Karen Onel, M.D. Division of Pediatric Rheumatology University of Chicago

1. Systemic Juvenile Idiopathic
Arthritis:
Where are We?
Karen Onel, M.D.
Division of Pediatric Rheumatology
University of Chicago

2. A child goes to see the
doctor with a history of
fever. They have knee pain
and swelling too!
What’s wrong?
How can we figure this out?
Is this Systemic JIA?

3. Juvenile Idiopathic Arthritis
 Most common rheumatic disease of
childhood
 Important cause of disability and blindness
 Syndrome of diverse etiologies--Idiopathic
 Criteria
– Age less than 16
– Arthritis (vs. arthralgia)-Joint inflammation not
just pain
– Duration > 6 weeks

4. Idiopathic
 We still don’t understand why children get
systemic JIA
 Not likely genetic-rare to have 2 family
members involved
 Some people think it belongs with the
autoinflammatory and periodic fever
syndromes

5. Types of JIA
 Oligoarthritis
 Extended Oligoarthritis
 Polyarthritis (either RF+ or -)
 Psoriatic Arthritis
 Enthesitis-related Arthritis
 Systemic Onset

6. Epidemiology
 Incidence--10/100,000/year in US
 Prevalence--100/100,000 children in US
 Age at onset extremely rare prior to 6
months
 Peak ages--
– 1-3 years (girls)
– 9 years (boys and girls)
 Lower extremities most often involved

7. Much more about Systemic
Juvenile Idiopathic Arthritis
Still’s Disease
Rarest subtype-at most 10%

8. Lots of things give kids fevers
and joint pains and joint
swelling
 Infections
– Infections in the bone or joint
 Cancer
– Especially cancer that involves the bone marrow
 Leukemia, lymphoma, neuroblastoma
 Other rheumatologic illness
– Lupus, Dermatomyositis, Vasculitis
– Reactive Arthritis
– Polyarticular JIA can present with fevers

9. Systemic Onset JIA-
Systemic Arthritis
 Joints may or may not be involved at the
beginning
 Sex ratio: equal
 May occur at any age (even adults)
 Uveitis rare
 Systemic signs (fever, rash, abnormal labs)
may precede the development of arthritis by
years (even 10!)

10. Clinical Features
 Diagnostic hallmark--high spiking fevers
with daily return to normal

11. Clinical Features
 Classic rash—usually flat red spots that
come and go but can be hives
 Rash is transient--Koebner’s phenomenon
 Rash can be very itchy

13. Clinical Features
 Joints can be severely involved
 Often very severe hip involvement
 Joint and muscle pain may be worse when
children have fever

15. Clinical Features
 Heart and lungs can be involved
 Liver and spleen can be involved as well
 Enlarged lymph nodes are common

16. Laboratory Evaluation
 Lab tests show a great deal of systemic
stress- ESR, platelet and white blood cells
can be very elevated. It would be surprising
if they were normal at the beginning
 Anemia of chronic disease is common and
children may not respond to oral iron
supplementation.

17. What about Macrophage
Activation Syndrome
 Acute Hemophagocytic Syndrome
– normal, activated macrophages (scavenger white blood
cells) eat up red and white blood cells, as well as
platelets.
– Liver function tests, ferritin and markers of coagulation
(blood clotting) are often abnormal
– Often early in disease or with flares
– Viruses probably play a role, especially EBV which
causes mono
– Treated with steroids, cyclosporine as well as other
medications

18. How do we make the
diagnosis?
 Above all, JIA is a clinical diagnosis
 Does the patient have swollen joints not just joint
pain?
 How long has the swollen joint been there?
 Are they below 16?
 Do they have any other medical problems?
 What is the fever pattern
 Do they have signs of MAS?
 Did you look for other possibilities?

19. What about labs?
 ANA is not useful to make the diagnosis of Systemic JIA
but helps to rule out other diseases
 RF useful for identifying RF+ poly but should be negative
here
 Expect acute phase reactants to be abnormal in active
Systemic Arthritis
 Exclude other causes of joint pain and swelling
BUT Systemic JIA is a clinical disease—there is not
one lab test that definitively makes the diagnosis

20. Consensus Treatment Plans
Definition of Systemic JIA
Patient should be/have
1. Age 6 months to 18 years
2. Fever for at least 2 weeks†
3. Arthritis in ≥1 joints (6 weeks' duration not required)‡
4. At least 1 of the following:
a. Evanescent erythematous rash
b. Generalized lymphadenopathy
c. Hepatomegaly or splenomegaly
d. Pericarditis, pleuritis, and/or peritonitis

21. Consensus Treatment Plans-
Exclusions
Patient should not have
1. Infection, including concomitant active or recurrent
chronic bacterial, fungal, or viral infection at presentation,
nor underlying infection that may mimic initial presentation
of systemic JIA
2. Malignancy
From De Witt, et al, A C and R, 64: 1001-1010, 2012

22. Treatment

23. NSAID’s
 Even in the biologic age, NSAIDs are
important.
 Gastritis is common but ulcers are rare
 Liquid preparations--ibuprofen, naproxen,
meloxicam and indomethacin
 Others can be dissolved in water or crushed
which destroys the enteric coating

