What is SJIA - How is it different than other diseases - Dr. Hermine Brunner

Systemic JIA Foundation
Systemic JIA FoundationSystemic JIA Foundation
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
2
7. Shenoi S, Wallace CA. J Pediatr. 2016;177:19-26.
3
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
4
 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.
5
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.
6
7
7. Shenoi S, Wallace CA. J Pediatr. 2016;177:19-26.
8. Petty RE et al. J Rheumatol. 2004;31:390-392.
8
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.
9
SJIA is mostly a disease
starting in childhood
10
11
12
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
13
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.
14
Pathogenetic Models
Peter Nigrovic; ARTHRITIS & RHEUMATOLOGY; Vol. 66, No. 6, June 2014, pp 1405–1413
15
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 diseases
Peter 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
16
Prognosis of SJIA
has markedly
improved with the
approval of IL1 and
IL6 blocking
medications
17
0
10
20
30
40
50
60
70
80
90
Persistent
Oligo
Extended
Oligo
Polyarthritis
(RF+)
Polyarthritis
(RF-)
Systemic
Disease Type
%ofpatients
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
18
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
19
In the past: progressive joint destruction in approximately 1/3 of the
children
More 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
20
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
22
Mortality
In SJIA mostly due to disease
complications:
 Infection
 MAS
 Myocarditis
 Amyloidosis
Systemic
64%
Poly
18%
Pauci
12%
Other
6%
23
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
24
Summary
25
1 of 24

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What is SJIA - How is it different than other diseases - Dr. Hermine Brunner

  • 1. What is SJIA - how is it different than other diseases HERMINE BRUNNER, MD MSC MBA PROFESSOR OF PEDIATRICS CHIEF, DIVISION OF RHEUMATOLOGY
  • 2. 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 2
  • 3. 7. Shenoi S, Wallace CA. J Pediatr. 2016;177:19-26. 3
  • 4. 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 4
  • 5.  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. 5
  • 6. 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. 6
  • 7. 7
  • 8. 7. Shenoi S, Wallace CA. J Pediatr. 2016;177:19-26. 8. Petty RE et al. J Rheumatol. 2004;31:390-392. 8
  • 9. 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. 9 SJIA is mostly a disease starting in childhood
  • 10. 10
  • 11. 11
  • 13. 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 13
  • 14. 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. 14
  • 15. Pathogenetic Models Peter Nigrovic; ARTHRITIS & RHEUMATOLOGY; Vol. 66, No. 6, June 2014, pp 1405–1413 15
  • 16. 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 diseases Peter 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 16
  • 17. Prognosis of SJIA has markedly improved with the approval of IL1 and IL6 blocking medications 17
  • 18. 0 10 20 30 40 50 60 70 80 90 Persistent Oligo Extended Oligo Polyarthritis (RF+) Polyarthritis (RF-) Systemic Disease Type %ofpatients 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 18
  • 19. 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 19
  • 20. In the past: progressive joint destruction in approximately 1/3 of the children More 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 20
  • 21. 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 22
  • 22. Mortality In SJIA mostly due to disease complications:  Infection  MAS  Myocarditis  Amyloidosis Systemic 64% Poly 18% Pauci 12% Other 6% 23
  • 23. 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 24