EmergingClinical Science

fromTHE 69TH ANNUAL SCIENTIFIC MEETING OF

THE AMERICAN COLLEGE OF RHEUMATOLOGY

SAN DIEGO, CALIFORNIA NOVEMBER 12-17, 2005

Abstracts and Expert Commentaryon the Prospective Management of

Rheumatoid Arthritis

Robert Offer, MD, FRCPCUniversity of British Columbia, Vancouver, BC

Penticton Regional Hospital, Penticton, British Columbia

McGill

Mary-Ann Fitzcharles, MD, ChB, FRCPCMcGill University, Montreal, Quebec

McGill University Health Centre, Montreal, Quebec

J. Carter Thorne, MD, FRCPC, FACPUniversity of Toronto, Toronto, Ontario

Southlake Regional Health Centre, Newmarket, Ontario

A McGill University CME accredited program

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Online Discussion:Forum on Emerging Clinical Science from

The 69th Annual Scientific Meeting ofThe 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 hisexpert 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 toobtain 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 righthand corner of the window.

4. Once you have obtained your password, log into the “Forum on Emerging Clinical Science from The 69thAnnual Scientific Meeting of The American College of Rheumatology: ACR 2005” by entering your emailaddress and password in the boxes on the web site and click on “Go”.

5. Comments and discussions of the other participants can be reviewed, as well as those of the moderator,Dr. Thorne, by accessing this site.

6. If you would like to add a comment or ask a question, simply type a heading into the “Subject” box, typeyour comment into the “Message” box, and click on “Add/Ajoutez”.

Accreditation

This event is approved for up to 2 credits by the Centre for Continuing Medical Education (CME). The Centre for CME, Faculty ofMedicine, McGill University, is fully accredited by the Committee on Accreditation of Canadian Medical Schools (CACMS), andthrough 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 theAmerican Academy of Family Physicians are eligible to receive credit hours for attendance at this meeting because of the reciprocalagreement 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 RoyalCollege 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 PhysiciansRecognition Award up to the maximum number of credit hours noted above. Each physician should claim only those hours of creditthat he/she actually spent in the educational activity.

Potential Conflict of Interest DisclosureDr. 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 fromAbbott 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 researchsupport 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 alsospoken for Abbott Laboratories Ltd., Amgen Canada Inc./Wyeth Pharmaceuticals, and Pfizer Canada Inc.

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Table of Contents

Selective T Cell Costimulation ModulatorsAbatacept Improves American College of Rheumatology Responses and Disease Activity Score 28 Remission Rates in Both Recent Onset andMore 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 UniversityArthritis Rheum 2005;52(9 Suppl):S138(Abstract 1494).

Sustained Improvements Through 18 Months with Abatacept in Rheumatoid Arthritis Patients with an Inadequate Responseto 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 TorontoPresented 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 withInadequate 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 UniversityArthritis 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 TorontoArthritis 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 withInadequate 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 ColumbiaArthritis Rheum 2005;52(9 Suppl):S258(Abstract 626).

B Cells as a New Therapeutic TargetImprovements in Patient Reported Outcomes Over 24 Weeks for Rituximab with Methotrexate in Rheumatoid Arthritis Patients in Phase IIb Trial (DANCER).

P. Mease, J. Szechinski, M. Greenwald, M. Leirisalo-Repo, A. Kivitz, L. Barile-Fabris, J. Kalsi, J. Eames.Expert Commentary by Mary-Ann Fitzcharles, MB, ChB, FRCPC, McGill UniversityArthritis Rheum 2005;52(9 Suppl):S138(Abstract 280).

Reconstitution of Peripheral Blood B Cells after Depletion with Rituximab in Patients with Rheumatoid Arthritis.M. J. Leandro, M. R. Ehrenstein, G. Cambridge, J. C. Edwards.Expert Commentary by Robert C. Offer, MD, FRCPC, University of British ColumbiaArthritis 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 TorontoArthritis 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 TorontoArthritis Rheum 2005;52(9 Suppl):S341(Abstract 860).

Improved Quality of Life with Rituximab Plus Methotrexate in Patients with Active Rheumatoid Arthritis who Experienced InadequateResponse 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 ColumbiaArthritis Rheum 2005;52(9 Suppl):S141(Abstract 287).

Interleukin-6, a Pleiotropic CytokineBlocking Interleukin-6 (IL-6) By Tocilizumab (A Humanized Anti-Interleukin-6 Receptor Monoclonal Antibody) Monotherapy Reduces JointDamage 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 UniversityPresented 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 ColumbiaArthritis Rheum 2005;52(9 Suppl):S725(Abstract 1956).

Conclusions

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Introduct ionRheumatoid 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.

The American College of Rheumatology Annual Meeting (ACR 2005) was held in San Diego, California on November 12-17,

2005, and brought together clinicians and research scientists from around the globe. This document contains selected

noteworthy abstracts presented at the meeting that reported the results of recent clinical trials evaluating these emerging

biologic therapies. The emphasis of this review is on three novel therapeutic approaches: 1) a selective T cell co-stimulation

modulator (abatacept); 2) a B cell depleting agent (rituximab [RTX]); and 3) an interleukin-6 inhibitor (tocilizumab [MRA]).

Each abstract is followed by expert commentary to provide clinicians with a concise overview of current research and

development in the treatment of RA. The three physicians provided their commentaries based on their acknowledged

expertise in the field of rheumatoid arthritis. They did so with complete and independent editorial freedom.

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.

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SELECTIVE T CELL COSTIMULATION MODULATORST cells have been recognized as central coordinators of the immune cascade that leads to inflammation and joint erosion.1 They require two signalsfrom antigen presenting cells (APC) for activation.2,3 The first is the antigen-specific interaction between the T cell receptor and the majorhistocompatibility complex on the surface of APC.4 Another costimulatory signal then takes place between CD28 molecules on T cells and CD80or CD86 molecules on APC. Together, the two signals trigger T cell proliferation and cytokine production, which initiates additional inflammatorycells.4 Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is an immunoregulatory protein that is expressed on the surface of T cells followingactivation. 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 studiesand large, multicentre trials have established the efficacy and safety of abatacept in treating the signs and symptoms of RA.6-9 These multicentretrials 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-ontreatment.

Numerous abstracts were presented recently at “The European League Against Rheumatism Annual Congress” (EULAR) and ACR conferencesbased 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;153:1378-1385.6. Moreland LW, Alten R, Van den Bosch F, et al. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-

controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 2002;46:1470-1479.7. 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;349:1907-1915.8. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to Tumor Necrosis Factor α inhibition. N Engl J Med 2005;353:1114-1123.9. 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.

ABATACEPT IMPROVES AMERICAN COLLEGE OF RHEUMATOLOGY RESPONSES AND DISEASE ACTIVITYSCORE 28 REMISSION RATES IN BOTH RECENT-ONSET AND MORE ESTABLISHED RHEUMATOID ARTHRITIS: RESULTS FROM THE AIM TRIAL J. Kremer1, R. Westhovens2, C. Abud-Mendoza3, R. Valente4, R. Aranda5, J-C Becker5, O. Mokliatchouk5, L. Moreland6.1Center for Rheumatology, Albany, NY; 2Universitaire Ziekenhuizen, Leuven, Belgium; 3Hospital Central Dr Ignacio Morones Prieto, San Luis Potosi, Mexico; 4ArthritisCenter 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 theselective co-stimulation modulator abatacept on ACR responses and its ability to induce remission (Disease Activity Score 28 [DAS28] <2.6) wereexamined 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 IIItrial of a fixed dose of abatacept approximating 10 mg/kg vs placebo with background MTX in patients with active RA and an inadequate responseto MTX. Study medication was administered on Days 1, 15 and 29, and then every 28 days thereafter by 30-minute intravenous infusion. ACRresponses 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 abataceptgroup 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 abataceptvs 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 variableswere 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 ofdisease duration, in RA patients with an inadequate response to MTX. These data suggest that the selective co-stimulation modulator abataceptis effective at inducing meaningful improvements in clinical responses in RA patients with high disease activity and in both recent-onset and moreestablished disease.

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Time of measurement ACR 20 responses n (%) ACR 50 responses n (%) ACR 70 responses n (%) DAS28* remission† n (%)

Abatacept Placebo Abatacept Placebo Abatacept Placebo Abatacept Placebo

All patients randomized and treated (n=424 for abatacept; n=214 for placebo)‡

6 months 288 (67.9)§ 85 (39.7) 169 (39.9)§ 36 (16.8) 84 (19.8)§ 14 (6.5) 62 (14.8)§ 6 (2.8)12 months 310 (73.1)§ 85 (39.7) 205 (48.3)§ 39 (18.2) 122 (28.8)§ 13 (6.1) 101 (23.8)§ 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 selectiveco-stimulation modulator, compared with placebo in the Phase III AIM (Abatacept in Inadequate responders to Methotrexate [MTX]) trial. The AIMtrial was an important study assessing efficacy, safety, and quality of life parameters in patients with early or more established disease andinadequate 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%improvement in ACR criteria from baseline. Improvements in disease activity were measured using DAS28 (using C-reactive protein levels). ACRresponses and DAS28 remission were evaluated in a post-hoc analysis of patients with disease durations at baseline of ≤2 years, >2-≤5 years,>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.

Overall, 433 patients were treated with abatacept and 219 patients with placebo. Patients had high baseline disease activity as evidenced by amean DAS28 score of 6.4. Mean baseline disease duration was 8.5 years and 8.9 years for the abatacept and placebo groups, respectively.Treatment with abatacept produced statistically significant improvements in ACR 20, 50, and 70 responses at 6 months and 1 year comparedwith 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%) inabatacept- and placebo-treated patients respectively (p<0.001). Most impressive was that these improvements in ACR responses and DAS28scores were sustained (and even increased) throughout the study duration.

