Ultra-rare genetic variation in relapsing polychondritis: a whole-exome sequencing study.

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.

Use of 18F-fluorodeoxyglucose positron emission tomography to standardize clinical trial recruitment in Takayasu's arteritis.

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.

Association of 18 F-Fluorodeoxyglucose-Positron Emission Tomography Activity With Angiographic Progression of Disease in Large Vessel Vasculitis.

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.

Longitudinal Characterization of Vascular Inflammation and Disease Activity in Takayasu Arteritis and Giant Cell Arteritis: A Single-Center Prospective Study.

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.