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Neuroimaging has a key role in identifying small-vessel vasculitis from common diseases it mimics, such as multiple sclerosis. Oftentimes, a multitude of these conditions present similarly, and thus diagnosis is difficult. To date, there is no standardized method to differentiate between these diseases. This review identifies and presents existing scoring tools that could serve as a starting point for integrating artificial intelligence/machine learning (AI/ML) into the clinical decision-making process for these rare diseases. A scoping literature review of EMBASE and MEDLINE included 114 articles to evaluate what criteria exist to diagnose small-vessel vasculitis and common mimics. This paper presents the existing criteria of small-vessel vasculitis conditions and mimics them to guide the future integration of AI/ML algorithms to aid in diagnosing these conditions, which present similarly and non-specifically.

Objectives: Chronic primary vasculitis describes a group of complex and rare diseases that are characterized by blood vessel inflammation. Classification of vasculitis subtypes is based predominantly on the size of the involved vessels and clinical phenotype. There is a recognized need to improve classification, especially for small-to-medium sized vessel vasculitides, that, ideally, is based on the underlying biology with a view to informing treatment. Methods: We performed RNA-Seq on blood samples from children (n = 41) and from adults (n = 11) with small-to-medium sized vessel vasculitis, and used unsupervised hierarchical clustering of gene expression patterns in combination with clinical metadata to define disease subtypes. Results: Differential gene expression at the time of diagnosis separated patients into two primary endotypes that differed in the expression of ~3,800 genes in children, and ~1,600 genes in adults. These endotypes were also present during disease flares, and both adult and pediatric endotypes could be discriminated based on the expression of just 20 differentially expressed genes. Endotypes were associated with distinct biological processes, namely neutrophil degranulation and T cell receptor signaling. Conclusions: Phenotypically similar subsets of small-to-medium sized vessel vasculitis may have different mechanistic drivers involving innate vs. adaptive immune processes. Discovery of these differentiating immune features provides a mechanistic-based alternative for subclassification of vasculitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gill, Smith, Gibson, Morishita, Lee, Falsafi, Graham, Foell, Benseler, Ross, Luqmani, Cabral, Hancock, Brown and the PedVas Initiative Investigators.)

Background: Rare chronic childhood vasculitides lack a reliable disease activity assessment tool. With emerging new treatment modalities such a tool has become increasingly essential for both clinical practice and therapeutic trials to reproducibly quantify change in disease state., Objective: To develop and validate a paediatric vasculitis activity assessment tool based on modification of the Birmingham Vasculitis Activity Score (BVASv.3)., Methods: A paediatric vasculitis registry was reviewed to identify clinical features missing in the BVASv.3. A modified nominal group technique was used to develop a working version of the Paediatric Vasculitis Activity Score (PVAS). Prospective validation provided tool reliability, reproducibility and responsiveness to change. Training of assessors was done according to the BVAS principles., Results: BVAS items were redefined (n=22) and eight paediatric items added in Cutaneous (n=4), Cardiovascular (n=3) and Abdominal (n=1) sections. The final PVAS has 64 active items in nine categories. The principles of new/worse and persistently active disease were retained as were the overall score and weighting of categories. The median PVAS in 63 children with systemic vasculitis was 4/63 (0-38/63). There was a high interobserver agreement for the overall as well as for subsystem scores (linear-weighted-κ ≥0.87). PVAS correlated with physician's global assessment (p<0.01); treatment decision (p=<0.01) and erythrocyte sedimentation rate (ESR) (p=0.01). In response to treatment, 15/19 patients assessed demonstrated a significant fall in PVAS (p=0.002), with good agreement among assessors for this change., Conclusions: The PVAS validity in children with systemic vasculitis was demonstrated. Like the BVAS, we anticipate that the PVAS will provide a robust tool to objectively define disease activity for clinical trials and future research.

Neuroimaging has a key role in identifying small-vessel vasculitis from common diseases it mimics, such as multiple sclerosis. Oftentimes, a multitude of these conditions present similarly, and thus diagnosis is difficult. To date, there is no standardized method to differentiate between these diseases. This review identifies and presents existing scoring tools that could serve as a starting point for integrating artificial intelligence/machine learning (AI/ML) into the clinical decision-making process for these rare diseases. A scoping literature review of EMBASE and MEDLINE included 114 articles to evaluate what criteria exist to diagnose small-vessel vasculitis and common mimics. This paper presents the existing criteria of small-vessel vasculitis conditions and mimics them to guide the future integration of AI/ML algorithms to aid in diagnosing these conditions, which present similarly and non-specifically. [ABSTRACT FROM AUTHOR]