Sub-analyses based on baseline disease duration also demonstrated marked improvements in all ACR 20, 50, and 70 responses with abatacepttreatment at 6 months and 1 year compared with placebo, regardless of disease duration. Furthermore, ACR responses generally improved from6 months to 1 year in abatacept-treated patients split by disease duration. No differences between response variables were observed during the1-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 withlonger disease duration are generally considered more resistant and less responsive to treatment.1 Thus, it is striking that patients with shorterdisease durations (even with early RA) responded fairly equally to those with more established disease (>10 years). Data from this analysis supportthe 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.

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SUSTAINED IMPROVEMENTS THROUGH 18 MONTHS WITH ABATACEPT IN RHEUMATOID ARTHRITIS PATIENTSWITH AN INADEQUATE RESPONSE TO ANTI-TNF THERAPY M. Genovese1, M. Luggen2, M. Schiff3, Y. Sherrer4, K. Sen5, R. Aranda5, J-C Becker5, M. Dougados6.1Stanford University Medical Center, Stanford, CA; 2University of Cincinnati Medical Center, Cincinnati, OH; 3Denver Arthritis Clinic, Denver, CO; 4Center forRheumatology, 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 aninadequate response to anti-TNF therapy. Abatacept, a selective co-stimulation modulator of T-cell activation, has shown efficacy in RApatients with an inadequate response to methotrexate and/or anti-TNF therapy1,2. In ATTAIN (Abatacept Trial in Treatment of Anti-TNFINadequate responders), ACR and Health Assessment Questionnaireresponses, and the Disease Activity Score 28 (DAS28; based onC-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 responseto ≥3 months of treatment with ≥1 TNF inhibitor due to lack ofefficacy. During the DB phase, patients were randomized to receivea fixed dose of abatacept (~10 mg/kg) or placebo intravenously onDays 1, 15 and 29, and every 28 days thereafter. All patients whocompleted the DB phase were eligible to enter the LTE, during whichall patients received a once-monthly fixed dose of abatacept(~10 mg/kg) in addition to ≥1 background DMARD. Following awashout period, no anti-TNF therapies were permitted.

Results: Of the 258 patients randomized to abatacept during the DBphase, 223 (86.4%) patients completed 6 months of treatment and218 (84.5%) entered the LTE. Of these, 168 patients completed18 months’ treatment. On Day 169 (end of DB phase), ACR 20, ACR50 and ACR 70 responses for the 218 patients who entered the LTE were 59.4%, 23.5% and 11.5%, respectively (Figure), and these responseswere 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 theabatacept-treated patients achieved DAS28-defined remission; twice as many patients experienced this improvement following the 1-year LTE(22.5%). Abatacept was generally safe and well tolerated.

Conclusion: These data support the sustained clinical benefit of abatacept through 18 months of treatment in patients with active RA and aninadequate response to anti-TNF therapy.1Genovese M, et al. ACR Annual Meeting, 16-21 October 2004:L162Kremer 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 TorontoEfficacy was demonstrated based on DAS28 remission in 22.5% of the patients who completed 18 months of abatacept treatment (6 monthsdouble-blind phase and 1-year long-term, open-label extension) in the ATTAIN trial. These remission rates increased two-fold compared with6-month remission rates (11.2%) and are encouraging in patients with inadequate response to MTX and/or anti-TNF therapy. ACR 50 and 70scores increased from 23.5% and 11.5% to 35.0% and 18.0%, respectively, at 18 months. However, ACR20 scores were comparable at 6 and18 months (59.4% vs 56.7%). All 6-month scores were significantly increased compared with placebo. Six month data from the ATTAIN trial hasrecently been reported by Genovese and colleagues.1 Clinically meaningful and statistically significant QoL improvements were also demonstratedin this refractory patient population at 6 months,1 although HAQ-DI scores declined marginally over the course of the open-label period (from54.4% at 6 months to 47% at 18 months) in abatacept-treated patients. It is possible that this observation may represent the gradual declinerelated to progression of damage present at study entry in this recalcitrant group. Clinical improvements in ACR and HAQ scores were noted soonafter 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 ofpatients discontinued treatment due to an AE. There were 16 discontinuations during the open-label period, 11 of which due to SAEs. One deathwas 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 areconsistent with previously reported data in MTX inadequate responders.2,3 Efficacy of treatment began early and was prolonged, providing somehope 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.

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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. Moreland4.1University of Alberta Hospital, Edmonton, AB, Canada; 2Center for Rheumatology, Albany, NY; 3Bristol-Myers Squibb, Princeton, NJ; 4University of Alabama Schoolof 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 selectiveco-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. Alsopresented are data from a 1-year, double-blind Phase II trial with a 2-year open-label long-term extension (LTE) where patients received abatacept10 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 RAdespite MTX treatment. Physical function was assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI) in AIM and themodified HAQ-DI (mHAQ-DI) in Phase II. The proportion of patients demonstrating a HAQ-DI response was evaluated, defined as an improvementof ≥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 duringassessment 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 theabatacept 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 clinicallymeaningful improvements in physical function and significant improvements from baseline in HAQ-DI scores and pain from Day 15 onwards (afterthe 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 inphysical function and reductions in pain in patients with inadequate responses to MTX; similar improvements were observed for up to 3 years ina Phase II study. These data suggest that abatacept treatment can provide tangible, sustained, real-life benefits to RA patients.

Assessment AIM trial* Phase II*†

6 months 1 year 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=84) (n=84)

HAQ-DI (AIM)/mHAQ-DI (Phase II): 20.9 35.2 19.6 37.3 18.2 49.4 46.3 49.3mean % improvement (SE) (2.7) (1.9)** (3.2) (2.3)** (7.2) (4.2) (5.5) (5.3)

HAQ-DI (AIM) /mHAQ-DI (Phase II) 97 259 84 270 23/66 46/84 39/73 34/64responder patients, n (%) (45.3) (61.1)** (39.3) (63.7)** (34.8) (54.8) (53.4) (53.1)

Pain: mean % improvement (SE) 3.5 42.5 8.0 50.5 35.4 52.4 50.2 55.6(7.4) (5.3)** (5.7) (4.0)** (5.7) (5.7) (6.6) (5.3)

*Patients continued with background MTX; †As-observed population; ‡Placebo-controlled phase; §Patients from one site were excluded from efficacyanalyses due to protocol violations; **p<0.001 vs placebo

EXPERT COMMENTARY by Mary-Ann Fitzcharles, MB, ChB, FRCPC, McGill UniversityRheumatoid arthritis produces marked functional impairment in many RA patients.1 Consequently, quality of life is considerably reduced, evenwith optimum current treatments such as TNF-α inhibitors.2-4 Pain is increasingly recognized as an important and disabling symptom in RA. Thisstudy provides Health-Related Quality of Life (HRQoL) data for 1 year in the Phase III AIM study, one of the longest studies examining HRQoLparameters 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 bysubject pain assessment on a Visual Analog Scale) were also seen starting on Day 15. Improvements were also sustained throughout the 3-yearstudy 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-blindbasis 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 continued50% reduction in pain at 3 years represents greatly improved quality of life. It is also noteworthy that there was good study patient retention to the3 year mark, suggesting patient satisfaction with the treatment and lack of important adverse events requiring discontinuation of treatment. Insummary, 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.

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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. Bingham6.1University 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 avariety of background anti-rheumatic therapies: two 1-year Phase II trials (background therapy=methotrexate [MTX] or etanercept) and threePhase III trials of 6 or 12 months’ duration (background therapy=MTX/variety of biologic and non-biologic DMARDs; patients with co-morbiditieswere 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 doseapproximating 10 mg/kg abatacept, representing 1527.4 person-years of exposure. The incidence of death and serious adverse events (SAEs) wassimilar between groups, with discontinuations due to SAEs and AEs slightly higher for abatacept (Table). The most commonly reported AEs (mostlymild-to-moderate in severity) were headache, upper respiratory tract infections, nausea and nasopharyngitis. There were small increases in theoverall incidence of infection and serious infection. Most of the infections were caused by expected pathogens, followed an expected course andresponded to treatment. One case of suspected tuberculosis, not confirmed bacteriologically, was reported with abatacept treatment. Malignantneoplasms were reported in a similar proportion of patients in both groups. One lymphoma was reported with abatacept treatment. Safety datafrom the small subset of patients receiving abatacept with biologic DMARDs demonstrated a higher incidence of AEs, SAEs and infections inabatacept-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 withnon-biologic background therapy, although slightly increased infections rates were observed. These safety data, coupled with improvements in RAsigns and symptoms1, support the use of the selective co-stimulation modulator abatacept for the treatment of RA.1Kremer J, et al. N Engl J Med 2003;349(20):1907-1915.

