Slide 28 -
1 Juvenile Rheumatoid Arthritis
Arthritis Advisory Committee Meeting
Division of Anesthesia, Analgesia and Rheumatology Products
November 29, 2006
Carolyn L. Yancey, MD
Medical Officer, DAARP
2 AGENDA Juvenile Rheumatoid Arthritis Epidemiology, Pathogenesis and Etiology
Classification of Juvenile Rheumatoid Arthritis
American College of Rheumatology (ACR) Criteria
Disease Course and Prognosis
Treatment of JRA and the State-of-the-Art Treatment Armamentarium
3 BACKGROUND Chronic Arthritis in Childhood characterized as
Juvenile Rheumatoid Arthritis
Age of onset < 16 years of age.
4 BACKGROUND Epidemiology
Overall prevalence of juvenile rheumatoid arthritis is estimated to be from 30 - 150 per 100,000 children.
In the United States and Canada there are an estimated 30,000 to 60,000 children and adolescents with juvenile rheumatoid arthritis. 5 BACKGROUND Pathogenesis and Etiology of JRA: Multi-factorial
Genetic, Hormonal, Immunologic
Characterized by chronic inflammation of the synovium;
Presence of articular cartilage damage;
Accompanied by extra-articular systemic manifestations.
Heterogeneity of JRA
At least 3 primary types of onset of JRA:
6 BACKGROUND Pathogenesis (Continued)
Basis of immune distinction between self and non-self is the major histocompatibility complex (MHC) that in humans is called the human leukocyte antigen (HLA).
HLA system comprises a family of polymorphic genes located on the short arm of chromosome 6.
Polymorphisms of JRA suggest a non-mendelian inheritance.
Differences in the sex ratio of JRA subtype onset
Pre-adolescent or post-adolescent peaks
7 BACKGROUND Immune Mechanisms
Disease process involves loss of tolerance towards auto-antigens chronic synovitis;
Production of auto-antibodies:
Anti-nuclear antibodies (ANA): associated with increased risk of iridocyclitis (eye inflammation);
Rheumatoid factors (RF): auto-antibodies directed against the Fc fragment of IgG (associated with ~10% of polyarticular JRA);
Complement activation by circulating immune complexes may also contribute to the disease process. 8 BACKGROUND Immune Mechanisms (Continued)
Cytokines: act on the immune system and other cells to initiate and sustain inflammation:
Intercellular mediators: Interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-);
Immunomodulatory cytokines produced by T-cells Interferon gamma (IFN-γ), IL-4, IL-2.
9 CLASSIFICATION OF JUVENILE RHEUMATOID ARTHRITIS American College of Rheumatology (ACR) pediatric criterion for juvenile rheumatoid arthritis was established in 1977.
10 CLASSIFICATION OF JRA ACR Criteria
Age at onset: < 16 years of age;
Arthritis - swelling or effusion or the presence of 2 or more of the following signs:
Limitation of range of motion,
Tenderness or pain on motion and
Increased heat in one or more joints;
Duration of disease > 6 weeks;
Onset type is defined by the type of disease in the first 6 months:
Oligoarticular (Pauciarticular) < 5 inflamed joints;
Polyarticular: > 5 inflamed joints;
Systemic onset: arthritis with characteristic fever.
Exclusion of other forms of childhood arthritis.
Modified from JT Cassidy, JT Levinson, RM Laxer, CB Lindsley. Textbook of Pediatric Rheum. 2005 11 CLINICAL MANIFESTATIONS of JRA 12 Characteristic
% Cases (F:M)
Age at onset
Thru childhood, peak 1-3 yr
Mild; unremitting articular involvement
Guarded to moderately good
Early childhood, peak 1-2 yr
None; uveitis (++)
Excellent except for eyesight
Systemic self-limited; chronic destructive
Moderate to poor JRA by the Type-of-Onset JT Cassidy, RE Petty, RM Laxer, CB Lindsley. Textbook of Pediatric Rheumatology, 2005 13 Extra-Articular Manifestations of JRA Fever
JT Cassidy, RE Petty. Textbook of Pediatric Rheumatology, 2001 14 PROGNOSIS OF JRA Pauciarticular JRA
Boys may be affected in older childhood or adolescence; this may represent an early manifestation of a spondyloarthropathy.
