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Osteoarthritis




Images from Ruddy S, Harris ED, Sledge CB eds. Kelly’s Textbook of Rheumatology. 6th ed.
Philadelphia, PA: W.B. Saunders Company; 2001.
Reprinted from Kelley’s Textbook of Rheumatology with permission from Elsevier.
Rheumatoid Arthritis




Images from Ruddy S, Harris ED, Sledge CB eds. Kelly’s Textbook of Rheumatology. 6th ed.
Philadelphia, PA: W.B. Saunders Company; 2001.
Reprinted from Kelley’s Textbook of Rheumatology with permission from Elsevier.
Proposed Pathogenesis of RA

          Triggering event (Antigenic stimulus)

     Non-T-Cell Dependent                         T-Cells (CD4+)
     Mechanisms
                                                  • Crucial to early immunological
     •Aberrant cytokine cascades                  response
     •Impaired growth and
     apoptosis                                    Proinflammatory cascade
     •Cell-cell interactions                      • Mediated by cytokines including IL-1, IL-6, IL-18, and
                                                    GM-CSF
                                                  • TNFα has pivotal role
                                                       --Bone and cartilage resorption
        Inflammation,                                  --HLA class II expression
        destructive pathways                           --Collagenase and PGE2 induction
                                                       --Chemotaxis
                                                       --á of additional proinflammatory cytokines
                                                       --Endothelial cell activation via adhesion
         Ongoing contribution to                         molecule
          chronic inflammation                         --T- and B-cell activation
1. Koopman WJ. JAMA. 2001; 285:648-650.
2. Buch M, et al. Hospital Pharmacist. 2002;9:5-10.
Modifying the Therapeutic Approach to
         RA — The Old Paradigm
• Progressive




                                                           In
                                                             tra
  addition to




                                                               -a
                                                                 rti
  foundation of                                 Experimental
                                          y




                                                                    cu
                                        er    drugs/procedures,




                                                                      lar
  DMARDs,                              g
                                     ur          cytotoxics




                                                                          ag
  starting with                 c   s




                                                                            en
                             edi




                                                                              ts
  least toxic
                           op




                                                                                ,c
                                         Penicillamine, methotrexate,
                        rth




                                                                                  or
                                                  azathioprine




                                                                                    tic
                       o
                   al,




                                                                                       os
                  c
                ni




                                                                                         te
                                                                                           ro
               a                     Hydroxychloroquine, sulfasalazine
             ch




                                                                                             id
            e




                                                                                               s
           M




                                                                                              fo
                                                                                                rf
                                              Antimalarials, gold




                                                                                                  lar
                                                                                                     es
                                        FOUNDATION:
                           Education, rest, exercise, social services
                               NSAID and/or salicylate therapy


1. Diagram adapted from: Primer on Rheumatic Diseases. 10th ed.Schumacher HR Klippel JH, Koopman WJ. eds.
   Atlanta, GA: Arthritis Foundation; 1993.
Modifying the Therapeutic Approach to
             RA — The New Paradigm
                                                            In
                                                              tra
• Rapid, early addition                                -a
  of DMARDs to                                           rti
                                            Surgery         cu
  prevent structural                                          lar
  damage                                                          ag
                                                                    en
                              l     Biologics + methotrexate          ts
                           ica                                          ,c
                          n                                               or
                        ha                                                  tic
                      ec                                                       os
                     M                                                           te
                                Change/add DMARDs ± methotrexate                   ro
                                                                                     id
                                                                                       s
                                                                                                  fo
                                                                                                    rf
                                                                                                      lar
                                        FOUNDATION:                                                      es
                          DMARDs within 3 months ±NSAID, ±Steroids
                        Education, occupational therapy, physical therapy


