97 results on '"van den Blink B"'
Search Results
2. Ziritaxestat, a novel autotaxin inhibitor, and lung function in idiopathic pulmonary fibrosis
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Maher, TM, Ford, P, Brown, KK, Costabel, U, Cottin, V, Danoff, SK, Groenveld, I, Helmer, E, Jenkins, RG, Milner, J, Molenberghs, G, Penninckx, B, Randall, MJ, Van Den Blink, B, Fieuw, A, Vandenrijn, C, Rocak, S, Seghers, I, Shao, L, Taneja, A, Jentsch, G, Watkins, TR, Wuyts, WA, Kreuter, M, Verbruggen, N, Prasad, N, Wijsenbeek, MS, Chambers, D, Chia, M, Corte, T, Glaspole, I, Goh, N, Holmes, M, Malouf, M, Thien, F, Veitch, E, Bondue, B, Dahlqvist, C, Froidure, A, Slabbynck, H, Wuyts, W, Cartagena Salinas, C, Feijoó Seoane, R, Martínez, V, Maturana, R, Pavie Gallegos, J, Rosenblut, A, Silva, R, Undurraga Pereira, A, Doubkova, M, Pauk, N, Plackova, M, Sterclova, M, Bendstrup, E, Shaker, SB, Titlestad, I, Budweiser, S, Grohé, C, Koschel, D, Prasse, A, Weber, M, Wirtz, H, Antoniou, K, Daniil, Z, Gaga, M, Papakosta, D, Izumi, S, Okamoto, M, Guerreros Benavides, A, Iberico Barrera, C, Peña Villalobos, AM, Campo Ezquibela, A, Cifrian Martinez, JM, Fernandez Fabrellas, E, Leiro, V, Molina-Molina, M, Nieto Barbero, A, Sellares Torres, J, Valenzuela, C, Cheng, S-L, Kuo, P-H, Lee, K-Y, Sheu, C-C, Gunen, H, Mogulkoc Bishop, N, Nayci, S, Adamali, H, Bianchi, S, Chaudhuri, N, Gibbons, M, Hart, S, Molyneaux, P, Parfrey, H, Saini, G, Spencer, LG, Wiscombe, S, Antin-Ozerkis, D, Bascom, R, Belperio, J, Britt, E, Fitzgerald, J, Gomez Manjarres, D, Gotfried, M, Gupta, N, Hotchkin, D, Kaye, M, Kreider, M, Kureishy, S, Lacamera, P, Lancaster, L, Lasky, J, Lorch, D, Mannem, H, Morrow, L, Moua, T, Nambiar, A, Raghu, G, Raj, R, Ramaswamy, M, Reddy, R, Russell, T, Scholand, MB, Shea, B, Suliman, S, Swigris, J, Thavarajah, K, Tolle, L, Tomic, R, Warshoff, N, Wesselius, L, Yung, G, Bergna, M, De Salvo, M, Fernandez Acquier, M, Rodriguez, A, Saez Scherbovsky, P, Assayag, D, Dhar, A, Khalil, N, Morisset, J, Provencher, S, Ryerson, C, Shapera, S, Bourdin, A, Crestani, B, Lebargy, F, Reynaud-Gaubert, M, Bonella, FT, Claussen, M, Hammerl, P, Karagiannidis, C, Keller, C, Randerath, W, Stubbe, B, Csánky, E, Medgyasszay, B, Muller, V, Adir, Y, Bar-Shai, A, Berkman, N, Fink, G, Kramer, M, Shitrit, D, Bargagli, E, Gasparini, S, Harari, S, Ravaglia, C, Richeldi, L, Vancheri, C, Ebina, M, Fujita, M, Ichikado, K, Inoue, Y, Ishikawa, N, Kato, M, Kawamura, T, Kondoh, Y, Nishioka, Y, Ogura, T, Owan, I, Saito, T, Sakamoto, N, Sakamoto, K, Shirai, M, Suda, T, Tomii, K, Chung, MP, Jeong, SH, Park, CS, Park, JS, Song, JW, Uh, S-T, Chavarria Martinez, U, Montano Gonzalez, E, Ramirez, A, Selman Lama, ME, Bresser, P, Kramer, H, Mostard, R, Nossent, E, Veltkamp, M, Wijsenbeek, M, Beckert, L, Chang, CL, Veale, A, Wilsher, M, Bednarek, M, Gasior, G, Jasieniak-Pinis, G, Jassem, E, Mroz, R, Piotrowski, W, Abdullah, I, Ambaram, A, Irusen, E, Van der Linden, M, Van Zyl-Smit, R, Williams, P, Allen, J, Averill, F, Belloli, E, Brown, A, Case, A, Chaudhary, S, Criner, G, DeBoer, K, Dilling, D, Dorf, J, Enelow, R, Ettinger, N, Feldman, J, Gibson, K, Golden, J, Hamblin, M, Hunninghake, G, Karunakara, R, Kim, H, Luckhardt, T, Menon, P, Morrison, L, Oldham, J, Patel, N, Schmidt, S, Strek, M, Summer, R, Sussman, R, Tita, J, Veeraraghavan, S, Whelan, T, and Zibrak, J
- Abstract
Importance There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg of ziritaxestat vs –147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]), and –173.9 mL (95% CI, −225.7 to −122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, −26.7 mL [95% CI, −100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was –173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg of ziritaxestat vs –176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]) and –174.9 mL (95% CI, −209.5 to −140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, −47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444
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- 2023
3. GLPG1205 shows reduction in lung volume decline over 26 weeks vs placebo when measured with novel volumetric CT analysis in IPF patients
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Thillai, M, primary, Kirov, K, additional, Santermans, E, additional, Roberts, M, additional, Molyneaux, P, additional, Kanavati, F, additional, Gallagher, D, additional, De Haas-Amatsaleh, A, additional, Van Der Aa, T, additional, Ford, P, additional, Seemayer, C, additional, Van Den Blink, B, additional, and Ruggiero, A, additional
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- 2022
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4. Assessment of a relationship between prognostic biomarkers and treatment response in ISABELA1 &2 IPF cohorts
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Randall, M, primary, De Bernard, S, additional, Seghers, I, additional, Verbruggen, N, additional, Lim, S, additional, Van Den Blink, B, additional, Andersen, C, additional, Pujuguet, P, additional, Prasad, N, additional, Ford, P, additional, and Bauer, Y, additional
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- 2022
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5. Fibrocytes are increased in lung and peripheral blood of patients with idiopathic pulmonary fibrosis
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Heukels, P., van Hulst, J. A. C., van Nimwegen, M., Boorsma, C. E., Melgert, B. N., van den Toorn, L. M., Boomars, K. A. T., Wijsenbeek, M. S., Hoogsteden, H., von der Thüsen, J. H., Hendriks, R. W., Kool, M., and van den Blink, B.
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- 2018
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6. Recombinant human serum amyloid P in healthy volunteers and patients with pulmonary fibrosis
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Dillingh, M.R., van den Blink, B., Moerland, M., van Dongen, M.G.J., Levi, M., Kleinjan, A., Wijsenbeek, M.S., Lupher, M.L., Jr., Harper, D.M., Getsy, J.A., Hoogsteden, H.C., and Burggraaf, J.
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- 2013
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7. Leflunomide as part of the treatment for multidrug-resistant cytomegalovirus disease after lung transplantation: case report and review of the literature
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Verkaik, N. J., Hoek, R. A.S., van Bergeijk, H., van Hal, P. Th.W., Schipper, M. E.I., Pas, S. D., Beersma, M. F.C., Boucher, C. A.B., Jedema, I., Falkenburg, F., Hoogsteden, H. C., van den Blink, B., and Murk, J. L.
