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Proteinase 3 (PR3) is the major antigen for anti-neutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3 anti-neutrophil cytoplasmic antibodies (PR3-ANCAs) recognize different epitopes on PR3. We aimed to study the effect of mutations on PR3 antigenicity.The recombinant PR3 variants, iPR3 (clinically used to detect PR3-ANCAs) and iHm5 (containing three point mutations in Epitope 15 generated for epitope mapping studies, immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) trials were used to screen the differential PR3-ANCA binding. A patient-derived monoclonal ANCA (moANCA518) that selectively binds to iHm5 within the mutation-free Epitope 3 and distant from the point mutations of iHm5 was used as a gauge of remote epitope activation. Selective binding was determined by inhibition experiments.Rather than reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared with iPR3. This differential binding of PR3-ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3-2 also induced recognition by moANCA518.The preferential binding of PR3-ANCAs from patients like the selective binding of moANCA518 to iHm5 is conferred by increased antigenicity of Epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR-2. This previously unrecognized characteristic of PR3-ANCA interactions with its target antigen has implications for studying antibody-mediated autoimmune diseases, understanding of variable performance characteristics of immunoassays and design of potential novel treatment approaches. This article is protected by copyright. All rights reserved.

Objectives To determine whether RA and interstitial lung disease (ILD) severity measures are associated with survival in patients with RA-ILD. Methods We studied US veterans with RA-ILD participating in a multicentre, prospective RA cohort study. RA disease activity (28-joint DAS [DAS28-ESR]) and functional status (multidimensional HAQ [MDHAQ]) were collected longitudinally while pulmonary function tests (forced vital capacity [FVC], diffusing capacity for carbon monoxide) were obtained from medical records. Vital status and cause of death were determined from the National Death Index and administrative data. Predictors of death were assessed using multivariable Cox regression models adjusting for age, sex, smoking status, ILD duration, comorbidity burden and medications. Results We followed 227 RA-ILD participants (93% male and mean age of 69 years) over 1073 person-years. Median survival after RA-ILD diagnosis was 8.5 years. Respiratory diseases (28%) were the leading cause of death, with ILD accounting for 58% of respiratory deaths. Time-varying DAS28-ESR (adjusted hazard ratio [aHR] 1.21; 95% CI: 1.03, 1.41) and MDHAQ (aHR 1.85; 95% CI: 1.29, 2.65) were separately associated with mortality independent of FVC and other confounders. Modelled together, the presence of either uncontrolled disease activity (moderate/high DAS28-ESR) or FVC impairment ( Conclusion Both RA and ILD disease severity measures are independent predictors of survival in RA-ILD. These findings demonstrate the prognostic value of monitoring the systemic features of RA-ILD.

XLSX file - 12K, Supplementary Table S3: Expression values for neutrophil-associated genes from the heatmap in Figure 5B.

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XLSX file - 29K, Supplementary Table S1: Expression values for myeloid cell signature genes from the heatmap in Figure 1E.

PDF file - 42K, Supplementary Figure S2: Additional figures on myeloid cell characterization based on tumor type and anatomical location.

XLSX file - 4K, Supplementary Table S4: Expression values for neutrophil cytokine-chemokine genes from the heatmap in Figure 6B.

XLSX file - 1K, Supplementary Table S6: Expression values for neutrophil granular effector molecules from the heatmap in Figure 7A.

PDF file - 136K, Supplementary Figure S1: Additional figures on myeloid cell characterization in different tumor models.

XLSX file - 2K, Supplementary Table S5: Expression values for PPARa-associated genes from the heatmap in Figure 6C.

Myeloid cells play important regulatory roles within the tumor environment by directly promoting tumor progression and modulating the function of tumor-infiltrating lymphocytes, and as such, they represent a potential therapeutic target for the treatment of cancer. Although distinct subsets of tumor-associated myeloid cells have been identified, a broader analysis of the complete myeloid cell landscape within individual tumors and also across different tumor types has been lacking. By establishing the developmental and transcriptomic signatures of infiltrating myeloid cells from multiple primary tumors, we found that tumor-associated macrophages (TAM) and tumor-associated neutrophils (TAN), while present within all tumors analyzed, exhibited strikingly different frequencies, gene expression profiles, and functions across cancer types. We also evaluated the impact of anatomic location and circulating factors on the myeloid cell composition of tumors. The makeup of the myeloid compartment was determined by the tumor microenvironment rather than the anatomic location of tumor development or tumor-derived circulating factors. Protumorigenic and hypoxia-associated genes were enriched in TAMs and TANs compared with splenic myeloid-derived suppressor cells. Although all TANs had an altered expression pattern of secretory effector molecules, in each tumor type they exhibited a unique cytokine, chemokine, and associated receptor expression profile. One such molecule, haptoglobin, was uniquely expressed by 4T1 TANs and identified as a possible diagnostic biomarker for tumors characterized by the accumulation of myeloid cells. Thus, we have identified considerable cancer-specific diversity in the lineage, gene expression, and function of tumor-infiltrating myeloid cells. Cancer Immunol Res; 2(7); 655–67. ©2014 AACR.

