Update on Arthritis in

Kids and Adults:

JIA, RA and OA
Barbara E. Ostrov, MD
Professor of Pediatrics and Medicine
Pediatric Rheumatology and Rheumatology
The Milton S. Hershey Medical Center

September 2017
Disclosures
• I have no actual or potential conflict of interest
in relation to this program/presentation.
• I will be discussing “off-label” uses of biologic
medications and will identify these instances
during the talk.
• All patient photos are from published literature
and/or ACR slide collections to be used for
educational purposes
 Case
• 1987: 6 yo with insidious onset polyarthritis
– 2-3 months of pain, 2 hrs am stiffness, and swelling
– Exam:
• Stiff neck, swollen wrists, MCP, PIP
• Swollen knees, stiff hips
• No rash, nodules
– Labs:
• ESR high, mild anemia
• + RF
– Treatment:
• SSZ, NSAID, then MTX,
oral corticosteroids
 Learning Objectives:
• You will:
– Understand the epidemiology of JIA, RA, OA
– Identify unique features of JIA versus RA
– Know clinical signs, and laboratory &
radiographic aspects of JIA, RA and OA
– Know differences in treatment of OA and
inflammatory arthritis
– Be aware of outcomes of JIA, RA and OA
Epidemiology: Who gets arthritis?
• > 80 different musculoskeletal disorders
• 40 million people have some type of arthritis
– 2/3 or 26 million are females
• Rheumatoid arthritis (RA) in 1% US population
– (3-4 million) aged 20-65
• 75-80% in females
• Juvenile Idiopathic Arthritis (JIA) in > 300,000 children in US
under 16 yo
• 70-80% in females
• Osteoarthritis (OA) in ~ 70-80% of 75 yo
• 75% in women (15 million people)
• Annual cost to US economy > $80 billion
– Meds, physicians visits, OT/PT, hospitalizations, surgeries
Considerations in Diagnosing and
Treating Arthritis
• Disease related
• variable presentation and course
• extra-articular complications
• response to treatment
• Treatment and Medication related
– Adherence to advice, PT, meds
– Tolerance and laboratory/side effect monitoring
• Health maintenance
– Nutrition/growth/pregnancy issues
– Vaccinations and risks of infections
– Malignancy risk from diseases or treatment
• Outcome and prognosis
Inflammatory Arthritis
• JIA • Crystalline
– 6 subtypes – Gout, pseudogout
• RA • Connective tissue
– RF+ versus RF- disease
• Spondyloarthropathy – SLE, MCTD, others
– Ankylosing spondylitis, • Infectious/ Post-
IBD related infectious
– Reactive – Lyme related
• Psoriatic arthritis
– 5 subtypes
Risks of Inflammatory Arthritis
• Genetic influences
– + family history in ~ 20-30 %
– Human leukocyte antigen (HLA) association
– + HLA DR4 = severe disease in RA and JIA
• Current theories of disease
– “Trigger” starts the inflammatory cascade
• Viral >>> bacterial
• Damaged collagen proteins
– Inflammatory cascade
• Prolongs and increases the inflammation
• Causes erosions of joints and inflammation of organs
– Systemic signs: fever, fatigue, weight loss
General features of RA
– Onset – subacute to chronic - over wks to mos
– Severity is variable
• Moderate swelling, stiffness, pain
• Moderate in 70-80%
• 10% mild, 10-20% severe
– Formation of erosions at joint margins
• develops during the first 3-12 months from onset
– Joint deterioration takes months to years
– Systemic symptoms/complications in > 25%
 PIP joint inflammation

Rheumatoid nodules

Inflammation and
subluxation of MCP joints
 RA of Hands Deformities:

Swan neck = MCP pulling

Boutonierre = PIP slipping

Muscle atrophy due to

inflammation causing nerve
compression at the wrist
(carpal tunnel syndrome)

https://www.youtube.com/watch?v=d6P0MCjz9T4
 RA Pathology

Normal synovium Inflamed RA synovium

RA inflammation of synovium

PANNUS fronds - appearance seen through

an arthroscope and under a microscope
 JIA Classification
• Oligo JIA (< 4 joints)
– Persistent
– Extended – more than 4
joints after initial 6 mos
• Poly JIA (> 5 joints)
– RF +
– RF -
• Systemic JIA
– Quotidian fever > 2 wks
– Rash, adenopathy, HSM,
serositis;
– > 1 joint
• Psoriatic arthritis
– Arthritis and 2 of 3:
• Dactylitis
• Nail changes
• + Family Hx psoriasis
• Enthesitis related
– Arthritis &/or enthesitis + 2
of:
• SI tenderness
• HLA B 27+
• Acute anterior uveitis
• Onset after 8 yo in a M
• + FHx of HLA B27 dx
• Undifferentiated JIA
– Not meeting these criteria or
meet criteria from >1 category
JIA – Oligoarticular Subtype
< 4 joints, uveitis in 30-40%
• girls < 7 yo, ANA + 60%
– Knees, Ankles, Wrists, Elbows
» ~ 30% remit
» 30% evolve to polyarticular
– 30-40% chronic uveitis
» ~ 5-10% eye disease onset
before arthritis
» Young F < 7 yo with +ANA =
high risk
– Late risks: vision loss; leg length
discrepancy; polyarthrititis
JIA – Polyarticular Subtype
> 5 joints; greatest risk to joints
• RF -
o girls > boys, any age
o ANA + 50%; uveitis risk
o 25-30% remit by teens
• RF +
o girls >> boys, age > 10
o ANA + 25%;
o most similar to RA
o worse prognosis
o Pre-1998 outcome data
• 50% total joint replacements by adulthood
Poly and Systemic JIA – Late Risks
• Corticosteroid use:
– Complications of mod to hi dose use
• Systemic JIA with polyarthritis
• Erosive disease
– Similar to RA
Moodiness, anxiety
Sleep disturbance Corticosteroid
Face: Moon facies, acne
Osteoporosis
Toxicity
Hypertension
Buffalo hump
Obesity
Endocrine: adrenal
insufficiency, growth delay
Thin, fragile skin
Striae
Oligomenorrhea
Muscle weakness
AVN
Traumatic purpura
Poor wound healing
 Poly JIA – Late Risks