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- 2013
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8. “Tree in bud” attributable to organising pneumonia
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Bots, E M T, den Bakker, M A, Wijsenbeek, M S, van den Toorn, L M, and van den Blink, B
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- 2013
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9. A pivotal role of protease-activated receptor-2 in bleomycin-induced pulmonary fibrosis: OC-WE-105
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Borensztajn, K S, Bresser, P, von der Thusen, J, van den Blink, B, Groot, A P, Daalhuisen, J, Peppelenbosch, M P, and Spek, A
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- 2009
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10. Long-term treatment with recombinant human pentraxin 2 protein in patients with idiopathic pulmonary fibrosis: an open-label extension study
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Raghu, G, van den Blink, B, Hamblin, M, Brown, A, Golden, J, Ho, L, Wijsenbeek, M, Vasakova, M, Pesci, A, Antin-Ozerkis, D, Meyer, K, Kreuter, M, Moran, D, Santin-Janin, H, Aubin, F, Mulder, G, Gupta, R, Richeldi, L, Raghu, Ganesh, van den Blink, Bernt, Hamblin, Mark J, Brown, A Whitney, Golden, Jeffrey A, Ho, Lawrence A, Wijsenbeek, Marlies S, Vasakova, Martina, Pesci, Alberto, Antin-Ozerkis, Danielle E, Meyer, Keith C, Kreuter, Michael, Moran, Donna, Santin-Janin, Hugues, Aubin, Francois, Mulder, Geert-Jan, Gupta, Renu, Richeldi, Luca, Raghu, G, van den Blink, B, Hamblin, M, Brown, A, Golden, J, Ho, L, Wijsenbeek, M, Vasakova, M, Pesci, A, Antin-Ozerkis, D, Meyer, K, Kreuter, M, Moran, D, Santin-Janin, H, Aubin, F, Mulder, G, Gupta, R, Richeldi, L, Raghu, Ganesh, van den Blink, Bernt, Hamblin, Mark J, Brown, A Whitney, Golden, Jeffrey A, Ho, Lawrence A, Wijsenbeek, Marlies S, Vasakova, Martina, Pesci, Alberto, Antin-Ozerkis, Danielle E, Meyer, Keith C, Kreuter, Michael, Moran, Donna, Santin-Janin, Hugues, Aubin, Francois, Mulder, Geert-Jan, Gupta, Renu, and Richeldi, Luca
- Abstract
Background: Patients with idiopathic pulmonary fibrosis (IPF) treated with PRM-151, a recombinant human pentraxin 2 protein, in a phase 2 double-blind, randomised controlled trial had significantly reduced decline in percentage of predicted forced vital capacity (FVC) and stabilised 6-min walking distance compared with placebo over a 28-week period. Here we report the 76-week results of an open-label extension study. Methods: Patients who completed the 28-week double-blind period of the PRM-151-202 trial were eligible to participate in the open-label extension study. Patients previously enrolled in the PRM-151 group continued this treatment and those previously in the placebo group crossed over to PRM-151. All patients received PRM-151 in 28-week cycles with loading doses of 10 mg/kg by 60 min intravenous infusions on days 1, 3, and 5 in the first week of each cycle followed by one infusion of 10 mg/kg every 4 weeks. The primary objective of the open-label extension study was to assess the long-term safety and tolerability of PRM-151, which were assessed by analysing adverse events (AEs) up to week 76 in all patients who received at least one dose of PRM-151 during the open-label extension study. Exploratory efficacy analyses were done by assessing changes from baseline in percentage of predicted FVC and 6-min walking distance, with descriptive statistics to week 76 and with random-intercept mixed models to week 52. This study is registered with ClinicalTrials.gov, number NCT02550873, and with EudraCT, number 2014-004782-24. Findings: Of 116 patients who completed the double-blind treatment period, 111 entered the open-label extension study (74 from the PRM-151 group and 37 from the placebo group). 84 (76%) of 111 patients received concomitant IPF therapy (pirfenidone n=55 or nintedanib n=29). AEs were consistent with long-term IPF sequelae. 31 (28%) patients had serious AEs. Those occurring in two or more patients were pneumonia (six [5%] of 111), IPF exacerbation
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- 2019
11. Dichotomal role of inhibition of p38 MAPK with SB 203580 in experimental colitis
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ten Hove, T, van den Blink, B, Pronk, I, Drillenburg, P, Peppelenbosch, M P, and van Deventer, S J H
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- 2002
12. Procoagulant protein levels are differentially increased during human endotoxemia
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Reitsma, P.H., Branger, J., Van Den Blink, B., Weijer, S., Van Der Poll, T., and Meijers, J.C.M.
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- 2003
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13. S828 A RANDOMIZED, DOUBLE BLIND PHASE 2 STUDY OF 3 DIFFERENT DOSES OF PRM-151 IN PATIENTS WITH MYELOFIBROSIS WHO WERE PREVIOUSLY TREATED WITH OR INELIGIBLE FOR RUXOLITINIB
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Verstovsek, S., primary, Talpaz, M., additional, Wadleigh, M., additional, Palmer, J., additional, Isidori, A., additional, te Boekhorst, P., additional, Savona, M., additional, Gotlib, J., additional, Hasserjian, R., additional, Pozdnyakova, O., additional, Weinberg, O., additional, Derlin, T., additional, Gupta, V., additional, Ritchie, E., additional, Mascarenhas, J., additional, Mesa, R., additional, van den Blink, B., additional, and Harrison, C., additional
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- 2019
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14. Long-Term Safety and Efficacy of Recombinant Human Pentraxin-2 in Patients with Idiopathic Pulmonary Fibrosis
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Raghu, G., primary, van den Blink, B., additional, Hamblin, M.J., additional, Brown, A.W., additional, Golden, J.A., additional, Ho, L.A., additional, Wijsenbeek, M.S., additional, Vasakova, M., additional, Pesci, A., additional, Antin-Ozerkis, D.E., additional, Meyer, K., additional, Kreuter, M., additional, Santin-Janin, H., additional, Aubin, F., additional, Mulder, G.-J.J., additional, Gupta, R., additional, and Richeldi, L., additional
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- 2019
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15. Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis a randomized clinical trial
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Raghu, G, Van Den Blink, B, Hamblin, M, Whitney Brown, A, Golden, J, Ho, L, Wijsenbeek, M, Vasakova, M, Pesci, A, Antin-Ozerkis, D, Meyer, K, Kreuter, M, Santin-Janin, H, Mulder, G, Bartholmai, B, Gupta, R, Richeldi, L, Raghu, Ganesh, Van Den Blink, Bernt, Hamblin, Mark J., Whitney Brown, A., Golden, Jeffrey A., Ho, Lawrence A., Wijsenbeek, Marlies S., Vasakova, Martina, Pesci, Alberto, Antin-Ozerkis, Danielle E., Meyer, Keith C., Kreuter, Michael, Santin-Janin, Hugues, Mulder, Geert-Jan, Bartholmai, Brian, Gupta, Renu, Richeldi, Luca, Raghu, G, Van Den Blink, B, Hamblin, M, Whitney Brown, A, Golden, J, Ho, L, Wijsenbeek, M, Vasakova, M, Pesci, A, Antin-Ozerkis, D, Meyer, K, Kreuter, M, Santin-Janin, H, Mulder, G, Bartholmai, B, Gupta, R, Richeldi, L, Raghu, Ganesh, Van Den Blink, Bernt, Hamblin, Mark J., Whitney Brown, A., Golden, Jeffrey A., Ho, Lawrence A., Wijsenbeek, Marlies S., Vasakova, Martina, Pesci, Alberto, Antin-Ozerkis, Danielle E., Meyer, Keith C., Kreuter, Michael, Santin-Janin, Hugues, Mulder, Geert-Jan, Bartholmai, Brian, Gupta, Renu, and Richeldi, Luca
- Abstract
IMPORTANCE Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. OBJECTIVE To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. DESIGN, SETTING, AND PARTICIPANTS Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC 50% and 90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [DLCO] 25% and 90% predicted; and distance of 150 m on the 6-minute walk test). Study period was August 2015-May 2017. INTERVENTIONS Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status. MAIN OUTCOMES AND MEASURES The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). RESULTS Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, -27.7 to 214.7]), quan
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- 2018
16. Linking cellular immunity to B cell (auto)immunity in idiopatic pulmonary fibrosis
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Heukels, P., Van Hulst, J., Wijsenbeek, M.S., Boorsma, Carian, Melgert, Barbro, Hoogsteden, Henk C., Hendriks, Rudi W., Corneth, Odilia B. J., Kool, M, van den Blink, B, Nanomedicine & Drug Targeting, Groningen Research Institute for Asthma and COPD (GRIAC), and Biopharmaceuticals, Discovery, Design and Delivery (BDDD)
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- 2015
17. Linking Cellular Immunity To B Cell (auto) immunity In Idiopathic Pulmonary Fibrosis
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Heukels, P., Van Hulst, J., Wijsenbeek, M. S., Boorsma, C. E., Melgert, B. N., Hoogsteden, H. C., Hendriks, R. W., Corneth, O. B. J., Kool, M., Van den Blink, B., Nanomedicine & Drug Targeting, Groningen Research Institute for Asthma and COPD (GRIAC), and Biopharmaceuticals, Discovery, Design and Delivery (BDDD)