Importance: Since the early days of the pandemic, COVID-19 hospitalizations have been used as a measure of pandemic severity. However, case definitions do not include assessments of disease severity, which may be impacted by prior vaccination.Objective: To measure how the severity of respiratory disease changed among inpatients with documented SARS-CoV-2 infection and to measure the impact of vaccination status on these trends, in order to evaluate the accuracy of the metric of “hospitalization plus a positive SARS-CoV-2 test” for tracking pandemic severity.Design: Retrospective cohort of inpatients with laboratory-confirmed SARS-CoV-2. All data were obtained from electronic health records.Setting: Multi-center, nationwide study conducted in the healthcare system of the US Department of Veterans Affairs (VA) from March 1, 2020, through June 30, 2021.Participants: All VA patients admitted to a VA hospital with a laboratory-confirmed SARS-CoV-2 infection within the 14-days prior to admission or during the hospital admission.Main Outcome: Moderate-to-severe COVID-19 disease, defined by use of any supplemental oxygen or documented SpO2 Exposure: SARS-CoV-2 vaccination status at the time of hospitalization. Patients were regarded as fully vaccinated starting 14 days after receiving the second of a 2-dose regimen or 14 days after receipt of a single-dose vaccine.Results: Among 47,742 admissions in 38,508 unique patients with laboratory-confirmed SARS-CoV-2, N=28,731 met the criteria for moderate-to-severe COVID-19. The proportion with moderate-to-severe disease prior to widespread vaccine availability was 64.0% (95% CI, 63.1-64.9%) versus 52.0% in the later period (95% CI, 50.9-53.2%), p-value for non-constant effect, Conclusions and Relevance: The proportion of hospitalizations that are due to severe COVID-19 has changed with vaccine availability, thus, increasing proportions of mild and asymptomatic cases are included in hospitalization reporting metrics. The addition of simple measures of disease severity to the case definition of a SARS-CoV-2 hospitalization is a straightforward and objective change that should improve the value of the metric for tracking SARS-CoV-2 disease burden.

Background Previous studies evaluated the SARS-CoV-2 vaccine safety or compared adverse events following vaccination to those from infection. Limited data about the impact of prior infection on post-vaccine adverse events are available. The objective of this study was to evaluate the impact of prior SARS-CoV-2 infection on outcomes shortly after vaccination using a longitudinal design. Methods Nationwide, multicenter, retrospective cohort study of hospitalization, death, and pre-specified adverse event rates among Veterans who received mRNA vaccines within the Veterans Health Administration between 12/11/2020 and 8/31/2021. Daily incidence rates were compared before and after vaccine doses, stratified by history of microbiologically-confirmed SARS-CoV-2. Results 3,118,802 patients received a first dose and 2,979,326 a second, including 102,829 with a history of SARS-CoV-2 infection. Daily incident hospitalization rates were unchanged before and after the second dose among patients without previous infection (28.8/100,000 post-dose versus 28.6/100,000 pre-dose, p = 0.92). In previously-infected patients, the hospitalization rate increased above baseline one day following vaccination (158.2/100,000 after dose 2 versus 57.3/100,000 pre-dose, p

Background We previously reported a transient increased risk of hospitalization after mRNA vaccination among patients with prior SARS-CoV-2, absolute risk ~ 1:1000. Here, we extend and expand this analysis to evaluate the impact of prior infection on hospitalization after a third (booster) dose. Methods Nationwide, retrospective cohort study of hospitalization among US Veterans who received a third dose of mRNA vaccine between 7/1/2021-2/28/2022. Daily rates of incident hospitalization were compared before and after booster doses, stratified by history of SARS-CoV-2. Results 1,632,806 patients received a third dose, including 90,174 with a history of SARS-CoV-2 infection. Hospitalization rates were unchanged before and after the booster dose among patients with (112.3/100,000 post-dose versus 100.2/100,000 pre-dose, p = 0.24) or without previous infection (32.1/100,000 post-dose versus 31.3/100,000 pre-dose, p = 0.71). Among 241 patients hospitalized after receipt of the initial vaccination, 90 received a booster, and none of these 90 patients were hospitalized. Conclusions There was not convincing evidence for increased hospitalizations shortly after booster vaccines, including in patients with a history of SARS-CoV-2 infection who required hospitalization after their initial vaccine. The size and design of the study prevent strong conclusions about absence of risk.

