Luminita Pricop

Cornell University, Итак, New York, United States

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Publications (35)272.17 Total impact

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    ABSTRACT: Background In a phase 2 study, the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis. We sought to evaluate the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in such patients. Methods In this double-blind, phase 3 study, 606 patients with psoriatic arthritis were randomly assigned in a 1:1:1 ratio to receive intravenous secukinumab (at a dose of 10 mg per kilogram) at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo. Patients in the placebo group were switched to subcutaneous secukinumab at a dose of 150 mg or 75 mg at week 16 or 24, depending on clinical response. The primary end point was the proportion of patients with an American College of Rheumatology 20 (ACR20) response at week 24, defined as a 20% improvement from baseline in the number of tender and swollen joints and at least three other important domains. Results ACR20 response rates at week 24 were significantly higher in the group receiving secukinumab at doses of 150 mg (50.0%) and 75 mg (50.5%) than in those receiving placebo (17.3%) (P<0.001 for both comparisons with placebo). Secondary end points, including the ACR50 response and joint structural damage, were significantly better in the secukinumab groups than in the placebo group. Improvements were sustained through 52 weeks. Infections, including candida, were more common in the secukinumab groups. Throughout the study (mean secukinumab exposure, 438.5 days; mean placebo exposure, 128.5 days), four patients in the secukinumab groups had a stroke (0.6 per 100 patient-years; 95% confidence interval [CI], 0.2 to 1.5), and two had a myocardial infarction (0.3 per 100 patient-years; 95% CI, 0.0 to 1.0), as compared with no patients in the placebo group. Conclusions Secukinumab was more effective than placebo in patients with psoriatic arthritis, which validates interleukin-17A as a therapeutic target. Infections were more common in the secukinumab groups than in the placebo group. The study was neither large enough nor long enough to evaluate uncommon serious adverse events or the risks associated with long-term use. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT01392326 .).
    No preview · Article · Sep 2015 · New England Journal of Medicine
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    ABSTRACT: Interleukin 17A is a proinflammatory cytokine that is implicated in the pathogenesis of psoriatic arthritis. We assessed the efficacy and safety of subcutaneous secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis. In this phase 3, double-blind, placebo-controlled study undertaken at 76 centres in Asia, Australia, Canada, Europe, and the USA, adults (aged ≥18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. Patients and investigators were masked to treatment assignment. The primary endpoint was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01752634. Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98). A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 [54%] patients; odds ratio versus placebo 6·81, 95% CI 3·42-13·56; p<0·0001), 150 mg (51 [51%] patients; 6·52, 3·25-13·08; p<0·0001), and 75 mg (29 [29%] patients; 2·32, 1·14-4·73; p=0·0399) versus placebo (15 [15%] patients). Up to week 16, the most common adverse events were upper respiratory tract infections (four [4%], eight [8%], ten [10%], and seven [7%] with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six [6%], four [4%], six [6%], and eight [8%], respectively). Serious adverse events were reported by five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) in the placebo group. No deaths were reported. Subcutaneous secukinumab 300 mg and 150 mg improved the signs and symptoms of psoriatic arthritis, suggesting that secukinumab is a potential future treatment option for patients with this disorder. Novartis. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Jun 2015 · The Lancet