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- 2015
18. Scalp hair cortisol: A promising new biomarker for psychological wellbeing in patients with sarcoidosis?
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Van Manen, M.J.G., primary, Wester, V.L., additional, Van den Toorn, L.M., additional, Van den Blink, B., additional, De Rijke, Y.B., additional, Dorst, K.Y., additional, Van Rossum, E.F.C., additional, and Wijsenbeek, M.S., additional
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- 2015
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19. Specific inhibition of c-Raf activity by semapimod induces clinical remission in severe Crohn's disease
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Lowenberg, M, Verhaar, A, van den Blink, B, van Deventer, S, Peppelenbosch, M, and Hommes, D
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FACTOR-KAPPA-B ,PHASE-I TRIAL ,FACTOR-ALPHA PRODUCTION ,ACTIVATED PROTEIN-KINASE ,SIGNAL-TRANSDUCTION PATHWAYS ,COLONY-STIMULATING FACTOR ,DENDRITIC CELLS ,MAP KINASES ,TUMOR-NECROSIS-FACTOR ,INFLAMMATORY-BOWEL-DISEASE - Abstract
There is a substantial need for novel treatment strategies in Crohn's disease (CD), a chronic relapsing inflammatory disease of the gut. In an earlier study, we reported clinical efficacy of a 2-wk treatment with semapimod (CNI-1493) in 12 patients with therapy resistant CD. The aim of this study was to identify the cellular target underlying semapimod action. In vitro experiments with murine macrophages showed impaired MAPK signaling and decreased cytokine production due to semapimod treatment. In vitro kinase assays revealed c-Raf as a direct molecular target of semapimod, and semapimod did not affect b-Raf enzymatic activity. Immunohistochemistry performed on paired colon biopsies obtained from CD patients (n = 6) demonstrated increased expression of phospho-MEK, the substrate of Raf. Strikingly, phospho-MEK levels were significantly decreased in patients with a good clinical response to semapimod, but no decrease in phospho-MEK expression was observed in a clinically nonresponsive patient. In conclusion, this study identifies c-Raf as a molecular target of semapimod action and suggests that decreased c-Raf activity correlates with clinical benefit in CD. Our observations indicate that c-Raf inhibitors are prime candidates for the treatment of CD.
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- 2005
20. In vivo signal transduction: mitogen activated protein kinases in inflammation
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van den Blink, B., van Deventer, S.J.H., Peppelenbosch, M.P., van der Poll, T., and Faculteit der Geneeskunde
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sense organs - Published
- 2002
21. Impaired survival of regulatory T cells in pulmonary sarcoidosis patients
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Broos, CE, primary, Van Nimwegen, M, additional, KleinJan, A, additional, Ten Berge, B, additional, Muskens, F, additional, In 't Veen, JCCM, additional, Hoogsteden, HC, additional, Hendriks, RW, additional, Lambrecht, BN, additional, Kool, M, additional, and van den Blink, B, additional
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- 2012
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22. “Tree in bud” attributable to organising pneumonia
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Bots, E M T, primary, den Bakker, M A, additional, Wijsenbeek, M S, additional, van den Toorn, L M, additional, and van den Blink, B, additional
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- 2012
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23. 700 The Clinical and Histological Characteristics of End-Stage Sarcoidosis Requiring Lung Transplantation; a Three Center Experience
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Shigemitsu, H., primary, Drent, M., additional, van den Blink, B., additional, Sharma, O., additional, van Suylen, R.J., additional, den Bakker, M.A., additional, and Koss, M.N., additional
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- 2012
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24. A novel method for isolating dendritic cells from human bronchoalveolar lavage fluid
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Ten Berge, B., primary, Muskens, F., additional, KleinJan, A., additional, Hammad, H., additional, Hoogsteden, H.C., additional, Lambrecht, B.N., additional, and Van den Blink, B., additional
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- 2009
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25. Essential role for c-Raf in steroid insensitive Crohn??s disease
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Lowenberg, M, primary, Verhaar, A, additional, van den Blink, B, additional, van Deventer, S, additional, Peppelenbosch, M, additional, and Hommes, D, additional
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- 2006
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26. Immunomodulatory effect of oxygen and pressure
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van den Blink, B, primary, van der Kleij, A.J, additional, Versteeg, H.H, additional, and Peppelenbosch, M.P, additional
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- 2002
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27. Granuloma formation in pulmonary sarcoidosis.
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Broos, Caroline E., van Nimwegen, M., Hoogsteden, Henk C., Hendriks, Rudi W., Kool, Mirjam, and van den Blink, B.
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SARCOIDOSIS ,LYMPHOPROLIFERATIVE disorders ,IMMUNOLOGY ,DENDRITIC cells ,LYMPHOCYTES - Abstract
Sarcoidosis is a granulomatous disorder of unknown cause, affecting multiple organs, but mainly the lungs. The exact order of immunological events remains obscure. Reviewing current literature, combined with careful clinical observations, we propose a model for granuloma formation in pulmonary sarcoidosis. A tight collaboration between macrophages, dendritic cells and lymphocyte subsets, initiates the first steps towards granuloma formation, orchestrated by cytokines and chemokines. In a substantial part of pulmonary sarcoidosis patients, granuloma formation becomes an on-going process, leading to debilitating disease and sometimes death. The immunological response, determining granuloma sustainment is not well understood. An impaired immunosuppressive function of regulatory T cells has been suggested to contribute to the exaggerated response. Interestingly, therapeutical agents commonly used in sarcoidosis, such as glucocorticosteroids and anti-TNF agents, interfere with granuloma integrity and restore the immune homeostasis in autoimmune disorders. Increasing insight into their mechanisms of action may contribute to the search for new therapeutical targets in pulmonary sarcoidosis. [ABSTRACT FROM AUTHOR]
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- 2013
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28. Duodenal Intraepithelial and Lamina Propria T Lymphocytes in Human Immunodeficiency Virus-Infected Patients with and without Diarrhoea
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Snijders, F., primary, Meenan, J., additional, Van Den Blink, B., additional, Van Deventer, S. J. H., additional, and Ten Kate, F. J. W., additional
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- 1996
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29. Dichotomal role of inhibition of p38 MAPK with SB 203580 in experimental colitis.
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Hove, T. ten, van den Blink, B., Pronk, I., Drillenburg, P., Peppelenbosch, M. P., and van Deventer, S. J. H.
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- 2002
30. Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease
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Hommes, D., Van Den Blink, B., Plasse, T., Bartelsman, J., Xu, C., Macpherson, B., Tytgat, G., Peppelenbosch, M., and Van Deventer, S.