24. Methotrexate
 We still don’t really know how it works
 Use of folic acid does not interfere with function like it
does for cancer
 Very slow onset of activity—often 2-3 months
 Sq form has better absorption but hard to find currently
due to drug shortage.
 Nausea is common but can and should be treated
 Risk of liver toxicity. Need to follow Liver function tests
every 2 months at least

25. Corticosteroids
 Continue to play an important role in the treatment
of JIA
 Growth side-effects especially problematic in
pediatrics
 Alternate day steroids generally not effective at
controlling inflammation
 Can be given by mouth, intravenous or in the joint
—depends on what you need

26. Cyclosporine
 From the transplanters but at lower doses
 Prevents T cells from becoming activated,
decreasing inflammation
 Mostly useful in the setting of MAS where it
plays a critical role

27. Other DMARDs
 Thalidomide
 Hydroxychloroquine
 Azathioprine
 Leflunamide
 Sulfasalazine

28. The cytokine soup…
 We love our biologics!!!!

29. RECOGNITION OF
OUTCOMES
By the early 1990s, long-term studies showed:
 Long-term morbidity:
• ↑ disability
• ↓ quality of life
 Mortality
 We needed a new strategy!!

30. BIOLOGICS
These drugs are targeted therapies directed
against specific pathologic mechanisms which are
present in inflamed joints.

31. APC

32. Pro-inflammatory

33. TNF Blockade
 TNF, made by macrophages and T cells is clearly
important in the pathogenesis of synovitis and joint
destruction
 Five available agents to interfere with TNF
signaling (two are approved for kids with JIA)
 Response in 70% polyarticular disease within 4
weeks with sustained response—Getting people off
is more complicated
 BUT-doesn’t work for Systemic JIA

34. Well…
What does work?

35. Role of IL-1
 IL-1 is responsible for bone and cartilage
destruction in arthritis
 IL-1 causes white blood cells to flock to site of
infection and to reset the center of the brain
responsible for regulating body temperature
leading to fever. IL-1 is, therefore, called an
endogenous pyrogen
 IL-1 is also responsible for increased pain
associated with fever.

36. Anikinra (Kineret TM )
 Anakinra is a recombinant version of the
human Interleukin-1 receptor antagonist (IL-
1Ra) and blocks IL-1 by competitively
inhibiting IL-1 binding to the Interleukin-1
type I receptor (IL-1RI)
 Given once daily as a sq injection
 Most common side effect is injection site
pain

37. ANAKINRA:
CLINICAL USES
Used in RA, but especially useful in:
 Systemic-Onset Arthritis
 Gout
 Cryopyrin-associated periodic syndromes (CAPS):
• Muckle-Wells syndrome
• Chronic infantile, neurologic, cutaneous and articular
syndrome (CINCA) / neonatal-onset multisystem
inflammatory disease (NOMID)
• Familial cold autoinflammatory syndrome

38. Anakinra and systemic JIA
From Nigrovic, et al. A and R 63:545-555, 2011

39. New Il-1 blockers
 Rilonocept (ArcalystTM)
 Canakinumab (IlarisTM)
 These drugs are currently indicated for the
treatment of CAPS but testing in Systemic
JIA is ongoing

40. Role of IL-6
Endothelial cells Mesenchymal cells,
Monocytes/
fibroblasts/
macrophages
synoviocytes
T-cell activation
IL-6 Hepatocytes
Acute-phase response
Maturation of Hepcidin, CRP
megakaryocytes ↓ CYP450
B-cells Osteoclast activation
Bone resorption
Thrombocytosis
Auto-antibodies (RF) Hyper-γ-globulinemia
Adapted from 1 Firestein GS. Nature. 2003; 423:356-361.
2 Smolen JS, et al. Nat Rev Drug Disc. 2003; 2:473-488.
Disc.

41. Tocilizumab (Actemra TM )
 Tocilizumab is a humanized, monoclonal antibody
that targets the IL-6 receptor and inhibits IL-6
signaling
 It is indicated for the treatment of active systemic
juvenile idiopathic arthritis in patients 2 years of
age and older.
 It is given intravenously every two weeks
 Common side effect upper respiratory tract
infection, headache, nasopharyngitis and
diarrhea.
 Can cause abnormal liver function tests,
decreased white blood cells, allergic reactions,
and lipid problems

42. Actemra and Systemic JIA
JIA absence of fever at Week 12 (TENDER TRIAL)

43. Rituximab (Rituxan TM )
 Currently indicated for relapsed or
refractory lymphoma and RA
 Used for many different types of rheumatic
diseases
 Binds to CD20 antigen on normal and
malignant pre-B and mature B cells
 One study showed potential for its use in
Systemic JIA

44. We always want more
 Greedy, greedy, greedy

45. 2011 version

46. Maybe we just need to know
which path to follow…
CARRA CONSENSUS TREATMENT PLANS

51. Stem Cell Transplant
 When all else fails, autologous stem cell
transplantation has been used successfully.
 Should be done by a center with experience

52. Prognosis
 Better each year!!!
 70-90% children with JIA have good outcome without
serious disability
 The hardest part is getting children to be medicine free-
that time will come!
 Delay in medical or physical therapy and
undertreatment are associated with poor prognosis