Background. Death within 30 days of a positive test for SARS-CoV-2 infection is used by some agencies in definitions of death from COVID-19. With omicron variants predominating in 2022, widespread immunity, and routine screening of asymptomatic patients in some healthcare systems, there is cause to systematically evaluate the proportion of deaths within 30 days of a positive test are COVID-19-related. Methods. Nationwide records in the Veterans Health Administration were used to identify all patients who died within 30 days after positive tests for SARS-CoV-2. Randomly-selected records of previously-vaccinated patients with positive tests in January-February, 2022, or June-August, 2022, underwent review for classification of death as caused by or contributed to by COVID-19, focused on death within 30 days. Multivariable logistic regression was used to determine demographic and clinical variables associated with classification of death as COVID-related, which included cause or contribution. Results. Among vaccinated patients who died within 30 days of a positive test in January-February, 2022 (omicron BA.1 predominance), death was COVID-related in 103/150 cases (69%), as the cause in 55% and contributor in 14%. In June-August, 2022 (BA.5 predominance), death was COVID-related in 70/150 cases (47%), as the cause in 22% and contributor in 25%. Variables positively associated with COVID-related death included medications for COVID-19, hypoxemia, immune-suppressive drugs, and age, whereas advanced cancer, time since positive test, and June-August time period had negative associations. Conclusions. As of mid-2022, “death within 30 days” alone no longer provided an accurate estimate of deaths from COVID-19 in a US healthcare system with routine asymptomatic screening. Over time, the proportion of cases where SARS-CoV-2 was a contributor, rather than the primary cause of death, has increased.

Objective To study the prevalence, risk and clinical associations of hypothyroidism among several forms of vasculitis. Methods Patients with GCA, Takayasu’s arteritis (TAK), PAN and the three forms of ANCA-associated vasculitis [AAV; granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA)] enrolled in a prospective, multicentre, longitudinal study were included. Results The study included data on 2085 patients [63% female, 90% White] with a mean age of 54.6 years (s.d. 17.2). Diagnoses were GCA (20%), TAK (11%), PAN (5%), GPA (42%), microscopic polyangiitis (8%) and EGPA (14%). Hypothyroidism was present in 217 patients (10%) (83% female), with a mean age 59.8 years (s.d. 14.5). Age- and sex-adjusted risk of hypothyroidism was GCA, odds ratio (OR) 0.61 (95% CI 0.41, 0.90); TAK, OR 0.57 (95% CI 0.31, 1.03); PAN, OR 0.59 (95% CI 0.25, 1.38); GPA, OR 1.51 (95% CI 1.12, 2.05); microscopic polyangiitis, OR 1.81 (95% CI 1.18, 2.80) and EGPA, OR 0.82 (95% CI 0.52, 1.30). Among patients with AAV, age- and sex-adjusted risk of hypothyroidism was higher with positive MPO-ANCA [OR 1.89 (95% CI 1.39, 2.76)]. The clinical manifestations of vasculitis were similar in patients with and without hypothyroidism, except transient ischaemic attacks, which were more frequently observed in patients with GCA and hypothyroidism (12% vs 2%; P = 0.001). Conclusions Differences in the risk of hypothyroidism among vasculitides may be due to genetic susceptibilities or immune responses. This study confirms an association of hypothyroidism with MPO-ANCA.

