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1. Response to: 'Correspondence on 'Safety and efficacy of faecal microbiota transplantation for active peripheral psoriatic arthritis: An exploratory randomised placebo-controlled trial' by McGonagle et al

Author: Kragsnaes, Maja Skov, Kjeldsen, Jens, Horn, Hans Christian, Munk, Heidi Lausten, Pedersen, Jens Kristian, Just, Søren Andreas, Ahlquist, Palle, Davidsen, Jesper Rømhild, Nilsson, Anna Christine, Röttger, Richard, Kruhøffer, Mogens, Marchesi, Julian R., Kristiansen, Karsten, Christensen, Robin, Ellingsen, Torkell, Kragsnaes, Maja Skov, Kjeldsen, Jens, Horn, Hans Christian, Munk, Heidi Lausten, Pedersen, Jens Kristian, Just, Søren Andreas, Ahlquist, Palle, Davidsen, Jesper Rømhild, Nilsson, Anna Christine, Röttger, Richard, Kruhøffer, Mogens, Marchesi, Julian R., Kristiansen, Karsten, Christensen, Robin, and Ellingsen, Torkell
Published: 2023

2. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce., Funding Agencies|NORDFORSK [90825]; Swedish Research Council [2018-02803]; Swedish innovation Agency (Vinnova); Innovationsfonden; The Research Council of Norway; Region Stockholm-Karolinska Institutet; Region Vasterbotten (ALF); Danish Rheumatism Association [R194-A6956, A1923, A3037, A3570]; Swedish Brain Foundation; Nils and Bibbi Jensens Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; South-Eastern Heath Region of Norway; Health Research Fund of Central Denmark Region; Region of Southern Denmark; A.P. Moller Foundation for the Advancement of Medical Science; Colitis-Crohn Foreningen; Novo Nordisk Foundation [NNF15OC0016932]; Aase og Ejnar Danielsens Fond; Beckett-Fonden; Augustinus Fonden; Knud and Edith Eriksens Mindefond; Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis Legat; Psoriasis Forskningsfonden; University of Aarhus; Region of Southern Denmarks PhD Fund [12/7725]; Department of Rheumatology, Frederiksberg Hospital; Research Council of Norway [229624, 223273]; South East and Western Norway Health Authorities; ERC AdG project SELECTionPREDISPOSED; Stiftelsen Kristian Gerhard Jebsen; Trond Mohn Foundation; Novo Nordisk Foundation; University of Bergen
Published: 2022
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3. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena, I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall, I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena, I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall, I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
Published: 2022
Full Text: View/download PDF

4. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena, I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall, I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena, I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall, I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
Published: 2022
Full Text: View/download PDF

5. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce., Funding Agencies|NORDFORSK [90825]; Swedish Research Council [2018-02803]; Swedish innovation Agency (Vinnova); Innovationsfonden; The Research Council of Norway; Region Stockholm-Karolinska Institutet; Region Vasterbotten (ALF); Danish Rheumatism Association [R194-A6956, A1923, A3037, A3570]; Swedish Brain Foundation; Nils and Bibbi Jensens Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; South-Eastern Heath Region of Norway; Health Research Fund of Central Denmark Region; Region of Southern Denmark; A.P. Moller Foundation for the Advancement of Medical Science; Colitis-Crohn Foreningen; Novo Nordisk Foundation [NNF15OC0016932]; Aase og Ejnar Danielsens Fond; Beckett-Fonden; Augustinus Fonden; Knud and Edith Eriksens Mindefond; Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis Legat; Psoriasis Forskningsfonden; University of Aarhus; Region of Southern Denmarks PhD Fund [12/7725]; Department of Rheumatology, Frederiksberg Hospital; Research Council of Norway [229624, 223273]; South East and Western Norway Health Authorities; ERC AdG project SELECTionPREDISPOSED; Stiftelsen Kristian Gerhard Jebsen; Trond Mohn Foundation; Novo Nordisk Foundation; University of Bergen
Published: 2022
Full Text: View/download PDF

6. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena, I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall, I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena, I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall, I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
Published: 2022
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7. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce., Funding Agencies|NORDFORSK [90825]; Swedish Research Council [2018-02803]; Swedish innovation Agency (Vinnova); Innovationsfonden; The Research Council of Norway; Region Stockholm-Karolinska Institutet; Region Vasterbotten (ALF); Danish Rheumatism Association [R194-A6956, A1923, A3037, A3570]; Swedish Brain Foundation; Nils and Bibbi Jensens Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; South-Eastern Heath Region of Norway; Health Research Fund of Central Denmark Region; Region of Southern Denmark; A.P. Moller Foundation for the Advancement of Medical Science; Colitis-Crohn Foreningen; Novo Nordisk Foundation [NNF15OC0016932]; Aase og Ejnar Danielsens Fond; Beckett-Fonden; Augustinus Fonden; Knud and Edith Eriksens Mindefond; Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis Legat; Psoriasis Forskningsfonden; University of Aarhus; Region of Southern Denmarks PhD Fund [12/7725]; Department of Rheumatology, Frederiksberg Hospital; Research Council of Norway [229624, 223273]; South East and Western Norway Health Authorities; ERC AdG project SELECTionPREDISPOSED; Stiftelsen Kristian Gerhard Jebsen; Trond Mohn Foundation; Novo Nordisk Foundation; University of Bergen
Published: 2022
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8. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena, I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall, I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena, I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall, I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
Published: 2022
Full Text: View/download PDF

9. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I., Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Søren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H.S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I., Olsson, Tomas, Ostrowski, Sisse Rye, Hørslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sørensen, Erik, Sørensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Søren, Steinsson, Kristján, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I., Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Søren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H.S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I., Olsson, Tomas, Ostrowski, Sisse Rye, Hørslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sørensen, Erik, Sørensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Søren, Steinsson, Kristján, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ∼1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-Alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-Alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
Published: 2022
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10. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I., Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Søren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H.S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I., Olsson, Tomas, Ostrowski, Sisse Rye, Hørslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sørensen, Erik, Sørensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Søren, Steinsson, Kristján, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I., Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Søren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H.S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I., Olsson, Tomas, Ostrowski, Sisse Rye, Hørslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sørensen, Erik, Sørensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Søren, Steinsson, Kristján, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ∼1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-Alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-Alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
Published: 2022
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11. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I., Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Søren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H.S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I., Olsson, Tomas, Ostrowski, Sisse Rye, Hørslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sørensen, Erik, Sørensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Søren, Steinsson, Kristján, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I., Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Søren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H.S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I., Olsson, Tomas, Ostrowski, Sisse Rye, Hørslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sørensen, Erik, Sørensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Søren, Steinsson, Kristján, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ∼1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-Alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-Alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
Published: 2022
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12. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce., Funding Agencies|NORDFORSK [90825]; Swedish Research Council [2018-02803]; Swedish innovation Agency (Vinnova); Innovationsfonden; The Research Council of Norway; Region Stockholm-Karolinska Institutet; Region Vasterbotten (ALF); Danish Rheumatism Association [R194-A6956, A1923, A3037, A3570]; Swedish Brain Foundation; Nils and Bibbi Jensens Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; South-Eastern Heath Region of Norway; Health Research Fund of Central Denmark Region; Region of Southern Denmark; A.P. Moller Foundation for the Advancement of Medical Science; Colitis-Crohn Foreningen; Novo Nordisk Foundation [NNF15OC0016932]; Aase og Ejnar Danielsens Fond; Beckett-Fonden; Augustinus Fonden; Knud and Edith Eriksens Mindefond; Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis Legat; Psoriasis Forskningsfonden; University of Aarhus; Region of Southern Denmarks PhD Fund [12/7725]; Department of Rheumatology, Frederiksberg Hospital; Research Council of Norway [229624, 223273]; South East and Western Norway Health Authorities; ERC AdG project SELECTionPREDISPOSED; Stiftelsen Kristian Gerhard Jebsen; Trond Mohn Foundation; Novo Nordisk Foundation; University of Bergen
Published: 2022
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13. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I., Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Søren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H.S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I., Olsson, Tomas, Ostrowski, Sisse Rye, Hørslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sørensen, Erik, Sørensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Søren, Steinsson, Kristján, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I., Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Søren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H.S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I., Olsson, Tomas, Ostrowski, Sisse Rye, Hørslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sørensen, Erik, Sørensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Søren, Steinsson, Kristján, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ∼1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-Alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-Alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
Published: 2022
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14. Impact of fibre and red/processed meat intake on treatment outcomes among patients with chronic inflammatory diseases initiating biological therapy:A prospective cohort study

