UBC Faculty Research and Publications

Comparing presenting clinical features of 48 children with microscopic polyangiitis (MPA) against 183… Cabral, David; Canter, Debra; Muscal, Eyal; Nanda, Kabita; Wahezi, Dawn; Spalding, Steven; Twilt, Marinka; Benseler, Susanne; Campillo, Sarah; Charuvanij, Sirirat; Dancey, Paul; Eberhard, Barbara; Elder, Melissa; Hersh, Aimee; Higgins, Gloria; Huber, Adam; Khubchandani, Raju; Kim, Susan; Klein-Gitelman, Marisa; Kostik, Mikhail; Lawson, Erica; Lee, Tzielan; Lubieniecka, Joanna; McCurdy, Deborah; Moorthy, Lakshmi; Morishita, Kimberly; Nielsen, Susan; O'Neil, Kathleen; Reiff, Andreas; Ristic, Goran; Robinson, Angela; Sarmiento, Angelyne; Shenoi, Susan; Toth, Mary; Van Mater, Heather; Wagner-Weiner, Linda; Weiss, Jennifer; White, Andrew; Yeung, Rae Apr 4, 2016

Warning
You are currently on our download blacklist and unable to view media. You will be unbanned within an hour.
To un-ban yourself please visit the following link and solve the reCAPTCHA, we will then redirect you back here.

Item Metadata

Download

Media
52383-Cabral_D_et_al_Comparing_presenting_features.pdf [ 815.38kB ]
Metadata
JSON: 52383-1.0308655.json
JSON-LD: 52383-1.0308655-ld.json
RDF/XML (Pretty): 52383-1.0308655-rdf.xml
RDF/JSON: 52383-1.0308655-rdf.json
Turtle: 52383-1.0308655-turtle.txt
N-Triples: 52383-1.0308655-rdf-ntriples.txt
Original Record: 52383-1.0308655-source.json
Full Text
52383-1.0308655-fulltext.txt
Citation
52383-1.0308655.ris

Full Text

For Peer Review      Comparing presenting clinical features of 48 children with microscopic polyangiitis (MPA) against 183 having granulomatosis with polyangiitis (GPA).   Journal: Arthritis & Rheumatology Manuscript ID ar-15-0775.R2 Wiley - Manuscript type: Full Length Date Submitted by the Author: 04-Apr-2016 Complete List of Authors: Cabral, David; Children's & Women's Health Centre of BC,  Canter, Debra; Texas Children's Hospital,  Muscal, Eyal; Texas Children's Hospital/Baylor College of Medicine, Pediatric Rheumatology and Neurology and Developmental Neuroscience Nanda, Kabita; Seattle Children’s Hospital, Pediatric Rheumatology Wahezi, Dawn; Children’s Hospital at Montefiore, Pediatric Rheumatology Spalding, Steven; Cleveland Clinic, Pediatric Rheumatology Twilt, Marinka; Alberta Children\'s Hospital, Rheumatology, Paediatrics Benseler, Susanne; Alberta Children\'s Hospital, Rheumatology, Paediatrics Campillo, Sarah; The Montreal Children's Hospital, McGill University Health Centre Charuvanij, Sirirat; Siriraj Hospital, Mahidol University,  Dancey, Paul; Janeway Children\'s Health and Rehabilitation Centre Eberhard, Barbara; Cohen Children's Medical Center of New York,  Elder, Melissa; University of Florida,  Hersh, Aimee; Univ of Utah School of Medicine, Pediatrics Higgins, Gloria; Nationwide Children's Hospital,  Huber, Adam; IWK Health Centre/Dalhousie University, Division of pediatric rheumatology Khubchandani, Raju; Breach Candy Hospital and Research Centre Kim, Susan; Children's Hospital of Boston Klein-Gitelman, Marisa; Ann & Robert H. Lurie Children's Hospital of Chicago,  Kostik, Mikhail; Saint-Petersburg State Pediatric Medical Academy, Hospital Pediatry Lawson, Erica; UC San Francisco, Pediatric Rheumatology; UC San Francisco, Arthritis Research Group Lee, Tzielan; Stanford University School of Medicine, Stanford Children's Health Lubieniecka, Joanna; Simon Fraser University,  McCurdy, Deborah; University of California, Los Angeles, Pediatric Rheumatology Moorthy, Lakshmi; Robert Wood Johnson Medical School,  Morishita, Kimberly; British Columbia's Children's Hospital, Pediatrics, Division of Rheumatology Nielsen, Susan; Rigshospitalet, Pediatrics John Wiley & SonsArthritis & RheumatologyFor Peer ReviewO'Neil, Kathleen; Riley Hospital for Children at IU Health,  Reiff, Andreas; CHLA, RHEUMATOLOGY Ristic, Goran; Mother and Child Health Care Institute of Serbia Robinson, Angela; Rainbow Babies and Children’s Hospital, Pediatric Rheumatology Sarmiento, Angelyne; Children's & Women's Health Centre of BC,  Shenoi, Susan; Seattle Childrens Hospital, Pediatric Rheumatology Toth, Mary; Akron Children's Hospital, Rheumatology Van Mater, Heather; Duke University, Pediatrics Wagner-Weiner, Linda; University of Chicago Comer Children\'s Hospital Weiss, Jennifer; Hackensack University Medical Center, Pediatric Rheumatology White, Andrew; Washington University, Pediatrics Yeung, Rae; The Hospital for Sick Children, Paediatrics Network, ARChiVe Investigators; BC Children\'s Hospital Keywords: ANCA-associated Vasculitis, Microscopic Polyangiitis, Granulomatosis with Polyangiitis (GPA), Registry, Vasculitis <B>Disease Category</b>: Please select the category from the list below that best describes the content of your manuscript.: Vasculitis     Page 1 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 1 1  Title:   Comparing presenting clinical features of 48 children with microscopic polyangiitis (MPA) against 183 having granulomatosis with polyangiitis (GPA).  An ARChiVe study.  Authors David A. Cabral1*, Debra L. Canter2*, Eyal Muscal2, Kabita Nanda3, Dawn M. Wahezi4, Steven J. Spalding5, Marinka Twilt6, Susanne M. Benseler6,  Sarah Campillo7, Sirirat Charuvanij8, Paul Dancey9, Barbara A. Eberhard10,  Melissa E. Elder11,  Aimee Hersh12, Gloria Higgins13, Adam M. Huber14, Raju Khubchandani15, Susan Kim16, Marisa Klein-Gitelman17,  Mikhail Kostik18, Erica Lawson19, Tzielan Lee20, Joanna M.Lubieniecka21, Deborah McCurdy22, Lakshmi N. Moorthy23, Kimberly A. Morishita1; Susan M. Nielsen24, Kathleen M. O'Neil25, Andreas Reiff26, Goran Ristic27, Angela B. Robinson28, Angelyne Sarmiento1, Susan Shenoi3, Mary B. Toth29, Heather Van Mater30, Linda Wagner-Weiner31, Jennifer E. Weiss32, Andrew J. White33, Rae S.M. Yeung34, and ARChiVe Investigators Network§ within the PedVas initiative   * Contributed equally as first Authors, with data analysis and primary manuscript drafts.  Affiliations 1 David A. Cabral, MBBS, Kimberly A. Morishita, MD, Angelyne Sarmiento, BSc,  BC Children’s Hospital, Vancouver, BC, Canada; 2Debra L Canter, MS, Eyal Muscal, MD, Texas Children's Hospital, Houston, TX; 3Kabita Nanda, MD, Susan Shenoi, MD, MS, Seattle Children's Hospital, Seattle, WA; 4Dawn Wahezi, MD,  Children's Hospital at Montefiore, Bronx, NY; 5Steven J. Spalding, MD, The Cleveland Clinic, Cleveland OH; 6Marinka Twilt, MD, Susanne Benseler, MD, Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada; 7Sarah Campillo, MD, The Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada; 8Sirirat Charuvanij, MD,Siriraj Hospital, Mahidol University, Bangkok, Thailand; 9Paul Dancey, MD, Janeway Childrens Health and Rehabilitation Centre, St. John’s, NL, Canada; 10Barbara A. Eberhard, MD, Cohen Children’s Medical Center of New York, New Hyde Park, NY; 11Melissa E. Elder, MD, University of Florida, Gainesville, FL; 12 Aimee Hersh, MD, University of Utah, Salt Lake City, UT; 13Gloria Higgins, MD, Nationwide Children’s Hospital, Columbus, OH; 14Adam M. Huber, MD, IWK Health Centre and Dalhousie University, Halifax, NS; 15Raju Khubchandani, MD, Breach Candy Hospital, Mumbai, India; 16Susan Kim, MD, Children’s Hospital of Boston, Boston, MA; 17Marisa Klein-Gitelman, MD, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; 18Mikhail Kostik, MD, Saint-Petersburg State Pediatric Medical University, Russia; 19 Erica Lawson, MD, University of California at San Francisco, San Francisco, CA; 20Tzielan Lee, MD, Stanford Children's Health, Stanford University School of Medicine, Stanford, CA; 21Joanna M. Lubieniecka, PhD, Simon Fraser University, Burnaby, BC;  22Deborah McCurdy, MD, University of California at Los Angeles, Los Angeles, CA; 23Lakshmi N. Moorthy, MD, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ; 24Susan M. Nielsen, MD, Rigshospitalet, Copenhagen, Denmark; 25Kathleen M. O'Neil, MD, Riley Children’s Hospital, Indianapolis, IN; 26Andreas Reiff, MD, Children’s Hospital LA, Los Angeles, CA; 27Goran Ristic, MD, Mother and Child Health Care Institute of Serbia, Belgrade, Serbia; 28Angela B. Robinson, MD, University Hospitals Case Medical Center, Rainbow Babies and Children's Hospital, Cleveland, OH; 29Mary B. Toth, MD, Akron Children's Hospital, Akron, OH; 30Heather Van Mater, MD, Duke Children’s Hospital and Health Center, Duke University Medical Center, Durham, NC; 31Linda Wagner-Weiner, MD, Comer Children's Hospital, Chicago, IL; 32Jennifer E. Weiss, MD, Joseph M. Sanzari Children’s Hospital, Hackensack University Medical Center, Hackensack, NJ; 33Andrew J. White, MD, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO; 34Rae S.M. Yeung, MD, Hospital for Sick Children, Toronto, ON, Canada.  § 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, 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 Page 2 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 2 2  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. 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 Page 3 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 3 3  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 Foel (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, USA: Leslie Abramson (Site Principal Investigator).  Wellington Hospital, Wellington, New Zealand: Arno Ebner (Site Principal Investigator).   Corresponding author David A. Cabral (dcabral@cw.bc.ca) Division of Rheumatology, Room K4-121, British Columbia Children's Hospital, Vancouver, BC V6H 3V4, Canada  Funding  Canadian Institutes of Health Research (DAC) grant FRN: TR2-119188 The Arthritis Society Vasculitis Foundation (DAC) Childhood Arthritis and Rheumatology Research Alliance Child and Family Research Institute of British Columbia Children’s Hospital  Keywords Pediatric vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis   Page 4 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 4 4  ABSTRACT 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.   Page 5 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 5 5  Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA, previously Wegener Granulomatosis) are primary systemic vasculitides that predominantly affect small blood vessels, and are collectively grouped under the umbrella term of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) (1;2). The limited available literature suggests that genetic, pathophysiologic and prognostic differences exist between MPA and GPA and this may be relevant to continuing biological discovery and targeted therapy (3). Distinguishing between these diseases is challenging because of overlapping clinical features, lack of standardized definitions, and absence of mutually exclusive classification criteria.  In the pediatric population especially, where there are few reported cases, accurate assessment of disease-specific epidemiologic data, prognostic implications and biological discovery has been particularly limited. The American College of Rheumatology (ACR) has the most commonly used system for classifying vasculitis. However, a pediatric adaptation of these ACR criteria, the European League against Rheumatism (EULAR), Pediatric Rheumatology International Trials Organization (PRINTO) and Pediatric Rheumatology European Society (PReS) criteria is reported to have improved specificity and sensitivity for classifying childhood GPA (4-6). Neither pediatric nor adult classification systems have categorical criteria for MPA, and as a result, many patients defined as having MPA might also be concurrently classified as having GPA or polyarteritis nodosa (PAN) depending on how disease definitions, such as those proposed by the Chapel Hill Consensus Conferences (CHCC) are interpreted by individual physicians (2;5;7;8). Many clinical studies and trials have avoided this conundrum by considering GPA and MPA collectively. On the other hand, Watts et al. proposed a classification algorithm, developed by consensus, and subsequently adopted by the European Medicines Agency (EMA) that can classify patients with all types of AAV and PAN into mutually exclusive diagnostic categories (9). Specifically the EMA algorithm has been adopted as a practical tool for clinical trials and clinical studies of AAV in adult patients (10;11), and also in our previous pediatric study where GPA and MPA are actively distinguished (5); it has not been adopted for routine clinical practice. Published work from the multi-center contemporary inception cohort called ARChiVe (A Registry for Childhood Vasculitis: e-entry) has described the largest cohort to date of children with GPA; however, descriptions of childhood MPA remain limited to a few studies of fewer than 26 patients and where included patients have not always been uniquely classified (12-16).   In this present study, we aimed to describe the presenting features of childhood MPA among the sub-cohort of AAV patients recruited to ARChiVe that are uniquely classified as MPA; that is, by using the EMA algorithm they have no features that would be considered surrogate markers of GPA. We also aimed to compare these MPA patients against a larger accumulated sub-cohort of patients formally classified as having GPA by either ACR or EULAR/PRINTO/PReS criteria, with the goal of identifying variations in clinical phenotype, diagnostic evaluations, and treatment.  PATIENTS AND METHODS  ARChiVe was first launched in March 2007, and at the time of censoring for this study, 45 pediatric rheumatologists at 45 geographically diverse institutions in Canada (n=6), the US (n=34), Europe (n=3) and Asia (n=2) have contributed patients.  Patient eligibility criteria, the Registry Dataset, and the strategy for establishing the time-of-diagnosis dataset have been described previously.(4) Briefly, eligible patients included those who were diagnosed by the treating physician (MD diagnosis) after January 1st 2004 and before the age of 18 as having a primary chronic systemic vasculitis. Patient data was collected retrospectively for those diagnosed before March 2007, and prospectively for those diagnosed subsequently, up to November 2015.  Specific patient data items for categorical capture included all criteria that are required for formal diagnosis using the 1990 ACR (17), or EULAR/PRINTO/PReS (6) systems of classification. Additionally included is other categorical information described in CHCC disease definitions that are incorporated  in the EMA algorithm for Page 6 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 6 6  classifying AAV subtypes and PAN.  Patients could then be formally re-classified according to any of these criteria by computation of data.  The specific experience of individual physicians in diagnosing and caring for children with chronic vasculitis is limited as described in a 2005 survey (18) where the median number of patients with an AAV diagnosed by any rheumatologist in one year is less than one. A recent 2015 international survey of 209 pediatric rheumatologists (Cabral unpublished) supports these earlier findings and also finds a non-uniform approach of respondents for sub-classifying AAV patients as having either GPA or MPA. Individuals used singly, or in varied combinations ACR (42%) or EULAR/PreS/ PRINTO (81%) classification criteria, cANCA/PR3 versus pANCA/MPO (82 %), CHCC disease definitions (46%), and other informal criteria (27%). One third of respondents said their final diagnosis was often AAV and they did not routinely sub-classify all patients to GPA or MPA.  