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    ABSTRACT: Background Secukinumab, a human anti–IL-17A monoclonal antibody, has demonstrated efficacy with an intravenous loading and subcutaneous (s.c.) maintenance regimen in psoriatic arthritis (PsA) (FUTURE 1; NCT01392326). Objectives To evaluate the efficacy and safety of s.c. loading and maintenance dosing with secukinumab in FUTURE 2 (NCT01752634), a randomized, double-blind, placebo (PBO)-controlled phase 3 study in patients (pts) with active PsA. Methods 397 adults with active PsA were randomized to s.c. secukinumab (300, 150 or 75 mg) or PBO at baseline, Week (Wk) 1, 2, 3, 4 and then every 4 wks thereafter. Randomization was stratified by prior exposure to anti-TNF therapy. The primary endpoint was ACR20 response at Wk 24. Secondary endpoints included PASI 75/90, Disease Activity Score 28 using C-reactive protein (DAS28-CRP), Short Form-36 Physical Component Summary (SF-36 PCS), Health Assessment Questionnaire-Disability Index (HAQ-DI), ACR50, dactylitis and enthesitis. Primary and secondary endpoints were included in a hierarchical testing analysis to adjust for multiplicity. Results At Wk 24, ACR20 responses were significantly greater with secukinumab 300, 150 and 75 mg than PBO: 54.0%, 51.0% and 29.3% vs 15.3%, respectively (P<0.0001 for secukinumab 300 and 150 mg; P <0.05 for 75 mg vs PBO). Secukinumab 300 and 150 mg also improved secondary endpoints, including significant improvements in PASI 75/90 scores and DAS-28 CRP vs PBO (Table). Exposure-adjusted rates of treatment-emergent AEs (maximum exposure to secukinumab: 372 days) were 222.2 and 309.3 per 100 pt-years amongst secukinumab (pooled) and PBO-treated subjects, respectively. The respective rates of serious AEs were 7.8 and 8.8. Conclusions Secukinumab 300 and 150 mg s.c. demonstrated clinically significant improvements in the signs and symptoms of PsA. The safety profile of secukinumab was satisfactory, suggesting that the drug is thus far well tolerated. Acknowledgements Medical writing support was provided by Rachel Mason at Seren Communications (Tytherington, UK), and was funded by Novartis. Disclosure of Interest I. McInnes Consultant for: Novartis, Amgen, Janssen, BMS, Pfizer, UCB, Abbvie, Celgene, and Lilly, P. Mease Grant/research support from: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Consultant for: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Covagen, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Speakers bureau: AbbVie, Amgen, Biogen Idec, BMS, Crescendo, Janssen, Lilly, Pfizer, and UCB, B. Kirkham Grant/research support from: AbbVie and UCB, Consultant for: Novartis, AbbVie, BMS, Lilly, and MSD, Speakers bureau: BMS, MSD, and UCB, A. Kavanaugh Consultant for: Novartis, C. Ritchlin Grant/research support from: Amgen and UCB, Consultant for: Novartis, P. Rahman Consultant for: Abbott, AbbVie, Amgen, BMS, Celgene, Janssen, Novartis, Pfizer, and Roche. Consultant to pharmaceutical companies dealing with biologic agents in rheumatology, D. van der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, Augurex, BMS, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, and Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, BMS, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, and Vertex, Paid instructor for: Director of Imaging Rheumatology bv, R. Landewé Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB, and Wyeth, Consultant for: Abbott/AbbVie, Ablynx, Amgen, AstraZeneca, Bristol-Myers Squibb, Centocor, GlaxoSmithKline, Novartis, Merck, Pfizer, Roche, Schering-Plough, UCB, and Wyeth, Paid instructor for: Director of Rheumatology Consultancy BV, which is a registered company under Dutch law, Speakers bureau: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Merck, Pfizer, Roche, Schering-Plough, UCB, and Wyeth, P. Conaghan Consultant for: Abbvie, Merck, Roche, Pfizer, Novartis, and UCB, Speakers bureau: Abbvie, Merck, Roche, Pfizer, Novartis, and UCB, A. Gottlieb Grant/research support from: Centocor (Janssen), Amgen, Abbott (Abbvie), Novartis, Celgene, Pfizer, Lilly, Coronado, Levia, Merck, and Xenoport, Consultant for: Amgen Inc., Astellas, Akros, Centocor (Janssen), Inc. Celgene Corp., Bristol-Myers Squibb Co., Beiersdorf, Inc., Abbott Labs. (Abbvie), DUSA, TEVA, Actelion, UCB, Novo Nordisk, Novartis, Dermipsor Ltd., Incyte, Pfizer, Canfite, Lilly, Coronado, Vertex, Karyopharm, CSL Behring Biotherapies for Life, GlaxoSmithKline, Xenoport, Catabasis, and Sanofi-Aventis, H. Richards Employee of: Novartis, G. Ligozio Shareholder of: Novartis, Employee of: Novartis, L. Pricop Shareholder of: Novartis, Employee of: Novartis, S. Mpofu Shareholder of: Novartis, Employee of: Novartis
