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Rheumatoid Arthritis: HELP
Articles from Albany Medical College
Based on 83 articles published since 2010
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These are the 83 published articles about Arthritis, Rheumatoid that originated from Albany Medical College during 2010-2020.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial Can Methotrexate Prevent Knee Arthroplasties in Patients with Rheumatoid Arthritis? 2015

Kremer, Joel M. ·Pfaff Family Professor of Medicine, Albany Medical College, Director of Research, Center for Rheumatology, 1367 Washington Ave., Albany, New York 12206, USA. jkremer@joint-docs.com. ·J Rheumatol · Pubmed #26628706.

ABSTRACT: -- No abstract --

2 Editorial Still trying to understand methotrexate. 2014

Kremer, Joel M. ·Pfaff Family Professor of Medicine, Albany Medical College, Director of Research, The Center for Rheumatology, Albany, New York, USA. jkremer@joint-docs.com. ·J Rheumatol · Pubmed #25362706.

ABSTRACT: -- No abstract --

3 Review Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies. 2018

Taylor, Peter C / Kremer, Joel M / Emery, Paul / Zuckerman, Steven H / Ruotolo, Giacomo / Zhong, Jinglin / Chen, Lei / Witt, Sarah / Saifan, Chadi / Kurzawa, Monika / Otvos, James D / Connelly, Margery A / Macias, William L / Schlichting, Douglas E / Rooney, Terence P / de Bono, Stephanie / McInnes, Iain B. ·Botnar Research Centre, Nuffield Department ofOrthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. · Center for Rheumatology, Albany Medical College, Albany, New York, USA. · Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK. · Eli Lilly and Company, Indianapolis, Indiana, USA. · IQVIA, Morrisville, North Carolina, USA. · Laboratory Corporation of America Holdings (LabCorp), Morrisville, North Carolina, USA. · Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. ·Ann Rheum Dis · Pubmed #29463520.

ABSTRACT: OBJECTIVES: Lipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs. METHODS: Lipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study. RESULTS: Treatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no significant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not significantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated. CONCLUSIONS: Baricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these findings and their possible clinical implications. TRIAL REGISTRATION NUMBER: NCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078.

4 Review Efficacy and safety of tofacitinib in patients with active rheumatoid arthritis: review of key Phase 2 studies. 2016

Fleischmann, Roy / Kremer, Joel / Tanaka, Yoshiya / Gruben, David / Kanik, Keith / Koncz, Tamas / Krishnaswami, Sriram / Wallenstein, Gene / Wilkinson, Bethanie / Zwillich, Samuel H / Keystone, Edward. ·Metroplex Clinical Research Center, Dallas, Texas, USA. · Center for Rheumatology, Albany Medical College, Albany, New York, USA. · First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Pfizer Inc., Groton, Connecticut, USA. · Pfizer Inc., New York, New York, USA. · Mount Sinai Hospital, Toronto, Ontario, Canada. ·Int J Rheum Dis · Pubmed #27451980.

ABSTRACT: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here, the safety and efficacy data from five Phase 2 studies of tofacitinib in patients with RA are summarized. Tofacitinib 1-30 mg twice daily was investigated, as monotherapy and in combination with methotrexate, in patients with RA. Tofacitinib 20 mg once daily was investigated in one study. Tofacitinib 5 and 10 mg twice daily were selected for investigation in Phase 3 studies; therefore, the efficacy and safety of tofacitinib 5 and 10 mg twice daily in Phase 2 studies are the focus of this review. Tofacitinib ≥ 5 mg twice daily was efficacious in a dose-dependent manner, with statistically significant and clinically meaningful reductions in the signs and symptoms of RA and patient-reported outcomes. The safety profile was consistent across studies. The efficacy and safety profile of tofacitinib in Phase 2 studies supported its further investigation and the selection of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for evaluation in Phase 3 studies.

5 Review Painful rheumatoid arthritis. 2011

Smith, Howard S / Smith, Alyssa R / Seidner, Pya. ·Albany Medical College, Department of Anesthesiology, Albany, NY 12208, USA. ·Pain Physician · Pubmed #21927056.

ABSTRACT: Rheumatoid arthritis is a crippling disease that is often associated with severe pain, suffering, and diminished function, thereby detracting from an optimal quality of life. Over the past decade a greater appreciation of the pathophysiology of rheumatoid arthritis has been gained. In the past "decade of pain research," biologic agents which may modify rheumatoid arthritis have emerged as potent therapeutic antirheumatic drugs. Biologic agents include 5 tumor necrosis factor alpha inhibitors (etanercept, infliximab, adalimumab, golimumab, certolizumab pegol), interleukin-1 blockers (anakinra), monocloncal antibodies against B cells (rituximab), T cell costimulation blocker (abatacept), and interleukin-6 inhibitors (tocilizumab). Currently, utilizing therapy aimed at targeting various abnormalities of rheumatoid arthritis may be possible. It appears that the combined use of etanercept and methotrexate may improve the imbalance of Th1/Th2 and Th17/regulatory T cells (Treg) (and related cytokines) often seen in rheumatoid arthritis. Furthermore, this improvement in Tcell ratios/cytokines is also associated with improvement in clinical indicators of rheumatoid arthritis severity. Although rheumatologists are generally the specialists "called on" to manage complex patients with rheumatoid arthritis, pain specialists may be asked to join interdisciplinary teams managing patients with advanced refractory rheumatoid arthritis with severe pain since one of the most common and debilitating symptoms of rheumatoid arthritis is pain. Thus, pain specialists should have some appreciation of the current thoughts regarding rheumatoid arthritis pathophysiology and treatment. This narrative review of rheumatoid arthritis is intended to familiarize the interventional pain specialist with current concepts surrounding rheumatoid arthritis.

6 Clinical Trial Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four-Month, Phase III Study. 2019

van der Heijde, Désirée / Strand, Vibeke / Tanaka, Yoshiya / Keystone, Edward / Kremer, Joel / Zerbini, Cristiano A F / Cardiel, Mario H / Cohen, Stanley / Nash, Peter / Song, Yeong-Wook / Tegzová, Dana / Gruben, David / Wallenstein, Gene / Connell, Carol A / Fleischmann, Roy / Anonymous1301041. ·Leiden University Medical Center, Leiden, The Netherlands. · Biopharmaceutical Consultant, Portola Valley, California. · University of Occupational and Environmental Health, Kitakyushu, Japan. · Mount Sinai Hospital, Toronto, Ontario, Canada. · Albany Medical College, Albany, New York. · Centro Paulista de Investigação Clinica, Sao Paulo, Brazil. · Centro de Investigacion Clinica de Morelia, Morelia, Mexico. · Metroplex Clinical Research Center, Dallas, Texas. · Nambour General Hospital, Nambour, Queensland, Australia, and University of Queensland, Brisbane, Queensland, Australia. · Seoul National University Hospital, Seoul, Republic of Korea. · Institute of Rheumatology, Prague, Czech Republic. · Pfizer, Inc., Groton, Connecticut. ·Arthritis Rheumatol · Pubmed #30666826.