Therefore, for this study, comparing MPA patients against GPA patients, we did not use physician diagnoses or physician classification as there are no standardized diagnostic criteria, and among physicians from 45 contributing sites, having varied experience with AAV, there was no uniform approach. To systematically ensure uniformity, we re-classified by computation of categorical data, all patients with completed data enrolled in the registry to November 2015 with the submitting physicians diagnoses as follows: GPA, limited GPA, MPA, ANCA-positive pauci-immune glomerulonephritis, eosinophilic granulomatosis with polyangiitis, polyarteritis nodosa and unclassified small/medium-vessel-vasculitis. GPA patients were classified according to ACR or EULAR/PRINTO/PReS criteria to also allow comparison against similarly defined GPA cohorts in other pediatric and adult studies. MPA patients were classified according to the EMA algorithm. As described previously (5;9), the EMA algorithm in a sequential stepwise manner applies different classification criteria, disease definitions and disease-specific ‘surrogate markers’ from the CHCC, to distinguish patients with individual AAV subtypes and PAN (Figure). After initially determining whether the patient does not have EGPA using the ACR or Lanham criteria, it determines whether a patient has GPA according to the ACR or (using a Pediatric modification of algorithm) EULAR/PRINTO/PReS criteria. These GPA patients were included in this study. In the next step the EMA algorithm assigns the classification of GPA to additional patients using the CHCC definitions, clinical surrogate features of GPA, and presence or absence of ANCA. We arbitrarily chose to exclude this group of patients from the study describing them as “unclassifiable AAV” as such patients were not included in the GPA cohorts of other comparator groups referred to in this manuscript. In the next step the algorithm determines whether a patient has MPA by the presence of defining CHCC histological features, clinical surrogates for renal vasculitis and ANCA. These MPA patients, with no overlapping features of GPA, were included in this study. Patients relegated to the final step of the EMA algorithm, wherein it is determined if they fulfill the CHCC PAN definition, were excluded from the study.   Basic demographics, clinical features, diagnostic data, and treatment modalities at baseline were primarily extracted for patients uniquely classified as having MPA or GPA.  Study data were collected and managed using REDCap electronic data capture tools hosted at the University of British Columbia (19). Written informed consent was obtained from each participant, and the study protocol was approved by the ethics committee at each participating hospital (see acknowledgments).   Descriptive statistics were generated using STATA (version 13.1 STATACorp, College Station, TX, USA).  Comparisons were made using X2 or Fisher’s exact tests for categorical variables, and Student’s t-tests or Mann-Whitney U tests for continuous variables.  RESULTS During the study period, among the 440 children enrolled into the ARChiVe cohort, 374 patients with the initial clinical diagnoses (MD diagnosis) of GPA or limited GPA (n=225), MPA (n=48), ANCA-positive pauci-immune Page 7 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 7 7  glomerulonephritis (n=16), PAN (n=40), eosinophilic granulomatosis with polyangiitis (n=10), or unclassified small vessel vasculitis (n=36) were selected for formal reclassification by computation (Table 1).   A total of 231 patients fulfilled the criteria for either MPA (n=48) or GPA (n=183) and were included in the current study. Patients with unclassifiable AAV (62), PAN or other unclassifiable vasculitis (N=71) were excluded. Sixty-five of the 183 patients with GPA have been previously described (20).  No patients could be concurrently classified as having both MPA and GPA.  Collectively, patients with either GPA or MPA were primarily white/Caucasian (55%), female (64%), and 90% (n=208) were ANCA positive. Children with MPA were significantly younger at the time of disease onset than those with GPA (median difference 3 years, p=0.004).   The interval between symptom onset and diagnosis (time-to-diagnosis) varied widely both between and within groups. For MPA patients, the median time-to-diagnosis was 1.6 months and for GPA patients, 2.1 months. Demographics, time-to-diagnosis interval, and initial MD diagnosis (prior to formal reclassification) are presented in Table 1. Presenting Clinical Features  For patients with MPA, the systems involved in a majority of patients in order of frequency were: constitutional (85%), renal (75%), gastrointestinal (58%), musculoskeletal (52%) and cutaneous (52%). For patients with GPA the systems involved in a majority of patients were constitutional (88%), renal (83%), pulmonary (74%), upper airways/ENT (70%), and musculoskeletal (65%).  The different frequency of pulmonary involvement in GPA (74%) versus MPA (44%) patients was statistically significant (p< 0.0001).  The difference in frequencies of upper airway involvement is not surprising as in the EMA algorithm specific ENT characteristics (described in upper airways section below) are considered “surrogate” markers of GPA. Their presence, in patients who otherwise do not completely fulfill classification criteria for GPA, precludes a “unique” diagnosis of MPA. (Figure) Such patients are designated as “unclassifiable AAV” and the frequencies of ENT and other features among this cohort are provided in a supplementary table.   Individual organ-specific clinical features, laboratory and imaging findings and histopathology are described below, with the frequencies of specific clinical features summarized in Table 2.  Renal  The frequency and type of renal involvement was similar between MPA and GPA patients with common manifestations of proteinuria, microscopic hematuria and/or red blood cell casts, abnormal protein to creatinine ratio, and impaired creatinine clearance. Serum creatinine was more often moderately to severely elevated (>30% age-adjusted upper limit of normal) among patients with MPA (48% MPA versus 34% GPA, p=0.06) but this was not statistically significant. Rates of nephrotic-range proteinuria, renal failure requiring dialysis, or end-stage renal disease, were similarly low but tended to be more frequent amongst MPA versus GPA patients.  Renal biopsies were obtained in 32 MPA patients and 108 GPA patients and among these, histopathology findings were consistent with pauci-immune and/or necrotizing glomerulonephritis in 25 (78%) of MPA and 86 (80%) of GPA patients; findings were consistent with vasculitis in 24 (75%) of MPA and 74 (69%) of GPA patients. Pulmonary  Pulmonary involvement was overall more frequent among GPA patients versus MPA patients as described above, and individual symptomatic features such as chronic cough and alveolar hemorrhage, massive hemoptysis were also significantly more frequent among GPA patients. Other features such as, supplemental oxygen requirements and respiratory failure also tended to be more frequent among GPA patients but not to Page 8 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 8 8  the level of statistical significance.  Pulmonary imaging was performed in 92% of GPA and 81% of MPA patients with abnormalities identified in 89% and 39% respectively. The presence of nodules, fixed infiltrates and/or cavitations, described as “surrogate features of GPA” in the EMA algorithm (see figure) excluded an MPA diagnosis, and they were therefore only found in GPA patients with frequencies respectively of 54%, 36% and 21%.  Of note, among the 63 patients considered to have “unclassifiable AAV”, only five patients (8%) had these surrogate pulmonary imaging findings (See supplementary table). Pleural effusions were found in both MPA (10%) and GPA (16 %) patients, and other findings such as fibrosis, septal thickening and pneumothoraces were identified in fewer than 10% of images in either group.  Of 31 GPA patients biopsied, 24 (77%) had findings that confirmed (48%) or were consistent with (29%) vasculitis. Granulomatous inflammation was identified in 4, and 7 had no evidence of vasculitis. Histopathology findings for the 3 and only patients with MPA who were biopsied, confirmed vasculitis in 2, were consistent with vasculitis in one, and no granulomas were seen in any biopsy.  Upper Airway Upper airway disease was a predominant presenting feature among patients with GPA (70%). The virtual absence of upper airway features among MPA patients is not surprising. Specifically, having any nasal / sinus involvement, or tracheal / subglottic stenosis qualifies a patient as having one of the specific EULAR/PRINTO/PRES classification criteria for GPA (3 of 6 required)(6). If patients with these characteristic ENT features do not completely fulfill classification criteria for GPA, these so-called “surrogate” markers of GPA, according to the EMA algorithm, still relegate the patient to a diagnosis of GPA, albeit “incomplete”. They are therefore precluded from an MPA diagnosis, and for the purposes of our study they are described as having “unclassifiable AAV” (Figure). Among the 62 patients considered to have unclassifiable AAV, 24 (39%) had upper airway (ENT) features (See supplementary table).  