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Dactylitis and enthesitis are common disabling manifestations of psoriatic arthritis (PsA) that have been reported according to multiple methods of assessment. Several measures of dactylitis and enthesitis were utilized in the phase 3 FUTURE 2 secukinumab study (NCT01752634)1 and are reported here. Objectives To evaluate the effects of subcutaneous (s.c.) secukinumab on dactylitis and enthesitis through Week (Wk) 24 in FUTURE 2. Methods 397 adults with active PsA were randomized to s.c. secukinumab (300, 150 or 75 mg) or PBO at baseline, Wk 1, 2, 3, 4 and then every 4 wks thereafter. The primary endpoint was ACR20 response at Wk 24. The proportions of pts with resolution of dactylitis and enthesitis at Wk 24 (of those with these conditions at baseline) were secondary endpoints. Additional measures utilized in this study were dactylitis counts, Leeds Dactylitis Index (LDI), and Leeds Enthesitis Index (LEI). Results At baseline, 138 pts (35%) had dactylitis and 253 pts (64%) had enthesitis. At Wk 24, comparing secukinumab 300 mg and 150 mg vs PBO respectively, 56.5% and 50.0% vs 14.8% of pts had complete resolution of dactylitis, and 48.2% and 42.2% vs 21.5% had complete resolution of enthesitis. Corresponding reductions in LDI, LEI and mean dactylitis counts were observed (Table). Conclusions Across multiple methods of assessment, secukinumab 300 and 150 mg s.c. reduced the number of dactylitic digits and enthesitis sites in pts with PsA and was associated with a greater proportion of patients achieving complete resolution of dactylitis/enthesitis compared with PBO. References Acknowledgements Medical writing support was provided by Rachel Mason at Seren Communications (Tytherington, UK), and was funded by Novartis. Disclosure of Interest B. Kirkham Grant/research support from: AbbVie and UCB, Consultant for: Novartis, AbbVie, BMS, Lilly, and MSD, Speakers bureau: BMS, MSD, and UCB, I. McInnes Consultant for: Novartis, Amgen, Janssen, BMS, Pfizer, UCB, Abbvie, Celgene, and Lilly, P. Mease Grant/research support from: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Consultant for: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Covagen, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Speakers bureau: AbbVie, Amgen, Biogen Idec, BMS, Crescendo, Janssen, Lilly, Pfizer, and UCB, J. Kremer Grant/research support from: Novartis, Lilly, BMS, Janssen, Pfizer, and UCB, S. Kandala Employee of: Novartis, L. Pricop Shareholder of: Novartis, Employee of: Novartis, S. Mpofu Shareholder of: Novartis, Employee of: Novartis
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objectives To investigate the effect of secukinumab, a human anti–interleukin-17A monoclonal antibody, on radiographic progression in PsA patients (pts) in the FUTURE 1 study (NCT01392326). Methods 606 adults with active PsA were randomized to secukinumab or placebo (PBO). Pts on secukinumab received 10 mg/kg i.v. loading dose at baseline, Week (Wk) 2 and Wk 4, then either 75 mg s.c. (10 IV→75 SC) or 150 mg s.c. (10 IV→150 SC) every 4 wks from Wk 8. PBO was given on the same schedules. At Wk 16, PBO pts who had ≥20% reduction in both tender and swollen joint count (responders) remained on PBO until Wk 24, and non-responders were re-randomized to secukinumab 75 or 150 mg. The van der Heijde modified Sharp total scores (mTSS), and erosion and joint space narrowing (JSN) scores were determined at baseline, Wks 16/24 (depending on clinical response) and 52. Analysis of effect on radiographic progression at Wk 24 used linear extrapolation for patients