Objectives Rituximab is an effective treatment in patients with established rheumatoid arthritis (RA). The objective of the IMAGE study was to determine the efficacy of rituximab in the prevention of joint damage and its safety in combination with methotrexate (MTX) in patients initiating treatment with MTX.
Methods In this double-blind randomised controlled phase III study, 755 MTX-naïve patients with active RA were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX. The primary end point at week 52 was the change in joint damage measured using a Genant-modified Sharp score.
Results 249, 249 and 250 patients were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX, respectively. At week 52, treatment with rituximab 2×1000 mg + MTX compared with MTX alone was associated with a reduction in progression of joint damage (mean change in total modified Sharp score 0.359 vs 1.079; p=0.0004) and an improvement in clinical outcomes (ACR50 65% vs 42%; p<0.0001); rituximab 2×500 mg + MTX improved clinical outcomes (ACR50 59% vs 42%; p<0.0001) compared with MTX alone but did not significantly reduce the progression of joint damage. Safety outcomes were similar between treatment groups.
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IMAGE Investigators Aelion J (Arthritis Clinic, Jackson, TN, USA); Afif N (Centre Hospitalier De Mulhouse-Hôpital, Emile Muller, France); Ahmadi F (Centrallasarettet, Västerås, Sweden); Aires F (Hospital Universitário De Brasília, Brazil); Alanis E (Clinica San Jose, Obregon, Mexico); Alonso CS (Centro De Investigacion Del Noroeste, S.C. Tijuana, Mexico); Alten R H-E (Schlosspark Klinik, Berlin, Germany); Alvaro-Gracia JM (Hospital De La Princesa, Madrid, Spain); Ashrafzadeh A (Pacific Arthritis Care Center, Los Angeles, CA, USA); Ballina J (Hospital University Central, De Asturias, Oviedo, Spain); Bambara L-M (Policlinico G. B. Rossi, Verona, Italy); Bao C (Renji Hospital, Shanghai, China); Bell M (Sunnybrook Health Science Centre, Toronto, Canada); Berney S (Louisiana State University Medical Center, Shreveport, LA, USA); Bessette L (Groupe De Recherche en Rhumatologie et Maladies Osseuses, Quebec City, Canada); Birbara C (Clinical Pharmacology Study Group, Worcester, MA, USA); Boling E (Boling Clinical Trials, Upland, CA, USA); Bourgeois P (Hôpital Pitié, Salpêtrière, Paris, France); Braun J (Rheumazentrum-Ruhrgebiet, St Josefs-Krankenhaus, Herne, Germany), Briones H (Private Practice, Guatemala City, Guatemala); Brzezicki J (Wojewodzki Szpital, Zespolony, Elblag, Poland); Burgos-Vargos R (Clinica Para El Diagnostico y Tratamiento de las Enfermedades Reumaticas Sc, Mexico City, Mexico); Burmester G (Charité–Uni Medizin, Berlin, Campus Mitte, Berlin, Germany); Burnett M (Tampa Medical Group, Tampa, FL, USA); Busch H (Family Arthritis Center, Jupiter, FL, USA); Cabello E (Hospital Alberto, Sabogal Sologuren, Callao, Peru); Calvo A (Clinica San Felipe, Lima, Peru); Cantagrel A (Hôpital Rangueil, Toulouse, France); Cantini F (Ospedale Misericordia, Dolce, Prato, Italy); Carlos Zea A (Hospital Ramon Y Cajal, Madrid, Spain); Carreño Perez L (Hospital General University Gregorio Maranon, Madrid, Spain); Chavez J (Reumacentro Sac, Lima, Peru); Cheoi Shim S (Eilji University Hospital, Daejeon, South Korea); Chindalore V (Pinnacle Research Group, Aniston, AL, USA); Chiriac R (Spitalul Clinic De Recuperare, Iasi, Romania), Codding C (Health Research of Oklahoma, Oklahoma City, OK, USA); Danda D (Christian Medical College and