Emerging
Clinical Science         from
         THE 69TH ANNUAL SCIENTIFIC MEETING OF
        THE AMERICAN COLLEGE OF RHEU...
Online Discussion:
                             Forum on Emerging Clinical Science from
                               The...
Table of Contents
Selective T Cell Costimulation Modulators
Abatacept Improves American College of Rheumatology Responses ...
Int roduct ion
Rheumatoid arthritis (RA) is a chronic systemic disease with progressive joint destruction that often resul...
SELECTIVE T CELL COSTIMULATION MODULATORS
T cells have been recognized as central coordinators of the immune cascade that ...
Time of
                                                                                                                  ...
SUSTAINED IMPROVEMENTS THROUGH 18 MONTHS WITH ABATACEPT IN RHEUMATOID ARTHRITIS PATIENTS
WITH AN INADEQUATE RESPONSE TO AN...
ABATACEPT INDUCES SUSTAINED IMPROVEMENTS IN PHYSICAL FUNCTION AND PAIN OVER 3 YEARS
IN RHEUMATOID ARTHRITIS PATIENTS WITH ...
SAFETY OF ABATACEPT IN RHEUMATOID ARTHRITIS PATIENTS IN FIVE DOUBLE-BLIND,
PLACEBO-CONTROLLED TRIALS
L. Moreland1, J. Kain...
In total, 1955 patients were treated with abatacept/DMARDs, representing 1527.4 person-years of exposure, while 989 patien...
Conclusions: In AIM, abatacept significantly improved sleep quality and reduced pain and fatigue, as well as significant, ...
B CELLS AS A NEW THERAPEUTIC TARGET
The role of B cells in RA is not as well defined as T cells. Recent research has indic...
in HAQ-DI, Pain VAS, FACIT-F, SF-36 PCS and SF-36 MCS are summarized in the Table. Mean changes from baseline in HAQ-DI, P...
CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski
CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski
CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski
CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski
CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski
CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski
CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski
CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski
CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski
CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski
CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski
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CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski

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Wrote the expert commentaries for the rheumatologists (key opinion leaders), introductions, and conclusions.

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CME writing sample_American College of Rheum. meeting_Crystal Kaczkowski

  1. 1. Emerging Clinical Science from THE 69TH ANNUAL SCIENTIFIC MEETING OF THE AMERICAN COLLEGE OF RHEUMATOLOGY e SAN DIEGO, CALIFORNIA NOVEMBER 12-17, 2005 pl m sa g in rit iw Abstracts and Expert Commentary sk w ko cz on the Prospective Management of Ka al st ry Rheumatoid Arthritis C Mary-Ann Fitzcharles, MD, ChB, FRCPC Robert Offer, MD, FRCPC McGill University, Montreal, Quebec University of British Columbia, Vancouver, BC McGill University Health Centre, Penticton Regional Hospital, Montreal, Quebec Penticton, British Columbia J. Carter Thorne, MD, FRCPC, FACP University of Toronto, Toronto, Ontario Southlake Regional Health Centre, Newmarket, Ontario A McGill University CME accredited program McGill
  2. 2. Online Discussion: Forum on Emerging Clinical Science from The 69th Annual Scientific Meeting of The American College of Rheumatology: ACR 2005 An online forum is available to allow physicians to discuss issues related to the prospective management of rheuma- toid arthritis as presented in this compilation. Dr. J. Carter Thorne will be available to answer questions and add his expert opinions to the forum. A self-assessment quiz is also available on the site. The web site address is: http://ww2.medicine.mcgill.ca/cme/ forum/index.php?fid=1139426071 CME credit (up to 2 credits) is also available to participants who meet the necessary requirements. If you wish to obtain credits, you must: • Log onto the forum and participate for 30 minutes in order to obtain 2 CME credits • Complete the self-assessment quiz To access the online forum, please follow these instructions: 1. Open your browser. 2. Go to the following McGill Faculty of Medicine Web site: http://ww2.medicine.mcgill.ca/cme/forum/index.php?fid=1139426071 3. To log in, you must first register on the McGill CME site by clicking on “click here” in the upper right hand corner of the window. 4. Once you have obtained your password, log into the “Forum on Emerging Clinical Science from The 69th Annual Scientific Meeting of The American College of Rheumatology: ACR 2005” by entering your email address and password in the boxes on the web site and click on “Go”. e pl m 5. Comments and discussions of the other participants can be reviewed, as well as those of the moderator, sa Dr. Thorne, by accessing this site. g in 6. If you would like to add a comment or ask a question, simply type a heading into the “Subject” box, type rit your comment into the “Message” box, and click on “Add/Ajoutez”. iw sk w ko Accreditation cz Ka al st ry C This event is approved for up to 2 credits by the Centre for Continuing Medical Education (CME). The Centre for CME, Faculty of Medicine, McGill University, is fully accredited by the Committee on Accreditation of Canadian Medical Schools (CACMS), and through the CACMS, is accredited to award AMA PRA (Physician’s Recognition Award) category 1 credits. This program meets the accreditation criteria of the College of Family Physicians of Canada for MAINPRO-M1 credits. Members of the American Academy of Family Physicians are eligible to receive credit hours for attendance at this meeting because of the reciprocal agreement with the College of Family Physicians of Canada. This event is an accredited group learning activity (Section 1) as defined by the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. The Centre for CME, Faculty of Medicine, McGill University designates, this activity for Category 1 credit towards the AMA Physicians Recognition Award up to the maximum number of credit hours noted above. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Potential Conflict of Interest Disclosure Dr. Fitzcharles has consulted for Janssen-Ortho Inc., Merck Frosst Canada Ltd., and Bristol-Myers Squibb Canada Inc. Dr. Offer consulted for Amgen Canada Inc., Schering Plough Corp., GlaxoSmithKline Inc., Merck Frosst Canada Ltd., Procter & Gamble Pharmaceuticals Canada, Inc., and Wyeth Pharmaceuticals. He has also received research support from Abbott Laboratories Ltd., Amgen Canada Inc., Hoffman-La Roche Ltd. (Canada), and Wyeth Pharmaceuticals Dr. Thorne is a member of the advisory boards of Abbott Laboratories Ltd., Amgen Canada Inc./Wyeth Pharmaceuticals, Bristol-Myers Squibb Canada Inc., Hoffmann-La Roche Ltd, Pfizer Canada Inc., and Janssen-Ortho Inc. He has received research support from Abbott Laboratories Ltd., Amgen Canada Inc., Bristol-Myers Squibb Canada Inc., Celltech Group PLC, Centocor Inc., Elan Corporation/Biogen Idec Canada Inc., Hoffmann-La Roche Ltd, and Takeda Pharmaceuticals North America, Inc. He has also spoken for Abbott Laboratories Ltd., Amgen Canada Inc./Wyeth Pharmaceuticals, and Pfizer Canada Inc.
