Data quality and patient characteristics in European ANCA-associated vasculitis registries: data retrieval by federated querying.

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.

EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update.

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.

Associations between plasma metabolism associated proteins and future development of giant cell arteritis: results from a prospective study.

OBJECTIVE: To investigate the relation between biomarkers associated with metabolism and subsequent development of giant cell arteritis (GCA). METHOD: Participants in the population-based Malmö Diet Cancer Study (MDCS; N = 30447), who were subsequently diagnosed with GCA, were identified in a structured process. Matched GCA-free controls were selected from the study cohort. Baseline plasma samples were analyzed using the antibody-based OLINK proteomics metabolism panel (92 metabolic proteins). Analyses were pre-designated as hypothesis-driven or hypothesis-generating. In the latter, principal component analysis was used to identify groups of proteins that explain the variance in the proteome. RESULTS: There were 95 cases with a confirmed incident diagnosis of GCA (median 12.0 years after inclusion). Among biomarkers with a priori hypotheses, Adhesion G protein-coupled receptor E2 (ADGRE2) was positively associated (odds ratio (OR) per standard deviation (SD) 1.67; 95% CI 1.08-2.57), and Fructose-1,6-bisphosphatase 1 (FBP1) negatively associated (OR per SD 0.59; 95% CI 0.35-0.99) with GCA. In particular, ADGRE2 levels were associated with subsequent GCA in the subset sampled <8.5 years before diagnosis. For meteorin-like protein (Metrnl), the highest impact on the risk of GCA was observed in those sampled closest to diagnosis with a decreasing trend with longer time to GCA (p= 0.03). In the hypothesis generating analyses, elevated levels of receptor tyrosine-like orphan receptor 1 (ROR1) were associated with subsequent GCA. CONCLUSION: Biomarkers identified years before clinical diagnosis indicated a protective role of gluconeogenesis (FBP1) and an association with macrophage activation (ADGRE2 and Metrnl) and proinflammatory signals (ROR1) for development of GCA.

Giant cells in temporal artery biopsies and the risk of large vessel involvement in patients with giant cell arteritis.

OBJECTIVES: 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 of 274 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). CONCLUSIONS: The negative association with giant cells in the TAB suggests that patients with LVI constitute a subset of GCA with particular disease mechanisms.

Classification Criteria for ANCA Associated Vasculitis - Ready for Prime Time?

PURPOSE OF REVIEW: This review aims to summarize the evolution and recent developments in the classification of ANCA associated vasculitis (AAV) and to summarize evaluations of the 2022 ACR/EULAR classification criteria of AAV in several cohorts. RECENT FINDINGS: The classification of AAV has been a field of controversy for some time. The parallel existence of classification criteria and disease definitions produced some overlap in classification, leading to challenges when comparing different cohorts. The 2022 ACR/EULAR classification criteria derived from the largest study ever conducted in vasculitis account for significant changes in vasculitis classification with the integration of ANCA and modern imaging. These criteria show good performance compared to previous ones but also raise questions as ANCA serotypes have substantial impact on classification. In addition, there are some discrepancies with earlier agreed histopathological features of AAV disease phenotypes. During the last 35 years, several sets of classification criteria have evolved to facilitate epidemiologic studies and clinical trials in AAV. While some of these criteria have been in use for many years, they were criticized due to either not using ANCA or not integrating surrogate markers for vasculitis but also due to overlapping when used in parallel. The long-awaited new ACR/EULAR criteria for AAV were published in 2022 and are the result of a large international study, introducing for the first time ANCA and modern imaging in the classification of AAV. Though the criteria show good performance, they bring several other challenges with practical application.

Evaluation of the ACR/EULAR 2022 criteria for classification of ANCA-associated vasculitis in a population-based cohort from Sweden.

