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1. Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases: an International Organization for Study of Inflammatory Bowel Diseases consensus

Author

Abreu, M, Ahuja, V, Allez, M, Ananthakrishnan, A, Bemelman, W, Bernstein, C, Braun, J, Chowers, Y, Colombel, J-F, Danese, S, D'Haens, G, D'Hoore, A, Dignass, A, Dotan, I, Dubinsky, M, Ekbom, A, Fleshner, P, Gasche, C, Gassull, MA, Gearry, R, Ghosh, S, Gibson, P, Griffiths, A, Halfvarson, J, Hanauer, S, Harpaz, N, Hart, A, Hibi, T, Kamm, M, Kaplan, G, Kaser, A, Korelitz, B, Kotze, P, Koutroubakis, I, Kruis, W, Lakatos, P, Lewis, J, Lindsay, J, Loftus, E, Louis, E, Lukas, M, Magro, F, Mahadevan, U, Mantzaris, G, Mary, J-Y, McGovern, D, Moum, B, Munkholm, P, Neurath, M, Ng, S, O'Morain, C, Oresland, T, Panaccione, R, Panes, J, Panis, Y, Pemberton, J, Peyrin-Biroulet, L, Prantera, C, Rachmilewitz, D, Ran, Z, Reinisch, W, Remzi, F, Rhodes, J, Riddell, R, Rogler, G, Rubin, D, Sachar, D, Sandborn, W, Sands, B, Sartor, B, Schoelmerich, J, Schreiber, S, Siegel, C, Siegmund, B, Silverberg, M, Söderholm, J, Sood, A, Spinelli, A, Stange, E, Steinwurz, F, Targan, S, Travis, S, Turner, D, Tysk, C, Vatn, M, Vermeire, S, Watanabe, M, Yamamoto, T, Yamamoto-Furusho, J, Ananthakrishnan, Ashwin N, Kaplan, Gilaad G, Bernstein, Charles N, Burke, Kristin E, Lochhead, Paul J, Sasson, Alexa N, Agrawal, Manasi, Tiong, Jimmy Ho Tuan, Steinberg, Joshua, Kruis, Wolfgang, Steinwurz, Flavio, Ahuja, Vineet, Ng, Siew C, Rubin, David T, Colombel, Jean-Frederic, and Gearry, Richard

Published
2022
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2. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.

Author

Rivas, Manuel, Graham, Daniel, Sulem, Patrick, Stevens, Christine, Desch, A, Goyette, Philippe, Gudbjartsson, Daniel, Jonsdottir, Ingileif, Thorsteinsdottir, Unnur, Degenhardt, Frauke, Mucha, Sören, Kurki, Mitja, Li, Dalin, DAmato, Mauro, Annese, Vito, Vermeire, Severine, Weersma, Rinse, Halfvarson, Jonas, Paavola-Sakki, Paulina, Lappalainen, Maarit, Lek, Monkol, Cummings, Beryl, Tukiainen, Taru, Haritunians, Talin, Halme, Leena, Koskinen, Lotta, Ananthakrishnan, Ashwin, Luo, Yang, Heap, Graham, Visschedijk, Marijn, MacArthur, Daniel, Neale, Benjamin, Ahmad, Tariq, Anderson, Carl, Brant, Steven, Duerr, Richard, Silverberg, Mark, Cho, Judy, Palotie, Aarno, Saavalainen, Päivi, Kontula, Kimmo, Färkkilä, Martti, McGovern, Dermot, Franke, Andre, Stefansson, Kari, Rioux, John, Xavier, Ramnik, Daly, Mark, Barrett, J, de Lane, K, Edwards, C, Hart, A, Hawkey, C, Jostins, L, Kennedy, N, Lamb, C, Lee, J, Lees, C, Mansfield, J, Mathew, C, Mowatt, C, Newman, B, Nimmo, E, Parkes, M, Pollard, M, Prescott, N, Randall, J, Rice, D, Satsangi, J, Simmons, A, Tremelling, M, Uhlig, H, Wilson, D, Abraham, C, Achkar, J, Bitton, A, Boucher, G, Croitoru, K, Fleshner, P, Glas, J, Kugathasan, S, Limbergen, J, Milgrom, R, Proctor, D, Regueiro, M, Schumm, P, Sharma, Y, Stempak, J, Targan, S, and Wang, M

Subjects
Alleles, Colitis, Ulcerative, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Mutation, Protein Transport, RNA, Messenger, Reproducibility of Results, Sequence Analysis, DNA, Ubiquitin-Protein Ligases
Abstract

Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.

