Arthritis and Juvenile Idiopathic Arthritis

Peter GowdiePaediatric Rheumatologist

General PaediatricianMonash Children’s Hospital

Royal Children’s HospitalOct 2014

Objectives

• Arthritis in children

• Juvenile Idiopathic Arthritis

– Approach to diagnosis

– Overview of JIA subtypes

– Approach to management

– Outcomes

• JIA mimics

What is arthritis?

• A clinical sign

• Joint effusion or

• 2 of…

– Joint line tenderness

– Limited range of motion

– ‘Stress’ pain

• 10 yo girl

• 5 month history of R ankle pain

▫ Swelling, pain, early morning stiffness/gelling

▫ No injury

▫ No preceding illness

• Previously well

• Born Australia, no travel, Greek ethnicity

• FHx: Maternal GF ?RA, Maternal GM psoriasis

Case - AR

• Seen by GP, podiatry, physiotherapy, orthotist, orthopaedics

• Normal blood tests

▫ Including: ANA, RF, ESR, CRP, FBE

• Orthotics of no benefit

• ? tarsal coalition

• MRI – synovial thickening and bone oedema.

AR

• On review:▫ Longstanding problems with other joints

▫ Many years of difficulty moving neck

▫ Strength hands/fingers

Unable to make fist

Never able to open bottles

AR

Examination

• Generalised severe polyarthritis

• Antalgic gait

– limited toeing off

• Cutaneous examination normal

• Systems review normal

Progress

• Started NSAID

• XR hands

– Reported as normal

– On review – severe erosions throughout suggesting destructive disease

• Review MRI ankle

– Consistent with synovitis

• Repeat bloods - normal

• Treatment:

– Methotrexate SC

– Prednisolone PO

– Intra-articular steroid injections large joints

Progress - 3 months post Methotrexate

– Oral steroids weaned

– Required further intra-articular steroids

– Persistent polyarthritis

– Meds well tolerated

– Adherent

Progress – 6 months post methotrexate

Progress

• commenced etanercept

– TNFα inhibitor

– Twice weekly SC injections

Progress – 2 months post etanercept

Juvenile Idiopathic Arthritis

• Clinical diagnosis

• Onset before 16 years age

• Arthritis present > 6 weeks

• No other cause

• Approx prevalence 1:1000

• Genetic predisposition

• Infection or other trigger

• Autoimmune dysregulation

JIA ClassificationHistorical Background

• Classification difficult for decades

– Why?

– Europe – US divide

– Juvenile Arthritis is:• Genetically heterogenous

• Phenotypically diverse

• No pathognomic diagnosis

– Current classification relies on clinical phenotype• Too loose vs too tight

Background

• 1970s

– Two sets of classification criteria

– 1) Juvenile Rheumatoid Arthritis

• Developed by ACR

– 2) Juvenile Chronic Arthritis

• Developed by EULAR

Beresford, Arch Dis Child Educ Pract Ed 2009;94:144–150

Juvenile Idiopathic Arthritis

JIA Subtype at 6 months

38%

21%4%

7%

6%

14%

10%Oligoarthritis (416)

RF Neg Polyarthritis (235)

RF Pos Polyarthritis (46)

sJIA (76)

Psoriatic (64)

ERA (157)

Undifferentiated (110)N=1104

Aetiology and Pathogenesis

Diagnosis of JIA

• History

• Examination

• Investigations

• Clinical diagnosis

• Must have onset before 16 years age

• Must have arthritis on exam!

• Must have been present > 6 weeks

Investigations in JIA

• ANA (up to 15% +ve in “normal children”)

– non-predictive of specific CTD developing

– May help predict risk of uveitis

• Rheumatoid factor (generally low yield)

– (anti-CCP abs: Cyclic Citrullinated Peptide - ? role)

• HLA B27 (approx 10% Caucasians +ve)

• Ferritin

– disproportionate elevation in SoJIA ??MAS

• Clotting / d-dimers / fibrinogen / LDH / TG / LFTs

– Markers of MAS

• Rule out mimics

– Viral serology, ASOT, FBE and film, BMA etc…

Red Flags

• Fever

• Night-time pain

• Pain out of keeping with the degree of inflammation

• Weight loss

• Lymphadenopathy, hepatosplenomegaly

• Bone pain

Features of JIA subtypes….