Author: Overgaard, Silja H., Sørensen, Signe B., Munk, Heidi L., Nexøe, Anders B., Glerup, Henning, Henriksen, Rikke H., Guldmann, Tanja, Pedersen, Natalia, Saboori, Sanaz, Hvid, Lone, Dahlerup, Jens F., Hvas, Christian L., Jawhara, Mohamad, Andersen, Karina W., Pedersen, Andreas K., Nielsen, Ole H., Bergenheim, Fredrik, Brodersen, Jacob B., Heitmann, Berit L., Halldorsson, Thorhallur I., Holmskov, Uffe, Bygum, Anette, Christensen, Robin, Kjeldsen, Jens, Ellingsen, Torkell, Andersen, Vibeke, Overgaard, Silja H., Sørensen, Signe B., Munk, Heidi L., Nexøe, Anders B., Glerup, Henning, Henriksen, Rikke H., Guldmann, Tanja, Pedersen, Natalia, Saboori, Sanaz, Hvid, Lone, Dahlerup, Jens F., Hvas, Christian L., Jawhara, Mohamad, Andersen, Karina W., Pedersen, Andreas K., Nielsen, Ole H., Bergenheim, Fredrik, Brodersen, Jacob B., Heitmann, Berit L., Halldorsson, Thorhallur I., Holmskov, Uffe, Bygum, Anette, Christensen, Robin, Kjeldsen, Jens, Ellingsen, Torkell, and Andersen, Vibeke
Abstract: Background: Biologic disease-modifying drugs have revolutionised the treatment of a number of chronic inflammatory diseases (CID). However, up to 60% of the patients do not have a sufficient response to treatment and there is a need for optimization of treatment strategies. Objective: To investigate if the treatment outcome of biological therapy is associated with the habitual dietary intake of fibre and red/processed meat in patients with a CID. Methods: In this multicentre prospective cohort study, we consecutively enrolled 233 adult patients with a diagnosis of Crohn's Disease, Ulcerative Colitis, Rheumatoid Arthritis (RA), Axial Spondyloarthritis, Psoriatic Arthritis and Psoriasis, for whom biologic therapy was planned, over a 3 year period. Patients with completed baseline food frequency questionnaires were stratified into a high fibre/low red and processed meat exposed group (HFLM) and an unexposed group (low fibre/high red and processed meat intake = LFHM). The primary outcome was the proportion of patients with a clinical response to biologic therapy after 14–16 weeks of treatment. Results: Of the 193 patients included in our primary analysis, 114 (59%) had a clinical response to biologic therapy. In the HFLM group (N = 64), 41 (64%) patients responded to treatment compared to 73 (56%) in the LFHM group (N = 129), but the difference was not statistically significant (OR: 1.48, 0.72–3.05). For RA patients however, HFLM diet was associated with a more likely clinical response (82% vs. 35%; OR: 9.84, 1.35–71.56). Conclusion: Habitual HFLM intake did not affect the clinical response to biological treatment across CIDs. HFLM diet in RA patients might be associated with better odds for responding to biological treatment, but this would need confirmation in a randomised trial. Trial registration: (clinicaltrials.gov), identifier [NCT03173144].
Published: 2022

15. Long-term Behavioral Changes During the COVID-19 Pandemic and Impact of Vaccination in Patients With Inflammatory Rheumatic Diseases

Author: Glintborg, Bente, Jensen, Dorte Vendelbo, Terslev, Lene, Hendricks, Oliver, Østergaard, Mikkel, Rasmussen, Simon Horskjær, Jensen, Mogens Pfeiffer, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Sørensen, Christian Møller, Krogh, Niels Steen, Agerbo, Jette Nørgaard, Ziegler, Connie, Hetland, Merete Lund, Glintborg, Bente, Jensen, Dorte Vendelbo, Terslev, Lene, Hendricks, Oliver, Østergaard, Mikkel, Rasmussen, Simon Horskjær, Jensen, Mogens Pfeiffer, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Sørensen, Christian Møller, Krogh, Niels Steen, Agerbo, Jette Nørgaard, Ziegler, Connie, and Hetland, Merete Lund
Abstract: Objective. To explore anxiety and self-isolation in patients with inflammatory rheumatic disease (IRD)15 months into the coronavirus disease 2019 (COVID-19) pandemic, including attitudes toward and effects of SARS-CoV-2 vaccination. Methods. A nationwide online survey was conducted at 3 timepoints: May 2020, November 2020, and May 2021. Patients with IRD followed in the Danish Rheumatology Quality Registry (DANBIO) were asked about the effects of the pandemic, including SARS-CoV-2 infection and their behavior, anxiety, and concerns. The May 2021 survey included attitudes toward SARS-CoV-2 and influenza vaccination. Characteristics associated with self-isolation in May 2021 were explored with adjusted logistic regression analyses that included patient characteristics and SARS-CoV-2 vaccination status. Results. Respondents to surveys 1, 2, and 3 included 12,789; 14,755; and 13,921 patients, respectively; 64% had rheumatoid arthritis and 63% were female. Anxiety and concerns were highest in May 2020 and decreased to stable levels in November 2020 and May 2021; 86%, 50%, and 52% of respondents reported self-isolation, respectively. In May 2021, 4% of respondents self-reported previous SARS-CoV-2 infection. The SARS-CoV-2 vaccine acceptance rate was 86%, and the proportion of patients vaccinated against influenza had increased from 50% in winter 2019-2020 to 64% in winter 2020-2021. The proportion of patients with anxiety appeared similar among those vaccinated and unvaccinated against SARS-CoV-2. In multivariable analyses, being unvaccinated, female gender, receiving biologic drugs, and poor quality of life were independently associated with self-isolation. Conclusion. Levels of anxiety and self-isolation decreased after the initial lockdown period in patients with IRD. Half of the patients reported self-isolation in May 2021, a phase that included widespread reopening of society and large-scale vaccination. The lack of prepandemic data prevented a full understanding
Published: 2022

16. Nationwide, large-scale implementation of an online system for remote entry of patient-reported outcomes in rheumatology:characteristics of users and non-users and time to first entry

