Systemic Juvenile Idiopathic Systemic Juvenile Idiopathic Arthritis:Arthritis:Where are We? Where are We?

Karen Onel, M.D.Karen Onel, M.D.

Division of Pediatric RheumatologyDivision of Pediatric RheumatologyUniversity of ChicagoUniversity of Chicago

A child goes to see the A child goes to see the doctor with a history of doctor with a history of fever. They have knee pain fever. They have knee pain and swelling too!and swelling too!

What’s wrong?What’s wrong?

How can we figure this out?How can we figure this out?

Is this Systemic JIA?Is this Systemic JIA?

Juvenile Idiopathic Juvenile Idiopathic ArthritisArthritis Most common rheumatic disease of Most common rheumatic disease of

childhoodchildhood Important cause of disability and blindnessImportant cause of disability and blindness Syndrome of diverse etiologies--Syndrome of diverse etiologies--IdiopathicIdiopathic CriteriaCriteria

– Age less than 16Age less than 16– Arthritis (vs. arthralgia)-Joint inflammation not Arthritis (vs. arthralgia)-Joint inflammation not

just painjust pain– Duration > 6 weeksDuration > 6 weeks

IdiopathicIdiopathic

We still don’t understand why children We still don’t understand why children get systemic JIAget systemic JIA

Not likely genetic-rare to have 2 Not likely genetic-rare to have 2 family members involvedfamily members involved

Some people think it belongs with the Some people think it belongs with the autoinflammatory and periodic fever autoinflammatory and periodic fever syndromessyndromes

Types of JIATypes of JIA

OligoarthritisOligoarthritis Extended OligoarthritisExtended Oligoarthritis Polyarthritis (either RF+ or -)Polyarthritis (either RF+ or -) Psoriatic ArthritisPsoriatic Arthritis Enthesitis-related ArthritisEnthesitis-related Arthritis Systemic OnsetSystemic Onset

EpidemiologyEpidemiology

Incidence--10/100,000/year in USIncidence--10/100,000/year in US Prevalence--100/100,000 children in USPrevalence--100/100,000 children in US Age at onset extremely rare prior to 6 Age at onset extremely rare prior to 6

monthsmonths Peak ages--Peak ages--

– 1-3 years (girls)1-3 years (girls)– 9 years (boys and girls)9 years (boys and girls)

Lower extremities most often involvedLower extremities most often involved

Much more about Systemic Much more about Systemic Juvenile Idiopathic Juvenile Idiopathic ArthritisArthritis

Still’s DiseaseStill’s Disease

Rarest subtype-at most 10%Rarest subtype-at most 10%

Lots of things give kids Lots of things give kids fevers and joint pains and fevers and joint pains and joint swellingjoint swelling InfectionsInfections

– Infections in the bone or jointInfections in the bone or joint CancerCancer

– Especially cancer that involves the bone marrowEspecially cancer that involves the bone marrow Leukemia, lymphoma, neuroblastomaLeukemia, lymphoma, neuroblastoma

Other rheumatologic illnessOther rheumatologic illness– Lupus, Dermatomyositis, VasculitisLupus, Dermatomyositis, Vasculitis– Reactive ArthritisReactive Arthritis– Polyarticular JIA can present with feversPolyarticular JIA can present with fevers

Systemic Onset JIA-Systemic Onset JIA-Systemic ArthritisSystemic Arthritis Joints may or may not be involved at Joints may or may not be involved at

the beginningthe beginning Sex ratio: equalSex ratio: equal May occur at any age (even adults)May occur at any age (even adults) Uveitis rareUveitis rare Systemic signs (fever, rash, abnormal Systemic signs (fever, rash, abnormal

labs) may precede the development of labs) may precede the development of arthritis by years (even 10!)arthritis by years (even 10!)

