UBC Faculty Research and Publications

Early Outcomes in Children with Antineutrophil Cytoplasmic Antibody (ANCA) Associated Vasculitis (AAV) Morishita, Kimberly; Moorthy, Lakshmi N.; Lubieniecka, Joanna M.; Twilt, Marinka; Yeung, Rae S.M.; Toth, Mary B.; Shenoi, Susan; Ristic, Goran; Nielsen, Susan M.; Li, Suzanne C.; Lee, Tzielan; Lawson, Erica; Kostik, Mikhail; Klein-Gitelman, Marisa; Huber, Adam M.; Hersh, Aimee O.; Foell, Dirk; Elder, Melissa E.; Eberhard, Barbara A.; Dancey, Paul; Charuvanij, Sirirat; Benseler, Susanne; Cabral, David Jun 9, 2017

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"This is the peer reviewed version of the following article: Arthritis Rheumatol. 2017 Jul;69(7):1470-1479. Epub 2017 Jun 9. which has been published in final form at 10.1002/art.40112. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."  Title:  Early Outcomes in Children with Antineutrophil Cytoplasmic Antibody (ANCA) Associated Vasculitis (AAV)  Authors Morishita KM1, Moorthy LN2, Lubieniecka JM3, Twilt M4, Yeung RSM5, Toth MB6, Shenoi S7, Ristic G8, Nielson SM9, Li SC10, Lee T11, Lawson E12, Kostik M13, Klein-Gitelman M14, Huber AM15, Hersh AO16, Foell D17, Elder ME18, Eberhard BA19, Dancey P20, Charuvanij S21, Benseler SM4 and Cabral DA1 for ARChiVe Investigators Network§ within the PedVas Initiative.  Affiliations  1 Kimberly A. Morishita, MD, MHSc, David A. Cabral, MBBS, BC Children’s Hospital, Vancouver, BC, Canada; 2Lakshmi N. Moorthy, MD, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ; 3Joanna M. Lubieniecka, PhD, Simon Fraser University, Burnaby, BC; 4Marinka Twilt, MD, PhD, Susanne Benseler, MD, PhD, Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada; 5Rae S.M. Yeung, MD, PhD, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; 6Mary B. Toth, MD, Akron Children's Hospital, Akron, OH; 7Susan Shenoi, MBBS, MS, Seattle Children's Hospital, Seattle, WA; 8Goran Ristic, MD, Mother and Child Health Care Institute of Serbia, Belgrade, Serbia; 9Susan M. Nielsen, MD, Rigshospitalet, Copenhagen, Denmark; 10Suzanne C. Li, MD, PhD, Joseph M. Sanzari Children’s Hospital, Hackensack, NJ; 11Tzielan Lee, MD, Stanford Children's Health, Stanford University School of Medicine, Stanford, CA; 12Erica Lawson, MD, University of California at San Francisco, San Francisco, CA; 13Mikhail Kostik, MD, Saint-Petersburg State Pediatric Medical University, Russia; 14Marisa Klein-Gitelman, MD, MPH, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; 15Adam M. Huber, MD, IWK Health Centre and Dalhousie University, Halifax, NS; 16Aimee O. Hersh, MD, University of Utah, Salt Lake City, UT; 17Dirk Foell, MD, University Children’s Hospital, Muenster, Germany; 18Melissa E. Elder, MD, University of Florida, Gainesville, FL; 19Barbara A. Eberhard, MBBS, MSc, Cohen Children’s Medical Center of New York, New Hyde Park, NY; 20Paul Dancey, MD, Janeway Childrens Health and Rehabilitation Centre, St. John’s, NL, Canada; 21Sirirat Charuvanij, MD, Siriraj Hospital, Mahidol University, Bangkok, Thailand.  §ARChiVe (A Registry for Children with Vasculitis) Investigator Network: Coordinating Center: British Columbia Children’s Hospital, Vancouver, BC, Canada: David A. Cabral (Study Principal Investigator); Angelyne Sarmiento, Qun Yang (Study Coordinators), Victor Espinosa (IT Manager), Joanna Lubieniecki (Statistician), Jaime Guzman, Kristin Houghton, Kimberly Morishita, Ross Petty, Lori Tucker, (Site Investigators).  Participating Centers: Akron Children’s Hosp, Akron, OH: Mary B. Toth (Site Principal Investigator).  Alberta Children’s Hospital, University of Calgary, Calgary, AB, 2  Canada: Susanne Benseler (Site Principal Investigator); Marinka Twilt (Site Investigator).  Alder Hey Children’s NHS Foundation Trust Hospital, Liverpool, UK: Michael Beresford (Site Principal Investigator); Eileen Baildam (Site Co-Principal Investigator). Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA: Marisa Klein-Gitelman (Site Principal Investigator); Michael Miller, Megan Curran (Site Investigators). Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK: Taunton Southwood (Site Principal Investigator).  Breach Candy Hospital, Mumbai, India: Raju Khubchandani (Site Principal Investigator).  Children’s Hospital at Montefiore, New York, NY, USA: Norman T Ilowite (Site Principal Investigator); Dawn M Wahezi (Site Investigator).  Children’s Hospital of Boston, Boston, MA, USA: Susan Kim (Site Principal Investigator); Fatma Dedeoglu, Robert Fuhlbrigge, Melissa Hazen, Mary Beth Son and Robert Sundel (Site Investigators).  Children’s Hospital LA, Los Angeles, CA, USA: Andreas Reiff (Site Principal Investigator); Diane Brown, Katherine Marzan, Anusha Ramanathan, and Bracha Shaham (Site Investigators).  Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada: Ciaran Duffy (Site Principal Investigator).  Children’s Hospital of Michigan, Detroit, MI, USA: Matthew Adams (Site Principal Investigator); Rudolf Valentini (Site Investigator).  Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA: Margalit Rosenkranz (Site Principal Investigator); Daniel Kietz, Elaine Cassidy and Kathryn Torok (Site Investigators).  Children's Mercy Hospital, Kansas, MO USA: Mara Becker (Site Principal Investigator).  Children's National Medical Center, Washington, DC USA: Lawrence K. Jung (Site Principal Investigator). Cleveland Clinic Foundation, Cleveland, OH, USA: Steven Spalding (Site Principal Investigator); Andrew Zeft (Site Investigator).  Cohen Children’s Medical Center of New York, New Hyde Park, NY, USA: Anne Eberhard (Site Principal Investigator); Bett Gottlieb and Cagri Toruner (Site Investigators).  Comer Children's Hospital, Chicago, IL USA: Linda Wagner-Weiner (Site Principal Investigator); Karen Onel, Charles Spencer, Deidre De Ranieri and Melissa Tesher (Site Investigators).  Morgan Stanley Children’s Hospital of New York-Presbyterian, New York, NY, USA: Andrew Eichenfield (Site Investigator); Lisa Imundo (Site Investigator).  Duke Children’s Hospital and Health Center, Duke University Medical Center, Durham, NC, USA: Heather Van Mater (Site Principal Investigator); C. Egla Rabinovich, Laura Schanberg and Jeffery Dvergsten (Site Investigators).  Great North Children’s Hospital, Newcastle, UK: Mark Friswell (Site Principal Investigator).  Hospital for Sick Children, Toronto, ON, Canada: Rae Yeung (Site Principal Investigator); Brian Feldman, Deborah Levy, Earl D Silverman, Ronald Laxer, Rayfel Schneider (Site Investigators).  Hospital Sant Joan de Deu Barcelona, Barcelona, Spain: Jordi Anton (Site Principal Investigator).  