Author: Glintborg, Bente, Jensen, Dorte Vendelbo, Terslev, Lene, Hendricks, Oliver, Østergaard, Mikkel, Rasmussen, Simon Horskjær, Jensen, Mogens Pfeiffer, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Sørensen, Christian Møller, Krogh, Niels Steen, Agerbo, Jette, Ziegler, Connie, Hetland, Merete Lund, Glintborg, Bente, Jensen, Dorte Vendelbo, Terslev, Lene, Hendricks, Oliver, Østergaard, Mikkel, Rasmussen, Simon Horskjær, Jensen, Mogens Pfeiffer, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Sørensen, Christian Møller, Krogh, Niels Steen, Agerbo, Jette, Ziegler, Connie, and Hetland, Merete Lund
Abstract: Aims In May 2020, a nationwide, web-based system for remote entry of patient-reported outcomes (PROs) in inflammatory rheumatic diseases was launched and implemented in routine care (DANBIO-from-home). After 1.5 years of use, we explored clinical characteristics of patients who did versus did not use the system, and the time to first entry of PROs. Methods All patients followed in DANBIO were informed about DANBIO-from-home by electronic invitations or when attending their clinic. Characteristics of patients who did/did not use DANBIO-from-home in the period after implementation were explored by multivariable logistic regression analyses including demographic and clinical variables (gender, age group, diagnosis, disease duration, use of biological disease-modifying agent (bDMARD), Health Assessment Questionnaire (HAQ), Patient Acceptable Symptom Scale (PASS)). Time from launch to first entry was presented as cumulative incidence curves by age group (<40/40-60/61-80/>80 years). Results Of 33 776 patients, 68% entered PROs using DANBIO-from-home at least once. Median (IQR) time to first entry was 27 (11-152) days. Factors associated with data entry in multivariate analyses (OR (95% CI)) were: female gender (1.19 (1.12 to 1.27)), bDMARD treatment (1.41 (1.33 to 1.50)), age 40-60 years (1.79 (1.63 to 1.97)), 61-80 years (1.87 (1.70 to 2.07), or age >80 years (0.57 (0.50 to 0.65)) (reference: age <40 years), lower HAQ (0.68 (0.65 to 0.71)) and PASS 'no' (1.09 (1.02 to 1.17). Diagnosis was not associated. Time to first entry of PROs was longest in patients <40 years of age (119 (24-184) days) and shortest in the 61-80 years age group (25 (8-139) days). Conclusion A nationwide online platform for PRO in rheumatology achieved widespread use. Higher age, male gender, conventional treatment and disability were associated with no use.
Published: 2022

17. Infliximab biosimilar-to-biosimilar switching in patients with inflammatory rheumatic disease:Clinical outcomes in real-world patients from the DANBIO registry

Author: Nabi, Hafsah, Hendricks, Oliver, Jensen, Dorte Vendelbo, Loft, Anne Gitte, Pedersen, Jens Kristian, Just, Søren Andreas, Danebod, Kamilla, Munk, Heidi Lausten, Kristensen, Salome, Manilo, Natalia, Colic, Ada, Linauskas, Asta, Thygesen, Pia Høger, Christensen, Louise Brot, Kalisz, Maren Høgberget, Lomborg, Niels, Chrysidis, Stavros, Raun, Johnny Lillelund, Andersen, Marlene, Mehnert, Frank, Krogh, Niels Steen, Hetland, Merete Lund, Glintborg, Bente, Nabi, Hafsah, Hendricks, Oliver, Jensen, Dorte Vendelbo, Loft, Anne Gitte, Pedersen, Jens Kristian, Just, Søren Andreas, Danebod, Kamilla, Munk, Heidi Lausten, Kristensen, Salome, Manilo, Natalia, Colic, Ada, Linauskas, Asta, Thygesen, Pia Høger, Christensen, Louise Brot, Kalisz, Maren Høgberget, Lomborg, Niels, Chrysidis, Stavros, Raun, Johnny Lillelund, Andersen, Marlene, Mehnert, Frank, Krogh, Niels Steen, Hetland, Merete Lund, and Glintborg, Bente
Abstract: Objective Successful uptake of biosimilars in rheumatology is limited by lack of real-world evidence regarding effectiveness of biosimilar-to-biosimilar switching. We investigated infliximab biosimilars CT-P13-to-GP1111 switching among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). Methods Observational cohort study from the DANBIO registry. Patients were classified as originator-naïve or originator-experienced. Retention rates of 1-year GP1111 treatment were explored (Kaplan-Meier). We identified baseline factors (at the time of switch) associated with withdrawal of GP1111 (multivariable Cox-regression analyses with HRs including originator treatment history). Changes in subjective and objective measures of disease activity 4 months before and after the switch were assessed in individual patients. Results Of 1605 patients (685 RA, 314 PsA and 606 AxSpA, median disease duration was 9 years, 37% in Clinical Disease Activity Index/Ankylosing Spondylitis Disease Activity Score remission), 1171 were originator-naïve. Retention rates at 1-year were 83% (95% CI: 81% to 85%) and 92% (95% CI: 90% to 95%) for the originator-naïve and originator-experienced, respectively. GP1111 retention rates were higher in originator-experienced compared to originator-naïve with RA (HR=0.4 (95% CI: 0.2 to 0.7)) and PsA (HR=0.2 (95% CI: 0.1 to 0.8)), but not significantly for AxSpA: HR=0.6 (95% CI: 0.3 to 1.2). Lower disease activity was associated with higher retention. Changes in disease activity preswitch and postswitch were close to zero. Conclusion This real-world observational study of more than 1600 patients with inflammatory arthritis showed high 1-year retention following a nationwide infliximab biosimilar-to-biosimilar switch. Retention was higher in originator-experienced and in patients with low disease activity, suggesting outcomes to be affected by patient-related rather than drug-related factors.
Published: 2022

18. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I., Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Søren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H.S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I., Olsson, Tomas, Ostrowski, Sisse Rye, Hørslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sørensen, Erik, Sørensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Søren, Steinsson, Kristján, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I., Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Søren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H.S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I., Olsson, Tomas, Ostrowski, Sisse Rye, Hørslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sørensen, Erik, Sørensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Søren, Steinsson, Kristján, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ∼1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-Alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-Alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
Published: 2022
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19. Impact of fibre and red/processed meat intake on treatment outcomes among patients with chronic inflammatory diseases initiating biological therapy:A prospective cohort study

Author: Overgaard, Silja H., Sørensen, Signe B., Munk, Heidi L., Nexøe, Anders B., Glerup, Henning, Henriksen, Rikke H., Guldmann, Tanja, Pedersen, Natalia, Saboori, Sanaz, Hvid, Lone, Dahlerup, Jens F., Hvas, Christian L., Jawhara, Mohamad, Andersen, Karina W., Pedersen, Andreas K., Nielsen, Ole H., Bergenheim, Fredrik, Brodersen, Jacob B., Heitmann, Berit L., Halldorsson, Thorhallur I., Holmskov, Uffe, Bygum, Anette, Christensen, Robin, Kjeldsen, Jens, Ellingsen, Torkell, Andersen, Vibeke, Overgaard, Silja H., Sørensen, Signe B., Munk, Heidi L., Nexøe, Anders B., Glerup, Henning, Henriksen, Rikke H., Guldmann, Tanja, Pedersen, Natalia, Saboori, Sanaz, Hvid, Lone, Dahlerup, Jens F., Hvas, Christian L., Jawhara, Mohamad, Andersen, Karina W., Pedersen, Andreas K., Nielsen, Ole H., Bergenheim, Fredrik, Brodersen, Jacob B., Heitmann, Berit L., Halldorsson, Thorhallur I., Holmskov, Uffe, Bygum, Anette, Christensen, Robin, Kjeldsen, Jens, Ellingsen, Torkell, and Andersen, Vibeke
Abstract: Background: Biologic disease-modifying drugs have revolutionised the treatment of a number of chronic inflammatory diseases (CID). However, up to 60% of the patients do not have a sufficient response to treatment and there is a need for optimization of treatment strategies. Objective: To investigate if the treatment outcome of biological therapy is associated with the habitual dietary intake of fibre and red/processed meat in patients with a CID. Methods: In this multicentre prospective cohort study, we consecutively enrolled 233 adult patients with a diagnosis of Crohn's Disease, Ulcerative Colitis, Rheumatoid Arthritis (RA), Axial Spondyloarthritis, Psoriatic Arthritis and Psoriasis, for whom biologic therapy was planned, over a 3 year period. Patients with completed baseline food frequency questionnaires were stratified into a high fibre/low red and processed meat exposed group (HFLM) and an unexposed group (low fibre/high red and processed meat intake = LFHM). The primary outcome was the proportion of patients with a clinical response to biologic therapy after 14–16 weeks of treatment. Results: Of the 193 patients included in our primary analysis, 114 (59%) had a clinical response to biologic therapy. In the HFLM group (N = 64), 41 (64%) patients responded to treatment compared to 73 (56%) in the LFHM group (N = 129), but the difference was not statistically significant (OR: 1.48, 0.72–3.05). For RA patients however, HFLM diet was associated with a more likely clinical response (82% vs. 35%; OR: 9.84, 1.35–71.56). Conclusion: Habitual HFLM intake did not affect the clinical response to biological treatment across CIDs. HFLM diet in RA patients might be associated with better odds for responding to biological treatment, but this would need confirmation in a randomised trial. Trial registration: (clinicaltrials.gov), identifier [NCT03173144].
Published: 2022

