OBJECTIVES:To investigate the relation between adherence to dietary recommendations, the quantified intake of the components of these recommendations, and the risk of developing giant cell arteritis (GCA). METHODS:Participants in the Malmö Diet and Cancer Study cohort who subsequently developed GCA were identified through register linkage and validated in a structured review. Four controls, matched for age, sex, and year of inclusion, were selected per case. Diet quality was assessed using the Swedish Dietary Guidelines Score (SDGS, range 0-5). The relations for the SDGS, adherence to recommendations for each component and total intake of each component with development of GCA were assessed using logistic regression, adjusted for total energy intake, leisure-time physical activity and alcohol intake. Potential misreporters of total energy intake were excluded. RESULTS:There were 193 incident cases of GCA. High adherence to dietary guidelines (SDGS 4-5 vs 0-1) was associated with subsequent development of GCA (adjusted odds ratio 2.70; 95% CI 1.43-5.10). In adjusted models, adherence to recommended intake of added sugar, fish and shellfish and vegetables and fruit was associated with an increased risk of GCA. A reduced risk was seen with higher quantified consumption of added sugar, and an increased risk with higher intakes of fiber and fish and shellfish. CONCLUSIONS:An overall high diet quality was independently associated with an increased risk of GCA. This is compatible with the concept of an increased risk of GCA in subjects with a healthy metabolic profile, and of metabolic regulation of early disease mechanisms in GCA.

OBJECTIVE:The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are heterogeneous disorders. The aim of this study was to identify and characterize subgroups of patients based on sex, ANCA, age at diagnosis, and organ involvement. METHODS:In total, 1,167 patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) were retrospectively recruited to the study. Data including cumulative involvement of 10 different organ systems, end-stage kidney disease (ESKD), sex, proteinase (PR) 3-ANCA, myeloperoxidase (MPO)-ANCA, age at diagnosis, disease duration, and relapse were obtained from medical records. Clinical variables were analyzed for associations with sex, age at diagnosis, and relapse using logistic regression analysis. Thirteen clinical variables were included in hierarchical cluster analyses using the Ward method. RESULTS:In patients with GPA, PR3-ANCA, renal and pulmonary involvement, and ESKD were significantly associated with male sex, whereas MPO-ANCA was associated with female sex. Patients with GPA who were younger than 32 years of age at diagnosis were significantly more often females and had more ear-nose-throat involvement than patients older than 32 years. In patients with MPA, female patients were significantly younger at diagnosis than male patients. Relapse was significantly associated with young age at diagnosis and pulmonary involvement in GPA and with musculoskeletal involvement in MPA. Hierarchical cluster analyses identified five and seven patient clusters among individuals with GPA and MPA, respectively. PR3-/MPO-ANCA defined the largest clusters, whereas heart, gastrointestinal, and central nervous system involvement were hallmarks for three clusters for both patients with GPA and MPA. CONCLUSION:Sex, age at diagnosis, and specific organ involvements define clinically relevant subgroups among patients with ANCA-associated vasculitides.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has a relapsing-remitting course and, even with the availability of effective maintenance therapies such as rituximab, relapse rates remain high. Relapse is associated with the accrual of organ damage stemming from both the underlying disease and from the effects of AAV treatments; thus, early detection and proactive prevention are crucial. AAV study populations typically include mixed cohorts of patients with new-onset and relapsing disease. Although data specifically addressing re-induction of remission after relapse are limited, available evidence suggests high remission rates when rituximab is combined with glucocorticoids. However, the balance between effective disease control and the potential treatment-related side effects must be carefully considered, and new therapeutic options may help improve this tradeoff. The aim of this review is to explore what is known about relapse risk and relapse management while considering emerging pathogenic and therapeutic paradigms.

