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
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
12.
13. Clinical Features
Joints can be severely involved
Often very severe hip involvement
Joint and muscle pain may be worse when
children have fever
14.
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
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
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.
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
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
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
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
46. Maybe we just need to know
which path to follow…
CARRA CONSENSUS TREATMENT PLANS
47.
48.
49.
50.
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
Hinweis der Redaktion
In the normal joint there is a balance between proinflammatory and anti-inflammatory events. A disequilibrium between pro- and anti-inflammatory cytokines within the joints of patients with rheumatoid arthritis exists. Both types of cytokines are up-regulated, however the balance is in favor of the proinflammatory cytokines. Some of these cytokines play a prominent role in the pathogenesis of RA. Proinflammatory cytokines such as TNF and IL-1 induce inflammatory mediators like prostaglandins, reactive oxygen species, and nitric oxide. They are also important in the connective tissue breakdown of cartilage, inhibition of matrix synthesis, and within bone via effects on osteoclasts and osteoblasts. Anti-inflammatory mediators such as IL-10, IL-1ra (IL-1 receptor antagonist) and sTNF-R (soluble TNF receptor) also exist and may play pro- and anti-inflammatory roles.