Systemic JIA the Clinical Picture

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. 6 th 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 arthritis- does not meet criteria for any subtype or meets more then one criteria.

4. S-JIA ILAR classification criteria < 16yo 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 4. Presence of RF IgM on at least 2 occasions 3 months apart ●

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 TNF α )

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 T enosynovitis

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 - H yperferritinemia - H emophagocytosis 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 IFN γ IL6, IL4, IL1, IL18, IL33, cytotoxic granule function 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.