OBJECTIVE: To evaluate the ACR/EULAR 2022 criteria for AAV classification and compare it to the EMA algorithm and to classification based only on ANCA serology. METHODS: In the analysis, 374 cases (47% female) were classified according to EMA algorithm, ANCA serology, and ACR/EULAR criteria. The agreement rate was calculated using the kappa (κ) statistic. RESULTS: Under EMA, 192 patients were classified as GPA, 159 as MPA, and 23 as EGPA. The ACR/EULAR criteria classified 199 patients as GPA, 136 as MPA, and 22 as EGPA. Four patients (1.1%) met criteria of two disease categories, and thirteen (3.5%) were unclassifiable. The observed agreement between EMA and ACR/EULAR was 85% for GPA, 75% for MPA, and 96% for EGPA. The unweighted κ statistic was 0.66 (95% CI 0.60-0.74). Of the 188 PR3-ANCA-positive patients, 186 (98.9%) were classified as GPA using ACR/EULAR criteria, and 135 of 161 (83.8%) MPO-ANCA-positive patients were classified as MPA. With a classification solely based on ANCA-specificity, agreement with ACR/EULAR was 99% for GPA and 88% for MPA. CONCLUSIONS: EMA and ACR/EULAR classification give similar results. A small proportion of patients cannot be classified or fall into two categories. Some patients exhibiting granuloma, a key feature of GPA, are nevertheless classified as MPA, conflicting with the current view of histopathology of AAV. There is high agreement of ANCA-based classification with that of ACR/EULAR, reflected in the considerable weight granted to ANCA in the new criteria. These crucial elements within the new criteria necessitate a consensus discussion among field experts.

High risk of stroke in ANCA-associated vasculitis-a population-based study.

OBJECTIVE: To determine the incidence rate, predictors and outcome of stroke in a population-based cohort of individuals with ANCA-associated vasculitis (AAV). METHODS: The study included 325 patients diagnosed with AAV from 1997 through 2016 in a defined geographic area of Sweden. Patients who suffered a stroke were identified from Riksstroke, a national Swedish stroke register established in 1994, and the Skåne Healthcare Register (SHR), which includes data for all inhabitants of Skåne since 1998. Case record review was carried out to confirm the diagnosis of stroke in AAV patients identified in the SHR. The incidence rate of stroke was calculated per 1000 person-years of follow-up. Using data from the Swedish general population, the standardized incidence ratio (SIR) of stroke was estimated. Cox regression analysis was utilized to investigate survival and predictors of stroke. RESULTS: Twenty-five subjects (8%) suffered a stroke during 2206 person-years of follow-up. The incidence rate of stroke in AAV was 11.3/1000 person-years (95% CI 6.9, 15.8). Patients with AAV showed an increased risk of stroke compared with the general population [SIR 1.85 (95% CI 1.27, 2.59)], with a greater risk for those <65 years of age [SIR 3.19 (95% CI 1.53, 5.88)]. Higher platelet count at AAV diagnosis was an independent predictor of stroke [hazard ratio 1.14 (95% CI 1.00, 1.29)]. There were no differences in survival or other outcome measures between AAV patients with and without stroke. CONCLUSIONS: The incidence rate of stroke in AAV is higher than in the general population. High platelet count at AAV diagnosis was associated with an increased risk of stroke.

Analyses of plasma inflammatory proteins reveal biomarkers predictive of subsequent development of giant cell arteritis: a prospective study.