  3. 3. Table of Contents Selective T Cell Costimulation Modulators Abatacept Improves American College of Rheumatology Responses and Disease Activity Score 28 Remission Rates in Both Recent Onset and More Established Rheumatoid Arthritis: Results from the AIM Trial. J. Kremer, R. Westhovens, C. Abud-Mendoza, R. Valente, R. Aranda, J-C Becker, O. Mokliatchouk, L. Moreland. Expert Commentary by Mary-Ann Fitzcharles, MB, ChB, FRCPC, McGill University Arthritis Rheum 2005;52(9 Suppl):S138(Abstract 1494). Sustained Improvements Through 18 Months with Abatacept in Rheumatoid Arthritis Patients with an Inadequate Response to Anti-TNF Therapy. M. Genovese, M. Luggen, M. Schiff, Y. Sherrer, K. Sen, R. Aranda, J-C Becker, M. Dougados. Expert Commentary by J. Carter Thorne, MD, FRCPC, FACP, University of Toronto Presented at: The 69th Annual Scientific Meeting of The American College of Rheumatology (ACR) 2005; November 12–17, 2005; San Diego, California. Late-breaking Abstract L16. Abatacept Induces Sustained Improvements in Physical Function and Pain over 3 Years in Rheumatoid Arthritis Patients with Inadequate Responses to Methotrexate. A. Russell, J. Kremer, Y. Zhou, O. Mokliatchouk, T. Li, L. Moreland. Expert Commentary by Mary-Ann Fitzcharles, MB, ChB, FRCPC, McGill University Arthritis Rheum 2005;52(9 Suppl):S659(Abstract 1778). Safety of Abatacept in Rheumatoid Arthritis Patients in Five Double-Blind, Placebo-Controlled Trials. L. Moreland, J. Kaine, L. Espinoza, T. McCann, R. Aranda, J-C Becker, J. Kremer, C. Bingham. Expert Commentary by J. Carter Thorne, MD, FRCPC, FACP, University of Toronto Arthritis Rheum 2005;52(9 Suppl):S350(Abstract 886). Abatacept Induces Sustained Improvements in Quality of Life, Sleep Quality and Fatigue over 3 Years in Rheumatoid Arthritis Patients with Inadequate Responses to Methotrexate. P. Emery, A. Russell, J. Markenson, Y. Zhou, O. Mokliatchouk, T. Li, R. Westhovens. Expert Commentary by Robert C. Offer, MD, FRCPC, University of British Columbia e pl Arthritis Rheum 2005;52(9 Suppl):S258(Abstract 626). m sa B Cells as a New Therapeutic Target g in Improvements in Patient Reported Outcomes Over 24 Weeks for Rituximab with Methotrexate in Rheumatoid Arthritis rit iw Patients in Phase IIb Trial (DANCER). sk P. Mease, J. Szechinski, M. Greenwald, M. Leirisalo-Repo, A. Kivitz, L. Barile-Fabris, J. Kalsi, J. Eames. w Expert Commentary by Mary-Ann Fitzcharles, MB, ChB, FRCPC, McGill University ko Arthritis Rheum 2005;52(9 Suppl):S138(Abstract 280). cz Ka Reconstitution of Peripheral Blood B Cells after Depletion with Rituximab in Patients with Rheumatoid Arthritis. al M. J. Leandro, M. R. Ehrenstein, G. Cambridge, J. C. Edwards. st Expert Commentary by Robert C. Offer, MD, FRCPC, University of British Columbia ry C Arthritis Rheum 2005;52(9 Suppl):S338(Abstract 854). Efficacy and Safety of Rituximab in Active RA Patients who Experienced an Inadequate Response to One or More Anti-TNF-α Therapies (REFLEX Study). S. B. Cohen, M. Greenwald, M. R. Dougados, P. Emery, R. Furie, T. M. Shaw, M. C. Totoritis. Expert Commentary by J. Carter Thorne, MD, FRCPC, FACP, University of Toronto Arthritis Rheum 2005;52(9 Suppl):S677(Abstract 1830). Safety and Tolerability of Rituximab Retreatment in Patients with Active Rheumatoid Arthritis. P. Emery, R. M. Fleischmann, K. Pavelka, A. T. Kaell, J. Z. Szechiski, M. M. Hooper, N. F. Li, J. P. Garg, K. A. Rowe, P. B. Lehane. Expert Commentary by J. Carter Thorne, MD, FRCPC, FACP, University of Toronto Arthritis Rheum 2005;52(9 Suppl):S341(Abstract 860). Improved Quality of Life with Rituximab Plus Methotrexate in Patients with Active Rheumatoid Arthritis who Experienced Inadequate Response to One or More Anti-TNF-α Therapies. E. C. Keystone, G. R. Burmester, R. Furie, J. E. Loveless, P. Emery, M. W. Cravets, F. Magrini. Expert Commentary by Robert C. Offer, MD, FRCPC, University of British Columbia Arthritis Rheum 2005;52(9 Suppl):S141(Abstract 287). Interleukin-6, a Pleiotropic Cytokine Blocking Interleukin-6 (IL-6) By Tocilizumab (A Humanized Anti-Interleukin-6 Receptor Monoclonal Antibody) Monotherapy Reduces Joint Damage in Active Rheumatoid Arthritis (RA): Evidence from an X-Ray Reader-Blinded Randomised Controlled Trial. N. Nishimoto, J. Hashimoto, N. Miyasaka, K. Yamamoto, S. Kawai, T. Takeuchi, N. Murata, D. van der Heijde, T. Kishimoto. Expert Commentary by Mary-Ann Fitzcharles, MB, ChB, FRCPC, McGill University Presented at: The 69th Annual Scientific Meeting of The American College of Rheumatology (ACR) 2005; November 12–17, 2005; San Diego, California. Late-breaking Abstract L27. Long-Term Treatment of Systemic Onset Juvenile Idiopathic Arthritis (SO-JIA) with Humanized Anti-IL-6 Receptor Monoclonal Antibody, Tocilizumab (Actemra®). S. Yokota, T. Miyamae, R. Kurosawa, R. Ozawa, T. Imagawa, M. Mori, N. Nishimoto. Expert Commentary by Robert C. Offer, MD, FRCPC, University of British Columbia Arthritis Rheum 2005;52(9 Suppl):S725(Abstract 1956). Conclusions
  4. 4. Int roduct ion Rheumatoid arthritis (RA) is a chronic systemic disease with progressive joint destruction that often results in major long- term disability, premature mortality, and great personal and socioeconomic burden. Joint damage occurs early in the course of the disease, with 30% of patients exhibiting radiographic evidence of erosions at the time of diagnosis, increasing to 60% within two years.1 Overall, the long-term prognosis for RA is poor. Therapeutic options available in the management of RA have advanced considerably in the last two decades. Biological therapies hold the promise of targeted intervention. Recent progress in the development of these therapies shows that rational targeting can provide clinical benefit to RA patients.2 Although the development of biologic agents (eg, tumour necrosis factor-α (anti-TNF-α) inhibitors, interleukin inhibitors) have revolutionized the management of RA, some patients still suffer from inadequate response to treatment.3 A substantial proportion of RA patients either do not respond to these agents or experience a reduction in their initial response.4,5 Furthermore, anti-TNF agents are associated with increased rates of infection, lymphoma, and tuberculosis. These issues of long-term efficacy and safety have created a compelling need to develop new therapeutic strategies. Ongoing research efforts have resulted in a clearer understanding of the role of inflammatory mediators and have led to the development of additional biologic agents. These agents fall into three major groups: those that target T cells, those that target B cells, and those that target the cytokine pathways involved in RA. Clinical trials are underway to investigate the efficacy and safety of these emerging therapeutic agents. e pl m The American College of Rheumatology Annual Meeting (ACR 2005) was held in San Diego, California on November 12-17, sa 2005, and brought together clinicians and research scientists from around the globe. This document contains selected g in rit noteworthy abstracts presented at the meeting that reported the results of recent clinical trials evaluating these emerging iw biologic therapies. The emphasis of this review is on three novel therapeutic approaches: 1) a selective T cell co-stimulation sk w modulator (abatacept); 2) a B cell depleting agent (rituximab [RTX]); and 3) an interleukin-6 inhibitor (tocilizumab [MRA]). ko cz Each abstract is followed by expert commentary to provide clinicians with a concise overview of current research and Ka development in the treatment of RA. The three physicians provided their commentaries based on their acknowledged al st ry expertise in the field of rheumatoid arthritis. They did so with complete and independent editorial freedom. C References: 1. van der Heijde DM. Joint erosions and patients with early rheumatoid arthritis. Br J Rheumatol 1995;34:74-78. 2. Carter RH. B cell signaling as therapeutic target. Ann Rheum Dis 2004;63(Suppl II):ii65-ii66. 3. Weinblatt ME. Will our current success in treating rheumatoid arthritis hinder new drug development? That is the question!! Ann Rheum Dis 2005;64:1529–1531. 4. Keystone EC. Tumor necrosis factor-α blockade in the treatment of rheumatoid arthritis. Rheum Dis Clin North Am 2001;27:427-443. 5. Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med 2004;350:2167-2179. 1