Hospital, Vellore, India); Del Guidice J (Arthritis Associates, Lubbock, TX, USA); De Vita S (Policlinico University, Udine, Italy); Digiovanni R (DMI Health Care Group Inc, Largo, FL, USA); Dikranian A (San Diego Arthritis and Osteoporosis Medical Clinic, San Diego, CA, USA); Eider W (Clinical Trials Northwest, Yakima, WA, USA); Fantini F (A O Istituto Ortopedico Gaetano Pini, Milano, Italy); Ferraccioli G (University of Cattolica Del Sacro Cuore, Roma, Italy); Fietchner J (Fietchner Research, East Lansing, MI, USA); Filipowicz-Sosnowska A (Instytut Reumatologii Im Prof Dr Hab Eleonory Reicher, Warszawa, Poland); Finnanger B (Sykehuset Ostfold Sarpsborg HF, Sarpsborg, Norway); Fiocco G (Gundersen Clinic, Onalaska, WI, USA); Fleck M (Klinik Der Uni Regensburg, Germany); Fleischmann R (Metroplex Clinical Research, TX, USA); Fraser A (Graves-Gilbert Clinic, KY, USA); Gaudin P (Centre Hospitalier Universitaire de Grenoble, France); Gauler G (Rheumatologische, Gemeinschaftspraxis, Osnabrück, Germany); Gaylis N (Arthritis and Rheumatism, Disease Specialties Aventura, FL, USA); Gerlag DM (AMC/University of Amsterdam, Amsterdam, The Netherlands); Godde J (Hôpital Saint Joseph, Marseille, France); Gomez Reino JJ (Hospital Clinico Uni De Santiago, Santiago De Compostela, Spain); Gornisiewicz M (Rheumatology Consultants, Knoxville, TN, USA); Gough W (Asheville Rheumatology and Osteoporosis Research Associates, Asheville, NC, USA); Greenwald M (Desert Medical Advances, Palm Desert, CA, USA); Guerra G (Isthmian Medical Research, Panama City, Panama); Hackshaw K (Ohio State University Columbus, OH, USA); Haentzschel HM (Med-Poliklinisches Institut Der Univ Leipzig, Leipzig, Germany); Hammond T (Maidstone Hospital, Maidstone, UK); Hazleman BL (Addenbrooke's Hospital, Cambridge, UK); Heilig B (Rheumapraxis Heidelberg, Heidelberg, Germany); Herenius MMJ (AMC/University of Amsterdam, Amsterdam, The Netherlands); Hilliquin P (Hôpital Sud Francilien Corbeil-Essonnes, France); Holt D (Hospital Alberto Sabo Spartanburg Medical Research Spartanburg, SC, USA); Huang F (General Hospital of Chinese PLA, Beijing, China); Huff J (Arthritis and Osteoporosis Center of South Texas, San Antonio, TX, USA); Huizinga T (Academisch Ziekenhuis Leiden, Leiden, The Netherlands); Isaacs J (Freeman Hospital, Newcastle upon Tyne, UK); Jaffer A (Allergy and Rheumatology Center, La Jolla, CA, USA); Jason Amante E (Asian Hospital and Medical Center, Manila, Philippines); Jeka S (Szpital Wojewodzki Im, Dr Jana Biziela, Bydgoszcz, Poland); Jimenez R (Seattle Arthritis Clinic, Seattle, WA, USA); Jones G (Menzies Research Institute, University of Tasmania, Hobart, Tasmania); Jones R (Clinic for Rheumatic Diseases, Tuscaloosa, AL, USA); Kaine J (Sarasota Arthritis Center, Sarasota, FL, USA); Kashif A (Arthritis and Osteoporosis Consultants of Carolinas, Charlotte, NC, USA); Kaufmann C (Sykehuset I Buskerud HF, Drammen, Norway); Kay J (Massachusetts General Hospital, Boston, MA, USA); Khraishi M (Nexus Clinical Research Centre, St John's, Canada); Kivitz A (Altoona Center for Clinical Research, Duncansville, PA, USA); Klinkhoff A (Arthritis Research Centre, Vancouver, Canada); Kraag G (Ottawa Hospital, Riverside Campus, Ottawa, Canada); Krystufkova O (Research Institute of Rheumatic Diseases, Praha, Czech Republic); Kucharz E (Samodzielny Publiczny, Szpital Kliniczny Nr Sl.A.M., Katowice, Poland); Lawson J (Piedmont Arthritis Clinic, Greenville, SC, USA); Leirisalo-Repo M (Helsinki University