Systemic JIA the Clinical Picture

1. Systemic JIA: The Clinical Picture
Michal J Cidon MD
Pediatric Rheumatology
February 7, 2015

2. Systemic JIA
• 1897 Sir Fredrick Still: 12 children with chronic arthritis,
adenopathy, splenomegaly, fevers
Variable Course:
-12-40 % with monophasic course
-5% have a polycyclic course
-55% with persistent course
High morbidity: short and long term
(MAS, FTT, joint damage, amyloidosis)
Poor prognostic indicators by 6 mo: persistent fever, steroid
dependency, thrombocytosis, polyarthritis, hip disease,
early joint damage, polymorphism of MIF gene
Cassidy et al. Textbook of pediatric rheumatology. 6th ed., Philadelphia: Saunders Elsevier; 2011

3. Juvenile Rheumatoid
Arthritis (ACR)
Juvenile Chronic
Arthritis (EULAR)
Juvenile Idiopathic
Arthritis (ILAR)
Systemic Systemic Systemic
Polyarticular Polyarticular (RF-) Polyarticular (RF-)
JRA (poly, RF+) Polyarticular (RF+)
Oligoarticular Pauciarticular Oligoarticular
(persistent)
Oligoarticular
(extended)
Juvenile psoriatic
arthritis
Psoriatic arthritis
Juvenile ankylosing
spondylitis
Enthesitis related
arthritis (ERA)
Undifferentiated

4. S-JIA ILAR classification criteria
1. < 16yo
2. Fever ≥2 weeks, quotidian in pattern
(≥39c once a day and return to ≤37c), documented daily for
≥3 days
3. Arthritis ≥1 joint ( for ≥6 weeks)
4. At least one of the following:
evanescent erythematous rash
generalized LND enlargement
Hepatomegaly and/or splenomegaly;
serositis
Exclusions:
1.Psoriasis or a history of psoriasis in a patient or first degree relative
2. Arthritis in HLAB27 male > 6yo
3. AS, enthesitis-related arthritis, sacroiilitis with IBD, Reiter’s syndrome, or acute anterior uveitis, or a history of one of
these disorders in a first degree relative
●

5. Systemic JIA
● Autoinflammatory syndrome
-Usually lacks autoantibodies
- No specific HLA, but
association with HLA-DR and a novel genomic
region on chromosome1
- No auto-reactive lymphocytes
● Disease driven cytokine dysregulation:
-Proinflammatory cytokines (IL1, IL6, IL18)
-Anti-inflammatory cytokine (IL-10)
● Promoter polymorphism (IL6 and TNFα)

6. Epidemiology
• Prevalence 3.5/100,000
• Incidence (0.4-0.9 per 100,000/year)
• 5-15% of JIA in North America and Europe
• No gender difference
• Equal age distribution vs. majority dx 0-5
yrs (74/136); peak at 2yo (17/136)*
● Variable ethnic composition
*Behrens el al. J Rheum 2008; 35 (2): 343

7. S-JIA : Early Clinical Manifestations
• Very ill: fatigue, anemia, fever, pain
• Systemic features predominate early in the course
and may overshadow or precede arthritis
Feature Frequency
Fever >98%
Typical Rash 95%
Arthritis >88%
HSM 85%
LAD 70%
Pericarditis 35%
Pleuritis 20%
Abdominal pain 10%

8. SJIA Quotidian Fever Curve

9. Arthritis in S- JIA
• Early symptom
• Early affected joints: wrists, knees, ankles
• Atypical joints (TMJ, cervical spine, hips)
• Chronic progressive arthritis (1/3-1/2 pts)
• Synovial cysts
• Tenosynovitis

10. Rash in S-JIA
● Evanescent, salmon colored, migratory,
fleeting, pruritic (5%)
● Worse with fever
● Biopsy: perivascular mononuclear cells and
neutrophils
● Activated keratinocytes express S100
proteins MRP8 and MRP14
● Leukocytes within epithelium of sweat gland
ducts

11. S-JIA manifestations
• LAD ( follicular hyperplasia)
• Splenomegaly ( 50%)
• Hepatic abnormalities (periportal infiltrates of
inflammatory cells, hyperplasia of kupffer cells)
• Serositis
- Primarily pericarditis (early presentation,
recurrent, rarely associated with myocarditis)
-Asymptomatic pleuritis and pleural effusions
● Myositis
● Not associated with uveitis