Systemic vasculitis, common forms of which include anti-neutrophil cytoplasmic antibody-associated small-vessel vasculitis, large-vessel vasculitis and Behçet syndrome, are frequently complicated by arterial or venous thrombotic events (AVTEs). Newly identified entities such as DADA2 (deficiency of adenosine deaminase 2) and VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, which are driven by genetic mutations, also exhibit vasculitic features and are associated with a high risk of AVTEs. AVTEs in systemic vasculitis, including monogenic forms of vasculitis, are due to the complex interaction of inflammation and coagulation. New insights into the pathogenetic mechanisms implicate endothelial dysfunction, immune complex deposition and the interplay of pro-inflammatory cytokines with prothrombotic factors, which collectively promote thrombus formation. AVTEs impose a substantial disease burden, complicate diagnosis and negatively affect prognosis by increasing the risk of morbidity and mortality. Early diagnosis and treatment are crucial to prevent lasting damage. Management strategies should target both thrombosis and underlying inflammation. Antithrombotic therapies, including low-dose aspirin, or oral anticoagulants should be used on the basis of individual thrombotic risk assessment. Immunosuppressive therapy is the cornerstone of treatment for arterial and venous thrombosis, particularly in Behçet syndrome, in which vascular inflammation has a crucial role in thrombotic complications. Systemic vasculitis, including monogenic forms, is associated with an increased risk of arterial and venous thromboembolic events (AVTEs). This Review highlights the latest advances in the understanding of the pathogenesis, clinical features and management of AVTEs in systemic and monogenic vasculitis.

Objective Giant cell arteritis (GCA) is a systemic disease with variable vascular involvement. The objective was to investigate predictors of time-dependent large-vessel involvement (LVI) in a population-based cohort of patients with GCA. Methods GCA patients with positive temporal artery biopsies (TAB) between 1997-2010 were identified through a regional pathology register. A structured review of histopathology reports and relevant imaging studies was performed. Cases with LVI through July 2016 were identified. Patients were followed to first LVI, death, migration from the area or July 29, 2016. Event free survival by clinical and histopathologic features was estimated using the Kaplan-Meier method. Potential predictors of LVI were examined using Cox regression models. Results A total of274 patients were included. The mean age at GCA diagnosis was 75.7 years. Fifty-one patients (19 %) had documented LVI during the follow-up, corresponding to an incidence rate of 2.4/100 person-years. The median time from GCA diagnosis to the diagnosis of LVI was 4.5 years (interquartile range 0.6-7.4). Thirty-four patients had aortic involvement (67% of those with LVI; 12% of all GCA cases). Survival free of LVI was longer in patients with giant cells in the TAB (75th percentile 14.0 vs 6.7 years; p=0.014). In age-adjusted analysis, the presence of giant cells in the TAB was associated with reduced risk of LVI (hazard ratio 0.48; 95 % confidence interval 0.27-0.86). Conclusion The negative association with giant cells in the TAB suggests that patients with LVI constitute a subset of GCA with particular disease mechanisms.

Objective:To identify predictors of GCA in patients with PMR. Methods:Patients with PMR were identified among participants in two population-based health surveys. Those with a registered diagnosis indicating PMR in national and regional registers (the latter including primary care) were included. Medical records from hospitals and primary care were systematically reviewed. PMR diagnoses were verified by a rheumatologist in an independent review. Potential predictors were examined using logistic regression analysis. Results:Of 1508 medical records, 1030 had sufficient data available. PMR diagnoses were verified in 626 patients (61%). GCA was diagnosed within 1 month of PMR diagnosis in 37 patients and at a later time point in 20 patients. Female patients were more likely to develop GCA at PMR diagnosis or later [odds ratio (OR) 2.38 (95% CI 1.23, 4.61)]. Higher ESR and CRP levels were also associated with GCA. A lower risk for GCA was seen in those presenting with pain/stiffness in the hip [OR 0.51 (95% CI 0.28, 0.92)]. Conclusion:In this large cohort of patients with verified PMR, GCA was diagnosed in a limited subset (9%) and was more common in females. A lower risk for GCA was seen in patients with pain/stiffness in the hip at onset of PMR, suggesting that prominent musculoskeletal symptoms and cranial arteritis represent different parts of the GCA-PMR spectrum.