IWK Health Centre and Dalhousie University, Halifax, NS, Canada: Adam M Huber (Site Principal Investigator); Bianca A Lang, Suzanne Ramsey and Elizabeth Stringer (Site Investigators).  Janeway Children’s Health and Rehabilitation Centre, St. John’s, NL, Canada: Paul Dancey (Site Principal Investigator).  Joseph M. Sanzari Children’s Hospital, Hackensack University Medical Center, Hackensack, NJ, USA: Suzanne C Li (Site Principal Investigator); Kathleen Haines, Yukiko Kimura, Ginger Janow and Jennifer Weiss (Site Investigators).  Leeds Children’s Hospital, Leeds, UK: Mark Wood (Site Principal Investigator). Mayo Eugenio Litta Children’s Hospital, Mayo Clinic, Rochester, MN, USA: Thomas Mason (Site Principal Investigator); Ann Reed (Site Investigator).  Medical College of Georgia, Augusta GA, USA: Rita Jerath (Site Principal Investigator).  Meyer Children’s Hospital, Firenze, Italy: Rolando Cimaz (Site Principal Investigator).  Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, TN: Thomas B. 3  Graham (Site Principal Investigator); Amy Woodward, Donna Hummel (Site Investigators).  Mother and Child Health Care Institute of Serbia, Belgrade, Serbia: Goran Ristic (Site Principal Investigator).  Nationwide Children’s Hospital, Columbus OH, USA: Gloria C Higgins (Site Principal Investigator).  Nuffield Orthopaedic Centre, University of Oxford: Raashid Luqmani (Site Principal Investigator).  Phoenix Children’s Hospital, Phoenix, AZ, USA: Kaleo Ede (Site Principal Investigator); Michael Shishov (Site Investigator).  Randall Children's Hospital at Legacy Emmanuel, Portland, OR, USA: Daniel J Kingsbury (Site Principal Investigator); Victoria Cartwright and Andrew Lasky (Site Investigator).  Rigshospitalet, Copenhagen, Denmark: Susan Nielsen (Site Principal Investigator).  Riley Children’s Hospital, Indianapolis, IN, USA: Kathleen O’Neil (Site Principal Investigator); Peter Chira, Susan Ballinger, Stacey Tarvin and Michael Blakley (Site Investigators).  Royal Hospital for Children, Glasgow, UK: Neil Martin (Site Principal Investigator).  Royal Manchester Children’s Hospital, Manchester, UK: Janet McDonagh (Site Principal Investigator).  Rutgers-Robert Wood Johnson Medical School, New Brunswich, NJ, USA: Lakshmi Nandini Moorthy (Site Principal Investigator); Alexis Boneparth (Site Investigator).  Saint Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA: Kevin Baszis (Site Principal Investigator); Andrew White (Site Investigator).  Saint-Petersburg State Pediatric Medical University, Russia: Mikhail Kostik (Site Principal Investigator).  Seattle Children’s Hospital, Seattle, WA, USA: Susan Shenoi (Site Principal Investigator); Kabita Nanda, Anne Stevens, Alexandra Aminoff and Carol Wallace (Site Investigators).  Sheffield Children’s NHS Foundation Trust, Sheffield, UK: Anne-Marie McMahon (Site Principal Investigator).  Siriraj Hospital, Mahidol University, Bangkok, Thailand: Sirirat Charuvanij (Site Principal Investigator).  Stanford Children's Health, Stanford University School of Medicine, Stanford, CA, USA: Tzielan Lee (Site Principal Investigator); Imelda Balboni, Michal Cidon, Jennifer Frankovich, Dana Gerstbacher, Joyce J Hsu and Christy Sandborg (Site Investigators).  Southampton General Hospital, Southampton, UK: Alice Leahy (Site Principal Investigator).  Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA: Eyal Muscal (Site Principal Investigator); Barry L Myones (Site Investigator).  The Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada; Sarah Campillo (Site Principal Investigator); Gaëlle Chédeville and Rosie Scuccimarri (Site Investigators).  The Hospital for Special Surgery, New York, NY: Thomas Lehman (Site Principal Investigator); Laura Barinstein, Emma MacDermott, Alexa Adams (Site Investigators).  University Children’s Hospital Muenster, Muenster, Germany: Dirk Foell (Site Principal Investigator).  University Hospitals Case Medical Center, Rainbow Babies and Children's Hospital, Cleveland, OH, USA: Angela Byun Robinson (Site Principal Investigator); Elizabeth B Brooks (Site investigator).  University of California at Los Angeles, Los Angeles, CA, USA: Deborah McCurdy (Site Principal Investigator).  University of California at San Francisco, San Francisco, CA, USA: Erica Lawson (Site Principal Investigator).  University of Florida, Gainesville, FL, USA: Melissa E. Elder (Site Principal Investigator).  University of Louisville School of Medicine, Louisville, KY, USA: Kenneth N Schikler (Site Principal Investigator).  University of Saskatchewan, Saskatoon, SK: Alan Rosenberg (Site Principal Investigator).  University of Texas Southwestern, Texas Scottish Rite Hospital, Dallas, TX: Marilynn Punaro (Site Principal Investigator); Lorien Nassi and Virginia Pascual (Site Investigators).  University of Salt Lake City, UT, USA: Aimee Hersh (Site Principal Investigator); CJ Inman, Sara Stern and John Bohnsack (Site Investigators).  University of Vermont, Burlington, VT, 4  USA: Leslie Abramson (Site Principal Investigator).  Wellington Hospital, Wellington, New Zealand: Arno Ebner (Site Principal Investigator). Running Head: Early Outcomes in Childhood AAV  Disclosures: None  Corresponding author  Kimberly Morishita (kmorishita@cw.bc.ca) Division of Rheumatology, Room K4-115, British Columbia Children's Hospital, Vancouver, BC V6H 3V4, Canada   5  Abstract  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 6  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.   7  INTRODUCTION  Childhood antineutrophil cytoplasmic antibody (ANCA) associated vasculitis is rare and outcome studies are limited.  ANCA-associated vasculitis (AAV) includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and localized disease variants, such as pauci-immune necrotizing glomerulonephritis (GN).  Although rare, these diseases are often organ- or life- threatening.  Prior to the introduction of treatment with glucocorticoids and cyclophosphamide, the disease was rapidly fatal in the majority of pediatric and adult cases (1).   Evolving treatment strategies have significantly improved survival and reduced morbidity for patients with AAV.  Due to the rarity of AAV in childhood, much of our knowledge about outcomes such as remission, relapse, and damage has come from adult based studies (2-9) or small pediatric case series (2,10-14). Data from adult studies show remission rates as high as 90% (15) and 5-year survival rates of 80% (16). Despite these advances, disease relapses occur in up to 30-50% of adult patients (17-19). In addition, even when patients achieve remission, damage can be seen early in the disease course and tends to increase over time (4).  