ABSTRACT: OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The phase III, 24-month, placebo-controlled Oral Rheumatoid Arthritis (ORAL) Scan trial was undertaken to evaluate the efficacy, including inhibition of structural progression, and safety of tofacitinib in patients with active RA and an inadequate response to methotrexate (MTX). Month 24 data from the completed study are reported here. METHODS: Patients were randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo, switched to tofacitinib 5 mg or 10 mg twice daily, with stable background MTX. Patients receiving placebo switched to tofacitinib at month 3 (nonresponders) or month 6 (remaining patients). Clinical efficacy, structural progression, and treatment-emergent adverse events were evaluated. Analyses were performed on the full analysis set with observed data or nonresponder imputation with no advancement penalty for clinical efficacy, and imputation by linear extrapolation for structural progression. RESULTS: Overall, 797 patients were treated; 539 (67.6%) completed 24 months of treatment. Responses according to the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70; the proportion of patients in whom remission or low disease activity was achieved according to the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate, Clinical Disease Activity Index, or Simplified Disease Activity Index; Boolean remission; and Health Assessment Questionnaire disability index scores were maintained from month 12 to 24 and were similar between tofacitinib dosages. Limited structural damage was observed at months 12 and 24. Safety events were similar in type and frequency for both tofacitinib dosages, and were consistent with those previously reported. CONCLUSION: Our findings indicate that clinical and radiographic treatment effects are sustained in months 12-24 in patients with RA receiving tofacitinib 5 mg or 10 mg twice daily plus MTX. The safety profile is consistent with that of other tofacitinib studies.

7 Clinical Trial Efficacy and Safety of Tofacitinib in Chinese Patients with Rheumatoid Arthritis. 2018

Li, Zhan-Guo / Liu, Yi / Xu, Hu-Ji / Chen, Zhi-Wei / Bao, Chun-De / Gu, Jie-Ruo / Zhao, Dong-Bao / An, Yuan / Hwang, Lie-Ju / Wang, Lisy / Kremer, Joel / Wu, Qi-Zhe. ·Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing 100044, China. · Department of Rheumatology and Immunology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. · Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China. · Department of Rheumatology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China. · Department of Rheumatology, Shanghai Renji Hospital, Shanghai 200000, China. · Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, China. · Department of Rheumatology and Immunology, Changhai Hospital of Shanghai, Shanghai 200433, China. · Statistician, Pfizer Inc, New York, NY 10017, USA (at the time of analysis). · Clinician, Pfizer Inc, Groton, CT 06340, USA. · Center for Rheumatology, Albany Medical College, Albany, NY 12208, USA. · Medical, Pfizer Inc, Beijing 100010, China. ·Chin Med J (Engl) · Pubmed #30425195.

ABSTRACT: Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies. Methods: ORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout. Results: ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population. Conclusions: Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population. Clinical Trial Identifier: NCT00856544 and NCT00413699.

8 Clinical Trial Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. 2018

Burmester, Gerd R / Kremer, Joel M / Van den Bosch, Filip / Kivitz, Alan / Bessette, Louis / Li, Yihan / Zhou, Yijie / Othman, Ahmed A / Pangan, Aileen L / Camp, Heidi S. ·Charité-Universitätsmedizin, Berlin, Germany. Electronic address: gerd.burmester@charite.de. · Albany Medical College, Albany, NY, USA. · VIB-UGent Center for Inflammation Research, Department of Internal Medicine, Ghent University, Ghent, Belgium; Department of Rheumatology, Ghent University Hospital, Ghent, Belgium. · Altoona Center for Clinical Research, Duncansville, PA, USA. · Laval University, Quebec, QC, Canada. · AbbVie Inc, North Chicago, IL, USA. ·Lancet · Pubmed #29908669.

ABSTRACT: BACKGROUND: Upadacitinib is a selective inhibitor of Janus kinase 1 and was efficacious in phase 2 studies in patients with moderate-to-severe rheumatoid arthritis. We aimed to assess the efficacy of upadacitinib in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). METHODS: This study is a double-blind, placebo-controlled trial at 150 sites in 35 countries. We enrolled patients aged 18 years or older with active rheumatoid arthritis for 3 months or longer, who had received csDMARDs for at least 3 months with a stable dose for at least 4 weeks before study entry, and had an inadequate response to at least one of the following csDMARDs: methotrexate, sulfasalazine, or leflunomide. Using interactive response technology, we randomly assigned patients receiving stable background csDMARDs (2:2:1:1) to receive a once-daily extended-release formulation of upadacitinib 15 mg or 30 mg, or placebo, for 12 weeks. Patients, investigators, and the funder were masked to allocation. After 12 weeks, patients taking placebo received 15 mg or 30 mg of upadacitinib once daily, according to the prespecified randomisation assignment. The primary endpoints were the proportion of patients at week 12 who achieved 20% improvement in American College of Rheumatology criteria (ACR20), and a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less. We did efficacy analyses in the full analysis set of all randomly assigned patients who received at least one dose of study drug, and used non-responder imputation for assessment of the primary outcomes. This study is registered with ClinicalTrials.gov, number NCT02675426. FINDINGS: Between Dec 17, 2015, and Dec 22, 2016, 1083 patients were assessed for eligibility, of whom 661 were recruited and randomly assigned to receive upadacitinib 15 mg (n=221), upadacitinib 30 mg (n=219), or placebo (n=221). All patients received at least one dose of study drug, and 618 (93%) completed 12 weeks of treatment. At week 12, ACR20 was achieved by 141 (64%; 95% CI 58-70) of 221 patients receiving upadacitinib 15 mg and 145 (66%; 60-73) of 219 patients receiving upadacitinib 30 mg, compared with 79 (36%; 29-42) of 221 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was met by 107 (48%; 95% CI 42-55) patients receiving upadacitinib 15 mg and 105 (48%; 41-55) patients receiving upadacitinib 30 mg, compared with 38 (17%; 12-22) patients receiving placebo (p<0·0001 for each dose vs placebo). Adverse events were reported in 125 (57%) of 221 patients receiving upadacitinib 15 mg, 118 (54%) of 219 patients receiving upadacitinib 30 mg, and 108 (49%) of 221 patients receiving placebo. The most frequently reported adverse events (≥5% of patients in any group) were nausea (16 [7%] of 221 in the upadacitinib 15 mg group; three [1%] of 219 in the upadacitinib 30 mg group; and seven [3%] of 221 in the placebo group), nasopharyngitis (12 [5%]; 13 [6%]; and nine [4%]), upper respiratory tract infection (12 [5%]; 12 [5%]; and nine [4%]), and headache (nine [4%]; seven [3%]; and 12 [5%]). More infections were reported for upadacitinib (64 [29%] of 221 patients receiving 15 mg and 69 [32%] of 219 patients receiving 30 mg) versus placebo (47 [21%] of 221 patients). There were three herpes zoster infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, and one [<1%] in the upadacitinib 30 mg group) and one primary varicella zoster virus infection (one [<1%] in the upadacitinib 30 mg group), two malignancies (both in the upadacitinib 30 mg group), one adjudicated major adverse cardiovascular event (in the upadacitinib 30 mg group), and five serious infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, three [1%] in the upadacitinib 30 mg group). No deaths were reported during the trial. INTERPRETATION: Patients with moderately to severely active rheumatoid arthritis who received upadacitinib (15 mg or 30 mg) in combination with csDMARDs showed significant improvements in clinical signs and symptoms. FUNDING: AbbVie Inc.