with X-ray assessments at Wk 16 and followed a pre-defined hierarchical testing procedure to adjust for multiplicity. Wk 52 analyses used evaluable data. Assessment of no structural progression, defined as a change in mTSS from baseline to Wk 24 of ≤0.5, was included as an exploratory endpoint. Results Secukinumab significantly inhibited radiographic progression at 24 wks; mean changes in mTSS from baseline to Wk 24 were 0.08 (pooled secukinumab doses), 0.13 (10 IV→150 SC) and 0.02 (10 IV→75 SC) vs 0.57 for PBO. Inhibition of joint structural damage was sustained with secukinumab through Wk 52. In x-ray completers, inhibition of radiographic progression was demonstrated in PBO pts who switched to secukinumab; mean change in mTSS from Wk 24 to Wk 52 was –0.03 (Table). The proportion of pts with no disease progression from baseline to Wk 24 was higher for secukinumab groups (10 IV→150 SC and 10 IV→75 SC, respectively) vs PBO; 82.3% and 92.3% vs 75.7%. Through Wk 24 to Wk 52 the proportion of pts with no disease progression was sustained in the secukinumab groups (85.7% and 85.8%), and increased in pts initially randomized to PBO following active treatment (86.8%). Conclusions Sustained inhibition of radiographic disease progression was observed with secukinumab through Wk 52. Switching to secukinumab inhibited radiographic disease progression in pts initially randomized to PBO. Acknowledgements Medical writing support was provided by Rachel Mason at Seren Communications (Tytherington, UK), and was funded by Novartis. Disclosure of Interest D. Van Der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, Augurex, BMS, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, and Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, BMS, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, and Vertex, Paid instructor for: Director of Imaging Rheumatology bv, R. Landewé Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB, and Wyeth, Consultant for: Abbott/AbbVie, Ablynx, Amgen, AstraZeneca, Bristol-Myers Squibb, Centocor, GlaxoSmithKline, Novartis, Merck, Pfizer, Roche, Schering-Plough, UCB, and Wyeth, Paid instructor for: RL is director of Rheumatology Consultancy BV, which is a registered company under Dutch law, Speakers bureau: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Merck, Pfizer, Roche, Schering-Plough, UCB, and Wyeth, P. Mease Grant/research support from: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Consultant for: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Covagen, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Speakers bureau: AbbVie, Amgen, Biogen Idec, BMS, Crescendo, Janssen, Lilly, Pfizer, and UCB, I. McInnes Consultant for: Novartis, Amgen, Janssen, BMS, Pfizer, UCB, Abbvie, Celgene, and Lilly, P. Conaghan Consultant for: Abbvie, Merck, Roche, Pfizer, Novartis, and UCB, Speakers bureau: Abbvie, Merck, Roche, Pfizer, Novartis, and UCB, L. Pricop Shareholder of: Novartis, Employee of: Novartis, G. Ligozio Shareholder of: Novartis, Employee of: Novartis, H. Richards Employee of: Novartis, S. Mpofu Shareholder of: Novartis, Employee of: Novartis
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Psoriatic arthritis (PsA) has a significant negative impact on patients' (pts) health-related quality of life (HRQoL). Secukinumab improved the signs and symptoms of active PsA in the randomized, double-blind, placebo (PBO)-controlled phase 3 FUTURE 2 study (NCT01752634).1 Objectives To investigate the effect of secukinumab through Week (Wk) 24 on patient-reported outcomes (PROs) in the FUTURE 2 study. Methods 397 adults with active PsA were randomized to subcutaneous (s.c.) secukinumab (300, 150 or 75 mg) or placebo (PBO) at baseline, Wks 1, 2, 3 and 4, and every 4 wks thereafter. At Wk 16, PBO non-responders were switched to secukinumab 300 or 150 mg (1:1). From Wk 24, all pts initially randomized to PBO received secukinumab 300 or 150 mg (1:1). PROs were assessed using the following instruments: Short Form-36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS); Health Assessment Questionnaire-Disability Index (HAQ-DI); Psoriatic Arthritis