Objectives and Agenda by annieparksi

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									 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


                                                L1
             American College of Rheumatology
                  Characteristics of JRA
                                      Pauciarticular          Polyarticular     Systemic Disease
                                         Course                 Course
     Frequency of cases                     60%                    30%                 10%
     Number of joints                        4                     5               Variable
     involved
     Age at onset                   Early childhood;           Throughout          Throughout
                                     peak at 1-3 yrs            childhood;         childhood;
                                                              peak at 6-7 yrs       no peak
                                                               and 8-11 yrs
     Female:male ratio                       5:1                   3:1                 1:1
     Systemic involvement              Not present               Moderate           Prominent
                                                               involvement
     Treatment paradigm                  Primarily             DMARDs or            DMARDs or
                                        NSAIDs or             biologics with    biologics; NSAIDs
                                      intra-articular           adjunctive      for fever and pain;
                                     corticosteroids             NSAIDs         corticosteroids for
                                                                                systemic features


Cassidy and Petty. Textbook of Pediatric Rheumatology, 2005                                           L2
             Pain is Commonly Reported in JRA
              Self report of pain from 462 children with JRA
                   Cincinnati Juvenile Arthritis Database
                           Percent of Patients Reporting Pain
                                                                70

                                                                60

                                                                50

                                                                40

                                                                30

                                                                20

                                                                10

                                                                 0
                                                                     First visit    1 year     5 years
                                                                              Years of Follow-up

Lovell and Walco. Pediatr Clin North Am 1989; 36:1015-27                                                 L3
                          Functional Impact of Pain in Children
                                       with JRA
                                          Varni/Thompson
                                    Pediatric Pain Questionnaire
                         70

                         60                          •   Parent’s assessment of
    Percent Occurrence




                         50                              activities affected by
                                                         child’s pain
                         40
                                                     •   22% pauciarticular course
                         30
                                                     •   48% polyarticular course
                         20                          •   26% systemic onset
                         10

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Varni et al. Pain 1987; 28:27-38.                                                    L4
               Articular Erosions in JRA Patients
               Articular erosions by disease onset subtype from
                       132 children with 5 years follow-up

                                      80
                                                                          69
                Percent of Patients




                                      60


                                      40
                                                        29

                                      20                            15


                                       0

                                           Systemic onset (N=21)
                                           Pauciarticular course (N=65)
                                           Polyarticular course (N=46)

Cassidy et al. Arthritis Rheum 1986; 29:274-81.                                L5
               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                  L6
     Remission Rates and Function in Studies
      Using ACR JRA Classification Criteria
                 Percent of patients in remission                              Function

    Flato 2003

Minden 2002                                                              Steinbrocker III/IV 7-27%

      Oen 2002                                                           Steinbrocker III/IV <1- 7%


Minden 2000                                                               Steinbrocker III/IV 10%


    Flato 1998

                      0         20            40   60     80       100

          Pauciarticular             Polyarticular      Systemic



Adib N et al. Rheumatology 2005;44:995-1001                                                           L7
    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

                                                                      L8
              NSAID Trials in JRA:
      Predating 1998 Approval of Celecoxib
                   for Adults
Treatments   Number of                Study Design              Source
              Patients
Tolmetin       107       12-week double-blind, parallel group   Levinson et al.
Aspirin                                                         1977

Naproxen        18       12-week, randomized, double-blind,     Makela
Aspirin                  crossover                              1977

Naproxen        23       8-week randomized, double-blind,       Moran et al.
Aspirin                  crossover (two 4-week periods)         1979
                         12-month open-label
Naproxen        80       24-week randomized, parallel group,    Kvien et al.
Aspirin                  double-blind                           1984

Ibuprofen       92       12-week, randomized, double-blind,     Giannini et al.
Aspirin                  parallel-group                         1990

Ibuprofen       86       24-week, open-label, multidose         Giannini et al.
                                                                1990

Oxaprozin       59       12-week open-label with                Bass et al.
                         9 month extension                      1985