- Abstract
Background & Aims:: We investigated if inhibition of mitogen-activated protein kinases (MAPKs) was beneficial in Crohn's disease. Methods:: Inhibition of JNK and p38 MAPK activation with CNI-1493, a guanylhydrazone, was tested in vitro. Twelve patients with severe Crohn's disease (mean baseline, CDAI 380) were randomly assigned to receive either 8 or 25 mg/m^2 CNI-1493 daily for 12 days. Clinical endpoints included safety, Crohn's Disease Activity Index (CDAI), Inflammatory Bowel Disease Questionnaire, and the Crohn's Disease Endoscopic Index of Severity. Methods:: Colonic biopsies displayed enhanced JNK and p38 MAPK activation. CNI-1493 inhibition of both JNK and p38 phosphorylation was observed in vitro. Treatment resulted in diminished JNK phosphorylation and tumor necrosis factor production as well as significant clinical benefit and rapid endoscopic ulcer healing. No serious adverse events were noted. A CDAI decrease of 120 at week 4 (P = 0.005) and 146.5 at week 8 (P = 0.005) was observed. A clinical response was seen in 67% of patients at 4 weeks and 58% at 8 weeks. Clinical remission was observed in 25% of patients at week 4 and 42% at week 8. Endoscopic improvement occurred in all but 1 patient. Response was seen in 3 of 6 infliximab failures, 2 of whom showed remission. Fistulae healing occurred in 4 of 5 patients, and steroids were tapered in 89% of patients. Conclusions:: Inflammatory MAPKs are critically involved in the pathogenesis of Crohn's disease and their inhibition provides a novel therapeutic strategy.
- Published
- 2002
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31. Idiopathic pulmonary fibrosis: molecular mechanisms and possible therapeutic strategies
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van den Blink B, Hm, Jansen, and Maikel Peppelenbosch
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Inflammation ,Herpesvirus 4, Human ,Mice ,Fibrinolysis ,Pulmonary Fibrosis ,T-Lymphocytes ,Animals ,Cytokines ,Humans ,Apoptosis ,fas Receptor ,Chemokines - Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating disease with an almost universally terminal outcome. In recent years much insight has been gained into the pathogenesis of IPF from both a bleomycin mice-model as well as ex vivo human tissue studies. Alveolar damage and inflammation of unknown etiology, eventually leading to interstitial fibrosis, characterize IPF. Apoptosis has emerged as an important factor in the pathogenesis of IPF. This review will outline the current understanding of the immunological and molecular mechanisms underlying IPF and discuss new therapeutic strategies.
32. Evidence for local dendritic cell activation in pulmonary sarcoidosis
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Berge Bregje, KleinJan Alex, Muskens Femke, Hammad Hamida, Hoogsteden Henk C, Hendriks Rudi W, Lambrecht Bart N, and Van den Blink Bernt
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Sarcoidosis ,Dendritic cells ,Bronchoalveolar lavage ,Granuloma ,TNFα ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Sarcoidosis is a granulomatous disease characterized by a seemingly exaggerated immune response against a difficult to discern antigen. Dendritic cells (DCs) are pivotal antigen presenting cells thought to play an important role in the pathogenesis. Paradoxically, decreased DC immune reactivity was reported in blood samples from pulmonary sarcoidosis patients. However, functional data on lung DCs in sarcoidosis are lacking. We hypothesized that at the site of disease DCs are mature, immunocompetent and involved in granuloma formation. Methods We analyzed myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in broncho-alveolar lavage (BAL) and blood from newly diagnosed, untreated pulmonary sarcoidosis patients and healthy controls using 9-color flowcytometry. DCs, isolated from BAL using flowcytometric sorting (mDCs) or cultured from monocytes (mo-DCs), were functionally assessed in a mixed leukocyte reaction with naïve allogeneic CD4+ T cells. Using Immunohistochemistry, location and activation status of CD11c+DCs was assessed in mucosal airway biopsies. Results mDCs in BAL, but not in blood, from sarcoidosis patients were increased in number when compared with mDCs from healthy controls. mDCs purified from BAL of sarcoidosis patients induced T cell proliferation and differentiation and did not show diminished immune reactivity. Mo-DCs from patients induced increased TNFα release in co-cultures with naïve allogeneic CD4+ T cells. Finally, immunohistochemical analyses revealed increased numbers of mature CD86+ DCs in granuloma-containing airway mucosal biopsies from sarcoidosis patients. Conclusion Taken together, these finding implicate increased local DC activation in granuloma formation or maintenance in pulmonary sarcoidosis.
- Published
- 2012
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33. A new MAP-kinase inhibitor, CNI-1493, is safe and effective in the treatment of moderate to severe Crohn's disease
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Hommes, D.W., van den Blink, B., van de Heisteeg, B., Plasse, T., de Ley, M., Macpherson, B., Bartelsman, J.F.W., and Van Deventer, S.J.H.
- Published
- 2001
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34. Long-term treatment with recombinant human pentraxin 2 protein in patients with idiopathic pulmonary fibrosis: an open-label extension study
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A. Whitney Brown, Renu Gupta, Ganesh Raghu, Luca Richeldi, Mark J. Hamblin, Lawrence A. Ho, Marlies S. Wijsenbeek, Bernt van den Blink, Jeffrey A. Golden, Hugues Santin-Janin, Michael Kreuter, Geert-Jan Mulder, Martina Vasakova, Danielle Antin-Ozerkis, Francois Aubin, Keith C. Meyer, Donna Moran, Alberto Pesci, Raghu, G, van den Blink, B, Hamblin, M, Brown, A, Golden, J, Ho, L, Wijsenbeek, M, Vasakova, M, Pesci, A, Antin-Ozerkis, D, Meyer, K, Kreuter, M, Moran, D, Santin-Janin, H, Aubin, F, Mulder, G, Gupta, R, Richeldi, L, and Pulmonary Medicine
- Subjects
Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Exacerbation ,Vital Capacity ,Settore MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO ,Placebo ,law.invention ,03 medical and health sciences ,FEV1/FVC ratio ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,Humans ,Medicine ,030212 general & internal medicine ,Extensive stage ,Aged ,idiopathic pulmonary fibrosis, pentraxin 2 ,Homeodomain Proteins ,Cross-Over Studies ,MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO ,business.industry ,medicine.disease ,Long-Term Care ,Crossover study ,Idiopathic Pulmonary Fibrosis ,Recombinant Proteins ,Serum Amyloid P-Component ,Treatment Outcome ,030228 respiratory system ,Tolerability ,Female ,idiopathic pulmonary fibrosis (IPF) ,business - Abstract
Background: Patients with idiopathic pulmonary fibrosis (IPF) treated with PRM-151, a recombinant human pentraxin 2 protein, in a phase 2 double-blind, randomised controlled trial had significantly reduced decline in percentage of predicted forced vital capacity (FVC) and stabilised 6-min walking distance compared with placebo over a 28-week period. Here we report the 76-week results of an open-label extension study. Methods: Patients who completed the 28-week double-blind period of the PRM-151-202 trial were eligible to participate in the open-label extension study. Patients previously enrolled in the PRM-151 group continued this treatment and those previously in the placebo group crossed over to PRM-151. All patients received PRM-151 in 28-week cycles with loading doses of 10 mg/kg by 60 min intravenous infusions on days 1, 3, and 5 in the first week of each cycle followed by one infusion of 10 mg/kg every 4 weeks. The primary objective of the open-label extension study was to assess the long-term safety and tolerability of PRM-151, which were assessed by analysing adverse events (AEs) up to week 76 in all patients who received at least one dose of PRM-151 during the open-label extension study. Exploratory efficacy analyses were done by assessing changes from baseline in percentage of predicted FVC and 6-min walking distance, with descriptive statistics to week 76 and with random-intercept mixed models to week 52. This study is registered with ClinicalTrials.gov, number NCT02550873, and with EudraCT, number 2014-004782-24. Findings: Of 116 patients who completed the double-blind treatment period, 111 entered the open-label extension study (74 from the PRM-151 group and 37 from the placebo group). 84 (76%) of 111 patients received concomitant IPF therapy (pirfenidone n=55 or nintedanib n=29). AEs were consistent with long-term IPF sequelae. 31 (28%) patients had serious AEs. Those occurring in two or more patients were pneumonia (six [5%] of 111), IPF exacerbation (four [4%]), IPF progression (four [4%]), and chest pain (two [2%]). 21 (19%) patients had severe AEs, of which IPF exacerbation and IPF progression each occurred in two (2%) patients. Two (2%) patients experienced life-threatening AEs (one had pneumonia and one had small-cell lung cancer extensive stage). A persistent treatment effect was observed for PRM-151 in patients who continued treatment, with a decline in percentage of predicted FVC of −3·6% per year and in 6-min walking distance of −10·5 m per year at week 52. In patients who started PRM-151 during the open-label extension study, compared with the slopes for placebo, decline reduced for percentage of predicted FVC (from −8·7% per year in weeks 0–28 to −0·9% per year in weeks 28–52, p
- Published
- 2019
35. T helper 17 cells and Regulatory T cells in Pulmonary Sarcoidosis : It takes two to tangle
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Broos, Caroline, Hendriks, Rudi, Kool, Mirjam, van den Blink, B, and Pulmonary Medicine
- Published
- 2017
36. ISABELA Studies: Plasma Exposure and Target Engagement Do Not Explain the Lack of Efficacy of Ziritaxestat in Patients with Idiopathic Pulmonary Fibrosis.