A recent retrospective study of 66 children with AAV from France reported outcomes in children who had been followed for a median of 5.2 years (20); 90% of patients achieved remission after a median time of 6.7 months (IQR 4.9 – 10.1) but 41% experienced at least one relapse after a median time of 29 months (IQR 14-89). To date this has been the largest pediatric study reporting follow up data for pediatric AAV, but because it was retrospective, remission or relapse rates at pre-specified times were not reported. 8   A better understanding of remission rates, relapse rates, and other outcomes (ideally using standardized pediatric specific tools), will only be possible through international collaborations and use of international registries.  Already, such initiatives have resulted in the development of pediatric specific classification criteria (21), the Pediatric Vasculitis Activity Score (PVAS) (22) and ongoing initiatives to develop pediatric specific vasculitis damage indices.  The impact of disease (activity, severity, damage) and its individual treatments (toxicity, safety and efficacy) may be different in children where the immune system is evolving and co-morbidities are likely to be different to adults. Moreover the impact on physical and psychosocial growth and development is unique to children and this requires long term follow-up study.  For these reasons, research specific to pediatric patients is critically important.  The Pediatric Vasculitis Initiative (PedVas) is an international collaborative translational research initiative funded by the Canadian Institutes of Health Research until 2017 (https://clinicaltrials.gov/ct2/show/NCT02006134) with the primary aim of improving the lives of children with chronic vasculitis. Clinical data is being collected through two previously established web-based registries ARChiVe and BRAINWORKS, respectively for the study of chronic systemic vasculitis and primary angiitis of the central nervous system. The primary objective of this current study was to describe the early disease course of children with AAV. Specifically the aims were to (i) describe baseline clinical features including organ involvement, disease activity and treatments initiated and (ii) characterize early disease course and outcomes by determining treatment response (remission, 9  improvement, inactive disease), relapse rates, and damage in the first 12-months of disease.  METHODS ARChiVe was established in March 2007 and initially collected time-of-diagnosis data only (23), but since January 2013, with the support of PedVas, retrospective and prospective follow-up data has been collected.  This study is an inception cohort study using data from patients entered into ARChiVe from 22 international sites.   Patients Patient eligibility criteria, the registry dataset, and the strategy for establishing the time-of-diagnosis dataset have been described previously (23). Eligible patients included were those diagnosed by the treating physician (MD diagnosis) after January 1st 2004 and before the age of 18 years as having a primary chronic systemic vasculitis. Patient data was collected retrospectively for those diagnosed before March 2007, and prospectively for those diagnosed subsequently.    For the purpose of this study, eligible subjects were children diagnosed with GPA, MPA, EGPA, and ANCA-positive pauci-immune GN before their eighteenth birthday, who had complete post-induction (4-6 months after diagnosis) and 12-month follow up data collected through November 2015. Patients with an MD diagnosis of ANCA-positive pauci-immune GN were included because on further review many of them met the classification criteria for GPA or could be classified as MPA after application of the European Medicines 10  Agency (EMA) algorithm. Each eligible patient was reviewed and classified as follows: EGPA: patients had to meet ACR (24) or Lanham criteria for EGPA (25); GPA: patients had to meet ACR (24) or EULAR/PReS/PRINTO classification criteria for GPA (21). Since there are no MPA specific classification criteria, diagnoses were formalized by applying a pediatric modification of the EMA algorithm for classifying AAV (incorporating EULAR/PRINTO/PReS classification criteria) (26). Patients were excluded if they could not be classified as GPA, MPA, or EGPA after application of above described criteria. ARChiVe uses a Web-based interface for entry of data at several time points including: time of diagnosis; post-induction (4-6 months after diagnosis); 12-months post diagnosis; and flare visits.  The study protocol was approved by the local research ethics board at each participating center. Informed consent for participation was obtained from parents, and informed consent or assent was obtained from patients for both retrospective and prospective recruitment. Study data were collected and managed using REDCap electronic data capture tools hosted at the University of British Columbia (27).  Data collection Categorical data collected included the following: demographic data; treating physician’s diagnosis; date of diagnosis; family and patient’s medical history; presenting symptoms and interval history; clinical features; results of laboratory testing; investigations, including diagnostic imaging or other procedures such as biopsies; medications, including corticosteroid doses; pediatric vasculitis activity scores (PVAS) (22); and a modified version of the vasculitis damage index (VDI) (28) for use in pediatrics.   11  Outcome assessments The primary outcome was remission at 12-months following diagnosis. Secondary outcomes included rates of inactive disease post-induction (4-6 months after diagnosis) and at 12-months, rates of improvement post-induction and at 12-months, damage at 12-months and relapse rates within 12-months. Definitions from the EULAR recommendations for conducting clinical studies in ANCA associated vasculitis (29) were used to define remission, improvement, relapse and damage.  In order to apply these definitions to pediatric data, PVAS was used in place of the Birmingham vasculitis activity score (BVAS)  (30) and a modified version of the VDI for use in pediatrics (pVDI) was used in place of the adult VDI (28). Remission was defined by a PVAS of 0 (inactive disease) and prednisone (or prednisone–equivalent) dose less than 0.2 mg/kg/day. Adult guidelines recommend that ‘remission’ should be defined as occurring only when a patient has attained a stable low dose of prednisone (≤7.5 mg/day) (29) which formed the basis of our weight based criterion of <0.2 mg/kg/day for remission in this pediatric cohort.  