Given the limited data on the epidemiology and outcomes of patients with Interstitial Lung Disease (ILD) associated with ANCA-associated Vasculitis (AAV) or positive ANCA and the conflicting results regarding the effectiveness of immunosuppressive treatments, our objective is to describe the long-term outcomes and evaluate the impact of immunosuppressive therapy on lung function. A European multicentre retrospective study encompassed patients with ILD-associated with AAV or ANCA. The diagnosis of ILD was confirmed by a CT chest pattern of usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), organising pneumonia or chronic hypersensitivity pneumonia. Time-to-event analyses were employed to evaluate both survival and respiratory survival, defined as independency from long-term oxygen treatment. The impact of immunosuppressive therapy was assessed by the relative change in percentage of predicted Forced Vital Capacity (FVC) and Diffusing Capacity for Carbon Monoxide (TLCOc) between treatment initiation and 12 months. 173 patients with ILD were included. 135 had ILD with ANCA positivity with vasculitis (AAV-ILD) and 38 had ILD with ANCA positivity without vasculitis (ANCA-ILD). The mean age at ILD diagnosis was 70 ± 11 years, and 82% was positive for MPO-ANCA. The most prevalent radiological pattern observed was UIP (66%) and the most common extrapulmonary involvement the kidney (70%). Median survival was 9.8 years, with a trend favouring earlier mortality in ANCA-ILD compared to AAV-ILD (log-rank, P = 0.053). Median respiratory survival for the entire cohort was 13 years. Over a median follow-up of 4.9 years (interquartile range 2–8), the adjusted mean annual rates of absolute decline were −3.1% for FVC % and −3.8% for TLCOc %. In multivariate Cox regression analysis age (Hazard ratio (HR) 1.1; 95% CI, 1.06 to 1.16), baseline FVC % (HR 0.9; 95% CI, 0.96 to 0.99), baseline TLCOc % (HR 0.9; 95% CI, 0.96 to 0.99), and long-term oxygen requirement (HR 2; 95% CI, 1.08 to 3.88) were identified as significant predictive factors for mortality. 90% of the cohort, received immunosuppressive treatment, which included cyclophosphamide (CYC) in 52%, rituximab (RTX) in 17%, combination in 12%, mycophenolate mofetil (MMF) or methotrexate in 9% as part of the induction regimen. Evaluating the impact of immunosuppression on lung progression over 12 months revealed slowing of the decline of FVC % and TLCO %, most evident in CYC and RTX-treated patients. Our study provides insights into the long-term outcomes of AAV and ANCA associated ILD, where lung severity emerged as a predominant risk factor for mortality. Immunosuppressive treatment appeared to retard progression of lung disease in the short term.

BACKGROUND:Following the results of the MANDARA trial, this real-life study aimed at comparing the effectiveness and safety profile of mepolizumab versus benralizumab in a European EGPA cohort. METHODS:We conducted a retrospective observational comparative study including EGPA patients, who received mepolizumab or benralizumab at the asthma dose. Patients were matched 1:1 by sex, age, BVAS and oral corticosteroid (OCS) dosage at the treatment initiation (T0). Complete response (CR) and partial response (PR), disease activity, OCS, pulmonary parameters, eosinophil count, relapses, and safety outcomes were also compared at 3, 6 and 12 months. RESULTS:Patients treated with mepolizumab or benralizumab (n = 88 each) were matched: 57 % were females, median age was 54 years (IQR 45-60), median OCS dose 10 (7.5-12.5) and 10 (7-13) mg/day, median BVAS 4 (2-7) and 3 (2-8), respectively. 45.4 % of patients in the mepolizumab group and 51.1 % in the benralizumab group achieved CR or PR at T3, with CR steadily increasing during follow-up for both treatments. At T12, a higher CR rate was found in the benralizumab group (48.1 % vs 32.4 %, p = 0.005). No differences in BVAS, OCS, and respiratory parameters were observed between groups at the different timepoints. Throughout the follow-up, both treatments reduced eosinophil count, although a deeper reduction was found in the benralizumab group at all timepoints (p < 0.0001). Safety profile was comparable between patient groups. CONCLUSION:Mepolizumab and benralizumab showed comparable overall effectiveness and safety in EGPA. However, benralizumab achieved a higher CR rate at T12, and a deeper peripheral eosinophil reduction.