ImportanceWith a large proportion of the US adult population vaccinated against SARS-CoV-2, it is important to identify who remains at risk of severe infection despite vaccination.ObjectiveTo characterize risk factors for severe COVID-19 disease in a vaccinated population.Design, Setting, and ParticipantsThis nationwide, retrospective cohort study included US veterans who received a SARS-CoV-2 vaccination series and later developed laboratory-confirmed SARS-CoV-2 infection and were treated at US Department of Veterans Affairs (VA) hospitals. Data were collected from December 15, 2020, through February 28, 2022.ExposuresDemographic characteristics, comorbidities, immunocompromised status, and vaccination-related variables.Main Outcomes and MeasuresDevelopment of severe vs nonsevere SARS-CoV-2 infection. Severe disease was defined as hospitalization within 14 days of a positive SARS-CoV-2 diagnostic test and either blood oxygen level of less than 94%, receipt of supplemental oxygen or dexamethasone, mechanical ventilation, or death within 28 days. Association between severe disease and exposures was estimated using logistic regression models.ResultsAmong 110 760 patients with infections following vaccination (97 614 [88.1%] men, mean [SD] age at vaccination, 60.8 [15.3] years; 26 953 [24.3%] Black, 11 259 [10.2%] Hispanic, and 71 665 [64.7%] White), 10 612 (9.6%) had severe COVID-19. The strongest association with risk of severe disease after vaccination was age, which increased among patients aged 50 years or older with an adjusted odds ratio (aOR) of 1.42 (CI, 1.40-1.44) per 5-year increase in age, such that patients aged 80 years or older had an aOR of 16.58 (CI, 13.49-20.37) relative to patients aged 45 to 50 years. Immunocompromising conditions, including receipt of different classes of immunosuppressive medications (eg, leukocyte inhibitor: aOR, 2.80; 95% CI, 2.39-3.28) or cytotoxic chemotherapy (aOR, 2.71; CI, 2.27-3.24) prior to breakthrough infection, or leukemias or lymphomas (aOR, 1.87; CI, 1.61-2.17) and chronic conditions associated with end-organ disease, such as heart failure (aOR, 1.74; CI, 1.61-1.88), dementia (aOR, 2.01; CI, 1.83-2.20), and chronic kidney disease (aOR, 1.59; CI, 1.49-1.69), were also associated with increased risk. Receipt of an additional (ie, booster) dose of vaccine was associated with reduced odds of severe disease (aOR, 0.50; CI, 0.44-0.57).Conclusions and RelevanceIn this nationwide, retrospective cohort of predominantly male US Veterans, we identified risk factors associated with severe disease despite vaccination. Findings could be used to inform outreach efforts for booster vaccinations and to inform clinical decision-making about patients most likely to benefit from preexposure prophylaxis and antiviral therapy.

Objectives ANCA-associated vasculitis (AAV) is a group of multisystem diseases that can have several ocular manifestations. There are published data on ocular manifestations of granulomatosis with polyangiitis (GPA), but few for eosinophilic granulomatosis with polyangiitis (EGPA) or microscopic polyangiitis (MPA). There is little information concerning chronicity, complications, and association with other cranial manifestations of AAV. Methods This study retrospectively analysed longitudinal multicentre cohorts of individuals with AAV followed between 2006 and 2022. Data included diagnosis, demographics, cranial manifestations of disease, presence of manifestations at onset of disease and/or follow-up, and ocular complications of disease. Univariate and multivariable logistic regression analysis assessed associations across disease manifestations. Results Data from 1441 patients were analysed, including 395 with EGPA, 876 with GPA, and 170 with MPA. Ocular manifestations were seen within 23.1% of patients: 39 (9.9%) with EGPA, 287 (32.7%) with GPA, and 12 (7.1%) with MPA at any time in the disease course. There were more ocular manifestations at onset (n = 224) than during follow-up (n = 120). The most common disease-related manifestations were conjunctivitis/episcleritis and scleritis. In multivariable analysis, dacryocystitis, lacrimal duct obstruction, and retro-orbital disease were associated with sinonasal manifestations of GPA; ocular manifestations were associated with hearing loss in MPA. The most common ocular complications and/or damage seen were cataracts (n = 168) and visual impairment (n = 195). Conclusion Ocular manifestations occur in all forms of AAV, especially in GPA. Clinicians should be mindful of the wide spectrum of ocular disease in AAV, caused by active vasculitis, disease-associated damage, and toxicities of therapy.

Background: The global COVID-19 pandemic is an opportunity to evaluate factors associated with high levels of adoption of different therapeutics in a real-world setting. The aim of this nationwide, retrospective cohort study was to evaluate the diffusion and adoption of novel therapeutics with an emerging evidence basis and to identify factors that influenced physicians’ treatment decisions. Methods: Cohort Creation: A cohort of Veteran patients with a microbiologically-confirmed diagnosis of SARS-CoV2 was identified and cases were classified by disease severity (outpatient, inpatient with mild and severe disease, ICU). After classification of disease severity, proportion of cases (outpatients) and admissions (inpatients) in each category receiving each type of medication were plotted as a function of time. Identification of Milestones and Guidance Changes: Key medications used for the management of COVID-19 milestones in the release of primary research results in various forms (e.g., via press release, pre-print, or publication in a traditional medical journal), policy events, and dates of key guidelines, were identified plotted as a timeline. After a timeline was created, timepoints were compared to changes in medication use, and factors potentially impacting the magnitude (i.e., proportion of patients who received the treatment) and the speed (i.e., the slope of the change in use) of practice changes were evaluated. Results: Dexamethasone and remdesivir, the first two medications with clinical trials data to support their use underwent the most rapid, complete, and sustained diffusion and adoption; the majority of practice changes occurred after press releases and pre-prints were available and prior to guideline changes, although some additional uptake occurred following guideline updates. Medications that were not “first in class,” were identified later in the pandemic, and that had higher perceived risk had slower and less complete uptake regardless of the strength and quality of the evidence supporting the intervention. Conclusions: Our findings suggest that traditional and social media platforms and pre-print releases were major catalysts of practice change, particularly prior to the identification of effective treatments. The “first available treatment in class” impact appeared to be the single most important factor determining the speed and spread of diffusion. Clinical Trial Registration: Not applicable