Leg length discrepancy from asymmetric knee synovitis and bone growth may cause flexion contractures, gait abnormalities and long-term growth abnormalities.
Eye involvement as anterior uveitis, may lead to scarring or blindness in ~ 15-20% of children.
Active arthritis into adulthood in 40% to 50% of patients.
Radiographic joint damage within 5 years.
15 PROGNOSIS OF JRA Polyarticular JRA and Systemic JRA
Active arthritis into adulthood: 50% to 70% of polyarticular or systemic onset JRA;
Long-term disabilities: 30% to 40% of children
Unemployment: 25% to 50% of adult JRA patients;
May need major surgery (joint replacement).
Radiographic joint damage within 2 years;
Mortality rate: 0.4% to 2% (greater risk with systemic JRA than with polyarticular JRA).
16 Traditional Approach to the Treatment of JRA Cytotoxic Drugs
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Before the 1990s …
Pyramid Approach 17 Evolving Treatment of JRA Paradigm shift….
The trend in managing JRA is much more aggressive treatment earlier in the disease course with the goal of preventing joint damage and slowing progressive articular damage. Since the 1990s and
into the 2000s… 18 Treatments with Indications for JRA Non-Selective NSAIDs
Aspirin, tolmetin sodium, ibuprofen, naproxen
Naproxen [Tablets and Suspension]
Indicated for patients 2 years and older with juvenile arthritis.
Daily dose: approximately 10 mg/kg/day as a BID dose (5 mg/kg given twice-a-day). Total daily dose is not to exceed 15 mg/kg/day.
Adverse events: gastrointestinal, central nervous system (headache, dizziness, drowsiness, vertigo), rash (ecchymoses, purpura), pruritus, sweating, special senses (tinnitus, visual disturbances, hearing disturbances), cardiovascular (edema, palpitations) prolonged bleeding times.
19 Treatments with Indications for JRA Non-Selective NSAIDs/COX-2 Selective Inhibitors
MOBIC (meloxicam) [Tablets and Suspension]
Indicated for the relief of the signs and symptoms of pauciarticular and polyarticular course JRA in patients 2 yrs and older.
0.125 mg/kg once daily up to a maximum of 7.5 mg.
Adverse events: abdominal pain/upper, vomiting, diarrhea, headache, infection (rhinitis), cough, pyrexia, rash. urticaria, slight increases in systolic blood pressure.
VIOXX (rofecoxib) [Tablets and Suspension]
Withdrawn from the global market September 2004.
Indicated for the relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 2 years and older.
20 Treatment of JRA Corticosteroids
Used for uncontrolled or life-threatening systemic disease;
Treatment of chronic uveitis as local ophthalmic drops; or
Intra-articular agents (Pauci- and polyarticular JRA)
Intermediate-acting corticosteroids: Prednisone; methyl-prednisolone (Intravenous pulse therapy for severely active JRA).
Prednisone low-dose as 0.1 to 0.2 mg/kg; higher-dose 0.25 to 1.0 mg/kg/day (maximum single dose 40 mg)
Adverse events: hypertension, iatrogenic Cushing’s syndrome, growth suppression, fractures, cataracts, increased susceptibility to infection.
21 Treatment of JRA DMARDs and Biologic DMARDs
Methotrexate (MTX): used when NSAIDs fail to bring relief.
Indicated for polyarticular JRA. MTX is the most widely used DMARD for JRA treatment.
Starting dose 7.5 mg/m2 per week; maximum dose of 15 mg/m2 per week.
Methotrexate compared to leflunomide (Lef): 240 JRA pts, 16-week DB + 6 mo Ext + optional 30 mo Ext in JRA; JRA Definition of Improvement > 30% (JRA DOI > 30): 89% MTX compared to 68% Lef.