Published
2016

4. OP40 PRA023 Demonstrated Efficacy and Favorable Safety as Induction Therapy for Moderately to Severely Active UC: Phase 2 ARTEMIS-UC Study Results

Author

Sands, B, primary, Peyrin-Biroulet, L, additional, Danese, S, additional, Rubin, D T, additional, Vermeire, S, additional, Laurent, O, additional, Luo, A, additional, Nguyen, D, additional, Lu, J D, additional, Wiechowska-Kozlowska, A, additional, Leszczyszyn, J, additional, Kempinski, R, additional, Kierkus, J, additional, Ma, C, additional, Ritter, T, additional, Feagan, B G, additional, and Targan, S, additional

Published
2023
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5. Author Correction: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease (Nature Communications, (2020), 11, 1, (995), 10.1038/s41467-019-14275-y)

Author

Serra E. G., Schwerd T., Moutsianas L., Cavounidis A., Fachal L., Pandey S., Kammermeier J., Croft N. M., Posovszky C., Rodrigues A., Russell R. K., Barakat F., Auth M. K. H., Heuschkel R., Zilbauer M., Fyderek K., Braegger C., Travis S. P., Satsangi J., Parkes M., Thapar N., Ferry H., Matte J. C., Gilmour K. C., Wedrychowicz A., Sullivan P., Moore C., Sambrook J., Ouwehand W., Roberts D., Danesh J., Baeumler T. A., Fulga T. A., Carrami E. M., Ahmed A., Wilson R., Barrett J. C., Elkadri A., Griffiths A. M., Zurek M., Strisciuglio C., Elawad M., Lo B., Arancibia-Carcamo C., Bailey A., Barnes E., Bird-Lieberman E. L., Brain O., Braden B., Collier J., East J., Howarth L., Keshav S., Klenerman P., Leedham S., Palmer R., Powrie F., Simmons A., Walker M., Tolkien Z., Kaptoge S., Allen D., Mehenny S., Mant J., Di Angelantonio E., Thompson S. G., Yilmaz B., Juillerat P., Geuking M., Wiest R., Macpherson A. J., Bravo F. D., Brugger L., Carstens O., Bigler U. G., Heimgartner B., Rusticeanu M., Schmid-Uebelhart S., Strebel B., Tatu A., Tutuian R., Oyas O., Ramon C., Stelling J., Franc Y., Fournier N., Pittet V. E. H., Burnand B., Egger M., Golay D., Marot A., Musso L., Rossel J. -B., Seematter V., Sommer J., Vulliamy R., Michetti P., Maillard M. H., Keller C., Nydegger A., Schoepfe A., Archanioti E., Ezri J., Fraga M., Schoepfer A., Muller C., Rogler G., Biedermann L., Blattmann M., Burk S., Dora B., Fried M., Misselwitz B., Mullhaupt B., Obialo N., Pohl D., Raschle N., Scharl M., Vavricka S., Von Kanel R., Zeitz J., Abdelrahman K., Ademi G., Borovicka J., Brand S., Frei R., Haarer J., Knellwolf-Grieger C., Krieger-Grubel C., Kunzler P., Meyenberger C., Meyer P., Rohrich N., Sawatzki M., Schelling M., Semadeni G. -M., Sulz M., Zimmermann D., Aepli P., Criblez D. H., Hess C., Richterich J. -P., Spalinger J., Staudenmann D., Stulz A., Wohrle S., Thomas A., Anderegg C., Kohler H., Kusche R., Antonino A. -T., Arrigoni E., Bengoa J. M., Cunningham S., de Saussure P., Girard L., de Jong D. B., Basturk P., Brunner S., Degen L., Hruz P., Bakker C. K. -D., Niess J., Balsiger B., Haldemann J., Saner G., Seibold F., Bauerfeind P., Becocci A., Belli D., Binek J., Hengstler P., Boehm S., Boldanov T., Buhr P., Koller R., Rueger V., Senning A., Burri E., Buyse S., Cao D. -T., D'Angelo F., Delarive J., Doerig C., Hessler R., Preissler C., Rentsch R., Risti B., Ritz M. A., Steuerwald M., Vogtlin J., Sagmeister M., Sauter B., Schibli S., Sokollik C., Schlauri H., Schnegg J. -F., Seirafi M., Spangenberger H., Stadler P., Staub P., Stenz V., Tempia-Caliera M., Thorens J., Truninger K., Urfer P., Viani F., Vouillamoz D., Zander S., Wyli T., Jostins L., Kennedy N. A., Ahmad T., Lamb C. A., Edwards C., Hart A., Hawkey C., Mansfield J. C., Mowat C., Newman W. G., Tremelling M., Lee J. C., Prescott N. J., Mathew C. G., Lees C. W., McGovern D. P. B., Targan S. R., Botwin G., Mengesha E., Fleshner P., Landers C., Li D., Rioux J. D., Bitton A., Cote-Daigneault J., Daly M. J., Xavier R., Morris K., Boucher G., Cho J. H., Abraham C., Merad M., Sands B., Peter I., Hao K., Itan Y., Duerr R. H., Konnikova