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3. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial

Author

Bijlsma, Johannes W J, Welsing, Paco M J, Woodworth, Thasia G, Middelink, Leonie M, Pethö-Schramm, Attila, Bernasconi, Corrado, Borm, Michelle E A, Wortel, Cornelis H, ter Borg, Evert Jan, Jahangier, Z Nazira, van der Laan, Willemijn H, Bruyn, George A W, Baudoin, Paul, Wijngaarden, Siska, Vos, Petra A J M, Bos, Reinhard, Starmans, Mirian J F, Griep, Eduard N, Griep-Wentink, Joanna R M, Allaart, Cornelia F, Heurkens, Anton H M, Teitsma, Xavier M, Tekstra, Janneke, Marijnissen, Anne Carien A, Lafeber, Floris P J, and Jacobs, Johannes W G

Published
2016
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6. OMERACT consensus-based operational definition of contextual factors in rheumatology clinical trials: A mixed methods study

Author

Nielsen, Sabrina Mai, primary, Boers, Maarten, additional, de Wit, Maarten, additional, Shea, Beverly, additional, van der Windt, Danielle A., additional, Reeves, Barnaby C., additional, Beaton, Dorcas, additional, Alten, Rieke, additional, Toupin April, Karine, additional, Boonen, Annelies, additional, Escorpizo, Reuben, additional, Flurey, Caroline, additional, Furst, Daniel E., additional, Guillemin, Francis, additional, Leong, Amye, additional, Pohl, Christoph, additional, Rasmussen, Marianne Uggen, additional, Singh, Jasvinder A., additional, Smolen, Josef S., additional, Strand, Vibeke, additional, Verstappen, Suzanne M.M., additional, Voshaar, Marieke, additional, Woodworth, Thasia G., additional, Ellingsen, Torkell, additional, March, Lyn, additional, Wells, George A., additional, Tugwell, Peter, additional, and Christensen, Robin, additional

Published
2021
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7. Harms reported by patients in rheumatology drug trials: a systematic review of randomized trials in the cochrane library from an OMERACT working group

Author

Berthelsen, Dorthe B., primary, Woodworth, Thasia G., additional, Goel, Niti, additional, Ioannidis, John P.A., additional, Tugwell, Peter, additional, Devoe, Dan, additional, Williamson, Paula, additional, Terwee, Caroline B., additional, Suarez-Almazor, Maria E., additional, Strand, Vibeke, additional, Leong, Amye L., additional, Conaghan, Philip G., additional, Boers, Maarten, additional, Shea, Beverley J., additional, Brooks, Peter M., additional, Simon, Lee S., additional, Furst, Daniel E., additional, and Christensen, Robin, additional

Published
2021
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9. Population characteristics as important contextual factors in rheumatological trials: an exploratory meta-epidemiological study from an OMERACT Working Group

Author

Nielsen, Sabrina Mai, Storgaard, Helene, Ellingsen, Torkell, Shea, Beverley J., Wells, George A., Welch, Vivian Andrea, Furst, Daniel E., De Wit, Maarten, Voshaar, Marieke, Juhl, Carsten Bogh, Boers, Maarten, Escorpizo, Reuben, Woodworth, Thasia G., Boonen, Annelies, Bliddal, Henning, March, Lyn M., Tugwell, Peter, Christensen, Robin, Psychology, Health & Technology, Interne Geneeskunde, MUMC+: MA Reumatologie (9), RS: CAPHRI - R3 - Functioning, Participating and Rehabilitation, Epidemiology and Data Science, and APH - Methodology

Subjects
medicine.medical_specialty, Epidemiology, Immunology, Population, Psychological intervention, Health literacy, Cochrane Library, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Rheumatic Diseases, medicine, Immunology and Allergy, QUALITY, Humans, 030212 general & internal medicine, education, Demography, Randomized Controlled Trials as Topic, 030203 arthritis & rheumatology, RISK, education.field_of_study, business.industry, OSTEOARTHRITIS TRIALS, Arthritis, n/a OA procedure, Clinical trial, SYSTEMATIC REVIEWS, Systematic review, Treatment Outcome, BIAS, Socioeconomic Factors, Outcomes research, Family medicine, business, EQUITY, CLINICAL-TRIALS, Patient education, INTERVENTIONS
Abstract