OBJECTIVE: To investigate the relation between biomarkers of inflammation and subsequent development of GCA. METHOD: Participants in the population-based Malmö Diet Cancer Study (MDCS; N = 30 447), established 1991-96, who were subsequently diagnosed with GCA, were identified in a structured process. GCA-free controls, matched for sex, year of birth and year of screening were selected from the study cohort. Baseline plasma samples were analysed using the antibody-based OLINK proteomics inflammation panel (92 inflammatory proteins). Analyses were pre-designated as hypothesis-driven or hypothesis-generating. In the latter, principal component analysis was used to identify groups of proteins that explain the variance in the proteome. Within components selected based on eigenvalues, proteins with a factor loading of >0.50 were investigated. RESULTS: Ninety-four cases with a confirmed incident diagnosis of GCA (median 11.9 years after inclusion) were identified. Among biomarkers with a priori hypotheses, IFN-γ was positively associated with GCA [odds ratio (OR) per s.d. 1.52; 95% CI 1.00, 2.30]. Eight biomarkers in the hypothesis-generating analyses were significantly associated with development of GCA. Among these, higher levels of IFN-γ (OR 2.37; 95% CI 1.14, 4.92) and monocyte chemotactic protein 3 (MCP3) (OR 4.27; 95% CI 1.26, 14.53) were particularly associated with increased risk of GCA in the subset sampled <8.5 years before diagnosis. Several other proteins known to be important for T cell function were also associated with GCA in these analyses, e.g. CXCL9, IL-2, CD40 and CCL25. CONCLUSION: Elevated IFN-γ levels were found years prior to diagnosis of GCA. T cell activation may precede the clinical onset of GCA.

Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis.

OBJECTIVE: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. CONCLUSIONS: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

An update on polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease affecting people older than 50 years and is 2-3 times more common in women. The most common symptoms are pain and morning stiffness in the shoulder and pelvic girdle and the onset may be acute or develop over a few days to weeks. General symptoms such as fatigue, fever and weight loss may occur, likely driven by systemic IL-6 signalling. The pathology includes synovial and periarticular inflammation and muscular vasculopathy. A new observation is that PMR may appear as a side effect of cancer treatment with checkpoint inhibitors. The diagnosis of PMR relies mainly on symptoms and signs combined with laboratory markers of inflammation. Imaging modalities including ultrasound, magnetic resonance imaging and positron emission tomography with computed tomography are promising new tools in the investigation of suspected PMR. However, they are still limited by availability, high cost and unclear performance in the diagnostic workup. Glucocorticoid (GC) therapy is effective in PMR, with most patients responding promptly to 15-25 mg prednisolone per day. There are challenges in the management of patients with PMR as relapses do occur and patients with PMR may need to stay on GC for extended periods. This is associated with high rates of GC-related comorbidities, such as diabetes and osteoporosis, and there are limited data on the use of disease-modifying antirheumatic drugs and biologics as GC sparing agents. Finally, PMR is associated with giant cell arteritis that may complicate the disease course and require more intense and prolonged treatment.

Infection is associated with increased risk of MPO- but not PR3-ANCA-associated vasculitis.

OBJECTIVES: To determine whether development of ANCA-associated vasculitis (AAV) shows a relationship with a prior infection and if prior infection affects disease characteristics and outcome. METHODS: All incident cases of AAV diagnosed in a defined region of Sweden from 2000 through 2016 were identified. For each case, 10 individuals from the general population, matched for age, sex and area of residence, were selected. Infections occurring in AAV patients and controls prior to the date of AAV diagnosis (index date for respective controls) were identified using an administrative database. Conditional logistic regression models were used to calculate odds ratios (OR) of developing AAV. Occurrence, clinical characteristics and outcome of AAV were analysed with respect to prior infection. RESULTS: Two-hundred and seventy patients with AAV (48% female) and 2687 controls were included. Prior to diagnosis/index date, 146 (54%) AAV patients had been diagnosed with infection vs 1282 (48%) controls, with OR for AAV 1.57 (95% CI 1.18, 2.19) in those with infections of the upper respiratory tract and 1.68 (1.02, 2.77) in those with pneumonia. Difference from controls was significant in patients with MPO-ANCA 1.99 (95% CI 1.25, 3.1) but not in those with PR3-ANCA 1.0 (0.61, 1.52). Patients with prior infection showed higher disease activity at AAV diagnosis. No differences in disease characteristics, comorbidities or outcome in those with and without prior infections were observed. CONCLUSIONS: Respiratory tract infections are positively associated with development of MPO- but not PR3-ANCA vasculitis. Prior infection is associated with higher disease activity at AAV diagnosis.

Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA.

OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). METHODS: Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. RESULTS: PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 × 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 × 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 × 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 × 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 × 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

Anti-neutrophil cytoplasmic antibodies predate symptom onset of ANCA-associated vasculitis. A case-control study.

OBJECTIVES: Anti-neutrophil cytoplasmic autoantibodies [ANCA) are important for diagnosis of ANCA-associated vasculitides (AAV). The timing of antibody development is not well established. To investigate the development of proteinase 3 (PR3)- and myeloperoxidase (MPO)-ANCA, blood samples collected before onset of symptoms of AAV were analysed. METHODS: To identify AAV patients with blood samples predating symptoms, the National Patient Register and Cause of Death register were scrutinized for ICD codes for AAV and linked to the registers of five biobanks. Diagnoses of AAV and time point for symptom onset were confirmed by reviewing 504 case-record. Eighty-five AAV cases (34 males, 51 females) with samples >1 month < 10 years from AAV symptom onset and two controls matched for sex, age, and sampling time for each case were included. Samples were screened using ELISAs for ANCA and further analysed for PR3-or MPO- specificities. RESULTS: In ANCA-screen 35.7% of the pre-symptomatic cases and 3.5% of controls tested positive (p < 0.01). 26.2% of the cases were PR3-ANCA+ and 10.7% MPO-ANCA+. Median (Q1-Q3) predating time for PR3-ANCA+ was 2.7 (0.3-7.7) years and MPO-ANCA+ 2.0 (0.9-3.5) years. PR3-ANCA was demonstrated in samples up to nine years before symptom onset. At symptom onset predating PR3-ANCA+ cases were younger than PR3-ANCA- (P < 0.01), and MPO-ANCA+ were older than MPO-ANCA- (p < 0.05). Predating MPO-ANCA+ cases vs. MPO-ANCA- and vs. PR3-ANCA+ cases had more often at symptoms onset manifestations from lungs, kidneys or peripheral nervous system (p < 0.01 and p < 0.05, respectively). CONCLUSION: The PR3-and MPO-ANCAs are present years before AAV symptom onset and represent distinct diseases.

Venous thromboembolism in ANCA-associated vasculitis: a population-based cohort study.

OBJECTIVE: To determine incidence rate and predictors of venous thromboembolic events (VTE) in a population-based cohort with ANCA-associated vasculitis (AAV). METHODS: The study comprised 325 patients diagnosed with AAV from 1997 to 2016. All cases of VTE from prior to vasculitis diagnosis to the end of the study period were identified. The BVAS was used to assess disease activity at diagnosis. Venous thromboembolisms occurring in a period beginning 3 months prior to AAV diagnosis were considered to be AAV-related. The standardized incidence ratio (SIR) and 95% CI of VTE were calculated using the incidence rate in the general population. RESULTS: Fifty-nine patients (18%) suffered 64 VTE events. Of these, 48 (81%) suffered AAV-related VTE [deep vein thrombosis (n = 23), pulmonary embolism (n = 18) and other (n = 9)]. The incidence rate of AAV-related VTE was 2.4 per 100 person-years (95% CI 1.7, 3.0) during 2039 person-years of follow-up. The incidence during the first 3 months post-AAV diagnosis was 20.4 per 100 person-years (95% CI 11.5, 29.4), decreasing to 8.9 (95% CI 0.2, 17.6) and 1.5 (95% CI 0.0, 3.5) in months 4-6 and months 7-12 post-AAV diagnosis, respectively. The SIR was 34.2 (95% CI 20.2, 48.1) for deep vein thrombosis and 10.4 (95% CI 5.6, 15.1) for pulmonary embolism. In multivariate Cox regression analyses, only age and BVAS were predictive of VTE. CONCLUSIONS: The incidence rate and SIR of AAV-related VTE is high, and higher early in the course of the disease. Vasculitis activity and age are positively associated with VTE.