L., Schwartz M. B., Proksell S., Johnston E., Miladinova V., Chen W., Brant S. R., Datta L., Silverberg M. S., Schumm L. P., Birch S., Giri M., Gettler K., Sharma Y., Stevens C., Lazarev M., Haritunians T., Snapper S. B., Shah N., Muise A. M., Wilson D. C., Uhlig H. H., Anderson C. A., Serra, E. G., Schwerd, T., Moutsianas, L., Cavounidis, A., Fachal, L., Pandey, S., Kammermeier, J., Croft, N. M., Posovszky, C., Rodrigues, A., Russell, R. K., Barakat, F., Auth, M. K. H., Heuschkel, R., Zilbauer, M., Fyderek, K., Braegger, C., Travis, S. P., Satsangi, J., Parkes, M., Thapar, N., Ferry, H., Matte, J. C., Gilmour, K. C., Wedrychowicz, A., Sullivan, P., Moore, C., Sambrook, J., Ouwehand, W., Roberts, D., Danesh, J., Baeumler, T. A., Fulga, T. A., Carrami, E. M., Ahmed, A., Wilson, R., Barrett, J. C., Elkadri, A., Griffiths, A. M., Zurek, M., Strisciuglio, C., Elawad, M., Lo, B., Arancibia-Carcamo, C., Bailey, A., Barnes, E., Bird-Lieberman, E. L., Brain, O., Braden, B., Collier, J., East, J., Howarth, L., Keshav, S., Klenerman, P., Leedham, S., Palmer, R., Powrie, F., Simmons, A., Walker, M., Tolkien, Z., Kaptoge, S., Allen, D., Mehenny, S., Mant, J., Di Angelantonio, E., Thompson, S. G., Yilmaz, B., Juillerat, P., Geuking, M., Wiest, R., Macpherson, A. J., Bravo, F. D., Brugger, L., Carstens, O., Bigler, U. G., Heimgartner, B., Rusticeanu, M., Schmid-Uebelhart, S., Strebel, B., Tatu, A., Tutuian, R., Oyas, O., Ramon, C., Stelling, J., Franc, Y., Fournier, N., Pittet, V. E. H., Burnand, B., Egger, M., Golay, D., Marot, A., Musso, L., Rossel, J. -B., Seematter, V., Sommer, J., Vulliamy, R., Michetti, P., Maillard, M. H., Keller, C., Nydegger, A., Schoepfe, A., Archanioti, E., Ezri, J., Fraga, M., Schoepfer, A., Muller, C., Rogler, G., Biedermann, L., Blattmann, M., Burk, S., Dora, B., Fried, M., Misselwitz, B., Mullhaupt, B., Obialo, N., Pohl, D., Raschle, N., Scharl, M., Vavricka, S., Von Kanel, R., Zeitz, J., Abdelrahman, K., Ademi, G., Borovicka, J., Brand, S., Frei, R., Haarer, J., Knellwolf-Grieger, C., Krieger-Grubel, C., Kunzler, P., Meyenberger, C., Meyer, P., Rohrich, N., Sawatzki, M., Schelling, M., Semadeni, G. -M., Sulz, M., Zimmermann, D., Aepli, P., Criblez, D. H., Hess, C., Richterich, J. -P., Spalinger, J., Staudenmann, D., Stulz, A., Wohrle, S., Thomas, A., Anderegg, C., Kohler, H., Kusche, R., Antonino, A. -T., Arrigoni, E., Bengoa, J. M., Cunningham, S., de Saussure, P., Girard, L., de Jong, D. B., Basturk, P., Brunner, S., Degen, L., Hruz, P., Bakker, C. K. -D., Niess, J., Balsiger, B., Haldemann, J., Saner, G., Seibold, F., Bauerfeind, P., Becocci, A., Belli, D., Binek, J., Hengstler, P., Boehm, S., Boldanov, T., Buhr, P., Koller, R., Rueger, V., Senning, A., Burri, E., Buyse, S., Cao, D. -T., D'Angelo, F., Delarive, J., Doerig, C., Hessler, R., Preissler, C., Rentsch, R., Risti, B., Ritz, M. A., Steuerwald, M., Vogtlin, J., Sagmeister, M., Sauter, B., Schibli, S., Sokollik, C., Schlauri, H., Schnegg, J. -F., Seirafi, M., Spangenberger, H., Stadler, P., Staub, P., Stenz, V., Tempia-Caliera, M., Thorens, J., Truninger, K., Urfer, P., Viani, F., Vouillamoz, D., Zander, S., Wyli, T., Jostins, L., Kennedy, N. A., Ahmad, T., Lamb, C. A., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Tremelling, M., Lee, J. C., Prescott, N. J., Mathew, C. G., Lees, C. W., Mcgovern, D. P. B., Targan, S. R., Botwin, G., Mengesha, E., Fleshner, P., Landers, C., Li, D., Rioux, J. D., Bitton, A., Cote-Daigneault, J., Daly, M. J., Xavier, R., Morris, K., Boucher, G., Cho, J. H., Abraham, C., Merad, M., Sands, B., Peter, I., Hao, K., Itan, Y., Duerr, R. H., Konnikova, L., Schwartz, M. B., Proksell, S., Johnston, E., Miladinova, V., Chen, W., Brant, S. R., Datta, L., Silverberg, M. S., Schumm, L. P., Birch, S., Giri, M., Gettler, K., Sharma, Y., Stevens, C., Lazarev, M., Haritunians, T., Snapper, S. B., Shah, N., Muise, A. M., Wilson, D. C., Uhlig, H. H., and Anderson, C. A.