Overall safety* Abatacept (n=1955) Placebo (n=989)

Person-years of exposure (years) 1688.1 794.5

Death 0.5 (9) 0.6 (6)

SAEs 13.6 (266) 12.3 (122)

AEs 88.8 (1736) 84.9 (840)

Discontinuations due to SAEs 2.7 (53) 1.6 (16)

Discontinuations due to AEs 5.5 (107) 3.9 (39)

Most commonly reported AEs:Headache 18.2 (356) 12.6 (125)URTI 12.7 (248) 12.0 (119)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 TorontoDue to their relative newness, limited data are available on the relative safety and efficacy of the approved TNF blockers. Increased rates ofinfections and lymphoma have been reported with use of these agents.1 This important abstract compiles safety and tolerability data from thedouble-blind phases of five controlled clinical trials in patients with active RA treated with abatacept as well as various biologic and nonbiologicalbackground DMARDs. Safety data were integrated from three Phase III studies of 6 or 12 months duration: AIM (n=652),2 ATTAIN (n=391),3 andASSURE (n=1441).4 Patient profiles were as follows: AIM patients were inadequate responders to MTX, ATTAIN patients were anti-TNF inadequateresponders, and ASSURE patients were patients taking any RA treatment. In these Phase III trials, patients were randomized to receive placeboor abatacept at 10 mg/kg. In addition, two 1-year Phase II studies in which patients were randomized to receive placebo or abatacept wereanalyzed.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 Patientsreceived etanercept plus abatacept with doses of 2 mg/kg (n=121) in the second trial.6

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In total, 1955 patients were treated with abatacept/DMARDs, representing 1527.4 person-years of exposure, while 989 patients were treated withplacebo/DMARDs. Results of the safety analyses demonstrated that overall deaths, adverse events (AEs), serious adverse events (SAEs), anddiscontinuations were comparable with abatacept or placebo treatment. Eighty-nine percent (88.8%) of patients treated with abatacept/DMARDsand 84.9% of patients treated with placebo/DMARDs reported an AE. The most commonly reported AEs with abatacept/DMARD treatmentoccurring 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% forplacebo/DMARD-treated patients). There were small increases in the overall incidence of mild and serious infections with abatacept treatment comparedwith 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 withbiologic DMARDs, higher rates of AEs, SAEs, and infections were reported. The clinician should note the increased rate of AEs and SAEs whenabatacept 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 beassociated with medically significant autoimmune symptoms and disorders, which were reported in 2.9% and 1.8% of patients in the abataceptand 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-biologicDMARDs. Like other biologic DMARDs, abatacept is associated with slightly increased rates of infection and serious infection. These adversereactions may be related to blockade of TNF-α and thus represent class effects of these agents.1 Results from long-term extension studies shouldgive further supportive evidence of relative safety. Registry databases which have been set up to monitor biologic therapies in a number of countrieswill 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 usein 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, 2005.2. Steinfeld S, Moreland L, Abud C, et al. Rapid and significant improvements in the components of the ACR criteria in abatacept-treated rheumatoid arthritis

patients in the Phase III AIM (Abatacept in Inadequate Responders to Methotrexate) trial. Ann Rheum Dis 2005;64(Suppl. 3):457(Abstract SAT0151).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;353:1114-1123.4. Weinblatt M, Combe B, White A, et al. Safety of abatacept in patients with active rheumatoid arthritis receiving background non-biologic and biologic DMARDS:

1-Year results of the ASSURE trial. Ann Rheum Dis 2005;64(Suppl. 3):60(Abstract OP0012).5. Emery P, Westhovens R, Leon G, et al. Beneficial effects of the selective co-stimulation modulator abatacept on biomarkers of rheumatoid arthritis immunopathology

in patients with an inadequate response to methotrexate or TNF-inhibitor treatment. Ann Rheum Dis 2005;64(Suppl. 3):432(Abstract SAT0074).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)

given monthly in combination with etanercept in active rheumatoid arthritis. Arthritis Rheum 2002;46(Suppl. 9):S204(Abstract464).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;349:1907-1915.8. 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.

ABATACEPT INDUCES SUSTAINED IMPROVEMENTS IN QUALITY OF LIFE, SLEEP QUALITY AND FATIGUE OVER3 YEARS IN RHEUMATOID ARTHRITIS PATIENTS WITH INADEQUATE RESPONSES TO METHOTREXATE P. Emery1, A. Russell2, J. Markenson3, Y. Zhou4, O. Mokliatchouk4, T. Li4, R. Westhovens5.1University 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 aspart 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. Alsopresented are data from a 1-year, double-blind, Phase II trial with a 2-year, open-label, long-term extension (LTE) where patients receivedabatacept 10 mg/kg plus MTX or placebo up to 1 year and the fixed dose approximating 10 mg/kg abatacept thereafter. Physical and mental healthwas 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 validatedMedical 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 patientsentered the LTE. In AIM, abatacept-treated patients demonstrated both clinically meaningful (change of ≥3 points) and statistically significantimprovements in all eight subscales and both MCS and PCS of the SF-36 vs. placebo. Clinically meaningful improvements were observed up to3 years in Phase II. Abatacept significantly improved sleep quality and reduced fatigue (Table).

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Conclusions: In AIM, abatacept significantly improved sleep quality and reduced pain and fatigue, as well as significant, clinically meaningfulimprovements in all eight domains of the SF-36 and both the MCS and PCS. Similar improvements in QoL and reductions in pain were observedat time points up to 3 years in the Phase II trial, demonstrating the tangible, sustained benefits of abatacept from the patients’ perspective.

AIM* Phase II trial*†

6 months 1 year 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 9.3baseline in PCS (AIM)/Mean (0.6) (0.4)†† (0.6) (0.4)†† (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 4.0baseline in MCS (AIM)/Mean (0.7) (0.5)** (0.7) (0.5)** (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(7.4) (5.3)†† (5.7) (4.0)†† (5.7) (5.7) (6.6) (5.3)

Adjusted mean change from -7.8 -10.2 -6.8 -10.4baseline in MOS-sleep (SE) (1.0) (0.7) (1.0) (0.7)** – – – –

Adjusted mean change from -17.2 -25.3 -16.4 -26.5baseline in fatigue (SE) (1.8) (1.2)†† (1.7) (1.2)†† – – – –

*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, allvs placebo

EXPERT COMMENTARY by Robert C. Offer, MD, FRCPC, University of British Columbia

Rheumatoid arthritis (RA) has a significant impact upon health-related quality of life (HRQoL). More than 50% of RA patients have difficultysleeping.1 It has been reported that RA patients have a 57% increase in sleep disturbances compared with the general population and use almost3 times more sleep medication.2 Clinically, one would expect RA patients to have improved sleep quality when treatment relieves inflammation thatis causing pain and stiffness at night. However, there are other factors that frequently disrupt sleep in these patients, including fibromyalgia,depression, lack of exercise, and medications such as prednisone. Many RA patients also complain of fatigue; prevalence has been estimated ashigh as 80%,3 and often fatigue is the most refractory symptom of rheumatoid arthritis. Although sleep disturbance and fatigue play a critical rolein patients’ quality of life, Dr. Emery pointed out during the presentation of this abstract that these parameters have rarely been studied in RApatients treated with biological agents. Tools such as the Health Assessment Questionnaire (HAQ) and Short Form 36 (SF-36) are well-validated anddirectly measure physical and emotional well-being. Quality of life, fatigue, pain, and sleep quality were measured in patients treated with abatacept,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. TheAIM trial was an important study assessing efficacy, safety, and quality of life parameters in patients with inadequate responses to methotrexate.

In the AIM study, clinically significant improvements (>3 points) were demonstrated for pain and all eight subscales of the physical and mentalcomponent summaries (PCS and MCS) of the SF-36, while similar improvements, though not statistically significant, were seen in the Phase IIlong-term extension (LTE). The absence of statistical significance may be due to the smaller sample sizes of the LTE. These data are particularlyinteresting considering that improvements were maintained over 3 years in abatacept-treated patients. Sleep quality and fatigue were alsosignificantly 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 responseto TNF-α inhibitors). In both trials, abatacept treatment led to statistically significant and clinically meaningful improvements in all eight SF-36domains, as well as the PCS and MCS. Together, these trials provide evidence of clinically meaningful QoL benefits in patients previously notresponding 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.

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B CELLS AS A NEW THERAPEUTIC TARGETThe 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 theimmune response.1 They function as antigen-presenting cells, secrete a number of pro-inflammatory cytokines (including TNF-α), producerheumatoid factor autoantibody, and directly activate T cells.1 Depletion of B cells in patients with RA substantially reduces the production ofcytokines, which have been implicated in the inflammation cascade.2 Therefore, B cells have emerged as a novel target for therapy in RA. CD20is 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 plasmacells. 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 refractoryB 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 ofthis Phase II trial and several sub-analyses were presented at recent EULAR and ACR conferences. All patients in this study received a short courseof corticosteroids, raising questions regarding the concomitant use of steroids. The DANCER (The Dose-ranging Assessment iNternational ClinicalEvaluation of Rituximab in RA) trial, also presented at this conference, addressed this issue by evaluating the effects of glucocorticosteroids whenused 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 abstractsfrom 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;83:435-445.6. 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

2004;350:2572-2581.7. Edwards JC, Leandro MJ, Cambridge G. B lymphocyte depletion in rheumatoid arthritis: targeting of CD20. Curr Dir Autoimmun 2005;8:175-192.

MabThera and Rituxan are registered trademarks of Roche.

IMPROVEMENTS IN PATIENT REPORTED OUTCOMES OVER 24 WEEKS FOR RITUXIMAB WITH METHOTREXATEIN RHEUMATOID ARTHRITIS PATIENTS INPHASE IIB TRIAL (DANCER) P. Mease1, J. Szechinski2, M. Greenwald3, M. Leirisalo-Repo4, A.Kivitz5, L. Barile-Fabris6, J. Kalsi7, J. Eames8.1Swedish Medical Ctr, Seattle, WA; 2Medical Univ. of Wroclaw, Wroclaw,Poland; 3Desert Medical Advances, Palm Desert, CA; 4Helsinki Univ. CentralHospital, Helsinki, Finland; 5Altoona Ctr for Clinical Research, Duncansville,PA; 6Hospital Angeles, Mexico City, Mexico; 7Roche Products Ltd, WelwynGarden City, United Kingdom; 8Genentech, South SF, CA

Arthritis Rheum 2005;52(9 Suppl):S138(Abstract 280).

Purpose: To evaluate the impact of treatment of Rituximab (RTX)with methotrexate (MTX) on patient reported outcomes (PROs).