Evaluation of revised classification criteria for giant cell arteritis and its clinical phenotypes.

BACKGROUND: GCA is a systemic vasculitis of the elderly, viewed by many as a disease with multiple and overlapping clinical phenotypes. Retrospective studies have shown differences in clinical presentation between these phenotypes. To reflect the heterogeneity of GCA and novel diagnostic methods, new classification criteria have been proposed. METHODS: This is a retrospective study of newly diagnosed patients with GCA at the outpatient rheumatology clinics at Skåne University Hospital (Malmö and Lund) between 2012 and 2018. All patients were evaluated using two sets of classification criteria, the ACR classification criteria from 1990 and a proposed revision of these criteria requiring objective findings (positive biopsy or imaging) for classification. Patients were further classified as one of four widely used clinical phenotypes. RESULTS: A total of 183 patients with a new diagnosis of GCA were identified. The diagnosis was confirmed by one or two experienced rheumatologists in 116 of these patients during a review of medical records. The ACR criteria were more sensitive than the revised criteria (93.1% vs 72.4%), but the revised criteria had higher specificity (94.0% vs 28.4%). The revised criteria tended to have higher sensitivity in the phenotype with constitutional symptoms compared with cranial GCA (P = 0.08). CONCLUSION: The specificity of the ACR classification criteria for GCA can be improved by using revised criteria requiring objective findings of vasculitis. In addition, the wider symptoms covered by the revised criteria may improve classification of patients with a phenotype characterized by constitutional symptoms.

Epidemiology of biopsy-confirmed giant cell arteritis in southern Sweden-an update on incidence and first prevalence estimate.

OBJECTIVE: To characterize the epidemiology of temporal artery biopsy-positive (TAB+) GCA, including trends in incidence, seasonal variation and prevalence in Skåne, the southernmost region of Sweden. METHODS: All histopathology reports of TABs from 1997 through 2019 were reviewed to identify patients diagnosed with TAB+ GCA. Incidence rates based on the 23-year period and the point-prevalence at 31 December 2014 were determined. An alternative prevalence calculation included only TAB+ GCA patients living in the study area and receiving immunosuppressant therapy on the point-prevalence date. RESULTS: One thousand three hundred and sixty patients were diagnosed with TAB+ GCA (71% female). The average annual incidence 1997-2019 was 13.3 (95% CI: 12.6, 14.0) per 100 000 inhabitants aged ≥50 years and was higher in females (17.8; 95% CI: 16.7, 18.9) than in males (8.2; 95% CI: 7.4, 9.0). The age- and sex-standardized incidence declined from 17.3 in 1997 to 8.7 in 2019, with incidence ratio (IR) of 0.98 per year (95% CI: 0.98, 0.99). A seasonal variation was observed with higher incidence during spring than winter [IR = 1.19 (95% CI: 1.03, 1.39)]. The overall point-prevalence of TAB+ GCA was 127.1/100 000 (95% CI: 117, 137.3) and was 75.5 (95% CI: 67.7, 83.3) when including only patients receiving immunosuppressants. CONCLUSION: Over the past 2 decades, the incidence of biopsy-confirmed GCA has decreased by ∼2% per year. Still, a high prevalence of GCA on current treatment was observed. More cases are diagnosed during spring and summer than in the winter.

Incidence and predictors of severe infections in ANCA-associated vasculitis: a population-based cohort study.