Among GPA patients included in the study, the most commonly reported abnormalities were chronic recurrent nasal symptoms (53%) and recurrent or chronic sinusitis (39%). Oral ulcers (15%), subglottic or tracheal stenosis /inflammation (10%), hearing loss (10%), and tissue damage from septal perforations or nasal collapse (8%) occurred less frequently. Sinus imaging was performed on 123 GPA and 11 MPA patients. There were no abnormalities identified among the MPA patients. Among the GPA patients specifically characterized abnormaliti s were: abnormal fluid levels or opacities (53%), bone destruction (6%) mass effect (5%), and other unspecified abnormalities were found in 31%. The results of paranasal sinus or upper airway biopsies performed in 36 GPA patients confirmed vasculitis in 8 (22%), were consistent with vasculitis in 13 (36%), and showed no evidence of vasculitis in 15 (42%). Other Systems  Gastrointestinal symptoms found in a majority of patients with MPA (58%) were significantly more frequent than for patients with GPA (36%); chronic nausea (33% MPA versus 12% GPA, p<0.04) was specifically more frequent in MPA. Nonspecific abdominal pain (38% MPA, 22% GPA) was relatively common in both. Severe gastrointestinal features of persistent diarrhea, bleeding or ischemic abdominal pain were each found in less than 5% of both MPA and GPA. Skin involvement was reported in 48% of all patients and most frequently included palpable purpura and/or petechial rash in 31% and 27% of patients with MPA and GPA, respectively.  Other skin findings found in fewer than 10% of patients in both groups included subcutaneous nodules (MPA 6%; GPA 8%), infarctions (MPA 65%; GPA 3%), livido (MPA 2%; GPA 1%); Raynaud syndrome (MPA 0%; GPA 3%) and subcutaneous swelling (MPA 4%; GPA 3%). Features of mucous membrane or eye involvement reported in 40% of all patients included red and/or painful eye conditions attributable to conjunctivitis, episcleritis, or another nonspecific condition. Three patients with GPA had proptosis with retro-orbital mass and one patient with MPA had retinal exudates / hemorrhages / aneurysms / vessel thrombosis. Relatively few patients with MPA (4%) or GPA (15%) presented with oral ulcers. Page 9 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 9 9  A majority of patients presented with non-specific musculoskeletal complaints (52% MPA, 65% GPA). Among all patients, neurological involvement was relatively uncommon with the more common features being seizures (MPA 8%; GPA 3%) and the non-specific complaints of headaches (MPA 13%; GPA 11%) and dizziness (MPA 4%; GPA 7%); severe neurological features, such as peripheral neuropathy, weakness or stroke were reported in fewer than 3% of all patients. Cardiovascular manifestations, primarily venous thromboses, were recorded for only 3 patients who had GPA. Other Laboratory Features The majority of all patients presented with elevated markers of inflammation and hematologic abnormalities. Marked elevation of ESR (>50mm/hr) was typical (MPA 65%; GPA 70%), while elevation of CRP was more frequently observed in patients with GPA (85%) than MPA (65%, p<0.01). Half of patients with GPA had elevated levels of both total white blood cells and neutrophils compared to one third of patients with MPA. Eosinophil levels were normal for most patients. Over 80% of all patients had anemia and approximately one third had elevated platelet counts. Von Willebrand antigen (tested in only 10 MPA and 59 GPA patients) was frequently elevated respectively in 60% and 69%.  Increased ASO titers were observed more frequently when tested among patients with MPA (39% MPA; 13 % GPA, p=0.006).  There was little evidence of other infectious causes or concurrent diseases such as tuberculosis or hepatitis B or C.  MPO-ANCA and/or p-ANCA was more frequent in patients with MPA (55%) than those with GPA (26%), p<0.01; whereas PR3-ANCA and/or c-ANCA was more common in patients with GPA (67%) compared to patients with MPA (17%), p<0.01. ANCA, tested by either immunofluorescence or ELISA, was not present in 26% of MPA patients and 5% of GPA patients.   Three patients had no ANCA testing. Initial Therapies The initial immunosuppressive therapies used for GPA and MPA patients were very similar (Table 3); nearly all patients received glucocorticoids (97%) usually combined with another immunosuppressive drug.  Most patients (76%) were treated with cyclophosphamide (69% MPA, 78% GPA), 11% used other conventional disease modifying anti-rheumatic drugs (DMARDS): methotrexate, azathioprine, or mycophenolate mofetil (25% MPA, 13% GPA) and 12% used rituximab (10% MPA, 13% GPA) either singly or in combination with another DMARD.  Six percent of patients did not receive any of these listed DMARDS or rituximab. Twenty-one percent of patients received plasmapheresis. A significantly smaller proportion of patients with MPA (21%) versus GPA (51%) received trimethoprim either for upper respiratory infection or Pneumocystis jiroveci pneumonia prophylaxis (p=0.0005). Antihypertensive agents and/or ACE inhibitors were administered in 41% of all cases.   Patients with Unclassifiable AAV The 63 patients in this group were predominantly female (76%), with MD diagnoses of GPA (55%), MPA (13%), ANCA-associated pauci-immune glomerulonephritis (6%), PAN (5%) or unclassified (21%). A majority of these patients had constitutional (63%) and pulmonary features (60%). Other systems involved in decreasing frequency were musculoskeletal (40%), renal (39%), upper airways / ENT (39%), cutaneous (32%), and gastrointestinal (30%). The results of ANCA status among the 59 tested were PR3-ANCA and/or c-ANCA (36%), MPO-ANCA and/or p-ANCA (32%) and ANCA-negative (32%). Details of demographic and clinical features of this group and  their ANCA status are summarized comparatively against MPA and GPA cohorts in three supplementary tables  DISCUSSION  Page 10 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 10 10  Our study describes the largest cohort of pediatric patients with AAV, albeit excluding patients with eosinophilic GPA (EGPA).  The relative ratio of GPA versus MPA patients from contributing centers is 4:1, and this likely reflects a predominantly Caucasian population of Northern European origin, in contrast to Japan and China (21;22) and perhaps Southern Europe (23) where MPA is more common than GPA.  The sub-cohort of 183 patients with GPA in the current study is the largest reported cohort of pediatric patients with that disease, and includes 65 patients previously recruited to ARChiVe up to November 2008 (4). The sub-cohort of 48 patients with pediatric MPA is larger than the 5 largest previous pediatric case series retrospectively reporting on patients with MPA from Turkey (n=26) (13), Japan (n=21) (12), Serbia (n=7) (14), Beijing (n=19) (16) and Guangzhou (n=16) (24).The earliest of these studies from Turkey (13) described 26 children with PAN among whom 24 might now be considered to have MPA using contemporary definitions. In the subsequent studies MPA patients were distinguished from those with GPA according to different disease definitions or descriptions that have evolved over time. In the studies from Serbia (14) and Beijing (16) the diagnosis of MPA versus GPA was ultimately determined by the presence of MPO or p-ANCA. In using the EMA algorithm (9) the present study is the only one to define patients as having MPA in a way that is mutually exclusive of the diagnosis of GPA, EGPA or PAN.  