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Taneja A, Jentsch G, Delage S, Randall MJ, van den Blink B, Bauer Y, and Namour F
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- Humans, Imidazoles pharmacokinetics, Pyrimidines pharmacokinetics, Fibrosis, Idiopathic Pulmonary Fibrosis drug therapy, Idiopathic Pulmonary Fibrosis chemically induced
- Abstract
Autotaxin (ATX) contributes to the production of lysophosphatidic acid (LPA), which is associated with fibrosis development in idiopathic pulmonary fibrosis (IPF). The ATX inhibitor ziritaxestat failed to reduce decline in forced vital capacity (FVC) in patients with IPF in ISABELA 1 and 2 (NCT03711162 and NCT03733444), two identically designed phase III studies. In the current analysis, we evaluated pharmacokinetic and pharmacodynamic data from the pooled ISABELA studies to determine whether the lack of efficacy could be attributed to insufficient exposure and/or target engagement. Nonlinear mixed effect modeling was performed to predict ziritaxestat exposure in individual patients and describe its effect on LPA C18:2 levels. We assessed whether there was a correlation between ziritaxestat and ATX concentration and evaluated the relationship between LPA C18:2 reduction and change from baseline in FVC. Ziritaxestat exposure in patients with IPF was numerically lower in those who received ziritaxestat on top of pirfenidone than in those who received ziritaxestat on top of nintedanib or ziritaxestat alone. In most patients, LPA C18:2 reduction was comparable to that reported in healthy volunteers. ATX concentrations increased over time and correlated weakly with ziritaxestat exposure and LPA C18:2 reduction. No correlation between reduction in LPA C18:2 and change from baseline in FVC was apparent. Based on these evaluations, exposure and target engagement are not thought to have contributed to the lack of efficacy observed. We hypothesize that the lack of efficacy of ziritaxestat in the ISABELA program, despite adequate LPA reduction, could be due to the involvement of an alternative pro-fibrotic pathway., (© 2023 Galapagos NV and The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2024
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37. Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.
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Maher TM, Ford P, Brown KK, Costabel U, Cottin V, Danoff SK, Groenveld I, Helmer E, Jenkins RG, Milner J, Molenberghs G, Penninckx B, Randall MJ, Van Den Blink B, Fieuw A, Vandenrijn C, Rocak S, Seghers I, Shao L, Taneja A, Jentsch G, Watkins TR, Wuyts WA, Kreuter M, Verbruggen N, Prasad N, and Wijsenbeek MS
- Subjects
- Aged, Humans, Male, Lung drug effects, Lung physiopathology, Quality of Life, Randomized Controlled Trials as Topic, Respiratory Physiological Phenomena drug effects, Treatment Outcome, Clinical Trials, Phase III as Topic, Multicenter Studies as Topic, Administration, Oral, Middle Aged, Female, Phosphodiesterase Inhibitors pharmacology, Phosphodiesterase Inhibitors therapeutic use, Idiopathic Pulmonary Fibrosis drug therapy, Idiopathic Pulmonary Fibrosis physiopathology, Respiratory System Agents pharmacology, Respiratory System Agents therapeutic use
- Abstract
Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF)., Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF., Design, Setting, and Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2., Interventions: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks., Main Outcomes and Measures: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life)., Results: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo., Conclusions and Relevance: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment., Trial Registration: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.
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- 2023
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38. Enhanced Bruton's tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis.
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Heukels P, van Hulst JAC, van Nimwegen M, Boorsma CE, Melgert BN, von der Thusen JH, van den Blink B, Hoek RAS, Miedema JR, Neys SFH, Corneth OBJ, Hendriks RW, Wijsenbeek MS, and Kool M
- Subjects
- Aged, Animals, Antibiotics, Antineoplastic toxicity, Autoantibodies blood, Bleomycin toxicity, Female, Humans, Idiopathic Pulmonary Fibrosis pathology, Lung drug effects, Lung metabolism, Lung pathology, Lymph Nodes drug effects, Lymph Nodes metabolism, Lymph Nodes pathology, Male, Mice, Middle Aged, Agammaglobulinaemia Tyrosine Kinase blood, B-Lymphocytes metabolism, Disease Progression, Idiopathic Pulmonary Fibrosis blood, Immunoglobulin A blood
- Abstract
Rationale: Idiopathic Pulmonary Fibrosis (IPF) is thought to be triggered by repeated alveolar epithelial cell injury. Current evidence suggests that aberrant immune activation may contribute. However, the role of B-cell activation remains unclear. We determined the phenotype and activation status of B-cell subsets and evaluated the contribution of activated B-cells to the development of lung fibrosis both in humans and in mice., Methods: B-cells in blood, mediastinal lymph node, and lung single-cell suspensions of IPF patients and healthy controls (HC) were characterized using 14-color flow cytometry. Mice were exposed to bleomycin to provoke pulmonary fibrosis., Results: More IgA
+ memory B-cells and plasmablasts were found in blood (n = 27) and lungs (n = 11) of IPF patients compared to HC (n = 21) and control lungs (n = 9). IPF patients had higher levels of autoreactive IgA in plasma, which correlated with an enhanced decline of forced vital capacity (p = 0.002, r = - 0.50). Bruton's tyrosine kinase expression was higher in circulating IPF B-cells compared to HC, indicating enhanced B-cell activation. Bleomycin-exposed mice had increased pulmonary IgA+ germinal center and plasma cell proportions compared to control mice. The degree of lung fibrosis correlated with pulmonary germinal center B-cell proportions (p = 0.010, r = 0.88)., Conclusion: Our study demonstrates that IPF patients have more circulating activated B-cells and autoreactive IgA, which correlate with disease progression. These B-cell alterations were also observed in the widely used mouse model of experimental pulmonary fibrosis. Autoreactive IgA could be useful as a biomarker for disease progression in IPF.- Published
- 2019
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39. Long-term treatment with recombinant human pentraxin 2 protein in patients with idiopathic pulmonary fibrosis: an open-label extension study.