9 Clinical Trial Mavrilimumab, a Fully Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor α Monoclonal Antibody: Long-Term Safety and Efficacy in Patients With Rheumatoid Arthritis. 2018

Burmester, Gerd R / McInnes, Iain B / Kremer, Joel M / Miranda, Pedro / Vencovský, Jiří / Godwood, Alex / Albulescu, Marius / Michaels, M Alex / Guo, Xiang / Close, David / Weinblatt, Michael. ·Charité - University Medicine Berlin, Berlin, Germany. · University of Glasgow, Glasgow, UK. · The Albany Medical College, Albany, New York. · Centro de Estudios Reumatológicos, Santiago, Chile. · Institute of Rheumatology, Prague, Czech Republic. · MedImmune, Cambridge, UK. · MedImmune, Gaithersburg, Maryland. · Brigham and Women's Hospital, Boston, Massachusetts. ·Arthritis Rheumatol · Pubmed #29361199.

ABSTRACT: OBJECTIVE: Mavrilimumab, a human monoclonal antibody, targets granulocyte-macrophage colony-stimulating factor receptor α. We undertook to determine the long-term safety and efficacy of mavrilimumab in rheumatoid arthritis patients in 2 phase IIb studies (1071 and 1107) and in 1 open-label extension study (ClinicalTrials.gov identifier: NCT01712399). METHODS: In study 1071, patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs) received mavrilimumab (30, 100, or 150 mg) or placebo every other week plus methotrexate. In study 1107, patients with an inadequate response to anti-tumor necrosis factor agents and/or DMARDs received 100 mg mavrilimumab every other week or 50 mg golimumab every 4 weeks plus methotrexate. Patients entering the open-label extension study received 100 mg mavrilimumab every other week plus methotrexate. Long-term safety and efficacy of mavrilimumab were assessed. RESULTS: A total of 442 patients received mavrilimumab (14 of 245 patients from study 1071, 9 of 70 patients from study 1107, and 52 of 397 patients from the open-label extension study discontinued mavrilimumab treatment throughout the studies). The cumulative safety exposure was 899 patient-years; the median duration of mavrilimumab treatment was 2.5 years (range 0.1-3.3 years). The most common treatment-emergent adverse events (AEs) were nasopharyngitis (n = 69; 7.68 per 100 patient-years) and bronchitis (n = 51; 5.68 per 100 patient-years). At weeks 74 and 104, 3.5% and 6.2% of patients, respectively, demonstrated reduction in forced expiratory volume in 1 second, while 2.9% and 3.4% of patients, respectively, demonstrated reduction in forced vital capacity (>20% reduction from baseline to <80% predicted). Most pulmonary changes were transient and only infrequently associated with AEs. Mavrilimumab at 100 mg every other week demonstrated sustained efficacy; at week 122, 65.0% of patients achieved a Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) of <3.2, and 40.6% of patients achieved a DAS28-CRP of <2.6. CONCLUSION: Long-term treatment with mavrilimumab maintained response and was well-tolerated with no increased incidence of treatment-emergent AEs. Safety data were comparable with those from both phase IIb qualifying studies.

10 Clinical Trial A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis. 2017

Burmester, Gerd R / McInnes, Iain B / Kremer, Joel / Miranda, Pedro / Korkosz, Mariusz / Vencovsky, Jiri / Rubbert-Roth, Andrea / Mysler, Eduardo / Sleeman, Matthew A / Godwood, Alex / Sinibaldi, Dominic / Guo, Xiang / White, Wendy I / Wang, Bing / Wu, Chi-Yuan / Ryan, Patricia C / Close, David / Weinblatt, Michael E / Anonymous250897. ·Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Free University, and Humboldt University Berlin, Berlin, Germany. · Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, UK. · Center for Rheumatology, Albany Medical College, Albany, New York, USA. · Universidad de Chile and Hospital San Juan de Dios, Santiago, Chile. · Division of Rheumatology, Department of Internal Medicine and Gerontology, Jagiellonian University Medical College, Krakow, Poland. · Institute of Rheumatology, Charles University, Prague, Czech Republic. · Department of Internal Medicine, University of Cologne, Cologne, Germany. · Organizacion Medica de Investigación, Buenos Aires, Argentina. · MedImmune, Cambridge, UK. · MedImmune, Gaithersburg, Maryland, USA. · MedImmune, Mountain View, California, USA. · Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA. ·Ann Rheum Dis · Pubmed #28213566.

ABSTRACT: OBJECTIVES: Despite the therapeutic value of current rheumatoid arthritis (RA) treatments, agents with alternative modes of action are required. Mavrilimumab, a fully human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, was evaluated in patients with moderate-to-severe RA. METHODS: In a phase IIb study (NCT01706926), patients with inadequate response to ≥1 synthetic disease-modifying antirheumatic drug(s), Disease Activity Score 28 (DAS28)-C reactive protein (CRP)/erythrocyte sedimentation rate ≥3.2, ≥4 swollen joints despite methotrexate (MTX) were randomised 1:1:1:1 to subcutaneous mavrilimumab (150, 100, 30 mg), or placebo every other week (eow), plus MTX for 24 weeks. Coprimary outcomes were DAS28-CRP change from baseline to week 12 and American College of Rheumatology (ACR) 20 response rate (week 24). RESULTS: 326 patients were randomised (150 mg, n=79; 100 mg, n=85; 30 mg, n=81; placebo, n=81); 305 completed the study (September 2012-June 2013). Mavrilimumab treatment significantly reduced DAS28-CRP scores from baseline compared with placebo (change from baseline (SE); 150 mg: -1.90 (0.14), 100 mg: -1.64 (0.13), 30 mg: -1.37 (0.14), placebo: -0.68 (0.14); p<0.001; all dosages compared with placebo).Significantly more mavrilimumab-treated patients achieved ACR20 compared with placebo (week 24: 73.4%, 61.2%, 50.6% vs 24.7%, respectively (p<0.001)). Adverse events were reported in 43 (54.4%), 36 (42.4%), 41 (50.6%) and 38 (46.9%) patients in the mavrilimumab 150, 100, 30 mg eow and placebo groups, respectively. No treatment-related safety signals were identified. CONCLUSIONS: Mavrilimumab significantly decreased RA disease activity, with clinically meaningful responses observed 1 week after treatment initiation, representing a novel mechanism of action with persuasive therapeutic potential. TRIAL REGISTRATION NUMBER: NCT01706926; results.

