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Juvenile Rheumatoid ArthritisJuvenile Rheumatoid Arthritis

Arthritis Advisory Committee MeetingArthritis Advisory Committee Meeting

Division of Anesthesia, Analgesia and Division of Anesthesia, Analgesia and Rheumatology ProductsRheumatology Products

November 29, 2006November 29, 2006

Carolyn L. Yancey, MDCarolyn L. Yancey, MDMedical Officer, DAARP Medical Officer, DAARP

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AGENDAAGENDAJuvenile Rheumatoid ArthritisJuvenile Rheumatoid Arthritis

Epidemiology, Pathogenesis and EtiologyEpidemiology, Pathogenesis and Etiology Classification of Juvenile Rheumatoid Classification of Juvenile Rheumatoid

ArthritisArthritis• American College of Rheumatology (ACR) American College of Rheumatology (ACR)

CriteriaCriteria Clinical ManifestationsClinical Manifestations Disease Course and PrognosisDisease Course and Prognosis Treatment of JRA and the State-of-the-Art Treatment of JRA and the State-of-the-Art

Treatment ArmamentariumTreatment Armamentarium

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BACKGROUNDBACKGROUND

Chronic Arthritis in Childhood Chronic Arthritis in Childhood characterized as characterized as

Juvenile Rheumatoid ArthritisJuvenile Rheumatoid Arthritis

JRA JRA

Age of onset < 16 years of age.Age of onset < 16 years of age.

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BACKGROUNDBACKGROUND

EpidemiologyEpidemiology• Overall prevalenceOverall prevalence of juvenile rheumatoid of juvenile rheumatoid

arthritis is estimated to be from 30 - 150 per arthritis is estimated to be from 30 - 150 per 100,000 children. 100,000 children.

• In the United States and Canada there are an In the United States and Canada there are an estimated 30,000 to 60,000 children and estimated 30,000 to 60,000 children and adolescents with juvenile rheumatoid arthritis.adolescents with juvenile rheumatoid arthritis.

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BACKGROUNDBACKGROUND Pathogenesis and Etiology of JRA: Multi-factorialPathogenesis and Etiology of JRA: Multi-factorial

• Genetic, Hormonal, ImmunologicGenetic, Hormonal, Immunologic• PathogenesisPathogenesis

Characterized by chronic inflammation of the Characterized by chronic inflammation of the synovium;synovium;

Presence of articular cartilage damage;Presence of articular cartilage damage; Accompanied by extra-articular systemic Accompanied by extra-articular systemic

manifestations. manifestations. • Heterogeneity of JRAHeterogeneity of JRA

At least 3 primary types of onset of JRA: At least 3 primary types of onset of JRA: • Pauciarticular (Oligoarticular) Pauciarticular (Oligoarticular) • Polyarticular and Polyarticular and • SystemicSystemic

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BACKGROUNDBACKGROUND Pathogenesis Pathogenesis (Continued)(Continued)

• GeneticGenetic Basis of immune distinction between self Basis of immune distinction between self

and non-self is the major histocompatibility and non-self is the major histocompatibility complex (MHC) that in humans is called the complex (MHC) that in humans is called the human leukocyte antigen (HLA). human leukocyte antigen (HLA).

HLA system comprises a family of HLA system comprises a family of polymorphic genes located on the short arm polymorphic genes located on the short arm of chromosome 6.of chromosome 6.

Polymorphisms of JRA suggest a non-Polymorphisms of JRA suggest a non-mendelian inheritance. mendelian inheritance.

