Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's) : an ARChiVe Cohort Study

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\u2009=\u200948) or GPA (n\u2009=\u2009183). 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

Early Outcomes in Children with Antineutrophil Cytoplasmic Antibody (ANCA) Associated Vasculitis (AAV)

Objective: To characterize early disease course in childhood onset antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) and 12-month outcomes. Methods: Eligible subjects were children diagnosed with GPA, MPA, EGPA, and ANCA-positive pauci-immune glomerulonephritis before their eighteenth birthday and entered into The Pediatric Vasculitis Initiative (PedVas) study. The primary outcome was remission (Pediatric Vasculitis Activity Score (PVAS) = 0 with corticosteroid dose (CS) <0.2mg/kg/day) at 12-months. Secondary outcomes included rates of inactive disease (PVAS 0, any CS dose) and improvement at post-induction (4-6 months after diagnosis) and at 12-months, damage at 12-months, and relapse rates. Results: 105 patients were included. Median age at diagnosis was 13.8 years (IQR 10.9 – 15.8 years); 42% achieved remission at 12-months, 49% had inactive disease at post-induction (4-6 months), and 61% had inactive disease at 12-months. The majority of patients improved even if they did not achieve inactive disease. An improvement in PVAS score of 50% from time-of-diagnosis to post-induction was seen in 92% of patients. Minor relapses occurred in 12 of 51 patients (24%) after achieving inactive disease at post-induction. The median damage score (measured by a modified pediatric vasculitis damage index (pVDI)) at 12-months was 1 (range 0-6). 63% of patients had ≥ 1 damage item scored at 12-months. Conclusion: This is the largest study to date reporting outcomes in pediatric AAV. Although a significant proportion of patients do not achieve remission, the majority of patients respond to treatment. Unfortunately, more than half of patients have damage early in their disease course.Medicine, Faculty ofNon UBCPediatrics, Department ofReviewedFacult

Early outcomes in children with antineutrophil cytoplasmic antibody-associated vasculitis

Objective To characterize the early disease course in childhood-onset antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and the 12-month outcomes in children with AAV. Methods Eligible subjects were children entered into the Pediatric Vasculitis Initiative study who were diagnosed before their eighteenth birthday as having granulomatosis with polyangiitis (Wegener’s), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or ANCA-positive pauciimmune glomerulonephritis. The primary outcome measure was achievement of disease remission (Pediatric Vasculitis Activity Score [PVAS] of 0) at 12 months with a corticosteroid dosage of &lt;0.2 mg/kg/day. Secondary outcome measures included the rates of inactive disease (PVAS of 0, with any corticosteroid dosage) and rates of improvement at postinduction (4–6 months after diagnosis) and at 12 months, presence of damage at 12 months (measured by a modified Pediatric Vasculitis Damage Index [PVDI]; score 05no damage, score 15one damage item present), and relapse rates at 12 months. Results In total, 105 children with AAV were included in the study. The median age at diagnosis was 13.8 years (interquartile range 10.9–15.8 years). Among the study cohort, 42% of patients achieved remission at 12 months, 49% had inactive disease at postinduction (4–6 months), and 61% had inactive disease at 12 months. The majority of patients improved, even if they did not achieve inactive disease. An improvement in the PVAS score of at least 50% from time of diagnosis to postinduction was seen in 92% of patients. Minor relapses occurred in 12 (24%) of 51 patients after inactive disease had been achieved postinduction. The median PVDI damage score at 12 months was 1 (range 0–6), and 63% of patients had ≥1 PVDI damage item scored as present at 12 months. Conclusion This is the largest study to date to assess disease outcomes in pediatric AAV. Although the study showed that a significant proportion of patients did not achieve remission, the majority of patients responded to treatment. Unfortunately, more than one-half of this patient cohort experienced damage to various organ systems early in their disease course.</p

Comparing presenting clinical features of 48 children with microscopic polyangiitis (MPA) against 183 having granulomatosis with polyangiitis (GPA)

Objectives: To uniquely classify children with MPA, describe their demographics, presenting features, initial treatments, and compare with GPA patients. Methods: The European Medicines Agency (EMA) classification algorithm, applied by computation to categorical data of patients recruited to A Registry for Childhood Vasculitis, censored to November 2015, uniquely distinguished MPA from GPA patients who were classified with adult and pediatric-specific criteria. Descriptive statistics were used for comparisons. Results: 231 (64% female) of 440 patients fulfilled classification criteria for either MPA (n=48) or GPA (n=183); respectively median time-to-diagnosis was 1.6 and 2.1 months, range to 39 and 73 months. Comparing MPA versus GPA patients respectively they were significantly younger (median 11 versus 14 years); constitutional features were equally common; pulmonary manifestations (44% versus 74%) were less frequent and less severe (hemorrhage, oxygen-requiring, pulmonary failure); renal features (76% versus 83%) were similarly frequent but tended towards greater severity (nephrotic-range proteinuria, dialysis-requirement, end-stage disease). Airway/eye involvement was absent among MPA patients as these GPA-defining features preclude an MPA diagnosis within the EMA algorithm. MPA and GPA patients respectively received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%) plus plasmapheresis (19% and 22%). Other treatments in decreasing frequencies from 13% to 3% were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. Conclusion: Younger onset age, and perhaps both gastrointestinal manifestations and worse kidney disease seem to characterize children with MPA versus GPA. Delay in diagnosis suggests suboptimal recognition. Compared to adults, initial treatments are comparable, but the complete reversal of female to male prevalence ratios is provocative.Medicine, Faculty ofNon UBCMedicine, Department ofRheumatology, Division ofPediatrics, Department ofReviewedFacultyOthe

A new horizon of moyamoya disease and associated health risks explored through RNF213

The cerebrovascular disorder moyamoya disease (MMD) was first described in 1957 in Japan, and is typically considered to be an Asian-specific disease. However, it is globally recognized as one of the major causes of childhood stroke. Although several monogenic diseases are known to be complicated by Moyamoya angiopathy, the ring finger protein 213 gene (RNF213) was identified as a susceptibility gene for MMD. RNF213 is unusual, because (1) it induces MMD with no other recognizable phenotypes, (2) the RNF213 p.R4810K variant is an Asian founder mutation common to Japanese, Korean and Chinese with carrier rates of 0.5–2 % of the general population but a low penetrance, and (3) it encodes a relatively largest proteins with a dual AAA+ ATPase and E3 Ligase activities. In this review, we focus on the genetics and genetic epidemiology of RNF213, the pathology of RNF213 R4810K, and the molecular functions of RNF213, and also address the public health contributions to current unresolved issues of MMD. We also emphasize the importance of a more updated definition for MMD, of qualified cohort studies based on genetic epidemiology and an awareness of the ethical issues associated with genetic testing of carriers