OBJECTIVE: To determine the incidence rate, predictors and outcome of severe infections in a population-based cohort of ANCA-associated vasculitis (AAV). METHODS: The study included 325 cases of AAV (152 female) diagnosed from 1997 through 2016 from a defined geographic area in Sweden. All severe infection events (requiring hospitalization and treatment with intravenous antimicrobials) were identified. The Birmingham vasculitis activity score (BVAS) was used to evaluate disease activity, and organ damage was assessed using the vasculitis damage index (VDI). Patients were followed from time of AAV diagnosis to death or December 2017. RESULTS: A total of 129 (40%) patients suffered at least one severe infection. In 2307 person-years (PY) of follow-up, 210 severe infections were diagnosed. The incidence rate of severe infections was 9.1/100 PY and was highest during the first year following AAV diagnosis at 22.1/100 PY (P < 0.001). Pneumonia, sepsis and urinary tract infection were the most common infections. Opportunistic infections constituted only 6% of all severe infections. In Cox regression analysis age and BVAS at diagnosis were the only factors independently predicting severe infection [hazard ratio: 1.54 (P < 0.001) and 1.27 (P = 0.001), respectively]. Severe infection was associated with poorer prognosis with respect to median VDI score 12 months post-AAV diagnosis, renal survival and mortality. Severe infections were the cause of death in 32 patients (22% of all deaths). CONCLUSION: . Severe infection is a common problem in AAV, with the most important prognostic factors being older age and high disease activity at diagnosis. Severe infections are associated with permanent organ damage and high mortality.

High risk of coronary artery aneurysm in Kawasaki disease.

OBJECTIVE: Kawasaki disease (KD) is a vasculitis of unknown aetiology with a high risk of coronary aneurysms if untreated. Timely treatment with intravenous immunoglobulin decreases the risk for coronary artery aneurysms (CAA). In this study, we set out to elucidate the factors associated with the risk of developing CAA. METHODS: Records of all KD-diagnosed children in Skåne between 2004 and 2014 were collected and clinical and demographic data were compiled. KD is defined according to the revised American Heart Association diagnostic criteria and classified as either complete KD (cKD) or incomplete KD (iKD). RESULTS: KD was diagnosed in 77 children and CAA was found in 31% (n = 24). Children with CAA were younger compared with children without (median; 20 vs 34 months) and intravenous immunoglobulin treatment within 10 days was less likely to be received (75% vs 91%). In children presenting with iKD, 47% developed CAA compared with 21% in cKD patients. Using multivariate analysis, an association between the risk of CAA with low age in children with iKD was observed. CONCLUSION: The risk of CAA development is disturbingly high in young children with iKD. This highlights the importance of rapid intense treatment and vigilance in infants, who are the most difficult to diagnose, in order to reduce the frequency of CAA.

Association of venous thromboembolic events with skin, pulmonary and kidney involvement in ANCA-associated vasculitis: a multinational study.

OBJECTIVE: To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America. METHODS: Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs. RESULTS: Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15-60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR <15 ml/min/1.73 m2, OR 6.71 (95% CI: 2.94, 15.33)] involvement were independent variables associated with a higher occurrence of VTE. CONCLUSION: Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE.

International Consensus on ANCA Testing in Eosinophilic Granulomatosis with Polyangiitis.

An international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in eosinophilic granulomatosis with polyangiitis (EGPA) is presented. ANCA, specific for myeloperoxidase (MPO), can be detected in 30-35% of EGPA patients. MPO-ANCA should be tested with antigen-specific immunoassays in any patient with eosinophilic asthma and clinical features suggesting EGPA, including constitutional symptoms, purpura, polyneuropathy, unexplained heart, gastrointestinal or kidney disease, and/or pulmonary infiltrates or hemorrhage. A positive MPO-ANCA result contributes to the diagnostic work­up for EGPA. Patients with MPO-ANCA associated EGPA have more frequently vasculitis features, such as glomerulonephritis, neuropathy, and skin manifestations than patients with ANCA negative EGPA. However, the presence of MPO-ANCA is neither sensitive nor specific enough to identify whether a patient should be subclassified as having "vasculitic" or "eosinophilic" EGPA. At present, ANCA status cannot guide treatment decisions, that is, whether cyclophosphamide, rituximab or mepolizumab should be added to conventional glucocorticoid treatment. In EGPA, monitoring of ANCA is only useful when MPO-ANCA was tested positive at disease onset.