Hospital, Helsinki, Finland); Levin R (Dunedin, FL, USA); Liang G (Northwestern University, Chicago, IL, USA); Liang P (CHUS Hôpital Fleurimont, Sherbrooke, QC, Canada); Limonta M (Ospedali Riuniti Di Bergamo, Bergamo, Italy); Lowenstein M (Arthritis Center Palm Harbor, FL, USA); Rodriguez-Lozano C (Hospital De Gran Canaria Dr Negrin, Las Palmas, Gran Canaria); Lue C (Little Rock Diagnostic Clinic, Little Rock, AR, USA); Mahowald M (VA Medical Center, Minneapolis, MN, USA); Maradiaga M (Hospital General De Culiacan Bernardo J, Gastelum, Culiacan, Mexico); Maricic M (Catalina Pointe Clinical Research, Tucson, AZ, USA); Mariette X (Hôpital Bicêtre, Le Kremlin-Bicêtre, France); Martin L (University of Calgary, Calgary, Canada); Massarotti E (New England Medical Center, Boston, MA, USA); Matucci Cerinic M (Ospedale Villa, Monnatessa, Firenze, Italy); Maurizio Montecucco C (IRCCS Policlinico San Matteo, Pavia, Italy); Mazurov V (Medical Academy of Postgraduate Education, St Petersburg, Russia); McNally J (Royal Berkshire Hospital, Reading, UK); Mehta D (Center for Arthritis and Osteoporosis, Elizabethtown, KY, USA); Meyer O (Hôpital Bichat Claude Bernard, Paris, France); Misra R (Sanyai Gandhi Post Graduate Inst. of Medical Sciences, Lucknow, India); Moreland LW (University of Alabama, Birmingham, USA); Mueller Ladner U (Kerckhoff-Klinik Gmbh, Bad Nauheim, Germany); Myerson G (Arthritis and Rheumatology of Georgia, Atlanta, GA, USA); Nasonov E (Institute of Rheumatology Rams, Moscow, Russia); Navarra S (St Luke's Medical Centre, Quezon City, Philippines); Navarro F (Hospital Virgen De La Macarena, Sevilla, Spain); Neal N (Valerius Medical Group and Research Center of Greater Long Beach, CA, USA); Olech E (Oklahoma Medical Research Foundation, Oklahoma City, OK, USA); Olsen N (University of Texas, Southwestern Medical, Center, TX, USA); Pablos JL (Hospital 12 De Octubre, Madrid, Spain); Pacheco C (Hospital Christus Muguerza Del Parque, Chihuahua, Mexico); Pal S (Apollo Hospital, Hyderabad, India); Palomo ER (Multimedica, Vistahermosa, Guatemala City, Guatemala); Pandith V (Jbn Medical Diagnostic Services Inc, Burlington, Canada); Penserga EG (Philippine General Hospital, Manila, Philippines); Prupas H (Arthritis Center of Reno, Reno, USA); Radominski S (Universidade Federal Do Parana, Curitiba, Portugal); Ramos-Remus C (Unidad De Enfermedades, Cronico Degenerativas, Guadalajara, Mexico); Reid D (Aberdeen Royal Infirmary, Aberdeen, UK); Riordan K (Centra Care Clinic, St Cloud, MN, USA); Rosenberg D (Florissant, MO, USA); Ruiz A (Hospital De Cruces, Barakaldo, Spain); Saadeh C (Amarillo Center for Clinical Research, Amarillo, TX, USA); Salvarani C (Ospedale Civile S. Maria Nuova, Reggio Emilia, Italy); Samuels A (East Penn Rheumatology Associates, Bethlehem, PA, USA); Sanmarti R, Sarzi Puttini P (Hospital Clinic Provincial, Barcelona, Spain); Saxe P (Delray Research Associates, Delray Beach, FL, USA); Schechtman J (Sun Valley Arthritis Center, Peoria, AZ, USA); Scoville C (Institute of Arthritis, Idaho Falls, ID, USA); Sedlackova M (Fakultni Thomayerova, Nemocnice, Praha, Czech Republic); Sedrish M (Clinical Research Network, Slidell, LA, USA); Sejer Hansen M (Herlev University Hospital, Herlev, Denmark); Sibilia J (Hopital De Hautepierre, Strasbourg, France); Siebert S (Princess of Wales Hospital, Bridgend, UK); Specker C (Klinik Für Rheumatologie and Klinische Immunologie, Essen, Germany); Stern S (Kentuckiana Center for Better Bone and Joint