11 Clinical Trial Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase IIb Study of Patients With Active Rheumatoid Arthritis. 2017

Kremer, Joel M / Genovese, Mark C / Keystone, Edward / Taylor, Peter C / Zuckerman, Steven H / Ruotolo, Giacomo / Schlichting, Douglas E / Crotzer, Victoria L / Nantz, Eric / Beattie, Scott D / Macias, William L. ·Albany Medical College, Albany, New York. · Stanford University Medical Center, Palo Alto, California. · University of Toronto, Toronto, Ontario, Canada. · University of Oxford, Oxford, UK. · Eli Lilly and Company, Indianapolis, Indiana. ·Arthritis Rheumatol · Pubmed #28029752.

ABSTRACT: OBJECTIVE: To assess the effects of baricitinib on lipid profiles in patients with moderate-to-severe rheumatoid arthritis. METHODS: Treatment with once-daily doses of baricitinib (1, 2, 4, or 8 mg) or placebo was studied in 301 randomized patients. Changes in lipid profile and lipoprotein particle size and particle number were assessed at weeks 12 and 24, and associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4 and 12 in the placebo group and the 4-mg and 8-mg baricitinib groups. RESULTS: Treatment with baricitinib resulted in dose-dependent increases in serum lipid levels from baseline to week 12 (low-density lipoprotein [LDL] cholesterol increases of 3.4 mg/dl and 11.8 mg/dl in the 1 mg and 8 mg treatment groups, respectively; high-density lipoprotein [HDL] cholesterol increases of 3.3 mg/dl and 8.1 mg/dl, respectively; triglycerides increases of 6.4 mg/dl and 15.4 mg/dl, respectively). Group-wise mean increases in LDL cholesterol were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A-I, apolipoprotein B, and apolipoprotein CIII were observed with 4-mg doses of baricitinib (9.5%, 6.8%, and 23.0%, respectively) and with 8-mg doses (12.2%, 7.1%, and 19.7%, respectively), with no increase in LDL-associated apolipoprotein CIII (-4.5% with 4-mg baricitinib; -9.0% with 8-mg baricitinib). Baricitinib reduced HDL-associated serum amyloid A when administered at 4 mg (-36.0%) and 8 mg (-32.0%); a significant reduction in lipoprotein (a) was observed only with 8-mg doses (-16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship. CONCLUSION: Baricitinib-associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes.

12 Clinical Trial Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). 2017

Kavanaugh, A / Kremer, J / Ponce, L / Cseuz, R / Reshetko, O V / Stanislavchuk, M / Greenwald, M / Van der Aa, A / Vanhoutte, F / Tasset, C / Harrison, P. ·University of California San Diego, San Diego, California, USA. · Center for Rheumatology, Albany Medical College, Albany, New York, USA. · Consulta Privada Dra. Lucia Ponce, Temuco, Chile. · Revita Reumatologiai Rendelo, Budapest, Hungary. · Regional Clinical Hospital, Saratov, Russia. · Vinnitsa Regional Clinical Hospital, Pirogov, Ukraine. · Desert Medical Advances, Palm Desert, California, USA. · Galapagos NV, Mechelen, Belgium. ·Ann Rheum Dis · Pubmed #27993828.

ABSTRACT: OBJECTIVES: To evaluate the efficacy and safety of different doses of filgotinib, an oral Janus kinase 1 inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) and previous inadequate response to methotrexate (MTX). METHODS: In this 24-week phase IIb study, patients with moderately to severely active RA were randomised (1:1:1:1) to receive 50, 100 or 200 mg filgotinib once daily, or placebo, after a ≥4-week washout from MTX. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR)20 response at week 12. RESULTS: Overall, 283 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib at any dose achieved ACR20 responses versus placebo (≥65% vs 29%, p<0.001). For other key end points at week 12 (ACR50, ACR70, ACR-N, Disease Activity Score based on 28 joints and C reactive protein, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index) significant differences from baseline in favour of filgotinib 100 and 200 mg versus placebo were seen; responses were maintained or improved through week 24. Rapid onset of action was observed for most efficacy end points. Dose-dependent increases in haemoglobin were observed. The percentage of patients with treatment-emergent adverse events (TEAE) was similar in the placebo and filgotinib groups (∼40%). Eight patients on filgotinib and one on placebo had a serious TEAE, and four patients, all of whom received filgotinib, experienced a serious infection. No tuberculosis or opportunistic infections were reported. CONCLUSIONS: Over 24 weeks, filgotinib as monotherapy was efficacious in treating the signs and symptoms of active RA, with a rapid onset of action. Filgotinib was generally well tolerated. TRIAL REGISTRATION NUMBER: NCT01894516.

13 Clinical Trial Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON). 2017

Smolen, Josef S / Kremer, Joel M / Gaich, Carol L / DeLozier, Amy M / Schlichting, Douglas E / Xie, Li / Stoykov, Ivaylo / Rooney, Terence / Bird, Paul / Sánchez Bursón, Juan Miguel / Genovese, Mark C / Combe, Bernard. ·Medical University of Vienna and Hietzing Hospital, Vienna, Austria. · Albany Medical College, Albany, New York, USA. · Eli Lilly and Company, Indianapolis, Indiana, USA. · University of New South Wales, Sydney, New South Wales, Australia. · Divisions of Rheumatology, Ophthalmology and Immunology, Valme University Hospital, Sevilla, Spain. · Stanford University Medical Center, Palo Alto, California, USA. · Lapeyronie Hospital, Montpellier University, Montpellier, France. ·Ann Rheum Dis · Pubmed #27799159.

ABSTRACT: OBJECTIVES: To assess baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis, who had insufficient response or intolerance to ≥1 tumour necrosis factor inhibitors (TNFis) or other biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: In this double-blind phase III study, patients were randomised to once-daily placebo or baricitinib 2 or 4 mg for 24 weeks. PROs included the Short Form-36, EuroQol 5-D, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, duration of morning joint stiffness (MJS) and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis. Treatment comparisons were performed with logistic regression for categorical measures or analysis of covariance for continuous variables. RESULTS: 527 patients were randomised (placebo, 176; baricitinib 2 mg, 174; baricitinib 4 mg, 177). Both baricitinib-treated groups showed statistically significant improvements versus placebo in most PROs. Improvements were generally more rapid and of greater magnitude for patients receiving baricitinib 4 mg than 2 mg and were maintained to week 24. At week 24, more baricitinib-treated patients versus placebo-treated patients reported normal physical functioning (HAQ-DI <0.5; p≤0.001), reductions in fatigue (FACIT-F ≥3.56; p≤0.05), improvements in PtGA (p≤0.001) and pain (p≤0.001) and reductions in duration of MJS (p<0.01). CONCLUSIONS: Baricitinib improved most PROs through 24 weeks compared with placebo in this study of treatment-refractory patients with previously inadequate responses to bDMARDs, including at least one TNFi. PRO results aligned with clinical efficacy data for baricitinib. TRIAL REGISTRATION NUMBER: NCT01721044; Results.