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Raghu G, van den Blink B, Hamblin MJ, Brown AW, Golden JA, Ho LA, Wijsenbeek MS, Vasakova M, Pesci A, Antin-Ozerkis DE, Meyer KC, Kreuter M, Moran D, Santin-Janin H, Aubin F, Mulder GJ, Gupta R, and Richeldi L
- Subjects
- Aged, Cross-Over Studies, Double-Blind Method, Female, Humans, Long-Term Care, Male, Recombinant Proteins therapeutic use, Treatment Outcome, Vital Capacity, Homeodomain Proteins therapeutic use, Idiopathic Pulmonary Fibrosis drug therapy, Serum Amyloid P-Component therapeutic use
- Abstract
Background: Patients with idiopathic pulmonary fibrosis (IPF) treated with PRM-151, a recombinant human pentraxin 2 protein, in a phase 2 double-blind, randomised controlled trial had significantly reduced decline in percentage of predicted forced vital capacity (FVC) and stabilised 6-min walking distance compared with placebo over a 28-week period. Here we report the 76-week results of an open-label extension study., Methods: Patients who completed the 28-week double-blind period of the PRM-151-202 trial were eligible to participate in the open-label extension study. Patients previously enrolled in the PRM-151 group continued this treatment and those previously in the placebo group crossed over to PRM-151. All patients received PRM-151 in 28-week cycles with loading doses of 10 mg/kg by 60 min intravenous infusions on days 1, 3, and 5 in the first week of each cycle followed by one infusion of 10 mg/kg every 4 weeks. The primary objective of the open-label extension study was to assess the long-term safety and tolerability of PRM-151, which were assessed by analysing adverse events (AEs) up to week 76 in all patients who received at least one dose of PRM-151 during the open-label extension study. Exploratory efficacy analyses were done by assessing changes from baseline in percentage of predicted FVC and 6-min walking distance, with descriptive statistics to week 76 and with random-intercept mixed models to week 52. This study is registered with ClinicalTrials.gov, number NCT02550873, and with EudraCT, number 2014-004782-24., Findings: Of 116 patients who completed the double-blind treatment period, 111 entered the open-label extension study (74 from the PRM-151 group and 37 from the placebo group). 84 (76%) of 111 patients received concomitant IPF therapy (pirfenidone n=55 or nintedanib n=29). AEs were consistent with long-term IPF sequelae. 31 (28%) patients had serious AEs. Those occurring in two or more patients were pneumonia (six [5%] of 111), IPF exacerbation (four [4%]), IPF progression (four [4%]), and chest pain (two [2%]). 21 (19%) patients had severe AEs, of which IPF exacerbation and IPF progression each occurred in two (2%) patients. Two (2%) patients experienced life-threatening AEs (one had pneumonia and one had small-cell lung cancer extensive stage). A persistent treatment effect was observed for PRM-151 in patients who continued treatment, with a decline in percentage of predicted FVC of -3·6% per year and in 6-min walking distance of -10·5 m per year at week 52. In patients who started PRM-151 during the open-label extension study, compared with the slopes for placebo, decline reduced for percentage of predicted FVC (from -8·7% per year in weeks 0-28 to -0·9% per year in weeks 28-52, p<0·0001) and 6-min walking distance (from -54·9 m per year to -3·5 m per year, p=0·0224)., Interpretation: Long-term treatment with PRM-151 was well tolerated and the effects on percentage of predicted FVC and 6-min walking distance were persistent on continuation and positive in patients who crossed over from placebo. These findings support further study of PRM-151 in larger populations of patients with IPF., Funding: Promedior., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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40. Effect of Recombinant Human Pentraxin 2 vs Placebo on Change in Forced Vital Capacity in Patients With Idiopathic Pulmonary Fibrosis: A Randomized Clinical Trial.
- Author
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Raghu G, van den Blink B, Hamblin MJ, Brown AW, Golden JA, Ho LA, Wijsenbeek MS, Vasakova M, Pesci A, Antin-Ozerkis DE, Meyer KC, Kreuter M, Santin-Janin H, Mulder GJ, Bartholmai B, Gupta R, and Richeldi L
- Subjects
- Aged, Double-Blind Method, Female, Homeodomain Proteins adverse effects, Homeodomain Proteins pharmacology, Humans, Idiopathic Pulmonary Fibrosis physiopathology, Least-Squares Analysis, Male, Middle Aged, Recombinant Proteins adverse effects, Recombinant Proteins pharmacology, Recombinant Proteins therapeutic use, Serum Amyloid P-Component adverse effects, Serum Amyloid P-Component pharmacology, Walk Test, Homeodomain Proteins therapeutic use, Idiopathic Pulmonary Fibrosis drug therapy, Serum Amyloid P-Component therapeutic use, Vital Capacity drug effects
- Abstract
Importance: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression., Objective: To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value., Design, Setting, and Participants: Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC ≥50% and ≤90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [Dlco] ≥25% and ≤90% predicted; and distance of ≥150 m on the 6-minute walk test). Study period was August 2015-May 2017., Interventions: Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status., Main Outcomes and Measures: The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m)., Results: Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2% [90% CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1% [90% CI, -2.2 to 4.3]), or measurement of Dlco (difference, -0.4 [90% CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5 m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, +31.3 m [90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%)., Conclusions and Relevance: In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety., Trial Registration: clinicaltrials.gov Identifier: NCT02550873.
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- 2018
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41. No evidence found for an association between prednisone dose and FVC change in newly-treated pulmonary sarcoidosis.
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Broos CE, Poell LHC, Looman CWN, In 't Veen JCCM, Grootenboers MJJH, Heller R, van den Toorn LM, Wapenaar M, Hoogsteden HC, Kool M, Wijsenbeek MS, and van den Blink B
- Subjects
- Adult, Dose-Response Relationship, Drug, Female, Humans, Linear Models, Male, Middle Aged, Pulmonary Diffusing Capacity, Retrospective Studies, Sarcoidosis, Pulmonary physiopathology, Vital Capacity, Weight Gain, Glucocorticoids administration & dosage, Prednisone administration & dosage, Sarcoidosis, Pulmonary drug therapy
- Abstract
Background: Prednisone is used as first-line therapy for pulmonary sarcoidosis. What dosing strategy has the best balance between effect and side-effects is largely unknown. We analyzed change in forced vital capacity (FVC) and weight during different prednisone doses used in daily practice for treatment naïve pulmonary sarcoidosis patients., Methods: Multilevel models were used to describe FVC and weight change over time. Correlations were calculated using linear regression models., Results: Fifty-four patients were included. FVC changed over time (p < 0.001), with an average increase of 9.6% predicted (95% CI: 7.2 to 12.1) at 12 months. Weight changed significantly over time (p < 0.001), with an average increase of 4.3 kg (95% CI: 3.0 to 5.6) at 12 months. Although FVC and weight changed significantly over time, there was little correlation between prednisone dose and FVC change, while weight increase correlated significantly with cumulative prednisone dose at 24 months. In patients treated with a high cumulative prednisone dose, baseline FVC was on average lower (p = 0.001) compared to low dose treated patients, while no significant differences were observed in need for second/third-line therapy or number of exacerbations. A strategy leading to a low cumulative dose at 12 months was defined by rapid dose tapering to 10 mg/day within 3.5 months., Conclusions: These results suggest that prednisone therapy aimed at improving or preserving FVC in newly- treated pulmonary sarcoidosis can often be reduced in dose, using a treatment regimen that is characterized by early dose tapering., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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42. Increased T-helper 17.1 cells in sarcoidosis mediastinal lymph nodes.