ObjectivesTo explore whether trial population characteristics modify treatment responses across various interventions, comparators and rheumatic conditions.MethodsIn this meta-epidemiological study, we included trials from systematic reviews available from the Cochrane Musculoskeletal Group published up to 23 April 2019 in Cochrane Library with meta-analyses of five or more randomised controlled trials (RCTs) published from year 2000. From trial reports, we extracted data on 20 population characteristics. For characteristics with sufficient data (ie, available for ≥2/3 of the trials), we performed multilevel meta-epidemiological analyses.ResultsWe identified 19 eligible systematic reviews contributing 187 RCTs (212 comparisons). Only age and sex were explicitly reported in ≥2/3 of the trials. Using information about the country of the trials led to sufficient data for five further characteristics, that is, 7 out of 20 (35%) protocolised characteristics were analysed. The meta-regressions showed effect modification by economic status, place of residence, and, nearly, from healthcare system (explaining 4.8%, 0.9% and 1.5% of the between-trial variation, respectively). No effect modification was demonstrated from age, sex, patient education/health literacy or predominant religion.ConclusionsThis study demonstrates the scarce reporting of most population characteristics, hampering investigation of their impact with meta-research. Our sparse results suggest that place of residence (ie, continent of the trial), economic status (based on World Bank classifications) and healthcare system (based on WHO index for health system performance) may be important in explaining the variation in treatment response across trials. There is an urgent need for consistent reporting of important population characteristics in trials.PROSPERO registration numberCRD42019127642

Published
2020

10. Population characteristics as important contextual factors in rheumatological trials:An exploratory meta-epidemiological study from an OMERACT Working Group

Author

Nielsen, Sabrina Mai, Storgaard, Helene, Ellingsen, Torkell, Shea, Beverley J., Wells, George A., Welch, Vivian Andrea, Furst, Daniel E., De Wit, Maarten, Voshaar, Marieke, Juhl, Carsten Bogh, Boers, Maarten, Escorpizo, Reuben, Woodworth, Thasia G., Boonen, Annelies, Bliddal, Henning, March, Lyn M., Tugwell, Peter, Christensen, Robin, Nielsen, Sabrina Mai, Storgaard, Helene, Ellingsen, Torkell, Shea, Beverley J., Wells, George A., Welch, Vivian Andrea, Furst, Daniel E., De Wit, Maarten, Voshaar, Marieke, Juhl, Carsten Bogh, Boers, Maarten, Escorpizo, Reuben, Woodworth, Thasia G., Boonen, Annelies, Bliddal, Henning, March, Lyn M., Tugwell, Peter, and Christensen, Robin

Abstract

Objectives To explore whether trial population characteristics modify treatment responses across various interventions, comparators and rheumatic conditions. Methods In this meta-epidemiological study, we included trials from systematic reviews available from the Cochrane Musculoskeletal Group published up to 23 April 2019 in Cochrane Library with meta-Analyses of five or more randomised controlled trials (RCTs) published from year 2000. From trial reports, we extracted data on 20 population characteristics. For characteristics with sufficient data (ie, available for ≥2/3 of the trials), we performed multilevel meta-epidemiological analyses. Results We identified 19 eligible systematic reviews contributing 187 RCTs (212 comparisons). Only age and sex were explicitly reported in ≥2/3 of the trials. Using information about the country of the trials led to sufficient data for five further characteristics, that is, 7 out of 20 (35%) protocolised characteristics were analysed. The meta-regressions showed effect modification by economic status, place of residence, and, nearly, from healthcare system (explaining 4.8%, 0.9% and 1.5% of the between-trial variation, respectively). No effect modification was demonstrated from age, sex, patient education/health literacy or predominant religion. Conclusions This study demonstrates the scarce reporting of most population characteristics, hampering investigation of their impact with meta-research. Our sparse results suggest that place of residence (ie, continent of the trial), economic status (based on World Bank classifications) and healthcare system (based on WHO index for health system performance) may be important in explaining the variation in treatment response across trials. There is an urgent need for consistent reporting of important population characteristics in trials. PROSPERO registration number CRD42019127642