                                                                                  L9
           NSAID Trials in JRA:
  Subsequent to 1998 Approval of Celecoxib
                 for Adults
Treatments   Number of                Study Design                Source
              Patients
Rofecoxib       310      12-week, randomized, double-blind        Reiff et al.
Naproxen                 52-week open-label active comparator-    2006
                         controlled extension
Meloxicam       225      12-week randomized, double-blind, with   Ruperto et al.
Naproxen                 a 40-week double-blind extension         2005

Meloxicam       207      12-week randomized, double-blind,        Gedalia et al.
Naproxen                 active-controlled                        2004
                         12-week open-label extension




                                                                                   L10
      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                      L11
                   Meloxicam vs Naproxen in JRA
                    Percent change from Baseline in ACR Pediatric 30
                              Core Measures at 12 Weeks
                                                   Meloxicam        Meloxicam        Naproxen
                                                0.125 mg/kg/day   0.25 mg/kg/day   10 mg/kg/day
                                                     N=73              N= 74          N= 78
     Patient/ parent overall
     assessment of well                                 -43%          -39%            -41%
     being

     MD global assessment of
                                                        -48%          -46%            -44%
     disease activity

     CHAQ index                                         -33%          -37%            -37%

     No. of joints with active
                                                        -52%          -46%            -43%
     arthritis
     No. of joints with limited
                                                        -44%          -29%            -37%
     range of motion

     ESR                                                +2%           -20%             -5%


     Parent’s assessment of pain                        -50%          -44%            -46%

Ruperto N et al. Arthritis Rheum 2005;52 (2): 563-572                                         L12
                         Meloxicam vs Naproxen in JRA
                           ACR Pediatric 30 Response Rate over 12 Months
    % Responders




                   M o n th 1 2




                    M o n th 3




                                  0         20                   40                 60   80   100

                                      Na p r o x e n 1 0 m g /k g /d N= 7 8
                                      M e lo x ic a m 0 .2 5 m g /k g /d   N= 7 4
                                      M e lo x ic a m 0 .1 2 5 m g /k g /d N= 7 3

Ruperto N et al. Arthritis Rheum 2005;52 (2): 563-572                                               L13
       Comparison of ACR Pediatric 30 Response
                Rates with Naproxen
         Study                           Number of        Dose         ACR
                                          Patients      mg/kg/day   Pediatric 30
                                                                     Response
                                                                      Week 12

         Reiff 2006                            101         15          55%

         Ruperto 2005                           78         10          64%

         Gedalia 2004                           75        10-15        68%

         Foeldvari 2006                         83         15          67%


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)                              L14
                NSAID-induced GI Pain and Injury
          Retrospective review of records from 570 patients seen in a
               pediatric rheumatology clinic over 3-year period

           Percent of Patients Reporting
                 Abdominal Pain
         30                                     • Among patients with
                                                  abdominal pain who
         25                                       underwent GI evaluation,
         20
                                                  gastroduodenal injury was
                                                  reported in:
         15
                                                   – 34% of patients taking
         10
                                                     NSAIDs
                                                • 7.1% of patients not taking
          5
                                                  NSAIDs
          0
                        No                      • No complicated events
                      NSAIDs NSAIDs
                      N = 226 N = 344
Dowd et al. Arthritis Rheum 1995; 38:1225-31.                                   L15
                          Intolerability of NSAIDs in
                              Children with JRA

                             101 Patients                                Mean age onset 6.7 years
                              > 1 NSAID                                  21% Systemic Onset
                                                                         23% Polyarticular Course
                                                                         57% Pauciarticular Course
             22%                             78% Discontinued
          No toxicity                       NSAID due to toxicity


                                   49%                        51% Repeat
                                No Toxicity                toxicity with NSAID



                                                 38% Different              62% Same
                                                    toxicity                  toxicity
NSAIDs: Aspirin 34%; Tolmetin 21%; Naproxen 12%; Fenoprofen 11%; Ibuprofen 8%, Other 14%
Toxicity = Laboratory abnormality or signs/ symptoms requiring NSAID discontinuation
Barron KS et al. Journal of Rheumatology 1982; 9:149-55.                                        L16
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



                                                                       L17

								
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