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Broos CE, Koth LL, van Nimwegen M, In 't Veen JCCM, Paulissen SMJ, van Hamburg JP, Annema JT, Heller-Baan R, Kleinjan A, Hoogsteden HC, Wijsenbeek MS, Hendriks RW, van den Blink B, and Kool M
- Subjects
- Adolescent, Adult, Aged, Biopsy, Fine-Needle, Bronchoalveolar Lavage Fluid, Case-Control Studies, Female, Flow Cytometry, Humans, Leukocytes, Mononuclear metabolism, Male, Middle Aged, Phenotype, Young Adult, Lung metabolism, Lymph Nodes pathology, Mediastinum pathology, Sarcoidosis, Pulmonary metabolism, Th17 Cells cytology
- Abstract
The lung-draining mediastinal lymph nodes (MLNs) are currently widely used to diagnose sarcoidosis. We previously reported that T-helper (Th) 17.1 cells are responsible for the exaggerated interferon-γ production in sarcoidosis lungs. In this study, we aimed to investigate 1) whether Th17.1 cells are also increased in the MLNs of sarcoidosis patients and 2) whether frequencies of the Th17.1 cells at diagnosis may correlate with disease progression.MLN cells from treatment-naive pulmonary sarcoidosis patients (n=17) and healthy controls (n=22) and peripheral blood mononuclear cells (n=34) and bronchoalveolar lavage fluid (BALF) (n=36) from sarcoidosis patients were examined for CD4
+ T-cell subset proportions using flow cytometry.Higher proportions of Th17.1 cells were detected in sarcoidosis MLNs than in control MLNs. Higher Th17.1 cell proportions were found in sarcoidosis BALF compared with MLNs and peripheral blood. Furthermore, BALF Th17.1 cell proportions were significantly higher in patients developing chronic disease than in patients undergoing resolution within 2 years of clinical follow-up.These data suggest that Th17.1 cell proportions in pulmonary sarcoidosis can be evaluated as a diagnostic and/or prognostic marker in clinical practice and could serve as a new therapeutic target., Competing Interests: Conflict of interest: C.E. Broos, R.W. Hendriks, M. Kool have a patent P117584NL00 (Th17.1 cells as biomarker for sarcoidosis disease prognosis) pending to C.E. Broos, R.W. Hendriks, M. Kool and J.R. Miedema., (Copyright ©ERS 2018.)- Published
- 2018
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43. Daily home spirometry to detect early steroid treatment effects in newly treated pulmonary sarcoidosis.
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Broos CE, Wapenaar M, Looman CWN, In 't Veen JCCM, van den Toorn LM, Overbeek MJ, Grootenboers MJJH, Heller R, Mostard RL, Poell LHC, Hoogsteden HC, Kool M, Wijsenbeek MS, and van den Blink B
- Subjects
- Adult, Female, Home Care Services, Humans, Male, Middle Aged, Monitoring, Ambulatory, Prospective Studies, Quality of Life, Respiratory Function Tests, Sarcoidosis, Pulmonary psychology, Vital Capacity, Prednisone therapeutic use, Sarcoidosis, Pulmonary therapy, Spirometry methods, Steroids therapeutic use
- Abstract
Competing Interests: Conflict of interest: None declared.
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- 2018
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44. What patients with pulmonary fibrosis and their partners think: a live, educative survey in the Netherlands and Germany.
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van Manen MJ, Kreuter M, van den Blink B, Oltmanns U, Palmowski K, Brunnemer E, Hummler S, Tak NC, van den Toorn L, Miedema J, Hoogsteden HC, and Wijsenbeek MS
- Abstract
Pulmonary fibrosis greatly impacts patients and their partners. Unmet needs of patients are increasingly acknowledged; the needs of partners often remain unnoticed. Little is known about the best way to educate patients and partners. We investigated pulmonary fibrosis patients' and partners' perspectives and preferences in care, and the differences in these between the Netherlands and Germany. Additionally, we evaluated whether interactive interviewing could be a novel education method in this population. Patients and partners were interviewed during pulmonary fibrosis patient information meetings. In the Netherlands, voting boxes were used and results were projected directly. In Germany, questionnaires were used. In the Netherlands, 278 patients and partners participated; in Germany, 51. Many participants experienced anxiety. Almost all experienced misunderstanding, because people do not know what pulmonary fibrosis is. All expressed a need for information, psychological support and care for partners. Use of the interactive voting system was found to be pleasant (70%) and informative (94%). This study improves the knowledge of care needs of patients with pulmonary fibrosis and their partners. There were no major differences between the Netherlands and Germany. Interactive interviewing could be an attractive method to acquire insights into the needs and preferences of patients and partners, while providing them with information at the same time., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at openres.ersjournals.com
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- 2017
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45. IFN-γ-Producing T-Helper 17.1 Cells Are Increased in Sarcoidosis and Are More Prevalent than T-Helper Type 1 Cells.
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Ramstein J, Broos CE, Simpson LJ, Ansel KM, Sun SA, Ho ME, Woodruff PG, Bhakta NR, Christian L, Nguyen CP, Antalek BJ, Benn BS, Hendriks RW, van den Blink B, Kool M, and Koth LL
- Subjects
- Adult, Aged, Bronchoalveolar Lavage Fluid immunology, Female, Flow Cytometry, Humans, Interferon-gamma metabolism, Male, Middle Aged, Th1 Cells metabolism, Th17 Cells metabolism, Interferon-gamma immunology, Sarcoidosis, Pulmonary immunology, Th1 Cells immunology, Th17 Cells immunology
- Abstract
Rationale: Pulmonary sarcoidosis is classically defined by T-helper (Th) cell type 1 inflammation (e.g., IFN-γ production by CD4(+) effector T cells). Recently, IL-17A-secreting cells have been found in lung lavage, invoking Th17 immunity in sarcoidosis. Studies also identified IL-17A-secreting cells that expressed IFN-γ, but their abundance as a percentage of total CD4(+) cells was either low or undetermined., Objectives: Based on evidence that Th17 cells can be polarized to Th17.1 cells to produce only IFN-γ, our goal was to determine whether Th17.1 cells are a prominent source of IFN-γ in sarcoidosis., Methods: We developed a single-cell approach to define and isolate major Th-cell subsets using combinations of chemokine receptors and fluorescence-activated cell sorting. We subsequently confirmed the accuracy of subset enrichment by measuring cytokine production., Measurements and Main Results: Discrimination between Th17 and Th17.1 cells revealed very high percentages of Th17.1 cells in lung lavage in sarcoidosis compared with controls in two separate cohorts. No differences in Th17 or Th1 lavage cells were found compared with controls. Lung lavage Th17.1-cell percentages were also higher than Th1-cell percentages, and approximately 60% of Th17.1-enriched cells produced only IFN-γ., Conclusions: Combined use of surface markers and functional assays to study CD4(+) T cells in sarcoidosis revealed a marked expansion of Th17.1 cells that only produce IFN-γ. These results suggest that Th17.1 cells could be misclassified as Th1 cells and may be the predominant producer of IFN-γ in pulmonary sarcoidosis, challenging the Th1 paradigm of pathogenesis.
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- 2016
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46. Validation of the King's Sarcoidosis Questionnaire (KSQ) in a Dutch sarcoidosis population.
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Van Manen MJ, Wapenaar M, Strookappe B, Drent M, Elfferich M, de Vries J, Gosker HR, Birring SS, Patel AS, van den Toorn L, van den Blink B, Boomars K, Hoitsma E, and Wijsenbeek MS
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- Female, Humans, Male, Middle Aged, Netherlands, Translations, Sarcoidosis diagnosis, Self Report
- Abstract
Background: The King's Sarcoidosis Questionnaire (KSQ) is a brief questionnaire assessing health status using five modules (General Health Status, Lung, Eyes, Skin, Medication) in patients with sarcoidosis. The KSQ was only validated in one English sarcoidosis cohort., Objective: The aim of this study was to validate the KSQ in a Dutch sarcoidosis population., Methods: The KSQ was translated according to international guidelines and tested in interviews with patients. Consecutive outpatients completed multiple questionnaires twice, two weeks apart. Construct validity, internal consistency and repeatability were determined., Results: Of the 98 patients included 85 had lung, 22 skin and 24 eye disease. There was good construct validity of the KSQ General Health Status module against the World Health Organization Quality of Life-BREF questionnaire. The Medication module correlated weak to moderate with most questionnaires. The correlations with organ-specific questionnaires varied from strong for Eyes (r=0.75), Skin (r=-0.62) to moderate for Lung (r=-0.45 with MRC breathlessness scale). Internal consistency was good for all KSQ modules (Cronbach's α 0.72-0.93). Intraclass correlation coefficients (0.70-0.90) and Bland-Altman plots showed good repeatability of the KSQ., Conclusion: The Dutch KSQ is the first translation of the English KSQ, validated in a Dutch sarcoidosis population.