Published
2022

6. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

Author

Sazonovs, A., Stevens, C.R., Venkataraman, G.R., Yuan, K., Avila, B., Abreu, M.T., Ahmad, T., Allez, M., Ananthakrishnan, A.N., Atzmon, G., Baras, A., Barrett, J.C., Barzilai, N., Beaugerie, L., Beecham, A., Bernstein, C.N., Bitton, A., Bokemeyer, B., Chan, A., Chung, D., Cleynen, I., Cosnes, J., Cutler, D.J., Daly, A., Damas, O.M., Datta, L.W., Dawany, N., Devoto, M., Dodge, S., Ellinghaus, E., Fachal, L., Farkkila, M., Faubion, W., Ferreira, M., Franchimont, D., Gabriel, S.B., Ge, T., Georges, M., Gettler, K., Giri, M., Glaser, B., Goerg, S., Goyette, P., Graham, D., Hamalainen, E., Haritunians, T., Heap, G.A., Hiltunen, M., Hoeppner, M., Horowitz, J.E., Irving, P., Iyer, V., Jalas, C., Kelsen, J., Khalili, H., Kirschner, B.S., Kontula, K., Koskela, J.T., Kugathasan, S., Kupcinskas, J., Lamb, C.A., Laudes, M., Levesque, C., Levine, A.P., Lewis, J.D., Liefferinckx, C., Loescher, B.S., Louis, E., Mansfield, J., May, S., McCauley, J.L., Mengesha, E., Mni, M., Moayyedi, P., Moran, C.J., Newberry, R.D., O'Charoen, S., Okou, D.T., Oldenburg, B., Ostrer, H., Palotie, A., Paquette, J., Pekow, J., Peter, I., Pierik, M.J., Ponsioen, C.Y., Pontikos, N., Prescott, N., Pulver, A.E., Rahmouni, S., Rice, D.L., Saavalainen, P., Sands, B., Sartor, R.B., Schiff, E.R., Schreiber, S., Schumm, L.P., Segal, A.W., Seksik, P., Shawky, R., Sheikh, S.Z., Silverberg, M.S., Simmons, A., Skeiceviciene, J., Sokol, H., Solomonson, M., Somineni, H., Sun, D., Targan, S., Turner, D., Uhlig, H.H., Meulen, A.E. van der, Vermeire, S., Verstockt, S., Voskuil, M.D., Winter, H.S., Young, J., Duerr, R.H., Franke, A., Brant, S.R., Cho, J., Weersma, R.K., Parkes, M., Xavier, R.J., Rivas, M.A., Rioux, J.D., McGovern, D.P.B., Huang, H.L., Anderson, C.A., Daly, M.J., Belgium IBD Consortium, Cedars-Sinai IBD, International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, NIHR IBD BioResource, Regeneron Genetics Center, SHARE Consortium, SPARC IBD Network, UK IBD Genetics Consortium, Interne Geneeskunde, MUMC+: MA Maag Darm Lever (9), RS: NUTRIM - R2 - Liver and digestive health, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Crohn Disease, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.

