1. L1 Juvenile Rheumatoid Arthritis Clinical Overview Daniel J. Lovell MD, MPH Levinson Professor of Pediatrics Division of Rheumatology Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio, USA

2. L2 American College of Rheumatology Characteristics of JRA Pauciarticular Course Polyarticular Course Systemic Disease Frequency of cases60%30%10% Number of joints involved 44 55 Variable Age at onsetEarly childhood; peak at 1-3 yrs Throughout childhood; peak at 6-7 yrs and 8-11 yrs Throughout childhood; no peak Female:male ratio5:13:11:1 Systemic involvementNot presentModerate involvement Prominent Treatment paradigmPrimarily NSAIDs or intra-articular corticosteroids DMARDs or biologics with adjunctive NSAIDs DMARDs or biologics; NSAIDs for fever and pain; corticosteroids for systemic features Cassidy and Petty. Textbook of Pediatric Rheumatology, 2005

3. L3 Pain is Commonly Reported in JRA Lovell and Walco. Pediatr Clin North Am 1989; 36:1015-27 Self report of pain from 462 children with JRA Cincinnati Juvenile Arthritis Database

4. L4 Functional Impact of Pain in Children with JRA Parent’s assessment of activities affected by child’s pain 22% pauciarticular course 48% polyarticular course 26% systemic onset Varni/Thompson Pediatric Pain Questionnaire Varni et al. Pain 1987; 28:27-38.

5. L5 Articular Erosions in JRA Patients Cassidy et al. Arthritis Rheum 1986; 29:274-81. Articular erosions by disease onset subtype from 132 children with 5 years follow-up

6. L6 Outcome Following Onset of JRA Systematic review of published outcome data in JIA, JCA, JRA 21 studies published over 10-year period 19 retrospective studies; 2 prospective Follow up varied –<5 years in 4 studies –>10 years in 14 studies Study sizes varied: 44 – 1082 patients –10 studies >200 patients –Total n = 5342 patients Adib N et al. Rheumatology 2005;44:995-1001

7. L7 Remission Rates and Function in Studies Using ACR JRA Classification Criteria Steinbrocker III/IV 7-27% Steinbrocker III/IV <1- 7% Steinbrocker III/IV 10% Percent of patients in remission Function Adib N et al. Rheumatology 2005;44:995-1001

8. L8 CV Thrombotic Adverse Events: CARRA Survey Childhood Arthritis and Rheumatology Research Alliance (CARRA) –98% pediatric rheumatologists in North America Survey (sponsored by CARRA) –Conducted post Vioxx withdrawal –Distributed to 130 pediatric rheumatologists –Request for information regarding frequency of vascular complications in JRA patients In association with NSAIDs and COX-2 inhibitors – Request for number of years of practice Results –73% responded (95/130) –1546 years of practice in pediatric rheumatology –0 vascular events in JRA population –1 pulmonary embolism event reported for possible psoriatic arthritis patient

9. L9 NSAID Trials in JRA: Predating 1998 Approval of Celecoxib for Adults TreatmentsNumber of Patients Study DesignSource Tolmetin Aspirin 10712-week double-blind, parallel group Levinson et al. 1977 Naproxen Aspirin 1812-week, randomized, double-blind, crossover Makela 1977 Naproxen Aspirin 238-week randomized, double-blind, crossover (two 4-week periods) 12-month open-label Moran et al. 1979 Naproxen Aspirin 8024-week randomized, parallel group, double-blind Kvien et al. 1984 Ibuprofen Aspirin 9212-week, randomized, double-blind, parallel-group Giannini et al. 1990 Ibuprofen8624-week, open-label, multidose Giannini et al. 1990 Oxaprozin5912-week open-label with 9 month extension Bass et al. 1985