Quality of Life (PsAQoL); Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) and Work Productivity and Activity Impairment Questionnaire (WPAI-GH). SF-36 PCS and HAQ-DI were secondary study endpoints that were included in a hierarchical testing analysis to adjust for multiplicity at Wk 24. The other PROs were exploratory endpoints. Statistical analyses used a mixed-effect model repeated measures method. Results At baseline, dose groups were comparable with respect to demographics and disease activity; subjects had moderate to severe physical impairment and fatigue levels, and impaired HRQoL. At Wk 24, secukinumab 300 and 150 mg improved SF-36 PCS scores vs PBO (P<0.01) and HAQ-DI (P<0.01 for 300 mg) (Table). In exploratory analyses, secukinumab also improved FACIT-F and PsAQoL scores (Table), as well as aspects of work productivity, as assessed by WPAI, vs PBO at Wk 24. Conclusions In pts with active PsA, secukinumab had a positive effect in terms of improving quality of life and reducing fatigue and the impact of disease on work productivity. References Acknowledgements Medical writing support was provided by Jessica Breen and Rachel Mason at Seren Communications (Tytherington, UK), and was funded by Novartis. Disclosure of Interest P. Rahman Consultant for: Abbott, AbbVie, Amgen, BMS, Celgene, Janssen, Novartis, Pfizer, and Roche. Consultant to pharmaceutical companies dealing with biologic agents in rheumatology, V. Strand Consultant for: AbbVie, Afferent, Amgen, Biogen Idec, Bioventus, BMS, Carbylan, Celgene, Celltrion, CORRONA, Crescendo, Genentech/Roche, GSK, Hospira, Iroko, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi, SKK, Takeda, UCB, and Vertex, I. McInnes Consultant for: Novartis, Amgen, Janssen, BMS, Pfizer, UCB, Abbvie, Celgene, and Lilly, H. Marzo-Ortega Consultant for: Abbvie, Celgene, Janssen, MSD, Pfizer, and UCB, E. Dokoupilová: None declared, M. Churchill: None declared, S. Kandala Employee of: Novartis, L. Pricop Shareholder of: Novartis, Employee of: Novartis, S. Mpofu Shareholder of: Novartis, Employee of: Novartis
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objectives To describe the safety profile of secukinumab, an anti–interleukin-17A monoclonal antibody, in patients (pts) with psoriatic arthritis (PsA) treated in phase 3 studies. Methods Safety data from two randomized, double-blind, placebo (PBO)-controlled, phase 3 studies in pts with active PsA, FUTURE 1 (NCT01392326) and FUTURE 2 (NCT01752634), were pooled. In FUTURE 1, 606 pts were randomized to secukinumab or PBO. Pts on secukinumab received 10 mg/kg i.v at baseline, Week (Wk) 2, and 4, followed by 150 or 75 mg s.c. every 4 wks from Wk 8. PBO was given according to the same i.v. and s.c. schedule. In FUTURE 2, 397 pts were randomized to receive s.c. secukinumab (300, 150, or 75 mg) or PBO at baseline, Wk 1, 2, 3, 4, and every 4 wks thereafter. At Wk16, PBO pts with ≤20% reduction in both tender and swollen joint count (nonresponders) were re-randomized to receive secukinumab 150 or 75 mg s.c. in FUTURE 1, and secukinumab 300 or 150 mg s.c. in FUTURE 2; responders were re-randomized at Wk 24. Anti-drug antibodies (ADAs) were assessed using a Meso Scale Discovery bridging assay with a stepwise approach for screening, confirmation and titration. All randomized pts were included in the pooled safety analysis. Results 974 pts received ≥1 dose of secukinumab (955 pt-years of exposure). Baseline demographics, disease/medical history and concomitant medications were similar between the pooled secukinumab and PBO populations. During the 16-wk PBO-controlled period, adverse events (AEs)/serious AEs (SAEs) were reported in 58.9%/3.4% and 58.3%/4.0% of pts in the pooled secukinumab and PBO groups, respectively. Exposure-adjusted AE/SAE incidence rates across the entire safety period (mean/max exposure: 358.1/721 days secukinumab; 128.6/233 days PBO) were 210.3/9.0 and 319.6/13.6 per 100 pt-years with secukinumab and PBO, respectively; 25 (2.6%) pts receiving secukinumab discontinued due to AEs during this period vs. 14 (4.7%) with PBO. Nasopharyngitis and upper respiratory tract infection (URTI) were the most frequent AEs with secukinumab and PBO in both the PBO-controlled period and throughout the entire safety period. There was one death due to intracranial hemorrhage in a pt with a history of CV disease who received secukinumab. The incidence of inflammatory bowel disease (IBD)/Crohn's, Candida infections, neutropenia, MACE and malignancy was low with secukinumab (Table). Injection site reactions with secukinumab were observed in 26 (2.7%) pts vs. 3 (1.0%) with PBO. Treatment-emergent ADAs were detected in 1 (0.1%) pt, with no associated loss of efficacy. Conclusions Secukinumab was well-tolerated in pts with active PsA, with a low incidence of SAEs and discontinuations due to AEs, and a low potential for immunogenicity. Acknowledgements Medical writing support was provided by Chris Strutynskyj-Stannard at Seren Communications (Tytherington, UK), and was funded by Novartis. Disclosure of Interest P. Mease Grant/research support from: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Consultant for: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Covagen, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Speakers bureau: AbbVie, Amgen, Biogen Idec, BMS, Crescendo, Janssen, Lilly, Pfizer, and UCB, I. McInnes Consultant for: Novartis, Amgen, Janssen, BMS, Pfizer, UCB, Abbvie, Celgene, and Lilly, H. Richards Employee of: Novartis, L. Pricop Shareholder of: Novartis, Employee of: Novartis, A. Widmer Employee of: Novartis, S. Mpofu Shareholder of: Novartis, Employee of: Novartis
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases

  • No preview · Article · May 2015 · Internal Medicine Journal

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    Full-text · Dataset · Feb 2013
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    ABSTRACT: Purpose: This study evaluated the potential of functional imaging to monitor disease activity and response to treatment with disease-modifying antirheumatic drugs (DMARD) in DMARD-naive patients with early rheumatoid arthritis (RA). Methods: The study involved 17 patients with active RA in whom combination therapy was initiated with methotrexate, sulfasalazine, hydroxychloroquine, and low-dose oral prednisolone. Clinical disease activity was assessed at screening, at baseline and after 2, 4, 8 and 12 weeks of therapy. (18)F-FDG PET/CT of all joints was performed at baseline and after 2 and 4 weeks of therapy. Results: (18)F-FDG maximum standardized uptake values showed a reduction of 22 ± 13 % in 76 % of patients from baseline to week 2 and a reduction of 29 ± 13 % in 81 % of patients from baseline to week 4. The percentage decrease in (18)F-FDG uptake from baseline to week 2 correlated with clinical outcome, as measured by the disease activity score (DAS-28) at week 12. In addition, changes in C-reactive protein levels and erythrocyte sedimentation rate were positively associated with changes shown by PET. Conclusion: (18)F-FDG PET/CT findings after 2 and 4 weeks of triple combination oral DMARD therapy correlated with treatment efficacy and clinical outcome in patients with early RA. (18)F-FDG PET/CT may help predict the therapeutic response to novel drug treatments.
    Full-text · Article · Nov 2012 · European Journal of Nuclear Medicine
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    ABSTRACT: TNF-alpha has both proinflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in systemic lupus erythematosus (SLE)-prone (New Zealand Black x New Zealand White)F(1) mice has been established, it remains uncertain whether this effect segregates at the individual TNFR. We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNFR1, in TNFR2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4(+) T lymphocytes, especially activated memory (CD44(high)CD62L(low)) CD4(+) T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNFR alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNF-alpha-mediated signaling was highly deleterious to the host in the New Zealand Mixed 2328 SLE model. These observations may have profound ramifications for the use of TNF and TNFR antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.