Autoreactive B cells are responsible for ANCA production in ANCA-associated vasculitis (AAV). Rituximab depletes circulating B cells including autoreactive ones. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV.Sequential flow-cytometry was performed on 148 samples of peripheral blood mononuclear cells from 23 proteinase-3 (PR3)-ANCAAt B cell recurrence, PR3The composition of autoreactive B cell pool varies significantly following rituximab treatment in AAV, and early plasmablast enrichment within the autoreactive pool is associated with future relapses.

Objective To describe clinical manifestations and outcomes in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in North America. Methods Analysis of patients aged 18 years or older who fulfilled the 1990 American College of Rheumatology Classification Criteria for EGPA enrolled in the Vasculitis Clinical Research Consortium from 2003 to 2019. Main clinical characteristics, treatments, outcomes, and accumulated damage were studied. Results The cohort included 354 patients; 59% female; age at diagnosis of 50.0 (±14) years; 39% were antineutrophil cytoplasm antibody (ANCA) positive. Time from diagnosis to last follow-up was 7.0 (±6.2) years; 49.4% had one or more relapse. Patients positive for ANCA more commonly had neurological and kidney involvement when compared with patients negative for ANCA, who had more cardiac and lung manifestations. At last study visit, only 35 (12.6%) patients had been off all therapy for more than 2 years during their follow-up. The overall mortality rate was 4.0% and did not differ by ANCA status or cyclophosphamide use. Scores on the Vasculitis Damage Index (VDI) for 134 patients with two or more visits and more than 1 year of follow-up increased from 1.7 (±1.8) at enrollment (3.7 [±5.1] years after diagnosis) to 3.35 (±2.1) at last follow-up (7.5 [±5.8] years after diagnosis), mainly represented by chronic asthma (67.5%), peripheral neuropathy (49.6%), and chronic sinusitis (31.3%). Longer duration of glucocorticoid use and relapse were associated with higher VDI scores. Conclusion This analysis describes the many clinical manifestations and varied outcomes of EGPA and highlights the ongoing need to attain more sustained, long-term remission to limit the accrual of disease-related damage.

OBJECTIVE. Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of vasculitis that can resemble polyarteritis nodosa (PAN). This study was undertaken to identify potential disease-causing sequence variants in ADA2 in patients with idiopathic PAN, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA). METHODS. Patients with idiopathic PAN (n = 118) and patients with GPA or MPA (n = 1,107) were screened for rare nonsynonymous variants in ADA2 using DNA sequencing methods. ADA-2 enzyme activity was assessed in selected serum samples. RESULTS. Nine of 118 patients with PAN (7.6%) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4%) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2%) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA-2 enzyme activity. ADA-2 enzyme testing of 86 additional patients revealed 1 individual with strongly reduced ADA-2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant in ADA2, with no other clinical differences noted. None of the patients with GPA or MPA carried biallelic variants in ADA2. CONCLUSION. A subset of patients with idiopathic PAN meet genetic criteria for DADA2. Given that tumor necrosis factor inhibition is efficacious in DADA2 but is not conventional therapy for PAN, these findings suggest that ADA-2 testing should strongly be considered in patients with hepatitis B virus–negative idiopathic PAN.