Methods: Patients randomized into 9 treatment arms in a 3x3configuration. RTX (placebo, 500mg or 1000mg) was given onDays 1 and 15 with 1 of 3 glucocorticoid options. Key inclusioncriteria were SJC and TJC >8; elevated CRP or ESR; ongoing MTX10-25 mg/week; and 1-5 prior DMARDs/biologics except MTX.Analyses were implemented for the intention-to-treat RF+ population(n=367). Within-group and between-group changes from baselinewere analyzed using paired and two sample t-tests. Because efficacywas not affected by glucocorticoids (GC), GC arms were combinedfor each treatment group. ANOVA will be presented for between-group differences.

Results: Baseline characteristics for the efficacy population were wellbalanced across treatment groups with overall means of: SJC=21,TJC=33, DAS28 score 6.8, MTX dose 15.5 mg/week, RA duration10.4 years, prior DMARD use 2.4, 32% had prior biologic therapy.Baseline HAQ-DI was 1.7, 1.8, 1.7 for placebo, RTX 500mg, andRTX 1000 mg respectively. Improvements at Week 24 from baseline

Mean (SD) Change from Baseline at Week 24

Placebo RTX 500 mg RTX 1000 mgN=122 N=123 N=12

HAQ-DI**

N 89 117 120

Mean -.28 -.46 -.49MCID = -.22 (.50)* (.62)* (.55)*

Pain VAS**

N 89 117 121

Mean -13.4 -21.5 -21.2MCID = -10.0 (25.6)* (29.1)* (28.0)*

FACIT-F**

N 89 116 121

Mean -3.91 -7.63 -8.20MCID = -3.0 (9.36)* (10.74)* (10.06)*

SF-36 PCS***

N 121 123 115

Mean 1.74 6.44 7.08MCID = 3.0 (6.41)* (8.07)* (8.17)*

SF-36 MCS***

N 121 123 115

Mean 1.39 4.09 2.90MCID = 3.0 (8.12) (12.37)* (11.45)*

Data not included if baseline assessment missing*Statistically significant difference from baseline at p<.01**Negative change = improvement***Positive change = improvement

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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 statisticallysignificant (p<.01) within group changes on all PROs except for SF-36 MCS placebo group. Changes clearly exceeded minimal clinically importantdifferences (MCID) for RTX 500mg and RTX 1000mg and were much smaller for placebo. There were no statistically significant differences betweenRTX 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 RApatients 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 limitsnormal daily living.1,2 Patient satisfaction with a treatment intervention is recognized as increasingly important and has an impact upon complianceand continuation of treatment in the real world. Data from this randomized, double-blind Phase IIB study (DANCER) provides patient-reportedoutcomes from those with active disease despite treatment with DMARDs (other than MTX) and/or biological response modifiers. Patients withbaseline 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 biologictreatment, the RA patients in this study represent patients with disease at the severe end of the spectrum. One third of the study group hadpreviously 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 andMCS) for the 500 mg RTX treatment group (p<0.05), and statistical significance for all measures except SF-36 MCS for the 1000 mg RTXtreatment group (p<0.05). There were no statistically significant differences between each dose of RTX on patient-reported outcomes. At studyendpoint, 63% and 67% of patients on RTX 500 mg and 1000 mg achieved minimal clinically important differences in HAQ-DI (defined asHAQ ≥0.22) compared with only 34% of patients on placebo. The placebo response in this study was, however, impressive, with significantchanges from baseline in all parameters measured, except for SF-36 MCS. Co-administration of steroids may have contributed to the overall groupimprovements.

In addition to other abstracts presented at ACR, results from the DANCER trial provide further evidence of clinically meaningful improvements inphysical function, fatigue reduction, and pain reduction in patients with inadequate responses to previous treatment strategies.

References:1. Arthritis Foundation. Living with Rheumatoid Arthritis: Unmet Needs. Available at: http://www.arthritis.org/conditions/diseasecenter/RA/RASurvey

WhitePaperFinal.pdf . Accessed November 23, 2005.2. 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

732 patients from the Early RA Study (ERAS). Rheumatology (Oxford) 2000;39:603-611.CRP: C-Reactive Protein; DMARDs: Disease-Modifying Anti-Rheumatic Drugs; ESR: Erythrocyte Sedimentation Rate; FACIT-F: Functional Assessment of Chronic Illness Therapy – Fatigue; HAQ-DI: Health Assessment Questionnaire – Disability Index; HRQoL: Health-Related Quality of Life; MTX: Methotrexate; RTX: Rituximab; SF-36: Short Form 36 (PCS: Physical Component Summary; MCS: Mental Component Summary); SJC: Swollen Joint Count; TJC: Tender Joint Count; VAS: Visual Analogue Scale.

RECONSTITUTION OF PERIPHERAL BLOOD B CELLS AFTER DEPLETION WITH RITUXIMAB IN PATIENTSWITH 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 patientswith 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 awhole blood tecnhique. Twenty one patients (27 treatments) were included and studied during depletion and repopulation of PB followingtreatment 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 exceptone patient. All B cell populations were depleted including plasma cell precursors. During depletion, a very small number of CD19+ cells couldbe detected, > 80% showing a memory or plasma cell precursor phenotype (CD19+IgD- or CD27+/++). Repopulation occurred a mean of 8 monthsafter 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 frequencyof 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 theirexpression 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 naïveB cells. The frequency of CD19+IgD+CD38++ cells usually returned to normal earlier than the frequency of CD19+CD5+ cells. Patients whorelapsed at the time or shortly after B cell repopulation tended to repopulate with higher frequencies of memory B cells (IgD-, CD27+) than patientswho relapsed later. Small numbers of CD3+CD20low+ cells (median 3.15% of CD3+ cells, SEM 1.24 ) and of CD3-CD56+CD20low cells (median1.71%, SEM 0.87) were detected. These cells were depleted following treatment with rituximab and repopulated earlier than B cells (mean

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5 months). The frequency of CD25high cells in the CD4+ T-cell population was reduced 1 month after treatment (p <= 0.05) but not at 3 months.All other T cell populations studied did not change significantly.

CONCLUSIONS: B-cell repopulation of PB following rituximab was dependent on production of naïve B cells rather than expansion of pre-existingmemory B cells. However, patients who relapsed with B-cell repopulation tended to repopulate with an increased frequency of memory B cells. Atrepopulation immature B cells could be identified in the PB and expressed CD5, similar to what has been described after bone marrowtransplantation and in newborns.

EXPERT COMMENTARY by Robert C. Offer, MD, FRCPC, University of British Columbia

This study examined repopulation of peripheral blood B cells following depletion with RTX in RA patients. Clinical studies demonstrate treatmentwith RTX is associated with nearly complete depletion of B cells.1 The long-term implications of B cell depletion are unknown. Previous researchhas suggested that restoration of B cells typically takes 6-18 months following RTX treatment.2 In this study, RTX depleted approximately 97% ofCD19+ cells (B cells) in the peripheral blood for over 3 months in all but one patient. Plasma cell precursors were also depleted. B cell countswere repopulated at a mean of 8 months, occurring more rapidly in a few patients. Although such profound B cell depletion and modulation ofB cell subset composition may imply a greater susceptibility to infection, studies have demonstrated comparable rates of infection in controlpatients.1 However, long-term treatment for RA will likely require maintenance doses, possibly in combination with other immunosuppressiveagents or biologic response modifiers.2

In a safety trial presented at this meeting, serious infection rates were low with RTX retreatment without evidence of cumulative toxicity despiteongoing peripheral B cell depletion.3 In another report from London, UK, Dr. J. Edwards outlined the longest available experience from an openlabel study of RA patients on rituximab.4 Sixteen patients have been treated with rituximab for longer than 5 years and 20 for 2-5 years. Only2 patients have received 4 cycles while 6 have received 3 cycles. Mean duration of benefit was 15 months and mean time to retreatment was18 months. IgM levels fell more often than IgG or IgA and IgM was undetectable in 3 patients after repeated cycles but without any adverse events.The overall continuation rate in this desperate group was 62% at 5 years. Given the extent and duration of CD20+ B cell depletion, however,further studies are critical in order to determine the long-term impact of CD20+ B cell depletion as well as the effect of B cell depletion on otherconcurrent medications. Additional investigation is also required on the safety and efficacy of the subsequent use of agents in patients who donot respond to rituximab or for whom it loses its effect.

References:1. 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

2004;350:2572-2581.2. Keystone E. B cell targeted therapies. Arthritis Res Ther 2005;7(Suppl 3):S13-S18. 3. Emery P, Fleischmann RM, Pavelka K, et al. Safety and tolerability of rituximab retreatment in patients with active rheumatoid arthritis. Arthritis Rheum

2005;52(9 Suppl):S341(Abstract 860).4. Edwards JC, Leandro MJ, Cambridge G. Repeated B lymphocyte depletion therapy in rheumatoid arthritis: 5 year follow-up. Arthritis Rheum 2005;52(9

Suppl):S133(Abstract 270).

EFFICACY AND SAFETY OF RITUXIMAB IN ACTIVE RA PATIENTS WHO EXPERIENCED AN INADEQUATERESPONSE TO ONE OR MORE ANTI-TNF-α THERAPIES (REFLEX STUDY) S. B. Cohen1, M. Greenwald2, M. R. Dougados3, P. Emery4, R. Furie5, T. M. Shaw6, M. C. Totoritis7.1Radiant Research-Dallas, Dallas, TX; 2Desert Medical Advances, Palm Desert, CA; 3Rene Descartes University, Paris, France; 4Leeds General Infirmary, Leeds, United Kingdom; 5North Shore LIJ Health System, Lake Success, NY; 6Roche Products Ltd, Welwyn Garden City, United Kingdom; 7Biogen Idec, San Diego, CA

Arthritis Rheum 2005;52(9 Suppl):S677(Abstract 1830).