    Full-text · Article · Mar 2009 · The Journal of Immunology
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    ABSTRACT: In otherwise non-autoimmune-prone C57BL/6 (B6) mice rendered genetically deficient in CD152 (CTLA-4), polyclonal hypergammaglobulinemia with increased levels of systemic lupus erythematosus (SLE)-associated IgG autoantibodies, glomerular IgG and C3 deposition, and interstitial nephritis all developed by 3-5 wk of age. Remarkably, superimposing genetic deficiency of BAFF (B cell-activating factor belonging to the TNF family) onto CD152 deficiency did not substantially attenuate humoral autoimmunity and immunopathology in these mice, despite the resulting marked reduction in B-lineage cells. Although superimposing a BAFF transgene (resulting in constitutive BAFF overexpression) onto CD152-deficient mice did lead to increases in B-lineage cells and serum levels of certain SLE-associated IgG autoantibodies, renal immunopathology remained largely unaffected. Taken together, these results demonstrate that global T cell dysregulation, even in an otherwise non-autoimmune-prone host, can promote systemic humoral autoimmunity and immunopathology in a BAFF-independent manner. Moreover, supraphysiologic expression of BAFF in the setting of ongoing autoimmunity does not necessarily lead to greater immunopathology. These findings may help explain the limited clinical efficacy appreciated to date of BAFF antagonists in human SLE.
    Full-text · Article · Aug 2008 · The Journal of Immunology
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    ABSTRACT: Human neutrophils express both activating and inhibitory Fcgamma receptors (FcgammaR), and their relative expression determines the inflammatory response to immune complexes. Tumor necrosis factor alpha (TNFalpha) up-regulates the expression of stimulatory FcgammaRIIa on neutrophils in vitro, and amplifies immune complex-induced activation of neutrophils in vivo. This study was undertaken to determine whether TNFalpha blockade in patients with rheumatoid arthritis (RA) alters the balance of activating FcgammaR and inhibitory FcgammaR and thereby decreases inflammation. We used fluorescence-activated cell sorting and Western blotting to examine FcgammaR expression on neutrophils in 24 patients with RA, preceding their first infusion of infliximab and immediately prior to >or=3 subsequent infusions. In 13 of 24 patients (54.2%), there was a decrease in the expression of the predominant activating FcgammaR, FcgammaRIIa, after treatment with infliximab, an effect that persisted over >or=3 months of treatment. Although prior to initiation of infliximab therapy the inhibitory FcgammaR, FcgammaRIIb, was undetectable in neutrophils from 23 of 24 patients with RA, FcgammaRIIb protein was detected by Western blotting in 9 patients (37.5%) at the time of the third infliximab infusion. The induction of inhibitory FcgammaRIIb was always associated with decreased levels of FcgammaRIIa, and improvement following infliximab therapy, measured using the Health Assessment Questionnaire, was significantly associated with down-regulation of FcgammaRIIa. Our findings indicate that TNFalpha inhibition may reduce inflammation in patients with RA by restoring the balance of activating and inhibitory FcgammaR and thereby raising the threshold for immune complex-mediated activation of neutrophils.
    Full-text · Article · Feb 2008 · Arthritis & Rheumatology
  • Noam Jacob · Luminita Pricop · Chaim O. Jacob · Michael Koss

    No preview · Article · Dec 2007
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    ABSTRACT: The inhibitory receptor FcγRIIb is a negative regulator of antibody production and inflammatory responses. The -343 G → C polymorphism in the human FCGR2B promoter is associated with systemic lupus erythematosus. The -343 C mutant promoter has decreased transcriptional activity. In the present study, we show that the transcriptional change correlates with quantitative differences in the interaction of the activating protein 1 complex with the mutant FCGR2B promoter. Promoter pulldown and chromatin immunoprecipitation assays demonstrated binding of c-Jun to the FCGR2B promoter. Phosphorylation of c-Jun was accompanied by transactivation of both FCGR2B promoter variants, whereas dephosphorylation of c-Jun by an inhibitor of c-Jun N-terminal kinase, markedly decreased the promoter activities. The -343 G → C substitution enabled the specific interaction of the transcription factor Yin-Yang 1 with the mutant FCGR2B promoter. Yin-Yang 1 competed with activating protein 1 for binding at the -343 site, and contributed to the repression of the mutant FCGR2B promoter activity. This mechanism could be responsible for the decreased expression of FcγRIIb associated with the -343 C/C homozygous FCGR2B genotype in lupus patients. These findings provide a rationale for the transcriptional defect mediated by the -343 C/C FCGR2B promoter polymorphism associated with systemic lupus erythematosus, and add to our understanding of the complex transcriptional regulation of the human FCGR2B promoter.