Published
2020

12. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor

Author

Changelian, Paul S., Flanagan, Mark E., Ball, Douglas J., Kent, Craig R., Magnuson, Kelly S., Martin, William H., Rizzuti, Bonnie J., Sawyer, Perry S., Perry, Bret D., Brissette, William H., McCurdy, Sandra P., Kudlacz, Elizabeth M., Conklyn, Maryrose J., Elliott, Eileen A., Koslov, Erika R., Fisher, Michael B., Strelevitz, Timothy J., Yoon, Kwansik, Whipple, David A., Sun, Jianmin, Munchhof, Michael J., Doty, John L., Casavant, Jeffrey M., Blumenkopf, Todd A., Hines, Michael, Brown, Matthew F., Lillie, Brett M., Subramanyam, Chakrapani, Shang-Poa, Chang, Milici, Anthony J., Beckius, Gretchen E., Moyer, James D., Su, Chunyan, Woodworth, Thasia G., Gaweco, Anderson S., Beals, Chan R., Littman, Bruce H., Fisher, Douglas A., Smith, James F., Zagouras, Panayiotis, Magna, Holly A., Saltarelli, Mary J., Johnson, Kimberly S., Nelms, Linda F., Des Etages, Shelley G., Hayes, Lisa S., Kawabata, Thomas T., Finco-Kent, Deborah, Baker, Deanna L., Larson, Michael, Si, Ming-Sing, Paniagua, Ricardo, Higgins, John, Holm, Bari, Reitz, Bruce, Zhou, Yong-Jie, Morris, Randall E., O'Shea, John J., and Borie, Dominic C.

Abstract

In spite of numerous treatment options for organ transplant and autoimmune disease patients (1), there remains a need for effective and safe immunosuppressive agents. The most significant complications of drugs [...], Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.

Published
2003

17. Towards consensus in defining and handling contextual factors within rheumatology trials: an initial qualitative study from an OMERACT working group.

Author

Nielsen, Sabrina Mai, Rasmussen, Marianne Uggen, Boers, Maarten, van der Windt, Danielle A., de Wit, Maarten, Woodworth, Thasia G., Flurey, Caroline A., Beaton, Dorcas, Shea, Beverley, Escorpizo, Reuben, Furst, Daniel E., Smolen, Josef S., Toupin-April, Karine, Boonen, Annelies, Voshaar, Marieke, Ellingsen, Torkell, Wells, George A., Reeves, Barnaby C., March, Lyn, and Tugwell, Peter

Subjects
EXPERIMENTAL design, CONSENSUS (Social sciences), RESEARCH, CLINICAL trials, FOCUS groups, RHEUMATOLOGY, RESEARCH methodology, EVALUATION research, MEDICAL cooperation, QUALITATIVE research, COMPARATIVE studies, PSYCHOLOGY of Research personnel, TERMS & phrases, RHEUMATISM
Abstract

Objectives: The Outcome Measures in Rheumatology Initiative established the Contextual Factors Working Group to guide the understanding, identification and handling of contextual factors for clinical trials. In clinical research, different uses of the term 'contextual factors' exist. This study explores the perspectives of researchers (including clinicians) and patients in defining 'contextual factor' and its related terminology, identifying such factors and accounting for them in trials across rheumatology.Methods: We conducted individual semistructured interviews with researchers (including clinicians) who have experience within the field of contextual factors in clinical trials or other potentially relevant areas, and small focus group interviews with patients with rheumatic conditions. We transcribed the interviews and applied qualitative content analysis.Results: We interviewed 12 researchers and 7 patients. Researcher's and patient's descriptions of contextual factors were categorised into two broad themes, each comprising two contextual factors types. The 'treatment effect' theme focused on factors explaining variations in treatment effects (A) among patients and (B) among studies. The 'outcome measurement' theme focused on factors that explain (C) variations in the measurement result itself (apart from actual changes/differences in the outcome) and (D) variations in the outcome itself (beside treatment of interest). Methods for identifying and handling contextual factors differed among these themes and types.Conclusions: Two main themes for contextual factors with four types of contextual factors were identified based on input from researchers and patients. This will guide operationalisation of contextual factors. Further research should refine our findings and establish consensus among relevant stakeholders. [ABSTRACT FROM AUTHOR]

Published
2021
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19. Phase I trial of an interleukin-2 fusion toxin (DAB486IL-2) in hematologic malignancies: complete response in a patient with Hodgkin's disease refractory to chemotherapy

Author

Tepler, Isidore, Schwartz, Gary, Parker, Karen, Charette, Jane, Kadin, Marshall E., Woodworth, Thasia G., and Schnipper, Lowell E.