PURPOSE: To evaluate the efficacy and safety of rituximab (RTX), a selective CD20+ B cell-targeted monoclonal antibody, plus methotrexate (MTX)in patients (pts) with rheumatoid arthritis (RA) who experienced an inadequate response (IR) to one or more anti-TNF-α therapies and have activedisease despite ongoing treatment with MTX and a TNF inhibitor.

METHODS: Pts on a background regimen of MTX (10-25 mg/week) were randomized to a single course of either RTX 1000 mg or placebo (PLC),given by IV infusion on Days 1 and 15. All pts received parenteral methylprednisolone (100 mg) immediately prior to each infusion, and a briefcourse of oral glucocorticoids between the two RTX infusions. Key inclusion criteria were: swollen joint count (SJC) and tender joint count (TJC)each ≥8; elevated C-reactive protein (≥1.5 mg/dL) and/or erythrocyte sedimentation rate (>28 mm/h); inadequate response to etanercept,infliximab or adalimumab. Clinical assessments were conducted every 4 weeks between Weeks 4 and 24. The primary endpoint was the proportionof pts in each group that achieved an ACR20 response at Week 24. Secondary endpoints included ACR50 and ACR70 responses, changes inDisease Activity Score (DAS28), and EULAR response.

RESULTS: Of 520 pts randomized, 499 (298 RTX, 201 PLC)comprised the primary intent to treat efficacy population, whichincluded both rheumatoid factor (RF) positive and negative pts(81% RF+). Pts were well matched at baseline in each group. Meanbaseline data were: SJC/TJC, 23/34; RA duration, 12 years; DAS28,6.9; number of prior anti-TNF-α therapies, 1.5; mean MTX dose,16.5 mg/week. Completers for the 24 weeks included 82% of pts inthe RTX group and 54% in the PLC group. Withdrawals due to a lackof efficacy to RTX or PLC were 12% and 40%, respectively, andwithdrawals due to adverse events (AEs) were low, 3% and <1%,respectively.

Treatment group

Week 24 (% pts) PLC RTX 1000 mg(n =201) (n =298)

ACR20 (%) 18 51*

ACR50 (%) 5 27*

ACR70 (%) 1 12*

Δ DAS28 -0.34 -1.83*

EULAR Mod/Good Response (%) 22 65*

*p<0.0001 compared to placebo.

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RTX was well tolerated; the most common AEs were infusion-associated and easily managed. Serious AEs occurred in 7% and 10% of pts in theRTX and PLC groups, respectively, and the incidence of serious infections was low in both groups (2% vs <1%, respectively).

CONCLUSIONS: These results confirm that RTX is a highly effective and well-tolerated therapy for active RA when given with MTX in pts who haveexperienced an inadequate response to one or more anti-TNF-α therapies.

EXPERT COMMENTARY by J. Carter Thorne, MD, FRCPC, FACP, University of Toronto

Rituximab has demonstrated substantial efficacy and safety in patients with RA.1-4 The REFLEX study examined efficacy and safety parametersin a large group of RA patients with active disease (n=499, ITT population) who had shown inadequate responses to one or more TNF inhibitorsdespite current MTX treatment. Patients had failed a mean of 2.5-2.6 TNF inhibitors, and had considerable baseline disease activity (mean diseaseduration of 12 years).

Following 24 weeks of treatment with RTX 1000 mg, ACR20, ACR50, ACR70, DAS28, and EULAR Moderate/Good Response scores were allsignificantly better than with placebo (p<0.0001). During his presentation of this abstract, Dr. Cohen also pointed out that joint space narrowingwas significantly improved with RTX treatment compared with placebo. He added that rheumatoid factor (RF) positive patients responded totreatment as well as RF negative patients.

Rituximab showed a rapid and sustained depletion of B cells upon the first infusion. Infusion-related reactions occurred at a rate of 8% and 23%in the placebo and RTX groups, respectively, after the first infusion, and decreased following the second infusion. In fact, the rate of infusionreactions was lower with RTX treatment (11% vs 8% for the placebo and RTX groups, respectively). Infections were also higher with RTX treatment,although the rate of serious infection was low (2% for RTX vs <1% for placebo). Withdrawals due to efficacy were moderate with RTX treatment andwere low due to adverse events (AEs) in both treatment groups.

These findings confirm that RTX is effective and well-tolerated in this patient population of anti-TNF inadequate responders. Other studies with RTXhave demonstrated efficacy at total doses between 300-400 mg in refractory RA patients with and without combination therapy,3 adding furtherevidence to confirm the efficacy of RTX in inadequate responders. Still, supplementary data from long-term controlled trials are required as is theneed to address a regimen for maintenance therapy. Additional studies are also required to explore the implications of long-term B cell depletion onsubsequent immune function, on potential interactions with other medications, and on the time interval required before other medications targetingRA can be administered to B cell depleted patients should they fail on RTX.

References:1. 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

2004;350:2572-2581.2. Edwards JCW, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology

2001;40:205-211.3. Leandro MJ, Edwards JCW, Cambridge G. Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum Dis

2002;61:883–888.4. Edwards JC, Leandro MJ, Cambridge G. B lymphocyte depletion in rheumatoid arthritis: targeting of CD20. Curr Dir Autoimmun 2005;8:175-192.

SAFETY AND TOLERABILITY OF RITUXIMAB RETREATMENT IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS P. Emery1, R. M. Fleischmann2, K. Pavelka3, A. T. Kaell4, J. Z. Szechinski5, M. M. Hooper6, N. F. Li7, J. P. Garg7, K. A. Rowe8, P. B. Lehane9.1Leeds Gen Infirmary, Leeds, United Kingdom; 2Uni of Texas Southwestern Medical Center, Dallas, TX; 3Inst of Rheumatology, Prague, Czech Republic; 4RheumatologyAssoc of Long Island, Smithtown, NY; 5Medical Uni of Wroclaw, Wroclaw, Poland; 6Case Western Reserve Uni, Cleveland, OH; 7Genentech, Inc, So San Francisco, CA;8Uni of Hertfordshire, Hatfield, United Kingdom; 9Roche Products Ltd, Welwyn Garden City, United Kingdom

Arthritis Rheum 2005;52(9 Suppl):S341(Abstract 860).

PURPOSE: To evaluate the safety and tolerability of retreatment of rituximab (RTX), a selective CD20+ B cell-targeted monoclonal antibody inpatients (pts) with active rheumatoid arthritis (RA).

METHODS: RA pts in either of 2 Phase II RTX clinical trials (IIa/DANCER) were eligible for RTX treatment in an open-label retreatment protocol ifthey had defined improvement in RA activity during the 1st course (C1) and active RA with ≥8/8 swollen/tender joints. During C1 pts received asingle course of RTX 500 or 1000 mg on Days 1 and 15 (with either placebo glucocorticoids [GC]; IV [100 mg x 2] GC premedication; or IVpremedication plus 510 mg oral GC for the 1st 2 wks). Extension treatment consisted of two 1000 mg infusions on Days 1 and 15, withconcomitant MTX (10-25 mg/wk), IV GC premedication and oral GC for 2 wks.

RESULTS: The safety population comprised 192 RTX-treated pts, 141 of whom received a 2nd course of RTX (C2); 25 pts received a 3rd course (C3).While AE reporting time varied between courses, there were fewer adverse events (AEs) overall during C2 & C3 than C1. AEs resulting in studywithdrawal occurred in 1/192 (0.5%) pts during C1, 2/141 (1.4%) during C2, and 0/25 during C3. Infusion-associated AEs (any AE within 24 hof infusion) during C1 occurred in 36% of pts after the 1st infusion and in 24% after the 2nd infusion, compared with 17% & 8% during C2,and 12% & 4% during C3, respectively. One HACA+ pt withdrew in C2 due to infusion-associated bronchospasm. 5 and 8 pts became HACA+after C1 & C2, respectively. Hyper- or hypotension during infusions occurred in 3-9% and 4-5% of pts in each course, respectively, withoutsequelae; 3/17 with peri-infusional HTN were treated. Serious AEs were reported during C1 in 10% of pts, during C2 in 11% of pts, and in nopt during C3. Any infectious event was reported in 36% of pts during C1 and in 21% and 24% of pts during C2 & C3, respectively. Seriousinfections were rare (overall rate 1.4/100 pt yrs [350 pt yrs observed]) and included pneumonia, septic arthritis, appendicitis, and urinary tractinfection. CD19+ counts were below the lower limit of normal in 17% of pts at the start of C1, and in 66% & 52% of pts at the start of C2 & C3,respectively. Peripheral B cells depleted immediately after each RTX infusion and remained depleted throughout the 24-wk observation period; asimilar recovery rate was observed after each course.

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CONCLUSIONS: Retreatment with RTX was well tolerated. The AE profile was consistent with previous trials. The serious infection rate was low andthere was no evidence of cumulative toxicity despite ongoing peripheral B cell depletion.

EXPERT COMMENTARY by J. Carter Thorne, MD, FRCPC, FACP, University of Toronto

Previous clinical trials with RTX have demonstrated considerable efficacy and safety in patients with RA.1-3 An open-label extension of two Phase IItrials evaluated the safety and tolerability of RTX retreatment in patients with active RA. Patients had highly-active, longstanding disease (about10 years). As of the September, 2004 data analysis, 192 patients who had received a first course of RTX in the Phase II studies enrolled in therepeated treatment extension study. In total, 141/192 patients received a second course of RTX (first retreatment course with 78 patientsevaluated for 24 weeks); 51 patients had not yet received a second retreatment as of September, 2004; 25 patients received a third course ofRTX with 19 patients evaluated for 24 weeks.