• Micrognathia
– TMJ erosions
• Cervical spine
– Fusion
– Subluxation
• Hip involvement
– Erosions
– Predicts disability
 TMJ Involvement
• Most frequently used joint –
2000 x a day
• Unusual synovial joint:
o Mandible growth plate under
condyle head
o Inflammation alters mandible
growth
• All subtypes, > poly/systemic
• Silent involvement in 2/3
o Clenching, fatiguing, HA,
asymmetric opening, neck ache Pediatric Rheumatology 2009, 7:11
Definitions: Osteoarthritis
• Terminology:
– Osteoarthritis, osteoarthrosis = OA
– Degenerative joint disease = DJD
– Degenerative arthritis
• General features:
– Develops very slowly
– Minimal inflammation or swelling
– Does not produce systemic manifestations
– Gradual deterioration of cartilage
– Osteophytes form slowly, over years
Risk Factors for OA
• Primary OA
– Female
– Caucasian
– Obesity (2 X risk for overweight F)
– Genetics
• Secondary OA
– Mechanical forces: scoliosis, congenital deformity
– Metabolic, endocrine disorders
– Prior trauma
– Prior RA and JIA or other inflammatory processes
Genetics and OA
• Women 10 x more risk
• Influence of multiple genetic factors
– Especially in hand OA
• Cartilage defects:
– Cartilage = collagen + mucopolysaccharides
– Collagen gene defects cause premature OA
– Example: mutations in gene for type II procollagen
» Collagen fragility
» Premature onset OA
OA vs RA vs JIA Differences
• Differences between OA and RA and JIA
– Characteristic age of onset
– Features of arthritis: distribution, subtypes
– Risk of complications differs
– Pathologic microscopic differences are distinct
– Radiographic appearance distinct
– Risks and types of complications
 • RA
OA vs RA/JIA
• OA
– Who?
• Onset after 40 yo • JIA
• 40% of 40 yo
• 80% of 80 yo
• F > M - - ratio: 2-3:1
– Why?
• Genetics, trauma, prior
inflammation, obesity,
metabolic disorders,
abnormal joint
mechanics
– Who?
• Onset after 18 yo
• 1 % of the US
• 100, 000 new cases/year
• F > M - - ratio: 4-5 : 1
– Who?
– Onset < 16 yo
– > 300,000 in US
– F>> M, varies with subtype
– Why?
• Genetic risk factors
• unknown trigger(s)
• Inflammatory cascade
worsens disease over time
 OA vs RA: What happens clinically?
• OA • JIA/RA
– symptoms
• Joint pain in a few
locations
• am stiffness < 1/2 hour
• swelling mild
– no systemic problems
directly due to OA
• no rash, fevers, systemic
signs
• pain causes symptoms
• osteophytes cause pain
– symptoms
• Often widespread joint
involvement and pain
• am stiffness > 1-2 hours
• swelling mild to severe
– systemic illness
• fevers, weight loss
• muscle atrophy
• internal organ problems 25%
– Eyes up to 25% or more
– Skin: rash, nodules, vasculitis
– Lungs, heart, nodes
 OA vs RA: Localization?
• OA • JIA/RA
– some common areas – almost any joint
– In some, OA only after: – joints involved
• injury • hands
• Knees, hips
• inflammation
• TMJ
– joints typically involved
• cervical spine
• hands
• Feet, ankles
• knees
• shoulders; elbows
• hips
– spared:
• entire spine
• DIP, mid-lower spine
• feet
 OA RA/JIA
Spine:
cervical,
lumbar

Hands:
base of
thumb,
PIP, DIP

Hips
Knees
Big toe
 Severe OA of hands

Lateral Medial

DIP = Heberden’s nodes PIP = Bouchard’s nodes

Medial right knee OA

= varus deformity
 DJD in a finger joint
cartilage damage
(eburnation on xray)

Osteophyte

OA - microscopic
Minimal inflammation
of synovium
 Normal finger joint

Normal cartilage

Normal
capsule, synovium
Comparison of Knees
• OA
– Stiffness, decreased motion
– Brief am stiffness < ½ hr
– Bowlegged (varus) or knock-
kneed (valgus) deformities
– crepitus (cracking) with motion
– Pain with patella motion
– Occasionally some swelling
– Pain with use, at rest, at night
• JIA/RA
– Stiffness, limited motion
– Warmth, swelling, and
pain with motion
– Often severe am stiffness
for > 1-2 hours
– Pain less at night,
improves mid-day and
worse again in evening
OA:
Moderate medial compartment RA:
right knee varus deformity Left knee swelling,
Right knee replaced

medial

lateral
 OA:
asymmetrical narrowing

NORMAL
KNEE

JIA/RA:
Symmetrical
narrowing
Rheumatic Disease Rx Goals
• Immediate:
o Relieve pain
o Control inflammation
• Long-term:
o Preserve function
o Prevent deformity
o Manage extra-articular disease
o Minimize side effects of treatment
o Promote normal growth and development
Rheumatology Drugs: Historical Perspective
1987 2017
NSAIDs NSAIDs/Cox2 Inhibitors
Anti-malarials Sulfasalazine
Sulfasalazine Methotrexate
D-penicillamine Leflunomide
Glucocorticoids Anti-malarials
Gold Corticosteroids
Methotrexate Cyclosporine
Cyclosporine
Biologics
•Etanercept •Tocilizumab
•Infliximab •Rituximab
•Adalimumab •Rilonacept
•Abatacept •Canakinumab
•Anakinra •Belimumab
•Certolizumab •Golimumab
•Tofacitinib
Approach to the Rx of OA
• Analgesics
• NSAIDs – non-steroidal anti-inflammatory
drugs
– low dose, high dose
– selective COX-2
• Corticosteroid injections
• Glucosamine sulfate
• Exercise, exercise, exercise
2012 ACR Recs for OA Rx
• Recommend:
• Analgesia: acetaminophen, oral NSAIDs, tramadol
• Intra-articular corticosteroid injections
• Do not recommend:
• Chondroitin sulfate and/or Glucosamine
• Have no position on use:
• Topical NSAIDs
• Intra-articular hyaluronate injections
• Duloxetine or opioid analgesics