14 Clinical Trial Tofacitinib in Combination With Conventional Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis: Patient-Reported Outcomes From a Phase III Randomized Controlled Trial. 2017

Strand, Vibeke / Kremer, Joel M / Gruben, David / Krishnaswami, Sriram / Zwillich, Samuel H / Wallenstein, Gene V. ·Stanford University School of Medicine, Palo Alto, California. · Albany Medical College, Albany, New York. · Pfizer Inc, Groton, Connecticut. ·Arthritis Care Res (Hoboken) · Pubmed #27565000.

ABSTRACT: OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared patient-reported outcomes (PROs) in patients with RA treated with tofacitinib or placebo in combination with conventional disease-modifying antirheumatic drugs (DMARDs). METHODS: In a 12-month, phase III randomized controlled trial (ORAL Sync), patients (n = 795) with active RA and previous inadequate response to therapy with ≥1 conventional or biologic DMARD were randomized 4:4:1:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, placebo advanced to 5 mg BID, or placebo to 10 mg BID, in combination with stable background DMARD therapy. PROs included patient global assessment of arthritis (PtGA), patient assessment of arthritis pain (Pain), physical function (Health Assessment Questionnaire disability index [HAQ DI]), health-related quality of life (Short Form 36 health survey [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), and sleep (Medical Outcomes Study Sleep [MOS Sleep]). RESULTS: At month 3, statistically significant improvements from baseline versus placebo were reported in PtGA, Pain, HAQ DI, all 8 SF-36 domains, FACIT-F, and MOS Sleep with tofacitinib 10 mg BID, and in PtGA, Pain, HAQ DI, 7 SF-36 domains, FACIT-F, and MOS Sleep with tofacitinib 5 mg BID. Improvements were sustained to month 12. Significantly more tofacitinib-treated patients reported improvements of greater than or equal to the minimum clinically important differences at month 3 versus placebo in all PROs, except the SF-36 role-emotional domain (significant for tofacitinib 10 mg BID). CONCLUSION: Patients with active RA treated with tofacitinib combined with background conventional DMARD therapy reported sustained, significant, and clinically meaningful improvements in PROs versus placebo.

15 Clinical Trial A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy. 2016

Kremer, Joel M / Emery, Paul / Camp, Heidi S / Friedman, Alan / Wang, Li / Othman, Ahmed A / Khan, Nasser / Pangan, Aileen L / Jungerwirth, Steven / Keystone, Edward C. ·Albany Medical College, Albany, New York. · University of Leeds and Leeds Teaching Hospitals NHS Trust, Leeds, UK. · AbbVie, North Chicago, Illinois. · Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. ·Arthritis Rheumatol · Pubmed #27389975.

ABSTRACT: OBJECTIVE: To compare the efficacy and safety of ABT-494, a novel selective JAK-1 inhibitor, with placebo in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti-tumor necrosis factor (anti-TNF) agent. METHODS: In this 12-week, double-blind, placebo-controlled, dose-ranging study, 276 RA patients receiving a stable dose of methotrexate (MTX) who had previously received treatment with at least 1 anti-TNF agent were randomized equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily or matching placebo twice daily. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12. RESULTS: At week 12, significantly more patients receiving ABT-494 (53-71%) than those receiving placebo (34%) achieved an ACR20 response (by nonresponder imputation analysis) (P < 0.05), with a dose-response relationship among all ABT-494 doses (P < 0.001). ACR50 and ACR70 response rates were significantly higher in those receiving ABT-494 (36-42% and 22-26%, respectively) than in those receiving placebo (16% and 4%, respectively). Changes from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) were significantly greater for all doses of ABT-494 than for placebo (P ≤ 0.01). Onset of action of ABT-494 was rapid, with significant differences from placebo at week 2 both in ACR20 response rate (for 12 and 18 mg) and in change in the DAS28-CRP (P < 0.001 for 6-18 mg). The most frequent adverse events (AEs) were headache, nausea, upper respiratory tract infection, and urinary tract infection. Infection rates were higher at higher doses of ABT-494, but no infections were serious. No deaths were reported among those receiving ABT-494. CONCLUSION: In patients with an inadequate response or intolerance to anti-TNF agents, ABT-494 added to MTX showed rapid, dose-dependent improvements in RA signs and symptoms, with safety and tolerability similar to those of other drugs of this class. No new AEs were identified.

16 Clinical Trial Baricitinib in Patients with Refractory Rheumatoid Arthritis. 2016

Genovese, Mark C / Kremer, Joel / Zamani, Omid / Ludivico, Charles / Krogulec, Marek / Xie, Li / Beattie, Scott D / Koch, Alisa E / Cardillo, Tracy E / Rooney, Terence P / Macias, William L / de Bono, Stephanie / Schlichting, Douglas E / Smolen, Josef S. ·From the Stanford University Medical Center, Palo Alto, CA (M.C.G.) · Albany Medical College, Albany, NY ( J.K.) · Rheumazentrum Favoriten (O.Z.) and the Medical University of Vienna ( J.S.S.) - both in Vienna · East Penn Rheumatology, Bethlehem, PA (C.L.) · Rheumatology Clinic, MAK-MED, Nadarzyn, Poland (M.K.) · and Eli Lilly, Indianapolis (L.X., S.D.B., A.E.K., T.E.C., T.P.R., W.L.M., S.B., D.E.S.). ·N Engl J Med · Pubmed #27028914.

ABSTRACT: BACKGROUND: In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose. RESULTS: Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels. CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044.).

17 Clinical Trial Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDs. 2015

Strand, Vibeke / Kremer, Joel / Wallenstein, Gene / Kanik, Keith S / Connell, Carol / Gruben, David / Zwillich, Samuel H / Fleischmann, Roy. ·Biopharmaceutical Consultant, Portola Valley, CA, USA. vstrand@aol.com. · Stanford University, Palo Alto, CA, USA. vstrand@aol.com. · Center for Rheumatology, Albany Medical College, Albany, NY, USA. jkremer@joint-docs.com. · Pfizer Inc, 445 Eastern Point Road, MS 8260-2515, Groton, CT, 06340, USA. Gene.wallenstein@pfizer.com. · Pfizer Inc, 445 Eastern Point Road, MS 8260-2515, Groton, CT, 06340, USA. keith.s.kanik@pfizer.com. · Pfizer Inc, 445 Eastern Point Road, MS 8260-2515, Groton, CT, 06340, USA. carol.a.connell@pfizer.com. · Pfizer Inc, 445 Eastern Point Road, MS 8260-2515, Groton, CT, 06340, USA. david.gruben@pfizer.com. · Pfizer Inc, 445 Eastern Point Road, MS 8260-2515, Groton, CT, 06340, USA. samuel.h.zwillich@pfizer.com. · Metroplex Clinical Research Center, Dallas, TX, USA. rfleischmann@arthdocs.com. ·Arthritis Res Ther · Pubmed #26530039.