Objective: Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is a rare, life‐threatening inflammation of blood vessels that can affect both adults and children. Compared to adult‐onset disease, AAV is especially rare in children, with an annual prevalence of 0.5–6.4 cases per million children. The etiology of AAV remains largely unknown, and both environmental and genetic factors are likely involved. The present study was undertaken to explore the genetic susceptibility factors recently identified in adult patients, including HLA–DP and HLA–DQ, in pediatric patients. Methods: We performed a genome‐wide association study of pediatric AAV in patients of European ancestry (n = 63 AAV cases, n = 315 population‐matched controls). Results: We identified a significant genetic association between pediatric AAV and the HLA–DPB1*04:01 allele (P = 1.5 × 10−8, odds ratio [OR] 3.5), with a stronger association observed in children with proteinase 3–ANCA positivity than in children with myeloperoxidase−ANCA positivity. Among the HLA alleles, the HLA–DPB1*04:01 allele was the most highly associated with AAV, although not significantly, in a follow‐up adult AAV cohort (P = 2.6 × 10−4, OR 0.4). T cell receptor and interferon signaling pathways were also shown to be enriched in the pediatric AAV cohort. Conclusion: The HLA–DPB1 locus showed an association with pediatric AAV, as similarly shown previously in adult AAV. Despite the difference in the age of onset, these findings suggest that childhood‐ and adult‐onset vasculitis share a common genetic predisposition. The identification of genetic variants contributing to AAV is an important step to improved classification tools and treatment strategies. [ABSTRACT FROM AUTHOR]

Objective: In 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence.Methods: A needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation.Results: Eleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations.Conclusion: The 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts. [ABSTRACT FROM AUTHOR]

Objective To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). Methods The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. Results In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. Conclusion Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding. [ABSTRACT FROM AUTHOR]

Background: Arterial vessel wall dissection is a rare, life-threatening and rarely described complication in childhood Takayasu Arteritis (cTA). Prevalence and risk factors for arterial dissection in cTA are unknown. We sought to study the prevalence and analyse risk factors for arterial dissection in cTA. Findings: A single center retrospective review of all children with cTA was performed. Patients with arterial dissection at cTA diagnosis were reported in detail and compared to the remaining single center retrospective cohort of children without dissection. Disease activity was assessed by the Pediatric Vasculitis Disease Activity Score (PVAS). A total of 27 cTA patients (74% girls) were included. Three children (11%) presented with dissection at diagnosis of cTA. They had higher PVAS (median 21 versus 10, p = 0.26), increased neutrophils (p < 0.0001) and lower albumin levels (p = 0.05). Arterial hypertension was common in both groups: in 67% of children with dissection and 54% of those without. Conclusions: Arterial dissection was more frequent in our cTA cohort than previously reported. Careful vascular imaging assessment is crucial to document this complication. High disease activity and markers of inflammation especially in combination with arterial hypertension, may be associated with the risk for vessel wall dissection in children with cTA. [ABSTRACT FROM AUTHOR]

Inflammatory brain diseases (IBrainDs) are a leading cause of devastating neurological deficits or neuropsychiatric syndromes in previously healthy children. The spectrum is expanding rapidly and new disease entities have been discovered in the last decade. IBrainD can occur as a primary disease or may occur secondary to an underlying cause. This review focuses on the clinical presentation, diagnostic features, pathology and histology characteristics and treatment of the primary childhood IBrainDs. [ABSTRACT FROM PUBLISHER]

Abstract: Inflammatory brain diseases in childhood are underrecognized and lead to life-threatening neurological deficits. Early recognition and diagnosis of inflammatory brain diseases is critical, as the reversibility of the neurological deficits is closely related to early initiation of treatment and prevention of secondary brain tissue damage. Primary childhood CNS vasculitis is the most common cause of inflammatory brain disease in childhood. Clinical features, laboratory tests and imaging can be non-conclusive and overlap with other inflammatory brain diseases, such as demyelinating diseases. This review focuses on recent publications on epidemiology, pathogenesis, and treatment in childhood CNS vasculitis and relevant publications from the rapidly expanding differential diagnosis for the subtypes of CNS vasculitis, particularly the demyelinating brain diseases. [Copyright &y& Elsevier]