• Hormonal FactorsHormonal Factors Differences in the sex ratio of JRA subtype Differences in the sex ratio of JRA subtype

onsetonset Pre-adolescent or post-adolescent peaksPre-adolescent or post-adolescent peaks

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BACKGROUNDBACKGROUND Immune MechanismsImmune Mechanisms

• Disease process involves loss of tolerance Disease process involves loss of tolerance towards auto-antigens towards auto-antigens chronic synovitis; chronic synovitis;

• Production of auto-antibodies:Production of auto-antibodies: Anti-nuclear antibodies (ANA): associated with Anti-nuclear antibodies (ANA): associated with

increased risk of iridocyclitis (eye increased risk of iridocyclitis (eye inflammation);inflammation);

Rheumatoid factors (RF): auto-antibodies Rheumatoid factors (RF): auto-antibodies directed against the Fc fragment of IgG directed against the Fc fragment of IgG (associated with ~10% of polyarticular JRA);(associated with ~10% of polyarticular JRA);

Complement activation by circulating immune Complement activation by circulating immune complexes may also contribute to the disease complexes may also contribute to the disease process.process.

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BACKGROUNDBACKGROUND Immune Mechanisms Immune Mechanisms (Continued)(Continued)

• CytokinesCytokines: act on the immune system and : act on the immune system and other cells to initiate and sustain inflammation:other cells to initiate and sustain inflammation:

• Intercellular mediators:Intercellular mediators: Interleukin-1 (IL- Interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha 1), IL-6, and tumor necrosis factor-alpha (TNF-(TNF-););

• Immunomodulatory cytokinesImmunomodulatory cytokines produced produced by T-cells by T-cells Interferon gamma (IFN- Interferon gamma (IFN-γγ), IL-), IL-4, IL-2.4, IL-2.

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CLASSIFICATION OF CLASSIFICATION OF JUVENILE RHEUMATOID ARTHRITISJUVENILE RHEUMATOID ARTHRITIS

American College of Rheumatology (ACR) American College of Rheumatology (ACR) pediatric criterion for juvenile pediatric criterion for juvenile rheumatoid arthritis was established in rheumatoid arthritis was established in 1977.1977.

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CLASSIFICATION OF JRACLASSIFICATION OF JRA ACR CriteriaACR Criteria

• Age at onset: < 16 years of age;Age at onset: < 16 years of age;• Arthritis - swelling or effusion or the presence of 2 Arthritis - swelling or effusion or the presence of 2

or more of the following signs: or more of the following signs: Limitation of range of motion, Limitation of range of motion, Tenderness or pain on motion andTenderness or pain on motion and Increased heat in one or more joints;Increased heat in one or more joints;

• Duration of disease Duration of disease >> 6 weeks; 6 weeks;

• Onset type is defined by the type of disease in the Onset type is defined by the type of disease in the first 6 months:first 6 months:

Oligoarticular (Pauciarticular)Oligoarticular (Pauciarticular) < 5 inflamed joints; < 5 inflamed joints; Polyarticular:Polyarticular: >> 5 inflamed joints; 5 inflamed joints; Systemic onset:Systemic onset: arthritis with characteristic fever. arthritis with characteristic fever.

• Exclusion of other forms of childhood arthritis.Exclusion of other forms of childhood arthritis.Modified from JT Cassidy, JT Levinson, RM Laxer, CB Lindsley. Textbook of Pediatric Rheum. 2005

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CLINICAL MANIFESTATIONS of JRACLINICAL MANIFESTATIONS of JRA

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Characteristic

% Cases (F:M)

# Joints

Age at onset

Systemic involvement

Chronic Uveitis

RF/ANA

Prognosis

Polyarticular

30 (3:1)

> 5

Thru childhood, peak 1-3 yr

Mild; unremitting

articular involvement

5%

10%/40-50%

Guarded to moderately

good

Pauciarticular

60 (5:1)

< 4

Early childhood, peak 1-2 yr

None; uveitis (++)

5-15%

Rare/75-85%

Excellent except for eyesight

Systemic

10 (1:1)

Variable

Thru childhood,

no peak

Systemic self-limited; chronic

destructive arthritis ~50%

Rare

Rare/10%

Moderate to poor

JRA by the Type-of-OnsetJRA by the Type-of-Onset

JT Cassidy, RE Petty, RM Laxer, CB Lindsley. Textbook of Pediatric Rheumatology, 2005