Subjects
Interleukin-2 -- Research, Hodgkin's disease -- Care and treatment, Antibody-toxin conjugates -- Testing, Recombinant molecules -- Research, Health
Abstract

Background. [DAB.sub.486]IL-2 is a recombinant fusion toxin in which the native diphtheria toxin-receptor binding-domain has been replaced with human interleukin-2 (IL-2). This molecule is specifically cytotoxic in vitro within 30 minutes for cells that express the high-affinity IL-2 receptor (IL-2R). Methods. This was a Phase I/II study of [DAB.sub.486]IL-2 as a brief infusion in 15 patients with refractory lymphoid malignancies. Five patients per cohort received [DAB.sub.486]IL-2 as a 30--60 minute intravenous infusion at dose levels of 0.075, 0.115, and 0.2 mg/kg daily for 5 days. Results. The maximal tolerated dose (MTD) of [DAB.sub.486]IL-2 was determined to be 0.2 mg/kg daily on the basis of hypersensitivity-like symptoms and reversible hepatic transaminase elevations. Other adverse effects included mild creatinine elevations, proteinuria, and hypoalbuminemia. The presence of antibodies to diphtheria toxin or [DAB.sub.486]IL-2 was correlated with hypersensitivity-like effects but did not prevent an antitumor effect. One complete response was observed in a patient with Hodgkin's disease in relapse with bilateral pulmonary nodules after autologous bone marrow transplantation. He remains free of disease more than 2 years after completion of therapy. Conclusions. The dramatic antitumor response seen in one patient and the relative tolerability of [DAB.sub.486]IL-2 indicates the potential utility of this targeted agent in IL-2-expressing hematologic malignancies. Cancer 1994; 73:1276--85. Key words: immunotoxins, diphtheria toxin, interleukin-2 receptors, interleukin-2, Hodgkin's disease, lymphoma, hematologic malignancies, recombinant fusion proteins.

Published
1994

21. Content and Construct Validity, Reliability, and Responsiveness of the Rheumatoid Arthritis Flare Questionnaire: OMERACT 2016 Workshop Report

Author

Bartlett, Susan J., primary, Barbic, Skye P., additional, Bykerk, Vivian P., additional, Choy, Ernest H., additional, Alten, Rieke, additional, Christensen, Robin, additional, den Broeder, Alfons, additional, Fautrel, Bruno, additional, Furst, Daniel E., additional, Guillemin, Francis, additional, Hewlett, Sarah, additional, Leong, Amye L., additional, Lyddiatt, Anne, additional, March, Lyn, additional, Montie, Pamela, additional, Pohl, Christoph, additional, Scholte Voshaar, Marieke, additional, Woodworth, Thasia G., additional, and Bingham, Clifton O., additional

Published
2017
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22. An OMERACT Initiative Toward Consensus to Identify and Characterize Candidate Contextual Factors: Report from the Contextual Factors Working Group

Author

Finger, Monika E., primary, Boonen, Annelies, additional, Woodworth, Thasia G., additional, Escorpizo, Reuben, additional, Christensen, Robin, additional, Nielsen, Sabrina M., additional, Leong, Amye L., additional, Scholte Voshaar, Marieke, additional, Flurey, Caroline A., additional, Milman, Nataliya, additional, Verstappen, Suzanne M., additional, Alten, Rieke, additional, Guillemin, Francis, additional, Kloppenburg, Margreet, additional, Beaton, Dorcas E., additional, Tugwell, Peter S., additional, March, Lyn M., additional, Furst, Daniel E., additional, and Pohl, Christoph, additional

Published
2017
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24. Identifying Provisional Generic Contextual Factor Domains for Clinical Trials in Rheumatology: Results from an OMERACT Initiative.

Author

Nielsen, Sabrina M., Tugwell, Peter, de Wit, Maarten P. T., Boers, Maarten, Beaton, Dorcas E., Woodworth, Thasia G., Escorpizo, Reuben, Shea, Beverley, Toupin-April, Karine, Guillemin, Francis, Strand, Vibeke, Singh, Jasvinder A., Kloppenburg, Margreet, Furst, Daniel E., Wells, George A., Smolen, Josef S., Veselý, Richard, Boonen, Annelies, Storgaard, Helene, and Voshaar, Marieke

Published
2019
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25. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial

Author

Lab Reumatologie/Klinische Immunologie, Other research (not in main researchprogram), Infection & Immunity, Epi Methoden Team 1, JC onderzoeksprogramma Methodologie, MS Reumatologie/Immunologie/Infectie, Regenerative Medicine and Stem Cells, Bijlsma, Johannes W J, Welsing, Paco M J, Woodworth, Thasia G, Middelink, Leonie M, Pethö-Schramm, Attila, Bernasconi, Corrado, Borm, Michelle E A, Wortel, Cornelis H, Ter Borg, Evert Jan, Jahangier, Z Nazira, van der Laan, Willemijn H, Bruyn, George A W, Baudoin, Paul, Wijngaarden, Siska, Vos, Petra A J M, Bos, Reinhard, Starmans, Mirian J F, Griep, Eduard N, Griep-Wentink, Joanna R M, Allaart, Cornelia F, Heurkens, Anton H M, Teitsma, Xavier M, Tekstra, Janneke, Marijnissen, Anne Carien A, Lafeber, Floris P J, Jacobs, Johannes W G, Lab Reumatologie/Klinische Immunologie, Other research (not in main researchprogram), Infection & Immunity, Epi Methoden Team 1, JC onderzoeksprogramma Methodologie, MS Reumatologie/Immunologie/Infectie, Regenerative Medicine and Stem Cells, Bijlsma, Johannes W J, Welsing, Paco M J, Woodworth, Thasia G, Middelink, Leonie M, Pethö-Schramm, Attila, Bernasconi, Corrado, Borm, Michelle E A, Wortel, Cornelis H, Ter Borg, Evert Jan, Jahangier, Z Nazira, van der Laan, Willemijn H, Bruyn, George A W, Baudoin, Paul, Wijngaarden, Siska, Vos, Petra A J M, Bos, Reinhard, Starmans, Mirian J F, Griep, Eduard N, Griep-Wentink, Joanna R M, Allaart, Cornelia F, Heurkens, Anton H M, Teitsma, Xavier M, Tekstra, Janneke, Marijnissen, Anne Carien A, Lafeber, Floris P J, and Jacobs, Johannes W G

Published
2016

28. Preface

Author

den Broeder, Alfons A., primary and Woodworth, Thasia G., additional

Published
2015
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29. Feasibility and Domain Validation of Rheumatoid Arthritis (RA) Flare Core Domain Set: Report of the OMERACT 2014 RA Flare Group Plenary

Author

Bartlett, Susan J., primary, Bykerk, Vivian P., additional, Cooksey, Roxanne, additional, Choy, Ernest H., additional, Alten, Rieke, additional, Christensen, Robin, additional, Furst, Daniel E., additional, Guillemin, Francis, additional, Halls, Serena, additional, Hewlett, Sarah, additional, Leong, Amye L., additional, Lyddiatt, Anne, additional, March, Lyn, additional, Montie, Pamela, additional, Orbai, Ana Maria, additional, Pohl, Christoph, additional, Voshaar, Marieke Scholte, additional, Woodworth, Thasia G., additional, and Bingham, Clifton O., additional

Published
2015
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32. Identifying Preliminary Domains to Detect and Measure Rheumatoid Arthritis Flares: Report of the OMERACT 10 RA Flare Workshop

Author

BINGHAM, CLIFTON O., primary, ALTEN, RIEKE, additional, BARTLETT, SUSAN J., additional, BYKERK, VIVIAN P., additional, BROOKS, PETER M., additional, CHOY, ERNEST, additional, CHRISTENSEN, ROBIN, additional, FURST, DANIEL E., additional, HEWLETT, SARAH E., additional, LEONG, AMYE, additional, MAY, JAMES E., additional, MONTIE, PAM, additional, POHL, CHRISTOF, additional, SANDERSON, TESSA C., additional, STRAND, VIBEKE, additional, and WOODWORTH, THASIA G., additional

Published
2011
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33. Developing a Standardized Definition for Disease “Flare” in Rheumatoid Arthritis (OMERACT 9 Special Interest Group): Table 1.

Author

BINGHAM, CLIFTON O., primary, POHL, CHRISTOPH, additional, WOODWORTH, THASIA G., additional, HEWLETT, SARAH E., additional, MAY, JAMES E., additional, RAHMAN, MAHBOOB U., additional, WITTER, JAMES P., additional, FURST, DANIEL E., additional, STRAND, C. VIBEKE, additional, BOERS, MAARTEN, additional, and ALTEN, RIEKE E., additional

Published
2009
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34. The human anti-IL-1β monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis

Author

Alten, Rieke, primary, Gram, Hermann, additional, Joosten, Leo A, additional, Berg, Wim, additional, Sieper, Joachim, additional, Wassenberg, Siegfrid, additional, Burmester, Gerd, additional, van Riel, Piet, additional, Diaz-Lorente, Maria, additional, Bruin, Gerardus JM, additional, Woodworth, Thasia G, additional, Rordorf, Christiane, additional, Batard, Yannik, additional, Wright, Andrew M, additional, and Jung, Thomas, additional