Inactive disease was defined as an absence of disease activity (PVAS of 0), regardless of steroid dose. Improvement was defined as a decrease in PVAS score by at least 50% post-induction or at 12-months as compared to time-of-diagnosis. This level of response is consistent with the definition of a clinically important improvement according to the EULAR recommendations (29). A decrease in PVAS score by 70% or more was also studied. Relapse was defined as recurrence or new onset of disease activity (an increase in PVAS ≥1, from 0) attributable to active inflammation. Major relapse was defined as the recurrence, or new onset of potentially organ-or life-threatening disease activity requiring an escalation in treatment, additional to corticosteroids. Other relapses were considered minor.  12  In adult vasculitis, damage is scored according to the VDI, which is a validated tool for assessing damage from disease, treatment or concurrent conditions (28). Damage is considered irreversible and must be present for at least three months to be counted as an item in the VDI. There is no validated tool to assess disease damage in children with vasculitis; thus, in order to apply the VDI to this cohort of patients we made the following modifications: 1) hypertension in the adult VDI is defined as a diastolic BP ≥ 95mmHg or requiring antihypertensive treatment, this was modified to diastolic BP > 95th percentile for height/age or requiring antihypertensive treatment; 2) proteinuria in the adult VDI is defined as ≥ 0.5g/24 hours, this was modified to > 0.3g/24 hours in order to correspond with how proteinuria data was collected in this registry. The PReS Vasculitis Working Group and Childhood Arthritis & Rheumatology Research Alliance (CARRA) are currently working towards validating a formal pediatric modification of the VDI (31). The modifications that were made to the VDI for this study align with the proposed changes by the Working Group. Further considerations by the Working Group include the addition of other pediatric specific items such as growth delay, delayed puberty, and new onset obesity. These items were also collected in the registry but not scored. Using the modified pediatric version of the VDI (referred to as the pVDI in this manuscript), a score of 0 indicates no damage, while a score of 1 indicates the presence of one damage item out of a potential 64 damage items in total. A copy of the modified version of the VDI used for this study is included in the Appendix.     Analysis 13  Descriptive statistics were used for baseline characteristics, remission-induction medications, rates of improvement, rates of inactive disease and rates of remission.  Comparisons were made using Fisher’s exact test for categorical data and t-test or Mann-Whitney U test for quantitative variables. Statistical analysis of the data was performed using Microsoft Excel Software 2007 or R version 3.2.2 (R Core Team (2015) (R: A language and environment for statistical computing. R  Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/).  RESULTS Patients One hundred and seven patients were eligible for inclusion. Two patients were not classifiable as AAV according to the defined classification criteria and were excluded. Of the remaining 105 children, 81% were classified as GPA, 13% as MPA and 6% as EGPA. Among the 105 patients, 68% were female and 50% were Caucasian.  One quarter of patients did not have complete ethnicity data or ethnicity data was unknown. Additional ethnicity data is shown in Table 1. Median age at diagnosis was 13.8 years (IQR 10.9 – 15.8 years). Median PVAS at diagnosis was 19 (IQR 14-24). The median PVAS for the different subtypes of AAV were 20 (IQR 14-24) for GPA, 17.5 (IQR 13.8-19.8) for MPA and 17 (IQR 11-26.8) for EGPA. The median interval between symptom onset and diagnosis was 2.2 months (IQR 0.9-5.6). 83 patients were diagnosed after March 2007 (prospective data collection) and 22 patients were diagnosed before March 2007 (retrospective data collection).   Clinical presentation and laboratory test results  14  The majority of patients had pulmonary (80%) and/or renal disease (78%).  Sixty-four patients (61%) had both pulmonary and renal disease. One-third of patients had alveolar hemorrhage or massive hemoptysis at presentation, and 10% were in respiratory failure.  Seventeen patients (16%) were in renal failure requiring dialysis, and five (5%) had end-stage renal disease. Other systems involved in a majority of patients were ear, nose and throat (ENT) (56%) and musculoskeletal (53%).  Additional baseline clinical features are shown in Table 1.  Of the 105 patients, 99 had ANCA immunofluorescence testing performed and among these 54% were cANCA positive (94% with PR3 specificity, 2% with MPO specificity, 4% with negative specificity), 32% were pANCA positive (91% with MPO specificity, 9% with PR3 specificity), 3% were mixed c- and p-ANCA positive, and 11% were ANCA negative. The six patients that did not have immunofluorescence testing had antigen specificity testing – four were PR3 positive and two were MPO positive.   Ninety-one patients (87%) had tissue biopsies performed as part of their diagnostic workup. 61 patients (58%) had renal biopsies, 20 patients (19%) had skin biopsies, and 9 patients (9%) had paranasal sinus biopsies. Other biopsy sites included gastrointestinal tract (8%), upper airways (6%), orbital masses (3%) and other (7%).  Treatment  Cyclophosphamide (CYC) was used for remission induction in 74 (70%) patients, methotrexate (MTX) in 17 (16%) patients, and rituximab (RTX) in 14 (13%) patients. Four 15  patients received both CYC and RTX.  All patients who received RTX were diagnosed after 2010. RTX use did not appear to be center-specific, as it was used at 9 different sites; however, all sites were either in Canada or the USA. Azathioprine (AZA) was used as the primary remission induction agent in two patients and Mycophenolate mofetil (MMF) was used in one patient. One patient received corticosteroid alone for remission induction without any other primary immunosuppressant treatment. Plasmapheresis was used in conjunction with CYC and/or RTX in 25 (24%) patients.  Of the 25 patients that received plasmapheresis, 24 (96%) had renal disease and 21 (84%) had both pulmonary and renal disease.  