20. Long-term Behavioral Changes During the COVID-19 Pandemic and Impact of Vaccination in Patients With Inflammatory Rheumatic Diseases

Author: Glintborg, Bente, Jensen, Dorte Vendelbo, Terslev, Lene, Hendricks, Oliver, Østergaard, Mikkel, Rasmussen, Simon Horskjær, Jensen, Mogens Pfeiffer, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Sørensen, Christian Møller, Krogh, Niels Steen, Agerbo, Jette Nørgaard, Ziegler, Connie, Hetland, Merete Lund, Glintborg, Bente, Jensen, Dorte Vendelbo, Terslev, Lene, Hendricks, Oliver, Østergaard, Mikkel, Rasmussen, Simon Horskjær, Jensen, Mogens Pfeiffer, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Sørensen, Christian Møller, Krogh, Niels Steen, Agerbo, Jette Nørgaard, Ziegler, Connie, and Hetland, Merete Lund
Abstract: Objective. To explore anxiety and self-isolation in patients with inflammatory rheumatic disease (IRD)15 months into the coronavirus disease 2019 (COVID-19) pandemic, including attitudes toward and effects of SARS-CoV-2 vaccination. Methods. A nationwide online survey was conducted at 3 timepoints: May 2020, November 2020, and May 2021. Patients with IRD followed in the Danish Rheumatology Quality Registry (DANBIO) were asked about the effects of the pandemic, including SARS-CoV-2 infection and their behavior, anxiety, and concerns. The May 2021 survey included attitudes toward SARS-CoV-2 and influenza vaccination. Characteristics associated with self-isolation in May 2021 were explored with adjusted logistic regression analyses that included patient characteristics and SARS-CoV-2 vaccination status. Results. Respondents to surveys 1, 2, and 3 included 12,789; 14,755; and 13,921 patients, respectively; 64% had rheumatoid arthritis and 63% were female. Anxiety and concerns were highest in May 2020 and decreased to stable levels in November 2020 and May 2021; 86%, 50%, and 52% of respondents reported self-isolation, respectively. In May 2021, 4% of respondents self-reported previous SARS-CoV-2 infection. The SARS-CoV-2 vaccine acceptance rate was 86%, and the proportion of patients vaccinated against influenza had increased from 50% in winter 2019-2020 to 64% in winter 2020-2021. The proportion of patients with anxiety appeared similar among those vaccinated and unvaccinated against SARS-CoV-2. In multivariable analyses, being unvaccinated, female gender, receiving biologic drugs, and poor quality of life were independently associated with self-isolation. Conclusion. Levels of anxiety and self-isolation decreased after the initial lockdown period in patients with IRD. Half of the patients reported self-isolation in May 2021, a phase that included widespread reopening of society and large-scale vaccination. The lack of prepandemic data prevented a full understanding
Published: 2022

21. Infliximab biosimilar-to-biosimilar switching in patients with inflammatory rheumatic disease:Clinical outcomes in real-world patients from the DANBIO registry

Author: Nabi, Hafsah, Hendricks, Oliver, Jensen, Dorte Vendelbo, Loft, Anne Gitte, Pedersen, Jens Kristian, Just, Søren Andreas, Danebod, Kamilla, Munk, Heidi Lausten, Kristensen, Salome, Manilo, Natalia, Colic, Ada, Linauskas, Asta, Thygesen, Pia Høger, Christensen, Louise Brot, Kalisz, Maren Høgberget, Lomborg, Niels, Chrysidis, Stavros, Raun, Johnny Lillelund, Andersen, Marlene, Mehnert, Frank, Krogh, Niels Steen, Hetland, Merete Lund, Glintborg, Bente, Nabi, Hafsah, Hendricks, Oliver, Jensen, Dorte Vendelbo, Loft, Anne Gitte, Pedersen, Jens Kristian, Just, Søren Andreas, Danebod, Kamilla, Munk, Heidi Lausten, Kristensen, Salome, Manilo, Natalia, Colic, Ada, Linauskas, Asta, Thygesen, Pia Høger, Christensen, Louise Brot, Kalisz, Maren Høgberget, Lomborg, Niels, Chrysidis, Stavros, Raun, Johnny Lillelund, Andersen, Marlene, Mehnert, Frank, Krogh, Niels Steen, Hetland, Merete Lund, and Glintborg, Bente
Abstract: Objective Successful uptake of biosimilars in rheumatology is limited by lack of real-world evidence regarding effectiveness of biosimilar-to-biosimilar switching. We investigated infliximab biosimilars CT-P13-to-GP1111 switching among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). Methods Observational cohort study from the DANBIO registry. Patients were classified as originator-naïve or originator-experienced. Retention rates of 1-year GP1111 treatment were explored (Kaplan-Meier). We identified baseline factors (at the time of switch) associated with withdrawal of GP1111 (multivariable Cox-regression analyses with HRs including originator treatment history). Changes in subjective and objective measures of disease activity 4 months before and after the switch were assessed in individual patients. Results Of 1605 patients (685 RA, 314 PsA and 606 AxSpA, median disease duration was 9 years, 37% in Clinical Disease Activity Index/Ankylosing Spondylitis Disease Activity Score remission), 1171 were originator-naïve. Retention rates at 1-year were 83% (95% CI: 81% to 85%) and 92% (95% CI: 90% to 95%) for the originator-naïve and originator-experienced, respectively. GP1111 retention rates were higher in originator-experienced compared to originator-naïve with RA (HR=0.4 (95% CI: 0.2 to 0.7)) and PsA (HR=0.2 (95% CI: 0.1 to 0.8)), but not significantly for AxSpA: HR=0.6 (95% CI: 0.3 to 1.2). Lower disease activity was associated with higher retention. Changes in disease activity preswitch and postswitch were close to zero. Conclusion This real-world observational study of more than 1600 patients with inflammatory arthritis showed high 1-year retention following a nationwide infliximab biosimilar-to-biosimilar switch. Retention was higher in originator-experienced and in patients with low disease activity, suggesting outcomes to be affected by patient-related rather than drug-related factors.
Published: 2022