Objectives To determine the incidence rate (IR) and predictors of myocardial infarction (MI) in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) as well as to estimate the IR ratio (IRR) of MI in AAV versus the background population.Methods 325 patients diagnosed with AAV 1997–2016 in Skåne, Sweden were included. Data were collected from the time of AAV diagnosis, and each patient was grouped with 10 age-matched and sex-matched reference subjects from the background population. MI after AAV diagnosis was identified using Swedish Web-System for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated According to Recommended Therapies and the Skåne Healthcare Register, and IR of first MI calculated. The IRR was computed by dividing the IR for 282 AAV patients by the corresponding rate in the 2763 reference subjects. Predictors of MI were analysed using Cox regression.Results 37 patients (11%) with AAV suffered an initial MI, yielding an IR of 1.6/100 person-years of follow-up (95% CI 1.2 to 2.2). The highest rate was recorded in the 3 months following AAV diagnosis, at 11.8/100 person-years (95% CI 6.2 to 22.7). The IRR of MI in AAV/reference was 1.9 (95% CI 1.3 to 2.8), highest in patients with myeloperoxidase-ANCA+disease (IRR 2.5, 95% CI 1.5 to 4.3) and those with high disease activity at diagnosis (2.1, 95% CI 1.3 to 3.3). Age at AAV diagnosis independently predicted MI.Conclusions The MI IR is greater in individuals diagnosed with AAV compared with background population, especially those with more severe disease, and highest in the 3 months following diagnosis. Age at diagnosis is the single independent predictor of MI in AAV in this study.

Objectives To determine clinical characteristics, outcome and occurrence of comorbidities in patients with biopsy-confirmed giant cell arteritis (GCA) treated with intravenous methylprednisolone (IVMP) vs those receiving oral glucocorticoids (OGC) only.Methods A retrospective study included patients with GCA diagnosed from 2004 through 2019. Clinical and laboratory characteristics, and cumulative GC dose were compared in patients receiving IVMP vs OGCs. Changes in visual acuity (VA), occurrence of comorbidities after GCA diagnosis, and mortality were analysed.Results A total of 419 patients (69% female) were included. In total, 111 patients were initially treated with IVMP, 104 (94%) of whom showed visual manifestations at onset and 308 received OGCs only. Ninety patients (21.5%) exhibited visual involvement at onset, verified by an ophthalmologist. Compared with OGC, patients receiving IVMP exhibited lower inflammatory response at presentation. There was a tendency for improvement in VA with the use of IVMP, but the results were not statistically significant (OR 1.19, 95% CI 0.35-4.01). Patients treated with IVMP had a higher risk of newly diagnosed diabetes mellitus within a year of GCA diagnosis (OR 2.59, 95% CI 1.19-5.63). This risk remained elevated after adjusting for cumulative OGC dose at three months (adjusted OR 3.30, 95% CI 1.29-8.43). There was no difference in survival between treatment groups.Conclusions Our study found no evidence supporting any benefit of using IVMP in improving VA or survival. IVMP may increase diabetes risk within a year of GCA diagnosis. Further studies are needed to evaluate the value of IVMP in GCA.

The etiology of giant cell arteritis (GCA) and its predictors are incompletely understood. Previous studies have indicated reduced risk of future development of GCA in individuals with obesity and/or diabetes mellitus. There is limited information on blood lipids before the onset of GCA. The objective of the study was to investigate the relation between apolipoprotein levels and future diagnosis of GCA in a nested case–control analysis. Individuals who developed GCA after inclusion in a population-based health survey (the Malmö Diet Cancer Study; N = 30,447) were identified by linking the health survey database to the local patient administrative register and the national patient register. A structured review of medical records was performed. Four controls for every validated case, matched for sex, year of birth, and year of screening, were selected from the database. Anthropometric measures, self-reported physical activity, based on a comprehensive, validated questionnaire, and non-fasting blood samples had been obtained at health survey screening. Concentrations of apolipoprotein A-I (ApoA-I) and apolipoprotein B (ApoB) in stored serum were measured using an immunonephelometric assay. Potential predictors of GCA were examined in conditional logistic regression models. There were 100 cases with a confirmed clinical diagnosis of GCA (81