    Preview · Article · Feb 2007 · Journal of Biological Chemistry
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    ABSTRACT: Receptors for IgG (FcgammaR) expressed in dendritic cells (DCs) influence the initiation of Ab-mediated immunity. Dynamic variations in FcgammaR expression allow DCs to adjust their capacity to capture Ab-opsonized Ag. The current paradigm predicts a progressive decline in FcgammaR-mediated phagocytic function upon DC maturation. Surprisingly, we find that expression of the phagocytic receptor FcgammaRIIa is preserved in immature and mature DCs at comparable levels with macrophages. Moreover, phagocytosis of antigenic peptides directed to FcgammaRIIa on DCs leads to dramatic increases in Ag cross-presentation and T cell activation. In immature DCs, high expression of inhibitory FcgammaRIIb correlates with decreased uptake and cross-presentation of Ab-Ag complexes. In contrast, engagement of FcgammaRIIb is not associated with changes in cross-presentation in mature DCs. We provide evidence that FcgammaRIIb expression is patently reduced in mature DCs, an effect that is modulated by treatment with cytokines. The regulated expression of activating and inhibitory FcgammaRs in DCs emerges as a critical checkpoint in the process of Ag uptake and cross-presentation.
    No preview · Article · Jan 2007 · The Journal of Immunology
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    ABSTRACT: Constitutive overexpression of B cell-activating factor belonging to the TNF family (BAFF) promotes development of systemic lupus erythematosus (SLE), and treatment of SLE mice with BAFF antagonists ameliorates disease. To determine whether SLE can develop de novo in BAFF-deficient hosts, BAFF-deficient New Zealand Mixed (NZM) 2328 (NZM.Baff(-/-)) mice were generated. In NZM.Baff(-/-) mice, spleen B cells (including CD5(+) B1a and CD5(-) B1b B cells), germinal centers, Ig-secreting cells, and T cells were reduced in comparison to NZM.Baff(+/+) mice. Serum total Ig and autoantibody levels were reduced at 4-6 mo but approached wild-type levels with increasing age, indicating that autoreactive B cells can survive and secrete autoantibodies despite the complete absence of BAFF. At least some of these autoantibodies are nephrophilic in that glomerular deposition of total IgG and IgG1 (but not of IgG2a, IgG2b, or C3) was substantial in NZM.Baff(-/-) mice by 12-13 mo of age. Despite proliferative glomerulonephritis, highlighted by widespread glomerular hyaline thrombi, being common among NZM.Baff(-/-) mice by 6-7 mo of age, severe proteinuria and mortality were greatly attenuated. These results demonstrate that the lifelong absence of BAFF does not protect NZM 2328 mice from serological autoimmunity and renal pathology. Nevertheless, the character of the renal pathology is altered, and the mice are largely spared from clinically overt disease (severe proteinuria and premature death). These observations may have profound ramifications for the use of BAFF antagonists in human SLE and related diseases.
    Full-text · Article · Sep 2006 · The Journal of Immunology

Publication Stats

851 Citations
272.17 Total Impact Points

Institutions

  • 1999-2009
    • Cornell University
      • Department of Medicine
      Итак, New York, United States
  • 1997-2006
    • Weill Cornell Medical College
      • Department of Medicine
      New York City, New York, United States
  • 2003
    • Hospital for Special Surgery
      • Arthritis and Tissue Degeneration Program
      New York City, New York, United States