Repeated courses of RTX were generally well-tolerated with adverse events (AEs) similar to those previously reported.1 Overall, withdrawals due toAEs were <1%. Following initiation of the second course of RTX treatment, 64% of patients reported an AE and 60% of patients reported an AEfollowing the third course. Most AEs were mild to moderate (Grade 1 or 2). Severe AEs (Grade 3 or 4) were reported in 19% and 8% of patientsin the first and second courses, while serious AEs were reported in 10% and 11% of patients in the first and second courses, respectively. Neithersevere nor serious AEs were reported during the third course. With each subsequent course of RTX, infusion-related adverse events were lessfrequent and less severe (from 43% to 21% to 16% after each course of RTX).

In each course, the most frequently reported infections were associated with the upper respiratory tract, lower respiratory tract, and urinary tract.The infection rate did not increase with subsequent RTX courses. There were 5 serious infections in this study. Overall, the incidence of seriousinfection from 350 patient-years was 1.4 infections per 100 patient-years.

CD19+ peripheral B-cell counts were depleted within 2 weeks following RTX, they remained depleted throughout the 24-week observation period.

While human anti-chimeric antibodies (HACA) positive rates increased after repeated RTX courses, the proportion of HACA-positive patients wasless than 10%.

A primary concern for novel treatments is safety. RTX has a dosing regimen that is unique among treatments for RA. A single short course of RTXprovides an extended duration of response. Because RTX has been used in the treatment of patients for non-Hodgkin’s lymphoma (NHL), a largebody of safety data has been collected (over 300 000 patient exposures),4,5 and has thus produced a well-characterized safety profile.5 This openlabel study characterized the safety profile of RTX in the treatment of RA patients. Early exposure data suggests that tolerability and safety maybe even better in RA patients, as the incidence and severity of AEs appears to be reduced in RA compared with non-Hodgkin’s lymphoma patients.1

Furthermore, there was no evidence of cumulative toxicity with repeated treatment in this extension study. AEs reported were acceptable andconsistent with those previously reported in RTX trials.1 Despite these positive findings, the safety of RTX with repeated treatments needs to beestablished. Clinical use of this agent necessitates a re-treatment strategy. A more rigorous blinded study design and analysis of re-treatment isrequired. In addition, though the safety data experience in NHL has not identified any significant ‘red flags’, the use of this agent in large numbersof patients outside a clinical trial, will require constant vigilance, emphasizing the potential importance of comprehensive registry databases.

References:1. 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

2004;350:2572-2581.2. Edwards JCW, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology

2001;40:205-211.3. Leandro MJ, Edwards JCW, Cambridge G. Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion Ann Rheum Dis

2002;61:883-888.4. Moreland L. Preface: B cell targeted therapy: a new approach to the treatment of rheumatoid arthritis. Arthritis Res Ther 2005;7(Suppl 3):S1.5. Shaw T, Quan J, Totoritis MC. B cell therapy for rheumatoid arthritis: the rituximab (anti-CD20) experience. Ann Rheum Dis 2003;62(Suppl II):ii55–ii59.

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IMPROVED QUALITY OF LIFE WITH RITUXIMAB PLUS METHOTREXATE IN PATIENTS WITH ACTIVE RHEUMATOIDARTHRITIS WHO EXPERIENCED INADEQUATE RESPONSE TO ONE OR MORE ANTI-TNF-α THERAPIES E. C. Keystone1, G. R. Burmester2, R. Furie3, J. E. Loveless4, P. Emery5, M. W. Cravets6, F. Magrini7.1University of Toronto, Toronto, ON, Canada; 2Charite University Medicine, Berlin, Germany; 3North Shore LIJ Health System, Lake Success, NY; 4IntermountainOrthopaedics, Boise, ID; 5Department of Rheumatology, Leeds General Infirmary, Leeds, United Kingdom; 6Biogen Idec Inc., San Diego, CA; 7Roche Products Ltd,Welwyn Garden City, United Kingdom

Arthritis Rheum 2005;52(9 Suppl):S141(Abstract 287).

Purpose: To evaluate treatment effects of rituximab (RTX), a CD20+ B cell-targeted monoclonal antibody, plus methotrexate (MTX) on patient-reported outcomes (PROs) in patients (pts) with active rheumatoid arthritis (RA) who experienced inadequate response to one or more anti-tumornecrosis factor-α (anti-TNF-α) therapies (etanercept, infliximab, and/or adalimumab).

Methods: Pts with active RA, defined by swollen and tender joint counts >/=8 and an elevated C-reactive protein and/or erythrocyte sedimentation rate,despite ongoing MTX, were randomized to receive a single course of either RTX (1000 mg given by intravenous [IV] infusion on Days 1 and 15) ormatching placebo infusions (PLC). All pts received concomitant MTX (10-25 mg/week) and peri-infusional glucocorticoids (GC) (100 mg) prior to eachinfusion, in addition to a brief course of oral GC. Clinical assessments were conducted at 4-weekly intervals between Weeks 4 and 24, and the primaryendpoint was the proportion of pts that achieved an ACR20 response at Week 24. PROs were collected using HAQ-DI, SF-36, and FACIT-F instruments.

Results: Overall, 520 pts with long-standing (mean duration 12 years)and active disease (mean DAS28 6.9) were randomized (499 ofwhich comprise the intent-to-treat analysis population). Ptdemographics and baseline disease characteristics were similaracross the treatment groups. RTX+MTX was more effective than MTXalone at the 24-week assessment in alleviating symptoms, asmeasured by PROs (see table).

Conclusions: Treatment with RTX+MTX led to statistically significantimprovements in all PROs (HAQ, SF-36, and FACIT-F) versus MTXalone. Improvements perceived by patients in their disease followingRTX treatment support previous efficacy results from other analyses(ACR and EULAR responses and DAS28) reported elsewhere, andshow that symptomatic improvements with rituximab are mirrored byimproved patient outcomes.

EXPERT COMMENTARY by Robert C. Offer, MD, FRCPC, University of British Columbia

Quality of life, as measured by the SF-36, is considerably impaired in RA patients despite advanced treatments.1-3 Patients in this study (REFLEX)fall into the category of particularly severe RA, as they were specifically selected as failures in treatment with one or more anti-TNF therapies (meanof 2.5-2.6 TNF inhibitors). They had a mean of 23 swollen and 34 tender joints at baseline despite MTX and were randomly assigned to receiveMTX (mean 16.7 mg/wk) + placebo (n=201) or MTX (mean 16.4 mg) + rituximab 1000 mg (n=298) administered on Days 1 and 15 by IV infusion.

Significantly more patients achieved an ACR20 response at 24 weeks, the primary endpoint, when treated with RTX compared with placebo(51% vs 18%, p<0.0001). ACR50 and ACR70 scores were also significantly higher with RTX treatment (Δ22% and 11%, respectively). Clinicalresponses were reflected in statistically significant improvements in all measures of disease activity and patient-reported outcomes at 24 weeks.

A feature of treatment with great significance to the RA patient is HRQoL. Patients continue to endure significant symptoms and compromisedquality of life and ability to complete their daily activities.3 These results provide evidence of clinically meaningful QoL benefits in those patientspreviously non-responsive to TNF inhibitors.

Rituximab is one of three new treatments examined in this ACR 2005 review which may become available in the near future for RA patients whofail on a TNF inhibitor. As the number of available biologic response modifiers increases, we will face some critical clinical questions, as will thethird party payers. As patients failing on one anti-TNF most often respond to a second and even a third anti-TNF, will it be best to cycle throughall the anti-TNF agents (in the absence of contraindications) and then use rituximab or abatacept? Or will we stratify the anti-TNF failures suchthat Type 1 failures (never responded) who have lower response rates to a second anti-TNF are changed directly to one of these newer agents witha different mechanism of action? And what will we do with the MTX intolerant patient who fails on anti-TNF monotherapy? The ASSURE studyprovides evidence that abatacept concomitant non-biologic DMARDs are safe.4

References:1. Fraenkel L, Bogardus ST, Concato J, et al. Patient preference for treatment of rheumatoid arthritis. Ann Rheum Dis 2004;63:1372-1378. 2. Wolfe F, Michaud K. Fatigue, rheumatoid arthritis, and anti-tumor necrosis factor therapy: an investigation in 24,831 patients. J Rheumatol 2004;31:2115-2120.3. Arthritis Foundation. Living with Rheumatoid Arthritis: Unmet Needs. Available at: http://www.arthritis.org/conditions/diseasecenter/RA/RASurvey

WhitePaperFinal.pdf . Accessed November 23, 2005.4. Coombe B, Weinblatt M, Birbara C, et al. Safety and patient-reported outcomes associated with abatacept in the treatment of rheumatoid arthritis patients

receiving background disease modifying anti-rheumatic drugs (DMARDs): the ASSURE trial. Arthritis Rheum 2005;52(9 Suppl):S709(Abstract 1918).

PROs: change from baseline to Week 24

RTX (n=298) PLC (n=201) p-valuea

HAQ-DI (mean % change)b -26.9 (34.93) -6.5 (33.38) <0.0001

SF-36 (mean change)c

Mental Health Summary 4.7 (11.75) 1.3 (9.43) 0.0002

Physical Health Summary 5.8 (8.47) 0.9 (5.65) <0.0001

FACIT-F (mean change) a,b -9.1 (11.31) -0.5 (9.84) <0.0001aAnalysis of covariance; bnegative change = improvement; cpositive change = improvement

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INTERLEUKIN-6, A PLEIOTROPIC CYTOKINEInterleukin 6 (IL-6) is a pleiotropic cytokine that plays an important role in immune response.1,2 It is involved in both initiation and maintenanceof inflammatory and immunologic responses in certain autoimmune diseases and plays a key role in acute phase protein induction as well as Band T cell growth and differentiation. In arthritic joints, IL-6 is produced by different cell types and has numerous target organs, includingsynovium, cartilage, and bone.3-5 IL-6 is also a component of a large and complex signaling network and, as such, is able to modulate the effectsof other cytokines and hormones. Therefore, the inhibition of the biologic functions of IL-6 may allow for a broader approach to the treatment ofrheumatic diseases such as RA and systemic juvenile idiopathic arthritis.