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Extra-Articular Manifestations of JRAExtra-Articular Manifestations of JRA

FeverRheumatoid rashRheumatoid nodulesHepatosplenomegalyLymphadenopathyChronic uveitisPericarditisPleuritisAbdominal pain

Polyarticular

30%2101055511

Pauciarticular

0%0000

20000

Systemic

100%955

85701

352010

JT Cassidy, RE Petty. Textbook of Pediatric Rheumatology, 2001

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PROGNOSIS OF JRAPROGNOSIS OF JRA Pauciarticular JRAPauciarticular JRA

• BoysBoys may be affected in older childhood or may be affected in older childhood or adolescence; this may represent an early adolescence; this may represent an early manifestation of a spondyloarthropathy.manifestation of a spondyloarthropathy.

• Leg length discrepancyLeg length discrepancy from asymmetric knee from asymmetric knee synovitis and bone growth may cause flexion synovitis and bone growth may cause flexion contractures, gait abnormalities and long-term contractures, gait abnormalities and long-term growth abnormalities.growth abnormalities.

• Eye involvementEye involvement as anterior uveitis, may lead as anterior uveitis, may lead to scarring or blindness in ~ 15-20% of to scarring or blindness in ~ 15-20% of children.children.

• Active arthritis into adulthoodActive arthritis into adulthood in 40% to 50% of in 40% to 50% of patients.patients.

• Radiographic joint damageRadiographic joint damage within 5 years. within 5 years.

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PROGNOSIS OF JRAPROGNOSIS OF JRA

Polyarticular JRA and Systemic JRAPolyarticular JRA and Systemic JRA• Active arthritis into adulthoodActive arthritis into adulthood: 50% to 70% of : 50% to 70% of

polyarticular or systemic onset JRA;polyarticular or systemic onset JRA;

• Long-term disabilitiesLong-term disabilities: 30% to 40% of children : 30% to 40% of children Unemployment: 25% to 50% of adult JRA Unemployment: 25% to 50% of adult JRA

patients; patients; May need major surgeryMay need major surgery (joint replacement).(joint replacement).

• Radiographic joint damageRadiographic joint damage within 2 years; within 2 years;

• Mortality rateMortality rate: 0.4% to 2% (greater risk with : 0.4% to 2% (greater risk with systemic JRA than with polyarticular JRA).systemic JRA than with polyarticular JRA).

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Traditional Approach to the Traditional Approach to the Treatment of JRA Treatment of JRA

Cytotoxic Drugs

Disease Modifying Anti-Rheumatic Drugs

(DMARDs)

Intra-Articular/Oral Corticosteroids

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Before the 1990s … Pyramid Approach

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Evolving Treatment of JRAEvolving Treatment of JRA

Paradigm shift….Paradigm shift….

The trend in managing JRA is much more The trend in managing JRA is much more aggressive treatment earlier in the disease course aggressive treatment earlier in the disease course with the goal of preventing joint damage and with the goal of preventing joint damage and slowing progressive articular damage.slowing progressive articular damage.

Since the 1990s and into the 2000s…

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Treatments with Indications for JRATreatments with Indications for JRA Non-Selective NSAIDsNon-Selective NSAIDs

• Aspirin, tolmetin sodium, ibuprofen, naproxenAspirin, tolmetin sodium, ibuprofen, naproxen• NaproxenNaproxen [Tablets and Suspension] [Tablets and Suspension]

Indicated for patients 2 years and older with Indicated for patients 2 years and older with juvenile arthritis.juvenile arthritis.

Daily dose: approximately 10 mg/kg/day as a Daily dose: approximately 10 mg/kg/day as a BID dose (5 mg/kg given twice-a-day). Total BID dose (5 mg/kg given twice-a-day). Total daily dose is not to exceed 15 mg/kg/day.daily dose is not to exceed 15 mg/kg/day.