Central nervous system vasculitis is an increasingly recognized inflammatory brain disease causing devastating neurological deficits and psychiatric manifestations in previously healthy children. Primary central nervous system vasculitis represents an isolated inflammatory attack targeting the cerebral vessels. In contrast, in children with secondary central nervous system vasculitis, an underlying condition can be identified. The spectrum of childhood primary and secondary central nervous system vasculitis is rapidly expanding, as is the differential diagnosis including nonvasculitic inflammatory brain diseases and noninflammatory vasculopathies. Early recognition, rapid diagnostic evaluation, and initiation of treatment have led to improved morbidity and mortality. This review focuses on clinical, laboratory, and neuroimaging characteristics of the distinct subtypes of primary childhood central nervous system vasculitis, reports the etiology of secondary central nervous system vasculitis, provides an overview of the differential diagnosis, and reviews the current approaches in treatment. [ABSTRACT FROM AUTHOR]

Objective. The main objective was to develop a trajectory for von Willebrand factor (vWF) antigen in childhood primary CNS vasculitis (cPACNS) after treatment and compare this with disease activity and other inflammatory markers.Methods. A single-centre cohort study of consecutive children diagnosed with cPACNS was performed. Demographic, clinical, laboratory, imaging and histological data were collected at diagnosis and during standardized clinic visits. Outcome measures included disease activity measured by physician global assessment and serial measures of vWF antigen. Analysis included descriptive statistics and parametric methods.Results. The study cohort consisted of 39 children diagnosed with cPACNS: 25 with angiography-negative cPACNS and 14 with angiography-positive disease. Twenty-one patients were female, median age at diagnosis was 9.8 years, and median follow-up was 18 months. All patients presented with neurological deficits. Disease activity and neurological outcome improved significantly during follow-up. vWF antigen levels were increased at diagnosis in 65% of children with cPACNS and were decreased significantly after treatment. In contrast, levels of CRP and ESR fluctuated over time. Higher vWF antigen levels at diagnosis were associated with lower measures of disease activity at 12 months.Conclusion. In our study, all children with cPACNS improved over time. Changes in CRP and ESR, other laboratory tests, and MRI did not consistently reflect altered disease activity. However, vWF antigen may help clinicians to identify changes in disease activity during follow-up and predict treatment response. Controlled studies are necessary to evaluate the sensitivity and specificity of vWF antigen as a biomarker of disease activity. [ABSTRACT FROM PUBLISHER]

Children and adults who present with severe, newly acquired neurological or psychiatric deficits should be evaluated for an underlying inflammatory brain disease--the inflammation could be reversible, if diagnosed and treated rapidly. In our experience, primary angiitis of the central nervous system (PACNS) is the most common inflammatory brain disease and is increasingly recognized across patients of all ages. Distinct disease subtypes have been reported with characteristic disease courses, neuroimaging features and histopathological findings. In this Review, we provide a comprehensive comparison of childhood and adult PACNS, revealing distinct gender distributions, characteristic presenting clinical phenotypes and tailored differential diagnosis evaluations in the different subtypes of PACNS. Novel and traditional laboratory markers can help to define disease subtype and activity, whilst MRI and angiography can aid diagnosis in both children and adults. Characteristic patterns of parenchymal lesions and vessel involvement have been identified in PACNS and differ markedly between subtypes. Brain histopathology has also revealed distinct inflammatory pathways at different ages. Immunosuppressive treatment protocols have been shown to be effective and safe across the age spectrum; overall, in the past few years, the mortality of PACNS has decreased dramatically. [ABSTRACT FROM AUTHOR]

Takayasu arteritis is a devastating vasculitis of the aorta and its major branches. The clinical manifestations in paediatric patients are less specific than in adults: in children the disease presents with fever, arthralgias and hypertension. Intramural inflammation results in narrowing of the blood vessel lumen and therefore hypoperfusion of the parenchyma. Conventional angiography is the gold standard diagnostic procedure. Corticosteroids, cyclophosphamide, MTX and biological therapies such as TNF-α blocking agents are treatment options. [ABSTRACT FROM PUBLISHER]

Objective: To quantify the impact of inflammatory brain diseases in the pediatric population on health-related quality of life, including the subdomains of physical, emotional, school and social functioning. Methods: This was a multicenter, observational cohort study of children (< 18 years of age) diagnosed with inflammatory brain disease (IBrainD). Patients were included if they had completed at least one Health Related Quality of Life Questionnaire (HRQoL). HRQoL was measured using the Pediatric Quality of Life Inventory Version 4.0 (PedsQL) Generic Core Scales, which provided a total score out of 100. Analyses of trends were performed using linear regression models adjusted for repeated measures over time. Results: In this study, 145 patients were included of which 80 (55%) were females. Cognitive dysfunction was the most common presenting symptoms (63%), and small vessel childhood primary angiitis of the CNS was the most common diagnosis (33%). The mean child's self-reported PedsQL total score at diagnosis was 68.4, and the mean parent's proxy-reported PedsQL score was 63.4 at diagnosis. Child's self-reported PedsQL scores reflected poor HRQoL in 52.9% of patients at diagnosis. Seizures or cognitive dysfunction at presentation was associated with statistically significant deficits in HRQoL. Conclusion: Pediatric IBrainD is associated with significantly diminished health-related quality of life. Future research should elucidate why these deficits occur and interventions should focus on improving HRQoL in the most affected subdomains, in particular for children presenting with seizures and cognitive dysfunction. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Childhood primary angiitis of the central nervous system: identifying disease trajectories and early risk factors for persistently higher disease activity," in the May 2012 issue.

