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