Objectives This study aims to describe the data structure and harmonisation process, explore data quality and define characteristics, treatment, and outcomes of patients across six federated antineutrophil cytoplasmic antibody-associated vasculitis (AAV) registries. Methods Through creation of the vasculitis-specific Findable, Accessible, Interoperable, Reusable, VASCulitis ontology, we harmonised the registries and enabled semantic interoperability. We assessed data quality across the domains of uniqueness, consistency, completeness and correctness. Aggregated data were retrieved using the semantic query language SPARQL Protocol and Resource Description Framework Query Language (SPARQL) and outcome rates were assessed through random effects meta-analysis. Results A total of 5282 cases of AAV were identified. Uniqueness and data-type consistency were 100% across all assessed variables. Completeness and correctness varied from 49%–100% to 60%–100%, respectively. There were 2754 (52.1%) cases classified as granulomatosis with polyangiitis (GPA), 1580 (29.9%) as microscopic polyangiitis and 937 (17.7%) as eosinophilic GPA. The pattern of organ involvement included: lung in 3281 (65.1%), ear-nose-throat in 2860 (56.7%) and kidney in 2534 (50.2%). Intravenous cyclophosphamide was used as remission induction therapy in 982 (50.7%), rituximab in 505 (17.7%) and pulsed intravenous glucocorticoid use was highly variable (11%–91%). Overall mortality and incidence rates of end-stage kidney disease were 28.8 (95% CI 19.7 to 42.2) and 24.8 (95% CI 19.7 to 31.1) per 1000 patient-years, respectively. Conclusions In the largest reported AAV cohort-study, we federated patient registries using semantic web technologies and highlighted concerns about data quality. The comparison of patient characteristics, treatment and outcomes was hampered by heterogeneous recruitment settings.

BACKGROUND:Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a heterogenous autoimmune disease. While traditionally stratified into two conditions, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the subclassification of ANCA-associated vasculitis is subject to continued debate. Here we aim to identify phenotypically distinct subgroups and develop a data-driven subclassification of ANCA-associated vasculitis, using a large real-world dataset. METHODS:In the collaborative data reuse project FAIRVASC (Findable, Accessible, Interoperable, Reusable, Vasculitis), registry records of patients with ANCA-associated vasculitis were retrieved from six European vasculitis registries: the Czech Registry of ANCA-associated vasculitis (Czech Republic), the French Vasculitis Study Group Registry (FVSG; France), the Joint Vasculitis Registry in German-speaking Countries (GeVas; Germany), the Polish Vasculitis Registry (POLVAS; Poland), the Irish Rare Kidney Disease Registry (RKD; Ireland), and the Skåne Vasculitis Cohort (Sweden). We performed model-based clustering of 17 mixed-type clinical variables using a parsimonious mixture of two latent Gaussian variable models. Clinical validation of the optimal cluster solution was made through summary statistics of the clusters' demography, phenotypic and serological characteristics, and outcome. The predictive value of models featuring the cluster affiliations were compared with classifications based on clinical diagnosis and ANCA specificity. People with lived experience were involved throughout the FAIRVASVC project. FINDINGS:A total of 3868 patients diagnosed with ANCA-associated vasculitis between Nov 1, 1966, and March 1, 2023, were included in the study across the six registries (Czech Registry n=371, FVSG n=1780, GeVas n=135, POLVAS n=792, RKD n=439, and Skåne Vasculitis Cohort n=351). There were 2434 (62·9%) patients with GPA and 1434 (37·1%) with MPA. Mean age at diagnosis was 57·2 years (SD 16·4); 2006 (51·9%) of 3867 patients were men and 1861 (48·1%) were women. We identified five clusters, with distinct phenotype, biochemical presentation, and disease outcome. Three clusters were characterised by kidney involvement: one severe kidney cluster (555 [14·3%] of 3868 patients) with high C-reactive protein (CRP) and serum creatinine concentrations, and variable ANCA specificity (SK cluster); one myeloperoxidase (MPO)-ANCA-positive kidney involvement cluster (782 [20·2%]) with limited extrarenal disease (MPO-K cluster); and one proteinase 3 (PR3)-ANCA-positive kidney involvement cluster (683 [17·7%]) with widespread extrarenal disease (PR3-K cluster). Two clusters were characterised by relative absence of kidney involvement: one was a predominantly PR3-ANCA-positive cluster (1202 [31·1%]) with inflammatory multisystem disease (IMS cluster), and one was a cluster (646 [16·7%]) with predominantly ear-nose-throat involvement and low CRP, with mainly younger patients (YR cluster). Compared with models fitted with clinical diagnosis or ANCA status, cluster-assigned models demonstrated improved predictive power with respect to both patient and kidney survival. INTERPRETATION:Our study reinforces the view that ANCA-associated vasculitis is not merely a binary construct. Data-driven subclassification of ANCA-associated vasculitis exhibits higher predictive value than current approaches for key outcomes. FUNDING:European Union's Horizon 2020 research and innovation programme under the European Joint Programme on Rare Diseases.

Background Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update. Methods Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations. Results Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4–5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV. Conclusions In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.