All patients received oral corticosteroids as part of their induction treatment.  Seventy-four patients (70%) were also treated with high dose methylprednisolone intravenous pulses at time of diagnosis. The dosage and number of pulses used were highly variable, ranging from 10-30mg/kg/dose and 1-12 pulses. Primary treatments used for remission induction are shown in Figure 1.  Treatments for remission maintenance were AZA in 45 patients (43%), MTX in 24 (23%), MMF in 14 (13%), CYC in 10 (9%) and RTX in 10 (9%) (Figure 2). At 12-months, 75 patients were either off corticosteroids (32 patients, 30%) or on, low dose <0.2mg/kg/day corticosteroids (43 patients, 41%).   Outcomes Remission: Forty-four patients (42%) achieved remission at 12-months (PVAS 0, corticosteroid dose <0.2mg/kg/day).  Twenty-one of these 44 patients (48%) were off corticosteroids completely.  All but three patients remained on maintenance treatment at 12-months (18 on AZA, 9 on MTX, 6 on RTX, 5 on MMF, 3 on CYC).  16   Inactive disease: Fifty-one of 105 patients (49%) had inactive disease (PVAS 0) post-induction (4-6 months) and 64 patients (61%) had inactive disease at 12-months (44 of these were described as being in remission in that they were on minimal or no corticosteroids, but 20 had inactive disease on higher doses of corticosteroids). Thirty-nine patients that had inactive disease post-induction continued to have inactive disease at 12-months.   Improvement: Post induction: The majority of patients improved even if they did not achieve inactive disease by the post-induction visit. An improvement in PVAS score of 50% from time of diagnosis to post-induction was seen in 92% of patients. An improvement in PVAS score of 70% was seen in 85% of patients. Four patients had no improvement or a worse PVAS score during the post-induction time period. 12-months: An improvement in PVAS score of 50% from time of diagnosis compared to 12-months was seen in 93% of patients and an improvement of 70% was seen in 90% of patients. One patient had a worse PVAS score at 12-months compared to time of diagnosis.  Relapses: Relapses occurred in 12 of 51 patients (24%) after achieving inactive disease at the post-induction visit. All relapses were considered minor. Twenty-two of 105 patients (21%) had a worsening of PVAS scores between the post-induction visit and the 12-month visit (PVAS 17  worsened by 1 or more point, regardless of whether inactive disease (PVAS 0) had been achieved at the post-induction visit).  Damage: One hundred and four patients had completed pVDI scores. The median pVDI score at 12-months was 1 (range 0-6). Sixty-six of the 104 patients (63%) had ≥ 1 item scored at 12-months, 35 (34%) had ≥ 2 items scored, and 19 (18%) had ≥ 3 items scored. The distribution of scores is shown in Figure 3, and the specific items scored are shown in Table 2.  One-third of the 104 patients had evidence of renal damage. The most frequent renal damage items scored were proteinuria (20%), an estimated/measured GFR ≤ 50% of normal (18%), and end-stage renal disease (ESRD) (12%). Two patients had received renal transplants. ENT damage was seen in 20% of patients and pulmonary damage was seen in 15% of patients. Investigators were given the opportunity to enter other items that they felt represented damage but which were not included in the scoring form. Items that were entered more than once included: chronic cough (3 patients), new onset obesity (3 patients), and significant striae (5 patients).   Hospitalizations and deaths: Following time-of-diagnosis, 43 patients required 80 hospitalizations. Hospitalizations for routine treatments were not included.  Almost half (46%) of the hospitalizations were in relation to disease flares; 16% due to infection; and 5% due to treatment or medication related adverse effects. Twelve (15%) hospitalizations were for other disease related reasons such as renal biopsies or other tissue biopsies (beyond time of diagnosis), 18  investigational procedures such as endoscopies, or in one patient three admissions were for physical rehabilitation. Fourteen (18%) hospitalizations were for reasons unrelated to the underlying disease or treatments according to the site investigator.  No deaths occurred.  Exploration of associations with remission at 12-months We conducted an exploratory, univariate analysis of a few selected baseline features to see whether they associated with remission at 12-months. We selected, a priori, age, gender, ANCA status, PVAS, and induction treatment as potential variables associated with remission based on previous research  (8,15,17,32-34).  The reported p-values were not corrected for multiple comparisons.  The median age of patients who achieved remission was 14 years compared to 13 years for patients that did not achieve remission (p=0.04). At 12-months, 55% of males versus 34% of females achieved remission (p=0.06). Treatment was dichotomized into two groups – aggressive versus moderate. Aggressive treatment was defined as induction medications including CYC and/or RTX +/- plasmapheresis. Moderate treatment was defined as induction medications including MTX, AZA, or MMF. The one patient that only received corticosteroid for induction treatment was excluded from the treatment analysis. Rates of remission at 12-months post diagnosis were similar between patients who received aggressive versus moderate treatment (43% on aggressive treatment versus 30% on moderate treatment achieved remission, p=0.32). The median baseline PVAS for the 19  patients that received aggressive treatment was 20 compared to 14 for the patients that received moderate treatment (p=0.0001).  There was minimal difference between baseline PVAS for patients who achieved remission at 12-months compared to those that did not (21 versus 19, p=0.18). Similarly, ANCA type was not associated with remission: 42% cANCA/PR3 patients versus 38% pANCA/MPO positive patients achieved remission at 12-months (p=0.83).   DISCUSSION This multicenter international study describes the early disease course and outcomes of 105 patients with childhood-onset AAV. This is the largest cohort to date reporting pediatric outcomes in this group of diseases. Despite numerous adult-based studies and clinical trials reporting short- and long-term outcomes in AAV, our knowledge of pediatric-specific outcomes remains limited. Until now, the two largest pediatric studies reporting outcomes included 66 and 35 patients with AAV respectively  (20,35).   