22. Nationwide, large-scale implementation of an online system for remote entry of patient-reported outcomes in rheumatology:characteristics of users and non-users and time to first entry

Author: Glintborg, Bente, Jensen, Dorte Vendelbo, Terslev, Lene, Hendricks, Oliver, Østergaard, Mikkel, Rasmussen, Simon Horskjær, Jensen, Mogens Pfeiffer, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Sørensen, Christian Møller, Krogh, Niels Steen, Agerbo, Jette, Ziegler, Connie, Hetland, Merete Lund, Glintborg, Bente, Jensen, Dorte Vendelbo, Terslev, Lene, Hendricks, Oliver, Østergaard, Mikkel, Rasmussen, Simon Horskjær, Jensen, Mogens Pfeiffer, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Sørensen, Christian Møller, Krogh, Niels Steen, Agerbo, Jette, Ziegler, Connie, and Hetland, Merete Lund
Abstract: Aims In May 2020, a nationwide, web-based system for remote entry of patient-reported outcomes (PROs) in inflammatory rheumatic diseases was launched and implemented in routine care (DANBIO-from-home). After 1.5 years of use, we explored clinical characteristics of patients who did versus did not use the system, and the time to first entry of PROs. Methods All patients followed in DANBIO were informed about DANBIO-from-home by electronic invitations or when attending their clinic. Characteristics of patients who did/did not use DANBIO-from-home in the period after implementation were explored by multivariable logistic regression analyses including demographic and clinical variables (gender, age group, diagnosis, disease duration, use of biological disease-modifying agent (bDMARD), Health Assessment Questionnaire (HAQ), Patient Acceptable Symptom Scale (PASS)). Time from launch to first entry was presented as cumulative incidence curves by age group (<40/40-60/61-80/>80 years). Results Of 33 776 patients, 68% entered PROs using DANBIO-from-home at least once. Median (IQR) time to first entry was 27 (11-152) days. Factors associated with data entry in multivariate analyses (OR (95% CI)) were: female gender (1.19 (1.12 to 1.27)), bDMARD treatment (1.41 (1.33 to 1.50)), age 40-60 years (1.79 (1.63 to 1.97)), 61-80 years (1.87 (1.70 to 2.07), or age >80 years (0.57 (0.50 to 0.65)) (reference: age <40 years), lower HAQ (0.68 (0.65 to 0.71)) and PASS 'no' (1.09 (1.02 to 1.17). Diagnosis was not associated. Time to first entry of PROs was longest in patients <40 years of age (119 (24-184) days) and shortest in the 61-80 years age group (25 (8-139) days). Conclusion A nationwide online platform for PRO in rheumatology achieved widespread use. Higher age, male gender, conventional treatment and disability were associated with no use.
Published: 2022

23. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce., Funding Agencies|NORDFORSK [90825]; Swedish Research Council [2018-02803]; Swedish innovation Agency (Vinnova); Innovationsfonden; The Research Council of Norway; Region Stockholm-Karolinska Institutet; Region Vasterbotten (ALF); Danish Rheumatism Association [R194-A6956, A1923, A3037, A3570]; Swedish Brain Foundation; Nils and Bibbi Jensens Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; South-Eastern Heath Region of Norway; Health Research Fund of Central Denmark Region; Region of Southern Denmark; A.P. Moller Foundation for the Advancement of Medical Science; Colitis-Crohn Foreningen; Novo Nordisk Foundation [NNF15OC0016932]; Aase og Ejnar Danielsens Fond; Beckett-Fonden; Augustinus Fonden; Knud and Edith Eriksens Mindefond; Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis Legat; Psoriasis Forskningsfonden; University of Aarhus; Region of Southern Denmarks PhD Fund [12/7725]; Department of Rheumatology, Frederiksberg Hospital; Research Council of Norway [229624, 223273]; South East and Western Norway Health Authorities; ERC AdG project SELECTionPREDISPOSED; Stiftelsen Kristian Gerhard Jebsen; Trond Mohn Foundation; Novo Nordisk Foundation; University of Bergen
Published: 2022
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24. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Arlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapaa-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce., Funding Agencies|NORDFORSK [90825]; Swedish Research Council [2018-02803]; Swedish innovation Agency (Vinnova); Innovationsfonden; The Research Council of Norway; Region Stockholm-Karolinska Institutet; Region Vasterbotten (ALF); Danish Rheumatism Association [R194-A6956, A1923, A3037, A3570]; Swedish Brain Foundation; Nils and Bibbi Jensens Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; South-Eastern Heath Region of Norway; Health Research Fund of Central Denmark Region; Region of Southern Denmark; A.P. Moller Foundation for the Advancement of Medical Science; Colitis-Crohn Foreningen; Novo Nordisk Foundation [NNF15OC0016932]; Aase og Ejnar Danielsens Fond; Beckett-Fonden; Augustinus Fonden; Knud and Edith Eriksens Mindefond; Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis Legat; Psoriasis Forskningsfonden; University of Aarhus; Region of Southern Denmarks PhD Fund [12/7725]; Department of Rheumatology, Frederiksberg Hospital; Research Council of Norway [229624, 223273]; South East and Western Norway Health Authorities; ERC AdG project SELECTionPREDISPOSED; Stiftelsen Kristian Gerhard Jebsen; Trond Mohn Foundation; Novo Nordisk Foundation; University of Bergen
Published: 2022
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25. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author: Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena, I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall, I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Stefansson, Kari, Saevarsdottir, Saedis, Stefansdottir, Lilja, Sulem, Patrick, Thorleifsson, Gudmar, Ferkingstad, Egil, Rutsdottir, Gudrun, Glintborg, Bente, Westerlind, Helga, Grondal, Gerdur, Loft, Isabella C., Sorensen, Signe Bek, Lie, Benedicte A., Brink, Mikael, Ärlestig, Lisbeth, Arnthorsson, Asgeir Orn, Baecklund, Eva, Banasik, Karina, Bank, Steffen, Bjorkman, Lena, I, Ellingsen, Torkell, Erikstrup, Christian, Frei, Oleksandr, Gjertsson, Inger, Gudbjartsson, Daniel F., Gudjonsson, Sigurjon A., Halldorsson, Gisli H., Hendricks, Oliver, Hillert, Jan, Hogdall, Estrid, Jacobsen, Soren, Jensen, Dorte Vendelbo, Jonsson, Helgi, Kastbom, Alf, Kockum, Ingrid, Kristensen, Salome, Kristjansdottir, Helga, Larsen, Margit H., Linauskas, Asta, Hauge, Ellen-Margrethe, Loft, Anne G., Ludviksson, Bjorn R., Lund, Sigrun H., Markusson, Thorsteinn, Masson, Gisli, Melsted, Pall, Moore, Kristjan H. S., Munk, Heidi, Nielsen, Kaspar R., Norddahl, Gudmundur L., Oddsson, Asmundur, Olafsdottir, Thorunn A., Olason, Pall, I, Olsson, Tomas, Ostrowski, Sisse Rye, Horslev-Petersen, Kim, Rognvaldsson, Solvi, Sanner, Helga, Silberberg, Gilad N., Stefansson, Hreinn, Sorensen, Erik, Sorensen, Inge J., Turesson, Carl, Bergman, Thomas, Alfredsson, Lars, Kvien, Tore K., Brunak, Soren, Steinsson, Kristjan, Andersen, Vibeke, Andreassen, Ole A., Rantapää-Dahlqvist, Solbritt, Hetland, Merete Lund, Klareskog, Lars, Askling, Johan, Padyukov, Leonid, Pedersen, Ole Bv, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari
Abstract: Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
Published: 2022
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26. Impact of the COVID-19 pandemic on treat-to-target strategies and physical consultations in >7000 patients with inflammatory arthritis