Health, Louisville, KY, USA); Szechinski J (Medical University of Wroclaw, Wroclaw, Poland); Tahir H (Whipps Cross Hospital, London, UK); Taylor A (Royal Perth Hospital, Shenton Park, Australia); Thompson PW (Poole General Hospital, Poole, UK); Tony H-P (Medizinische Poliklinik Der Uni Würzburg, Würzburg, Germany); Tornero J (Hospital General Univ. De Guadalajara, Guadalajara, Mexico); Trapp R (Arthritis Center Springfield, IL, USA); Tremblay J-L (Centre de Recherche Musculo-Squelettique, Trois-Rivieres, Quebec City, Canada); Valesini G (Policlinico Umberto, Universita' La Sapienza, Roma, Italy); Van Den Bosch F (Universitair Ziekenhuis, Gent, Belgium); Wanchu A (Post Graduate Institute of Medical Education and Research, Chandigarh, India); Wassenberg S (Evangelisches, Fachkrankenhaus, Ratingen, Germany); Ximenes AC (Hospital Geral De Goiania, Goiania, Brazil); Youn Kim H (Kang-Nam St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea); Zanetakis E (Oklahoma Center for Arthritis Therapy and Research, Tulsa, OK, USA); Zazueta B (Unidad de Reumatologia, Rehabilitacion Integral, Mexico); Zerbini C (Hospital Heliopolis, Sao Paulo, Brazil).
Funding Financial support for this study was obtained from F Hoffmann-La Roche Ltd, Genentech Inc and Biogen Idec. This work was supported in part by NIH grant M01 RR00043 to the General Clinical Research Center at the University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
Competing interests PPT has served as a paid consultant to Abbott Laboratories Ltd, Astellas, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Funxional Therapeutics, GlaxoSmithKline, Johnson and Johnson, Merck Serono, Novartis, NovImmune, NovoNordisk, Roche and Wyeth Pharmaceuticals. He has been paid lecture fees by Abbott Laboratories Ltd and Roche and received a payment from a commercial entity that sponsored the study (Roche), and received grant support from The Netherlands Organization for Health Research and Development (ZonMw) in assignment of The Netherlands Organization for Scientific Research (NWO), the Dutch Arthritis Association, the European Community, SmartMix SenterNovem (NWO and the Dutch Ministry of Economic Affairs), Bristol-Myers Squibb Int. Corp, MedImmune Limited, Merck Serono SA, Novartis Pharma AG, NovoNordisk A/S, Roche and Wyeth Pharmaceuticals. WFR has served as a paid consultant for Roche, Genentech and Biogen Idec, has been paid lecture fees by Genentech and Biogen Idec and has received grant support from Roche. AR-R has served as a paid consultant to Roche, Wyeth, Chugai, Essex and been paid lecture fees by Roche, UCB and Bristol-Myers Squibb. CGP is an employee of Spire Sciences LLC which provides clinical trial services to pharmaceutical companies. RFvV has served as a paid consultant, been paid lecture fees and received grant support from Roche. WS has served as a paid consultant to Human Genome Sciences and has received grant support from NIAMS, Genentech, Human Genome Sciences, Arthritis Foundation Southern California Chapter and Xencor. EH holds shares in Roche and is an employee of Roche. AC is an employee of Genentech, a member of the Roche Group. HT is an employee of Roche and has received payment from a commercial entity that sponsored the study. TMS holds shares in Roche and is an employee of Roche.
Ethics approval The study was approved by the institutional review board or the ethics committee at each study site. All patients gave written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.