  5. 5. SELECTIVE T CELL COSTIMULATION MODULATORS T cells have been recognized as central coordinators of the immune cascade that leads to inflammation and joint erosion.1 They require two signals from antigen presenting cells (APC) for activation.2,3 The first is the antigen-specific interaction between the T cell receptor and the major histocompatibility complex on the surface of APC.4 Another costimulatory signal then takes place between CD28 molecules on T cells and CD80 or CD86 molecules on APC. Together, the two signals trigger T cell proliferation and cytokine production, which initiates additional inflammatory cells.4 Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is an immunoregulatory protein that is expressed on the surface of T cells following activation. It binds to CD80 or CD86, and prevents interaction with CD28, thus reducing T cell proliferation and cytokine production.5 Presentations and posters at ACR examined the first of these agents, CTLA4-Ig. Abatacept (CTLA4-Ig) Abatacept is a chimeric fusion protein of CTLA4, a surface receptor on T cells and the Fc portion of Immunoglobulin (Ig)G1. Initial pilot studies and large, multicentre trials have established the efficacy and safety of abatacept in treating the signs and symptoms of RA.6-9 These multicentre trials include: Abatacept in Inadequate Responders to Methotrexate (AIM – Phase III), evaluating efficacy, safety, and quality of life (QoL) parameters. Abatacept Trial in Treatment of Anti-TNF INadequate Responders (ATTAIN – Phase III), evaluating efficacy, safety, and QoL parameters. Abatacept Study of Safety in Use with other Rheumatoid Arthritis thErapies (ASSURE – Phase III), assessing safety during 1 year of add-on treatment. Numerous abstracts were presented recently at “The European League Against Rheumatism Annual Congress” (EULAR) and ACR conferences based on these studies. The following are selected abatacept scientific abstracts from the ACR 2005 conference along with expert commentary. References: 1. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344:907-916. 2. Greenfield EA, Nguyen KA, Kuchroo VK. CD28/B7 costimulation: a review. Crit Rev Immunol 1998;18:389-418. 3. Goronzy JJ, Weyand CM. T-cell regulation in rheumatoid arthritis. Curr Opin Rheumatol 2004;16:212-217. 4. Singh R, Robinson DB, El-Gabalawy HS. Curr Opin Rheumatol 2005;17:274-279. 5. Verwilghen J, Lovis R, De Boer M, et al. Expression of functional B7 and CTLA4 on rheumatoid synovial T cells. J Immunol 1994;153:1378-1385. e 6. Moreland LW, Alten R, Van den Bosch F, et al. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo- pl m controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 2002;46:1470-1479. sa 7. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J g Med 2003;349:1907-1915. in 8. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to Tumor Necrosis Factor α inhibition. N Engl J Med 2005;353:1114-1123. rit iw 9. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a sk phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:2263-2271. w ko cz Ka ABATACEPT IMPROVES AMERICAN COLLEGE OF RHEUMATOLOGY RESPONSES AND DISEASE ACTIVITY al st SCORE 28 REMISSION RATES IN BOTH RECENT-ONSET AND MORE ESTABLISHED RHEUMATOID ARTHRITIS: ry C RESULTS FROM THE AIM TRIAL J. Kremer1, R. Westhovens2, C. Abud-Mendoza3, R. Valente4, R. Aranda5, J-C Becker5, O. Mokliatchouk5, L. Moreland6. 1 Center for Rheumatology, Albany, NY; 2Universitaire Ziekenhuizen, Leuven, Belgium; 3Hospital Central Dr Ignacio Morones Prieto, San Luis Potosi, Mexico; 4Arthritis Center of Nebraska, Lincoln, NE; 5Bristol-Myers Squibb, Princeton, NJ; 6University of Alabama at Birmingham School of Medicine, Birmingham, AL Arthritis Rheum 2005;52(9 Suppl):S138(Abstract 1494). Purpose: Different immunopathologic mechanisms may drive recent-onset versus more established rheumatoid arthritis (RA). The effects of the selective co-stimulation modulator abatacept on ACR responses and its ability to induce remission (Disease Activity Score 28 [DAS28] <2.6) were examined in RA patients with early or more established disease and an inadequate response to methotrexate (MTX). Methods: AIM (Abatacept in Inadequate responders to MTX) was a 1-year, randomized, double-blind, placebo-controlled, multicenter, Phase III trial of a fixed dose of abatacept approximating 10 mg/kg vs placebo with background MTX in patients with active RA and an inadequate response to MTX. Study medication was administered on Days 1, 15 and 29, and then every 28 days thereafter by 30-minute intravenous infusion. ACR responses and DAS28 remission were evaluated in a post-hoc analysis of patients with baseline disease durations of ≤2 years, >2-≤5 years, >5-≤10 years and >10 years. Results: A total of 433 and 219 patients were randomized and treated with abatacept or placebo, respectively, with 385 (88.9%) of the abatacept group and 162 (74.0%) of the placebo group completing 1 year. Mean baseline disease duration was 8.5 ± 7.3 vs 8.9 ± 7.1 years for abatacept vs placebo and mean baseline DAS28 was 6.4 for all, indicating high disease activity. Overall, abatacept-treated patients exhibited significant, sustained and increasing ACR responses and DAS28 remission rates vs placebo through 1 year (Table). No differences between response variables were observed during the 1-year study in patients with recent-onset vs more established disease (Table). Conclusion: In this study, abatacept induced consistent clinical improvements in signs and symptoms and in DAS28 remission, irrespective of disease duration, in RA patients with an inadequate response to MTX. These data suggest that the selective co-stimulation modulator abatacept is effective at inducing meaningful improvements in clinical responses in RA patients with high disease activity and in both recent-onset and more established disease. 2
  6. 6. Time of DAS28* remission† n (%) measurement ACR 20 responses n (%) ACR 50 responses n (%) ACR 70 responses n (%) Abatacept Placebo Abatacept Placebo Abatacept Placebo Abatacept Placebo All patients randomized and treated (n=424 for abatacept; n=214 for placebo)‡ 288 (67.9)§ 169 (39.9)§ 84 (19.8)§ 62 (14.8)§ 6 months 85 (39.7) 36 (16.8) 14 (6.5) 6 (2.8) § 205 (48.3)§ 122 (28.8)§ 101 (23.8)§ 12 months 310 (73.1) 85 (39.7) 39 (18.2) 13 (6.1) 4 (1.9) Disease duration ≤2 years (n=95 for abatacept; n=41 for placebo)** 6 months 67 (70.5) 19 (46.3) 43 (45.3) 11 (26.8) 22 (23.2) 4 (9.8) 16 (17.0) 1 (2.5) 12 months 76 (80.0) 16 (39.0) 52 (54.7) 7 (17.1) 33 (34.7) 5 (12.2) 31 (32.6) 2 (5.0) Disease duration >2-≤5 years (n=91 for abatacept; n=46 for placebo) ** 6 months 64 (70.3) 20 (43.5) 40 (44.0) 8 (17.4) 25 (27.5) 2 (4.3) 16 (18.0) 1 (2.2) 12 months 62 (68.1) 22 (47.8) 42 (46.2) 11 (23.9) 27 (29.7) 3 (6.5) 22 (24.2) 0 (0.0) Disease duration >5-≤10 years (n=105 for abatacept; n=54 for placebo) ** 6 months 72 (68.6) 22 (40.7) 43 (41.0) 9 (16.7) 21 (20.0) 6 (11.1) 17 (16.2) 1 (1.9) 12 months 75 (71.4) 21 (38.9) 51 (48.6) 10 (18.5) 30 (28.6) 3 (5.6) 21 (20.0) 1 (1.9) Disease duration >10 years (n=133 for abatacept; n=73 for placebo) ** 6 months 85 (63.9) 24 (32.9) 43 (32.3) 8 (11.0) 1 24.1) 2 (2.7) 27 (20.3) 2 (1.4) *DAS28 C-reactive protein was used; †Last observation carried forward analysis shown; ‡Patients from one site were excluded due to compliance issues; § p<0.001 vs placebo + MTX; **Statistical comparisons between abatacept- and placebo-treated patients were not performed on the post-hoc analysis EXPERT COMMENTARY by Mary-Ann Fitzcharles, MB, ChB, FRCPC, McGill University ACR responses and Disease Activity Score 28 (DAS28) <2.6 remission rates were measured in RA patients treated with abatacept, a selective co-stimulation modulator, compared with placebo in the Phase III AIM (Abatacept in Inadequate responders to Methotrexate [MTX]) trial. The AIM trial was an important study assessing efficacy, safety, and quality of life parameters in patients with early or more established disease and inadequate responses to MTX. This abstract focuses on the efficacy of abatacept in RA. ACR 20, 50, and 70 scores were assessed, corresponding to a 20%, 50%, or 70% e pl improvement in ACR criteria from baseline. Improvements in disease activity were measured using DAS28 (using C-reactive protein levels). ACR m responses and DAS28 remission were evaluated in a post-hoc analysis of patients with disease durations at baseline of ≤2 years, >2-≤5 years, sa >5-≤10 years and >10 years. A weakness of this study was that statistical analyses were not performed on the post-hoc analysis of disease duration. g in Overall, 433 patients were treated with abatacept and 219 patients with placebo. Patients had high baseline disease activity as evidenced by a rit iw mean DAS28 score of 6.4. Mean baseline disease duration was 8.5 years and 8.9 years for the abatacept and placebo groups, respectively. sk Treatment with abatacept produced statistically significant improvements in ACR 20, 50, and 70 responses at 6 months and 1 year compared w with placebo (p<0.001). DAS28 remission rates were also significantly higher at 6 months (14.8% vs 2.8%) and 1 year (23.8% vs 1.9%) in ko cz abatacept- and placebo-treated patients respectively (p<0.001). Most impressive was that these improvements in ACR responses and DAS28 Ka scores were sustained (and even increased) throughout the study duration. al Sub-analyses based on baseline disease duration also demonstrated marked improvements in all ACR 20, 50, and 70 responses with abatacept st ry treatment at 6 months and 1 year compared with placebo, regardless of disease duration. Furthermore, ACR responses generally improved from C 6 months to 1 year in abatacept-treated patients split by disease duration. No differences between response variables were observed during the 1-year study in patients with recent-onset vs a longer disease duration. Noteworthy points of this study were that ACR and DAS28 responses were generally similar in patients of varying disease duration. Patients with longer disease duration are generally considered more resistant and less responsive to treatment.1 Thus, it is striking that patients with shorter disease durations (even with early RA) responded fairly equally to those with more established disease (>10 years). Data from this analysis support the use of abatacept at any stage of disease. Reference: 1. Weinblatt ME. Will our current success in treating rheumatoid arthritis hinder new drug development? That is the question!! Ann Rheum Dis 2005;64:1529–1531. 3