A variety of other criteria, definitions, etcetera used by pediatric rheumatologists for sub-classifying patients as having MPA versus GPA were identified in an international survey completed by a majority of physicians contributing patients to ARChiVe. These results, describing a non-uniform approach to classification, are provided in the methodology as rationale for our decision to systematically reclassify our patient cohort. Of note, among the 62 patients with “unclassifiable AAV” not included in these analyses, the assigned MD diagnosis of GPA versus MPA of 4:1 was similar to the study group. The predominance of females was similar to both the GPA and MPA cohorts. Generally patients in this cohort had more limited disease and arguably having fewer systems involved they were less likely to fulfill formal classification criteria. The frequencies PR3-ANCA and/or c-ANCA (36%) versus MPO-ANCA and/or p-ANCA (32%) versus negative-ANCA (32%) was evenly distributed and in this regard was not indicative of the group being more like either GPA or MPA.   MPA cohort  The discrepancy in frequency of patients formally classified with MPA according to the EMA algorithm, versus those having an MD diagnosis of MPA was evaluated and discussed in depth in our previous manuscript describing an earlier smaller cohort of patients recruited to ARChiVe (5). Several patients who were classified formally as having GPA were given the MD-diagnosis of MPA, seemingly on the basis of the type of ANCA (i.e. pANCA with specificity for MPO).   The mean age of onset for patients with MPA in our study of 10.8 years falls within the mean age ranges (9-12 years) from other pediatric series (12-16). Our marked female predominance of 73% was also characteristic of the other series with described frequencies of up to 90%; only the Turkish series (13) had a lower female frequency of 53%.   This is in complete contrast to adult studies demonstrating a male predominance in MPA ranging from 55 - 60% (11;25;26).Notably the two more recent of these 3 studies employed algorithmic classification of GPA (11; 25) The frequencies of involvement of different organ systems (and specific presenting clinical features) of our MPA cohort are listed in Table 2. The frequencies of the more commonly involved systems fell within the wide range of frequencies described in the other pediatric series (12-16).  The frequency of general constitutional symptoms (85%) was in the low end of the ranges reported. Renal disease present in 75% of patients was also in the low end of the range, and contrasts with reports from departments of nephrology where renal disease was present in 100% of patients. Skin manifestations, predominantly palpable purpura or petechiae occurred in a majority (52%) of our patients and was in line with other reported frequencies (15% -100%); it should be noted that the 100% frequency occurred in the Serbian study that included only 7 patients.  In spite of the Page 11 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 11 11  characteristic of the EMA algorithm to preclude a diagnosis of MPA among patients with selected lung features on imaging, pulmonary involvement occurring in a minority (44%) of our patients was in the mid range of reported frequencies (15% to 62%) (12-16). Gastrointestinal involvement occurred in just over half of our patients, nonspecific abdominal pain and chronic nausea representing the primary manifestations, with gastrointestinal bleeding occurring in only one patient. Gastrointestinal involvement was not typically characterized in other series, but where described, occurred in 15% to 55% of patients (12;14-16).  Nervous system involvement was infrequent; notably peripheral neuropathy was not reported, similar to other pediatric and adult series where a diagnosis of PAN is actively excluded (12;14-16). GPA Cohort  The sub cohort of 183 patients with GPA is triple the two previous largest pediatric series of 56 patients from the PRINTO database (27) and 65 patients from our earlier ARChiVe report (4). In the earlier ARChiVe report, patients were classified as having GPA according the ACR criteria; however, since that time pediatric-specific criteria have become available and both the PRINTO study and this current report classify patients according to the EULAR/PRINTO/PRES criteria (5). Despite the difference in population pools and classification criteria, the results of this much larger series overall support the findings of the previous studies.  The female and Caucasian preponderance was similar in all 3 reports. The median age of disease onset of 14 years (median diagnostic delay of 2.1 months) was slightly older than reported for the PRINTO registry with median age of disease onset of 11.7 years (median diagnostic delay of 4.2 months). Comparing the current with earlier ARChiVe report, the frequencies of organ system involvement among GPA patients were very similar, although in the newer report, cutaneous findings were reported more frequently (47% versus 35%). Both venous thrombosis (3 patients) and periorbital masses (3 patients) were only reported in the later and larger cohort.  Comparing presenting features from the current ARChiVe cohort to that of the PRINTO registry, respectively, the following features were less frequent in ARChiVe: ENT findings (70% versus 91%), eye findings (12% versus 35%), the presence of fixed lung infiltrates (36% versus 47%); whereas the following features were more frequent in ARChiVe: renal disease defined by hematuria and/or casts (72% versus 63%), gastrointestinal findings (36% versus 16%), the presence of hemoptysis/alveolar hemorrhage (42% versus 25%), or pulmonary nodules (54% versus 30%).   In spite of the slight variations in frequencies of clinical features, our findings overall support the conclusions of the PRINTO registry report, in that when compared to the adults series (using the same comparators as they used (28-30)), adult patients showed lower frequencies of constitutional, respiratory, and renal involvement, and higher frequency of conductive hearing loss; unlike the PRINTO series, we did not demonstrate a higher frequency of ENT findings in our pediatric cohort compared to adults. In contrast to the adult experience, so called limited or localized GPA defined by the absence of kidney disease occurred in a minority of children at diagnosis, and presentation. This apparent difference might reflect the known difficulties in formally classifying children as having GPA  when they only have single  organ involvement at presentation, for example subglottic stenosis, chronic sinusitis, episcleritis or retro-orbital mass. Indeed such patients are more frequent in the “unclassifiable AAV (incomplete GPA) cohort of 62 patients where the time-to-diagnosis (diagnostic delay) was also longer than for either GPA or MPA  Comparing GPA and MPA cohorts In the absence of any formal classification criteria for MPA, we have applied a pediatric modified EMA algorithm and used categorical data provided by the contributing physicians to uniquely classify patients as MPA (i.e. without overlapping features of GPA).  Using this strategy we were able to overcome the potentially differing diagnostics/classification principles used by the variety of pediatric rheumatologists at the 45 diverse institutions that have contributed patients to ARChiVe.  Page 12 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 12 12  While both GPA and MPA are included among the spectrum of differential diagnoses for pulmonary-renal syndromes, only a minority (44%) of patients with MPA presented with any respiratory features. Patients with GPA also tended to have more frequent and severe pulmonary manifestations (i.e. hemorrhage, requirement for oxygen or pulmonary failure) than patients with MPA. For MPA patients, the age of onset was younger, and although renal disease was similarly frequent to GPA, it tended to be more severe in phenotype (details below).  Gastrointestinal manifestations also occurred more frequently in MPA.  For GPA patients, however, three quarters presented with lower respiratory tract manifestations and the disease was associated with ANCA directed against PR3 antigen. The presence in patients of other “surrogate markers” of GPA (including upper respiratory tract manifestations of nasal and sinus involvement) as incorporated in the EMA algorithm, preclude the diagnosis of MPA. Similarly, the less frequent, but relatively specific manifestations of tracheal and subglottic stenosis or inflammatory eye disease were found only in GPA.   