ABSTRACT: INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. METHOD: In this 6-month, phase 3, randomized, placebo-controlled trial, 611 patients with inadequate response to disease-modifying anti-rheumatic drugs (DMARD-IR) were randomized 4:4:1:1 to receive: tofacitinib 5 mg BID or tofacitinib 10 mg BID for the duration of the study, or placebo for 3 months followed by tofacitinib 5 mg BID or tofacitinib 10 mg BID. Patient-reported outcomes (PROs) included: Patient Global Assessment of Disease Activity (PtGA); Patient Assessment of Pain (Pain); Health Assessment Questionnaire-Disability Index (HAQ-DI); Medical Outcomes Survey (MOS) Short Form-36 (SF-36); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); and MOS Sleep Scale. Time-to-event data (PtGA and Pain) were collected using an interactive voice response system daily diary (baseline through day 14). RESULTS: At month 3, tofacitinib 5 and 10 mg BID demonstrated statistically significant improvements versus placebo in PtGA (both p < 0.0001), Pain (both p < 0.0001), HAQ-DI (both p < 0.0001), SF-36 Physical (p < 0.0001) and Mental (p < 0.05 [5 mg BID] and p < 0.0001 [10 mg BID]), Component Summary scores and all domain scores (p < 0.05-p < 0.0001) and FACIT-F (both p < 0.0001). Statistically significant changes from baseline in MOS Sleep Scale were reported for 10 mg BID (p < 0.05). Benefits of tofacitinib treatment were rapid in onset and significant improvements were reported at week 2 for PtGA, Pain and HAQ-DI, and differentiation from baseline was seen as early as 3 days after treatment initiation for interactive voice response system (IVRS) PtGA and IVRS Pain. The numbers needed to treat for patients to report changes greater than or equal to the minimum clinically important difference in PtGA, Pain, HAQ-DI, SF-36 Physical Component Summary score and FACIT-F ranged between 4.0-6.1 (5 mg BID) and 3.2-5.0 (10 mg BID). CONCLUSION: Tofacitinib monotherapy in DMARD-IR patients resulted in statistically significant and clinically meaningful improvements in multiple PROs versus placebo at month 3, with sustained improvements over 6 months. TRIAL REGISTRATION: Clinicaltrials.gov registration NCT00814307 , registered 22 December 2008.

18 Clinical Trial Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial. 2015

Kremer, Joel M / Kivitz, Alan J / Simon-Campos, Jesus A / Nasonov, Evgeny L / Tony, Hans-Peter / Lee, Soo-Kon / Vlahos, Bonnie / Hammond, Constance / Bukowski, Jack / Li, Huihua / Schulman, Seth L / Raber, Susan / Zuckerman, Andrea / Isaacs, John D. ·Albany Medical College and The Center for Rheumatology, Albany, NY, USA. jkremer@joint-docs.com. · Altoona Center for Clinical Research, Duncansville, PA, USA. ajkivitz@yahoo.com. · Hospital CEM/BIOCEM, Merida, Mexico. jabrahamsimon@yahoo.com.mx. · Nasonova State Institute of Rheumatology, Moscow, Russia. nasonov@irramn.ru. · University Hospital Würzburg, Würzburg, Germany. Tony_H@ukw.de. · Yonsei University College of Medicine, Seoul, South Korea. SOOKONLEE@yuhs.ac. · Pfizer Inc, Collegeville, PA, USA. bonnie.vlahos@pfizer.com. · Pfizer Inc, Collegeville, PA, USA. connie.hammond@pfizer.com. · Pfizer Inc, Collegeville, PA, USA. JACK.BUKOWSKI@PFIZER.COM. · Pfizer Inc, Collegeville, PA, USA. Huihua.Li@pfizer.com. · Pfizer Inc, Collegeville, PA, USA. seth.schulman@pfizer.com. · Pfizer Inc, San Diego, CA, USA. susan.raber@pfizer.com. · Pfizer Inc, Groton, CT, USA. andrea.zuckerman@pfizer.com. · National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle-upon-Tyne, UK. John.Isaacs@newcastle.ac.uk. ·Arthritis Res Ther · Pubmed #25889308.

ABSTRACT: INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). During the clinical development programme, increases in mean serum creatinine (SCr) of approximately 0.07 mg/dL and 0.08 mg/dL were observed which plateaued early. This study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to placebo in patients with active RA. METHODS: This was a randomised, placebo-controlled, Phase 1 study (NCT01484561). Patients were aged ≥18 years with active RA. Patients were randomised 2:1 to oral tofacitinib 10 mg twice daily (BID) in Period 1 then placebo BID in Period 2 (tofacitinib → placebo); or oral placebo BID in both Periods (placebo → placebo). Change in mGFR was evaluated by iohexol serum clearance at four time points (run-in, pre-dose in Period 1, Period 1 end, and Period 2 end). The primary endpoint was the change in mGFR from baseline to Period 1 end. Secondary endpoints included: change in mGFR at other time points; change in estimated GFR (eGFR; Cockcroft-Gault equation) and SCr; efficacy; and safety. RESULTS: 148 patients were randomised to tofacitinib → placebo (N = 97) or placebo → placebo (N = 51). Baseline characteristics were similar between groups. A reduction of 8% (90% confidence interval [CI]: 2%, 14%) from baseline in adjusted geometric mean mGFR was observed during tofacitinib treatment in Period 1 vs placebo. During Period 2, mean mGFR returned towards baseline during placebo treatment, and there was no difference between the two treatment groups at the end of the study--ratio (tofacitinib → placebo/placebo → placebo) of adjusted geometric mean fold change of mGFR was 1.04 (90% CI: 0.97, 1.11). Post-hoc analyses, focussed on mGFR variability in placebo → placebo patients, were consistent with this conclusion. At study end, similar results were observed for eGFR and SCr. Clinical efficacy and safety were consistent with prior studies. CONCLUSION: Increases in mean SCr and decreases in eGFR in tofacitinib-treated patients with RA may occur in parallel with decreases in mean mGFR; mGFR returned towards baseline after tofacitinib discontinuation, with no significant difference vs placebo, even after post-hoc analyses. Safety monitoring will continue in ongoing and future clinical studies and routine pharmacovigilance. TRIAL REGISTRATION: Clinicaltrials.gov NCT01484561. Registered 30 November 2011.