Author: Glintborg, Bente, Jensen, Dorte Vendelbo, Terslev, Lene, Pfeiffer Jensen, Mogens, Hendricks, Oliver, Østergaard, Mikkel, Engel, Sara, Horskjær Rasmussen, Simon, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Møller Sørensen, Christian, Krogh, Niels Steen, Nørgaard Agerbo, Jette, Ziegler, Connie, Hetland, Merete Lund, Glintborg, Bente, Jensen, Dorte Vendelbo, Terslev, Lene, Pfeiffer Jensen, Mogens, Hendricks, Oliver, Østergaard, Mikkel, Engel, Sara, Horskjær Rasmussen, Simon, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Møller Sørensen, Christian, Krogh, Niels Steen, Nørgaard Agerbo, Jette, Ziegler, Connie, and Hetland, Merete Lund
Abstract: OBJECTIVES: To explore the impact of the COVID-19 pandemic on treat-to-target strategies (disease activity, remission rates) and access to physical consultations in patients with inflammatory rheumatic disease, as well as to explore characteristics of patients with/without physical consultations in the clinic and the impact of early vs established disease. METHODS: Patients with RA, PsA or axial SpA (axSpA) prospectively followed in the nationwide DANBIO registry answered online questionnaires and reported patient-reported outcomes (PROs) in June and November 2020. Patient characteristics, disease activity and physical consultations in the clinic before and during the pandemic were identified in DANBIO [all patients and subgroups with early disease (disease duration ≤2 years)]. In individual patients, changes in PROs before and during the pandemic were calculated. Characteristics of patients with/without physical consultations were described (age, gender, education level, comorbidities, disease duration, treatment). RESULTS: We included 7836 patients (22% of eligible patients), 12% of which had early disease. PROs were stable before and during the pandemic, with median changes approximating zero, as well as in patients with early disease. Remission rates were stable. The relative decrease in the number of patients with physical consultations was 21-72%, which was highest in axSpA. Characteristics of patients with/without physical consultations were similar. Self-reported satisfaction with treatment options and access was >70%; the preferred contact form was physical consultation (66%). CONCLUSION: In this nationwide study performed during the first 8 months of the pandemic, patient satisfaction was high and the PROs and remission rates remained stable despite the remarkable reduction in physical consultations, as well as in patients with early disease. Characteristics of patients with/without physical consultations appeared similar.
Published: 2021

27. Safety and efficacy of faecal microbiota transplantation for active peripheral psoriatic arthritis:An exploratory randomised placebo-controlled trial

Author: Kragsnaes, Maja Skov, Kjeldsen, Jens, Horn, Hans Christian, Munk, Heidi Lausten, Pedersen, Jens Kristian, Just, Søren Andreas, Ahlquist, Palle, Pedersen, Finn Moeller, de Wit, Maarten, Möller, Sören, Andersen, Vibeke, Kristiansen, Karsten, Kinggaard Holm, Dorte, Holt, Hanne Marie, Christensen, Robin, Ellingsen, Torkell, Kragsnaes, Maja Skov, Kjeldsen, Jens, Horn, Hans Christian, Munk, Heidi Lausten, Pedersen, Jens Kristian, Just, Søren Andreas, Ahlquist, Palle, Pedersen, Finn Moeller, de Wit, Maarten, Möller, Sören, Andersen, Vibeke, Kristiansen, Karsten, Kinggaard Holm, Dorte, Holt, Hanne Marie, Christensen, Robin, and Ellingsen, Torkell
Abstract: Objectives: Although causality remains to be established, targeting dysbiosis of the intestinal microbiota by faecal microbiota transplantation (FMT) has been proposed as a novel treatment for inflammatory diseases. In this exploratory, proof-of-concept study, we evaluated the safety and efficacy of FMT in psoriatic arthritis (PsA). Methods: In this double-blind, parallel-group, placebo-controlled, superiority trial, we randomly allocated (1:1) adults with active peripheral PsA (≥3 swollen joints) despite ongoing treatment with methotrexate to one gastroscopic-guided FMT or sham transplantation into the duodenum. Safety was monitored throughout the trial. The primary efficacy endpoint was the proportion of participants experiencing treatment failure (ie, needing treatment intensification) through 26 weeks. Key secondary endpoints were change in Health Assessment Questionnaire Disability Index (HAQ-DI) and American College of Rheumatology (ACR20) response at week 26. Results: Of 97 screened, 31 (32%) underwent randomisation (15 allocated to FMT) and 30 (97%) completed the 26-week clinical evaluation. No serious adverse events were observed. Treatment failure occurred more frequently in the FMT group than in the sham group (9 (60%) vs 3 (19%); risk ratio, 3.20; 95% CI 1.06 to 9.62; p=0.018). Improvement in HAQ-DI differed between groups (0.07 vs 0.30) by 0.23 points (95% CI 0.02 to 0.44; p=0.031) in favour of sham. There was no difference in the proportion of ACR20 responders between groups (7 of 15 (47%) vs 8 of 16 (50%)). Conclusions: In this first preliminary, interventional randomised controlled trial of FMT in immune-mediated arthritis, we did not observe any serious adverse events. Overall, FMT appeared to be inferior to sham in treating active peripheral PsA. Trial registration number: NCT03058900.
Published: 2021

28. Anxiety and concerns related to the work situation during the second wave of the COVID-19 pandemic in >5000 patients with inflammatory rheumatic disease followed in the DANBIO registry

Author: Glintborg, Bente, Jensen, Dorte Vendelbo, Engel, Sara, Terslev, Lene, Pfeiffer Jensen, Mogens, Hendricks, Oliver, Østergaard, Mikkel, Horskjær Rasmussen, Simon, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Møller Sørensen, Christian, Krogh, Niels Steen, Nørgaard Agerbo, Jette, Ziegler, Connie, Lund Hetland, Merete, Glintborg, Bente, Jensen, Dorte Vendelbo, Engel, Sara, Terslev, Lene, Pfeiffer Jensen, Mogens, Hendricks, Oliver, Østergaard, Mikkel, Horskjær Rasmussen, Simon, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Møller Sørensen, Christian, Krogh, Niels Steen, Nørgaard Agerbo, Jette, Ziegler, Connie, and Lund Hetland, Merete
Published: 2021

29. Comparative effectiveness of two adalimumab biosimilars in 1318 real-world patients with inflammatory rheumatic disease mandated to switch from originator adalimumab:Nationwide observational study emulating a randomised clinical trial

