mutations are likely to be relevant to clinicians who care for patients with rheumatological diseases, with particular focus on the pathogenetic mechanisms of the VEXAS syndrome., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2021. This work is written by a US Government employee and is in the public domain in the US.)

Objective: Relapsing polychondritis (RP) is a systemic inflammatory disorder of cartilage that lacks validated disease activity measures. Our objective was to test physician global assessment (PhGA), a measure of disease activity commonly used in rheumatic diseases, in a cohort of patients with RP, which has not been done before., Methods: Adult patients in an observational cohort of RP underwent standardized, comprehensive evaluation at approximately 6-month intervals. PhGA was scored by 3 physicians from the evaluating institution on a scale of 0-10 for each visit. A random subset of 20 visits was scored by 3 independent physicians not affiliated with the evaluating institution. Treatment change between consecutive visits was categorized as increased, decreased, or unchanged., Results: In total, 78 patients were evaluated over 164 visits. The intraclass correlation coefficient (ICC 2,1 ) for the 3 raters from the evaluating institution was excellent (0.79 [95% confidence interval (95% CI) 0.73, 0.84]) but was poor in the subset of cases scored by the additional raters (ICC 2,1 0.27 [95% CI -0.01, 0.53]). Median PhGA was 3 (range 0-7). PhGA weakly correlated with C-reactive protein level (r s = 0.30, P < 0.01). In response to increased treatment, median PhGA decreased from 3 (interquartile range [IQR] 2, 4) to 2 (IQR 2, 3) (P < 0.01) but rarely went to 0., Conclusion: Within a single center, PhGA can be used to quantify disease activity and monitor disease response in RP. Persistent disease activity despite treatment, rather than a relapsing-remitting pattern, is observed for most patients with RP. Reliability of PhGA may not generalize across different institutions. A validated disease-specific activity index is needed in RP., (© 2021 American College of Rheumatology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Objective: To assess markers of neutrophil activation such as calprotectin and N-formyl methionine (fMET) in anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) and large-vessel vasculitis (LVV)., Methods: Levels of fMET, and calprotectin, were measured in the plasma of healthy controls (n=30) and patients with AAV (granulomatosis with polyangiitis (GPA, n=123), microscopic polyangiitis (MPA, n=61)), and LVV (Takayasu's arteritis (TAK, n=58), giant cell arteritis (GCA, n=68)), at times of remission or flare. Disease activity was assessed by physician global assessment. In vitro neutrophil activation assays were performed in the presence or absence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporine H., Results: Levels of calprotectin, and fMET were elevated in patients with vasculitis as compared to healthy individuals. Levels of fMET correlated with markers of systemic inflammation: C-reactive protein (r=0.82, p<0.0001), and erythrocyte sedimentation rate (r=0.235, p<0.0001). The neutrophil activation marker, calprotectin was not associated with disease activity. Circulating levels of fMET were associated with neutrophil activation (p<0.01) and were able to induce de novo neutrophil activation via FPR1-mediated signaling., Conclusion: Circulating fMET appears to propagate neutrophil activation in AAV and LVV. Inhibition of fMET-mediated FPR1 signaling could be a novel therapeutic intervention for systemic vasculitides., (© 2022. The Author(s).)

Objective: In addition to aiding in diagnosis, histopathologic findings from temporal artery biopsy (TAB) specimens in giant cell arteritis (GCA) may be valuable for their associations with clinical features of the disease. This study was undertaken to compare histopathologic findings on TAB with biopsy interpretation and demographic, clinical, and imaging features at time of diagnosis., Methods: Patients with a clinical diagnosis of GCA who had a TAB were selected from an international, multicenter observational cohort of vasculitis. Associations between demographic, clinical, radiographic, and histopathologic features were identified using bivariate testing and multivariate regression modeling., Results: Of 705 patients with GCA who underwent TAB, 69% had histopathologic evidence of definite vasculitis. Specific histopathologic findings included the presence of giant cells (51%), fragmentation of the internal elastic lamina (41%), intimal thickening (33%), and predominantly mononuclear leukocyte infiltration (32%). Histopathologic interpretation of definite vasculitis was independently associated with giant cells (odds ratio [OR] 151.8 [95% confidence interval (95% CI) 60.2-551.6]), predominantly mononuclear leukocyte infiltration (OR 11.8 [95% CI 5.9-24.9]), and fragmentation of the internal elastic lamina (OR 3.7 [95% CI 1.9-7.4]). A halo sign on temporal artery ultrasound and luminal damage of large arteries on angiography were significantly associated with presence of giant cells (OR 2.6 [95% CI 1.1-6.5] and OR 2.4 [95% CI 1.1-5.2], respectively). Specific histopathologic findings were associated with older age, but no associations were identified with vision loss or other clinical features., Conclusion: Histopathologic findings in GCA are strongly associated with the clinical diagnosis of GCA but have a limited role in identifying patterns of disease., (© 2020 American College of Rheumatology.)