In our study, the majority of children had GPA. The median age of onset (13.8 years) and female predominance are consistent with other pediatric studies  (20,35). The high rates of renal (78%) and pulmonary (80%) disease at presentation are also consistent with previous reports; however, children in our study had lower rates of ENT disease (56%) compared to reported rates of 70-90% in other recent studies  (11,20,35,36). Treatment strategies were also consistent with previous reports, with the majority of patients receiving CYC in conjunction with corticosteroids for remission induction and switching to 20  AZA or MTX for remission maintenance  (20,35). Disease activity, as measured by PVAS, was not easily comparable to other studies as it has only been reported in one previous study - the French Vasculitis Study Group cohort - where the median PVAS scores were 9.5 for MPA, 12 for GPA and 14.5 for EGPA  (35). The median baseline PVAS in our patients was higher at 19. The use of plasmapheresis in one quarter of patients may be an indicator of severe disease; however, it may also be a reflection of more recent practices or jurisdiction based capacity or preferences.   A significant proportion of patients were not in remission at 12-months. The 12-month remission rate of 42% was significantly lower than the 73% remission rate (post-induction) and 90% remission rate (overall remission rate including secondary remissions after a median time of 6.7 months) reported by Sacri et al. in their cohort (20). In the Sacri et al cohort, remission was assessed after initial induction therapy, but criteria for remission did not need to be met within a specified time frame. Remission in that study was defined as a BVAS or BWAS/WG of 0 and corticosteroid dose of ≤7.5 mg once daily (regardless of weight) which was similar to the criteria used in this study. Differences in remission rates between our study and the Sacri et al study might be explained by several factors: different patient characteristics – there were more MPA patients in the French cohort and fewer patients with pulmonary disease; disease activity scoring was applied retrospectively in the French cohort compared to by an automated online calculator in conjunction with a clinic visit for the majority of patients in the PedVas cohort; and different timing of assessments (in our study inactive disease was assessed at post-induction (specifically 4-6 months after diagnosis), and remission was assessed at the 12-21  month visit). Treatments for induction in the French cohort were used in similar proportions to our study (66% received cyclophosphamide, 14% received rituximab and 17% received plasmapheresis); however, direct comparisons between patient baseline disease activity, specifics of treatment regimens and the basis behind treatment decisions could not be made.  Reported remission rates in several adult clinical trials in AAV have also shown variability with ranges between 53% and 93%  (37-39). The lower reported remission rates in some adult trials have been attributed to several potential factors – stricter corticosteroid weaning protocols (for example, complete weaning by 6-months versus weaning by 12-months), stricter definitions of remission (BVAS of 0 versus BVAS< 2), and longer duration of inactivity to define remission  (3 months of inactive disease versus no minimum duration of inactive disease).  For our study, remission required a minimum corticosteroid dose at 12-months and there was no minimum duration of inactive disease required; however, our criterion for disease activity was strict (PVAS 0). These definitions were selected based on adult recommendations for reporting outcomes in clinical trials (29) which were introduced in an attempt to reduce heterogeneity in outcomes reporting. It is acknowledged that the strict inclusion and exclusion criteria of clinical trials in addition to the highly systematic approach to disease assessment, medication administration and weaning is not directly comparable to observational cohorts. Selection of patients in clinical trials and strict protocols may allow for easier attainment of remission criteria at certain time points and may also result in selecting patients who are more likely to respond to treatment. Our registry included all patients with AAV regardless of baseline disease 22  severity, disease activity, organ involvement or specific treatments which would all be important factors in determining chance of remission. In addition, physician practices to continue treating with prednisone at doses more than or less than 0.2 mg/kg/day might represent their individual practice approach, rather than a patient specific requirement to maintain control of inflammation. The reported remission rates in this study may be a better reflection of remission rates in clinical practice compared to what is reported from clinical trials.   Despite a significant proportion of patients not achieving inactive disease post-induction or remission at 12-months, the majority of patients met the definition of treatment response with 92% of patients having an improvement in PVAS of 50% at post-induction. This is similar to the high rate of treatment response reported in the Sacri et al study (20). Relapses occurred in 24% of patients who achieved remission post-induction. This rate is lower than reported rates of 40 – 80% in other pediatric studies, but our duration of follow up was only one-year compared to median follow up times of two to eight years in other studies  (20,35,40). Longer follow up data is required to examine relapse rates with current treatment regimens.   More than half of patients (63%) had evidence of damage by 12-months. The Iudici et al. study also assessed damage in their cohort of children (35). They used the VDI to score damage and reported a median score of 1 at last follow up (median 96 months), which was the same as our median score at 12-months. The percentage of patients who had evidence of damage was not reported in the Iudici study so it is difficult to make further 23  comparisons. Robson et al summarized rates of damage from six EUVAS studies and found a similarly high rate of damage (87%) at 12-months in adult patients with AAV (4). As in adult studies, the most frequently scored damage items were renal items such as proteinuria and reduced GFR, followed by ENT items (4). The fact that so many children already have evidence of renal damage within 12-months is concerning considering that adults compared to children are more likely to have underlying pre-existing renal disease whereas we speculate that  children might  have some degree of renal reserve.  