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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.

Importance and objective The aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care (SOC), for clinical management of inpatients with moderate to severe COVID-19 disease. Design Two-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus sarilumab. The trial used a randomized play-the-winner design and was fully embedded within the electronic health record (EHR) system. Setting 5 VA Medical Centers. Participants Hospitalized patients with clinical criteria for moderate to severe COVID-19 but not requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2. Interventions Sarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could vary over time, e.g., to include antiviral or other anti-inflammatory drugs. Main outcomes and measures The primary outcome was intubation or death within 14 days of randomization. All data were extracted remotely from the EHR. Results Among 162 eligible patients, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the sarilumab and SOC arms respectively, with the majority occurring in the initial 9 participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. Conclusions and relevance This randomized trial of patients hospitalized due to respiratory compromise from COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when added to an evolving SOC. The numbers of patients and events were too low to allow definitive conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods developed and piloted during this trial will be useful in conducting future studies more efficiently. Trial registration Clinicaltrials.gov—NCT04359901; https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&draw=2&rank=1.

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 < 0.01). Patients in cluster two had significantly more bilateral disease in the carotid and subclavian arteries (P < 0.01). Compared with clusters one and two, patients in cluster three had asymmetric disease with fewer involved territories (P < 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.

Objective To 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. Methods VTE 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). Results VTE 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

Objective.We evaluated potential circulating biomarkers of disease activity in giant cell arteritis (GCA), Takayasu arteritis (TA), polyarteritis nodosa (PAN), and eosinophilic granulomatosis with polyangiitis (EGPA).Methods.A panel of 22 serum proteins was tested in patients enrolled in the Vasculitis Clinical Research Consortium Longitudinal Studies of GCA, TA, PAN, or EGPA. Mixed models were used for most analyses. A J48 classification tree method was used to find the most relevant markers to differentiate between active and inactive GCA.Results.Tests were done on 418 samples from 152 patients (60 GCA, 29 TA, 26 PAN, 37 EGPA), during both active vasculitis and remission. In GCA, these showed significant (p < 0.05) differences between disease states: B cell–attracting chemokine 1 (BCA)-1/CXC motif ligand 13 (CXCL13), erythrocyte sedimentation rate (ESR), interferon-γ—induced protein 10/CXC motif chemokine 10, soluble interleukin 2 receptor α (sIL-2Rα), and tissue inhibitor of metalloproteinase-1 (TIMP-1). In EGPA, these showed significant increases during active disease: granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage—CSF, interleukin (IL)-6, IL-15, and sIL-2Rα. BCA-1/CXCL13 also showed such increases, but only after adjustment for treatment. In PAN, ESR and matrix metalloprotease (MMP)-3 showed significant differences between disease states. Differences in biomarker levels between diseases were significant for 11 markers and were more striking (all p < 0.01) than differences related to disease activity. A combination of lower values of TIMP-1, IL-6, interferon-γ, and MMP-3 correctly classified 87% of samples with inactive GCA.Conclusion.We identified novel biomarkers of disease activity in GCA and EGPA. Differences of biomarker levels between diseases, independent of disease activity, were more apparent than differences related to disease activity. Further studies are needed to determine whether these serum proteins have potential for clinical use in distinguishing active disease from remission or in predicting longer-term outcomes.

Objectives To evaluate large-vessel (LV) abnormalities on serial imaging in patients with giant cell arteritis (GCA) and discern predictors of new lesions. Methods Clinical and imaging data from patients with GCA (including subjects diagnosed by LV imaging) enrolled in a prospective, multicenter, longitudinal study and/or a randomized clinical trial were included. New arterial lesions were defined as a lesion in a previously unaffected artery. Results The study included 187 patients with GCA, 146 (78%) female, mean (±SD) age at diagnosis 68.5 ± 8.5 years; 39% diagnosed by LV imaging. At least one arterial lesion was present in 123 (66%) on the first study. The most frequently affected arteries were subclavian (42%), axillary (32%), and thoracic aorta (20%). In 106 patients (57%) with serial imaging, new arterial lesions were noted in 41 patients (39%), all of whom had a baseline abnormality, over a mean (±SD) follow-up of 4.39 (2.22) years. New abnormalities were observed in 33% patients by year 2; clinical features of active disease were present at only 50% of these cases. There were no differences in age, sex, temporal artery biopsy positivity, or disease activity in patients with or without new lesions. Conclusions In this cohort of patients with GCA, LV abnormalities on first imaging were common. Development of new arterial lesions occurred in patients with arterial abnormalities at first imaging, often in the absence of symptoms of active disease. Arterial imaging should be considered in all patients with GCA at diagnosis and serial imaging at least in patients with baseline abnormalities.

Glucocorticoids are standard of care for many chronic inflammatory conditions, including juvenile dermatomyositis (JDM) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We sought to define pharmacodynamic biomarkers of therapeutic efficacy and safety concerns of glucocorticoid treatment for these two disorders. Previous proteomic profiling of patients with Duchenne muscular dystrophy (DMD) and inflammatory bowel disease (IBD) treated with glucocorticoids identified candidate biomarkers for efficacy and safety concerns of glucocorticoids. Serial serum samples from patients with AAV (n = 30) and JDM (n = 12) were obtained during active disease, and after treatment with glucocorticoids. For AAV, 8 of 11 biomarkers of the anti-inflammatory response to glucocorticoids were validated (P-value ≤0.05; CD23, macrophage-derived cytokine, interleukin-22 binding protein, matrix metalloproteinase-12, T lymphocyte surface antigen Ly9, fibrinogen gamma chain, angiopoietin-2 [all decreased], and protein C [increased]), as were 5 of 7 safety biomarkers (P-value ≤0.05; afamin, matrix metalloproteinase-3, insulin growth factor binding protein-5, angiotensinogen, leptin [all increased]). For JDM, 10 of 11 efficacy biomarkers were validated (P-value ≤0.05; all proteins except fibrinogen gamma chain) and 6 of 7 safety biomarkers (P-value ≤0.05; AAV proteins plus growth hormone binding protein). The identified efficacy biomarkers may be useful as objective outcome measures for early phase proof-of-concept studies when assessing novel anti-inflammatory drugs in JDM and AAV, and likely in other inflammatory disorders. Similarly, safety biomarkers may also be helpful assessing toxicity of alternatives to glucocorticoids.