Objectives: Relapsing polychondritis (RP) is a rare, heterogeneous, systemic inflammatory disease that targets cartilage. Patient-reported outcome measures may differ from physician assessment. This study compared patient global assessment (PtGA) and physician global assessment (PhGA) scores in a prospective cohort of patients with RP., Methods: Adult patients with RP underwent a standardized comprehensive evaluation at ∼6 month intervals. At each visit, three physicians scored PhGA by consensus. The patient independently completed four patient-reported outcomes: PtGA, 36-item Short Form Health Survey (SF-36), Brief Illness Perception Questionnaire (BIPQ) and Multidimensional Fatigue Inventory (MFI). Patient-physician discordance was defined as a difference between PtGA and PhGA of ≥3 on a 0-10 scale., Results: A total of 76 patients were evaluated over 154 visits. The median PhGA was 3 [interquartile range (IQR) 2-3] and the median PtGA was 5 (IQR 4-7). PtGA and PhGA were concordant in 66 visits (42.9%) and patients scored disease severity ≥3 points higher than physicians scored disease activity (positive discordance) in 84 visits (54.5%). Compared with visits with concordance, visits with positive discordance were associated with significantly worse scores on the MFI, BIPQ, SF-36 physical component score and SF-36 mental component score., Conclusion: Patients with RP typically self-report high PtGA that does not align with PhGA. Discordance is likely driven by the high physical and psychological burden of illness experienced by patients. Multifaceted treatment approaches that address the burden of disease in RP from the patient perspective are needed., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2021. This work is written by a US Government employee and is in the public domain in the US.)