Adverse events: gastrointestinal, central Adverse events: gastrointestinal, central nervous system (headache, dizziness, nervous system (headache, dizziness, drowsiness, vertigo), rash (ecchymoses, drowsiness, vertigo), rash (ecchymoses, purpura), pruritus, sweating, special senses purpura), pruritus, sweating, special senses (tinnitus, visual disturbances, hearing (tinnitus, visual disturbances, hearing disturbances), cardiovascular (edema, disturbances), cardiovascular (edema, palpitations) prolonged bleeding times.palpitations) prolonged bleeding times.

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Treatments with Indications for JRATreatments with Indications for JRA Non-Selective NSAIDs/COX-2 Selective InhibitorsNon-Selective NSAIDs/COX-2 Selective Inhibitors

• MOBIC (meloxicam) MOBIC (meloxicam) [Tablets and Suspension][Tablets and Suspension] Indicated for the relief of the signs and symptoms of Indicated for the relief of the signs and symptoms of

pauciarticular and polyarticular course JRA in patients pauciarticular and polyarticular course JRA in patients 2 yrs and older.2 yrs and older.

0.125 mg/kg once daily up to a maximum of 7.5 mg.0.125 mg/kg once daily up to a maximum of 7.5 mg. Adverse events: abdominal pain/upper, vomiting, Adverse events: abdominal pain/upper, vomiting,

diarrhea, headache, infection (rhinitis), cough, diarrhea, headache, infection (rhinitis), cough, pyrexia, rash. urticaria, slight increases in systolic pyrexia, rash. urticaria, slight increases in systolic blood pressure.blood pressure.

• VIOXX (rofecoxib)VIOXX (rofecoxib) [Tablets and Suspension] [Tablets and Suspension] Withdrawn from the global market September 2004. Withdrawn from the global market September 2004. Indicated for the relief of the signs and symptoms of Indicated for the relief of the signs and symptoms of

juvenile rheumatoid arthritis in patients 2 years and juvenile rheumatoid arthritis in patients 2 years and older.older.

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Treatment of JRATreatment of JRA CorticosteroidsCorticosteroids

• Used for uncontrolled or life-threatening Used for uncontrolled or life-threatening systemic disease; systemic disease;

• Treatment of chronic uveitis as local Treatment of chronic uveitis as local ophthalmic drops; orophthalmic drops; or

• Intra-articular agents (Pauci- and polyarticular Intra-articular agents (Pauci- and polyarticular JRA)JRA)

• Intermediate-acting corticosteroids: Intermediate-acting corticosteroids: Prednisone; methyl-prednisolone (Intravenous Prednisone; methyl-prednisolone (Intravenous pulse therapy for severely active JRA).pulse therapy for severely active JRA).

Prednisone low-dose as 0.1 to 0.2 mg/kg; Prednisone low-dose as 0.1 to 0.2 mg/kg; higher-dose 0.25 to 1.0 mg/kg/day higher-dose 0.25 to 1.0 mg/kg/day (maximum single dose 40 mg)(maximum single dose 40 mg)

Adverse events: hypertension, iatrogenic Adverse events: hypertension, iatrogenic Cushing’s syndrome, growth suppression, Cushing’s syndrome, growth suppression, fractures, cataracts, increased susceptibility fractures, cataracts, increased susceptibility to infection.to infection.

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Treatment of JRATreatment of JRA DMARDs and Biologic DMARDsDMARDs and Biologic DMARDs

• Methotrexate (MTX):Methotrexate (MTX): used when NSAIDs fail to used when NSAIDs fail to bring relief.bring relief.

Indicated for polyarticular JRA. MTX is the most Indicated for polyarticular JRA. MTX is the most widelywidely used DMARD for JRA treatment.used DMARD for JRA treatment.

Starting dose 7.5 mg/mStarting dose 7.5 mg/m2 2 per week; maximum per week; maximum dose of 15 mg/mdose of 15 mg/m22 per week. per week.