  7. 7. SUSTAINED IMPROVEMENTS THROUGH 18 MONTHS WITH ABATACEPT IN RHEUMATOID ARTHRITIS PATIENTS WITH AN INADEQUATE RESPONSE TO ANTI-TNF THERAPY M. Genovese1, M. Luggen2, M. Schiff3, Y. Sherrer4, K. Sen5, R. Aranda5, J-C Becker5, M. Dougados6. 1 Stanford University Medical Center, Stanford, CA; 2University of Cincinnati Medical Center, Cincinnati, OH; 3Denver Arthritis Clinic, Denver, CO; 4Center for Rheumatology, Immunology and Arthritis, Fort Lauderdale, FL; 5Bristol-Myers Squibb, Princeton, NJ; 6Rene Descartes University, Paris, France Presented at: The 69th Annual Scientific Meeting of The American College of Rheumatology (ACR) 2005; November 12–17, 2005; San Diego, California. Late-breaking Abstract L16. Purpose: To evaluate the sustained efficacy and safety of abatacept through 18 months of treatment in rheumatoid arthritis (RA) patients with an inadequate response to anti-TNF therapy. Abatacept, a selective co- stimulation modulator of T-cell activation, has shown efficacy in RA patients with an inadequate response to methotrexate and/or anti- TNF therapy1,2. In ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders), ACR and Health Assessment Questionnaire responses, and the Disease Activity Score 28 (DAS28; based on C-reactive protein levels), were assessed over 18 months, comprising 6 months of double-blind (DB) treatment and a 1-year, open-label, long-term extension (LTE). Methods: At entry, all patients in ATTAIN had an inadequate response to ≥3 months of treatment with ≥1 TNF inhibitor due to lack of efficacy. During the DB phase, patients were randomized to receive a fixed dose of abatacept (~10 mg/kg) or placebo intravenously on Days 1, 15 and 29, and every 28 days thereafter. All patients who completed the DB phase were eligible to enter the LTE, during which all patients received a once-monthly fixed dose of abatacept (~10 mg/kg) in addition to ≥1 background DMARD. Following a washout period, no anti-TNF therapies were permitted. e pl Results: Of the 258 patients randomized to abatacept during the DB m sa phase, 223 (86.4%) patients completed 6 months of treatment and 218 (84.5%) entered the LTE. Of these, 168 patients completed g in 18 months’ treatment. On Day 169 (end of DB phase), ACR 20, ACR rit iw 50 and ACR 70 responses for the 218 patients who entered the LTE were 59.4%, 23.5% and 11.5%, respectively (Figure), and these responses sk were sustained through the 1-year LTE (on Day 533: 56.7%, 35.0% and 18.0%, respectively). At the end of the DB phase, 11.2% of the w abatacept-treated patients achieved DAS28-defined remission; twice as many patients experienced this improvement following the 1-year LTE ko (22.5%). Abatacept was generally safe and well tolerated. cz Ka Conclusion: These data support the sustained clinical benefit of abatacept through 18 months of treatment in patients with active RA and an al inadequate response to anti-TNF therapy. st ry 1 Genovese M, et al. ACR Annual Meeting, 16-21 October 2004:L16 C 2 Kremer JM, Dougados M, Emery P, et al. Arthritis Rheum 2005;52(8):2263-2271. EXPERT COMMENTARY by J. Carter Thorne, MD, FRCPC, FACP, University of Toronto Efficacy was demonstrated based on DAS28 remission in 22.5% of the patients who completed 18 months of abatacept treatment (6 months double-blind phase and 1-year long-term, open-label extension) in the ATTAIN trial. These remission rates increased two-fold compared with 6-month remission rates (11.2%) and are encouraging in patients with inadequate response to MTX and/or anti-TNF therapy. ACR 50 and 70 scores increased from 23.5% and 11.5% to 35.0% and 18.0%, respectively, at 18 months. However, ACR20 scores were comparable at 6 and 18 months (59.4% vs 56.7%). All 6-month scores were significantly increased compared with placebo. Six month data from the ATTAIN trial has recently been reported by Genovese and colleagues.1 Clinically meaningful and statistically significant QoL improvements were also demonstrated in this refractory patient population at 6 months,1 although HAQ-DI scores declined marginally over the course of the open-label period (from 54.4% at 6 months to 47% at 18 months) in abatacept-treated patients. It is possible that this observation may represent the gradual decline related to progression of damage present at study entry in this recalcitrant group. Clinical improvements in ACR and HAQ scores were noted soon after treatment commenced (at Day 15). Sustained improvements continued throughout the 18-month study duration. During the open-label period, the incidence of AEs of all types was 90.5%, and of severe adverse events (SAEs) was 26.5%. Five percent of patients discontinued treatment due to an AE. There were 16 discontinuations during the open-label period, 11 of which due to SAEs. One death was reported during the LTE after approximately 1.5 years of exposure to abatacept and background DMARD therapy, due to pneumonia, pseudeomonal sepsis, retroperitoneal hemorrage, hematoma, and respiratory failure. Overall, abatacept was safe and well tolerated. This study provides further evidence of the efficacy of abatacept over a period of 18 months in difficult-to-treat patients. These results are consistent with previously reported data in MTX inadequate responders.2,3 Efficacy of treatment began early and was prolonged, providing some hope for this patient population. Safety data were within acceptable limits. References: 1. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition. N Engl J Med 2005;353:1114-1123. 2. Kremer JM, Westhovens R, Leon M. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349:1907-1915. 3. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a Phase IIb, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:2263-2271. 4
  8. 8. ABATACEPT INDUCES SUSTAINED IMPROVEMENTS IN PHYSICAL FUNCTION AND PAIN OVER 3 YEARS IN RHEUMATOID ARTHRITIS PATIENTS WITH INADEQUATE RESPONSES TO METHOTREXATE A. Russell1, J. Kremer2, Y. Zhou3, O. Mokliatchouk3, T. Li3, L. Moreland4. 1 University of Alberta Hospital, Edmonton, AB, Canada; 2Center for Rheumatology, Albany, NY; 3Bristol-Myers Squibb, Princeton, NJ; 4University of Alabama School of Medicine, Birmingham, AL Arthritis Rheum 2005;52(9 Suppl):S659(Abstract 1778). Purpose: Patients with rheumatoid arthritis (RA) exhibit significant levels of pain and impairments in physical function. The effect of the selective co-stimulation modulator, abatacept, on these issues was examined in the Phase III AIM (Abatacept in Inadequate responders to Methotrexate [MTX]) trial and in a similar patient population treated with abatacept for up to 3 years as part of a Phase II trial. Methods: AIM was a 1-year, double-blind, placebo-controlled trial evaluating a fixed dose of abatacept approximating 10 mg/kg plus MTX. Also presented are data from a 1-year, double-blind Phase II trial with a 2-year open-label long-term extension (LTE) where patients received abatacept 10 mg/kg or placebo plus MTX up to 1 year and a fixed dose approximating 10 mg/kg abatacept plus MTX thereafter. All patients had active RA despite MTX treatment. Physical function was assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI) in AIM and the modified HAQ-DI (mHAQ-DI) in Phase II. The proportion of patients demonstrating a HAQ-DI response was evaluated, defined as an improvement of ≥0.3 units in HAQ-DI or mHAQ-DI for AIM and Phase II, respectively. Pain was measured using a 100 mm Visual Analog Scale during assessment of ACR responses. Responses were measured prior to study drug administration. Results: In AIM, 433 and 219 patients were randomized and treated with abatacept or placebo treatment, respectively, with 385 (88.9%) of the abatacept group and 162 (74.0%) of the placebo group completing 1 year. In the Phase II trial, 84 (73.0%) abatacept-treated patients and 67 (56.3%) placebo-treated patients entered the LTE. In AIM, a significant proportion of abatacept-treated patients demonstrated clinically meaningful improvements in physical function and significant improvements from baseline in HAQ-DI scores and pain from Day 15 onwards (after the first dose), and through 1 year, vs placebo. Similar improvements in mHAQ-DI and pain were sustained through 3 years in the Phase II study (Table). These improvements were consistent with clinical responses. Conclusions: Consistent with symptomatic improvements, abatacept demonstrated rapid, significant and clinically meaningful improvements in physical function and reductions in pain in patients with inadequate responses to MTX; similar improvements were observed for up to 3 years in a Phase II study. These data suggest that abatacept treatment can provide tangible, sustained, real-life benefits to RA patients. e pl Phase II*† m Assessment AIM trial* sa 1 year‡ 6 months 1 year 2 years 3 years g in Placebo Abatacept Placebo Abatacept Placebo Abatacept Abatacept Abatacept rit (n=214)§ (n=424)§ (n=214)§ (n=424)§ iw (n=67) (n=84) (n=84) (n=84) sk HAQ-DI (AIM)/mHAQ-DI (Phase II): 20.9 35.2 19.6 37.3 18.2 49.4 46.3 49.3 w (1.9)** (2.3)** mean % improvement (SE) (2.7) (3.2) (7.2) (4.2) (5.5) (5.3) ko cz HAQ-DI (AIM) /mHAQ-DI (Phase II) 97 259 84 270 23/66 46/84 39/73 34/64 Ka (61.1)** (63.7)** responder patients, n (%) (45.3) (39.3) (34.8) (54.8) (53.4) (53.1) al st Pain: mean % improvement (SE) 3.5 42.5 8.0 50.5 35.4 52.4 50.2 55.6 ry (5.3)** (4.0)** (7.4) (5.7) (5.7) (5.7) (6.6) (5.3) C *Patients continued with background MTX; †As-observed population; ‡Placebo-controlled phase; §Patients from one site were excluded from efficacy analyses due to protocol violations; **p<0.001 vs placebo EXPERT COMMENTARY by Mary-Ann Fitzcharles, MB, ChB, FRCPC, McGill University Rheumatoid arthritis produces marked functional impairment in many RA patients.1 Consequently, quality of life is considerably reduced, even with optimum current treatments such as TNF-α inhibitors.2-4 Pain is increasingly recognized as an important and disabling symptom in RA. This study provides Health-Related Quality of Life (HRQoL) data for 1 year in the Phase III AIM study, one of the longest studies examining HRQoL parameters with biologic treatments for RA, and in a Phase II long-term extension for up to 3 years. Results from the AIM trial demonstrated clinically meaningful improvements in physical function as measured by the HAQ-DI starting at 2 months. Efficacy was maintained throughout the duration of the study. Rapid and significantly improved HAQ-DI scores and pain relief (measured by subject pain assessment on a Visual Analog Scale) were also seen starting on Day 15. Improvements were also sustained throughout the 3-year study period. Mean improvements in HAQ-DI seen in the Phase II extension with abatacept treatment were 49.4%, 46.3%, and 49.3% at 1, 2, and 3 years respectively. These results are particularly noteworthy as similar outcomes were demonstrated in the Phase II trial on a double-blind basis for the first year,5 and a further 2 years in open-label treatment, lending credence of a real-life setting. This report further extends the experience of abatacept in RA to 3 years. The impressive continued benefit out to 3 years is encouraging. A continued 50% reduction in pain at 3 years represents greatly improved quality of life. It is also noteworthy that there was good study patient retention to the 3 year mark, suggesting patient satisfaction with the treatment and lack of important adverse events requiring discontinuation of treatment. In summary, these 3-year data provide evidence of benefit of abatacept therapy in regards to HRQoL improvements and pain reduction in RA patients. References: 1. Young A, Dixey J, Cox N, et al. How does functional disability in early rheumatoid arthritis (RA) affect patients and their lives? Results of 5 years of follow-up in 732 patients from the Early RA Study (ERAS). Rheumatology (Oxford) 2000;39:603-611. 2. Fraenkel L, Bogardus ST, Concato J, et al. Patient preference for treatment of rheumatoid arthritis. Ann Rheum Dis 2004;63:1372-1378. 3. Wolfe F, Michaud K. Fatigue, rheumatoid arthritis, and anti-tumor necrosis factor therapy: an investigation in 24,831 patients. J Rheumatol 2004;31:2115-2120. 4. Arthritis Foundation. Living with Rheumatoid Arthritis: Unmet Needs. Available at: http://www.arthritis.org/conditions/diseasecenter/RA/RASurveyWhitePaperFinal.pdf. Accessed November 23, 2005. 5. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase IIb, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:2263-2271. 5
  9. 9. SAFETY OF ABATACEPT IN RHEUMATOID ARTHRITIS PATIENTS IN FIVE DOUBLE-BLIND, PLACEBO-CONTROLLED TRIALS L. Moreland1, J. Kaine2, L. Espinoza3, T. McCann4, R. Aranda4, J-C Becker4, J. Kremer5, C. Bingham6. 1 University of Alabama School of Medicine, Birmingham, AL; 2Sarasota Arthritis Center, Sarasota, FL; 3Louisiana State University Health Sciences Center, New Orleans, LA; 4Bristol-Myers Squibb, Princeton, NJ; 5Center for Rheumatology, Albany, NY; 6Johns Hopkins University, Baltimore, MD Arthritis Rheum 2005;52(9 Suppl):S350(Abstract 886). Purpose: The safety of the selective co-stimulation modulator abatacept in rheumatoid arthritis (RA) patients was evaluated during the double- blind portions of 5 controlled clinical trials. Methods: Clinical safety data were integrated from 5 randomized, double-blind, placebo-controlled studies in patients with active RA taking a variety of background anti-rheumatic therapies: two 1-year Phase II trials (background therapy=methotrexate [MTX] or etanercept) and three Phase III trials of 6 or 12 months’ duration (background therapy=MTX/variety of biologic and non-biologic DMARDs; patients with co-morbidities were included). Patients received abatacept (10 mg/kg [Phase III]) and 2 or 10 mg/kg [Phase II]) or placebo. Results: A total of 1955 and 989 patients were treated with abatacept or placebo, respectively: 1765 patients received 10 mg/kg or a fixed dose approximating 10 mg/kg abatacept, representing 1527.4 person-years of exposure. The incidence of death and serious adverse events (SAEs) was similar between groups, with discontinuations due to SAEs and AEs slightly higher for abatacept (Table). The most commonly reported AEs (mostly mild-to-moderate in severity) were headache, upper respiratory tract infections, nausea and nasopharyngitis. There were small increases in the overall incidence of infection and serious infection. Most of the infections were caused by expected pathogens, followed an expected course and responded to treatment. One case of suspected tuberculosis, not confirmed bacteriologically, was reported with abatacept treatment. Malignant neoplasms were reported in a similar proportion of patients in both groups. One lymphoma was reported with abatacept treatment. Safety data from the small subset of patients receiving abatacept with biologic DMARDs demonstrated a higher incidence of AEs, SAEs and infections in abatacept-treated patients receiving concomitant biologic RA therapy. Conclusion: In this large population (almost 2000 patients), abatacept appears generally safe and well tolerated, particularly when combined with non-biologic background therapy, although slightly increased infections rates were observed. These safety data, coupled with improvements in RA signs and symptoms1, support the use of the selective co-stimulation modulator abatacept for the treatment of RA. 1 Kremer J, et al. N Engl J Med 2003;349(20):1907-1915. e pl Overall safety* Abatacept (n=1955) Placebo (n=989) m sa Person-years of exposure (years) 1688.1 794.5 g in Death 0.5 (9) 0.6 (6) rit iw SAEs 13.6 (266) 12.3 (122) sk AEs 88.8 (1736) 84.9 (840) w ko Discontinuations due to SAEs 2.7 (53) 1.6 (16) cz Discontinuations due to AEs 5.5 (107) 3.9 (39) Ka Most commonly reported AEs: al Headache 18.2 (356) 12.6 (125) st ry URTI 12.7 (248) 12.0 (119) C Nausea 11.5 (224) 10.6 (105) Nasopharyngitis 11.5 (225) 9.1 (90) Infection 53.8 (1051) 48.3 (478) Serious infection 3.0 (58) 1.9 (19) Malignant neoplasms 1.2 (24) 1.0 (10) Safety split by background therapy* Abatacept + biologic Placebo + biologic Abatacept + non-biologic Placebo + non-biologic background therapy background therapy background therapy background therapy (n=204) (n=134) (n=1755) (n=855) SAEs 19.6 (40) 9.0 (12) 12.9 (226) 12.9 (110) AEs 94.1 (192) 84.3 (113) 88.2 (1544) 85.0 (727) Infections 63.7 (130) 43.3 (58) 52.6 (921) 49.1 (420) Serious infections 4.4 (9) 1.5 (2) 2.8 (49) 2.0 (17) *Data shown as % (n) unless otherwise indicated; URTI=Upper respiratory tract infection EXPERT COMMENTARY by J. Carter Thorne, MD, FRCPC, FACP, University of Toronto Due to their relative newness, limited data are available on the relative safety and efficacy of the approved TNF blockers. Increased rates of infections and lymphoma have been reported with use of these agents.1 This important abstract compiles safety and tolerability data from the double-blind phases of five controlled clinical trials in patients with active RA treated with abatacept as well as various biologic and nonbiological background DMARDs. Safety data were integrated from three Phase III studies of 6 or 12 months duration: AIM (n=652),2 ATTAIN (n=391),3 and ASSURE (n=1441).4 Patient profiles were as follows: AIM patients were inadequate responders to MTX, ATTAIN patients were anti-TNF inadequate responders, and ASSURE patients were patients taking any RA treatment. In these Phase III trials, patients were randomized to receive placebo or abatacept at 10 mg/kg. In addition, two 1-year Phase II studies in which patients were randomized to receive placebo or abatacept were analyzed.5,6 Emery et al, (2005) administered abatacept doses of either 2 mg/kg or 10 mg/kg to MTX inadequate responders (n=339).5 Patients received etanercept plus abatacept with doses of 2 mg/kg (n=121) in the second trial.6 6
  10. 10. In total, 1955 patients were treated with abatacept/DMARDs, representing 1527.4 person-years of exposure, while 989 patients were treated with placebo/DMARDs. Results of the safety analyses demonstrated that overall deaths, adverse events (AEs), serious adverse events (SAEs), and discontinuations were comparable with abatacept or placebo treatment. Eighty-nine percent (88.8%) of patients treated with abatacept/DMARDs and 84.9% of patients treated with placebo/DMARDs reported an AE. The most commonly reported AEs with abatacept/DMARD treatment occurring at a rate > 2% higher than placebo/DMARD treatment were headache (18.2%), nasopharyngitis (11.5%), dizziness (9.4%), hypertension (6.6%), and dyspepsia (6.4%). The most frequently reported SAEs were musculoskeletal and connective tissue disorders (3.0% for abatacept/DMARD-treated patients vs 3.7% for placebo/DMARD-treated patients). There were small increases in the overall incidence of mild and serious infections with abatacept treatment compared with placebo (3.0% vs 1.9%, respectively). The majority of infections were mild in intensity (35.8% vs 32.3%) for abatacept vs placebo treatment. Safety profiles were similar in patients receiving nonbiologic DMARDs and abatacept or placebo. However, when abatacept was administered with biologic DMARDs, higher rates of AEs, SAEs, and infections were reported. The clinician should note the increased rate of AEs and SAEs when abatacept is co-administered with biological DMARDs, and use due caution. Abatacept is not recommended in combination with biologic DMARDs. Abatacept was well tolerated; acute infusion-related AEs were similar between treatments. Treatment with abatacept does not appear to be associated with medically significant autoimmune symptoms and disorders, which were reported in 2.9% and 1.8% of patients in the abatacept and placebo groups, respectively. This large analysis of almost 2000 patients provides meaningful insight into the safety of abatacept by examining data from five double-blind, controlled studies. Results indicate that abatacept is generally safe and well-tolerated, especially when given in combination with non-biologic DMARDs. Like other biologic DMARDs, abatacept is associated with slightly increased rates of infection and serious infection. These adverse reactions may be related to blockade of TNF-α and thus represent class effects of these agents.1 Results from long-term extension studies should give further supportive evidence of relative safety. Registry databases which have been set up to monitor biologic therapies in a number of countries will be required to satisfy many clinicians as to the safety of these products, when administered outside the constraints of a clinical trial. In light of this safety data and symptomatic improvements in other trials,3,5,7,8 Dr. Moreland’s abstract concluded with support of abatacept for use in the treatment of RA in combination with non-biologic DMARDs. References: 1. US Food and Drug Administration: Arthritis Advisory Committee March 4, 2003. Update on the TNF-α Blocking Agents. Available at http://www.fda.gov/ohrms/dockets/ac/03/briefing/3930B1_01_B-TNF.Briefing.htm Accessed November 23, 2005. e pl 2. Steinfeld S, Moreland L, Abud C, et al. Rapid and significant improvements in the components of the ACR criteria in abatacept-treated rheumatoid arthritis m patients in the Phase III AIM (Abatacept in Inadequate Responders to Methotrexate) trial. Ann Rheum Dis 2005;64(Suppl. 3):457(Abstract SAT0151). sa 3. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition. N Engl J Med 2005;353:1114-1123. g in 4. Weinblatt M, Combe B, White A, et al. Safety of abatacept in patients with active rheumatoid arthritis receiving background non-biologic and biologic DMARDS: rit 1-Year results of the ASSURE trial. Ann Rheum Dis 2005;64(Suppl. 3):60(Abstract OP0012). iw 5. Emery P, Westhovens R, Leon G, et al. Beneficial effects of the selective co-stimulation modulator abatacept on biomarkers of rheumatoid arthritis immunopathology sk in patients with an inadequate response to methotrexate or TNF-inhibitor treatment. Ann Rheum Dis 2005;64(Suppl. 3):432(Abstract SAT0074). w ko 6. Weinblatt M, Schiff M, Goldman M, et al. A Pilot, Multi-center, randomized, double-blind, placebo controlled of a co-stimulation blocker CTLA4Ig (2 mg/kg) cz given monthly in combination with etanercept in active rheumatoid arthritis. Arthritis Rheum 2002;46(Suppl. 9):S204(Abstract464). Ka 7. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-Cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349:1907-1915. al st 8. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a ry Phase IIb, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:2263-2271. C ABATACEPT INDUCES SUSTAINED IMPROVEMENTS IN QUALITY OF LIFE, SLEEP QUALITY AND FATIGUE OVER 3 YEARS IN RHEUMATOID ARTHRITIS PATIENTS WITH INADEQUATE RESPONSES TO METHOTREXATE P. Emery1, A. Russell2, J. Markenson3, Y. Zhou4, O. Mokliatchouk4, T. Li4, R. Westhovens5. 1 University of Leeds, Leeds, United Kingdom; 2University of Alberta Hospital, Edmonton, AB; 3Hospital for Special Surgery, New York, NY; 4Bristol-Myers Squibb, Princeton, NJ; 5Universitaire Ziekenhuizen, Leuven, Belgium Arthritis Rheum 2005;52(9 Suppl):S258(Abstract 626). Purpose: Quality of life (QoL), sleep disturbance, fatigue and inadequate pain relief are significant issues for rheumatoid arthritis patients (RA). The effects of the selective co-stimulation modulator abatacept on QoL, fatigue, pain and sleep quality were examined in the Phase III AIM (Abatacept in Inadequate responders to Methotrexate [MTX]) trial and in a similar patient population treated with abatacept for up to 3 years as part of a Phase II trial. Methods: AIM was a 1-year, double-blind, placebo-controlled trial evaluating a fixed dose of abatacept approximating 10 mg/kg plus MTX. Also presented are data from a 1-year, double-blind, Phase II trial with a 2-year, open-label, long-term extension (LTE) where patients received abatacept 10 mg/kg plus MTX or placebo up to 1 year and the fixed dose approximating 10 mg/kg abatacept thereafter. Physical and mental health was measured using the Short Form (SF)-36, encompassing 4 physical and 4 mental domains, and physical and mental component summaries (MCS and PCS, respectively; weighted linear combinations of the 8 individual domains). In AIM, sleep quality was measured using the validated Medical Outcomes Study sleep scale (MOS-sleep). Fatigue and pain were measured using a 100 mm Visual Analog Scale. Results: In AIM, 433 vs. 219 patients were randomized and treated with abatacept or placebo, with 385 (88.9%) of the abatacept group and 162 (74.0%) of the placebo group completing 1 year. In Phase II, 84 (73.0%) abatacept-treated patients and 67 (56.3%) placebo-treated patients entered the LTE. In AIM, abatacept-treated patients demonstrated both clinically meaningful (change of ≥3 points) and statistically significant improvements in all eight subscales and both MCS and PCS of the SF-36 vs. placebo. Clinically meaningful improvements were observed up to 3 years in Phase II. Abatacept significantly improved sleep quality and reduced fatigue (Table). 7