Neutrophils are implicated in multiple homeostatic and pathological processes, but whether functional diversity requires discrete neutrophil subsets is not known. Here, we apply single-cell RNA sequencing to neutrophils from normal and inflamed mouse tissues. Whereas conventional clustering yields multiple alternative organizational structures, diffusion mapping plus RNA velocity discloses a single developmental spectrum, ordered chronologically. Termed here neutrotime, this spectrum extends from immature pre-neutrophils, largely in bone marrow, to mature neutrophils predominantly in blood and spleen. The sharpest increments in neutrotime occur during the transitions from pre-neutrophils to immature neutrophils and from mature marrow neutrophils to those in blood. Human neutrophils exhibit a similar transcriptomic pattern. Neutrophils migrating into inflamed mouse lung, peritoneum and joint maintain the core mature neutrotime signature together with new transcriptional activity that varies with site and stimulus. Together, these data identify a single developmental spectrum as the dominant organizational theme of neutrophil heterogeneity., Differentiating neutrophil functional states is difficult. Here the authors show, using single cell RNA-sequencing and trajectory analyses, that mouse neutrophils can be presented as a transcriptome continuum rather than discrete subsets, but are affected by inflammation to express distinct transcriptional states.

BACKGROUND Patient-based registries can help advance research on rare diseases such as eosinophilic granulomatosis with polyangiitis (EGPA), a complex multiorgan form of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. OBJECTIVE The aim of this study is to compare patient-reported and physician-reported data on manifestations, treatments, and outcomes for patients with EGPA. METHODS We completed a comparative analysis of patients ≥18 years with EGPA in Canada and the United States from the following 2 cohorts: (1) The Vasculitis Patient-Powered Research Network (VPPRN), a self-enrolled secure portal with patient-entered data updated quarterly (2014-2019) and (2) the Vasculitis Clinical Research Consortium (VCRC) observational studies, a physician-entered database (2003-2019) of patients who fulfilled the 1990 American College of Rheumatology classification criteria for EGPA. The studied parameters included demographic characteristics, clinical manifestations, ANCA status, treatments, and relapses. RESULTS Data from 195 patients with a validated diagnosis of EGPA in the VPPRN and 354 patients enrolled in the VCRC were analyzed. Compared to the VCRC cohort, the patients in the VPPRN cohort were more likely to be female (135/195, 69.2% compared to 209/354, 59%; P=.02) and younger at diagnosis (47.3 compared to 50.0 years; P=.03); both cohorts reported similar frequencies of asthma (177/184, 96.2% in the VPPRN cohort compared to 329/354, 92.9% in the VCRC cohort; P=.13) and cardiac manifestations (44/153, 28.8% compared to 75/354, 21.2%; P=.06), but the VPPRN cohort reported less frequent lung manifestations other than asthma and more frequent disease manifestations in all other organ systems. The ANCA positivity was 48.9% (64/131) in the VPPRN patients compared to 38.9% (123/316; P=.05) in the VCRC cohort. Relapsing disease after study enrollment was reported in 32.3% (63/195) of patients in the VPPRN compared to 35.7% (99/277) of patients in the VCRC. Most therapies (GC, cyclophosphamide, mepolizumab) were used at similar frequencies in both groups, except for rituximab with VPPRN patients reporting more use than the VCRC cohort (47/195, 24.1% compared to 29/277, 10.5%; P CONCLUSIONS Overall, patients and physicians report manifestations of EGPA at similar frequencies. However, observed differences between patient and physician reports imply the potential occurrence of selection biases. These results support the use of patient-reported data in EGPA but also the need for careful consideration of disease-specific definitions for the study of EGPA and how patient- and physician-reported data are collected. CLINICALTRIAL ClinicalTrials.gov NCT00315380, https://clinicaltrials.gov/ct2/show/NCT00315380; ClinicalTrials.gov NCT01241305, https://clinicaltrials.gov/ct2/show/NCT01241305

Background Patient-based registries can help advance research on rare diseases such as eosinophilic granulomatosis with polyangiitis (EGPA), a complex multiorgan form of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. Objective The aim of this study is to compare patient-reported and physician-reported data on manifestations, treatments, and outcomes for patients with EGPA. Methods We completed a comparative analysis of patients ≥18 years with EGPA in Canada and the United States from the following 2 cohorts: (1) The Vasculitis Patient-Powered Research Network (VPPRN), a self-enrolled secure portal with patient-entered data updated quarterly (2014-2019) and (2) the Vasculitis Clinical Research Consortium (VCRC) observational studies, a physician-entered database (2003-2019) of patients who fulfilled the 1990 American College of Rheumatology classification criteria for EGPA. The studied parameters included demographic characteristics, clinical manifestations, ANCA status, treatments, and relapses. Results Data from 195 patients with a validated diagnosis of EGPA in the VPPRN and 354 patients enrolled in the VCRC were analyzed. Compared to the VCRC cohort, the patients in the VPPRN cohort were more likely to be female (135/195, 69.2% compared to 209/354, 59%; P=.02) and younger at diagnosis (47.3 compared to 50.0 years; P=.03); both cohorts reported similar frequencies of asthma (177/184, 96.2% in the VPPRN cohort compared to 329/354, 92.9% in the VCRC cohort; P=.13) and cardiac manifestations (44/153, 28.8% compared to 75/354, 21.2%; P=.06), but the VPPRN cohort reported less frequent lung manifestations other than asthma and more frequent disease manifestations in all other organ systems. The ANCA positivity was 48.9% (64/131) in the VPPRN patients compared to 38.9% (123/316; P=.05) in the VCRC cohort. Relapsing disease after study enrollment was reported in 32.3% (63/195) of patients in the VPPRN compared to 35.7% (99/277) of patients in the VCRC. Most therapies (GC, cyclophosphamide, mepolizumab) were used at similar frequencies in both groups, except for rituximab with VPPRN patients reporting more use than the VCRC cohort (47/195, 24.1% compared to 29/277, 10.5%; P Conclusions Overall, patients and physicians report manifestations of EGPA at similar frequencies. However, observed differences between patient and physician reports imply the potential occurrence of selection biases. These results support the use of patient-reported data in EGPA but also the need for careful consideration of disease-specific definitions for the study of EGPA and how patient- and physician-reported data are collected. Trial Registration ClinicalTrials.gov NCT00315380, https://clinicaltrials.gov/ct2/show/NCT00315380; ClinicalTrials.gov NCT01241305, https://clinicaltrials.gov/ct2/show/NCT01241305

