Hoffman, Gary S.

ObjectiveImproved 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.MethodsTwenty‐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.ResultsForty‐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‐2Rα 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.ConclusionSerum 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.

Objective To identify and validate, using computer‐driven methods, patterns of arterial disease in Takayasu arteritis (TAK) and giant cell arteritis (GCA). Methods Patients with TAK or GCA were studied from the Diagnostic and Classification Criteria for Vasculitis (DCVAS) cohort and a combined North American cohort. Case inclusion required evidence of large‐vessel involvement, defined as stenosis, occlusion, or aneurysm by angiography/ultrasonography, or increased 18 F‐fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET) in at least 1 of 11 specified arterial territories. K‐means cluster analysis identified groups of patients based on the pattern of arterial involvement. Cluster groups were identified in the DCVAS cohort and independently validated in the North American cohort. Results A total of 1,068 patients were included (DCVAS cohort: TAK = 461, GCA = 217; North American cohort: TAK = 225, GCA = 165). Six distinct clusters of patients were identified in DCVAS and validated in the North American cohort. Patients with TAK were more likely to have disease in the abdominal vasculature, bilateral disease of the subclavian and carotid arteries, or focal disease limited to the left subclavian artery than GCA ( P < 0.01). Patients with GCA were more likely to have diffuse disease, involvement of bilateral axillary/subclavian arteries, or minimal disease without a definable pattern than TAK ( P < 0.01). Patients with TAK were more likely to have damage by angiography, and patients with GCA were more likely to have arterial FDG uptake by PET without associated vascular damage. Conclusion Arterial patterns of disease highlight both shared and divergent vascular patterns between TAK and GCA and should be incorporated into classification criteria for large‐vessel vasculitis.

Abstract Objectives To develop and replicate, using data-driven methods, a novel classification system in Takayasu’s arteritis based on distribution of arterial lesions. Methods Patients were included from four international cohorts at major academic centres: India (Christian Medical College Vellore); North America (National Institutes of Health, Vasculitis Clinical Research Consortium and Cleveland Clinic Foundation). All patients underwent whole-body angiography of the aorta and branch vessels, with categorization of arterial damage (stenosis, occlusion or aneurysm) in 13 territories. K-means cluster analysis was performed to identify subgroups of patients based on pattern of angiographic involvement. Cluster groups were identified in the Indian cohort and independently replicated in the North American cohorts. Results A total of 806 patients with Takayasu’s arteritis from India (n = 581) and North America (n = 225) were included. Three distinct clusters defined by arterial damage were identified in the Indian cohort and replicated in each of the North American cohorts. Patients in cluster one had significantly more disease in the abdominal aorta, renal and mesenteric arteries (P &lt; 0.01). Patients in cluster two had significantly more bilateral disease in the carotid and subclavian arteries (P &lt; 0.01). Compared with clusters one and two, patients in cluster three had asymmetric disease with fewer involved territories (P &lt; 0.01). Demographics, clinical symptoms and clinical outcomes differed by cluster. Conclusion This large study in Takayasu’s arteritis identified and replicated three novel subsets of patients based on patterns of arterial damage. Angiographic-based disease classification requires validation by demonstrating potential aetiological or prognostic implications.

ObjectiveTo assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)–Associated Vasculitis (RAVE) trial and identify novel potential risk factors.MethodsVTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA‐associated vasculitis (AAV).ResultsVTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0–2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247–134.842]; P = 0.006), positive proteinase 3 (PR3)–ANCA (HR 7.731 [95% CI 1.021–58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448–10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491–69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566–185.805]; P = 0.005), PR3‐ANCA (HR 9.12 [95% CI 1.158–71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453–10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607–75.075]; P < 0.001) remained.ConclusionPatients diagnosed as having AAV with pulmonary hemorrhage, positive PR3‐ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.