  11. 11. Conclusions: In AIM, abatacept significantly improved sleep quality and reduced pain and fatigue, as well as significant, clinically meaningful improvements in all eight domains of the SF-36 and both the MCS and PCS. Similar improvements in QoL and reductions in pain were observed at time points up to 3 years in the Phase II trial, demonstrating the tangible, sustained benefits of abatacept from the patients’ perspective. Phase II trial*† AIM* 1 year‡ 6 months 1 year 2 years 3 years Placebo Abatacept Placebo Abatacept Placebo Abatacept Abatacept Abatacept (n=214)§ (n=424)§ (n=214)§ (n=424)§ (n=67) (n=84) (n=73) (n=63) Adjusted mean change from 4.8 8.8 5.0 9.1 4.5 9.7 9.2 9.3 (0.4)†† (0.4)†† baseline in PCS (AIM)/Mean (0.6) (0.6) (1.0) (1.1) (1.2) (1.2) change from baseline (Phase II) (SE) Adjusted mean change from 3.8 6.2 4.7 6.9 2.5 6.1 4.6 4.0 (0.5)** (0.5)** baseline in MCS (AIM)/Mean (0.7) (0.7) (1.3) (1.2) (1.3) (1.2) change from baseline (Phase II) (SE) Mean improvement in pain % (SE) 3.5 42.5 8.0 50.5 35.4 52.4 50.2 55.6 (5.3)†† (4.0)†† (7.4) (5.7) (5.7) (5.7) (6.6) (5.3) Adjusted mean change from -7.8 -10.2 -6.8 -10.4 (0.7)** baseline in MOS-sleep (SE) (1.0) (0.7) (1.0) – – – – Adjusted mean change from -17.2 -25.3 -16.4 -26.5 (1.2)†† (1.2)†† baseline in fatigue (SE) (1.8) (1.7) – – – – * All patients continued with background MTX; †As-observed population, n=81, 71 and 62 for mean improvement in pain at 1, 2 and 3 years, respectively, for abatacept; ‡Placebo-controlled phase; §Patients from 1 site were excluded from efficacy analyses due to compliance issues; ††p<0.001, **p<0.05, all vs placebo EXPERT COMMENTARY by Robert C. Offer, MD, FRCPC, University of British Columbia e pl m Rheumatoid arthritis (RA) has a significant impact upon health-related quality of life (HRQoL). More than 50% of RA patients have difficulty sa sleeping.1 It has been reported that RA patients have a 57% increase in sleep disturbances compared with the general population and use almost g 3 times more sleep medication.2 Clinically, one would expect RA patients to have improved sleep quality when treatment relieves inflammation that in rit is causing pain and stiffness at night. However, there are other factors that frequently disrupt sleep in these patients, including fibromyalgia, iw depression, lack of exercise, and medications such as prednisone. Many RA patients also complain of fatigue; prevalence has been estimated as sk high as 80%,3 and often fatigue is the most refractory symptom of rheumatoid arthritis. Although sleep disturbance and fatigue play a critical role w ko in patients’ quality of life, Dr. Emery pointed out during the presentation of this abstract that these parameters have rarely been studied in RA cz patients treated with biological agents. Tools such as the Health Assessment Questionnaire (HAQ) and Short Form 36 (SF-36) are well-validated and Ka directly measure physical and emotional well-being. Quality of life, fatigue, pain, and sleep quality were measured in patients treated with abatacept, al a selective co-stimulation modulator, in the Phase III AIM trial and a comparable patient population treated up to 3 years in a Phase II trial. The st ry AIM trial was an important study assessing efficacy, safety, and quality of life parameters in patients with inadequate responses to methotrexate. C In the AIM study, clinically significant improvements (>3 points) were demonstrated for pain and all eight subscales of the physical and mental component summaries (PCS and MCS) of the SF-36, while similar improvements, though not statistically significant, were seen in the Phase II long-term extension (LTE). The absence of statistical significance may be due to the smaller sample sizes of the LTE. These data are particularly interesting considering that improvements were maintained over 3 years in abatacept-treated patients. Sleep quality and fatigue were also significantly improved in patients treated with abatacept for 1 year in the AIM trial; these parameters were not measured in the LTE. The AIM results are consistent with the ATTAIN trial (abatacept /methotrexate vs placebo/methotrexate in RA patients with inadequate response to TNF-α inhibitors). In both trials, abatacept treatment led to statistically significant and clinically meaningful improvements in all eight SF-36 domains, as well as the PCS and MCS. Together, these trials provide evidence of clinically meaningful QoL benefits in patients previously not responding well to treatment. References: 1. Drewes AM, Nielsen KD, Hansen B, Taagholt SJ, Bjerregard K, Svendsen L. A longitudinal study of clinical symptoms and sleep parameters in rheumatoid arthritis. Rheumatology (Oxford) 2000;39:1287-1289. 2. Wolfe F, Michaud K. Sleep disturbance: rates, predictors and correlates in 10,000 patients with rheumatoid arthritis. Presented at: The Annual European Congress of Rheumatology; June 10, 2004; Berlin, Germany. Abstract THU0218. 3. Wolfe F, Michaud K. Fatigue, rheumatoid arthritis, and anti-tumor necrosis factor therapy: an investigation in 24,831 patients. J Rheumatol 2004;31:2115-2120. 8
  12. 12. B CELLS AS A NEW THERAPEUTIC TARGET The role of B cells in RA is not as well defined as T cells. Recent research has indicated that B cells have an essential function in regulating the immune response.1 They function as antigen-presenting cells, secrete a number of pro-inflammatory cytokines (including TNF-α), produce rheumatoid factor autoantibody, and directly activate T cells.1 Depletion of B cells in patients with RA substantially reduces the production of cytokines, which have been implicated in the inflammation cascade.2 Therefore, B cells have emerged as a novel target for therapy in RA. CD20 is a surface antigen present on pre-B and mature B cells.3 It is not present on stem cells and is lost prior to differentiation of B cells into plasma cells. Anti-CD20 monoclonal antibodies have demonstrated efficacy as B cell depleters.4,5 Rituximab (MabThera®/Rituxan®) Rituximab is a genetically engineered chimeric monoclonal antibody against CD20, currently approved for the treatment of relapsed or refractory B cell non-Hodgkin’s lymphoma. It is now being investigated for treatment of RA, with early studies showing promising results. A Phase II randomized, double-blind controlled study of 161 patients with RA compared the efficacy and safety of treatment with methotrexate (MTX) with that of rituximab, either as a monotherapy or in combination with either MTX or cyclophosphamide.6 A two-year follow up analysis of this Phase II trial and several sub-analyses were presented at recent EULAR and ACR conferences. All patients in this study received a short course of corticosteroids, raising questions regarding the concomitant use of steroids. The DANCER (The Dose-ranging Assessment iNternational Clinical Evaluation of Rituximab in RA) trial, also presented at this conference, addressed this issue by evaluating the effects of glucocorticosteroids when used in combination with rituximab. In addition, the DANCER trial assessed the efficacy and safety of different rituximab single dosing regimens. Results are just emerging from another trial examining rituximab, the REFLEX study, reported at ACR 2005. The following are selected abstracts from the ACR 2005 conference examining rituximab, along with expert commentary. References: 1. Dorner T, Burmester GR. The role of B cells in rheumatoid arthritis: mechanisms and therapeutic targets. Curr Opin Rheumatol 2003:15;246-252. 2. Tekemura S, Klimuik PAA, Braun A, et al. T cell activation in rheumatoid synovium is B cell dependant. J Immunol 2001;167;4710-4718. 3. Valentine MA, Meier KE, Rossie S, et al. Phosphorylation of the CD20 phosphoprotein in resting B lymphocytes. Regulation by protein kinase C. J Biol Chem 1989;264:11282-11287. 4. Press OW, Appelbaum F, Ledbetter JA, et al. Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas. Blood 1987;69:584-591. 5. Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994;83:435-445. e 6. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med pl 2004;350:2572-2581. m sa 7. Edwards JC, Leandro MJ, Cambridge G. B lymphocyte depletion in rheumatoid arthritis: targeting of CD20. Curr Dir Autoimmun 2005;8:175-192. g MabThera and Rituxan are registered trademarks of Roche. in rit iw sk IMPROVEMENTS IN PATIENT REPORTED OUTCOMES OVER 24 WEEKS FOR RITUXIMAB WITH METHOTREXATE w ko IN RHEUMATOID ARTHRITIS PATIENTS IN cz Mean (SD) Change from Baseline at Week 24 Ka PHASE IIB TRIAL (DANCER) Placebo RTX 500 mg RTX 1000 mg al st P. Mease1, J. Szechinski2, M. Greenwald3, M. Leirisalo-Repo4, A. N=122 N=123 N=12 ry Kivitz5, L. Barile-Fabris6, J. Kalsi7, J. Eames8. C HAQ-DI** 1 Swedish Medical Ctr, Seattle, WA; 2Medical Univ. of Wroclaw, Wroclaw, N 89 117 120 Poland; 3Desert Medical Advances, Palm Desert, CA; 4Helsinki Univ. Central Mean -.28 -.46 -.49 Hospital, Helsinki, Finland; 5Altoona Ctr for Clinical Research, Duncansville, MCID = -.22 (.50)* (.62)* (.55)* PA; 6Hospital Angeles, Mexico City, Mexico; 7Roche Products Ltd, Welwyn Garden City, United Kingdom; 8Genentech, South SF, CA Pain VAS** Arthritis Rheum 2005;52(9 Suppl):S138(Abstract 280). N 89 117 121 Purpose: To evaluate the impact of treatment of Rituximab (RTX) Mean -13.4 -21.5 -21.2 MCID = -10.0 (25.6)* (29.1)* (28.0)* with methotrexate (MTX) on patient reported outcomes (PROs). Methods: Patients randomized into 9 treatment arms in a 3x3 FACIT-F** configuration. RTX (placebo, 500mg or 1000mg) was given on N 89 116 121 Days 1 and 15 with 1 of 3 glucocorticoid options. Key inclusion Mean -3.91 -7.63 -8.20 criteria were SJC and TJC >8; elevated CRP or ESR; ongoing MTX MCID = -3.0 (9.36)* (10.74)* (10.06)* 10-25 mg/week; and 1-5 prior DMARDs/biologics except MTX. SF-36 PCS*** Analyses were implemented for the intention-to-treat RF+ population N 121 123 115 (n=367). Within-group and between-group changes from baseline Mean 1.74 6.44 7.08 were analyzed using paired and two sample t-tests. Because efficacy MCID = 3.0 (6.41)* (8.07)* (8.17)* was not affected by glucocorticoids (GC), GC arms were combined for each treatment group. ANOVA will be presented for between- SF-36 MCS*** group differences. N 121 123 115 Results: Baseline characteristics for the efficacy population were well Mean 1.39 4.09 2.90 balanced across treatment groups with overall means of: SJC=21, MCID = 3.0 (8.12) (12.37)* (11.45)* TJC=33, DAS28 score 6.8, MTX dose 15.5 mg/week, RA duration Data not included if baseline assessment missing 10.4 years, prior DMARD use 2.4, 32% had prior biologic therapy. *Statistically significant difference from baseline at p<.01 Baseline HAQ-DI was 1.7, 1.8, 1.7 for placebo, RTX 500mg, and **Negative change = improvement RTX 1000 mg respectively. Improvements at Week 24 from baseline ***Positive change = improvement 9
  13. 13. in HAQ-DI, Pain VAS, FACIT-F, SF-36 PCS and SF-36 MCS are summarized in the Table. Mean changes from baseline in HAQ-DI, Pain VAS, FACIT-F, and SF-36 PCS were statistically significantly better for RTX 500mg and 1000mg (p<.05) than placebo. All three treatment groups had statistically significant (p<.01) within group changes on all PROs except for SF-36 MCS placebo group. Changes clearly exceeded minimal clinically important differences (MCID) for RTX 500mg and RTX 1000mg and were much smaller for placebo. There were no statistically significant differences between RTX 500mg and 1000mg on all the PROs. Conclusion: These results demonstrate that a single course of RTX, combined with MTX, resulted in clinically meaningful PRO improvement in RA patients previously treated with DMARDS and biologics. EXPERT COMMENTARY by Mary-Ann Fitzcharles, MB, ChB, FRCPC, McGill University Rheumatoid arthritis takes a considerable toll on patients’ HRQoL. Even with advanced treatment, most patients report that their disease limits normal daily living.1,2 Patient satisfaction with a treatment intervention is recognized as increasingly important and has an impact upon compliance and continuation of treatment in the real world. Data from this randomized, double-blind Phase IIB study (DANCER) provides patient-reported outcomes from those with active disease despite treatment with DMARDs (other than MTX) and/or biological response modifiers. Patients with baseline disease activity that was moderate to severe were randomly assigned to receive a single course of placebo (n=122), RTX 500 mg (n=123), or RTX 1000 mg (n=122) administered on Days 1 and 15 by IV infusion. All patients received concurrent therapy with MTX weekly for the 24- week study duration. Corticosteroids were administered in 1 of 3 dosing regimens for all patients. As is commonly seen in studies of biologic treatment, the RA patients in this study represent patients with disease at the severe end of the spectrum. One third of the study group had previously received biologic treatment, although it is not specified that patients were biologic failures. Significant differences versus placebo were demonstrated for all measured parameters, including HAQ-DI, pain VAS, FACIT-F, and SF-36 (PCS and MCS) for the 500 mg RTX treatment group (p<0.05), and statistical significance for all measures except SF-36 MCS for the 1000 mg RTX treatment group (p<0.05). There were no statistically significant differences between each dose of RTX on patient-reported outcomes. At study endpoint, 63% and 67% of patients on RTX 500 mg and 1000 mg achieved minimal clinically important differences in HAQ-DI (defined as HAQ ≥0.22) compared with only 34% of patients on placebo. The placebo response in this study was, however, impressive, with significant changes from baseline in all parameters measured, except for SF-36 MCS. Co-administration of steroids may have contributed to the overall group improvements. In addition to other abstracts presented at ACR, results from the DANCER trial provide further evidence of clinically meaningful improvements in e physical function, fatigue reduction, and pain reduction in patients with inadequate responses to previous treatment strategies. pl m References: sa 1. Arthritis Foundation. Living with Rheumatoid Arthritis: Unmet Needs. Available at: http://www.arthritis.org/conditions/diseasecenter/RA/RASurvey g in WhitePaperFinal.pdf . Accessed November 23, 2005. rit 2. Young A, Dixey J, Cox N, et al. How does functional disability in early rheumatoid arthritis (RA) affect patients and their lives? Results of 5 years of follow-up in iw 732 patients from the Early RA Study (ERAS). Rheumatology (Oxford) 2000;39:603-611. sk CRP: C-Reactive Protein; DMARDs: Disease-Modifying Anti-Rheumatic Drugs; ESR: Erythrocyte Sedimentation Rate; w ko FACIT-F: Functional Assessment of Chronic Illness Therapy – Fatigue; HAQ-DI: Health Assessment Questionnaire – Disability Index; cz HRQoL: Health-Related Quality of Life; MTX: Methotrexate; RTX: Rituximab; SF-36: Short Form 36 (PCS: Physical Component Summary; Ka MCS: Mental Component Summary); SJC: Swollen Joint Count; TJC: Tender Joint Count; VAS: Visual Analogue Scale. al st ry RECONSTITUTION OF PERIPHERAL BLOOD B CELLS AFTER DEPLETION WITH RITUXIMAB IN PATIENTS C WITH RHEUMATOID ARTHRITIS M. J. Leandro, M. R. Ehrenstein, G. Cambridge, J. C. Edwards. University College London, London, United Kingdom Arthritis Rheum 2005;52(9 Suppl):S338(Abstract 854). PURPOSE: We studied the quantitative and phenotypic reconstitution of peripheral blood (PB) B cells following depletion with rituximab in patients with rheumatoid arthritis. METHODS: Three- and four-colour flow cytometry was used to study the different B and T cell populations in PB. Samples were prepared using a whole blood tecnhique. Twenty one patients (27 treatments) were included and studied during depletion and repopulation of PB following treatment with rituximab. Baseline data was available in 14 patients (15 treatments). RESULTS: Treatment with rituximab depleted a mean of 97% of CD19+ cells (B cells) in the peripheral blood for more than 3 months in all except one patient. All B cell populations were depleted including plasma cell precursors. During depletion, a very small number of CD19+ cells could be detected, > 80% showing a memory or plasma cell precursor phenotype (CD19+IgD- or CD27+/++). Repopulation occurred a mean of 8 months after treatment (range 5 to 11). Normal B cell counts were rapidly achieved in a few patients but more frequently took several months. Repopulation occurred mainly with naïve B cells with increased expression of CD38, increased frequency of CD5+ B cells and decreased frequency of CD27+ cells. When compared to baseline, the frequency of immature CD19+IgD+CD38++ cells increased from a median of 8.16% (SEM 3.66) to 51.1% (SEM 4.33) (p <= 0.0001), and the frequency of CD19+CD5+ cells increased from a median of 33.73% (SEM 6.39) to 85.35% (SEM 4.82) (p <= 0.001). We found that IgD+CD38++ cells were immature B cells rather than germinal centre founder cells based on their expression of low levels of CD10 but high levels of CD24. In the majority of these cells IgD expression was similar to that found on mature naïve B cells. The frequency of CD19+IgD+CD38++ cells usually returned to normal earlier than the frequency of CD19+CD5+ cells. Patients who relapsed at the time or shortly after B cell repopulation tended to repopulate with higher frequencies of memory B cells (IgD-, CD27+) than patients who relapsed later. Small numbers of CD3+CD20low+ cells (median 3.15% of CD3+ cells, SEM 1.24 ) and of CD3-CD56+CD20low cells (median 1.71%, SEM 0.87) were detected. These cells were depleted following treatment with rituximab and repopulated earlier than B cells (mean 10

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