Rare Pulmonary Diseases in Systemic JIA. This presentation tracks the increased use of biologics to treat SJIA and observes the trends in rare pulmonary diseases.

1. 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

2. sJIA Treatment Overview:
Pre-Biologics
• NSAIDs and aspirin
• Glucocorticoids
• Methotrexate
• Cyclosporine
• Thalidomide
• Cyclophosphamide
• Hematopoietic stem cell transplantation

3. 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

4. IL-1 inhibition in sJIA
Pascual V et al JEM 201; 2005
Nigrovic P et al. Arthritis Rheum 63; 2011

5. Other IL1 inhibitors:
Canakinumab (IL1 beta mAb)
Ruperto N, et al. NEJM 367;25, 2012

6. IL6 inhibition in sJIA
Tocilizumab (IL6r mAb)
DeBenedetti F, et al. NEJM 367:25, 2012

7. 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)

8. Current vs Ever Used Medications in sJIA
CARRA Registry Patients
0
20
40
60
80
100
Current Use
Ever Used
N=418

9. Current medication usage patterns
CARRA Registry sJIA Patients

10. 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

11. 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

12. 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

13. Demographic Features
Study Cohort
N=25
CARRA Registry
N=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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. Year of Onset of
Systemic JIA & Pulmonary Disease
Study Cohort
N=25
CARRA Registry
N=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

21. 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

22. 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)

23. 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

24. 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)

25. 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

26. Acknowledgments
CARRA 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