Objective: To identify patients with VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) from a single-center cohort of Italian patients with vasculitis, using a clinically oriented phenotype-first approach., Methods: We retrospectively reviewed the clinical records of 147 consecutive male patients followed up in our vasculitis clinic from 2013 to date. All patients with a diagnosis of vasculitis and treatment-resistant manifestations of inflammation, persistently elevated inflammation markers, and hematologic abnormalities were identified. Bone marrow aspirates were examined for the presence of vacuoles. Sequencing of ubiquitin-activating enzyme E1 (UBA-1) was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue., Results: Seven patients with vasculitis and concomitant features of VEXAS syndrome were identified. A final diagnosis of VEXAS syndrome was made in 3 of the 5 patients who underwent sequencing of UBA-1 (diagnosis was made postmortem for 1 patient). In all 3 patients, examination of the bone marrow aspirate revealed vacuoles characteristic of VEXAS syndrome, and all 3 patients met the definitive World Health Organization criteria for myelodysplastic syndrome. Cytogenetic analysis showed normal karyotypes in all 3 patients., Conclusion: To our knowledge, this is the first report of VEXAS syndrome associated with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Our data emphasize the need to consider VEXAS syndrome when evaluating patients with various forms of systemic vasculitis. The novel association between VEXAS syndrome and ANCA-associated vasculitis reported herein warrants further investigation., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To provide evidence-based recommendations and expert guidance for the management of Kawasaki disease (KD), focusing on clinical scenarios more commonly addressed by rheumatologists., Methods: Sixteen clinical questions regarding diagnostic testing, treatment, and management of KD were developed in the Patient/Population, Intervention, Comparison, and Outcomes (PICO) question format. Systematic literature reviews were conducted for each PICO question. We used the Grading of Recommendations, Assessment, Development and Evaluation method to assess the quality of evidence and formulate recommendations. Each recommendation required consensus from at least 70% of the Voting Panel., Results: We present 1 good practice statement, 11 recommendations, and 1 ungraded position statement to guide the management of KD and clinical scenarios of suspected KD. These recommendations for KD are focused on situations in which input from rheumatologists may be requested by other managing specialists, such as in cases of treatment-refractory, severe, or complicated KD. The good practice statement affirms that all patients with KD should receive initial treatment with intravenous immunoglobulin (IVIG). In addition, we developed 7 strong and 4 conditional recommendations for the management of KD or suspected KD. Strong recommendations include prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in the setting of unexplained macrophage activation syndrome or shock. Conditional recommendations include use of IVIG with other adjuvant agents for patients with KD and high-risk features of IVIG resistance and/or coronary artery aneurysms. These recommendations endorse minimizing risk to the patient by using established therapy promptly at disease onset and identifying situations in which adjunctive therapy may be warranted., Conclusion: These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and use of echocardiography in patients with suspected or confirmed KD., (© 2022 American College of Rheumatology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Objective: To provide evidence-based recommendations and expert guidance for the management of Kawasaki disease (KD), focusing on clinical scenarios more commonly addressed by rheumatologists., Methods: Sixteen clinical questions regarding diagnostic testing, treatment, and management of KD were developed in the Patient/Population, Intervention, Comparison, and Outcomes (PICO) question format. Systematic literature reviews were conducted for each PICO question. We used the Grading of Recommendations, Assessment, Development and Evaluation method to assess the quality of evidence and formulate recommendations. Each recommendation required consensus from at least 70% of the Voting Panel., Results: We present 1 good practice statement, 11 recommendations, and 1 ungraded position statement to guide the management of KD and clinical scenarios of suspected KD. These recommendations for KD are focused on situations in which input from rheumatologists may be requested by other managing specialists, such as in cases of treatment-refractory, severe, or complicated KD. The good practice statement affirms that all patients with KD should receive initial treatment with intravenous immunoglobulin (IVIG). In addition, we developed 7 strong and 4 conditional recommendations for the management of KD or suspected KD. Strong recommendations include prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in the setting of unexplained macrophage activation syndrome or shock. Conditional recommendations include use of IVIG with other adjuvant agents for patients with KD and high-risk features of IVIG resistance and/or coronary artery aneurysms. These recommendations endorse minimizing risk to the patient by using established therapy promptly at disease onset and identifying situations in which adjunctive therapy may be warranted., Conclusion: These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and use of echocardiography in patients with suspected or confirmed KD., (© 2022 American College of Rheumatology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Objective: To develop and validate classification criteria for microscopic polyangiitis (MPA)., Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 5 phases: 1) identification of candidate items using consensus methodology, 2) prospective collection of candidate items present at the time of diagnosis, 3) data-driven reduction of the number of candidate items, 4) expert panel review of cases to define the reference diagnosis, and 5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators., Results: The development set for MPA consisted of 149 cases of MPA and 408 comparators. The validation set consisted of an additional 142 cases of MPA and 414 comparators. From 91 candidate items, regression analysis identified 10 items for MPA, 6 of which were retained. The final criteria and their weights were as follows: perinuclear antineutrophil cytoplasmic antibody (ANCA) or anti-myeloperoxidase-ANCA positivity (+6), pauci-immune glomerulonephritis (+3), lung fibrosis or interstitial lung disease (+3), sino-nasal symptoms or signs (-3), cytoplasmic ANCA or anti-proteinase 3 ANCA positivity (-1), and eosinophil count ≥1 × 10 9 /liter (-4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having MPA with a cumulative score of ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 91% (95% confidence interval [95% CI] 85-95%) and the specificity was 94% (95% CI 92-96%)., Conclusion: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for MPA are now validated for use in clinical research., (© 2022 American College of Rheumatology.)