Tocilizumab

Tocilizumab is the first humanized anti-IL-6 receptor antibody to reach Phase III clinical trials. It is now being studied in RA patients, with earlystudies showing promising results.6-9 Although Phase III trials are currently being conducted involving several thousand patients, results from allstudies are not currently available. The following are abstracts from the ACR 2005 conference examining tocilizumab in human clinical trials ofarthritis, along with expert commentary.

References:1. Kishimoto T. Interleukin-6 and its receptor in autoimmunity. J Autoimmune 1992;5:I123-132.2. Guerne PA, Zuraw BL, Vaughan JH, et al. Synovium as a source of interleukin-6 in vitro. Contribution to local and systemic manifestations of arthritis. J Clin

Invest 1989;83:585-592.3. Houssiau FA, Devogelaer JP, Van Damme J, et al. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory

arthritides. Arthritis Rheum 1988;31:784-788.4. Dasgupta B, CorkillM, Kirkhan B, et al. Serial estimation of interleukin-6 as a measure of systemic disease in rheumatic arthritis. J Rheumatol 1992;19:22-35.5. Kotake S, Sato K, Kim KJ, et al. Interleukin-6 and soluable interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for

osteoclast-like cell formation. J Bone Miner Res 1996;11:88-95.6. Nishimoto N, Yoshizaki K, Miyasaka N, et al. Long-term safety and efficacy of anti-Interleukin-6 receptor antibody (MRA) in patients with rheumatoid arthritis.

Paper presented at: Program and Abstracts of the American College of Rheumatology 67th Annual Scientific Meeting; October 23-28, 2003; Orlando, Florida.Abstract S216.

7. Nishimoto N, Yoshizaki K, Maeda K, et al. Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin-6receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. J Rheumatol 2003;30:1426-1435.

8. Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind,placebo-controlled trial. Arthritis Rheum 2004;50:1761-1769.

9. Maini RN, Taylor PC, Pavelka K, et al. Efficacy of IL-6 receptor antagonist MRA in rheumatoid arthritis patients with an incomplete response to methotrexate(CHARISMA). Paper presented at: Program and Abstracts of the American College of Rheumatology 67th Annual Scientific Meeting; October 23-28, 2003;Orlando, Florida. Abstract S1704.

BLOCKING INTERLEUKIN-6 (IL-6) BY TOCILIZUMAB (A HUMANIZED ANTI-INTERLEUKIN-6 RECEPTORMONOCLONAL ANTIBODY) MONOTHERAPY REDUCES JOINT DAMAGE IN ACTIVE RHEUMATOID ARTHRITIS (RA):EVIDENCE FROM A X-RAY READER-BLINDED RANDOMISED CONTROLLED TRIAL Norihiro Nishimoto1, Jun Hashimoto1, Nobuyuki Miyasaka2, Kazuhiko Yamamoto3, Shinichi Kawai4, Tsutomu Takeuchi5, Norikazu Murata6, Désiréevan der Heijde7, Tadamitsu Kishimoto1.1Osaka University, Osaka, Japan; 2Tokyo Medical and Dental University, Tokyo, Japan; 3University of Tokyo, Tokyo, Japan; 4Toho University Omori Medical Center, Tokyo,Japan; 5Saitama Medical Center/School, Saitama, Japan; 6Kyowakai Hospital, Osaka, Japan; 7University Hospital Maastricht, Maastricht, The Netherlands

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.

Objectives: To evaluate the ability of tocilizumab monotherapy to inhibit progression of structural joint damage, clinical efficacy and tolerability,in patients with active RA.

Methods: 306 patients with active early RA of <5 years’ duration were randomly allocated to receive either tocilizumab at 8 mg/kg IV every 4 weeksor conventional DMARDs for 52 weeks. In the control group, the dose, type and combination of DMARDs could be varied according to diseaseactivity, but anti-TNF agents and leflunomide were not permitted. The efficacy endpoints included change from baseline to week 52 in van derHeijde modified Sharp score, evaluated by 2 readers blinded for treatment and order of films, and ACR response rates. Adverse events (AEs) andlaboratory values were monitored for safety.

Results: A total of 302 patients (157 on tocilizumab and 145 on DMARDs ) received study drugs. MTX was the most popular treatment (80%) inthe DMARDs group at study start. All baseline characteristics were similar in the two groups. Patients had a mean disease duration of 2.3 years,DAS28 score of 6.9 and CRP of 4.8 mg/dL at baseline, indicating very active disease. Mean Total Sharp Score (TSS) at baseline was 30.0, whichwas very high despite relatively short disease duration. At week 52, patients in the tocilizumab group showed statistically significantly lessradiographic progression, as measured by change in TSS, than those receiving DMARDs (2.3 ± 5.6 versus 6.1 ± 11.4; p=0.001). Tocilizumabwas superior to DMARDs in preventing both erosion and joint space narrowing (p<0.001 and p=0.018 respectively). The percentages of patientswho achieved ACR20, 50 and 70 were 89%, 70% and 47% in the tocilizumab group and 35%, 14% and 6% in the DMARDs group (LOCF data;p<0.001, p<0.001, p<0.001 respectively). The overall incidences of AEs including laboratory abnormalities were 96% and 87% (serious AEs:19% and 13%) in the tocilizumab and DMARDs groups, respectively. Nasopharyngitis, and mild, transient increases in LFTs were frequentlyobserved in both groups. Lipid increases were predominantly reported in the tocilizumab group but the mean cholesterol level became stable(217 ± 39.3 mg/dL) at around the normal upper limit. No tuberculosis was observed.

Conclusion: This is the first trial showing superiority of blocking IL-6 with tocilizumab to conventional DMARDs in inhibiting radiographicprogression. Tocilizumab monotherapy was generally well tolerated.

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EXPERT COMMENTARY by Mary-Ann Fitzcharles, MB, ChB, FRCPC, McGill University

Tocilizumab is the first humanized anti-IL-6 receptor antibody to reach Phase III clinical trials and has demonstrated considerable efficacy inprevious studies.1-4 This pivotal trial of 307 patients demonstrated impressive efficacy for treatment in patients with high disease activity. Patientswere randomized to receive 8 mg/kg tocilizumab or conventional DMARDs for 52 weeks. The focus of this report is to describe radiographicchanges over a period of a year in RA patients.

ACR20, 50, and 70 scores of 89%, 70% and 47%, respectively, in the tocilizumab group were significantly higher than in the control group(DMARDs) (p<0.001). Numerically, these ACR scores are also substantially higher than those reported in most clinical trials with biologicals.However, these patients had RA for <5 years duration. These results are consistent with other studies by Nishimoto et al where patients treatedwith 8 mg/kg tocilizumab for 21 months achieved an ACR50 response in 72% of patients in an open-label, long-term extension trial.1 In a Phase I/IItrial, 9/15 patients achieved ACR 20 at 6 weeks, while at 24 weeks, 13/15 patients achieved ACR 20 and 5/15 patients achieved ACR 50.2

In 164 patients with refractory RA, 78% and 40% achieved an ACR20 and ACR50 response with three intravenous injections of 8 mg/kg.3 ACR50responses were reached in 26% of patients who received 4 mg/kg doses. The study population is somewhat unusual in that patients already hadconsiderable radiographic changes within a relatively short duration of disease. Although methotrexate was the most commonly used DMARD, thedose or method of administration is not mentioned. There is also no comment regarding steroid use.

The European CHARISMA study also evaluated the efficacy of tocilizumab as monotherapy or in combination with MTX in RA patients with activedisease despite treatment with MTX.4 After four monthly infusions of tocilizumab (4 and 8 mg/kg), significant improvements in signs andsymptoms were observed in patients receiving tocilizumab and MTX (p<0.05). DAS28 scores were also reduced.

Treatment was generally well-tolerated. Elevated lipid levels were observed with tocilizumab as seen in previous trials,3 and increases innasopharyngitis and liver function tests were seen in both treatment groups.

Overall, tocilizumab has demonstrated efficacy as a treatment for RA with excellent efficacy data. Additional controlled, long-term trials arerequired to examine efficacy and safety parameters.

References:1. Nishimoto N, Yoshizaki K, Miyasaka N, et al. Long-term safety and efficacy of anti-interleukin-6 receptor antibody (MRA) in patients with rheumatoid arthritis.

Paper presented at: The American College of Rheumatology 67th Annual Scientific Meeting; October 23-28, 2003; Orlando, Florida. Abstract S216.2. Nishimoto N, Yoshizaki K, Maeda K, et al. Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin-6

receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. J Rheumatol 2003;30:1426-1435.3. Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind,

placebo-controlled trial. Arthritis Rheum 2004;50:1761-1769.4. Maini RN, Taylor PC, Pavelka K, et al. Efficacy of IL-6 receptor antagonist MRA in rheumatoid arthritis patients with an incomplete response to methotrexate

(CHARISMA). Paper presented at: The American College of Rheumatology 67th Annual Scientific Meeting; October 23-28, 2003; Orlando, Florida. Abstract S1704.

LONG-TERM TREATMENT OF SYSTEMIC ONSET JUVENILE IDIOPATHIC ARTHRITIS (SO-JIA) WITH HUMANIZEDANTI-IL-6 RECEPTOR MONOCLONAL ANTIBODY, TOCILIZUMAB (ACTEMRA®) Shumpei Yokota1, Takako Miyamae1, Rumiko Kurosawa1, Remi Ozawa1, Tomoyuki Imagawa1, Masaaki Mori1, Norihiro Nishimoto2.1Departmet of Pediatrics, Yokohama City University School of medicine, Yokohama, Japan; 2Osaka University, Osaka, Japan

Arthritis Rheum 2005;52(9 Suppl):S725(Abstract 1956).