Feature Oligoarticular Polyarticular Systemic Psoriatic ERA

Frequency

Gender (F:M)

Age at onset

RF present

ANA present

Cassidy JT et al. Textbook of Paediatric Rheumatology. 2011.

75-85%

Early

Rarely

F> M

50-80%

40-50%

Two peaks

15%

F> M

15-25%

Rarely

Throughout

Rarely

F= M

5-15%

30-60%

Two peaks

Rarely

F> M

5-10%

Rarely

Late

Rarely

F< M

5-10%

JIA – Features

Oligoarticular JIA

• ≤4 joints in 1st 6 months

• Large joints

• NB: hip involvement unusual - think mimic or ERA

• Female : male approx 4:1

• ANA +ve approx 60%

• Asymptomatic anterior uveitis 20-30% risk– Within 2 yrs but continue slit lamp screening until 10 to 12 yrs

Polyarticular JIA

• > 4 joints

• Clinically - small and large joint, symmetrical

• other sites eg TMJ, cervical spine

• Rheumatoid factor seropositive <10%

• Sero+ve tend to be adult RA pattern eg nodules, early erosions, ? lower rate of remission

Systemic onset JIA• Arthritis

• rash - evanescent, salmon pink, macular, +/-pruritic

• quotidian fever

• lymphadenopathy

• hepatosplenomegaly

• serositis

• arthritis may develop later (hence PUO presentation)

• Differential diagnoses:

– Infection

– Kawasaki disease

– Malignancy

Systemic JIA

• about 5-10% of cases

• M=F

• no peak age of onset

• Anaemia chronic disease

• Growth failure common

• Complication: macrophage activation syndrome (MAS)

Enthesitis related arthritis (ERA)

• Arthritis and enthesitis

• HLA B27 positive

• Typically boys >6 yrs

• Inflammatory lower back pain and/or sacroiliitis

• Family history of ankylosing spondylitis

• Associated with acute anterior uveitis

Psoriatic JIA

• Arthritis and psoriasis

• Dactylitis

• nail pits +/- skin involvement

• asymmetric large/small distribution

• family history psoriasis

• uveitis common

JIA – Clinical Manifestations

• 1/1000 children

• Arthritis – common feature of all subtypes– morning stiffness, joint swelling, effusions, ROM– Any joint– Large > small– also axial, SI and TMJ– Pain not as common as in adults

• Systemic symptoms – Fever, LOW, anaemia, fatigue

• Extra-articular– Growth – local and general – Osteopenia– Cardiopulmonary (sJIA)– uveitis

JIA – complications

Macrophage Activation Syndrome

Macrophage haemophagocytosis in bone marrow

MAS and sJIA

• Severe complication and important cause for mortality and morbidity

• Frequency ~7-13%

• Mortality 8-22%

• M=F, at any age

• Any time during the course of the disease, may be seen at time of diagnosis

• Triggers can include infections, drugs

• NK cell function in SoJIA– Low NK activity with low numbers of NK cells and increased perforin

– Low NK activity with mildly decreased NK cells but low perforin expression

Grom et al. J Pediatric 2003

• Prevalence of occult MAS in children with sJIAreceiving bone marrow aspirates

– Patients diagnosed with sJIA as part of workup for FUO

– 15 patients identified 1998-2005

– Most had quotidian fever, evanescent rash or synovitis

– Lower Hb and more LNS than those diagnosed without BMA

– No differences in WBC, platelets, ESR, ferritin or age

– 53% had occult MAS on their BMA, 13% were diagnosed clinically

SoJIA vs. MAS Summary

Ramanan and Kelly. Curr Opin Rheum, 2007

Immune Response in MAS

• Pro-inflammatory cytokines

– fever, hyperferritinemia, coagulopathy

– bone marrow suppression with cytopenias

• Infiltration of T cells, APCs and macrophages

– bone marrow, liver, spleen, lymph nodes, brain

• Persistent T activation and NK cell dysfunction

– propagation of vicious cycle with more cytokines and

further activation of immune cells

HLH diagnostic guidelinesHLH 2004 protocol

Filipovich, A.H., Curr Opin Allergy Clin Immunol, 2006. 6(6): p. 410-5.