Published
2022

10. Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases: an International Organization for Study of Inflammatory Bowel Diseases consensus

Author

Ananthakrishnan, Ashwin N, primary, Kaplan, Gilaad G, additional, Bernstein, Charles N, additional, Burke, Kristin E, additional, Lochhead, Paul J, additional, Sasson, Alexa N, additional, Agrawal, Manasi, additional, Tiong, Jimmy Ho Tuan, additional, Steinberg, Joshua, additional, Kruis, Wolfgang, additional, Steinwurz, Flavio, additional, Ahuja, Vineet, additional, Ng, Siew C, additional, Rubin, David T, additional, Colombel, Jean-Frederic, additional, Gearry, Richard, additional, Abreu, M, additional, Ahuja, V, additional, Allez, M, additional, Ananthakrishnan, A, additional, Bemelman, W, additional, Bernstein, C, additional, Braun, J, additional, Chowers, Y, additional, Colombel, J-F, additional, Danese, S, additional, D'Haens, G, additional, D'Hoore, A, additional, Dignass, A, additional, Dotan, I, additional, Dubinsky, M, additional, Ekbom, A, additional, Fleshner, P, additional, Gasche, C, additional, Gassull, MA, additional, Gearry, R, additional, Ghosh, S, additional, Gibson, P, additional, Griffiths, A, additional, Halfvarson, J, additional, Hanauer, S, additional, Harpaz, N, additional, Hart, A, additional, Hibi, T, additional, Kamm, M, additional, Kaplan, G, additional, Kaser, A, additional, Korelitz, B, additional, Kotze, P, additional, Koutroubakis, I, additional, Kruis, W, additional, Lakatos, P, additional, Lewis, J, additional, Lindsay, J, additional, Loftus, E, additional, Louis, E, additional, Lukas, M, additional, Magro, F, additional, Mahadevan, U, additional, Mantzaris, G, additional, Mary, J-Y, additional, McGovern, D, additional, Moum, B, additional, Munkholm, P, additional, Neurath, M, additional, Ng, S, additional, O'Morain, C, additional, Oresland, T, additional, Panaccione, R, additional, Panes, J, additional, Panis, Y, additional, Pemberton, J, additional, Peyrin-Biroulet, L, additional, Prantera, C, additional, Rachmilewitz, D, additional, Ran, Z, additional, Reinisch, W, additional, Remzi, F, additional, Rhodes, J, additional, Riddell, R, additional, Rogler, G, additional, Rubin, D, additional, Sachar, D, additional, Sandborn, W, additional, Sands, B, additional, Sartor, B, additional, Schoelmerich, J, additional, Schreiber, S, additional, Siegel, C, additional, Siegmund, B, additional, Silverberg, M, additional, Söderholm, J, additional, Sood, A, additional, Spinelli, A, additional, Stange, E, additional, Steinwurz, F, additional, Targan, S, additional, Travis, S, additional, Turner, D, additional, Tysk, C, additional, Vatn, M, additional, Vermeire, S, additional, Watanabe, M, additional, Yamamoto, T, additional, and Yamamoto-Furusho, J, additional

Published
2022
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13. Antibodies to proinflammatory cytokines

Author

Karp, L. C., Targan, S. R., Williams, C. N., editor, Bursey, R. F., editor, Gall, D. G., editor, Martin, F., editor, McLeod, R. S., editor, Sutherland, L. R., editor, and Wallace, J. L., editor

Published
2000
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16. Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis

Author

Sands, B. E., Sandborn, W. J., Panaccione, R., O'Brien, C. D., Zhang, H., Johanns, J., Adedokun, O. J., Li, K., Peyrin-Biroulet, L., Van Assche, G., Danese, S., Targan, S., Abreu, M. T., Hisamatsu, T., Szapary, P., Brown S, Marano C., Connor, S, De Cruz, P, Ding, Nj, Florin, T, Hendy, P, Leong, R, Moore, G, Pavli, P, Sparrow, M, Gassner, S, Vogelsang, H, Baert, F, Colard, A, De Vos, M, D'Heygere, F, Ferrante, M, Louis, E, Staessen, D, Berova, T, Churchev, J, Draganova, R, Gancheva, D, Ivanova, N, Marinova, I, Markov, M, Nikolov, R, Tsonev, N, Vassileva, G, Afif, W, Berstein, C, Bressler, B, Jairath, V, Lachance, Jr, Singh, R, Tilbe, K, Komarek, V, Kozeluhova, J, Lukas, M, Volfova, M, Dahlerup, J, Altwegg, R, Beorchia, S, Bouguen, G, Cadiot, G, Dupas, Jl, Desreumaux, P, Flourie, B, Grimaud, Jc, Guillaud, O, Moreau, J, Roblin, X, Zerbib, F, Baumgart, D, Beckebaum, S, Bokemeyer, B, Ebert, M, Hasselblatt, P, Lügering, A, Maaser, C, Schiefke, I, Schreiber, S, Seidler, U, Altorjay, I, Kiss, Gg, Literati-Nagy, B, Patai, A, Pecsi, G, Salamon, A, Schnabel, R, Székely, A, Tulassay, Z, Varga, M, Fich, A, Fishman, S, Konikoff, F, Lichtenstein, L, Rainis, T, Sbeit, W, Schwartz, D, Annese, V, Biancone, L, Bossa, F, Costintino, R, Danese, S, Fries, W, Gasbarrini, A, Guidi, L, Kohn, A, Maconi, G, Rocca, R, Rogai, F, Villa, E, Zoli, G, Akiho, H, Aoyama, N, Arisawa, T, Hidaka, H, Hisamatsu, T, Horiki, N, Inaba, T, Inoue, S, Ishida, T, Ishida, H, Ishiguro, Y, Ishihara, S, Iwabuchi, M, Kato, J, Katsushima, S, Kobayashi, T, Kojima, Y, Kurihara, H, Masuo, T, Matsui, T, Matsumoto, T, Matsuoka, K, Mitsuyama, K, Motoya, S, Nakagawa, T, Nakai, K, Nakamura, S, Niihara, T, Ohnishi, Y, Ohta, A, Osada, T, Ryuichi, I, Sakai, Y, Sakata, Y, Sameshima, Y, Sano, K, Shibatoge, M, Shibuya, T, Suzuki, Y, Takeshima, F, Tanaka, S, Taruishi, M, Tokito, S, Ueo, T, Watanabe, K, Yamagami, H, Cheon, Jh, Cho, Kb, Knowles, Kim, Kim, Hj, Kim, Y, Lee, Km, Yang, Sk, D'Haens, G, Pierik, M, Gearry, R, Inns, S, Rowbotham, D, Schultz, M, Bochenek, A, Gawdis-Wojnarska, B, Kleczkowski, D, Leszczyszyn, J, Malecka-Panas, E, Mamos, A, Petryka, R, Regula, J, Rozciecha, J, Stefanuik, P, Wozniak-Stolarska, B, Cimpoeru, N, Craciun, E, Ovidiu, Cf, Goldis, E, Ionita-Radu, F, Lazar, D, Suciu, I, Abdulkhakov, R, Alikhanov, B, Apartsin, K, Bakulin, I, Belousova, E, Gofman, A, Grinevich, V, Kulyapin, A, Nizov, A, Osipenko, M, Simanenkov, V, Tkachev, A, Uspenskiy, Y, Valuyskikh, E, Jovanovic, I, Nagorni, A, Svorcan, P, Zdravkovic, N, Bunganic, I, Abrahamovych, O, Bilianskyi, L, Datsenko, O, Golovchenko, O, Kharchenko, N, Klymenko, V, Levchenko, O, Lozynskyy, Y, Murenets, N, Oliinyk, O, Prystupa, L, Pyrogovskyi, V, Reznikova, V, Rishko, I, Stanislavchuk, M, Vizir, V, Yatsyshyn, R, Arasaradnam, R, Bloom, S, Cummings, F, Iqbal, T, Irving, P, Kaser, A, Shonde, A, Subramanian, S, Aberra, F, Aguilar, H, Araya, V, Bakken, A, Beaulieu, D, Cappa, Ja, Chiorean, M, Cohen, N, Dryden, G, Duvall, G, Ehrlich, A, Eisner, M, Ertan, A, Fogel, R, Friedenberg, K, Gatof, D, Glover, S, Grosman, I, Gunaratnam, N, Gupta, N, Haynes, P, Hemaidan, A, Higgins, P, Hou, J, Hudesman, D, Iskandar, H, Jazrawi, S, Jones, M, Karnam, U, Khurana, S, Killpack, M, Kreines, M, Lawlor, G, Lee, S, Loftus, E, Lukin, Dj, Marcet, J, Mattar, M, Melmed, G, Minor, T, Mirkin, K, Mutlu, E, Nichols, M, Nudell, J, Rai, R, Ramos, C, Mcleod, Randall, Rausher, D, Ritter, T, Singh Saini, S, Salzberg, B, Saubermann, L, Scherl, E, Sedghi, S, Sellin, J, Shafran, I, Sorrentino, D, Suiter, D, Swaminath, A, Tiongco, F, Vrabie, R, Walp, K, Warner, N, Winstead, N, Wolf, Dc, Woods, J, Yen, E, Younes, Z., Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Humanitas Clinical and Research Center [Rozzano, Milan, Italy], RS: NUTRIM - R2 - Liver and digestive health, MUMC+: MA Maag Darm Lever (9), Interne Geneeskunde, Sands, Be, Sandborn, Wj, Panaccione, R, O'Brien, Cd, Zhang, H, Johanns, J, Adedokun, Oj, Li, K, Peyrin-Biroulet, L, Van Assche, G, Danese, S, Targan, S, Abreu, Mt, Hisamatsu, T, Szapary, P, and Marano, C