OBJECTIVE. Only a few small case series, case reports, and one small clinical trial suggested some benefit of leflunomide (LEF) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and other vasculitides. We analysed the clinical efficacy and tolerability of LEF in a large cohort of patients with various vasculitides. METHODS. This was a retrospective analysis of patients who received LEF for treatment of their vasculitis enrolled in the Vasculitis Clinical Research Consortium (VCRC) Longitudinal Study and in 3 additional centres from the Canadian vasculitis research network (CanVasc). RESULTS. Data for 93 patients were analysed: 45 had granulomatosis with polyangiitis (GPA), 8 microscopic polyangiitis (MPA), 12 eosinophilic granulomatosis with polyangiitis (EGPA), 14 giant-cell arteritis (GCA), 9 Takayasu’s arteritis (TAK), and 5 polyarteritis nodosa (PAN). The main reason for initiation of LEF was active disease (89%). LEF was efficacious for remission induction or maintenance at 6 months for 62 (67%) patients (64% with GCA, 89% with TAK, 80% with PAN, 69% with GPA, 75% with MPA, 33% with EGPA); 20% discontinued LEF before achieving remission because of persistent disease activity. Overall, 22 adverse events (gastrointestinal symptoms being the most common) led to drug discontinuation in 18 (19%) patients, of which 12 stopped LEF before month 6, before showing any benefit in 8/12 of these patients. CONCLUSION. Leflunomide can be an effective therapeutic option for various vasculitides, especially for non-severe refractory or relapsing ANCA-associated vasculitis or large-vessel vasculitis. No new safety signals for LEF were identified in this population.

Background and objective The communicable nature of many infectious diseases, including SARS-CoV-2, creates challenges for implementing and obtaining regulatory-compliant written informed consent. The goal of this project was to identify and evaluate processes that address these barriers while maintaining clinical and research staff safety. Methods We reviewed Federal Drug Administration (FDA), World Health Organization (WHO), and VA Office of Research and Development (ORD) guidance about informed consent during the COVID-19 pandemic, and identified and pilot-tested several mechanisms for obtaining regulatory-compliant consent during our COVID-19 therapeutics clinical trial. Results Several processes were identified. These included a standard face-to-face consent with a plan for maintaining a paper copy of the signed consent form, a phone or video chat consent process that included taking a picture of the signed consent form or a screen shot of the signed document during a video chat, integration of the consent forms into software embedded within the electronic health record, and secure software programs with electronic signature. These processes are FDA-compliant but time-intensive, often requiring four or more hours of coordination between the clinical team, research staff, patients, and legally authorized representatives. Conclusions Future studies could evaluate how to improve efficiency, and whether some elements of the consenting process, such as the requirement for documented written signed consent, rather than a witnessed oral consent, is an acceptable standard for research participants with communicable diseases.

(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 (p0.0001). 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.

Although implementation of evidence-based practices takes an average of 17 years, in the context of the global pandemic, coronavirus disease 2019 (COVID-19) interventions were adopted in a greatly compressed time frame. This rapid uptake creates major challenges for conducting COVID-19 clinical research studies, because quickly evolving standards make it difficult to adapt in real time. The rapid dissemination and implementation of COVID-19 interventions is the realization of goals long pursued by the implementation science community. However, the downside of the rapid implementation is that low-quality evidence with little to no scientific vetting may be quickly integrated into clinical care, resulting in lost opportunities to advance our scientific understanding about how to manage infected patients. In the future, novel adaptive designs embedded into electronic health records (Embedded Quantified, Integrated-into-Practice Trial [EQuIPT] designs) that allow for easier and better access to clinical trials may simultaneously improve care and advance healthcare innovations.

ObjectivesEvaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial.MethodsPatients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse.Results188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections.ConclusionsThis large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.

Given the high case fatality rate of SARS-CoV-2, for which there is no cure and no vaccine, clinicians are forced to make decisions about how best to manage patients with limited high-quality evidence to guide treatment. Traditional randomized controlled trials provide strong experimental evidence, however, tend to be slow, inflexible, and have limited generalizability. Adaptive and pragmatic designs are an attractive alternative, which meet our ethical obligation during the SARS-CoV-2 pandemic to balance speed, agility, and generalizability with both prospective study and scientific rigor.

Objectives. To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes.Methods. This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m(2)). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission.Results. RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse.Conclusion. Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.

Objective To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods A genome-wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta-analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function. Results Among the genome-wide significant associations identified, the largest effect on risk of AAV came from the single-nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA–DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA–DPB1 gene and HLA–DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)–reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top-scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3-ANCAs and those with myeloperoxidase-ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%. Conclusion This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

The growth factor receptor Kit is involved in hematopoietic and nonhematopoietic development. Mice bearing Kit defects lack mast cells; however, strains bearing different Kit alleles exhibit diverse phenotypes. Herein, we investigated factors underlying differential sensitivity to IgG-mediated arthritis in 2 mast cell–deficient murine lines: KitWsh/Wsh, which develops robust arthritis, and KitW/Wv, which does not. Reciprocal bone marrow transplantation between KitW/Wv and KitWsh/Wsh mice revealed that arthritis resistance reflects a hematopoietic defect in addition to mast cell deficiency. In KitW/Wv mice, restoration of susceptibility to IgG-mediated arthritis was neutrophil independent but required IL-1 and the platelet/megakaryocyte markers NF-E2 and glycoprotein VI. In KitW/Wv mice, platelets were present in numbers similar to those in WT animals and functionally intact, and transfer of WT platelets did not restore arthritis susceptibility. These data implicated a platelet-independent role for the megakaryocyte, a Kit-dependent lineage that is selectively deficient in KitW/Wv mice. Megakaryocytes secreted IL-1 directly and as a component of circulating microparticles, which activated synovial fibroblasts in an IL-1–dependent manner. Transfer of WT but not IL-1–deficient megakaryocytes restored arthritis susceptibility to KitW/Wv mice. These findings identify functional redundancy among Kit-dependent hematopoietic lineages and establish an unanticipated capacity of megakaryocytes to mediate IL-1–driven systemic inflammatory disease.