Clinical FeaturesClinical Features

Diagnostic hallmark--high spiking Diagnostic hallmark--high spiking fevers with daily return to normalfevers with daily return to normal

Clinical FeaturesClinical Features

Classic rash—usually flat red spots Classic rash—usually flat red spots that come and go but can be hivesthat come and go but can be hives

Rash is transient--Koebner’s Rash is transient--Koebner’s phenomenonphenomenon

Rash can be very itchyRash can be very itchy

Clinical FeaturesClinical Features

Joints can be severely involvedJoints can be severely involved Often very severe hip involvementOften very severe hip involvement Joint and muscle pain may be worse Joint and muscle pain may be worse

when children have feverwhen children have fever

Clinical FeaturesClinical Features

Heart and lungs can be involvedHeart and lungs can be involved Liver and spleen can be involved as Liver and spleen can be involved as

wellwell Enlarged lymph nodes are commonEnlarged lymph nodes are common

Laboratory EvaluationLaboratory Evaluation

Lab tests show a great deal of Lab tests show a great deal of systemic stress- ESR, platelet and systemic stress- ESR, platelet and white blood cells can be very white blood cells can be very elevated. It would be surprising if they elevated. It would be surprising if they were normal at the beginningwere normal at the beginning

Anemia of chronic disease is common Anemia of chronic disease is common and children may not respond to oral and children may not respond to oral iron supplementation.iron supplementation.

What about Macrophage What about Macrophage Activation SyndromeActivation Syndrome

Acute Hemophagocytic SyndromeAcute Hemophagocytic Syndrome– normal, activated macrophages (scavenger white normal, activated macrophages (scavenger white

blood cells) eat up red and white blood cells, as blood cells) eat up red and white blood cells, as well as platelets. well as platelets.

– Liver function tests, ferritin and markers of Liver function tests, ferritin and markers of coagulation (blood clotting) are often abnormalcoagulation (blood clotting) are often abnormal

– Often early in disease or with flaresOften early in disease or with flares– Viruses probably play a role, especially EBV Viruses probably play a role, especially EBV

which causes monowhich causes mono– Treated with steroids, cyclosporine as well as Treated with steroids, cyclosporine as well as

other medicationsother medications

How do we make the How do we make the diagnosis?diagnosis? Above all, JIA is a clinical diagnosisAbove all, JIA is a clinical diagnosis Does the patient have swollen joints not just Does the patient have swollen joints not just

joint pain?joint pain? How long has the swollen joint been there?How long has the swollen joint been there? Are they below 16?Are they below 16? Do they have any other medical problems?Do they have any other medical problems? What is the fever patternWhat is the fever pattern Do they have signs of MAS?Do they have signs of MAS? Did you look for other possibilities?Did you look for other possibilities?

What about labs?What about labs?

ANA is not useful to make the diagnosis of ANA is not useful to make the diagnosis of Systemic JIA but helps to rule out other diseasesSystemic JIA but helps to rule out other diseases

RF useful for identifying RF+ poly but should be RF useful for identifying RF+ poly but should be negative herenegative here

Expect acute phase reactants to be abnormal in Expect acute phase reactants to be abnormal in active Systemic Arthritisactive Systemic Arthritis

Exclude other causes of joint pain and swellingExclude other causes of joint pain and swelling

BUT Systemic JIA is a clinical disease—there is BUT Systemic JIA is a clinical disease—there is not one lab test that definitively makes the not one lab test that definitively makes the diagnosisdiagnosis

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

Consensus Treatment PlansDefinition of Systemic JIA

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

 

Consensus Treatment Plans-Exclusions

From De Witt, et al, A C and R, 64: 1001-1010, 2012

TreatmentTreatment

NSAID’sNSAID’s

Even in the biologic age, NSAIDs are Even in the biologic age, NSAIDs are important. important.

Gastritis is common but ulcers are rare Gastritis is common but ulcers are rare Liquid preparations--ibuprofen, Liquid preparations--ibuprofen,

naproxen, meloxicam and indomethacinnaproxen, meloxicam and indomethacin Others can be dissolved in water or Others can be dissolved in water or

crushed which destroys the enteric crushed which destroys the enteric coatingcoating

MethotrexateMethotrexate

We still don’t really know how it worksWe still don’t really know how it works Use of folic acid does not interfere with function Use of folic acid does not interfere with function

like it does for cancerlike it does for cancer Very slow onset of activity—often 2-3 monthsVery slow onset of activity—often 2-3 months Sq form has better absorption but hard to find Sq form has better absorption but hard to find

currently due to drug shortage.currently due to drug shortage. Nausea is common but can and should be treatedNausea is common but can and should be treated Risk of liver toxicity. Need to follow Liver function Risk of liver toxicity. Need to follow Liver function

tests every 2 months at leasttests every 2 months at least

CorticosteroidsCorticosteroids

Continue to play an important role in the Continue to play an important role in the treatment of JIAtreatment of JIA

