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Rare Pulmonary Diseases in Systemic JIA

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Rare Pulmonary Diseases in Systemic JIA Yukiko Kimura, MD Professor of Pediatrics Joseph M Sanzari Children’s Hospital Hackensack University Medical Center Chair Elect Childhood Arthritis & Rheumatology Research Alliance
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  • Rare Pulmonary Diseases in Systemic JIA

    Yukiko Kimura, MDProfessor of Pediatrics

    Joseph M Sanzari Childrens HospitalHackensack University Medical Center

    Chair ElectChildhood Arthritis & Rheumatology Research Alliance

  • sJIA Treatment Overview:Pre-Biologics

    NSAIDs and aspirin

    Glucocorticoids

    Methotrexate

    Cyclosporine

    Thalidomide

    Cyclophosphamide

    Hematopoietic stem cell transplantation

  • Treatment of sJIA with Biologics:TNF inhibitors

    Etanercept First available biologic

    Disappointing response Quartier P et al (Arthritis Rheum 2003)

    Kimura Y et al (J Rheum 2005)

    Infliximab Limited success

    Higher doses able to be given (20mg/kg every 2-4 weeks)

    Anti-TNF used for mostly arthritis vs systemic disease Ringold S et al (Arthritis Care Res 2013): JIA treatment guidelines

    update

  • IL-1 inhibition in sJIA

    Pascual V et al JEM 201; 2005

    Nigrovic P et al. Arthritis Rheum 63; 2011

  • Other IL1 inhibitors:Canakinumab (IL1 beta mAb)

    Ruperto N, et al. NEJM 367;25, 2012

  • IL6 inhibition in sJIATocilizumab (IL6r mAb)

    DeBenedetti F, et al. NEJM 367:25, 2012

  • The CARRA Registry of Pediatric Rheumatic Diseases

    70%

    10%

    7%

    4%

    2%2% 2%

    1%1% 1% 0% 0%

    N = 8533 JIA (5965)

    SLE (876)

    JDM (568)

    L Scl (324)

    Vasculitis (176)

    MCTD (147)

    JPFS (164)

    Uveitis (77)

    Autoinflammatory (58)

    SS (52)

  • Current vs Ever Used Medications in sJIACARRA Registry Patients

    0

    20

    40

    60

    80

    100

    Current Use

    Ever Used

    N=418

  • Current medication usage patterns CARRA Registry sJIA Patients

  • BACKGROUND Pulmonary Disease in SJIA

    Isolated case reports of pulmonary disease in sJIA and Adult Onset Stills Disease Pulmonary Hypertension (PH) Interstitial Lung Disease (ILD) Alveolar Proteinosis (AP) Lipoid Pneumonia (LP)

    Increased spontaneous reporting of cases through pediatric rheumatology listserv since 2008

    Concern regarding potential recent triggers including exposure to biologic agents

    Study aims: Identify sJIA patients who developed rare pulmonary diseases Assess medication exposures and disease characteristics Compare patients and medications to CARRA Registry sJIA patients

  • METHODS

    Retrospective review of pulmonary disease cases in sJIA solicited through a pediatric rheumatology listserv

    Questionnaire Demographic features Systemic JIA disease features Pulmonary disease features Medication exposures Outcomes

    Comparisons made to baseline data obtained of sJIA patients in the CARRA Registry

  • Patient Cohorts Study cohort (n=25)

    PH: 16 (64%) ILD: 7 (28%) AP: 3 (12%) LP: 2 (8%) 6 combination

    PAH and ILD (3) PAH and LP (1) PAH and AP (1) ILD and LP (1)

    CARRA Registry cohort (n=389) Systemic JIA patients enrolled as of 4/30/12

  • Demographic FeaturesStudy CohortN=25

    CARRA RegistryN=389

    P value

    sJIA diagnosis age (yrs) 7.4 + 6 (1-17) 5.8 + 4 (0.2-16) NS

    Race/Ethnicity NS

    Caucasian 17 (68) 302 (78)

    Black 7 (28) 45 (12)

    Asian 1 (4) 20 (5)

    Other 0 (0) 20 (5)

    Hispanic 5 (20) 50 (13)

    Country of residence US (19), Brazil (2), Italy (1), Spain (1), UK (1), Netherlands (1)

    US (all)

    Disease duration (mos) 51.6 + 29 (8-173) 62 + 51 (0.6-220) 0.012

    Female 19 (76%) 213 (55%) 0.04

  • sJIA Disease Features

    Feature Study Cohort CARRA Registry P value

    Arthritis 25 (100%) 378 (100%) NS

    Fever 25 (100%) 353 (93%) NS

    Rash 34 (92%) 326 (87%) NS

    Hepato/splenomegaly 20 (80%) 102 (31%)

  • Pulmonary Disease Features

    Pulmonary symptoms Dyspnea on exertion: 18 (72%) Shortness of breath: 16 (64%) Cough: 11 (44%) Clubbing: 10 (40%) Chest pain: 5 (20%)

    Pulmonary disease duration at last follow up Median: 30 (IQR 19-58) months

    Months between symptoms to diagnosis Median: 1 (0-5) months One patient diagnosed at autopsy