12. Macrophage Activation Syndrome
• Uninhibited production and activation of macrophage and T
cells leading to a inflammatory multi-organ failure:
- Liver dysfunction - CNS inflammation
- Pancytopenia - Hyperferritinemia
- Hemophagocytosis
• Incidence of overt MAS (6.7-13%) with mortality rate of 8-
22%
• Incidence “occult MAS” (30%)
- CD163 staining in BM (Behrens et al, 2007)
- sIL2R and sCD163(Bleesing et al, 2007)

13. MAS Diagnosis
IL10
IFNγ
Severe
MAS
Monogenic defect in cytotoxic granule
exocytosis (FHL causative genes)
OR
HLH-2004 criteria ≥5/8
Clinical: Fever, Splenomegaly
Labs:,
Cytopenia>2 cell lines :Hb<9, Neutrophils<1000,
Platelets<100
Ferritin>500mg/l
Fibrinogen<150,
Triglycerides>265mg/dl
sCD25 ( soluble IL2 receptor)>2400U/ml,
Low or absent NK cell activity,
Hemophagocytosis in bone marrow, spleen
or LNDS
healthy
Behrens, ACR 2014
Mild
MAS

14. Cardiopulmonary complications
Arthritis Care Res (Hoboken). 2013
May;65(5):745-52. doi: 10.1002/acr.21889.
Pulmonary hypertension and other potentially
fatal pulmonary complications in systemic
juvenile idiopathic arthritis.
Kimura Y el al.
- Case of pulmonary interstitial and intra-alveolar cholesterol granulomas
(Schultz R. et al, 2001)
- Cross sectional study: restrictive pulmonary function (Van der Net J. el al,1997)
- Case report of pulmonary hypertension (Padeh S. el al, 1991)
- PFT abnormalities ( Wagener J. el al, 1981)
- Interstitial pulmonary disease in 8/191 JRA pts ( Athreya el al, 1980)

15. S-JIA cases with pulmonary
complications at Stanford
Age of s-
JIA dx
Gender CP disease Time to
CP
Outcome
Case1 13mo Male ILD 14months Stable
Case 2 3yo Female PH/
vasculopathy
20
months
Fatal
Case 3 14yo Female PH/ILD? 46months Improved
Case 4 17yo Female PH/ILD 17
months
Fatal
Case 5 17yo Female ILD 29months Improved
Case 6 9 yo Female PH unclear improved

16. S-JIA Treatment
Historically: NSAIDS, IVIG, corticosteroids,
methotrexate, anti-TNF, cyclosporin, thalidomide,
cyclophosphamide, autologous stem cell transplant
Current: targeted biologic therapy :
-anti-IL1: (Anakinra: IL1Ra, Rilonacept: IL1R-AcP, Canakinumab: mab IL1)
ssCrontstein el al, 2013
Cronstein el al, 2013

17. S-JIA Treatment
Current: targeted biologic therapy :
-Anti-IL6 ( Tocilizumab)
-Binds with IL-6 receptor
on cell membranes or
in soluble form
-New recommended guidelines by the ACR ( 2013)
-Consensus Treatment Plans ( CARRA, 2012):
4 arms: GC only, Methotrexate, Anakinra, Tocilizumab

18. Questions
• What disease models can we use to learn
about the predisposition to ILD in s-JIA?
• Does ILD in s-JIA have unique
pathophysiologic determinants?
• What is the role of biologic medications in the
development of ILD in s-JIA?

19. References
1.Behrens E.M., T. Beukelman, L. Gallo et al., “Evaluation of the presentation of systemic onset
juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis
Registry (PASOJAR),” Journal of Rheumatology, vol. 35, no. 2, pp. 343–348, 2008.
2. Beukelman T. Treatment advances in systemic juvenile idiopathic arthritis. F1000Prime Rep.
2014 Apr 1;6:21.
3.Bleesing J. el al. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor
alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile
idiopathic arthritis. Arthritis Rheum. 2007 Mar;56(3):965-71.
4. Cassidy, J.T, and Petty, R.E el al. (Sixth Ed). (2010). Textbook of Pediatric Rheumatology. San
Francisco, CA: Saunders.
5. Dewitt EM el al. Consensus treatment plans for new-onset systemic Juvenile idiopathic
arthritis. Arthritis Care Res (Hoboken). 2012 Jul;64(7):1001-10.
6. Gurion R. el al. Systemic Arthritis in Children: A Review of Clinical Presentation and Treatment.
Inte J Inflam. 2012; 2012:271569.
6.Kimura Y el al. Pulmonary hypertension and other potentially fatal pulmonary complications in
systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2013 May; 65 (5): 745-52.
7. Petty RE, Southwood TR, Manners P et al. International league of associations for
rheumatology classification of juvenile idiopathic arthritis: second revision,
Edmonton, 2001. J Rheumatol 2004;31:390–2.