Arthritis Care & Research 2012; 64:465–474

OA Treatment
• Acetaminophen
 1st choice
 Better than placebo
 Recommended as 1st line Rx
 Can combine with low dose NSAIDs
 Maximum dose < 3000 mg a day
• Exercise
– Thigh weakness increases knee arthritis sx
– BUT ?? increase OA in older athletes due to repeat use
• 2-3 X increase x-ray OA knees/hips in long term female athletes
• BUT no increase symptoms
• Recommendations:
• ROM, strength, aerobic, wt bearing, isometric, aquatics
2017 AHRQ Summary Recs
Improved Improved
Benefit Pain Function
Weight loss – medium term/long term  
Home based therapy – short/medium term  
TENS use – short/medium term  
Tai Chi – short/medium term  
General exercise – medium/long term  
Agility training – short/long term  
Self-help skills train – short/medium term  

AHRQ, Dept HHS, May 2017; www.ahrq.gov

2012 ACR Non-drug Rx for Knee OA
• Strongly recommend for knee OA:
–Aerobic, resistance land-based and/or Aquatic exercise
–Weight loss, when appropriate
• Recommend for knee OA:
–Participate in self-management programs
–Manual therapy in combo with supervised exercise
–Psychosocial interventions
–Use medially directed patellar taping and/or wedged insoles
–Consider CAMS: heat, acupuncture, Tai Chi, TENS
•No definitive recommendations on:
–Participation in balance exercises or manual therapy alone
–Wearing knee braces or lateral patellar taping
Arthritis Care & Research 2012; 64:465–474
Alternative OA Rx - Diet
• Pts very interested in these Rx
• Nutraceuticals
– Anti-inflammatory similar to NSAIDs
• Fish oil - Omega 3 fatty acids
• Plant oils - Omega 6 fatty acids
» Ref: J Rheum 2002; 29:1708
– Supplements
• Glucosamine sulfate
» Ref: Arch Intern Med, 2002; 162:2113
» AHRQ May 2017 Recommendation for short term
benefit
 Intra-articular Injections
• JIA - Intra-articular Steroids
– Safe and effective, prevents leg length discrepancy
– Triamcinolone hexacentonide has longest lasting
results Cleary, Arch Dis Child; 2003; 88:192
• RA/OA - Intra-articular Steroids
– Flares - acute pain/swelling
• R/O infection, injury, crystals
• OA - Intra-articular
viscosupplementation

Pascal Richette et al. RMD Open 2015;1:e000071

NSAIDs
• Anti-inflammatory and analgesic benefits
– COX II selective NSAIDs
– May be safer – in older OA population
• and in people with bleeding disorders
• Side effects of NSAIDs
– GI complications: 40% clinical, 75% on EGD
– Renal failure, high blood pressure
– Edema, rash
– Cardiovascular concerns in older and at-risk pts
 Tissue