Summary Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)–ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3–ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3–ANCA was transient, but could recur. In the second cohort, IgM PR3–ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3–ANCA (45·3 versus 15·8%; P

A 57-year-old woman presented with fatigue, night sweats, weight loss, headache, abdominal pain, and skin lesions. Laboratory testing revealed hypergammaglobulinemia and hypocomplementemia. Diagnostic tests were performed.

Background: Immunopathologic features predict renal function at baseline and follow-up in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). The interstitial infiltrate consists predominantly of T lymphocytes, but their pathophysiologic significance is unclear, especially in light of the success of B-cell-directed therapy. Methods: Renal biopsies from 33 patients treated with cyclophosphamide (CYC; n = 17) or rituximab (RTX; n = 16) in the RTX in ANCA-associated vasculitis (RAVE) trial were classified according to the new ANCA GN classification. T- and B-cell infiltration in the interstitium was assessed by immunostaining for CD3 and CD20. Correlations of clinical and histologic parameters with renal function at set time points were examined. Results: The mean (SD) baseline estimated glomerular filtration rate was 36 (20) mL/min/1.73 m2. ANCA GN class distribution was 46% focal, 33% mixed, 12% sclerotic and 9% crescentic. The interstitial infiltrate consisted of >50% CD3 positive cells in 69% of biopsies, but >50% CD20 positive cells only in 8% of biopsies. In a multiple linear regression model, only baseline glomerular filtration rate (GFR) correlated with GFR at 6, 12, and 18 months. Interstitial B- and T-cell infiltrates had no significant impact on long-term prognosis, independent of the treatment limb. A differential effect was noted only at 6 months, where a dense CD3 positive infiltrate predicted lower GFR in the RTX group and a CD20 positive infiltrate predicted higher GFR in the CYC group. Conclusions: In ANCA-associated GN, the interstitial infiltrate contains mainly T lymphocytes. However, it is neither reflecting baseline renal function nor predictive of response to treatment, regardless of the immunosuppression regimen employed.

Objective S100A8/A9 (calprotectin) has shown promise as a biomarker for predicting relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was undertaken to investigate serum S100A8/A9 level as a biomarker for predicting future relapse in a large cohort of patients with severe AAV.Methods Serum levels of S100A8/A9 were measured at baseline and months 1, 2, and 6 following treatment initiation in 144 patients in the Rituximab in ANCA-Associated Vasculitis trial (cyclophosphamide/azathioprine versus rituximab [RTX] for induction of remission) in whom complete remission was attained.Results Patients were divided into 4 groups: proteinase 3 (PR3)-ANCA with relapse (n=37), PR3-ANCA without relapse (n=56), myeloperoxidase (MPO)-ANCA with relapse (n=6), and MPO-ANCA without relapse (n=45). Serum S100A8/A9 level decreased in all groups during the first 6 months of treatment. The percentage reduction from baseline to month 2 was significantly different between patients who experienced a relapse and those who did not in the PR3-ANCA group (P=0.046). A significantly higher risk of relapse was associated with an increase in S100A8/A9 level between baseline and month 2 (P=0.0043) and baseline and month 6 (P=0.0029). Subgroup analysis demonstrated that patients treated with RTX who had increased levels of S100A8/A9 were at greatest risk of future relapse (P=0.028).Conclusion An increase in serum S100A8/A9 level by month 2 or 6 compared to baseline identifies a subgroup of PR3-ANCA patients treated with RTX who are at higher risk of relapse by 18 months. Since RTX is increasingly used for remission induction in PR3-ANCA-positive patients experiencing a relapse, S100A8/A9 level may assist in identifying those patients requiring more intensive or prolonged treatment.

Objective: To investigate serum IL-6 (sIL-6) levels during active disease, complete remission (CR), and relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and to explore the association of changes in sIL-6 with clinical outcomes.Methods: sIL-6 levels were measured at baseline and longitudinally over 18 months, in 78 patients with AAV enrolled in a randomized controlled trial comparing treatment with either rituximab (RTX) or cyclophosphamide (CYC)/azathioprine (AZA). Outcome variables included baseline clinical features, ANCA specificity, disease activity (active disease versus CR), time to relapse events, B cell repopulation, and ANCA titer increases.Results: At baseline, sIL6 levels were detectable in 81% of patients; 73% (n = 57) of subjects were proteinase 3 (PR3)-ANCA positive, sIL-6 levels were higher in subjects with PR3-ANCAs and positively correlated with their levels (r(s) = 0.36,p 0.05).Conclusion: At baseline, sIL-6 concentrations correlate with PR3-ANCA titers and are associated with specific clinical manifestations of AAV. Baseline sIL6 concentrations do not predict CR at 6 months, but the increase in sIL-6 concentrations during CR is associated with subsequent severe relapse among RTX-treated patients. Further investigation into the mechanistic role of IL6 in AAV might lead to identifying this pathway as a potential therapeutic target in this disease.

