Rare Pulmonary Diseases in Systemic JIA
Yukiko Kimura, MDProfessor of Pediatrics
Joseph M Sanzari Children’s 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 Still’s 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%) <0.001
Lymphadenopathy 19 (76%) 147 (46%) <0.001
Serositis 14 (56%) Unknown
MAS 20 (80%) Unknown
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/c’d 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%) <0.001
Methotrexate 22 (88%) 232 (78%) NS
Cyclosporine 18 (72%) 45 (12%) <0.001
Cyclophosphamide 5 (20%) 7 (2%) 0.001
Etoposide 6 (24%) Not reported
Thalidomide 4 (16%) Not reported
Tacrolimus 2 (8%) 8 (2%) NS
Mycophenolate 3 (12%) 12 (3%) NS
Gold 1 Not reported
Penicillamine 1 Not reported
Exposure to Biologics:Cohort vs Registry
Medication(ever used)
Study cohort CARRA Registry P value
IL1 Inhibitor (any) 20 (80%) 168 (43%) <0.001
Anakinra 20 (80%) 156 (40%) <0.001
Canakinumab 3 (12%) 7 (2%) <0.001
Rilonacept 4 (16%) 27 (7%) 0.018
Tocilizumab 5 (20%) 29 (8%) 0.044
IVIG 7 (28%) 24 (6%) 0.001
TNF inhibitor (any) 15 (60%) 174 (45%) NS
Rituximab 0 2 (1%) NS
Year of Onset ofSystemic JIA & Pulmonary Disease
Study CohortN=25
CARRA RegistryN=89
P value
Decade of sJIA disease onset 0.0068
1980’s 1 (4%) 0
1990’s 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 O’Neil
K Nanda
K Peterson