Author: Nabi, Hafsah, Georgiadis, Stylianos, Loft, Anne Gitte, Hendricks, Oliver, Andersen, Marlene, Chrysidis, Stavros, Colic, Ada, Danebod, Kamilla, Hussein, Mohamad Redha, Kalisz, Maren Høgberget, Kristensen, Salome, Lomborg, Niels, Manilo, Natalia, Munk, Heidi Lausten, Pedersen, Jens Kristian, Raun, Johnny Lillelund, Mehnert, Frank, Krogh, Niels Steen, Hetland, Merete Lund, Glintborg, Bente, Nabi, Hafsah, Georgiadis, Stylianos, Loft, Anne Gitte, Hendricks, Oliver, Andersen, Marlene, Chrysidis, Stavros, Colic, Ada, Danebod, Kamilla, Hussein, Mohamad Redha, Kalisz, Maren Høgberget, Kristensen, Salome, Lomborg, Niels, Manilo, Natalia, Munk, Heidi Lausten, Pedersen, Jens Kristian, Raun, Johnny Lillelund, Mehnert, Frank, Krogh, Niels Steen, Hetland, Merete Lund, and Glintborg, Bente
Abstract: Objectives: In 2018, a nationwide mandatory switch from originator to biosimilar adalimumab was conducted in Denmark. The available biosimilar was GP2017 (Hyrimoz) in Eastern regions and SB5 (Imraldi) in Western regions. We aimed to assess the comparative effectiveness of GP2017 versus SB5 in patients with rheumatoid arthritis (RA)/psoriatic arthritis (PsA)/axial spondyloarthritis (AxSpA). Methods: Observational cohort study based on the DANBIO registry with geographical cluster pseudo-randomisation, analysed by emulating a randomised clinical trial. Main outcome was adjusted 1-year treatment retention (Cox regression). Furthermore, 6 months' remission rates (logistic regression), reasons for withdrawal and back-switching to originator were investigated (overall and stratified by indication). Results: Overall, of 1570 eligible patients, 1318 switched and were included (467 RA/321 PsA/530 AxSpA); 623 (47%) switched to GP2017, 695 (53%) to SB5. Baseline characteristics of the two clusters were largely similar, but some differences in registration practice were observed. The combined 1-year retention rate for the two biosimilars was 89.5%. Compared with SB5, estimated risk of withdrawal for GP2017 was lower (HR 0.60; 95% CI 0.42 to 0.86) and 6 months' remission rate was higher (OR 1.72; 95% CI 1.25 to 2.37). Stratified analyses gave similar results (statistically significant for RA). During 1 year, 8.5% and 12.9% withdrew GP2017 and SB5, respectively (primarily lack of effect and adverse events), of whom 48 patients (3.6%) back-switched. Conclusion: This head-to-head comparison of GP2017 versus SB5 following a mandatory switch from the originator indicated differences in effectiveness in routine care. This may reflect a true difference, but other explanations, for example, differences in excipients, differences between clusters and residual confounding cannot be ruled out.
Published: 2021

30. Self-protection strategies and health behaviour in patients with inflammatory rheumatic diseases during the COVID-19 pandemic:Results and predictors in more than 12 000 patients with inflammatory rheumatic diseases followed in the Danish DANBIO registry

Author: Glintborg, Bente, Jensen, Dorte Vendelbo, Engel, Sara, Terslev, Lene, Pfeiffer Jensen, Mogens, Hendricks, Oliver, Ostergaard, Mikkel, Horskjær Rasmussen, Simon, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Møller Sørensen, Christian, Krogh, Niels Steen, Agerbo, Jette, Ziegler, Connie, Hetland, Merete, Glintborg, Bente, Jensen, Dorte Vendelbo, Engel, Sara, Terslev, Lene, Pfeiffer Jensen, Mogens, Hendricks, Oliver, Ostergaard, Mikkel, Horskjær Rasmussen, Simon, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Møller Sørensen, Christian, Krogh, Niels Steen, Agerbo, Jette, Ziegler, Connie, and Hetland, Merete
Abstract: Aims In Danish patients with inflammatory rheumatic diseases to explore self-protection strategies and health behaviour including adherence to disease-modifying antirheumatic treatment (DMARD) during the initial phase of the COVID-19 pandemic and again after the reopening of the society started. Furthermore, to identify characteristics of patients with high levels of anxiety and self-isolation. Methods Patients in routine care followed prospectively in the nationwide DANBIO registry were invited to answer an online questionnaire regarding disease activity and COVID-19 infection, behaviour in March and June 2020. Responses were linked to patient data in DANBIO. Characteristics potentially associated with anxiety, self-isolation and medication adherence (gender/age/diagnosis/education/work status/comorbidity/DMARD/smoking/EQ-5D/disease activity) were explored with multivariable logistic regression analyses. Results We included 12 789 patients (8168 rheumatoid arthritis/2068 psoriatic arthritis/1758 axial spondyloarthritis/795 other) of whom 65% were women and 36% treated with biological DMARD. Self-reported COVID-19 prevalence was 0.3%. Patients reported that they were worried to get COVID-19 infection (March/June: 70%/45%) and self-isolated more than others of the same age (48%/38%). The fraction of patients who changed medication due to fear of COVID-19 were 4.1%/0.6%. Female gender, comorbidities, not working, lower education, biological treatment and poor European Quality of life, 5 dimensions were associated with both anxiety and self-isolation. Conclusion In >12 000 patients with inflammatory arthritis, we found widespread anxiety and self-isolation, but high medication adherence, in the initial phase of the COVID-19 pandemic. This persisted during the gradual opening of society during the following months. Attention to patients' anxiety and self-isolation is important during this and potential future epidemics.
Published: 2021

31. Self-protection strategies and health behaviour in patients with inflammatory rheumatic diseases during the COVID-19 pandemic:Results and predictors in more than 12 000 patients with inflammatory rheumatic diseases followed in the Danish DANBIO registry

Author: Glintborg, Bente, Jensen, Dorte Vendelbo, Engel, Sara, Terslev, Lene, Pfeiffer Jensen, Mogens, Hendricks, Oliver, Ostergaard, Mikkel, Horskjær Rasmussen, Simon, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Møller Sørensen, Christian, Krogh, Niels Steen, Agerbo, Jette, Ziegler, Connie, Hetland, Merete, Glintborg, Bente, Jensen, Dorte Vendelbo, Engel, Sara, Terslev, Lene, Pfeiffer Jensen, Mogens, Hendricks, Oliver, Ostergaard, Mikkel, Horskjær Rasmussen, Simon, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Møller Sørensen, Christian, Krogh, Niels Steen, Agerbo, Jette, Ziegler, Connie, and Hetland, Merete
Abstract: Aims In Danish patients with inflammatory rheumatic diseases to explore self-protection strategies and health behaviour including adherence to disease-modifying antirheumatic treatment (DMARD) during the initial phase of the COVID-19 pandemic and again after the reopening of the society started. Furthermore, to identify characteristics of patients with high levels of anxiety and self-isolation. Methods Patients in routine care followed prospectively in the nationwide DANBIO registry were invited to answer an online questionnaire regarding disease activity and COVID-19 infection, behaviour in March and June 2020. Responses were linked to patient data in DANBIO. Characteristics potentially associated with anxiety, self-isolation and medication adherence (gender/age/diagnosis/education/work status/comorbidity/DMARD/smoking/EQ-5D/disease activity) were explored with multivariable logistic regression analyses. Results We included 12 789 patients (8168 rheumatoid arthritis/2068 psoriatic arthritis/1758 axial spondyloarthritis/795 other) of whom 65% were women and 36% treated with biological DMARD. Self-reported COVID-19 prevalence was 0.3%. Patients reported that they were worried to get COVID-19 infection (March/June: 70%/45%) and self-isolated more than others of the same age (48%/38%). The fraction of patients who changed medication due to fear of COVID-19 were 4.1%/0.6%. Female gender, comorbidities, not working, lower education, biological treatment and poor European Quality of life, 5 dimensions were associated with both anxiety and self-isolation. Conclusion In >12 000 patients with inflammatory arthritis, we found widespread anxiety and self-isolation, but high medication adherence, in the initial phase of the COVID-19 pandemic. This persisted during the gradual opening of society during the following months. Attention to patients' anxiety and self-isolation is important during this and potential future epidemics.
Published: 2021

32. Anxiety and concerns related to the work situation during the second wave of the COVID-19 pandemic in >5000 patients with inflammatory rheumatic disease followed in the DANBIO registry