In our exploratory analyses, no significant associations with remission were found between gender, age, ANCA status, induction treatment, and PVAS at baseline. Previous adult studies have suggested that female sex, older age, less aggressive treatment and PR3 ANCA status are associated with treatment resistance, reduced chance of remission, or higher relapse rates  (8,17,33,34).  Higher disease activity as measured by BVAS has been associated with higher chance of remission (independent of treatment) but poorer survival in adults with AAV  (34,41). We recognize that disease activity as measured by PVAS and treatment are likely to be related; however, due to limited patient numbers we did not have the power to assess the effect of treatment as a modifier, nor were we able to incorporate the effects of maintenance treatments. The purpose of this analysis was to test for simple associations of baseline factors previously reported to be associated with outcome in adults. It is possible that the factors associated with remission in adults are not the same for pediatric patients; however, it is also possible that the sample size limited our power to detect associations. Sample size limited our analysis to remission as the primary outcome measure; however, predictive factors for other outcomes such as relapse, damage and survival are also of 24  interest especially over the longer term. Increased patient numbers will enable analyses with multiple variables and outcomes that will likely be more informative.  Our study had the following limitations. Formal training in scoring PVAS was not required by site investigators; however, a comprehensive manual and an instructional PVAS video were provided to each site. The database was designed specifically to collect the clinical data required to calculate PVAS; however, it is possible that items were incorrectly entered or missing. Patient data was collected at pre-specified time points (time of diagnosis, post-induction, and 12-months) which meant that we were unable to capture precisely what happened between visits. For example, if a patient achieved remission after their post-induction visit, then had a minor relapse prior to the 12-month visit (resulting in a PVAS > 0), then we would not have captured the remission or the relapse for such a patient. We feel these instances are few because investigators were asked at each visit whether their patient had experienced a relapse since the last visit and all such instances were reviewed; however, subtle relapses according to our definition may not necessarily have been captured especially if the investigator did not routinely calculate PVAS between study visits. Our study used a modified version of the VDI to assess damage in this cohort because there is currently no validated pediatric specific VDI. It is not known whether scoring damage in this way is meaningful in the pediatric population and further studies, including validation studies, are needed to determine the extent to which this tool will effectively capture damage accrual in pediatric vasculitis patients. Finally, for the 22 patients in the cohort who were diagnosed before March 2007, data was entered retrospectively and may 25  have been subject to recall bias or missing data. The reliability and utility of retrospectively entered PVAS and pVDI scores has not been studied.  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. Ongoing collection of clinical and biological data through the PedVas initiative and other international collaborations will allow for further exploration and comparison of early as well as longer term outcomes. A study of outcome predictors is currently underway.    26  References   (1) Moorthy AV, Chesney RW, Segar WE, Groshong T. Wegener granulomatosis in childhood: prolonged survival following cytotoxic therapy. J Pediatr 1977 Oct;91(4):616-618. (2) Li X, Liang S, Zheng C, Zeng C, Zhang H, Hu W, et al. 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The clinical features of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis in Chinese children. Pediatr Nephrol 2006 Apr;21(4):497-502. (13) Valentini RP, Smoyer WE, Sedman AB, Kershaw DB, Gregory MJ, Bunchman TE. Outcome of antineutrophil cytoplasmic autoantibodies-positive glomerulonephritis and vasculitis in children: a single-center experience. J Pediatr 1998 Feb;132(2):325-328. 27  (14) Arulkumaran N, Jawad S, Smith SW, Harper L, Brogan P, Pusey CD, et al. Long- term outcome of paediatric patients with ANCA vasculitis. Pediatr Rheumatol Online J 2011 Jun 19;9:12-0096-9-12. (15) Mukhtyar C, Flossmann O, Hellmich B, Bacon P, Cid M, Cohen-Tervaert JW, et al. Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force. Ann Rheum Dis 2008 Jul;67(7):1004-1010. (16) Flossmann O, Berden A, de Groot K, Hagen C, Harper L, Heijl C, et al. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis 2011 Mar;70(3):488-494. (17) Pagnoux C, Hogan SL, Chin H, Jennette JC, Falk RJ, Guillevin L, et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts. Arthritis Rheum 2008 Sep;58(9):2908-2918. (18) Li ZY, Chang DY, Zhao MH, Chen M. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated vasculitis: a study of 439 cases in a single Chinese center. Arthritis Rheumatol 2014 Jul;66(7):1920-1926. (19) Walsh M, Flossmann O, Berden A, Westman K, Hoglund P, Stegeman C, et al. Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2012 Feb;64(2):542-548. (20) Sacri AS, Chambaraud T, Ranchin B, Florkin B, See H, Decramer S, et al. Clinical characteristics and outcomes of childhood-onset ANCA-associated vasculitis: a French nationwide study. Nephrol Dial Transplant 2015 Apr;30 Suppl 1:i104-12. (21) Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, et al. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis 2010 May;69(5):798-806. (22) Dolezalova P, Price-Kuehne FE, Ozen S, Benseler SM, Cabral DA, Anton J, et al. Disease activity assessment in childhood vasculitis: development and preliminary validation of the Paediatric Vasculitis Activity Score (PVAS). Ann Rheum Dis 2013 Oct;72(10):1628-1633. (23) Cabral DA, Uribe AG, Benseler S, O'Neil KM, Hashkes PJ, Higgins G, et al. Classification, presentation, and initial treatment of Wegener's granulomatosis in childhood. Arthritis Rheum 2009 Nov;60(11):3413-3424. (24) Fries JF, Hunder GG, Bloch DA, Michel BA, Arend WP, Calabrese LH, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Summary. Arthritis Rheum 1990 Aug;33(8):1135-1136. (25) Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore ) 1984 03;63(2):65-81. (26) Watts R, Lane S, Hanslik T, Hauser T, Hellmich B, Koldingsnes W, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis 2007 02;66(2):222-227. 