Adverse events: stomatitis, leukopenia, nausea/ abdominal pain, gastrointestinal bleeding, anorexia, malaise, fatigue, chills and fever, headache, alopecia, rash, decreased resistance to infection, elevated hepatic enzymes. 22 Treatment of JRA DMARDs and Biologic DMARDs (Continued)
Indicated for polyarticular JRA who have responded inadequately to salicylates or other non-steroidal anti-inflammatory drugs.
Children 6 yrs and older: 40 - 60 mg/kg/day divided into 3 to 6 doses.
Maintenance dose: 30 mg/kg/day divided into 4 doses.
Adverse events: anorexia, headache, vomiting, gastric distress, rash, urticaria, hemolytic anemia.
23 Treatment in JRA DMARDs and Biologic DMARDs (Continued)
ENBREL (etanercept): a cytokine antagonist
Indicated for moderate to severe polyarticular course JRA patients 4 to 17 years of age who had an inadequate response to one or more DMARDs.
Dosage: 0.4 mg/kg/week (maximum 25 mg/ dose given twice weekly) as subcutaneous injection pre-filled syringe, 72-96 hrs. apart.
Adverse events: headache, nausea, abdominal pain, and vomiting. Infection was reported in 43 of 69 (62%) of JRA patients during the 3-month (open-label phase). Serious AEs reported in the study: varicella, gastroenteritis, depression/ personality disorder, cutaneous ulcer, esophagitis/ gastritis, group A streptococcal septic shock, Type 1 diabetes, soft tissue and post-operative wound infection.
24 Treatment in JRA DMARDs indicated for RA without an indication for JRA
Hydroxychloroquine, injectable gold, leflunomide and d-penicillamine.
Other Immunomodulatory or Cytotoxic Drugs
Indicated in RA without a JRA indication:
Without a RA or a JRA indication:
25 Treatment of JRA in 2006 Pauciarticular
25% to 33% will respond to NSAIDs;
Patients not responsive to NSAIDS after 4 - 6 weeks with flexion contractures or leg length discrepancy intra-articular corticosteroids.
Patients with extended pauciarticular JRA or small joint involvement treat as polyarticular JRA.
Modified from Laxer R, Hashkes PJ. Medical Treatment of Juvenile Idiopathic Arthritis. JAMA, October 5, 2005. Vol 294, No. 13, pp 1671-1684. 26 Treatment of JRA in 2006 Polyarticular
RF (-) or (+), NSAID (symptom control) alone is usually not as effective as a NSAID + DMARD.
NSAID trial for several weeks add oral MTX.
If oral MTX is not effective parenteral route MTX.
If NSAID + MTX (oral or parenteral) is not effective anti-TNF medication.
No current evidence whether a combination of MTX + anti-TNF medication are more effective than 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.
27 Treatment of JRA in 2006 Systemic
NSAIDs 2 to 3 weeks with caution risk of Disseminated Intravascular Coagulation (DIC), (macrophage activation syndrome);
Intravenous pulse methylprednisolone;
Lowest effective dose;
Steroid sparing immunomodulatory approach is under evaluation for steroid sparing effects.
Modified from Laxer R, Hashkes PJ. Medical Treatment of Juvenile
Idiopathic Arthritis. JAMA, October 5, 2005. Vol 294, No. 13, p1671-1684.
28 CELEBREX (celecoxib) Non-Selective NSAID/COX-2 Selective Inhibitor
Proposed Formulation: a capsule (50 mg, option to use as a sprinkle onto applesauce)
Pivotal Study: 12-wk DB + 12-wk OL Ext (242 pts); celecoxib oral investigational suspension and naproxen oral suspension (active comparator)
Proposed Dosing in Patients with JRA
50 mg capsule BID (100 mg/day): Patient weight 10 - 25 kg.
100 mg capsule BID (200 mg/day): Patient weight > 25 kg.