What is SJIA - how is it different than other diseases

HERMINE BRUNNER, MD MSC MBA

PROFESSOR OF PEDIATRICS

CHIEF, DIVISION OF RHEUMATOLOGY

Sir George Frederic Stills(27 February 1868 – 28 June 1941)

England’s first professor of childhood medicine

First described 22 children with SJIA in 1897

…also the first to describe attention deficit hyperactivity disorder

Still G F. On a form of

chronic joint disease in

children.Med-Chir Trans

1897; 80: 47-59.

Systemic-onset

juvenile chronic

arthritis

Systemic-onset

juvenile rheumatoid

arthritis

Systemic juvenile idiopathic arthritis

Still’s disease

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7. Shenoi S, Wallace CA. J Pediatr. 2016;177:19-26.

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Rash

Nonpruritic, evanescent, urticarial-like, maculopapular, salmon colored

Koebner phenomenon

Histologic evidence of sparse: Cellular perivascular infiltrate

Just as in other inflammatory processes (such as psoriasis, lichen planus, cutaneous lupus or wound healing)

Activated keratinocytes expressing proinflammatory S100-proteins

M. Frosch, et al., “Expression of myeloidrelated proteins 8 and

14 in SJRA. A&R vol. 48, no. 9, pp. 2622–2626, 2003

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Pericardial effusion > pleural effusion > peritoneal fluid

Pericarditis

Typical anterior chest pain, shortness of breath, friction rub on auscultation

Diagnosed by x-ray, EKG, echocardiography

Myocarditis much less common

4% in one study

Serositis

J. et al., “Symptomatic cardiac involvement in juvenile

rheumatoid arthritis,” International Journal of Cardiology, vol. 34,

no. 1, pp. 57–62, 1992.

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Fever

(Double) quotidian fever

(2) fever spike(s) per day, not induced by antipyretic medications

About the same time every day

DD: Malaria, Leishmaniasis

The classic pattern with 1 spike in the evening is only

seen in 37% of the patients during initial presentation

Morning fevers (12%),

Twice daily fevers (15%)

Intermittent fevers (27%)

Unremitting fevers (5%)

E. M. Behrens et al: Evaluation of the presentation of sJRA . J Rheumatol, vol. 35, no. 2, pp. 343–348, 2008.

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7. Shenoi S, Wallace CA. J Pediatr. 2016;177:19-26.

8. Petty RE et al. J Rheumatol. 2004;31:390-392.

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SJIA – One of the Types of juvenile idiopathic Arthritis

Group of Diseases

Shared features

Chronic Arthritis of unknown etiology

Presentation by 16th birthday

Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, He X, Maldonado-Cocco J, Orozco-Alcala J, Prieur AM, Suarez-Almazor ME, Woo P: International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004, 31(2):390–392. Stoll, Matthew L., and Randy Q. Cron. "Treatment of juvenile idiopathic arthritis: a revolution in care." Pediatric rheumatology 12.1 (2014): 13.

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SJIA is mostly a disease starting in childhood

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Why do children get Systemic JIA ?

Overactive

immune

system

Environmental triggers

Genetic factors

Other

Systemic JIA – Not A Single Gene Disease

More than a monogenic inflammatory disease

SJIA rarely runs in families

Polygenic auto-inflammatory disease

1. No auto-reactive T cells or antibodies at onset

2. No strong human leucocyte antigen (HLA) associations

3. Microarray studies innate immune activity involving a cellular structures called “inflammasomes”

S. Vastert, B. Prakken 232 / Best Practice & Research Clinical Rheumatology 28 (2014) 229-246

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Non-systemic Forms of JIA – Adaptive Immune System Activation

T cell subsets (Th17) and different Treg cells are very important for the development/course of other JIA forms

RNA-containing immune complexes (IC) against citrullinated peptide antigens (collagen, fibrinogen) induce netosis

B cell activation perpetuates IC formation

Downstream ↑ Syk signaling, esp. with certain genetic mutations (e.g.

Zap-70, low affinity Fc receptor)

S. Vastert, B. Prakken 232 / Best Practice & Research Clinical Rheumatology 28 (2014)Chauhan AK, Moore TL, Bi Y, Chen C. J Biol Chem (2016) 291:1368–86.

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Pathogenetic ModelsPeter Nigrovic; ARTHRITIS & RHEUMATOLOGY; Vol. 66, No. 6, June 2014, pp 1405–1413

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Window of Opportunity – Basic Science Evidence

High IL-1, IL6, TNF levels facilitate differentiation of pathogenic Th17 cells

Esp. with genetic (environment) predisposition

Shift to chronicity of Th17 response with sJIA (and other forms of JIA)

Th17 cell pool expands with arthritis progression

Th17 depleted arthritis mice do not get joint diseasesPeter Nigrovic; ARTHRITIS & RHEUMATOLOGY; Vol. 66, No. 6, June 2014, pp 1405–1413; S. Vastert, B. Prakken 232 / Best Practice & Research Clinical Rheumatology 28 (2014) 229-246

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Prognosis of SJIA

has markedly

improved with the

approval of IL1 and

IL6 blocking

medications

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0

10

20

30

4050

60

70

80

90

Persistent

Oligo

Extended

Oligo

Polyarthritis

(RF+)

Polyarthritis

(RF-)

Systemic

Disease Type

% o

f p

ati

en

ts

CRM CR

Course of Disease & Clinical Remission on/off Medications

Monocyclic, polycyclic, persistent

40-50% active disease for at least 10 years

Duration of CR off medications

44% (196) patients achieved CR

28% - CR lasted one year

18% - CR lasted two years

3% - CR lasted five years

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SJIA Poor prognostic Clinical Indicators

Early age at onset

Cumulative active disease

Platelets > 600K at 6 months,

Hip involvement by 6 months

Generalized lymphadenopathy

Toronto Cohort

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In the past: progressive joint destruction in approximately 1/3 of the childrenMore common in patients with polyarthritis

Ankylosis in cervical spine, carpal &tarsal areas

Joint space narrowing & erosions

Apophyseal fusion of

C2-C4 and undergrowth

of adjacent vertebrae

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Growth Delay

Generalized - Localized

Intensified by corticosteroid therapy

Likely due to IL-6 effects

Growth hormone therapy possible in some patients

Need to control inflammation

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Mortality

In SJIA mostly due to disease complications:

Infection

MAS

Myocarditis

Amyloidosis

Systemic

64%

Poly

18%

Pauci

12%

Other

6%

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Amyloidosis

Very rare in North America

Biopsy required for diagnosis

Deposited in kidneys, liver, gastro-intestinal tract, heart, peripheral nerves

Proteinuria, diarrhea, hepato-splenomegaly, unexplained anemia

Amyloid A deposition in kidneys detected by staining with Congo Red dye

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Summary

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