Objective The objective of this study was to validate claims-based algorithms for identifying acute giant cell arteritis (GCA) that will help generate real-world evidence on comparative effectiveness research and epidemiologic studies. Among patients identified by the GCA algorithm, we further investigated whether GCA flares could be detected by using claims data. Methods We developed five claims-based algorithms based on a combination of International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes, specialist visits, and dispensed medications using Medicare Parts A, B, and D linked to electronic medical records (2006-2014). Acute cases of GCA were determined by chart review using the treating physician's diagnosis of GCA as the gold standard. Among the patients identified with acute GCA, we assessed if a GCA flare occurred during the year after initial diagnosis. Results The number of patients identified by each algorithm ranged from 220 to 896. Positive predictive values (PPVs) of the algorithms ranged from 60.7% to 84.8%. Requirement for disease-specific workups, multiple diagnosis codes, or specialist visits improved the PPVs. The highest PPV (84.8%) was noted in an algorithm that required two or more diagnosis codes of GCA from inpatient, emergency department, or outpatient rheumatology visits plus a prednisone-equivalent dose greater than or equal to 40 mg/day occurring 14 days before or after the second ICD-9 diagnosis date, with the cumulative days' supply greater than or equal to 14 days. Among patients identified as having GCA, 18.2% of patients had definite evidence of a flare and 25% had a potential flare. Conclusion A claims-based algorithm requiring two or more ICD-9 diagnosis codes from inpatient, emergency department, or outpatient rheumatology visits and high-dose glucocorticoid dispensing can be a useful tool to identify acute GCA cases in large administrative claims databases.

Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 x 10(-s)) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets., National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [R01 AR070148]; National Institute of Arthritis and Musculoskeletal and Skin DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [U54 AR057319, U01 AR51874 04]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [U54 RR019497]; Office of Rare Diseases Research of the National Center for Advancing Translational Sciences; Imperial College, National Institute for Health Research, Biomedical Research Centre; Wellcome TrustWellcome TrustEuropean Commission [WT107881]; Medical Research CouncilUK Research & Innovation (UKRI)Medical Research Council UK (MRC)European Commission [MC_UU_00002/4], This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health grant R01 AR070148 to A.H.S. The Vasculitis Clinical Research Consortium has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54 AR057319 and U01 AR51874 04), the National Center for Research Resources (U54 RR019497), and the Office of Rare Diseases Research of the National Center for Advancing Translational Sciences. J.C.M., A.P.K., and R.M.M. acknowledge support from the Imperial College, National Institute for Health Research, Biomedical Research Centre. C.W. and G.R. acknowledge support from The Wellcome Trust (WT107881) and the Medical Research Council (MC_UU_00002/4). This work was supported by the use of study data downloaded from the dbGaP website, under dbGaP: phs000272.v1.p1, phs000431.v2.p1, phs000583.v1.p1, and phs000444.v1.p1.

(1) describe imaging features of CIA, (2) compare dilation rate and wall thickening of aortic aneurysms in patients with CIA versus those with giant cell arteritis/aortitis (GCA), (3) present clinical outcomes of CIA patients. Retrospective search of electronic records from 2004 to 2018 yielded 71 patients, 52 of whom were female, with a mean age of 67.5 ± 9.0 years old, with a new clinical diagnosis of cranial or extracranial GCA (GCA group), and giant cell aortitis revealed by the aortic biopsy (CIA group). Comparisons between groups were conducted using the Wilcoxon rank-sum and Fisher’s exact tests. Survival from the date of initial diagnosis to the end of data collection was compared between the two groups through a log-rank test. CIA patients (n = 23; 32%) presented with cardiovascular symptoms, and none had systemic inflammatory symptoms. Inflammatory markers were significantly higher among GCA patients than among CIA patients (p < 0.0001). The CIA group demonstrated thoracic aortic aneurysms without wall thickening. None of the GCA patients (n = 48; 68%) had aneurysmal dilation in the aorta at the time of diagnosis. None of the four CIA patients had FDG uptake in the aorta, while nine out of 13 GCA patients had FDG uptake in the vessels. There was no statistically significant difference in the survival between the two groups (p = 0.12). CIA patients presented with cardiovascular symptoms and was characterized by aneurysm of the aorta without the involvement of the infrarenal aortic segment. The role of FDG-PET/CT in CIA is less certain, though none of the patients in this cohort had FDG uptake in the vessels.