Growth side-effects especially problematic Growth side-effects especially problematic in pediatricsin pediatrics

Alternate day steroids generally not Alternate day steroids generally not effective at controlling inflammationeffective at controlling inflammation

Can be given by mouth, intravenous or in Can be given by mouth, intravenous or in the joint—depends on what you needthe joint—depends on what you need

CyclosporineCyclosporine

From the transplanters but at lower From the transplanters but at lower dosesdoses

Prevents T cells from becoming Prevents T cells from becoming activated, decreasing inflammationactivated, decreasing inflammation

Mostly useful in the setting of MAS Mostly useful in the setting of MAS where it plays a critical rolewhere it plays a critical role

Other DMARDsOther DMARDs

ThalidomideThalidomide Hydroxychloroquine Hydroxychloroquine AzathioprineAzathioprine LeflunamideLeflunamide SulfasalazineSulfasalazine

The cytokine soup…The cytokine soup…

We love our biologics!!!!We love our biologics!!!!

RECOGNITIONRECOGNITION OF OF OUTCOMESOUTCOMES

By the early 1990s, long-term studies showed: By the early 1990s, long-term studies showed:

Long-term morbidity:Long-term morbidity:• ↑ ↑ disabilitydisability• ↓ ↓ quality of lifequality of life

MortalityMortality

We needed a new strategy!!We needed a new strategy!!

BIOLOGICSBIOLOGICS

These drugs are targeted therapies directed against specific pathologic mechanisms which are

present in inflamed joints.

APC

Pro-inflammatory

TNF BlockadeTNF Blockade TNF, made by macrophages and T cells is TNF, made by macrophages and T cells is

clearly important in the pathogenesis of clearly important in the pathogenesis of synovitis and joint destructionsynovitis and joint destruction

Five available agents to interfere with TNF Five available agents to interfere with TNF signaling (two are approved for kids with JIA)signaling (two are approved for kids with JIA)

Response in 70% polyarticular disease within 4 Response in 70% polyarticular disease within 4 weeks with sustained response—Getting people weeks with sustained response—Getting people off is more complicatedoff is more complicated

BUT-doesn’t work for Systemic JIABUT-doesn’t work for Systemic JIA

Well…Well…

What does work?What does work?

Role of IL-1 Role of IL-1

IL-1 is responsible for bone and cartilage IL-1 is responsible for bone and cartilage destruction in arthritisdestruction in arthritis

IL-1 causes white blood cells to flock to site of IL-1 causes white blood cells to flock to site of infection and to reset the center of the brain infection and to reset the center of the brain responsible for regulating body temperature responsible for regulating body temperature leading to fever. IL-1 is, therefore, called an leading to fever. IL-1 is, therefore, called an endogenous pyrogen endogenous pyrogen

IL-1 is also responsible for increased pain IL-1 is also responsible for increased pain associated with fever.associated with fever.

Anikinra (KineretAnikinra (KineretTMTM))

Anakinra is a recombinant version of Anakinra is a recombinant version of the human Interleukin-1 receptor the human Interleukin-1 receptor antagonist (IL-1Ra) and blocks IL-1 by antagonist (IL-1Ra) and blocks IL-1 by competitively inhibiting IL-1 binding to competitively inhibiting IL-1 binding to the Interleukin-1 type I receptor (IL-the Interleukin-1 type I receptor (IL-1RI)1RI)

Given once daily as a sq injectionGiven once daily as a sq injection Most common side effect is injection Most common side effect is injection

site painsite pain

ANAKINRA:ANAKINRA:CLINICAL USESCLINICAL USES

Used in RA, but especially useful in:Used in RA, but especially useful in: Systemic-Onset ArthritisSystemic-Onset Arthritis GoutGout Cryopyrin-associated periodic syndromes Cryopyrin-associated periodic syndromes