The article offers views on central nervous system (CNS) vasculitis in children. According to the authors, CNS vasculitis is a treatable and reversible inflammation of the blood vessels when treated with immunosuppresants. They believe diagnosis of CNS vasculitis remains a challenge because of a dearth of specific, clinical, laboratory and neuroimaging markers. They add that children with large-to-medium CNS vasculitis have a better neurological outcome when treated with immunosuppressants.

Summary: Background: There is no treatment protocol or standardised documentation of neurological outcome for patients with small vessel childhood primary angiitis of the CNS, a rare inflammatory brain disease. We aimed to assess a treatment regimen and describe long-term neurological outcomes in a cohort of children with this disorder. Methods: We did a single-centre open-label cohort study in children with small vessel childhood primary angiitis of the CNS who were less than 18 years old at diagnosis. The treatment protocol consisted of induction therapy with steroids and pulses of intravenous cyclophosphamide followed by maintenance therapy with either azathioprine or mycophenolate mofetil. Clinical and neurological assessments, quality of life measures, and laboratory markers were done at baseline, 3, 6, 9, 12, 18, and 24 months, and every year thereafter. Brain imaging was done at baseline, 6, 12, 18, and 24 months. The primary outcome was the paediatric stroke outcome measure (PSOM) score at 24 months. Findings: From January, 2002, to December, 2009, 127 patients were enrolled, 19 of whom met the inclusion criteria and were given induction therapy. Median age at diagnosis was 9·8 years (range 5·5–17·8) and median follow-up was 33 months (range 1–86). 14 patients completed induction and received maintenance therapy with azathioprine (n=9) or mycophenolate mofetil (n=5). 13 patients completed 24 months'' follow-up, nine of whom had a good neurological outcome by PSOM. Eight of 19 patients experienced disease flares. Four patients achieved remission of disease off medication. Interpretation: This treatment protocol of immunosuppressive therapy may improve long-term neurological outcome in children with small vessel childhood primary angiitis of the CNS. Identification and appropriate diagnosis of children with the disorder is crucial because with standardised treatment good neurological outcome is a realistic goal. Funding: None. [Copyright &y& Elsevier]

Background: There is no treatment protocol or standardised documentation of neurological outcome for patients with small vessel childhood primary angiitis of the CNS, a rare inflammatory brain disease. We aimed to assess a treatment regimen and describe long-term neurological outcomes in a cohort of children with this disorder.Methods: We did a single-centre open-label cohort study in children with small vessel childhood primary angiitis of the CNS who were less than 18 years old at diagnosis. The treatment protocol consisted of induction therapy with steroids and pulses of intravenous cyclophosphamide followed by maintenance therapy with either azathioprine or mycophenolate mofetil. Clinical and neurological assessments, quality of life measures, and laboratory markers were done at baseline, 3, 6, 9, 12, 18, and 24 months, and every year thereafter. Brain imaging was done at baseline, 6, 12, 18, and 24 months. The primary outcome was the paediatric stroke outcome measure (PSOM) score at 24 months.Findings: From January, 2002, to December, 2009, 127 patients were enrolled, 19 of whom met the inclusion criteria and were given induction therapy. Median age at diagnosis was 9·8 years (range 5·5-17·8) and median follow-up was 33 months (range 1-86). 14 patients completed induction and received maintenance therapy with azathioprine (n=9) or mycophenolate mofetil (n=5). 13 patients completed 24 months' follow-up, nine of whom had a good neurological outcome by PSOM. Eight of 19 patients experienced disease flares. Four patients achieved remission of disease off medication.Interpretation: This treatment protocol of immunosuppressive therapy may improve long-term neurological outcome in children with small vessel childhood primary angiitis of the CNS. Identification and appropriate diagnosis of children with the disorder is crucial because with standardised treatment good neurological outcome is a realistic goal.Funding: None. [ABSTRACT FROM AUTHOR]