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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