Takayasu's arteritis (TAK) is a clinically heterogenous disease. Patterns of clinical presentation in TAK at diagnosis have not been well described, and a "triphasic pattern" of constitutional symptoms evolving into vascular inflammation and fibrosis has been reported but never systematically evaluated.Patients with TAK were prospectively recruited from the National Institutes of Health (NIH) and the Vasculitis Clinical Research Consortium (VCRC). Based on clinical presentation at diagnosis, patients were divided into five categories: (1) constitutional symptoms alone, (2) carotidynia, (3) other vascular-associated symptoms, (4) major ischemic event, or (5) asymptomatic. Associated clinical characteristics were evaluated in each category. Preceding symptoms were also assessed to determine the presence of a triphasic disease pattern.A total of 275 patients with TAK were included (VCRC=208; NIH=67). Similar heterogeneity of clinical presentation was identified in each cohort: constitutional symptoms (8%), carotidynia (13-15%), other vascular symptoms (43-47%), major ischemic event (28-30%), and asymptomatic (2-6%). An increased relative proportion of males was seen in patients who presented with constitutional symptoms or were asymptomatic at diagnosis (p0.01). Patients who presented with constitutional symptoms and major ischemic events were youngest at diagnosis. Patients in the asymptomatic group were oldest at diagnosis and often were not treated (p0.01). Relapse was most frequent in patients who presented with carotidynia (p0.01). A minority of patients (19%) who presented with a major ischemic event reported a triphasic pattern of disease.There are diverse clinical presentations at diagnosis in TAK. Patients do not necessarily progress sequentially through phases of disease.

Importance: With a large proportion of the US adult population vaccinated against SARS-CoV-2, it is important to identify who remains at risk of severe disease in the event of infection.Objective: To characterize risk factors for severe COVID-19 disease in a vaccinated population.Design: Nationwide, retrospective cohort study.Setting: US Department of Veterans Affairs Hospitals.Participants: US Veteran patients who received a COVID-19 vaccination series and later developed a laboratory-confirmed SARS-CoV-2 infection.Exposures: Demographics, comorbidities, immunocompromised states, and vaccination-related variables.Main Outcome and Measures: Development of severe versus non-severe COVID-19 disease. Severe disease was defined as hospitalization within 14 days of a positive SARS-CoV-2 diagnostic test and either SpO2 < 94%, receipt of supplemental oxygen or dexamethasone, mechanical ventilation, or death within 28 days.Results: Among 110,760 patients with breakthrough infections, 10,612 (9.6%) had severe COVID-19 or died within 28 days of the COVID-19 diagnosis. The strongest risk factor for severe disease despite vaccination was age, which increased with every 5-year increase in age > 50 (approximate adjusted odds ratio (aOR), 1.5). Risk among patients ≥ 80 years old was particularly high (aOR 16.1, CI 13.1 – 19.9, relative to patients 45-50 years old. Immunocompromising conditions, including receipt of different classes of immunosuppressive medications (aORs 1.73 – 2.44, CIs 1.37 – 2.99) or cytotoxic chemotherapy (aOR 2.69, CI 2.25 – 3.21) prior to breakthrough infection, or leukemias/lymphomas (aOR 1.84, CI 1.59 – 2.14) and chronic conditions associated with end-organ disease, such as heart failure, dementia, and chronic kidney disease, were also associated with increased risk. Receipt of an additional (booster) dose of vaccine was associated with reduced odds of severe disease.Conclusions and Relevance: In this nationwide, retrospective cohort of US Veterans, we identified risk factors for severe disease despite vaccination. Findings could be used to inform outreach efforts for booster vaccinations and to inform clinical decision making about identifying patients who might benefit from pre-exposure prophylaxis and antiviral therapy.

BACKGROUND Little is known about the autoreactive B cells in antineutrophil cytoplasmic antibody–associated (ANCA-associated) vasculitis (AAV). We aimed to investigate tolerance checkpoints of circulating antigen-specific proteinase 3–reactive (PR3+) B cells. METHODS Multicolor flow cytometry in combination with bioinformatics and functional in vitro studies were performed on baseline samples of PBMCs from 154 well-characterized participants of the RAVE trial (NCT00104299) with severely active PR3-AAV and myeloperoxidase-AAV (MPO-AAV) and 27 healthy controls (HCs). Clinical data and outcomes from the trial were correlated with PR3+ B cells (total and subsets). RESULTS The frequency of PR3+ B cells among circulating B cells was higher in participants with PR3-AAV (4.77% median [IQR, 3.98%–6.01%]) than in participants with MPO-AAV (3.16% median [IQR, 2.51%–5.22%]) and participants with AAV compared with HCs (1.67% median [IQR, 1.27%–2.16%], P < 0.001 for all comparisons), implying a defective central tolerance checkpoint in patients with AAV. Only PBMCs from participants with PR3-AAV contained PR3+ B cells capable of secreting PR3-ANCA IgG in vitro, proving they were functionally distinct from those of participants with MPO-AAV and HCs. Unsupervised clustering identified subtle subsets of atypical autoreactive PR3+ memory B cells accumulating through the maturation process in patients with PR3-AAV. PR3+ B cells were enriched in the memory B cell compartment of participants with PR3-AAV and were associated with higher serum CXCL13 levels, suggesting an increased germinal center activity. PR3+ B cells correlated with systemic inflammation (C-reactive protein and erythrocyte sedimentation rate, P < 0.05) and complete remission (P < 0.001). CONCLUSION This study suggests the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with PR3-AAV, elucidating the selection process of autoreactive B cells. Trial registration ClinicalTrials.gov NCT00104299. Funding The Vasculitis Foundation, the National Institute of Allergy and Infectious Diseases of the NIH, and the Mayo Foundation for Education and Research.