10. L10 NSAID Trials in JRA: Subsequent to 1998 Approval of Celecoxib for Adults TreatmentsNumber of Patients Study DesignSource Rofecoxib Naproxen 31012-week, randomized, double-blind 52-week open-label active comparator- controlled extension Reiff et al. 2006 Meloxicam Naproxen 22512-week randomized, double-blind, with a 40-week double-blind extension. Ruperto et al. 2005 Meloxicam Naproxen 20712-week randomized, double-blind, active-controlled 12-week open-label extension Gedalia et al. 2004

11. L11 American College of Rheumatology (ACR) Pediatric 30 Response ACR Pediatric 30 Response Criterion: ≥ 30% improvement in any 3 of 6 core set measures with no more than 1 of the remaining measures worsening by > 30%. Core Set Measures Physician’s Global Assessment of Disease Activity Patient/Parent Global Assessment of Overall Well Being Assessment of Physical Function Number of joints with active arthritis Number of joints with limited range of motion Laboratory measure of inflammation Giannini E et al. Arthritis Rheum 1997;40(7):1202-1209

12. L12 Meloxicam vs Naproxen in JRA Meloxicam 0.125 mg/kg/day N=73 Meloxicam 0.25 mg/kg/day N= 74 Naproxen 10 mg/kg/day N= 78 Patient/ parent overall assessment of well being -43%-39%-41% MD global assessment of disease activity -48%-46%-44% CHAQ index-33%-37% No. of joints with active arthritis -52%-46%-43% No. of joints with limited range of motion -44%-29%-37% ESR+2%-20%-5% Parent’s assessment of pain-50%-44%-46% Percent change from Baseline in ACR Pediatric 30 Core Measures at 12 Weeks Ruperto N et al. Arthritis Rheum 2005;52 (2): 563-572

13. L13 Meloxicam vs Naproxen in JRA ACR Pediatric 30 Response Rate over 12 Months % Responders Ruperto N et al. Arthritis Rheum 2005;52 (2): 563-572

14. L14 Comparison of ACR Pediatric 30 Response Rates with Naproxen StudyNumber of Patients Dose mg/kg/day ACR Pediatric 30 Response Week 12 Reiff 20061011555% Ruperto 2005781064% Gedalia 20047510-1568% Foeldvari 2006831567% Reiff A et al. J Rheum 2006;33: 985-995 Ruperto N et al. Arthritis Rheum 2005;52 (2): 563-572 Gedalia A et al. Arthritis Rheum 2004;50(suppl)S95 Foeldvari et al. 2006. Arthritis Rheum 2006;54(suppl)

15. L15 NSAID-induced GI Pain and Injury Among patients with abdominal pain who underwent GI evaluation, gastroduodenal injury was reported in: –34% of patients taking NSAIDs 7.1% of patients not taking NSAIDs No complicated events Dowd et al. Arthritis Rheum 1995; 38:1225-31. Percent of Patients Reporting Abdominal Pain No NSAIDs N = 226 NSAIDs N = 344 Retrospective review of records from 570 patients seen in a pediatric rheumatology clinic over 3-year period

16. L16 Intolerability of NSAIDs in Children with JRA Barron KS et al. Journal of Rheumatology 1982; 9:149-55. Mean age onset 6.7 years 21% Systemic Onset 23% Polyarticular Course 57% Pauciarticular Course 22% No toxicity 78% Discontinued NSAID due to toxicity 49% No Toxicity 101 Patients > 1 NSAID 51% Repeat toxicity with NSAID 38% Different toxicity 62% Same toxicity Toxicity = Laboratory abnormality or signs/ symptoms requiring NSAID discontinuation NSAIDs: Aspirin 34%; Tolmetin 21%; Naproxen 12%; Fenoprofen 11%; Ibuprofen 8%, Other 14%

17. L17 Conclusion: JRA and Current Treatments JRA comprises a group of heterogeneous yet related disorders in children Chronic inflammatory arthritis with significant impact on function and health-related quality of life Treatment effects include disease modification and symptom control –NSAIDs are used by most patients at some point in their disease NSAIDs are generally well tolerated –GI adverse symptoms commonly reported –Serious GI complications uncommon