  1.   O’Dell JR et al. Patient Care.1997;March 15:81-99.
  2.   ACR. Arthritis Rheum. 1996;39:713-722.
  3.   ACR. Arthritis Rheum. 2002;46:328-346.
  4.   Diagram adapted from: Primer on Rheumatic Diseases. 10th ed.Schumacher HR Klippel JH, Koopman WJ. eds.
       Atlanta, GA: Arthritis Foundation; 1993.
Demographic Characteristics and
          Baseline Disease Characteristics1
                                                                    Meloxicam        Meloxicam             Meloxicam*
                                                     Placebo
                                                                     7.5 mg           15 mg                 22.5 mg
                                                      n=292
                                                                     n=306            n=293                  n=293
Age (years), mean (SD)                               53.6 (12.9)     55.7 (11.2)     54.6 (12.0)             55.4 (12.6)
Gender                                 Male             21%             18%              23%                    18%
                                      Female            79%             82%              77%                    82%
Race                                 Caucasion          89%             90%              90%                    90%
                                       Black            3%              4%                  5%                   2%
                                       Asian            7%              6%                  5%                   7%
RA History (years), mean (SD)                         9.0 (8.6)      10.3 (9.3)        9.3 (8.2)              9.7 (9.0)
RA                                    ≤5 Years          42%             37%              39%                    39%
                                      ≥5 Years          58%             63%              61%                    61%
Active joints at screening (SD)        Painful       14.0 (9.9)      14.3 (10.6)     14.6 (10.8)             13.3 (9.5)
                                       Swollen        9.6 (7.5)       9.6 (7.8)        9.7 (7.8)              9.2 (7.2)
Number of second-line                      0            24%             18%              24%                    25%
RA therapies used                          1            36%             45%              39%                    38%
                                           2            32%             30%              27%                    28%
                                      3 or more          8%             7%               10%                    10%

*Meloxicam 22.5 mg is not an approved dosage. In clinical trials, no incremental benefit was
 observed with the 22.5 mg dose compared to the 15 mg dose. Higher doses of meloxicam (22.5 mg
 and greater) have been associated with increased risk of serious gastrointestinal events; therefore
 the daily dose of meloxicam should not exceed 15 mg. Please see Important Safety Information at
 the end of this presentation and full Prescribing Information, including boxed WARNING, provided
 at this presentation.
                                                                                                   Some sub-columns in table do not add
1. Kivitz A, et al. Poster presented at ACR/ARHP Annual Scientific Meeting, October 2004.          up to 100% because of rounding.
ACR 20 Responder Rate at 12 Weeks
                    for Evaluable Patients1
                    60                                                 53.9†
                         *P=.0008 vs. placebo                         (158/293)                 49.8†
                         †P<.0001 vs. placebo
                                                    45.1*                                      (146/293)
                    50
                                                  (138/306)
   Responders (%)




                    40       33.2
                            (97/292)

                    30


                    20


                    10


                     0
                           Placebo              Mel. 7.5 mg/d      Mel. 15 mg/d             Mel. 22.5 mg/d ‡
‡Meloxicam  22.5 mg is not an approved dosage. In clinical trials, no incremental benefit was
observed with the 22.5 mg dose compared to the 15 mg dose. Higher doses of meloxicam (22.5 mg
and greater) have been associated with increased risk of serious gastrointestinal events; therefore
the daily dose of meloxicam should not exceed 15 mg. Please see Important Safety Information at
the end of this presentation and full Prescribing Information, including boxed WARNING, provided
at this presentation.
1. Kivitz A, et al. Poster presented at ACR/ARHP Annual Scientific Meeting, October 2004.
ACR 20 Responder Rates
                            Results Over Time1,2
                  60
                  50             **                       **                               *
                                                                                           *
   Responders %




                  40             *                         *                               *
                  30
                  20
                                                                        *P<.05 vs. placebo
                  10
                  0
                           4 Weeks                   8 Weeks                     12 Weeks
                       Placebo        Mel. 7.5 mg           Mel. 15 mg              Mel. 22.5 mg†
†Meloxicam  22.5 mg is not an approved dosage. In clinical trials, no incremental benefit was
observed with the 22.5 mg dose compared to the 15 mg dose. Higher doses of meloxicam (22.5 mg
and greater) have been associated with increased risk of serious gastrointestinal events; therefore
the daily dose of meloxicam should not exceed 15 mg. Please see Important Safety Information at
the end of this presentation and full Prescribing Information, including boxed WARNING, provided
at this presentation.
1.Kivitz A et al. Poster presented at ACR/ARHP Annual Scientific Meeting , October 2004.
2. Data on file, Boehringer Ingelheim Pharmaceuticals, Inc.
Results: Secondary Efficacy Endpoints1
Number of Painful/Tender Joints Over Time                                                 Patient Assessment of Pain Over Time
     *P<.05 vs. placebo for all doses of meloxicam at 4, 8, and 12 weeks (both graphs)2