Methotrexate compared to leflunomide (Lef): Methotrexate compared to leflunomide (Lef): 240 JRA pts, 16-week DB + 6 mo Ext + 240 JRA pts, 16-week DB + 6 mo Ext + optional 30 mo Ext in JRA; JRA Definition of optional 30 mo Ext in JRA; JRA Definition of Improvement Improvement >> 30% (JRA DOI 30% (JRA DOI >> 30): 89% 30): 89% MTX compared to 68% Lef.MTX compared to 68% Lef.

Adverse events: stomatitis, leukopenia, Adverse events: stomatitis, leukopenia, nausea/ abdominal pain, gastrointestinal nausea/ abdominal pain, gastrointestinal bleeding, anorexia, malaise, fatigue, chills and bleeding, anorexia, malaise, fatigue, chills and fever, headache, alopecia, rash, decreased fever, headache, alopecia, rash, decreased resistance to infection, elevated hepatic resistance to infection, elevated hepatic enzymes.enzymes.

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Treatment of JRATreatment of JRA DMARDs and Biologic DMARDs DMARDs and Biologic DMARDs (Continued)(Continued)

• SulfasalazineSulfasalazine Indicated for polyarticular JRA who have Indicated for polyarticular JRA who have

responded inadequately to salicylates or other responded inadequately to salicylates or other non-steroidal anti-inflammatory drugs.non-steroidal anti-inflammatory drugs.

Children 6 yrs and older: 40 - 60 mg/kg/day Children 6 yrs and older: 40 - 60 mg/kg/day divided into 3 to 6 doses.divided into 3 to 6 doses.

Maintenance dose: 30 mg/kg/day divided into Maintenance dose: 30 mg/kg/day divided into 4 doses.4 doses.

Adverse events: anorexia, headache, Adverse events: anorexia, headache, vomiting, gastric distress, rash, urticaria, vomiting, gastric distress, rash, urticaria, hemolytic anemia.hemolytic anemia.

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Treatment in JRATreatment in JRA DMARDs and Biologic DMARDs DMARDs and Biologic DMARDs (Continued)(Continued)

• ENBREL (etanercept): ENBREL (etanercept): a cytokine antagonista cytokine antagonist Indicated for moderate to severe polyarticular course Indicated for moderate to severe polyarticular course

JRA patients 4 to 17 years of age who had an inadequate JRA patients 4 to 17 years of age who had an inadequate response to one or more DMARDs.response to one or more DMARDs.

Dosage: 0.4 mg/kg/week (maximum 25 mg/ dose given Dosage: 0.4 mg/kg/week (maximum 25 mg/ dose given twice weekly) as subcutaneous injection pre-filled twice weekly) as subcutaneous injection pre-filled syringe, 72-96 hrs. apart. syringe, 72-96 hrs. apart.

Adverse events: headache, nausea, abdominal pain, and Adverse events: headache, nausea, abdominal pain, and vomiting. Infection was reported in 43 of 69 (62%) of JRA vomiting. Infection was reported in 43 of 69 (62%) of JRA patients during the 3-month (open-label phase). Serious patients during the 3-month (open-label phase). Serious AEs reported in the study: varicella, gastroenteritis, AEs reported in the study: varicella, gastroenteritis, depression/ personality disorder, cutaneous ulcer, depression/ personality disorder, cutaneous ulcer, esophagitis/ gastritis, group A streptococcal septic esophagitis/ gastritis, group A streptococcal septic shock, Type 1 diabetes, soft tissue and post-operative shock, Type 1 diabetes, soft tissue and post-operative wound infectionwound infection. .

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Treatment in JRATreatment in JRA

DMARDs indicated for RA without an indication for DMARDs indicated for RA without an indication for JRAJRA• Hydroxychloroquine, injectable gold, Hydroxychloroquine, injectable gold,

leflunomide and d-penicillamine.leflunomide and d-penicillamine.