28  (27) Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009 Apr;42(2):377-381. (28) Exley AR, Bacon PA, Luqmani RA, Kitas GD, Gordon C, Savage CO, et al. Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum 1997 Feb;40(2):371-380. (29) Hellmich B, Flossmann O, Gross WL, Bacon P, Cohen-Tervaert JW, Guillevin L, et al. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis 2007 May;66(5):605-617. (30) Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM 1994 Nov;87(11):671-678. (31) Dolezalova P. SAT0286 Paediatric Vasculitis Damage Index: A New Tool for Standardised Disease Assessment. Ann Rheum Dis 06 /2014;73(suppl 2):696.4; 696.4-697; 697. (32) Lionaki S, Blyth ER, Hogan SL, Hu Y, Senior BA, Jennette CE, et al. Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum 2012 Oct;64(10):3452-3462. (33) Hogan SL, Falk RJ, Chin H, Cai J, Jennette CE, Jennette JC, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med 2005 Nov 1;143(9):621-631. (34) Koldingsnes W, Nossent JC. Baseline features and initial treatment as predictors of remission and relapse in Wegener's granulomatosis. J Rheumatol 2003 Jan;30(1):80-88. (35) Iudici M, Puechal X, Pagnoux C, Quartier P, Agard C, Aouba A, et al. Brief Report: Childhood-Onset Systemic Necrotizing Vasculitides: Long-Term Data From the French Vasculitis Study Group Registry. Arthritis Rheumatol 2015 Jul;67(7):1959-1965. (36) Bohm M, Gonzalez Fernandez MI, Ozen S, Pistorio A, Dolezalova P, Brogan P, et al. Clinical features of childhood granulomatosis with polyangiitis (wegener's granulomatosis). Pediatr Rheumatol Online J 2014 May 26;12:18-0096-12-18. eCollection 2014. (37) Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010 Jul 15;363(3):221-232. (38) De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005 Aug;52(8):2461-2469. (39) de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009 May 19;150(10):670-680. 29  (40) Rottem M, Fauci AS, Hallahan CW, Kerr GS, Lebovics R, Leavitt RY, et al. Wegener granulomatosis in children and adolescents: clinical presentation and outcome. J Pediatr 1993 01;122(1):26-31. (41) Gayraud M, Guillevin L, le Toumelin P, Cohen P, Lhote F, Casassus P, et al. Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum 2001 Mar;44(3):666-675.                     30  Table 1. Baseline clinical features of 105 children with ANCA associated vasculitis   Clinical feature      Total patients (n = 105)   Female, n (%)        71 (68%) Ethnicity, n (%) Caucasian       52 (50%) East Indian/South Asian     5 (5%) Asian        4 (4%) Hispanic       3 (3%) Aboriginal       2 (2%) African American      2 (2%) Middle Eastern      1 (1%) Mixed        10 (10%) Median age at diagnosis in years (IQR)    13.8 (10.9-15.8) Median interval between symptom onset and diagnosis  2.2 (0.9-5.6)      in months (IQR) Clinical features, n (%)  Constitutional symptoms      84 (80%)  Pulmonary involvement      84 (80%)   Alveolar hemorrhage/massive hemoptysis   34   Respiratory failure      11   Abnormal chest imaging     75 Renal involvement       82 (78%)   Hematuria       77   Proteinuria (>0.3g/24hr)     73   Rise in creatinine > 10% or fall in creatinine   37    clearance > 25%   Renal failure requiring dialysis    17   End-stage renal disease     5  Ear, nose and throat involvement     59 (56%)   Nasal discharge/crusts/ulcers/granuloma   38   Paranasal sinus involvement     25   Subglottic stenosis      9  Musculoskeletal involvement     56 (53%)   Arthralgia/myalgia      48      Arthritis       23    Mucous membrane/ocular involvement    42 (40%)      Gastrointestinal involvement     41 (39%)  Cutaneous involvement      39 (37%) 31   Nervous system involvement      20 (19%)  Cardiovascular involvement     6 (6%)                          32      Figure 1. Primary treatments used for remission induction CYC, cyclophosphamide; MTX, methotrexate; RTX, rituximab; Pheresis, plasmapheresis * Other primary inductions medications included two patients on azathioprine, one patient on mycophenolate mofetil, and one patient on corticosteroids only. ^ Plasmapheresis patients – 25 patients received plasmapheresis in the following combinations: CYC and plasmapheresis (21), CYC and RTX and plasmapheresis (3), RTX and plasmapheresis (1).          0%10%20%30%40%50%60%70%80%90%100%CYC (74) MTX (17) RTX (14) Other (4)* Pheresis (25)^% of patients Induction medication (n) 33    Figure 2. Primary treatments used for remission maintenance  AZA, azathioprine; MTX, methotrexate; MMF, mycophenolate mofetil; CYC, cyclophosphamide; RTX, rituximab                 0%10%20%30%40%50%60%70%80%90%100%AZA (45) MTX (24) MMF (14) CYC (10) RTX (10) Nothing (5)% of patients Maintenance medication (n) 34    Figure 3. Percentage and number of patients with pVDI scores ranging from 0 to 6, at 1 year                           0%10%20%30%40%50%60%70%80%90%100%0 (38) 1 (31) 2 (16) 3 (10) 4 (5) 5 (2) 6 (2)% of patients pVDI score (n) 35   Table 2.  pVDI items scored at 12-months in 104 patients _________________________________________________________  System       number of patients affected (%)             _________________________________________________________  Renal       36 (35%)                   Proteinuria      21    Decreased GFR     19    End stage renal disease     12    Hypertension      8  ENT       21 (20%)    Nasal bridge collapse/septal peforation  8    Nasal blockage/chronic discharge/ crusting 7    Chronic sinusitis     6    Subglottic stenosis     5    Hearing loss      4  Pulmonary      16 (15%)    Impaired lung function    11    Chronic asthma     6    Chronic breathlessness    2    Pulmonary fibrosis     1    Pulmonary infarct     1  Ocular       9 (9%)    Cataract      8    Retinopathy      1    Visual impairment/diplopia    1  Musculoskeletal     4 (3%)    Avascular necrosis     2    Osteoporosis/vertebral collapse   2    Significant muscle atrophy    1  Cardiovascular     3 (3%)    Valvular disease     2    Pericarditis ≥ 3 months or pericardectomy  1  Skin/mucous membranes    2 (2%)    Alopecia      1    Cutaneous ulcers     1 Gastrointestinal     2 (2%)    Chronic peritonitis     2  Neuropsychiatric     1 (1%)                    Peripheral neuropathy    1  Peripheral vascular disease    0  ____________________________________________________________________________ 

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