(CAPS):(CAPS):• Muckle-Wells syndromeMuckle-Wells syndrome• Chronic infantile, neurologic, cutaneous and articular Chronic infantile, neurologic, cutaneous and articular

syndrome (CINCA) / neonatal-onset multisystem syndrome (CINCA) / neonatal-onset multisystem inflammatory disease (NOMID)inflammatory disease (NOMID)

• Familial cold autoinflammatory syndrome Familial cold autoinflammatory syndrome

Anakinra and systemic JIAAnakinra and systemic JIA

From Nigrovic, et al. A and R 63:545-555, 2011

New Il-1 blockersNew Il-1 blockers

Rilonocept (ArcalystRilonocept (ArcalystTMTM)) Canakinumab (IlarisCanakinumab (IlarisTMTM))

These drugs are currently indicated These drugs are currently indicated for the treatment of CAPS but testing for the treatment of CAPS but testing in Systemic JIA is ongoingin Systemic JIA is ongoing

Role of IL-6Role of IL-6Monocytes/

macrophages

T-cell activation

Endothelial cells Mesenchymal cells,fibroblasts/

synoviocytes

Hepatocytes

Acute-phase responseHepcidin, CRP

↓ CYP450Maturation ofmegakaryocytes

Thrombocytosis

Osteoclast activationBone resorption

B-cells

Hyper--globulinemiaAuto-antibodies (RF)

Adapted from 1 Firestein GS. Adapted from 1 Firestein GS. Nature.Nature. 2003; 423:356-361. 2003; 423:356-361. 2 Smolen JS, et al. 2 Smolen JS, et al. Nat Rev Drug DiscNat Rev Drug Disc. 2003; 2:473-488. . 2003; 2:473-488.

IL-6

Tocilizumab (ActemraTocilizumab (ActemraTMTM)) Tocilizumab is a humanized, monoclonal antibody Tocilizumab is a humanized, monoclonal antibody

that targets the IL-6 receptor and inhibits IL-6 that targets the IL-6 receptor and inhibits IL-6 signaling signaling

It is indicated for the treatment of active systemic It is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age juvenile idiopathic arthritis in patients 2 years of age and older. and older.

It is given intravenously every two weeksIt is given intravenously every two weeks Common side effect upper respiratory tract infection, Common side effect upper respiratory tract infection,

headache, nasopharyngitis and diarrhea.headache, nasopharyngitis and diarrhea. Can cause abnormal liver function tests, decreased Can cause abnormal liver function tests, decreased

white blood cells, allergic reactions, and lipid white blood cells, allergic reactions, and lipid problemsproblems

Actemra and Systemic JIAActemra and Systemic JIA

JIA absence of fever at Week 12 (TENDER TRIAL)

Genentech, 2012

Rituximab (RituxanRituximab (RituxanTMTM))

Currently indicated for relapsed or Currently indicated for relapsed or refractory lymphoma and RArefractory lymphoma and RA

Used for many different types of Used for many different types of rheumatic diseasesrheumatic diseases

Binds to CD20 antigen on normal and Binds to CD20 antigen on normal and malignant pre-B and mature B cellsmalignant pre-B and mature B cells

One study showed potential for its use One study showed potential for its use in Systemic JIAin Systemic JIA

We always want moreWe always want more

Greedy, greedy, greedyGreedy, greedy, greedy

2011 version2011 version

Maybe we just need to Maybe we just need to know which path to know which path to follow…follow…

CARRA CONSENSUS TREATMENT PLANS

Stem Cell TransplantStem Cell Transplant

When all else fails, autologous stem When all else fails, autologous stem cell transplantation has been used cell transplantation has been used successfully.successfully.

Should be done by a center with Should be done by a center with experienceexperience

PrognosisPrognosis

Better each year!!!Better each year!!! 70-90% children with JIA have good outcome 70-90% children with JIA have good outcome

without serious disabilitywithout serious disability The hardest part is getting children to be The hardest part is getting children to be

medicine free-that time will come!medicine free-that time will come! Delay in medical or physical therapy and Delay in medical or physical therapy and

undertreatment are associated with poor undertreatment are associated with poor prognosisprognosis