                                                                                                             *          *
                                             *                                                                      *            *
                                                           *
                                     *                                     *                                **                   *
                                         *            **                   *                                        *            *
                                                                           *
                                                                               †                                                 †




†Meloxicam  22.5 mg is not an approved dosage. In clinical trials, no incremental benefit was
observed with the 22.5 mg dose compared to the 15 mg dose. Higher doses of meloxicam (22.5 mg
and greater) have been associated with increased risk of serious gastrointestinal events; therefore
the daily dose of meloxicam should not exceed 15 mg. Please see Important Safety Information at
the end of this presentation and full Prescribing Information, including boxed WARNING, provided
at this presentation.

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Medical Sample 20

  • 1. Osteoarthritis Images from Ruddy S, Harris ED, Sledge CB eds. Kelly’s Textbook of Rheumatology. 6th ed. Philadelphia, PA: W.B. Saunders Company; 2001. Reprinted from Kelley’s Textbook of Rheumatology with permission from Elsevier.
  • 2. Rheumatoid Arthritis Images from Ruddy S, Harris ED, Sledge CB eds. Kelly’s Textbook of Rheumatology. 6th ed. Philadelphia, PA: W.B. Saunders Company; 2001. Reprinted from Kelley’s Textbook of Rheumatology with permission from Elsevier.
  • 3. Proposed Pathogenesis of RA Triggering event (Antigenic stimulus) Non-T-Cell Dependent T-Cells (CD4+) Mechanisms • Crucial to early immunological •Aberrant cytokine cascades response •Impaired growth and apoptosis Proinflammatory cascade •Cell-cell interactions • Mediated by cytokines including IL-1, IL-6, IL-18, and GM-CSF • TNFα has pivotal role --Bone and cartilage resorption Inflammation, --HLA class II expression destructive pathways --Collagenase and PGE2 induction --Chemotaxis --á of additional proinflammatory cytokines --Endothelial cell activation via adhesion Ongoing contribution to molecule chronic inflammation --T- and B-cell activation 1. Koopman WJ. JAMA. 2001; 285:648-650. 2. Buch M, et al. Hospital Pharmacist. 2002;9:5-10.
  • 4. Modifying the Therapeutic Approach to RA — The Old Paradigm • Progressive In tra addition to -a rti foundation of Experimental y cu er drugs/procedures, lar DMARDs, g ur cytotoxics ag starting with c s en edi ts least toxic op ,c Penicillamine, methotrexate, rth or azathioprine tic o al, os c ni te ro a Hydroxychloroquine, sulfasalazine ch id e s M fo rf Antimalarials, gold lar es FOUNDATION: Education, rest, exercise, social services NSAID and/or salicylate therapy 1. Diagram adapted from: Primer on Rheumatic Diseases. 10th ed.Schumacher HR Klippel JH, Koopman WJ. eds. Atlanta, GA: Arthritis Foundation; 1993.
  • 5. Modifying the Therapeutic Approach to RA — The New Paradigm In tra • Rapid, early addition -a of DMARDs to rti Surgery cu prevent structural lar damage ag en l Biologics + methotrexate ts ica ,c n or ha tic ec os M te Change/add DMARDs ± methotrexate ro id s fo rf lar FOUNDATION: es DMARDs within 3 months ±NSAID, ±Steroids Education, occupational therapy, physical therapy 1. O’Dell JR et al. Patient Care.1997;March 15:81-99. 2. ACR. Arthritis Rheum. 1996;39:713-722. 3. ACR. Arthritis Rheum. 2002;46:328-346. 4. Diagram adapted from: Primer on Rheumatic Diseases. 10th ed.Schumacher HR Klippel JH, Koopman WJ. eds. Atlanta, GA: Arthritis Foundation; 1993.