Diagnostic criteria for MAS

Ravelli, A. et al., J Ped, 2005. 146(5): p. 598

Compared 74 pts with SoJIA and MAS with SoJIApts with “high disease activity”

MAS diagnostic criteria

• Ravelli et al

• Delphi survey of 160 Paed Rheum

• Aim to facilitate early dx and treatment

Top 10 features (clinical, lab, path) considered most diagnostic of MAS in SoJIA

1. Falling platelets2. Bone marrow haemophagocytosis3. Elevated Ferritin4. Fever 5. Falling leucs6. Elevated LFTs 7. Falling ESR8. Raised TG9. Hypofibrinogenemia10. CNS dysfunction

Uveitis

Juvenile Idiopathic Arthritis: Uveitis

Ocular redness

Photophobia

Pain

Blurred vision

“Asymptomatic”

Chronic (insidious, persistent)

Acute (sudden, limited) Ocular redness

Photophobia

Pain

Blurred vision

“Symptomatic”

0-25%

0-20%

0-8%

Change in vision

Ocular pain and/or redness

Photophobia

Acute (sudden, limited) Ocular redness

Photophobia

Pain

Blurred vision

“Symptomatic”

Cassidy JT et al. Textbook of Paediatric Rheumatology. 2011.

Juvenile Idiopathic Arthritis: Uveitis

Feature Oligoarticular Polyarticular Systemic Psoriatic ERA

<1% <1% <1% 5-10%

30% 5% <1% <1%10%

ANA present 75-85% 40-50% Rarely 30-60% Rarely40-50% 30-60%

Juvenile Idiopathic Arthritis: Uveitis

• Majority develop arthritis before uveitis

– In minority, uveitis precedes arthritis

• Bilateral disease in 70-80%

• Highest risk within 4 years of onset

Onset of Uveitis in JIA

Saurenmann RK et al. Arthritis Rheum. 2007.

% of patientswith JIA

% of patientswith uveitis

age at diagnosis in years

0

2

4

6

8

10

14

12

16

0

5

30

25

20

15

10

35

45

40

50

0 2 4 6 8 10 1412 161 3 5 7 9 11 1513 17

142 of 1,081 (13%)developed uveitis

Onset of Uveitis in JIA

Saurenmann RK et al. Arthritis Rheum. 2007.

% of patients

-4 40 8-2 62 10

0.05

0.10

0.15

0.20

0.25

0.30

0.35

75% of uveitis diagnosed

within 3 years of arthritis

years since arthritis diagnosis

Onset of Uveitis in JIA

Saurenmann RK et al. Arthritis Rheum. 2007.

% of patients

-4 40 8-2 62 10

0.05

0.10

0.15

0.20

0.25

0.30

0.35

years since arthritis diagnosis

12.7% of uveitisdiagnosed before arthritis

Risk Factors for Uveitis in JIA

Saurenmann RK et al. Arthritis Rheum. 2007.

Saurenmann RK et al. Arthritis Rheum. 2010.

• Age <6 years at diagnosis of JIA

• Female

• ANA positivity

• RF negativity

• JIA subgroup

• Female

• JIA subgroup

Screening Guidelines in JRA

Cassidy J et al. Pediatrics. 2006.

Risk Characteristics Screening

Age ≤6 years at onset of arthritis

≤4 years duration

ANA positive

Age >6 years at onset of arthritis or

>4 years duration or

ANA negative

>1 ‘moderate’ risk or

>7 years duration or

Every 6 months

Every 12 months

Every 3 monthsHigh

Moderate

Low

Age ≤6 years at onset of arthritis

≤4 years duration

ANA positive

Every 3 months

Age >6 years at onset of arthritis or

>4 years duration or

ANA negative

Every 6 months

Systemic disease

Complications of Paediatric Uveitis

Macular edema Glaucoma

Retinal Vasculitis / Detachment

Paediatric JIA: Ocular Complications

Saurenmann RK et al. Arthritis Rheum. 2007.

• of uveitis patients ≥1 complication

23% cataracts

22% synechiae

37%

• No difference based on year of diagnosis

16% glaucoma

14% band keratopathy

5% macular edema

JIA – a Diagnosis of Exclusion

Oligoarticular

• Infection– Septic arthritis, osteomyelitis;

Lyme

• Malignancy– Ewing’s, sarcoma, leukemia,

lymphoma

• Trauma

• Vascular malformation

• Orthopedic

Polyarticular

• Malignancy– Leukemia, lymphoma

• Infection– Systemic, localized

• Autoimmune– SLE, scleroderma, vasculitis

• Metabolic-genetic– Collagen mutations, bone

dysplasias, hypermobility syndromes

Management

Goals of treatment:

• Reduce inflammation

• Reduce pain

• Preserve range of motion and strength

• Allow for normal growth and development

• Do no harm

Team Approach

• Rheumatology specialist nurse

• Rehabilitation – PT/OT

• Podiatry/Orthotics

• Ophthalmology

• Mental Health

• Dental

• Orthopaedic

• Others…

• Transitional care

Medication Adherence

Ringold et al J Rheumatol 2013; 40: 80-86

• NSAIDs– Naproxen, indomethacin

• DMARDs– Methotrexate, sulfasalazine, leflunomide

• Corticosteroids

– Intra-articular, oral, IV

• DMARDs– Methotrexate

• Biologics– Anti-TNF agents (etanercept, infliximab, adalimumab)

– Anti-cell surface markers (rituximab, abatacept)

– Anti-IL-1 (anakinra) and anti IL-6 (tocilizumab)

Treatment - Then and Now

Joint injections

Methotrexate

Administration

• 15 mg/m2

• Weekly

• Oral or subcutaneous

• Folic acid

• Varicella vaccination before

Toxicity and Monitoring

• FBE, LFTs 3 monthly

• Mouth ulcers

• Nausea

• Headache, “foggy”

• Infection

Methotrexate

• Efficacy

– 72% of patients with JIA respond to methotrexate

– 60% of patients flare on stopping methotrexate

Joint damage, without biologics

Solari et al A C and R 2008

Treatment - Then and Now

• NSAIDs– Naproxen, indomethacin

• DMARDs– Methotrexate, sulfasalazine, leflunomide

• Corticosteroids

– Intra-articular, oral, IV

• DMARDs– Methotrexate

• Biologics– Anti-TNF agents (etanercept, infliximab, adalimumab)

– Anti-cell surface markers (rituximab)

– Anti-IL-1 (anakinra) and anti IL-6 (tocilizumab)

Biologics

Biologic therapy

Administration

• Weekly, bi-weekly or monthly subcut

or Q4-8weekly IV

• At home or inpatient

• If IV may need pre-treatment

• Varicella vaccination before

Toxicity and Monitoring

• FBE, LFTs

• Injection site reactions

• Infusion reactions

• Infection– PPD mandatory

• MS-like reaction

• Other immune-related illnesses

• ?? malignancy

Immunisations

• Killed vaccines are safe to administer

• All patients should have an annual flu shot

• Immunize against varicella PRIOR to starting MTX or biologics

Role of the General Pediatrician

• Monitor growth

• Nutrition

• Bone health

• Immunization

• Adherence

• Coordinate care

Outcomes for kids with JIA

Prognosis

• QOL studies - significant impact even in ‘mild’disease

• Oligo JIA – persistent disease 40-50%

• Poly JIA and sJIA – persistent disease 50-70%

• 30-40% long term disability (incl unemployment)

• NB: most long term follow-up studies are from pre current therapeutic approach

• Delay in referral and initiation of therapy is associated with poorer outcome.

• Sequelae of treatment – unknown…

… beware JIA mimics

JIA – a Diagnosis of Exclusion...

Limp

Septic Arthritis

Osteomyelitis

Transient synovitis

Reactive arthritis

ViralInflammatory

• JIA

• IBD

• SLE

• Vasculitis (HSP, KD)

• Periodic fever

• Haemarthrosis

• Drug induced

Malignancy

Leukaemia

Solid tumours

Neuroblastoma

Mechanical

Trauma

AVN

SUFE

Toddlers #

Foreign body

NAI

Inflammatory

Infection

Neoplastic

Mechanical

Case 1 – AM

• 2 yr boy previously well, IUTD

• Acute onset R knee swelling and limp

• Otherwise well, no fever

• No trauma

• URTI few days prior

• On examination:– Afebrile

– R Knee – effusion, LOM, mildly warm and tender

– weight bearing with limp

– No other joints involved

AM

• Seen by Ortho

• Aspiration blood

• arthroscopy haemarthrosis

– Biopsy = chronic synovitis

• Bloods– FBE Hb 116 WCC 6.7 (Neut 3.02 Lymph 2.61) plt 316

– CRP and ESR normal

– clotting studies - normal

Progress

• Frequent painful episodes of swelling R knee

– Suprapatellar

– Duration 30 min

– Triggered by being carried with hip/knee flexed

• Referred to Rheumatology

• Further Examination:

– mass medial suprapatellar pouch

– no wasting or leg length difference

– full ROM

– MSK examination otherwise normal

• Imaging – US and MRI

Arterio-venous Malformation

Limp

Infection

Septic Arthritis

Osteomyelitis

Transient synovitis

Reactive arthritis

Viral

• JIA

• IBD

• SLE

• Vasculitis (HSP, KD)

• Periodic fever

• Haemarthrosis

• Drug induced

Malignancy

Leukaemia

Solid tumours

Neuroblastoma

Mechanical

Trauma

AVN

SUFE

Toddlers #

Foreign body

NAI

Inflammatory

Case 2 - JB

• 14 yo boy

• Previously well

• Greek and Cypriot background

• 1 year ago on holiday in Greece

• 3 discrete episodes of monoarthritis each 2 weeks apart (knee, ankle, wrist)

• No preceding illness.

• Associated fever

• Total duration of each episode 24 hours.

JB

• Well next 9 months.

• Now presents with further episode (wrist)

– Same features as previous

• On review

– Well

– Mild synovitis R wrist (mostly resolved)

– Rash

– Murmur

• Harsh, pansystolic, loudest at apex, radiates axilla and back.

• No cardiac failure

JB

• Differential diagnosis

– Acute Rheumatic fever

– Periodic fever Syndrome

• how to explain murmur and rash?

• Ix

– Inflammatory markers – ESR 22, CRP 16

– Echo – MR

– ECG

– ASOT >500, antiDNAseB >2000

Limp

Septic Arthritis

Osteomyelitis

Transient synovitis

Reactive arthritis

(incl ARF)

Viral Inflammatory

• JIA

• IBD

• SLE

• Vasculitis (HSP, KD)

• Periodic fever

• Haemarthrosis

• Drug induced

Malignancy

Leukaemia

Solid tumours

Neuroblastoma

Mechanical

Trauma

AVN

SUFE

Toddlers #

Foreign body

NAI

Infection

Limp

Septic Arthritis

Osteomyelitis

Transient synovitis

Reactive arthritis

ViralInflammatory

• JIA

• IBD

• SLE

• Vasculitis (HSP, KD)

• Periodic fever

• Haemarthrosis

• Drug induced

Leukaemia

Solid tumours

Neuroblastoma

Mechanical

Trauma

AVN

SUFE

Toddlers #

Foreign body

NAI

Neoplastic

Case 3 - KL

• 14yo girl

• Previously well

• R hip pain

– Past 2 weeks constant throughout day

– Intermittent in month prior

– Anterior

– Early morning stiffness

– Wakes at night

• R knee pain intermittently

• 4 lbs weight loss

• Otherwise systems review unremarkable

KL

• Background

– Born in Canada

– Travel to UK in 2009

– No sick contacts

• On examination

– Significant stress pain and LOM (IR and flex)

– Positive Trendelenberg R side

– MSK otherwise normal

– Systems unremarkable

Sept

Oct

Nov Idiopathic adolescent AVN

Limp

Infection

Septic Arthritis

Osteomyelitis

Transient synovitis

Reactive arthritis

Viral Inflammatory

• JIA

• IBD

• SLE

• Vasculitis (HSP, KD)

• Periodic fever

• Haemarthrosis

• Drug induced

Malignancy

Leukaemia

Solid tumours

Neuroblastoma

Trauma

AVN

SUFE

Toddlers #

Foreign body

NAI

Mechanical

Arthritis in Systemic Rheumatic disease….

SLE

JDM

Periodic fever syndromes

Systemic Scleroderma andMixed Connective Tissue Disease

Morphoea

Summary

Objectives

Diagnosis of JIA

Treatment approach

JIA mimics and cause of limp

Reviewed

Diagnosis of JIAEpidemiologySubtypesRed flags

Treatment approachIntra-articular corticosteroidsMethotrexateBiologicsIssues for the paediatrician

Approach to child with a limp

Resources available

• Ask your local Rheumatologist!!

• Literature:

– Review of JIA in Pediatric Clinics of North America, Paed

Rheum addition 2013

• RCH website www.rch.org.au/rheumatology

• NHMRC GP Juvenile Arthritis guidelines

• Arthritis Australia

• Paediatric Rheumatology European Society

www.printo.it/pediatric-rheumatology/

Thank you