# Presentation: 195463

## Juvenile  Rheumatoid Arthritis

- Arthritis Advisory Committee Meeting
- Division of Anesthesia, Analgesia and Rheumatology Products
- November 29, 2006
- Carolyn L. Yancey, MD
- Medical Officer, DAARP

## AGENDAJuvenile Rheumatoid Arthritis

- Epidemiology, Pathogenesis and Etiology
- Classification of Juvenile Rheumatoid Arthritis
- American College of Rheumatology (ACR) Criteria
- Clinical Manifestations
- Disease Course and Prognosis
- Treatment of JRA and the State-of-the-Art Treatment Armamentarium

## BACKGROUND

- Chronic Arthritis in Childhood characterized as
- Juvenile Rheumatoid Arthritis
- JRA
- Age of onset < 16 years of age.

## 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.

## BACKGROUND

- Pathogenesis and Etiology of JRA: Multi-factorial
- Genetic, Hormonal, Immunologic
- Pathogenesis
- 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:
- Pauciarticular (Oligoarticular)
- Polyarticular and
- Systemic

## BACKGROUND

- Pathogenesis *(Continued)*
- Genetic
- 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.
- Hormonal Factors
- Differences in the sex ratio of JRA subtype onset
- Pre-adolescent or post-adolescent peaks

**Notes:**
Infectious Etiology
Rubella virus, Epstein-Barr virus (EBV), Borrelia Burgdorferi (spirochete of Lyme disease), mycoplasma...

## 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.

## 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.

## CLASSIFICATION OF JUVENILE RHEUMATOID ARTHRITIS

- American College of Rheumatology (ACR)            pediatric criterion for juvenile rheumatoid arthritis was established in 1977.

## 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

## CLINICAL MANIFESTATIONS of JRA

## JRA by the Type-of-Onset

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

## Extra-Articular Manifestations of JRA

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

## 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.

## 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).

**Notes:**
ADD TRANSITION:  UNEMPLOYMENT

## Traditional Approach to the 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**

## 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...**

## 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.

**Notes:**
VIOXX: 2 to 11 years of age: 0.6 mg/kg to a maximum of 25 mg once daily. Pts < 40 kg, recommended to use 12.5 mg/5 mL suspension. 
12 to 17 yrs, 25 mg once daily. Maximum daily dose  25 mg.
Adverse Events: Upper/abdominal pain, headache, upper respiratory tract infection, pyrexia, skin/subcutaneous disorders, insomnia, dizziness, elevated hepatic enzymes, edema, pseudoporphyria. 

## 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.

## 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.

## 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.

**Notes:**
MTX: ADD AE PROFILE
LAST BULLET NEEDS TO BE MODIFIED

## Treatment of JRA

- DMARDs and Biologic DMARDs *(Continued)*
- Sulfasalazine
- 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.

## 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.

## 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:
- Azathioprine
- Cyclosporine A
- Without a RA or a JRA indication:
- Chlorambucil
- Thalidomide

## 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.

## 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.

## 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;
- Oral corticosteroids 
- 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.

## 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.