19 Clinical Trial A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. 2012

Kremer, Joel M / Cohen, Stanley / Wilkinson, Bethanie E / Connell, Carol A / French, Jonathan L / Gomez-Reino, Juan / Gruben, David / Kanik, Keith S / Krishnaswami, Sriram / Pascual-Ramos, Virginia / Wallenstein, Gene / Zwillich, Samuel H. ·Albany Medical College, Albany, New York 12206, USA. jkremer@joint-docs.com ·Arthritis Rheum · Pubmed #22006202.

ABSTRACT: OBJECTIVE: To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy. METHODS: In this 24-week, double-blind, phase IIb study, patients with active RA (n = 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS: At week 12, ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P ≤ 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. The most common treatment-emergent adverse events occurring in >10% of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed. CONCLUSION: In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.

20 Clinical Trial Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. 2011

Kremer, Joel M / Blanco, Ricardo / Brzosko, Marek / Burgos-Vargas, Ruben / Halland, Anne-Marie / Vernon, Emma / Ambs, Petra / Fleischmann, Roy. ·Albany Medical College and Center for Rheumatology, Albany, New York 12206, USA. jkremer@joint-docs.com ·Arthritis Rheum · Pubmed #21360490.

ABSTRACT: OBJECTIVE: To assess the efficacy and safety of tocilizumab plus methotrexate (MTX) versus MTX alone in preventing structural joint damage and improving physical function and disease activity in patients with moderate-to-severe rheumatoid arthritis and inadequate responses to MTX. METHODS: A total of 1,196 patients were enrolled in a 2-year, randomized, double-blind, placebo-controlled trial. Patients received tocilizumab (8 mg/kg or 4 mg/kg) or placebo every 4 weeks plus MTX. Rescue treatment was available from week 16. Results from year 1 are presented. RESULTS: Mean change in the total Genant-modified Sharp score was 0.29 and 0.34 with tocilizumab 8 mg/kg plus MTX and 4 mg/kg plus MTX, respectively, versus 1.13 with placebo plus MTX (P < 0.0001 for both comparisons). Analysis of variance of the area under the curve for change from baseline in the disability index of the Health Assessment Questionnaire showed greater decreases with tocilizumab 8 mg/kg and 4 mg/kg (-144.1 and -128.4 units, respectively) than with placebo (-58.1 units; P < 0.0001 for both comparisons). Proportions of patients with American College of Rheumatology 20%, 50%, and 70% improvement and with Disease Activity Score in 28 joints remission were higher in those receiving 8 mg/kg tocilizumab than in those receiving placebo (P < 0.0001 for all comparisons). The safety profile of tocilizumab was consistent with the profiles in previous studies. Infections were the most common adverse and serious adverse events. CONCLUSION: The findings of this study show that tocilizumab plus MTX results in greater inhibition of joint damage and improvement in physical function than does MTX alone. Tocilizumab has a well-characterized safety profile.

21 Clinical Trial Golimumab, a new human anti-tumor necrosis factor alpha antibody, administered intravenously in patients with active rheumatoid arthritis: Forty-eight-week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study. 2010

Kremer, Joel / Ritchlin, Christopher / Mendelsohn, Alan / Baker, Daniel / Kim, Lilianne / Xu, Zhenhua / Han, John / Taylor, Peter. ·Albany Medical College and The Center for Rheumatology, Albany, New York 12206, USA. jkremer@joint-docs.com ·Arthritis Rheum · Pubmed #20131276.

ABSTRACT: OBJECTIVE: To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis (RA). METHODS: Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate (MTX) at a dosage of 15-25 mg/week for > or = 4 weeks were randomized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg, with or without MTX, every 12 weeks through week 48. Patients with <20% improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment (week 16) or could have their dose regimen adjusted (week 24). The primary end point was the proportion of patients achieving a 50% response according to the American College of Rheumatology improvement criteria (ACR50) at week 14. RESULTS: The primary study end point was not met (at week 14, an ACR50 response was observed in 21% of the patients treated with golimumab plus MTX compared with 13% of the patients treated with placebo plus MTX [P = 0.051]). By week 24, significantly more patients treated with golimumab plus MTX had achieved an ACR50 response. Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 (16% versus 13%) or week 24 (10% versus 9%). At week 48, the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX (70% and 48%, respectively). Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab. The most commonly reported adverse events through week 48 were infections (48% of patients treated with golimumab with or without MTX and 41% of patients receiving placebo plus MTX). CONCLUSION: The primary end point was not met. However, intravenously administered golimumab plus MTX appears to have benefit in the longer-term reduction of RA signs/symptoms in MTX-resistant patients, with no unexpected safety concerns.

22 Article Real-World Comparative Effectiveness of Tofacitinib and Tumor Necrosis Factor Inhibitors as Monotherapy and Combination Therapy for Treatment of Rheumatoid Arthritis. 2019

Reed, George W / Gerber, Robert A / Shan, Ying / Takiya, Liza / Dandreo, Kimberly J / Gruben, David / Kremer, Joel / Wallenstein, Gene. ·Corrona Research Foundation, Albany, NY, USA. greed@corrona.org. · University of Massachusetts Medical School, Worcester, MA, USA. greed@corrona.org. · Pfizer Inc, Groton, CT, USA. · Corrona, LLC, Waltham, MA, USA. · Pfizer Inc, Collegeville, PA, USA. · Albany Medical College, Albany, NY, USA. ·Rheumatol Ther · Pubmed #31707603.

ABSTRACT: INTRODUCTION: No published studies exist comparing the effectiveness of tofacitinib with other advanced therapies for the treatment of rheumatoid arthritis (RA) in real-world clinical practice. Here, we report differences in effectiveness of tofacitinib compared with standard of care, tumor necrosis factor inhibitors (TNFi), with or without concomitant methotrexate (MTX), using US Corrona registry data. METHODS: This observational cohort study included RA patients receiving tofacitinib (from 6 November 2012; N = 558) or TNFi (from 1 November 2001; N = 8014) with or without MTX until 31 July 2016. Efficacy outcomes at 6 months included modified American College of Rheumatology 20% responses, Clinical Disease Activity Index (CDAI) and Pain. Outcomes were compared between patients receiving TNFi and tofacitinib with or without MTX and by line of therapy. Outcomes within therapy lines were compared using propensity-score matching; between-group differences were estimated using mixed-effects regression models. RESULTS: Patients receiving tofacitinib had longer RA duration and a greater proportion had previously received biologics than those receiving TNFi; other baseline characteristics were comparable. In patients receiving second- and third-line TNFi therapy, CDAI low disease activity/remission response rates were significantly better with concomitant MTX. Too few patients received tofacitinib as second line for meaningful assessment. No significant differences were observed in outcomes between tofacitinib as monotherapy and tofacitinib with concomitant MTX. CONCLUSIONS: In clinical practice, TNFi efficacy is improved with concomitant MTX in the second and third line. In the third/fourth line, patients are likely to achieve similar efficacy with tofacitinib monotherapy, or TNFi or tofacitinib in combination with MTX. FUNDING: Pfizer Inc.