BackgroundProgress in therapeutic research is slowed by the regulatory burden of clinical trials, which provide the best evidence for guiding treatment. There is a long delay from evidence generation to adoption, highlighting the need for designs that link evidence generation to implementation.ObjectiveTo identify clinical trial designs that confer minimal risk above that inherent in clinical care, to obviate the need for cumbersome consenting processes to enrol patients in prospective clinical research studies. These designs extend the scope of the Learning Healthcare System, a framework for leveraging retrospective ‘big data’ to advance clinical research, to include data collected from prospective controlled trials.SummaryPragmatic trials may use simplified eligibility criteria, unblinded interventions and objective outcome measures that can all be monitored through the electronic health records (EHR), to reduce costs and speed study conduct. Most pragmatic trials continue to suffer from substantial regulatory burden. Written consent to participate in research can be waived only if the research produces minimal risk above what is encountered in everyday life. However, the ‘consent’ processes for prescribing Federal Drug Administration-approved medications in clinical medicine are informal, even when they involve decisions of uncertain benefit and higher levels of risk. We propose that trial designs that mimic clinical decision-making in areas of uncertainty (clinical equipoise) and in which no data are generated outside of usual care (ideally by EHR embedding) confer minimal additional risk. Trial designs meeting this standard could, therefore, be conducted with minimal documentation of consent, even when interventions contain different risks. To align with risk encountered in clinical practice, allocation to treatment arms should change (adaptive randomisation) as data are collected and analysed. Embedding of informatics tools into the EHR has the additional benefit that, as adaptive randomisation progresses, evidence-generation transitions into implementation via decision-support tools—the ultimate realisation of the Learning Healthcare System.

Objective Improved biomarkers of current disease activity and prediction of relapse are needed in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). For clinical relevance, biomarkers must perform well longitudinally in patients on treatment and in patients with nonsevere flares. Methods Twenty-two proteins were measured in 347 serum samples from 74 patients with AAV enrolled in a clinical trial. Samples were collected at Month 6 after remission induction, then every 3 months until Month 18, or at the time of flare. Associations of protein concentrations with concurrent disease activity and with future flare were analyzed using mixed-effects models, Cox proportional hazards models, and conditional logistic regression. Results Forty-two patients had flares during the 12-month follow-up period, and 32 remained in remission. Twenty-two patients had severe flares. Six experimental markers (CXCL13, IL-6, IL-8, IL-15, IL-18BP, and matrix metalloproteinase-3 [MMP-3]) and ESR were associated with disease activity using all three methods (P < 0.05, with P < 0.01 in at least one method). A rise in IL-8, IL-15, or IL-18BP was associated temporally with flare. Combining C-reactive protein (CRP), IL-18BP, neutrophil gelatinase-associated lipocalin (NGAL), and sIL-2R alpha improved association with active AAV. CXCL13 and MMP-3 were increased during treatment with prednisone, independent of disease activity. Marker concentrations during remission were not predictive of future flare. Conclusion Serum biomarkers of inflammation and tissue damage and repair have been previously shown to be strongly associated with severe active AAV were less strongly associated with active AAV in a longitudinal study that included mild flares and varying treatment. Markers rising contemporaneously with flare or with an improved association in combination merit further study.

Summary In recent decades, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis has transformed from an almost uniformly fatal disease to a treatable form of primary systemic vasculitis. Substantial disease heterogeneity exists within ANCA-associated vasculitis and the increasing understanding of this heterogeneity has implications for guiding treatment decisions. Approaches to induction and maintenance therapy vary depending on disease severity, clinical manifestations, and patient-specific factors. In this narrative Review, we examine how disease heterogeneity in ANCA-associated vasculitis, with respect to disease severity, clinical presentations, and ANCA specificity, influences therapeutic decision making. Many questions regarding therapeutic strategies in ANCA-associated vasculitis remain unanswered, and these should guide future research in this complex group of diseases.