Purpose: In the previous study a humanized anti-IL-6 receptor monoclonal antibody, tocilizumab, was effective to treat patients with so-JIA andthe safety profile was acceptable. This extension study was conducted to establish the long-term efficacy of tocilizumab, to evaluate serum IL-6,and to confirm the absence of unexpected late or cumulative adverse effect.

Methods: This was an open-label, dose-titration study, followed by a treatment extension for 3 years. 11 patients with intractable SO-JIA wereenrolled. All completing the short-course study moved to this extension phase and received 2 to 8 mg/kg of tocilizumab every other week.Proinflammatory cytokines were simultaneously evaluated. Fixed doses of NSAIDs, cyclosporine, MTX were allowed, but anti-TNF alpha agents andparenteral steroids were not allowed throughout the study. Disease activity was assessed by JIA core set variables. The primary end point wasdefined as a 30% improvement in the JIA core set.

Results: Patients received tocilizumab for 10 to 35 months in total. During the extension phase, the dose of tocilizumab was adjusted to maintainboth lower levels of disease activity and inflammatory markers while tapering off steroids. Ten patients achieved 70% improvement of JIA core setat the last visit evaluation. Laboratory features improved and remained so during the treatment. Serum IL-6/IL-6R was found the uniqueproinflammatory cytokine, but the levels of TNF-α and IL-1-b were undetectable or trace at the enrollment. After the initial administration oftocilizumab IL-6 levels abruptly and paradoxically increased, and with the maintenance doses the IL-6 levels were 1) gradually decreased,2) continuously fluctuated, or 3) spontaneously fluctuated, basically with no changes of CRP or ESR. However, when patients manifestedinfectious episodes, IL-6 levels and CRP were concomitantly increased. Ten patients could successfully reduce the dose of steroids. No deaths ormalignancies were reported. The adverse events (AEs) were mild infections, and transient elevation of ALT and total cholesterol. One patient waswithdrawn due to duodenum perforation at 10 months of treatment that could be caused by the long-term steroids and NSAIDs. The most seriousAEs were pneumonia in 2.

Conclusions: The treatment with tocilizumab resulted in significant improvements of so-JIA and the improvements were sustained for up to 3 years.The dose of steroids was successfully tapered or ceased over the time. Serum IL-6/IL-6R levels again indicated the pathogenic role in so-JIA, andcould be one of the relevant markers of disease-activity. The efficacy and safety of tocilizumab in SO-JIA are being confirmed in a larger placebo-controlled study involving over 50 patients in Japan.

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EXPERT COMMENTARY by Robert C. Offer, MD, FRCPC, University of British Columbia

Systemic onset juvenile idiopathic arthritis (SO-JIA, formerly called Still’s disease) is characterized by fever, rash and arthritis. Over the age of 16,it is called Adult Onset Still’s disease (AOSD). In children, it accounts for 10%-15% of cases of juvenile idiopathic arthritis. In adults it is veryrare. In either case, treatment has been problematic until recently, and has been primarily, corticosteroids. The biologic response modifiers havebeen a welcome addition but responses to the TNF inhibitors have often been disappointing. On the other hand, daily injections of the interleukin-1(IL-1) receptor antagonist anakinra have been dramatically effective in a growing number of cases of AOSD1-7 and a few cases of SO-JIA.8,9 A longeracting IL-1 trap may prove useful in these disorders in the future. However, more options are sorely needed for this very ill and sometimes refractorygroup of patients.

Tocilizumab has demonstrated efficacy in pediatric populations with systemic onset juvenile idiopathic arthritis (SO-JIA).1 This small, open-label,dose-titration trial demonstrated significant sustained improvements in SO-JIA in an extension phase up to 3 years. Patients were randomized toreceive 2-8 mg/kg tocilizumab every other week.

Eleven patients were treated between 10 and 35 months. At the last evaluation, 10 of these patients achieved a 70% improvement in the juvenileidiopathic arthritis core set.

Minor infections, and transient elevations in cholesterol and alanine transaminase were reported. Serious AEs included pneumonia in two patients.

Overall, the results of this study that demonstrate reduction in signs and symptoms are encouraging. Tocilizumab has also shown potential in thetreatment of RA.2,3 Ongoing efficacy and safety trials in larger patient populations with SO-JIA are anticipated.

References:11. Rudinskaya A, Trock D. Successful treatment of a patient with refractory adult onset Still’s disease with anakinra. J Clin Rheum 2003;9:330-332.12. Haraoui B, Bourelle D, Kamienska A, et al. Anakinra in the treatment of adult onset Still’s disease. Presented at: The Annual European Congress of

Rheumatology, The European League Against Rheumatism (EULAR 2004), June 9-12, 2004; Berlin, Germany. Abstract FRI0148. 13. Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of Interleukin-1 in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical

response to Interleukin-1 blockade. J Exp Med 2005;201:1479-1486.14. Fitzgerald A, LeClerq S, Yan A, Homik J, Dinarello C. Rapid response to anakinra in patients with refractory adult onset Still’s disease. Arthritis Rheum

2005;52:1794-1803.15. Lequerre T, Mejjad O, Vittecoq O, Klemmer N, Pouplin S, LeLoet X. Adult onset Still’s disease: effectiveness of Interleukin-1 receptor antagonist (anakinra)

after unsuccessful infliximab treatment. Presented at: The Annual European Congress of Rheumatology, The European League Against Rheumatism (EULAR2004), June 9-12, 2004; Berlin, Germany. Abstract AB0335.

16. Chu C-Q, Hughes G, Karr N, Gardner G. Interleukin-1 blockade is an effective treatment of adult onset Still’s disease. Presented at: The 69th Annual ScientificMeeting of the American College of Rheumatology; November 15, 2005; San Diego, CA. Late-breaking Abstract F92.

17. Aarntzen E, van Riel P, Barrera P. Refractory adult onset Still’s disease and hypersensivity to NSAIDs and COX-2 inhibitors: are biologicals the solution? AnnRheum Dis 2005;64:1523-1524.

18. Irigoyen P, Olson J, Ilowite N. Treatment of systemic onset juvenile rheumatoid arthritis with anakinra. Presented at: The 68th Annual Scientific Meeting of theAmerican College of Rheumatology; October 19, 2004; San Antonio, TX. Abstract 1098.

19. Henrickson M. Efficacy of anakinra in refractory systemic arthritis. Presented at: The 68th Annual Scientific Meeting of the American College of Rheumatology;October 19, 2004; San Antonio, TX. Abstract 1099.

10. Woo P, Wilkinson N, Prieur A, et al. Proof of principle of the efficacy of Il-6 receptor blockade in severe systemic juvenile idiopathic arthritis (SJIA). AnnRheum Dis 2005;64(Suppl III):Abstract 84.

11. Nishimoto N, Yoshizaki K, Maeda K, et al. Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin-6receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. J Rheumatol 2003;30:1426-1435.

12. Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 2004;50:1761-1769.

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ConclusionsPatients with RA continue to suffer disability and pain despite currently available treatment agents, such as biologic

DMARDs and anti-TNF agents. The ability of patients to continue their normal daily activities without pain and disability is

intrinsic to treatment success. However, despite advances in biological therapies, the need for alternative treatments

remains. Emerging therapies offer further potential for disease and symptom relief, and are well tolerated by patients. T cell

costimulation modulation (eg, abatacept) has shown striking effectiveness in Phase III studies for patients who have failed

on traditional DMARDs (AIM) or on anti-TNF agents (ATTAIN), with a good safety profile (ASSURE). B cell inhibition by anti-

CD20 monoclonal antibodies (eg, rituximab) has resulted in significant improvement in RA patients. The DANCER (Phase IIb)

trial analyzed responses of patients to rituximab who no longer responded to DMARDs or biologics (including anti-TNF

agents). The recent REFLEX (Phase III) study examined the responses of patients who had experienced an inadequate

response to anti-TNF agents. IL-6 inhibition (eg, tocilizumab) is under investigation in the management of patients with RA

and sJIA, and early results show promise.

Clinical trials are progressing in the investigation of each these classes of agents, with evaluation of abatacept being the

most advanced. Long-term studies investigating both the efficacy and safety of new therapies are required to establish the

impact of these agents over longer periods of time, particularly given the long duration of rituximab’s impact on B cells.

With the discovery of new treatments for RA comes renewed hope for patients and physicians alike. These potential new

agents offer alternatives for targeted therapy. Continued research is providing innovative therapeutic strategies for the

treatment of RA.

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Online Discussion:Forum on Emerging Clinical Science from

The 69th Annual Scientific Meeting ofThe American College of Rheumatology: ACR 2005

An online forum is available to allow physicians to discuss issues related to the prospectivemanagement of rheumatoid arthritis as presented in this compilation. Dr. J. Carter Thorne willbe available to answer questions and add his expert opinions to the forum. A self-assessmentquiz 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 ClinicalScience from The 69th Annual Scientific Meeting of The American College ofRheumatology: ACR 2005” by entering your email address and password in the boxeson the web site and click on “Go”.

5. Comments and discussions of the other participants can be reviewed, as well as thoseof the moderator, Dr. Thorne, by accessing this site.

6. If you would like to add a comment or ask a question, simply type a heading into the“Subject” box, type your comment into the “Message” box, and click on“Add/Ajoutez”.

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This publication has been made possible A Continuing Medical Education by an educational grant from program with the support of

Bristol-Myers Squibb Canada Inc. SNELL Medical Communication Inc.

S N E L L

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