Objective: To develop and validate revised classification criteria for granulomatosis with polyangiitis (GPA)., Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 5 phases: 1) identification of candidate criteria items using consensus methodology, 2) prospective collection of candidate items present at the time of diagnosis, 3) data-driven reduction of the number of candidate items, 4) expert panel review of cases to define the reference diagnosis, and 5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators., Results: The development set for GPA consisted of 578 cases of GPA and 652 comparators. The validation set consisted of an additional 146 cases of GPA and 161 comparators. From 91 candidate items, regression analysis identified 26 items for GPA, 10 of which were retained. The final criteria and their weights were as follows: bloody nasal discharge, nasal crusting, or sino-nasal congestion (+3); cartilaginous involvement (+2); conductive or sensorineural hearing loss (+1); cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3 ANCA positivity (+5); pulmonary nodules, mass, or cavitation on chest imaging (+2); granuloma or giant cells on biopsy (+2); inflammation or consolidation of the nasal/paranasal sinuses on imaging (+1); pauci-immune glomerulonephritis (+1); perinuclear ANCA or antimyeloperoxidase ANCA positivity (-1); and eosinophil count ≥1 × 10 9 /liter (-4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having GPA if the cumulative score was ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 93% (95% confidence interval [95% CI] 87-96%) and the specificity was 94% (95% CI 89-97%)., Conclusion: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for GPA demonstrate strong performance characteristics and are validated for use in research., (© 2022 American College of Rheumatology.)

Objective: To develop and validate revised classification criteria for eosinophilic granulomatosis with polyangiitis (EGPA)., Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate criteria items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators., Results: The development set for EGPA consisted of 107 cases of EGPA and 450 comparators. The validation set consisted of an additional 119 cases of EGPA and 437 comparators. From 91 candidate items, regression analysis identified 11 items for EPGA, 7 of which were retained. The final criteria and their weights were as follows: maximum eosinophil count ≥1×10 9 /L (+5), obstructive airway disease (+3), nasal polyps (+3), cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3-ANCA positivity (-3), extravascular eosinophilic predominant inflammation (+2), mononeuritis multiplex/motor neuropathy not due to radiculopathy (+1) and haematuria (-1). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having EGPA if the cumulative score was ≥6 points. When these criteria were tested in the validation data set, the sensitivity was 85% (95% CI 77% to 91%) and the specificity was 99% (95% CI 98% to 100%)., Conclusion: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis demonstrate strong performance characteristics and are validated for use in research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop and validate revised classification criteria for eosinophilic granulomatosis with polyangiitis (EGPA)., Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 5 phases: 1) identification of candidate criteria items using consensus methodology, 2) prospective collection of candidate items present at the time of diagnosis, 3) data-driven reduction of the number of candidate items, 4) expert panel review of cases to define the reference diagnosis, and 5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators., Results: The development set for EGPA consisted of 107 cases of EGPA and 450 comparators. The validation set consisted of an additional 119 cases of EGPA and 437 comparators. From 91 candidate items, regression analysis identified 11 items for EPGA, 7 of which were retained. The final criteria and their weights were as follows: maximum eosinophil count ≥1 × 10 9 /liter (+5), obstructive airway disease (+3), nasal polyps (+3), cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3 ANCA positivity (-3), extravascular eosinophilic predominant inflammation (+2), mononeuritis multiplex/motor neuropathy not due to radiculopathy (+1), and hematuria (-1). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having EGPA if the cumulative score was ≥6 points. When these criteria were tested in the validation data set, the sensitivity was 85% (95% confidence interval [95% CI] 77-91%) and the specificity was 99% (95% CI 98-100%)., Conclusion: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for EGPA demonstrate strong performance characteristics and are validated for use in research., (© 2022 American College of Rheumatology.)

Objective: To develop and validate revised classification criteria for granulomatosis with polyangiitis (GPA)., Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate criteria items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators., Results: The development set for GPA consisted of 578 cases of GPA and 652 comparators. The validation set consisted of an additional 146 cases of GPA and 161 comparators. From 91 candidate items, regression analysis identified 26 items for GPA, 10 of which were retained. The final criteria and their weights were as follows: bloody nasal discharge, nasal crusting or sino-nasal congestion (+3); cartilaginous involvement (+2); conductive or sensorineural hearing loss (+1); cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3 ANCA positivity (+5); pulmonary nodules, mass or cavitation on chest imaging (+2); granuloma or giant cells on biopsy (+2); inflammation or consolidation of the nasal/paranasal sinuses on imaging (+1); pauci-immune glomerulonephritis (+1); perinuclear ANCA or antimyeloperoxidase ANCA positivity (-1); and eosinophil count ≥1×10 9  /L (-4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having GPA if the cumulative score was ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 93% (95% CI 87% to 96%) and the specificity was 94% (95% CI 89% to 97%)., Conclusion: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for GPA demonstrate strong performance characteristics and are validated for use in research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)