Background: We recently reported that, in a small number of subjects, the proportion of proteinase 3 (PR3)-specific B cells was higher in patients with PR3-ANCA-associated vasculitis (AAV) compared to healthy controls (HCs). Objectives: The objectives of this work were to replicate our previous findings on a larger number of subjects, including myeloperoxidase (MPO)-AAV patients as disease controls, and to study the association of PR3-specific B cell proportions with clinical and biological features in patients with PR3-AAV. Methods: We analyzed frozen PBMCs from 166 patients who participated in the RAVE trial, including 113 patients with PR3-AAV and 53 patients with MPO-AAV, as well as 27 HCs. We measured the proportion of PR3-specific B cells and subsets among PBMCs using a multi-color flow cytometry panel including CD19, IgD, CD27, CD38, CD24, and a biotinylated PR3 revealed by fluorescent streptavidin. In parallel, one million PBMCs from each sample were cultivated in vitro for 12 days and stimulated by CpG, BAFF, and IL-21. PR3-ANCAs were quantified in the culture supernatants and in the serum. Results: The mean (SD) proportion of PR3-specific B cells was higher in patients with PR3-AAV compared to patients with MPO-AAV and to HCs: 2.78% (2.64) vs 1.97% (1.2) vs 1.24% (0.49) respectively, p Conclusion: The proportion of circulating PR3-specific B cells is higher in patients with PR3-AAV than in patients with MPO-AAV and HCs, and importantly, their repartition is shifted towards a memory phenotype. Further studies are ongoing to characterize the dynamics of the PR3-specific B cells after therapy, and to understand the differences of these autoreactive B cells between patients with PR3-AAV and HCs. Reference [1] Cornec D, Berti A, Hummel A, Peikert T, Pers JO, Specks U. Identification and phenotyping of circulating autoreactive proteinase 3-specific B cells in patients with PR3-ANCA associated vasculitis and healthy controls. J Autoimmun. 2017Nov;84:122-131. Disclosure of Interests: Divi Cornec: None declared, Alvise Berti: None declared, Amber Hummel: None declared, Eva Carmona: None declared, Tobias Peikert: None declared, Carol Langford: None declared, Paul Monach: None declared, Peter Merkel: None declared, Philip Seo: None declared, Robert Spiera Grant/research support from: Roche-Genentech, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, Cytori, Chemocentryx, Corbux, Consultant for: Roche-Genentech, GlaxoSmithKline, CSL Behring, Sanofi Aventis, E. William St. Clair Grant/research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Fernando Fervenza: None declared, Kristina Harris: None declared, John H. Stone Grant/research support from: F. Hoffmann-La Roche, Genentech, Xencor, Consultant for: Chugain, F. Hoffmann-La Roche, Genentech, Xencor, Jacques-Olivier Pers: None declared, Peter Heeringa: None declared, Wayel Abdulahad: None declared, Ulrich Specks: None declared

Objective Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have an elevated risk of cardiovascular disease (CVD). This study was undertaken to develop a clearer understanding of the association between changes in disease activity and lipid levels in AAV, which may inform CVD risk stratification in this population. Methods Lipid levels were assessed in stored serum samples (obtained at baseline and month 6) from the Rituximab for ANCA-Associated Vasculitis (RAVE) trial, which randomized patients to receive either rituximab or cyclophosphamide followed by azathioprine. Paired t-tests and multivariable linear regression were used to assess changes in lipid levels. Results Of the 142 patients with serum samples available, the mean ± SD age was 52.3 ± 14.7 years, 72 (51%) were male, 95 (67%) were proteinase 3 (PR3)-ANCA positive, 72 (51%) had received a new diagnosis of AAV, and 75 (53%) were treated with rituximab. Several lipid levels increased between baseline and month 6, including total cholesterol (+12.4 mg/dl [95% confidence interval (95% CI) +7.1, +21.0]), low-density lipoprotein (+10.3 mg/dl [95% CI +6.1, +17.1]), and apolipoprotein B (+3.5 mg/dl [95% CI +1.0, +8.3]). These changes were observed among newly diagnosed and PR3-ANCA-positive patients but not among those with relapsing disease or myeloperoxidase-ANCA-positive patients. There was no difference in change in lipid levels between rituximab-treated patients and cyclophosphamide-treated patients. Changes in lipid levels correlated with changes in erythrocyte sedimentation rate but not with other inflammatory markers or glucocorticoid exposure. Conclusion Lipid levels increased during remission induction among patients with newly diagnosed AAV and those who were PR3-ANCA positive. Disease activity and ANCA type should be considered when assessing lipid profiles to stratify CVD risk in patients with AAV.

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.

ObjectiveProteinase 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.MethodsThe recombinant PR3 variants, iPR3 which is clinically used to detect PR3-ANCAs and iHm5 which contains three point mutations in Epitope 1 and 5 generated for epitope mapping studies, immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) clinical trials were used to screen the differential PR3-ANCA binding. Selective binding was determined by inhibition experiments.ResultsRather than a reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared with iPR3. A monoclonal ANCA (moANCA518) from a patient with GPA was found to selectively bind to iHm5 within the mutation-free Epitope 3 and distant from the point mutations of iHm5 contained in Epitope 1 and 5. Binding of iPR3 to monoclonal antibody MCPR3-2 also induced recognition by moANCA518.ConclusionThe 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 it is 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.

Objectives To describe tracheobronchial disease in patients with granulomatosis with polyangiitis (GPA) and evaluate the utility of dynamic expiratory CT to detect large-airway disease. Methods Demographic and clinical features associated with the presence of subglottic stenosis (SGS) or endobronchial involvement were assessed in a multicentre, observational cohort of patients with GPA. A subset of patients with GPA from a single-centre cohort underwent dynamic chest CT to evaluate the airways. Results Among 962 patients with GPA, SGS and endobronchial disease were identified in 95 (10%) and 59 (6%) patients, respectively. Patients with SGS were more likely to be female (72% vs 53%, P < 0.01), younger at time of diagnosis (36 vs 49 years, P < 0.01), and have saddle-nose deformities (28% vs 10%, P < 0.01), but were less likely to have renal involvement (39% vs 62%, P < 0.01). Patients with endobronchial disease were more likely to be PR3-ANCA positive (85% vs 66%, P < 0.01), with more ENT involvement (97% vs 77%, P < 0.01) and less renal involvement (42% vs 62%, P < 0.01). Disease activity in patients with large-airway disease was commonly isolated to the subglottis/upper airway (57%) or bronchi (32%). Seven of 23 patients screened by dynamic chest CT had large-airway pathology, including four patients with chronic, unexplained cough, discovered to have tracheobronchomalacia. Conclusion SGS and endobronchial disease occur in 10% and 6% of patients with GPA, respectively, and may occur without disease activity in other organs. Dynamic expiratory chest CT is a potential non-invasive screening test for large-airway involvement in GPA.