NSAIDS Phospholipids

Arachadonic Acid
 First line Rx for
JIA, RA, OA
Cyclo-oxygenase
 naproxen, Stimulated by
Endotoxins,
cytokines
ibuprofen, choline COX 1 COX 2
magnesium
trisalicylate, Pathologic
Physiologic (inducible)
indomethacin (constitutive) Prostaglandins
available as liquid Prostaglandins Sites of inflammation
Central mediator of
GI protection Some pain, fever
Renal blood flow physiologic role
Platelet aggregation Brain, kidney, ovary/uterus,
bone/cartilage, healing PUD
COX-2 inhibitors: summary
 Risk greatest in adults w/ CAD or > 65 yo
o Long term (> 18 mos) and hi dose use mainly
 Thought to be safe in children
o No reports of thrombotic events in children
 Special niche in pts with GI intolerance, bleeding
risk factors
 Important lesson:
o need for caution with newer agents and unexpected
adverse side effects
Case: Age 18 “RA”
• 1999: age 18
o Continued with inflammatory arthritis
o Joint damage in hips, knees, cervical spine
o Failed MTX, NSAID, low to mod dose steroids
o OT/PT, splinting, wheelchair for distance
• Biologic Rx options:
o Infliximab for RA
o Etanercept for RA, JIA
Rheumatology Drugs: Historical Perspective
1987 2017
NSAIDs NSAIDs/Cox2 Inhibitors
Anti-malarials Sulfasalazine
Sulfasalazine Methotrexate
D-penicillamine Leflunomide
Glucocorticoids Anti-malarials
Gold Corticosteroids
Methotrexate Cyclosporine
Cyclosporine
Biologics
•Etanercept •Tocilizumab
•Infliximab •Rituximab
•Adalimumab •Rilonacept
•Abatacept •Canakinumab
•Anakinra •Belimumab
•Certolizumab •Golimumab
•Tofacitinib
Methotrexate
• Mechanism:
– Folic acid analogue
• competitive inhibitor of dihydrofolate reductase
– May inhibit thymidylate synthase =  synthesis of DNA
• Inhibits purine biosynthetic
• Secondary inhibition of adenosine deaminase
– leads to  release of adenosine
– potent inhibitor of neutrophil adherence
• Mechanism of MTX in arthritis thought to be due to anti-
inflammatory effects of  adenosine
• Must allow 4-8 weeks for clinical effect
Response to Methotrexate
• Varying response to MTX in different JIA subtypes
o Oligo > poly >> systemic
o RA and JIA overall:
 Up to 60% respond and/or remission with MTX

60

50

40
percent

30

20

10

0
none partial moderate remission

response rate

systemic poly oligo

Cytokine Networks in RA/JIA
Biologic Approaches to Rx
• Based on pathogenesis
• “Designer Drugs” based on immunologic
mechanisms
o Targets key pro-inflammatory cytokines
 TNF, IL-1, IL-6
• Produced by macrophages, T-lymphocytes, fibroblasts
• Elevated levels may be identified in synovial tissue
o Target cellular mechanisms
 T cell co-stimulatory actions
 B cell activation and Ab production
 Small molecules in cytokine production paths
Timeline of
Biologics
1998
BIOLOGIC ERA
Lead-in to the begins for
BIOLOGIC ERA Rheumatology
Vaccines (mid-
to-late 1800s)

Hybridomas
and Mabs
• 1975
O’Shea. 2014.
Cell 157:227
 Etanercept

% RA pts improved
60

50

• FDA approved for RA in 1998, JIA 40

in 1999 30

20
• Recent approval for psoriasis, AS, 10

psoriatic arthritis 0
3 12 24 36

• Results: ACR50 ACR70

months

– Controls disease well in 80% JIA and 90

> 50% RA

% JIA improved
80
70

– Better when combined with MTX 60

50

– Prevents erosive disease 40

30

• May heal erosions already present 20

10
0

7 mos 1 yr 2 yr
JRA50 JRA7
0
Etanercept
• Radiographic studies after 1 yr of treatment
o Prevents erosive disease in RA
– May heal erosions already present
– Best results when combined with MTX
Infliximab
• Not FDA approved for JIA
o Approved for RA, IBD, AS, psoriatic arthritis
• Infusions may have more short term side
effects than other anti-TNF agents
o Infusion rxns, infections
80
70
60
% improvement