When comparing specific clinical manifestations in patients with MPA and GPA in our cohort, features that were more prevalent among patients with MPA included nephrotic range proteinuria with edema, renal failure requiring dialysis, and chronic nausea. While we described 75% of MPA patients in our cohort as having renal disease, previous studies (predominantly from Nephrology Departments) have described renal manifestations in 100% of patients with MPA (12-16).  The frequency of nephrotic syndrome (23%) was similar in our cohort to the other 2 series from China (30%) (15) and Serbia (29%) (14). Requirement for dialysis for renal failure, around the time of diagnosis, was only described in the Serbian study (14) and occurred in 29% of patients, similar to 25% in the present study. Gastrointestinal involvement (specifically chronic nausea) was seen in a half of MPA versus a third of GPA patients, a finding that is somewhat unique to our study and its relevance remains unclear. That being stated, it seems plausible that chronic nausea, in particular, may also reflect more severe renal disease in MPA patients.  Prompt identification of AAV followed by initiation of appropriate immunosuppressive treatment is crucial to preventing adverse outcomes.   Several adult studies have identified the level of kidney function at presentation and, in particular, whether dialysis is required, as independent risk factors for mortality in patients with AAV (31;32). We demonstrated wide variations in time-to-diagnosis and speculate that variations in the rate of onset and severity of prodromal symptoms may delay disease recognition in some patients. Additionally, because of its rarity, primary health care might not always consider pediatric AAV among the diagnostic possibilities.    Both MPA and GPA are rare, yet potentially devastating systemic vasculitides affecting small to medium-sized arteries in multiple organ systems.  In the absence of definitive diagnostic tests, classification criteria are an essential tool for characterizing and comparing patients with overlapping clinical phenotypes across studies. Although in this comparative description of MPA versus GPA the number of MPA patients is relatively small, the findings are consistent with the previously described smaller cohorts. Nevertheless our following limited conclusions should be viewed with caution. Our study has allowed us to delineate differences between MPA and GPA, notably an earlier age of onset and perhaps more severe renal disease presentation in children with MPA. The marked female predominance in pediatric MPA patients, compared to the male predominance in similarly classified adult patients, invokes a cautionary note against making broad generalizations about the similarities between adult versus pediatric vasculitis. International collaborations in childhood vasculitis have led to the development and validation of childhood vasculitis classification criteria, advanced our understanding of the clinical phenotype at presentation of childhood AAV, and improved our ability to capture disease activity and determine treatment choices (33).  Ongoing biomarker-driven studies may complement systems for sub-classifying patients with AAV, and will further shape our understanding of these diseases.  Several challenges remain with regard to evaluating the safety and efficacy of current treatment strategies, which have been largely derived from studies of adults, and assessing the long term morbidity for children with AAV.    Page 13 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 13 13    Page 14 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 14 14   REFERENCES   (1)  Bosch X, Guilabert A, Font J. Antineutrophil cytoplasmic antibodies. L 2006; 368(9533):404-18.  (2)  Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65(1):1-11.  (3)  Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med 2012; 367(3):214-23.  (4)  Cabral DA, Uribe AG, Benseler SM, O'Neil KM, Hashkes PJ, Higgins G et al. Classification, presentation and initial treatment of Wegener's Granulomatosis in Childhood. Arthritis Rheum 2009; 60.  (5)  Uribe AG, Huber AM, Kim S, O'Neil KM, Wahezi DM, Abramson L et al. Increased sensitivity of the European medicines agency algorithm for classification of childhood granulomatosis with polyangiitis. J Rheumatol 2012; 39(8):1687-97.  (6)  Ruperto N, Ozen S, Pistorio A, Dolezalova P, Brogan P, Cabral DA et al. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part I: Overall methodology and clinical characterisation. Ann Rheum Dis 2010; 69(5):790-7.  (7)  Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37(2):187-92.  (8)  Watts RA, Jolliffe VA, Carruthers DM, Lockwood M, Scott DG. Effect of classification on the incidence of polyarteritis nodosa and microscopic polyangiitis. Arthritis Rheum 1996; 39(7):1208-12.  (9)  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; 66(2):222-7.  (10)  Liu LJ, Chen M, Yu F, Zhao MH, Wang HY. Evaluation of a new algorithm in classification of systemic vasculitis. Rheumatology (Oxford) 2008; 47(5):708-12.  (11)  Mohammad AJ, Jacobsson LT, Mahr AD, Sturfelt G, Segelmark M. Prevalence of Wegener's granulomatosis, microscopic polyangiitis, polyarteritis nodosa and Churg-Strauss syndrome within a defined population in southern Sweden. Rheumatology (Oxford) 2007; 46(8):1329-37.  (12)  Hattori M, Kurayama H, Koitabashi Y. Antineutrophil cytoplasmic autoantibody-associated glomerulonephritis in children. J Am Soc Nephrol 2001; 12(7):1493-500.  (13)  Besbas N, Ozen S, Saatci U, Topaloglu R, Tinaztepe K, Bakkaloglu A. Renal involvement in polyarteritis nodosa: evaluation of 26 Turkish children. Pediatr Nephrol 2000; 14(4):325-7.  (14)  Peco-Antic A, Bonaci-Nikolic B, Basta-Jovanovic G, Kostic M, Markovic-Lipkovski J, Nikolic M et al. Childhood microscopic polyangiitis associated with MPO-ANCA. Pediatr Nephrol 2006; 21(1):46-53.  (15)  Sun L, Wang H, Jiang X, Mo Y, Yue Z, Huang L et al. Clinical and pathological features of microscopic polyangiitis in 20 children. J Rheumatol 2014; 41(8):1712-9.  (16)  Yu F, Huang JP, Zou WZ, Zhao MH. The clinical features of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis in Chinese children. Pediatr Nephrol 2006; 21(4):497-502. Page 15 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 15 15   (17)  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; 33(8):1135-6.  (18)  Wilkinson NM, Page J, Uribe AG, Espinosa V, Cabral DA. Establishment of a pilot pediatric registry for chronic vasculitis is both essential and feasible: a Childhood Arthritis and Rheumatology Alliance (CARRA) survey. J Rheumatol 2007; 34(1):224-6.  (19)  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; 42(2):377-81.  (20)  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; 60(11):3413-24.  (21)  Fujimoto S, Watts RA, Kobayashi S, Suzuki K, Jayne DR, Scott DG et al. Comparison of the epidemiology of anti-neutrophil cytoplasmic antibody-associated vasculitis between Japan and the U.K. Rheumatology (Oxford) 2011; 50(10):1916-20.  (22)  Chen M, Yu F, Zhang Y, Zhao MH. Clinical [corrected] and pathological characteristics of Chinese patients with antineutrophil cytoplasmic autoantibody associated systemic vasculitides: a study of 426 patients from a single centre. Postgrad Med J 2005; 81(961):723-7.  (23)  Watts RA, Lane SE, Scott DG, Koldingsnes W, Nossent H, Gonzalez-Gay MA et al. Epidemiology of vasculitis in Europe. Ann Rheum Dis 2001; 60(12):1156-7.  (24)  Sun L, Wang H, Jiang X, Mo Y, Yue Z, Huang L et al. Clinical and pathological features of microscopic polyangiitis in 20 children. J Rheumatol 2014; 41(8):1712-9.  (25)  Ahn JK, Hwang JW, Lee J, Jeon CH, Cha HS, Koh EM. Clinical features and outcome of microscopic polyangiitis under a new consensus algorithm of ANCA-associated vasculitides in Korea. Rheumatol Int 2012; 32(10):2979-86.  (26)  Guillevin L, Durand-Gasselin B, Cevallos R, Gayraud M, Lhote F, Callard P et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999; 42(3):421-30.  (27)  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; 12:18.  (28)  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; 363(3):221-32.  (29)  Koldingsnes W, Nossent H. Epidemiology of Wegener's granulomatosis in northern Norway. Arthritis Rheum 2000; 43(11):2481-7.  (30)  Mahr AD, Neogi T, Lavalley MP, Davis JC, Hoffman GS, McCune WJ et al. Assessment of the item selection and weighting in the Birmingham vasculitis activity score for Wegener's granulomatosis. Arthritis Rheum 2008; 59(6):884-91.  (31)  Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K et al. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol 2010; 21(10):1628-36. Page 16 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 16 16   (32)  de Lind van Wijngaarden RA, Hauer HA, Wolterbeek R, Jayne DR, Gaskin G, Rasmussen N et al. Clinical and histologic determinants of renal outcome in ANCA-associated vasculitis: A prospective analysis of 100 patients with severe renal involvement. J Am Soc Nephrol 2006; 17(8):2264-74.  (33)  Twilt M, Benseler S. Childhood antineutrophil cytoplasmic antibodies associated vasculitides. Curr Opin Rheumatol 2014; 26(1):50-5.          Page 17 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 17 17  TABLE 1.  Characteristics of ARChiVe study participants (N=231) classified as having MPA (n=48) or GPA (n=183) Characteristic / Feature MPA  (n=48)  GPA  (n=183) Female, n (%) 35 (73)  113 (61) Ethnicity, n (%)      Asian 1 (2)  5 (3) Black 0 (0)  4 (2) Hispanic* 6 (13)  6 (3) White* 20 (42)  107 (59) Other/Unknown 21 (44)  61 (33) Age at diagnosis (years)**       Mean age at diagnosis ± sd 11.2 ±4.5  13.4 ±3.2  Median age at diagnosis (range) 12 (1-18)  14 (2-18) Age at onset (years)**       Mean age at onset ± sd 10.8 ±4.7  12.9 ±3.3  Median age at onset (range) 11 (1-18)  14 (2-18) Time–to-diagnosis  (months)       Mean time-to-diagnosis ± sd 5.6 ±9.6  5.5 ±10.6  Median time-to-diagnosis (range) 1.6 (0-39)  2.1 (0-73) MD diagnosis (pre classification), n (%)      MPA or isolated MPA 16 (33)  20 (11) GPA or limited GPA 10 (21)  153 (84) ANCA+ pauci-immune GN 7 (15)  2 (1) PAN 6 (13)  0 (0) Not classified 9 (19)  8 (4) *p<0.05, **p<0.01, ***p<0.001 ANCA, antineutrophil cytoplasmic antibody; EGPA, eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome); EMA, European Medicines Agency; GPA, granulomatosis with polyangiitis Page 18 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 18 18  (Wegener’s granulomatosis); MPA, microscopic polyangiitis; GN, glomerulonephritis; Time-to-diagnosis = interval between onset of attributable symptoms and diagnosis, months.   Values expressed as number (percentage) or mean ±standard deviation unless otherwise noted   Page 19 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 19 19  TABLE 2.  Presenting features of ARChiVe study participants (N=231) classified as having MPA (n=48) or GPA (n=183) Clinical Feature, n (%) MPA (n=48)  GPA  (n=183) Constitutional/General  41 (85)  160 (88)  Malaise, fatigue 37 (77)  152 (83)  Fever 25 (52)  97 (53)  Weight loss 15 (31)  80 (44) Renal 36 (76)  151 (83)  Hypertension (age-adjusted) 16 (33)  39 (21)  Clinically "nephrotic" with edema* 11 (23)  20 (11)  Renal failure requiring dialysis* 12 (25)  24 (13)  End-stage renal disease 5 (10)  12 (7)  Impaired creatinine clearance (decreased >25%  .  …LLN)  or abnormal Protein/Creatinine ratio 28 (58)  99 (54)  Proteinuria  33 (69)  132 (72)  Hematuria >1+ or ≥10 rbc/hpf or red cell casts 29 (60)  132 (72)  Biopsy-proven glomerulonephritis                             30 of 32 (94) 101 of 108 (94) Pulmonary*** 21 (44)  136 (74)  Chronic cough*** 11 (23)  99 (54)  Wheeze or expiratory dyspnea 2 (4)  15 (8)  Alveolar hemorrhage / massive hemoptysis***  7 (15)  76 (42)  Pleurisy 4 (8)  25 (14)  Supplemental oxygen requirement 6 (13)  40 (22)  Respiratory failure 2 (4)  22 (12)  Imaging findings        Nodules 0 (0)  97 (54)   Fixed pulmonary infiltrates 0 (0)  64 (36)   Cavitations 0  (0)  38 (21) Page 20 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 20 20  Ear, Nose and Throat 0 (0)  128 (70)  Septal perforation or nasal collapse 0 (0)  15 (8)  Recurrent nasal bloody discharge/ crusting/  Obstruction / ulcer 0 (0)  98 (53)  Chronic or recurrent sinusitis 0 (0)  71 (39)  Conductive or sensorineural hearing loss 0 (0)  19 (10)  Otitis/mastoiditis 0 (0)  31 (17)  Subglottic involvement 0 (0)  19 (10)  Oral ulcers / granulomata 2 (4)  27 (15) Eyes 15 (31)  78 (43)  Conjunctivitis 3 (6)  21 (11)  Nonspecific redeye 1 (2)  19 (10)  Epi-scleritis 2 (4)  15 (8)  Proptosis or retro-orbital mass 0 (0)  3 (2)  Retinal exudates or hemorrhages or aneurysms      or vessel thrombosis 1 (2)  0 (0) Cutaneous 25 (52)  86 (47)  Palpable purpura / petechial rash 15 (31)  49 (27) Gastrointestinal** 28 (58)  66 (36)  Nonspecific abdominal pain* 18 (38)  41 (22)  Chronic nausea*** 16 (33)  22 (12) Musculoskeletal  25 (52)  118 (65)  Arthralgia or confirmed arthritis 20 (42)  112 (61)  Myalgia, muscle weakness, or confirmed . . . . . . . .  myositis  9 (19)  24 (14) Nervous system 10 (21)  36 (20)  Headache 6 (13)  20 (11)  Dizziness 2 (4)  12 (7) Page 21 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 21 21  Cardiovascular  3 (6)  10 (5)  Venous thrombosis 0 (0)  3 (2) *p<0.05; **p<0.01; ***p<0.001     Page 22 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 22 22   TABLE 3: Initial treatments for ARChiVe Study participants (N=231) classified as having MPA (n=48) or GPA (n-=183) Medication use (%) MPA (n=48) GPA (n=183) Corticosteroids 44 (92) 179 (98) Corticosteroids PLUS Cyclophosphamide 33 (69) 142 (78) DMARDs§ collectively 44 (92) 173 (95) • Cyclophosphamide (oral or IV) 33 (69) 142 (78) • Methotrexate (oral or subcutaneous) 4 (8) 20 (11) • Mycophenolate m fetil 4 (8) 2 (1) • Azathioprine 4 (8) 2 (1) Rituximab 5 (10) 23 (13) Intravenous immunoglobulin 2 (4) 10 (5) Plasmapheresis 9 (19) 40 (22) Trimethoprim sulfamethoxazole***                                              10 (21) 90 (50) Other adjuvant medications 41 (85) 135 (74) Antihypertensive(s) ± Angiotensin converting Enzyme inhibitors* 26 (54) 68 (38) *p<0.05; **p<0.01, ***p<0.001 §DMARDs = Disease-modifying anti-rheumatic drugs (cyclophosphamide, methotrexate, mycophenolate mofetil, azathioprine)     Page 23 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 23 23   Figure Legend  Figure. The formal classification of GPA and MPA assigned among an ARChiVe cohort of 374 patients with MD diagnosis of AAV, PAN, or Unclassified small/medium vessel Vasculitis according to either ACR or EULAR/PRINTO/PReS Criteria for classifying GPA, and for MPA according to the European Medicines Agency (EMA) classification algorithm for classifying AAV and polyarteriitis nodosa.   AAV= Antineutrophil cytoplasmic Antibody (ANCA)-associated vasculitis; ACR= American College of Rheumatology; ANCA= antineutrophil cytoplasmic antibodies; ARChiVe= A Registry for Childhood Vasculitis; CHCC= Chapel Hill Consensus Conference; EGPA= eosinophilic granulomatosis with polyangiitis; EMA= European Medicines Agency; EULAR= European League Against Rheumatism; GPA= granulomatosis with polyangiitis; MPA= microscopic polyangiitis; MPO= myeloperoxidase; PAN= polyarteriitis nodosa; PRES= Pediatric Rheumatology European Society; PRINTO= Pediatric Rheumatology International Trials Organisation; PR3= proteinase 3.    