Objective. To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: antimyeloperoxidase (MPO)-ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener's) (GPA). Methods. We performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA-Associated Vasculitis trial comparing patients with MPO-ANCA-positive GPA and patients with ANCA-negative GPA to patients with proteinase 3 (PR3)-ANCA-positive GPA and patients with MPO-ANCA-positive microscopic polyangiitis (MPA). Results. Of the 365 patients analyzed, 273 (75%) had PR3-ANCA-positive GPA, 33 (9%) had MPO-ANCA-positive GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA-positive MPA. MPO-ANCA-positive GPA patients were younger at diagnosis compared to MPO-ANCA-positive MPA patients (53 versus 61 years; P=0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA-positive GPA patients. Relapse was more frequent in MPO-ANCA-positive GPA patients than in patients with MPO-ANCA-positive MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3-ANCA-positive patients with GPA (4.5 versus 7.7; P

Objective.To evaluate the performance of the Birmingham Vasculitis Activity Score (BVAS) in the assessment of disease activity in giant cell arteritis (GCA).Methods.Patients with GCA enrolled in a prospective, multicenter, longitudinal study with symptoms of active vasculitis during any visit were included. Spearman’s rank correlation was used to explore the association of the BVAS with other measures of disease activity.Results.During a mean (SD) followup of 2.3 (1.6) years, symptoms of active GCA were present in 236 visits in 136 subjects (100 female, 74%). Median (range) BVAS1 (new/worse symptoms) was 1 (0–10) and median (range) BVAS2 (persistent symptoms) was 0 (0–5). Median (range) physician’s global assessment (PGA) was 4 (0–9) for disease activity in the past 28 days and 2 (0–9) for activity on the day of the visit. Important ischemic manifestations of active vasculitis not recorded by the BVAS included tongue/jaw claudication (27%), upper extremity claudication (15%), lower extremity claudication (5%), carotidynia (7%), and ischemic retinopathy (5%). During 25 visits (11%) with active disease, all symptoms of active vasculitis were placed in the “Other” category yet still resulted in a BVAS1 and BVAS2 of 0. BVAS1 moderately correlated with PGA for the past 28 days (Spearman’s correlation 0.50) and physician-rated disease activity for the past 28 days (Spearman’s correlation 0.46).Conclusion.The BVAS has limited utility in GCA. Patients with active GCA can have a BVAS of 0. Many important ischemic symptoms attributable to active vasculitis are not included in the composite score.

Background:Bartonellosis is an emerging anthropozoonosis caused by infection with intracellular Gram-negativeBartonellaspecies. It leads to necrotizing granulomas and endothelial damage and causes acute and chronic human diseases, such as cat scratch disease, bacillary angiomatosis and endocarditis. Endocarditis due toBartonella henselaeandB. quintanais reported to produce anti-neutrophil cytoplasmic antibodies (ANCAs) that disappear with effective antimicrobial treatment.Objectives:Hypothesizing a role forBartonellainfection in ANCA-associated vasculitis (AAV), which also includes granulomatous and vascular inflammation, we studied the seroprevalence of 5Bartonellaspecies in patients with AAV.Methods:The study used plasma samples from patients with granulomatosis with polyangiitis and microscopic polyangiitis that were enrolled in the Rituximab for AAV (RAVE) trial and from healthy controls living in the United States. Western blot assays were used for serological testing of infection withB. quintana,B. henselaeHouston-1,B. elizabethae,B. vinsoniisubsp.berkhoffiiandB. alsatica. The associations of positive serology results and AAV were expressed as odds ratios (OR). Clinical characteristics of seropositive and seronegative patients, assessed by the BVAS/WG instrument, were compared. These comparisons were done for 9 organ systems; in case they showed differences withPResults:We analyzed blood samples of 187 patients with AAV (collected at start of the trial) and of 127 controls. There were no significant differences between the cases and controls for mean age (P=0.148) and proportion of males (P=0.36).Bartonellaspp. serological testing was positive for 112 (60%) cases and 40 (31%) controls (OR 3.25 [95% CI 2.02–5.22],PPP=0.017), newly-diagnosed (OR 3.89 [95% CI 2.21–6.86],PPB. henselae(cases: 27%, controls: 0.8%; OR 39.93 [95% CI 5.42–293.90];PBartonellaspp., AAV patients testing seropositive forBartonellaspp. had significantly more bloody nasal discharge (P=0.046), sinus involvement (P=0.035) and conjunctivitis/episcleritis (P=0.016).Conclusion:This study reveals higher seroprevalence ofBartonella, especiallyB. henselae, in patients with AAV than in healthy controls. Although cross-reactivity ofBartonellawith other microorganisms cannot be excluded, these results may support an etiopathogenic role ofBartonellainfection in AAV that deserves further investigation.Disclosure of Interests:Alfred Mahr Consultant of: Celgene, Speakers bureau: Roche, Chugai, Sophie Edouard: None declared, Divi Cornec: None declared, Solange GONZALEZ-CHIAPPE: None declared, Jörg Goronzy: None declared, Philippe Guilpain: None declared, Carol Langford: None declared, Pierre-Yves Lévy: None declared, Peter A. Merkel: None declared, Paul Monach: None declared, E. William St. Clair: None declared, Philip Seo: None declared, Robert Spiera Grant/research support from: Roche-Genetech, GSK, Boehringer Ingelheim, Chemocentryx, Corbus, Forbius, Sanofi, Inflarx, Consultant of: Roche-Genetech, GSK, CSL Behring, Sanofi, Janssen, Chemocentryx, Forbius, Mistubishi Tanabe, Cornelia Weyand: None declared, John H. Stone Grant/research support from: Roche, Consultant of: Roche, Didier Rauolt: None declared, Ulrich Specks: None declared