Subjects
Adult, Male, Infusions, [SDV]Life Sciences [q-bio], Injections, Subcutaneous, Anti-Inflammatory Agents, Ulcerative, Klinikai orvostudományok, Article, Injections, Maintenance Chemotherapy, Dose-Response Relationship, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, INFLIXIMAB, Colitis, Ulcerative, Dose-Response Relationship, Drug, Female, Humans, Induction Chemotherapy, Infusions, Intravenous, Patient Acuity, Remission Induction, Ustekinumab, ComputingMilieux_MISCELLANEOUS, ACTIVITY INDEXES, Subcutaneous, Orvostudományok, General Medicine, EFFICACY, Colitis, 3. Good health, INFECTIONS, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Drug, Intravenous
Abstract

The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown.We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore1 [range, 0 to 3] on any of the four Mayo scale components).The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo.Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).

Published
2019

23. Ustekinumab as induction and maintenance therapy for Ulcerative Colitis

Author

Sands, B, Sandborn, W, Panaccione, R, O'Brien, C, Zhang, H, Johanns, J, Adedokun, O, Li, K, Peyrin-Biroulet, L, Van Assche, G, Danese, S, Targan, S, Abreu, M, Hisamatsu, T, Szapary, P, Marano, C, UNIFI Study Group, Biancone, L, inclusa nell’ UNIFI Study Group, and vedi articolo e, P

Subjects
Settore MED/12
Published
2019

33. Summary

Author

RUTGEERTS, P. J. and TARGAN, S. R.

Published
1999

36. Efficacy and Safety of Ustekinumab as Maintenance Therapy in Ulcerative Colitis: Week 44 Results from UNIFI

Author

Sandborn, WJ, additional, Sands, BE, additional, Panaccione, R, additional, O'Brien, CD, additional, Zhang, H, additional, Johanns, J, additional, Peyrin-Biroulet, L, additional, van Assche, G, additional, Danese, S, additional, Targan, S, additional, Abreu, MT, additional, Hisamatsu, T, additional, Szapary, P, additional, and Marano, C, additional

Published
2019
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37. Efficacy in Biologic Failure and Nonbiologic-Failure Populations in a Phase 3 Study of Ustekinumab in Moderate-Severe Ulcerative Colitis: UNIFI

Author

Sands, BE, additional, Peyrin-Biroulet, L, additional, Marano, C, additional, O'Brien, CD, additional, Zhang, H, additional, Johanns, J, additional, Szapary, P, additional, Rowbotham, D, additional, Leong, RW, additional, Arasaradnam, RP, additional, Danese, S, additional, van Assche, G, additional, Targan, S, additional, and Sandborn, WJ, additional

Published
2019
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39. OP37 Efficacy and safety of ustekinumab as maintenance therapy in ulcerative colitis: Week 44 results from UNIFI

Author

Sandborn, W J, primary, Sands, B E, additional, Panaccione, R, additional, O’Brien, C D, additional, Zhang, H, additional, Johanns, J, additional, Peyrin-Biroulet, L, additional, Van Assche, G, additional, Danese, S, additional, Targan, S R, additional, Abreu, M T, additional, Hisamatsu, T, additional, Szapary, P, additional, and Marano, C, additional

Published
2019
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40. P312 Efficacy in biologic failure and non-biologic-failure populations in a Phase 3 study of ustekinumab in moderate–severe ulcerative colitis: UNIFI

Author

Sands, B E, primary, Peyrin-Biroulet, L, additional, Marano, C, additional, O'Brien, C D, additional, Zhang, H, additional, Johanns, J, additional, Szapary, P, additional, Rowbotham, D, additional, Leong, R W, additional, Arasaradnam, R P, additional, Danese, S, additional, Van Assche, G, additional, Targan, S, additional, and Sandborn, W J, additional

Published
2019
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42. DOP54 Efficacy and safety of ustekinumab through Week 16 in patients with moderate-to-severe ulcerative colitis randomised to ustekinumab: results from the UNIFI induction trial