Other Immunomodulatory or Cytotoxic DrugsOther Immunomodulatory or Cytotoxic Drugs• Indicated in RA without a JRA indication: Indicated in RA without a JRA indication:

Azathioprine Azathioprine Cyclosporine ACyclosporine A

• Without a RA or a JRA indication: Without a RA or a JRA indication: Chlorambucil Chlorambucil ThalidomideThalidomide

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Treatment of JRA in 2006Treatment of JRA in 2006

PauciarticularPauciarticular • 25% to 33% will respond to NSAIDs;25% to 33% will respond to NSAIDs;• Patients not responsive to NSAIDS after 4 - 6 Patients not responsive to NSAIDS after 4 - 6

weeks with flexion contractures or leg length weeks with flexion contractures or leg length discrepancy discrepancy intra-articular corticosteroids. intra-articular corticosteroids.

• Patients with extended pauciarticular JRA or Patients with extended pauciarticular JRA or small joint involvement small joint involvement treat as polyarticular treat as polyarticular JRA.JRA.

Modified from Laxer R, Hashkes PJ. Medical Treatment of Juvenile Idiopathic Arthritis. JAMA, October 5, 2005. Vol 294, No. 13, pp 1671-1684.

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Treatment of JRA in 2006Treatment of JRA in 2006

PolyarticularPolyarticular • RF (-) or (+), NSAID (symptom control) alone is RF (-) or (+), NSAID (symptom control) alone is

usually not as effective as a NSAID + DMARD.usually not as effective as a NSAID + DMARD.• NSAID trial for several weeks NSAID trial for several weeks add oral MTX. add oral MTX. • If oral MTX is not effective If oral MTX is not effective parenteral route parenteral route

MTX.MTX.• If NSAID + MTX (oral or parenteral) is not effective If NSAID + MTX (oral or parenteral) is not effective

anti-TNF medication. anti-TNF medication. No current evidence whether a combination of No current evidence whether a combination of

MTX + anti-TNF medication are more effective MTX + anti-TNF medication are more effective

than only anti-TNF medicationthan only anti-TNF medication..

Modified from Laxer R, Hashkes PJ. Medical Treatment of Juvenile Idiopathic Arthritis. JAMA, October 5, 2005. Vol 294, No. 13, pp 1671-1684.

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Treatment of JRA in 2006Treatment of JRA in 2006

SystemicSystemic• NSAIDs 2 to 3 weeks with caution NSAIDs 2 to 3 weeks with caution risk of risk of

Disseminated Intravascular Coagulation (DIC), Disseminated Intravascular Coagulation (DIC), (macrophage activation syndrome);(macrophage activation syndrome);

• Intravenous pulse methylprednisolone;Intravenous pulse methylprednisolone;• Oral corticosteroids Oral corticosteroids

Lowest effective dose;Lowest effective dose; Steroid sparing Steroid sparing immunomodulatory immunomodulatory

approach is under evaluation for steroid approach is under evaluation for steroid sparing effects.sparing effects.

Modified from Laxer R, Hashkes PJ. Medical Treatment of Juvenile Idiopathic Arthritis. JAMA, October 5, 2005. Vol 294, No. 13, p1671-1684.

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CELEBREX (celecoxib)CELEBREX (celecoxib)

Non-Selective NSAID/COX-2 Selective InhibitorNon-Selective NSAID/COX-2 Selective Inhibitor• Proposed Formulation:Proposed Formulation: a a capsule (50 mg, option capsule (50 mg, option

to use as a sprinkle onto applesauce)to use as a sprinkle onto applesauce)• Pivotal Study:Pivotal Study: 12-wk DB + 12-wk OL Ext (242 12-wk DB + 12-wk OL Ext (242

pts); celecoxib oral investigational suspension pts); celecoxib oral investigational suspension and naproxen oral suspension (active and naproxen oral suspension (active comparator)comparator)

• Proposed Dosing in Patients with JRAProposed Dosing in Patients with JRA 50 mg capsule BID (100 mg/day):50 mg capsule BID (100 mg/day):

Patient weight 10 - 25 kg. Patient weight 10 - 25 kg. 100 mg capsule BID (200 mg/day): 100 mg capsule BID (200 mg/day):

Patient weight > 25 kg. Patient weight > 25 kg.