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- 2016
47. Recombinant human pentraxin-2 therapy in patients with idiopathic pulmonary fibrosis: safety, pharmacokinetics and exploratory efficacy.
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van den Blink B, Dillingh MR, Ginns LC, Morrison LD, Moerland M, Wijsenbeek M, Trehu EG, Bartholmai BJ, and Burggraaf J
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- Adult, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, Double-Blind Method, Exercise Test, Female, Homeodomain Proteins adverse effects, Humans, Male, Middle Aged, Netherlands, Recombinant Proteins adverse effects, Recombinant Proteins pharmacokinetics, Respiratory Function Tests, Serum Amyloid P-Component adverse effects, Treatment Outcome, United States, Homeodomain Proteins pharmacokinetics, Idiopathic Pulmonary Fibrosis drug therapy, Lung physiopathology, Serum Amyloid P-Component pharmacokinetics
- Abstract
Abnormal fibrogenic repair response upon alveolar injury is believed to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). PRM-151 (recombinant human pentraxin-2, also known as serum amyloid P), has been shown to reduce fibrosis in preclinical lung fibrosis models, and was well tolerated with a favourable pharmacokinetic profile in an earlier single-dose phase I study.A randomised, double-blind, placebo-controlled, multiple ascending dose trial was performed to assess the tolerability and pharmacokinetic and pharmacodynamic characteristics of multiple doses of PRM-151 in IPF patients. Subjects in three successive cohorts (1, 5, or 10 mg·kg(-1) versus placebo) received intravenous study drug on days 1, 3, 5, 8 and 15, and were followed-up to day 57.PRM-151 was well tolerated at all dose levels, with no serious adverse reactions. Administration of PRM-151 resulted in two- to eight-fold dose-dependent increases in circulating pentraxin-2 levels. Forced vital capacity and 6-min walk test showed trends towards improvement in the combined PRM-151 dose groups. On high-resolution computed tomography scans, stable or improved lung volume unoccupied by interstitial lung abnormality was noted in some PRM-151 subjects compared to placebo subjects on day 57.The efficacy of PRM-151 in IPF remains to be investigated in dedicated future trials., (Copyright ©ERS 2016.)
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- 2016
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48. Ten-Year Survival in Patients with Idiopathic Pulmonary Fibrosis After Lung Transplantation.
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ten Klooster L, Nossent GD, Kwakkel-van Erp JM, van Kessel DA, Oudijk EJ, van de Graaf EA, Luijk B, Hoek RA, van den Blink B, van Hal PT, Verschuuren EA, van der Bij W, van Moorsel CH, and Grutters JC
- Subjects
- Cohort Studies, Exercise Test, Female, Humans, Hypertension, Pulmonary epidemiology, Idiopathic Pulmonary Fibrosis epidemiology, Idiopathic Pulmonary Fibrosis mortality, Male, Middle Aged, Netherlands epidemiology, Oxygen Inhalation Therapy statistics & numerical data, Pulmonary Wedge Pressure, Retrospective Studies, Survival Rate, Waiting Lists mortality, Idiopathic Pulmonary Fibrosis surgery, Lung Transplantation
- Abstract
Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal fibrosing lung disease with a median survival of approximately 3 years after diagnosis. The only medical option to improve survival in IPF is lung transplantation (LTX). The purpose of this study was to evaluate trajectory data of IPF patients listed for LTX and to investigate the survival after LTX., Methods and Results: Data were retrospectively collected from September 1989 until July 2011 of all IPF patients registered for LTX in the Netherlands. Patients were included after revision of the diagnosis based on the criteria set by the ATS/ERS/JRS/ALAT. Trajectory data, clinical data at time of screening, and donor data were collected. In total, 98 IPF patients were listed for LTX. During the waiting list period, 30 % of the patients died. Mean pulmonary artery pressure, 6-min walking distance, and the use of supplemental oxygen were significant predictors of mortality on the waiting list. Fifty-two patients received LTX with a median overall survival after transplantation of 10 years., Conclusions: This study demonstrated a 10-year survival time after LTX in IPF. Furthermore, our study demonstrated a significantly better survival after bilateral LTX in IPF compared to single LTX although bilateral LTX patients were significantly younger.
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- 2015
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49. Impaired survival of regulatory T cells in pulmonary sarcoidosis.
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Broos CE, van Nimwegen M, Kleinjan A, ten Berge B, Muskens F, in 't Veen JC, Annema JT, Lambrecht BN, Hoogsteden HC, Hendriks RW, Kool M, and van den Blink B
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- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers metabolism, Bronchoalveolar Lavage Fluid cytology, Bronchoalveolar Lavage Fluid immunology, CTLA-4 Antigen metabolism, Case-Control Studies, Cell Survival, Cells, Cultured, Coculture Techniques, Fas Ligand Protein metabolism, Female, Flow Cytometry, Forkhead Transcription Factors metabolism, Humans, Immunophenotyping methods, Interleukin-2 Receptor alpha Subunit metabolism, Male, Middle Aged, Phenotype, Sarcoidosis, Pulmonary immunology, Sarcoidosis, Pulmonary metabolism, Signal Transduction, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Time Factors, Young Adult, Apoptosis, Sarcoidosis, Pulmonary pathology, T-Lymphocytes, Regulatory pathology
- Abstract
Background: Impaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear. Moreover, it is not known if increased apoptotic susceptibility of Tregs may contribute to an impaired immunosuppressive function in sarcoidosis. Therefore, the aim of this study is to analyze proportions, phenotype, survival, and apoptotic susceptibility of Tregs in sarcoidosis., Methods: Patients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis. Tregs were analyzed in broncho-alveolar lavage fluid and peripheral blood of patients and healthy controls (HC)., Results: In sarcoidosis patients no evidence was found for a relative deficit of Tregs, neither locally nor systemically. Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease. Sarcoidosis circulating Tregs displayed adequate expression of FoxP3, CD25 and CTLA4. Remarkably, in sarcoidosis enhanced CD95 expression on circulating activated CD45RO(+) Tregs was observed compared with HC, and proportions of these cells were significantly increased. Specifically sarcoidosis Tregs--but not Th cells--showed impaired survival compared with HC. Finally, CD95L-mediated apoptosis was enhanced in sarcoidosis Tregs., Conclusion: In untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L. Increased apoptosis likely contributes to the insufficient immunosuppressive function of sarcoidosis Tregs. Further research into this field will help determine whether improvement of Treg survival holds a promising new therapeutic approach for chronic sarcoidosis patients.
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- 2015
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50. Decreased Cytotoxic T-Lymphocyte Antigen 4 Expression on Regulatory T Cells and Th17 Cells in Sarcoidosis: Double Trouble?
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Broos CE, van Nimwegen M, In 't Veen JC, Hoogsteden HC, Hendriks RW, van den Blink B, and Kool M
- Subjects
- Biomarkers metabolism, Case-Control Studies, Humans, T-Lymphocytes, Regulatory metabolism, Th17 Cells metabolism, CTLA-4 Antigen metabolism, Sarcoidosis immunology, T-Lymphocytes, Regulatory immunology, Th17 Cells immunology
- Published
- 2015
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- View/download PDF
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