  • 6. Demographic Characteristics and Baseline Disease Characteristics1 Meloxicam Meloxicam Meloxicam* Placebo 7.5 mg 15 mg 22.5 mg n=292 n=306 n=293 n=293 Age (years), mean (SD) 53.6 (12.9) 55.7 (11.2) 54.6 (12.0) 55.4 (12.6) Gender Male 21% 18% 23% 18% Female 79% 82% 77% 82% Race Caucasion 89% 90% 90% 90% Black 3% 4% 5% 2% Asian 7% 6% 5% 7% RA History (years), mean (SD) 9.0 (8.6) 10.3 (9.3) 9.3 (8.2) 9.7 (9.0) RA ≤5 Years 42% 37% 39% 39% ≥5 Years 58% 63% 61% 61% Active joints at screening (SD) Painful 14.0 (9.9) 14.3 (10.6) 14.6 (10.8) 13.3 (9.5) Swollen 9.6 (7.5) 9.6 (7.8) 9.7 (7.8) 9.2 (7.2) Number of second-line 0 24% 18% 24% 25% RA therapies used 1 36% 45% 39% 38% 2 32% 30% 27% 28% 3 or more 8% 7% 10% 10% *Meloxicam 22.5 mg is not an approved dosage. In clinical trials, no incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose. Higher doses of meloxicam (22.5 mg and greater) have been associated with increased risk of serious gastrointestinal events; therefore the daily dose of meloxicam should not exceed 15 mg. Please see Important Safety Information at the end of this presentation and full Prescribing Information, including boxed WARNING, provided at this presentation. Some sub-columns in table do not add 1. Kivitz A, et al. Poster presented at ACR/ARHP Annual Scientific Meeting, October 2004. up to 100% because of rounding.
  • 7. ACR 20 Responder Rate at 12 Weeks for Evaluable Patients1 60 53.9† *P=.0008 vs. placebo (158/293) 49.8† †P<.0001 vs. placebo 45.1* (146/293) 50 (138/306) Responders (%) 40 33.2 (97/292) 30 20 10 0 Placebo Mel. 7.5 mg/d Mel. 15 mg/d Mel. 22.5 mg/d ‡ ‡Meloxicam 22.5 mg is not an approved dosage. In clinical trials, no incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose. Higher doses of meloxicam (22.5 mg and greater) have been associated with increased risk of serious gastrointestinal events; therefore the daily dose of meloxicam should not exceed 15 mg. Please see Important Safety Information at the end of this presentation and full Prescribing Information, including boxed WARNING, provided at this presentation. 1. Kivitz A, et al. Poster presented at ACR/ARHP Annual Scientific Meeting, October 2004.
  • 8. ACR 20 Responder Rates Results Over Time1,2 60 50 ** ** * * Responders % 40 * * * 30 20 *P<.05 vs. placebo 10 0 4 Weeks 8 Weeks 12 Weeks Placebo Mel. 7.5 mg Mel. 15 mg Mel. 22.5 mg† †Meloxicam 22.5 mg is not an approved dosage. In clinical trials, no incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose. Higher doses of meloxicam (22.5 mg and greater) have been associated with increased risk of serious gastrointestinal events; therefore the daily dose of meloxicam should not exceed 15 mg. Please see Important Safety Information at the end of this presentation and full Prescribing Information, including boxed WARNING, provided at this presentation. 1.Kivitz A et al. Poster presented at ACR/ARHP Annual Scientific Meeting , October 2004. 2. Data on file, Boehringer Ingelheim Pharmaceuticals, Inc.
  • 9. Results: Secondary Efficacy Endpoints1 Number of Painful/Tender Joints Over Time Patient Assessment of Pain Over Time *P<.05 vs. placebo for all doses of meloxicam at 4, 8, and 12 weeks (both graphs)2 * * * * * * * * ** * * ** * * * * † † †Meloxicam 22.5 mg is not an approved dosage. In clinical trials, no incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose. Higher doses of meloxicam (22.5 mg and greater) have been associated with increased risk of serious gastrointestinal events; therefore the daily dose of meloxicam should not exceed 15 mg. Please see Important Safety Information at the end of this presentation and full Prescribing Information, including boxed WARNING, provided at this presentation.