Background:Giant cell arteritis (GCA), the most common systemic vasculitis in adults, is often associated with significant morbidity and mortality. A claims-based algorithm that accurately identifies GCA patients in large real-world data can offer new opportunities for future epidemiological studies.Objectives:We aimed to develop and validate a claims-based algorithm for GCA.Methods:We developed and tested 5 claims-based GCA algorithms using U.S. Medicare claims (Parts A/B/D) linked to electronic medical record data from a large academic medical center, 2006-2014:Algorithm 1) ≥1 International Classification of Diseases, Ninth Revision (ICD-9) code for GCA (446.5x) by any physician, high dose steroid dispensing (i.e., prednisone equivalent ≥40 mg/day for ≥14 days), and ≥1 Current Procedural Terminology (CPT) code for ESR/CRP;2) ≥1 ICD-9 for GCA by a rheumatologist, high dose steroid dispensing, and ESR/CRP;3) ≥2 ICD-9 for GCA by a rheumatologist separated by 7-30 days and high dose steroid dispensing;4) ≥1 ICD-9 for GCA by a rheumatologist, high dose steroid dispensing, ESR/CRP, and CPT code for temporal artery biopsy; and5) ≥1 ICD-9 for GCA or its subtypes (447.6, 437.4, 417.8) by a rheumatologist, high dose steroid dispensing, ESR/CRP, and CPT code for chest imaging. For all algorithms, the index date was defined as the date of first steroid dispensing. Two physicians reviewed medical records for the gold standard definition of GCA: documentation of GCA by the treating physician or a temporal biopsy result consistent with GCA. Probable GCA cases based on treating physician’s records were included as well. Positive predictive value (PPV) and 95% confidence intervals (CI) of the algorithms were calculated.Results:We identified 1,930 patients with Medicare claims data linked to electronic medical records. Among these, 799 unique records with physician notes documenting GCA or biopsy results were included in the PPV calculations. Algorithm 1, which identified the greatest number of patients (n=896), yielded the lowest PPV of 60.7%. Algorithms 4 and 5, which required disease-specific workups (temporal artery biopsy or chest imaging), mildly improved the PPV to 76.2% and 68.2%, respectively. The PPV was highest in algorithm 3 (84.8%), which required 2 or more diagnoses of GCA by a rheumatologist in addition to high dose steroid dispensing.Table.PPV of Claims-based AlgorithmsNo. of patientsAlgorithm #Records IdentifiedRecords ReviewedAdequate RecordsPPV* (95% CI)1896446†206 (46.2%)60.7% (53.7-67.4)2471471270 (57.3%)78.6% (73.2-83.3)3220220125 (57.4%)84.8% (77.3-90.6)4296296172 (58.1%)76.2% (69.1-82.3)5474726 (55.3%)68.2% (48.2-85.7)* True positive cases included both definitive and probable GCA patients†446 records were randomly selected for chart review.Conclusion:A claims-based algorithm including two or more diagnosis codes for GCA by a rheumatologist separated by 7-30 days and high dose steroid dispensing (prednisone equivalent ≥40 mg/day for ≥14 days) can be a useful tool for identifying patients with GCA, allowing for future large real-world data studies.References:[1]Crow RW et al. Giant cell arteritis and mortality. J Gerontol A Biol Sci Med Sci. 2009 Mar;64(3):365-9.Acknowledgments:This study was supported by an investigator-initiated research grant from Genentech/Roche. The sponsor was given the opportunity to make non-binding comments on a draft of the abstract, but the authors retained the right of publication and to determine the final wording.Disclosure of Interests:Hemin Lee: None declared, Sarah Chen Employee of: After finishing the work for this abstract, she has moved to work for Gilead., Sara Tedeschi: None declared, Paul Monach: None declared, Jun Liu: None declared, Attila Pethoe-Schramm Shareholder of: Current employee of F. Hoffmann-La Roche and own company stocks/stock options, Employee of: Current employee of F. Hoffmann-La Roche, Vincent Yau Shareholder of: Current employee of F. Hoffmann-La Roche/Genetech and own company stocks/stock options, Employee of: Current employee of F. Hoffmann-La Roche/Genetech, Seoyoung Kim Grant/research support from: Seoyoung C Kim has received research grants from AbbVie, Roche, Bristol-Myers Squibb and Pfizer.

Background:Proteinase 3 (PR3)-reactive B cells are present in PR3-ANCA-associated vasculitis (AAV) at levels higher than healthy controls.Objectives:To evaluate the dynamics of the PR3-reactive B cell repopulation in patients with PR3-AAV after treatment with rituximab, and to analyze possible associations between these immunological changes and long-lasting remissions.Methods:We analyzed all available frozen peripheral blood mononuclear cells (n=148) from 23 randomly-selected PR3-AAV patients who participated in the RAVE trial and achieved complete remission (BVAS=0, prednisone=0) after treatment with rituximab.We measured PR3-reactive B cells and the relative subsets by a multi-color flow cytometry panel including CD19, IgD, CD27, CD38, CD24, and a biotinylated PR3 revealed by fluorescent streptavidin. The clinical data of the trial were correlated with flow-cytometry data.Results:10/23 (43%) patients relapsed during the follow up, 8/10 relapses were severe. At baseline, clinical features, PR3-ANCA levels, % of total PR3-reactive B cells and PR3-reactive B cell subsets were similar between relapsers and non-relapsers. All patients were followed until the end of the trial, for a mean of 44 months (25-75%IQR 31-54), without difference in follow-up time between relapsers and non-relapsers (p=0.98).The majority of patients had B cell repopulation at 12 (range 12-24) months after rituximab. At the time of B cell repopulation, transitional (CD19+CD24+CD38+) and naïve (CD19+CD27+IgD-) B cells were higher compared to baseline, while total plasmablasts (PB) were unchanged, and mature B cells significantly decreased in both relapsers and non relapsers. PR3-reactive B cells reappeared in all the patients, and the % of PR3-reactive of B cells were higher at the B cell repopulation visit compared to baseline (5.82% vs 4.25%, pWithin PR3-reactive B cells, only the % of PB (CD19+CD27+CD38+PR3+) were higher in relapsers vs. non-relapsers (median [25-75%IQR]; 1.95% [1.315-3.845] vs 0.84% [0.05-1.66], p=0.022) and severe relapsers vs non-severe relapsers (2.165% [1.66-4.315] vs 0.84% [0.1-1.74], p=0.015). Time-to-relapse and time-to severe-relapse were significantly shorter in patients with circulating PR3-PB higher than the median value of the cohort (1.6%) during B cell reconstitution (Figure 1A-B).Conclusion:In PR3-AAV, during B cell reconstitution after rituximab, the total fraction of PR3-B cells increases, due to the expansion of the transitional and naïve B cell compartments. Circulating PR3-PB within PR3-B cells are enriched in the peripheral blood of relapsing and severely relapsing patients compared to non-relapsing patients. Higher levels of PR3-PB after rituximab during B cell reappearance significantly increased the risk of subsequent relapse and severe relapse.References:[1]Cornec D, Berti A, Hummel A, et al. J Autoimmun. 2017Disclosure of Interests:Alvise Berti: None declared, Sophie Hillion: None declared, Amber Hummel: None declared, Eva Carmona: None declared, Tobias Peikert: None declared, Carol Langford: None declared, Peter A. Merkel: None declared, Paul Monach: None declared, Philip Seo: None declared, Robert Spiera Grant/research support from: Roche-Genetech, GSK, Boehringer Ingelheim, Chemocentryx, Corbus, Forbius, Sanofi, Inflarx, Consultant of: Roche-Genetech, GSK, CSL Behring, Sanofi, Janssen, Chemocentryx, Forbius, Mistubishi Tanabe, E. William St. Clair: None declared, Fernando Fervenza: None declared, Kristina Harris: None declared, John H. Stone Grant/research support from: Roche, Consultant of: Roche, Jacques-Olivier Pers: None declared, Ulrich Specks: None declared, Divi Cornec: None declared