23 Article Molecular profiling of rheumatoid arthritis patients reveals an association between innate and adaptive cell populations and response to anti-tumor necrosis factor. 2019

Farutin, Victor / Prod'homme, Thomas / McConnell, Kevin / Washburn, Nathaniel / Halvey, Patrick / Etzel, Carol J / Guess, Jamey / Duffner, Jay / Getchell, Kristen / Meccariello, Robin / Gutierrez, Bryan / Honan, Christopher / Zhao, Ganlin / Cilfone, Nicholas A / Gunay, Nur Sibel / Hillson, Jan L / DeLuca, David S / Saunders, Katherine C / Pappas, Dimitrios A / Greenberg, Jeffrey D / Kremer, Joel M / Manning, Anthony M / Ling, Leona E / Capila, Ishan. ·Momenta Pharmaceuticals Inc., 301 Binney Street, Cambridge, MA, 02142, USA. · Corrona LLC, Waltham, MA, USA. · DeLuca Data Science, Wietze, Germany. · Department of Medicine, Division of Rheumatology, Columbia University School of Medicine, New York, NY, USA. · New York University School of Medicine, New York, NY, USA. · Albany Medical College, Albany, NY, USA. · Momenta Pharmaceuticals Inc., 301 Binney Street, Cambridge, MA, 02142, USA. lling@momentapharma.com. · Momenta Pharmaceuticals Inc., 301 Binney Street, Cambridge, MA, 02142, USA. icapila@gmail.com. ·Arthritis Res Ther · Pubmed #31647025.

ABSTRACT: BACKGROUND: The goal of this study is to use comprehensive molecular profiling to characterize clinical response to anti-TNF therapy in a real-world setting and identify reproducible markers differentiating good responders and non-responders in rheumatoid arthritis (RA). METHODS: Whole-blood mRNA, plasma proteins, and glycopeptides were measured in two cohorts of biologic-naïve RA patients (n = 40 and n = 36) from the Corrona CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) registry at baseline and after 3 months of anti-TNF treatment. Response to treatment was categorized by EULAR criteria. A cell type-specific data analysis was conducted to evaluate the involvement of the most common immune cell sub-populations. Findings concordant between the two cohorts were further assessed for reproducibility using selected NCBI-GEO datasets and clinical laboratory measurements available in the CERTAIN database. RESULTS: A treatment-related signature suggesting a reduction in neutrophils, independent of the status of response, was indicated by a high level of correlation (ρ = 0.62; p < 0.01) between the two cohorts. A baseline, response signature of increased innate cell types in responders compared to increased adaptive cell types in non-responders was identified in both cohorts. This result was further assessed by applying the cell type-specific analysis to five other publicly available RA datasets. Evaluation of the neutrophil-to-lymphocyte ratio at baseline in the remaining patients (n = 1962) from the CERTAIN database confirmed the observation (odds ratio of good/moderate response = 1.20 [95% CI = 1.03-1.41, p = 0.02]). CONCLUSION: Differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.

24 Article Assessing disease severity in bio-naïve patients with RA on treatment with csDMARDs: insights from the Corrona Registry. 2019

Harrold, Leslie R / Patel, Pankaj A / Griffith, Jenny / Litman, Heather J / Feng, Hua / Schlacher, Casey A / Kremer, Joel M. ·University of Massachusetts Medical School, Worcester, MA, USA. LHarrold@corrona.org. · Corrona, LLC, 1440 Main Street, Suite 310, Waltham, MA, 02451, USA. LHarrold@corrona.org. · AbbVie, Mettawa, IL, USA. · Corrona, LLC, 1440 Main Street, Suite 310, Waltham, MA, 02451, USA. · Albany Medical College and the Center for Rheumatology, Albany, NY, USA. ·Clin Rheumatol · Pubmed #31637609.

ABSTRACT: INTRODUCTION: This study aimed to characterize disease burden among patients with rheumatoid arthritis (RA) with moderate-to-high disease activity who had received conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) monotherapy for ≥ 6 months but had not advanced to a biologic therapy. METHODS: Patients enrolled in the US Corrona RA Registry between June 1, 2014, and January 30, 2018, with 6 months of continuous csDMARD monotherapy, with moderate-to-high disease activity, who remained biologic naive, and who had ≥ 1 follow-up visit were identified. Disease activity was assessed among patients with a 6-month follow-up visit (± 3 months). Descriptive statistics were used to compare demographics and disease characteristics between patients with or without treatment advancement. RESULTS: The study included 409 patients with a disease activity assessment at 6 months (mean (SD) age 65.9 (12.6) years; mean duration of csDMARD therapy 407 (221) days). Of those patients, more than half (54%, n = 219) remained in moderate-to-high disease activity. Patients remaining in moderate-to-high vs. remission-to-low disease activity had higher baseline swollen (6.1) and tender joint counts (6.8). Over the 6-month period, treatment advancement occurred in 29% of patients. Those who advanced treatment (n = 118) vs. did not advance treatment (n = 291) were younger, had a shorter duration of RA, had higher disease activity, and reported higher levels of pain and fatigue. CONCLUSIONS: The substantial number of patients with persistent moderate-to-high disease on csDMARDs over a 6-month period and who did not advance treatment indicates that there is considerable need for a treat-to-target approach to care for patients with RA. Key Points •For patients with RA and an inadequate response to treatment with initial csDMARD monotherapy, guidelines recommend treatment advancement; however, this may not be occurring in real-world clinical settings. •In the current study, a substantial proportion of patients (54%) on csDMARDs had persistent moderate-to-severe disease activity at the 6-month (± 3 months) follow-up visit; however, only 29% of patients had their medication treatment advanced, indicating that there is considerable need for a treat-to-target approach to care for patients with RA. •Patients with younger age, shorter RA duration, and higher disease activity were more likely to have their medication treatment advanced, which suggests that potentially more aggressive treatment of disease activity is needed across the whole RA population.

25 Article Association among anti-citrullinated protein antibody status, erosive disease and healthcare resource utilization in patients with rheumatoid arthritis. 2019

Harrold, Leslie R / Shan, Ying / Connolly, Sean E / Alemao, Evo / Rebello, Sabrina / Guo, Lin / Kremer, Joel M. ·Corrona, LLC , Waltham , MA , USA. · Bristol-Myers Squibb , Princeton , NJ , USA. · Albany Medical College and The Center for Rheumatology , Albany , NY , USA. ·Curr Med Res Opin · Pubmed #31612736.

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