Page 24 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewMPA versus GPA 26032015      Cabral, Canter et al. page 24 24  Acknowledgements  The authors would like to acknowledge all participating patients and their families, without whom this study would not be possible. We also thank the ARChiVe site coordinators and research assistants for their dedicated work:   Jessica Kracker, Ann Pokelsek and Debbie Giebner, Akron Children’s Hospital, Akron, OH USA; Anastasia Dropol, Alberta Children’s Hospital, Calgary AB; Erin Thomas and Alexandra Martyniuk, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Ana Cabrera, Children’s Hospital LA, Los Angeles, CA, USA; Annica Bryson, Cohen Children’s Medical Center of New York, New Hyde Park, NY; Rebecca Puplava, Comer Children's Hospital, Chicago, IL USA; Chelsea Smith, Children’s Mercy Hospital, Kansas MO, USA; Janet Wootton, Duke Children’s Hospital and Health Center, Duke University Medical Center, Durham, NC, USA; Shehla Sheikh, Hospital for Sick Children, Toronto ON Canada; Cindy Campbell and Monica Gunter, IWK Health Centre and Dalhousie University, Halifax, NS, Canada; Mary Ellen Riordan and Justine Zasa, Joseph M. Sanzari Children’s Hospital, Hackensack University Medical Center, Hackensack, NJ, USA; Abigail Hillard, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, TN, USA; Courtney Chun and Bette Manulik, Randall Children's Hospital at Legacy Emanuel, Portland, OR, USA; Andrea Hudgins, Riley Children’s Hospital, Indianapolis, IN, USA; Elizabeth Roy, Srujana Minuka and Dipa Puwar, Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Lucas Reichley, Seattle Children's Hospital, Seattle, WA; Debra Canter, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA; Pantelis Konstantinopoulos, The Cleveland Clinic, Cleveland OH; Michele Gibbon, The Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada; Heather Bell-Brunson and Christel Gross, University of Florida, Gainesville, FL; Adrienne Michels and Lauren Rayborn, University of Louisville School of Medicine, Louisville, KY, USA; Suzy Jones, University of Utah’s Primary Children’s Medical center, Salt Lake City, UT, USA.  The origins of this project were in the Childhood Arthritis and Rheumatology Research Alliance (CARRA); although the ARChiVe network now extends beyond this, we gratefully acknowledge that it would not be sustainable without the endorsement and ongoing support of CARRA and its membership. We are similarly grateful for the ongoing support of the Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI), the primary home of the principle investigator and other contributers to ARChiVe in Canada. This study is being supported by the Canadian Institutes of Health Research under the Pediatric Vasculitis (PedVas) Initiative (www.cihr-irsc.gc.ca).    Page 25 of 31John Wiley & SonsArthritis & RheumatologyFor Peer Review     186x223mm (300 x 300 DPI)    Page 26 of 31John Wiley & SonsArthritis & RheumatologyFor Peer Review  SUPPLEMENTARY TABLE 4:   Characteristics of ARChiVe study participants (N=293) classified as having MPA (n=48), GPA (n=183), or Unclassifiable AAV (n=62) Characteristic / Feature MPA  (n=48)  GPA  (n=183)  Unclassifiable AAV (n=62) Female, n (%) 35 (73)  113 (61)  47 (76) Ethnicity, n (%)         Asian 1 (2)  5 (3)  1 (2) Black 0 (0)  4 (2)  3 (5) Hispanic* 6 (13)  6 (3)  9 (15) White* 20 (42)  107 (59)  25 (40) Other/Unknown 21 (44)  61 (33)  24 (39) Age at diagnosis (years)**          Mean age at diagnosis ± sd 11.2 ±4.5  13.4 ±3.2  12.1 +4.7  Median age at diagnosis (range) 12 (1-18)  14 (2-18)  13.2 (1-18) Age at onset (years)**          Mean age at onset ± sd 10.8 ±4.7  12.9 ±3.3  11.1 +4.3  Median age at onset (range) 11 (1-18)  14 (2-18)  12.5 (1-18) Time–to-diagnosis  (months)          Mean time-to-diagnosis ± sd 5.6 ±9.6  5.5 ±10.6  12.3 +28.4  Median time-to-diagnosis (range) 1.6 (0-39)  2.1 (0-73)  3 (0-173) MD diagnosis (pre classification), n (%)         MPA or isolated MPA 16 (33)  20 (11)  7 (11) GPA or limited GPA 10 (21)  153 (84)  35 (55) ANCA+ pauci-immune GN 7 (15)  2 (1)  4 (6) PAN 6 (13)  0 (0)  3 (5) Not classified 9 (19)  8 (4)  13 (21) ANCA, antineutrophil cytoplasmic antibody; EGPA, eosinophilic granulomatosis with polyangiitis (Churg–Page 27 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewStrauss syndrome); EMA, European Medicines Agency; GPA, granulomatosis with polyangiitis (Wegener’s granulomatosis); MPA, microscopic polyangiitis; GN, glomerulonephritis; Time-to-diagnosis = interval between onset of attributable symptoms and diagnosis, months. Values expressed as number (percentage) or mean ±standard deviation unless otherwise noted.     Page 28 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewSUPPLEMENTARY TABLE 5.  Presenting features of ARChiVe study participants (N=293) classified as having MPA (n=48), GPA (n=183) or Unclassified AAV (n=62) Clinical Feature, n (%) MPA  (n=48)  GPA  (n=183)  Unclassifiable  AAV (n=62) Constitutional/General  41 (85)  160 (88)  39 (63)  Malaise, fatigue 37 (77)  152 (83)  33 (53)  Fever 25 (52)  97 (53)  22 (35)  Weight loss 15 (31)  80 (44)  10 (16) Renal 36 (76)  151 (83)  24 (39)  Hypertension (age-adjusted) 16 (33)  39 (21)  8 (13)  Clinically "nephrotic" with edema 11 (23)  20 (11)  2 (3)  Renal failure requiring dialysis 12 (25)  24 (13)  4 (6)  End-stage renal disease 5 (10)  12 (7)  2 (3)  Impaired creatinine clearance (decreased >25%  .  …LLN)  or abnormal Protein/Creatinine ratio 28 (58)  99 (54)   6  (10)  Proteinuria  33 (69)  132 (72)  20 (32  Hematuria >1+ or ≥10 rbc/hpf or red cell casts 29 (60)  132 (72)  19 (31)  Biopsy-proven glomerulonephritis                             30 of 32 (94) 101 of 108 (94)  17 (27) Pulmonary 21 (44)  136 (74)  37 (60)  Chronic cough 11 (23)  99 (54)  18 (29)  Wheeze or expiratory dyspnea 2 (4)  15 (8)  5 (8)  Alveolar hemorrhage / massive hemoptysis 7 (15)  76 (42)  9 (15)  Pleurisy 4 (8)  25 (14)  3 (5)  Supplemental oxygen requirement 6 (13)  40 (22)  5 (8)  Respiratory failure 2 (4)  22 (12)  4 (6)  Imaging findings           Nodules 0 (0)  97 (54)  3 (4)   Fixed pulmonary infiltrates 0 (0)  64 (36)  4 (6)   Cavitations 0  (0)  38 (21)  3 (5) Page 29 of 31John Wiley & SonsArthritis & RheumatologyFor Peer ReviewEar, Nose and Throat 0 (0)  128 (70)  24 (38)  Septal perforation or nasal collapse 0 (0)  15 (8)  3 (5)  Recurrent nasal bloody discharge/ crusting/  Obstruction / ulcer 0 (0)  98 (53)   6  (10)  Chronic or recurrent sinusitis 0 (0)  71 (39)  5 (8)  Conductive or sensorineural hearing loss 0 (0)  19 (10)  3 (5)  Otitis/mastoiditis 0 (0)  31 (17)  5 (8)  Subglottic involvement 0 (0)  19 (10)  6 (10)  Oral ulcers / granulomata 2 (4)  27 (15)  3 (50 Eyes 15 (31)  78 (43)  19 (31)  Conjunctivitis 3 (6)  21 (11)  3 (5)  Nonspecific redeye 1 (2)  19 (10)  6 (10)  Epi-scleritis 2 (4)  15 (8)  4 (6)  Proptosis or retro-orbital mass 0 (0)  3 (2)  7 (11)  Retinal exudates or hemorrhages or aneurysms      or vessel thrombosis 1 (2)  0 (0)   0  (0) Cutaneous 25 (52)  86 (47)  20 (32)  Palpable purpura / petechial rash 15 (31)  49 (27)  8 (13) Gastrointestinal 28 (58)  66 (36)  18 (29)  Nonspecific abdominal pain 18 (38)  41 (22)  11 (18)  Chronic nausea 16 (33)  22 (12)  7 (11) Musculoskeletal  25 (52)  118 (65)  25 (40)  Arthralgia or confirmed arthritis 20 (42)  112 (61)  24 (39)  Myalgia, muscle weakness, or confirmed . . . . . . . .  myositis  9 (19)  24 (14)  4 (7) Nervous system 10 (21)  36 (20)  15 (24)  Headache 6 (13)  20 (11)  9 (15)  Dizziness 2 (4)  12 (7)  5 (8) Cardiovascular  3 (6)  10 (5)  2 (3) Page 30 of 31John Wiley & SonsArthritis & RheumatologyFor Peer Review Venous thrombosis 0 (0)  3 (2)  2 (3)   Page 31 of 31John Wiley & SonsArthritis & RheumatologyFor Peer Review SUPPLEMENTARY TABLE 6.  ANCA test results of ARChiVe study participants (N=293) classified as having MPA (n=48), GPA (n=183), or unclassifiable AAV (n=62) ANCA testing by ELISA or immunofluorescence MPA  (n=45) GPA  (n=171) Unclassifiable AAV (n=59) cANCA/PR3 positive (%) 17 67 36 pANCA/MPO positive (%) 55 26 32 Specificities positive for both PR3 + MPO (%) 2 2 0 ANCA negative testing by either ELISA or Immunofluorescence (%) 26 5 32 ANCA, antineutrophil cytoplasmic antibody; pANCA, perinuclear immunofluorescence staining ANCA pattern; cANCA, cytoplasmic immunofluorescence staining ANCA pattern; GPA, granulomatosis with polyangiitis (Wegener’s granulomatosis); MPA, microscopic polyangiitis; AAV, ANCA-associated vasculitis Page 32 of 31John Wiley & SonsArthritis & Rheumatology

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
https://iiif.library.ubc.ca/presentation/dsp.52383.1-0308655/manifest

Comment

Related Items