50
40
30
20
10
0
0 0.5 1 1.5 2
years

MTX MTX + Infliximab q 8 wks

Concerns about Biologic Rx

Laboratory
interference

MTB
Cost

Patient preferences

IBD: What drugs in what patients? Hanauer; 2016; Medical Director, Digestive Health Center Northwestern
Biologics: Additional Concerns
• Monitoring:
o TB screening before instituting – annual recheck TB screen
u PPD, interferon-gamma release assays
o Infection assessment, Rx, prevention
u VZ, bacterial, fungal; prevention is key
o Labs:
u CBC, LFTs 2 X a year; Lipid profile for tocilizumab
• SQ teaching
• Vaccination:
o Hold drug in stable pt for 1-2 doses if must vaccinate
n No live virus vaccines
n No vaccines for ~ 1 month after anti-B cell therapies
Biologics: Additional Concerns
• Pregnancy – no clear data; probably safe
o Small # of VATER cases reported in 2006-7; none since
• Monitor for rare possible side effects:
o Demyelinating neurologic
o Aplastic anemia
o Hepatitis
– IBD pts on infliximab
– Rarely in others
o Drug-induced lupus
– + ANA after anti-TNF Rx reported
– Particularly with infliximab – common anti-ds-DNA ab
 Biologics and Cancer Risk
• Pediatric risk warning: October 2009 FDA
o Malignancies in JIA (15) and IBD (25)
 Majority had prior immunosuppressant use
o # of malignancies with anti-TNF concerned FDA
• JIA: National Medicaid claims 2000-05 for 7300 pts
o Rate of cancer in JIA higher than ADHD and Asthma
 Similar to RA and Psoriatic arthritis
o 1413 exposed to anti-TNFs; ZERO malignancies after Rx
• RA - Increased risk lymphoma due to RA itself
 No increase following anti-TNF, biologics
o Possible increase recurrence melanoma, skin ca.
o Challenging decision making in prior ca. population

Kay, EULAR 2012; Biologics and Cancer Risk in RA: A Treatment Guide
Concern: Patient Preference
• Toxicity anxiety?
• Mode: SQ, IV, PO ?
• Pain on admin SQ or IV?
• Cost? Insurance?
• Preference for infusion site?
– Home or infusion center?
– Multispecialty vs single?
Concern: Patient Preference
Adalimumab 10
9
8
+/- Lidocaine
Pain scale
7
6
5
value before
4
3 after
2
1
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Patient Number

Infusion Preference
1. Content in multispecialty
2. Content with PSCH Infusion Center multispecialty
3. Prefer multispecialty

Ayala, ACR 2011

Ostrov, Patient Pref Adher 2014:8 755
Scalzi, PRSYM 2017
Case: JIA to “RA” to 2 OA
• By age 20, severe end stage secondary OA in
hips and knees
– Knees then hips replaced by age 25
Surgery in JIA, RA and OA Pts
• Joint replacements
– What are the reasons?
• Severe pain
• Trouble functioning with the damaged joint
• Disability due to severe joint damage
• Who can have joint replacements?
• Generally healthy individuals
• Medical screening required
– Complications:
• in < 10% of patients
• infection, blood clots, loosening of new joint
 Joint Replacement Surgery
• 1.5 % of US have TKR
• 0.8 % have THR
• F are 2X > M to have TKR
• Age factor:
> 50 year old:
• 2.3% THR vs 4.6% TKR
80 year old:
• 6 % THR vs 10 % TKR
• OA most common in US
• JIA and RA also common but less with improved
medical treatment
Sorting it all out
• NSAIDs – limit trial duration
• Intra-articular injections
• Low dose, short term steroids
• DMARDs – especially MTX
• OT/PT, weight control, health advice
• Biologic agents for RA, JIA
o usually combined with MTX
o Careful monitoring for infections, other
health concerns
o Monitor xrays, joint damage, complications
o Maintain maximal Quality of life
Conclusions
• JIA, RA and OA are different diseases with varying
Common diagnoses but with varying therapies
• Treatments need to be focused on the pathophysiology
and immunology
• pathology but overlapping symptoms
• Inadequately treated or poorly responsive JIA and RA
will develop 2 OA in the long-term
• Patients need your expertise in managing pain,
dysfunction and potential disability

• QUESTIONS?