ObjectiveTo examine the association between macrophage migration inhibitory factor (MIF) promoter polymorphisms and granulomatosis with polyangiitis (GPA) in human subjects, and to assess the role of MIF in a murine model of granulomatous vasculitis.MethodsThe human study involved 1,077 patients with GPA and healthy controls whose serum was genotyped by capillary electrophoresis for the MIF −794 CATT5−8 promoter microsatellite (rs5844572). MIF promoter, CATT‐length–dependent gene expression in response to β‐glucan was assessed by gene reporter assays. In mouse studies, granulomatous disease was induced by injection of Candida albicans β‐glucan into wild‐type (WT) or Mif‐knockout (Mif‐KO) C57BL/6 mice and C57BL/6 mice transgenically overexpressing Mif in lung epithelium (Mif lung–Tg2.1). Mice were treated with a neutralizing anti‐MIF antibody and analyzed for the density of pulmonary granulomas, expression of inflammatory chemokines, and frequency of mortality.ResultsThe percentage of human subjects carrying >5 CATT repeats in each MIF allele (high genotypic MIF expressers) was 60.2% among patients with GPA and 53.9% among healthy controls (adjusted P = 0.049). In response to granulomatous stimulation, human MIF gene expression increased proportionally with CATT length. Mif lung–Tg2.1 mice exhibited more pulmonary granulomas than WT mice, which in turn showed more granulomas than Mif‐KO mice. A significantly higher percentage of Mif lung–Tg2.1 mice, compared to Mif‐KO or WT mice, died when injected with Candida albicans β‐glucan, and treatment of these mice with an anti‐MIF monoclonal antibody protected against a lethal outcome. Levels of MIF‐dependent neutrophil/macrophage chemokines were elevated in the bronchoalveolar lavage fluid or plasma of Mif lung–Tg2.1 mice.ConclusionPatients with GPA have an increased frequency of high MIF expression CATT alleles. Higher Mif expression increases the incidence of mortality and pulmonary granulomas in Mif lung–Tg2.1 mice, while anti‐MIF treatment protects these mice against death. Blockade of MIF in high genotypic MIF expressers may therefore offer a selective pharmacologic therapy for GPA.

ObjectiveTo evaluate circulating cytokine profiles in patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV), classified by antineutrophil cytoplasmic antibody (ANCA) specificity (proteinase 3 ANCA [PR3‐ANCA] versus myeloperoxidase ANCA [MPO‐ANCA]) or by clinical diagnosis (granulomatosis with polyangiitis [GPA] versus microscopic polyangiitis [MPA]).MethodsA panel of 29 cytokines was tested in 186 patients with active AAV at inclusion into the Rituximab in AAV trial. Cytokine concentrations were compared between groups within each classification system. Multivariable analyses adjusted for age, sex, and renal insufficiency were performed, with each biomarker as a dependent variable and ANCA specificity and clinical diagnosis as explanatory variables of interest.ResultsLevels of 9 circulating cytokines (interleukin‐6 [IL‐6], granulocyte–macrophage colony‐stimulating factor [GM‐CSF], IL‐15, IL‐18, CXCL8/IL‐8, CCL‐17/thymus and activation–regulated chemokine [TARC], IL‐18 binding protein [IL‐18 BP], soluble IL‐2 receptor α [sIL‐2Rα], and nerve growth factor β [NGFβ]) were significantly higher in PR3‐AAV than MPO‐AAV, 4 cytokines (sIL6R, soluble tumor necrosis factor receptor type II [sTNFRII], neutrophil gelatinase–associated lipocalin [NGAL], and soluble intercellular adhesion molecule 1 [sICAM‐1]) were higher in MPO‐AAV than in PR3‐AAV, 6 cytokines (IL‐6, GM‐CSF, IL‐15, IL‐18, sIL‐2Rα, and NGFβ) were higher in GPA than in MPA, and 3 cytokines (osteopontin, sTNFRII, and NGAL) were higher in MPA than in GPA (all P < 0.05). For nearly all cytokines, the difference between PR3‐AAV and MPO‐AAV was larger than that between GPA and MPA. The multivariate analysis showed that 8 cytokines (IL‐15, IL‐8, IL‐18 BP, NGF‐β, sICAM‐1, TARC, osteopontin, and kidney injury molecule 1 (P < 0.05) distinguished patients with AAV better (lower P values and larger effect sizes) when grouped by ANCA specificity than by clinical diagnosis.ConclusionDistinct cytokine profiles were identified for PR3‐AAV versus MPO‐AAV and for GPA versus MPA. Differences in these circulating immune mediators are more strongly associated with ANCA specificity than with clinical diagnosis, suggesting that heterogeneity in the AAV subtypes extends beyond clinical phenotypes.