Objective. To 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]).Methods. A 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.Results. Levels 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 [sIL-2R], and nerve growth factor [NGF]) 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-2R, and NGF) were higher in GPA than in MPA, and 3 cytokines (osteopontin, sTNFRII, and NGAL) were higher in MPA than in GPA (all P Conclusion. Distinct 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.

Background The deregulated overproduction of interleukin (IL)−6 has been implicated in several inflammatory and antibody-mediated autoimmune diseases. Objectives To investigate serum IL-6 levels (sIL-6) during active disease, remission, and relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and to explore the association of changes in sIL-6 with repopulation of blood B cells and disease relapse. Methods sIL-6 levels (explanatory variable) were measured longitudinally over 18 months in 78 patients with AAV enrolled in a prospective, double-blinded, randomised, control trial comparing treatment with rituximab (RTX) (n=45) or cyclophosphamide (CYC)/azathioprine (AZA) (n=33). Outcome variables included baseline clinical features, ANCA type and titers, disease activity (status of active disease versus complete remission (CR)), time to B cell repopulation, relapse and severe relapse. Results Baseline sIL6 levels were detectable (>0.49 pg/ml) in 81% of patients. At baseline, s IL-6 positively correlated with proteinase (PR3)-ANCA levels (r s =0.36, p s =−0.17, p=0.47). Higher baseline sIL-6 levels were associated with the presence of fever, pulmonary nodules/cavities, PR3-ANCA, and absence of renal involvement (p The median sIL-6 level was higher at baseline and promptly declined with induction therapy at following time-points (baseline, median [25%>75% IQR], 2.66 [0.76–20.98]; month 6th, 0.49 [0.49–1.16]; p An increase in sIL-6 during clinical remission was a predictor for subsequent severe relapse in RTX-treated patients (Hazard Ratio (HR) 7.24, p=0.01), but not in CYC/AZA-treated patients (HR 0.62, p=0.50). In RTX-treated B cell depleted patients (CD19 +B cell/microliter 75%IQR: 0–184.25; range 0–210 days). Conclusions At baseline, sIL-6 correlates with PR3-ANCA titers and associates with the presence of fever and pulmonary nodules/cavities. A rise in sIL-6 levels after complete remission is associated with subsequent severe relapse only in RTX-treated patients. The observed discrepancies between treatments deserve confirmation and further study. References [1] Nishimoto N, et al. Interleukin 6: from bench to bedside. Nat Clin Pract Rheumatol. 2006;2(11):619–26. [2] Stone JH, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. The New England journal of medicine2010;363(3):221–32. Disclosure of Interest None declared

Background Prior work has shown that urinary soluble CD163 (usCD163) displays excellent biomarker characteristics for detection of active renal vasculitis using samples that included new diagnoses with highly active renal disease. This study focused on the use of usCD163 in the detection of the more clinically relevant state of mild renal flare and compared results of usCD163 testing directly to testing of urinary monocyte chemoattractant protein-1 (uMCP-1). Methods Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV, n = 88) were identified within a serially sampled, longitudinal and multicentre cohort. Creatinine-normalized usCD163 and uMCP-1 levels were measured by enzyme-linked immunosorbent assay and, both alone and in combination, were compared between times of active renal AAV and during remission and/or active non-renal AAV. Results Samples from 320 study visits included times of active renal vasculitis (n = 39), remission (n = 233) and active extrarenal vasculitis (n = 48). Median creatinine levels were 0.9 mg/dL [interquartile range (IQR) 0.8–1.2] in remission and 1.4 mg/dL (IQR 1.0–1.8) during renal flare. usCD163 levels were higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 162 ng/mmol (IQR 79–337), 44 (17–104) and 38 (7–76), respectively (P Conclusion A combination of usCD163 and uMCP-1 measurements appears to be useful in identifying the diagnosis of subtle renal vasculitis flare.

OBJECTIVE. The pathogenesis of eosinophilic granulomatosis with polyangiitis (EGPA) remains poorly understood, and may overlap with eosinophilic asthma and primary hypereosinophilic syndrome (HES). The aim of this study was to analyse a panel of serum cytokines and chemokines as markers of disease activity in patients with these conditions. METHODS. The levels of 54 cytokines and chemokines were measured in the sera of 40 patients with active EGPA, 10 of these patients during inactive disease, 6 patients with HES, 8 with asthma, and 10 healthy controls. Serum cytokine/chemokines measured included interleukin (IL)-1α, 1β, 3, 4, 5, 6, 8, 13, 15, 17A, 17E(25), 18, 23 and 33, soluble IL-2 receptor alpha, eotaxin-1 (CCL11), -2 (CCL24) and -3 (CCL26), macrophage-derived chemokine (MDC/CCL22), macrophage inflammatory protein (MIP)-1a and -1b, and tumour necrosis factor (TNF)-α. Results were compared between disease and control groups using regression analysis, with Bonferroni correction for multiple comparisons (significant p-value ≤0.00093). RESULTS. Significant differences were observed only in serum levels of MDC, IL-8, MIP-1a and -1b, TNF-α, each of which were lower in patients with active EGPA than in healthy controls (p