Author

Danese, S, primary, Sands, B E, additional, O'Brien, C D, additional, Zhang, H, additional, Johanns, J, additional, Sloan, S, additional, Izanec, J, additional, Szapary, P, additional, Marano, C, additional, Leong, R W, additional, Rowbotham, D, additional, Targan, S R, additional, and Van Assche, G, additional

Published
2019
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43. DOP47 Sustained remission in patients with moderate to severe ulcerative colitis: Results from the Phase 3 UNIFI maintenance study

Author

Van Assche, G, primary, Targan, S R, additional, Baker, T, additional, O’Brien, C D, additional, Zhang, H, additional, Johanns, J, additional, Szapary, P, additional, Marano, C, additional, Leong, R W, additional, Rowbotham, D, additional, Hisamatsu, T, additional, Danese, S, additional, Sands, B E, additional, and Peyrin-Biroulet, L, additional

Published
2019
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47. Safety, tolerance and activity of multiple doses of subcutaneous recombinant human interleukin-10 (rHuIL-10) in patients with mild to moderate active Crohn's disease 11.02

Author

Fedorak, R. N., Gangl, A., Elson, C. O., Gasche, C., Rutgeerts, P., D'Haens, G., Schreiber, S., Wild, G., Hanauer, S. B., Sninsky, C. A., Wilson, J. H. P., Tilg, H., Isaacs, K., Jacyna, M., Colombel, J. F., Desreumaux, P., van Deventer, S. J. H., Wright, J. P., Irvine, E. J., Levine, D. S., Tremaine, W. J., Laschner, B. A., Warner, A. S., McDermott, R., Mayer, L., Koningsberger, J. C., van Gossum, A., Befrits, R., Deusch, K., Targan, S., Gibson, P., Cohard, M., Grint, P., Kilian, A., and LeBeaut, A.

Published
1997

49. Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population.

Author

Williams, SM, Rivas, MA, Avila, BE, Koskela, J, Huang, H, Stevens, C, Pirinen, M, Haritunians, T, Neale, BM, Kurki, M, Ganna, A, Graham, D, Glaser, B, Peter, I, Atzmon, G, Barzilai, N, Levine, AP, Schiff, E, Pontikos, N, Weisburd, B, Lek, M, Karczewski, KJ, Bloom, J, Minikel, EV, Petersen, B-S, Beaugerie, L, Seksik, P, Cosnes, J, Schreiber, S, Bokemeyer, B, Bethge, J, International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, T2D-GENES Consortium, Heap, G, Ahmad, T, Plagnol, V, Segal, AW, Targan, S, Turner, D, Saavalainen, P, Farkkila, M, Kontula, K, Palotie, A, Brant, SR, Duerr, RH, Silverberg, MS, Rioux, JD, Weersma, RK, Franke, A, Jostins, L, Anderson, CA, Barrett, JC, MacArthur, DG, Jalas, C, Sokol, H, Xavier, RJ, Pulver, A, Cho, JH, McGovern, DPB, Daly, MJ, Williams, SM, Rivas, MA, Avila, BE, Koskela, J, Huang, H, Stevens, C, Pirinen, M, Haritunians, T, Neale, BM, Kurki, M, Ganna, A, Graham, D, Glaser, B, Peter, I, Atzmon, G, Barzilai, N, Levine, AP, Schiff, E, Pontikos, N, Weisburd, B, Lek, M, Karczewski, KJ, Bloom, J, Minikel, EV, Petersen, B-S, Beaugerie, L, Seksik, P, Cosnes, J, Schreiber, S, Bokemeyer, B, Bethge, J, International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, T2D-GENES Consortium, Heap, G, Ahmad, T, Plagnol, V, Segal, AW, Targan, S, Turner, D, Saavalainen, P, Farkkila, M, Kontula, K, Palotie, A, Brant, SR, Duerr, RH, Silverberg, MS, Rioux, JD, Weersma, RK, Franke, A, Jostins, L, Anderson, CA, Barrett, JC, MacArthur, DG, Jalas, C, Sokol, H, Xavier, RJ, Pulver, A, Cho, JH, McGovern, DPB, and Daly, MJ

Abstract

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10-100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel con

Published
2018

50. Long-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy

Author

Sandborn, W. J., primary, Rutgeerts, P., additional, Gasink, C., additional, Jacobstein, D., additional, Zou, B., additional, Johanns, J., additional, Sands, B. E., additional, Hanauer, S. B., additional, Targan, S., additional, Ghosh, S., additional, de Villiers, W. J. S., additional, Colombel, J.-F., additional, and Feagan, B. G., additional

Published
2018
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