Published
2008
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36. Cutaneous Injection of Human Subjects with Macrophage Inflammatory Protein-1α Induces Significant Recruitment of Neutrophils and Monocytes

Author

Lee, Sang Chin, primary, Brummet, Mary E., additional, Shahabuddin, Syed, additional, Woodworth, Thasia G., additional, Georas, Steve N., additional, Leiferman, Kristin M., additional, Gilman, Steven C., additional, Stellato, Cristiana, additional, Gladue, Ron P., additional, Schleimer, Robert P., additional, and Beck, Lisa A., additional

Published
2000
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38. Interleukin-2 diphtheria fusion protein (dab486il-2) in refractory rheumatoid arthritis a double-blind, placebo-controlled trial with open-label extension

Author

Moreland, Larry W., primary, Sewell, K. Lea, additional, Trentham, David E., additional, Bucy, R. Pat, additional, Sullivan, William F., additional, Schrohenloher, Ralph E., additional, Shmerling, Robert H., additional, Parker, Karen C., additional, Swartz, William G., additional, Woodworth, Thasia G., additional, and Koopman, William J., additional

Published
1995
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40. Phase I Trial of a Genetically Engineered Interleukin-2 Fusion Toxin (DAB486IL-2) as a 6 Hour Intravenous Infusion in Patients with Hematologic Malignancies

Author

Platanias, Leonidas C., primary, Ratain, Mark J., additional, O'brien, Sheila, additional, Larson, Richard A., additional, Vardiman, James W., additional, Shaw, Jill P., additional, Williams, Stephanie F., additional, Baron, Joseph M., additional, Parker, Karen, additional, and Woodworth, Thasia G., additional

Published
1994
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50. The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis.

Author

Alten R, Gram H, Joosten LA, van den Berg WB, Sieper J, Wassenberg S, Burmester G, van Riel P, Diaz-Lorente M, Bruin GJ, Woodworth TG, Rordorf C, Batard Y, Wright AM, and Jung T

Subjects
Adult, Aged, Animals, Antibodies, Monoclonal physiology, Arthralgia pathology, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid pathology, Cohort Studies, Double-Blind Method, Humans, Inflammation immunology, Inflammation therapy, Inflammation Mediators physiology, Mice, Mice, Inbred DBA, Middle Aged, NIH 3T3 Cells, Antibodies, Monoclonal therapeutic use, Arthralgia immunology, Arthralgia therapy, Arthritis, Rheumatoid therapy, Disease Models, Animal, Inflammation Mediators therapeutic use, Interleukin-1beta immunology
Abstract

Introduction: IL-1beta is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production., Methods: ACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1beta, was generated to study the potent and long-lasting neutralization of IL-1beta in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA)., Results: The mouse IL-1 receptor cross-reacts with human IL-1beta, and it was demonstrated that ACZ885 can completely suppress IL-1beta-mediated joint inflammation and cartilage destruction in mice. This observation prompted us to study the safety, tolerability and pharmacodynamic activity of ACZ885 in RA patients in a small proof-of-concept study--the first to be conducted in humans. Patients with active RA despite treatment with stable doses of methotrexate were enrolled in this dose escalation study. The first 32 patients were split into four cohorts of eight patients each (six were randomly assigned to active treatment and two to placebo). ACZ885 doses were 0.3, 1, 3 and 10 mg/kg, administered intravenously on days 1 and 15. To explore efficacy within 6 weeks of treatment, an additional 21 patients were randomly assigned to the 10 mg/kg cohort, resulting in a total of 20 patients dosed with 10 mg/kg and 15 patients treated with placebo. There was clinical improvement (American College of Rheumatology 20% improvement criteria) at week 6 in the 10 mg/kg treatment group; however, this did not reach statistical significance (P = 0.085). A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group. Onset of action was rapid, because most responders exhibited improvement in their symptoms within the first 3 weeks. C-reactive protein levels decreased in patients treated with ACZ885 within 1 week. ACZ885 was well tolerated. Three patients receiving ACZ885 developed infectious episodes that required treatment. No anti-ACZ885 antibodies were detected during the study., Conclusion: ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients. Additional studies to characterize efficacy in RA and to determine the optimal dose regimen appear warranted., Trial Registration: ClinicalTrials.gov identifier NCT00619905.

Published
2008
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