  • Systemic Disease Features at Pulmonary Disease Onset

    23 (92%) had concomitant systemic features Fever (15) Splenomegaly (12) Serositis (11) Hepatomegaly (11) Rash (7) Lymphadenopathy (6)

    16 (64%) had Macrophage Activation Syndrome 15 (60%) fulfilled Ravelli criteria (J Pediatr 146(5) 2005) 5 had positive tissue confirmation 1 had hemophagocytosis in multiple organs at autopsy

  • Concurrent Meds at Pulmonary Diagnosis*Medication Number (%) Mean exposure (mos)

    Glucocorticoids 24 (96) 47 + 48 (3-161)

    Methotrexate 13 (52) 33 + 38 (1-126)

    Cyclosporine 7 (28) 6 + 7 (1-22)

    Any biologic 17 (68)

    IL1 inhibitor (any) 12 (48) 15 + 15 (3-47)

    Anakinra 10 (40) 17 + 16 (3-47)

    Canakinumab 1 (4) 6

    Rilonacept 1 (4) 6

    TNF inhibitor (any) 3 (12) 17 + 13 (2-26)

    Adalimumab 2 (8) 13 + 15 (2-23)

    Etanercept 1 (4) 26

    Tocilizumab 2 (8) 6 + 7 (1-11)

    Etoposide, thalidomide, gold 1 each (4)

    *or d/cd within a month prior to diagnosis

  • Exposure to Non-biologics:Cohort vs Registry

    Medication (ever used)

    Study cohort CARRA Registry P value

    Prednisone 25 (100%) 336 (86%) NS

    IV steroid pulses 23 (92%) 122 (31%)

  • Exposure to Biologics:Cohort vs Registry

    Medication(ever used)

    Study cohort CARRA Registry P value

    IL1 Inhibitor (any) 20 (80%) 168 (43%)

  • Year of Onset ofSystemic JIA & Pulmonary Disease

    Study CohortN=25

    CARRA RegistryN=89

    P value

    Decade of sJIA disease onset 0.0068

    1980s 1 (4%) 0

    1990s 5 (20%) 35 (9%)

    2000 and later 19 (76%) 335 (87%)

    Pulmonary disease onset

    Prior to 2000 1 (4%) NA

    2000-2004 4 (16%) NA

    2005 and after 20 (80%) NA

  • Mortality

    17 of 25 patients (68%) died as of June 2012 Mean time to death (from pulmonary disease onset)

    10 + 13 (0-44) months

    Diagnoses: PH (11), AP (4), ILD (3) PH+ILD, PAH+AP, AP+ILD (1 of each)

    8 surviving patients as of June 2012 Mean survival: 56.2 35.3 (range 16-106) months Diagnoses

    PH (5), AP (2), ILD (4) PH+ILD (2), PAH+AP (1)

    As of Feb 2015: 6 alive 2 died (1 after MUD BMT): 1 PH, 1 PH+ILD

  • Treatments given after pulmonary disease

    Cyclophosphamide 4 of 5 patients used post pulmonary disease 2 of 4 patients alive

    Etoposide 5 of 6 patients post pulmonary disease 2 of 5 patients alive

    Cyclosporine 15 of 18 patients post pulmonary disease 5 of 15 patients alive

    Combination Etoposide+Cyclosporine: 4 (1 alive) Cyclophosphamide+Cyclosporine: 4 (2 alive)

  • Other treatments

    Incompletely reported with mixed results

    Immunosuppressive meds

    Anakinra, pulse IV and oral steroids, mycophenolate, tacrolimus, thalidomide

    Lung disease specific treatments

    Bosentan, nitric oxide, sildenafil, albuterol, whole lung lavage

  • CONCLUSIONS

    PH, ILD, LP and AP are potentially fatal, under-recognized complications of systemic JIA

    Associated with severe uncontrolled systemic disease, including MAS

    Most known cases reported after 2000

    Increased exposure to biologic medications (especially IL1 inhibitors)

  • Thanks

    Jennifer Weiss

    Kathryn Haroldson

    Tzielan Lee

    Marilynn Punaro

    Sheila Oliveira

    Egla Rabinovich

    Meredith Riebschleger

    Jordi Anton

    Peter Blier

    Valeria Gerloni

    Melissa Hazen

    Elizabeth Kessler

    Karen Onel

    Murray Passo

    Robert Rennebohm

    Carol Wallace

    Patricia Woo

    Nico Wulffraat

  • AcknowledgmentsCARRA Registry Investigators

    L Abramson

    T Beukelman

    J Birmingham

    S Bowyer

    E Chalom

    F Dedeoglu

    P Ferguson

    D Goldsmith

    B Gottlieb

    T Graham

    R Hollister

    A Huttenlocher

    N Ilowite

    L Imundo

    S Prahalad

    A Quintero

    S Ringold

    D Rothman

    N Ruth

    C Sandborg

    K Schikler

    D Sherry

    N Singer

    S Spalding

    R Syed

    K Torok

    R Vehe

    E von Scheven

    A White

    A Yalcinadg

    L Zemel

    C Inman

    R Jerath

    L Jung

    P Kahn

    D Kingsbury

    M Klein-Gitelman

    T Lehman

    C Lindsley

    D McCurdy

    N Moorthy

    B Myones

    A Lasky

    J Lopez-Benitez

    J Olson

    K ONeil

    K Nanda

    K Peterson


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