Author: Glintborg, Bente, Jensen, Dorte Vendelbo, Engel, Sara, Terslev, Lene, Pfeiffer Jensen, Mogens, Hendricks, Oliver, Østergaard, Mikkel, Horskjær Rasmussen, Simon, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Møller Sørensen, Christian, Krogh, Niels Steen, Nørgaard Agerbo, Jette, Ziegler, Connie, Lund Hetland, Merete, Glintborg, Bente, Jensen, Dorte Vendelbo, Engel, Sara, Terslev, Lene, Pfeiffer Jensen, Mogens, Hendricks, Oliver, Østergaard, Mikkel, Horskjær Rasmussen, Simon, Adelsten, Thomas, Colic, Ada, Danebod, Kamilla, Kildemand, Malene, Loft, Anne Gitte, Munk, Heidi Lausten, Pedersen, Jens Kristian, Østgård, René Drage, Møller Sørensen, Christian, Krogh, Niels Steen, Nørgaard Agerbo, Jette, Ziegler, Connie, and Lund Hetland, Merete
Published: 2021

33. Impact of red and processed meat and fibre intake on treatment outcomes among patients with chronic inflammatory diseases:protocol for a prospective cohort study of prognostic factors and personalised medicine

Author: Christensen, Robin, Heitmann, Berit L., Andersen, Karina Winther, Nielsen, Ole Haagen, Sørensen, Signe Bek, Jawhara, Mohamad, Bygum, Anette, Hvid, Lone, Grauslund, Jakob, Wied, Jimmi, Glerup, Henning, Fredberg, Ulrich, Villadsen, Jan Alexander, Kjær, Søren Geill, Fallingborg, Jan, Moghadd, Seyed A. G. R., Knudsen, Torben, Brodersen, Jacob, Frøjk, Jesper, Dahlerup, Jens Frederik, Bojesen, Anders Bo, Sørensen, Grith Lykke, Thiel, Steffen, Færgeman, Nils J., Brandslund, Ivan, Bennike, Tue Bjerg, Stensballe, Allan, Schmidt, Erik Berg, Franke, Andre, Ellinghaus, David, Rosenstiel, Philip, Raes, Jeroen, Boye, Mette, Werner, Lars, Nielsen, Charlotte Lindgaard, Munk, Heidi Lausten, Nexoe, Anders Bathum, Ellingsen, Torkell, Holmskov, Uffe, Kjeldsen, Jens, Andersen, Vibeke, Christensen, Robin, Heitmann, Berit L., Andersen, Karina Winther, Nielsen, Ole Haagen, Sørensen, Signe Bek, Jawhara, Mohamad, Bygum, Anette, Hvid, Lone, Grauslund, Jakob, Wied, Jimmi, Glerup, Henning, Fredberg, Ulrich, Villadsen, Jan Alexander, Kjær, Søren Geill, Fallingborg, Jan, Moghadd, Seyed A. G. R., Knudsen, Torben, Brodersen, Jacob, Frøjk, Jesper, Dahlerup, Jens Frederik, Bojesen, Anders Bo, Sørensen, Grith Lykke, Thiel, Steffen, Færgeman, Nils J., Brandslund, Ivan, Bennike, Tue Bjerg, Stensballe, Allan, Schmidt, Erik Berg, Franke, Andre, Ellinghaus, David, Rosenstiel, Philip, Raes, Jeroen, Boye, Mette, Werner, Lars, Nielsen, Charlotte Lindgaard, Munk, Heidi Lausten, Nexoe, Anders Bathum, Ellingsen, Torkell, Holmskov, Uffe, Kjeldsen, Jens, and Andersen, Vibeke
Published: 2018

34. Efficacy and safety of faecal microbiota transplantation in patients with psoriatic arthritis:protocol for a 6-month, double-blind, randomised, placebo-controlled trial

Author: Kragsnæs, Maja Skov, Kjeldsen, Jens, Horn, Hans Christian, Munk, Heidi Lausten, Pedersen, Finn Møller, Holt, Hanne Marie, Pedersen, Jens Kristian, Holm, Dorte Kinggaard, Glerup, Henning, Andersen, Vibeke, Fredberg, Ulrich, Kristiansen, Karsten, Christensen, Robin, Ellingsen, Torkell, Kragsnæs, Maja Skov, Kjeldsen, Jens, Horn, Hans Christian, Munk, Heidi Lausten, Pedersen, Finn Møller, Holt, Hanne Marie, Pedersen, Jens Kristian, Holm, Dorte Kinggaard, Glerup, Henning, Andersen, Vibeke, Fredberg, Ulrich, Kristiansen, Karsten, Christensen, Robin, and Ellingsen, Torkell
Published: 2018

35. Impact of red and processed meat and fibre intake on treatment outcomes among patients with chronic inflammatory diseases:protocol for a prospective cohort study of prognostic factors and personalised medicine

Author: Christensen, Robin, Heitmann, Berit L., Andersen, Karina Winther, Nielsen, Ole Haagen, Sørensen, Signe Bek, Jawhara, Mohamad, Bygum, Anette, Hvid, Lone, Grauslund, Jakob, Wied, Jimmi, Glerup, Henning, Fredberg, Ulrich, Villadsen, Jan Alexander, Kjær, Søren Geill, Fallingborg, Jan, Moghadd, Seyed A. G. R., Knudsen, Torben, Brodersen, Jacob, Frøjk, Jesper, Dahlerup, Jens Frederik, Bojesen, Anders Bo, Sørensen, Grith Lykke, Thiel, Steffen, Færgeman, Nils J., Brandslund, Ivan, Bennike, Tue Bjerg, Stensballe, Allan, Schmidt, Erik Berg, Franke, Andre, Ellinghaus, David, Rosenstiel, Philip, Raes, Jeroen, Boye, Mette, Werner, Lars, Nielsen, Charlotte Lindgaard, Munk, Heidi Lausten, Nexoe, Anders Bathum, Ellingsen, Torkell, Holmskov, Uffe, Kjeldsen, Jens, Andersen, Vibeke, Christensen, Robin, Heitmann, Berit L., Andersen, Karina Winther, Nielsen, Ole Haagen, Sørensen, Signe Bek, Jawhara, Mohamad, Bygum, Anette, Hvid, Lone, Grauslund, Jakob, Wied, Jimmi, Glerup, Henning, Fredberg, Ulrich, Villadsen, Jan Alexander, Kjær, Søren Geill, Fallingborg, Jan, Moghadd, Seyed A. G. R., Knudsen, Torben, Brodersen, Jacob, Frøjk, Jesper, Dahlerup, Jens Frederik, Bojesen, Anders Bo, Sørensen, Grith Lykke, Thiel, Steffen, Færgeman, Nils J., Brandslund, Ivan, Bennike, Tue Bjerg, Stensballe, Allan, Schmidt, Erik Berg, Franke, Andre, Ellinghaus, David, Rosenstiel, Philip, Raes, Jeroen, Boye, Mette, Werner, Lars, Nielsen, Charlotte Lindgaard, Munk, Heidi Lausten, Nexoe, Anders Bathum, Ellingsen, Torkell, Holmskov, Uffe, Kjeldsen, Jens, and Andersen, Vibeke
Published: 2018

36. Efficacy and safety of faecal microbiota transplantation in patients with psoriatic arthritis:protocol for a 6-month, double-blind, randomised, placebo-controlled trial

Author: Kragsnæs, Maja Skov, Kjeldsen, Jens, Horn, Hans Christian, Munk, Heidi Lausten, Pedersen, Finn Møller, Holt, Hanne Marie, Pedersen, Jens Kristian, Holm, Dorte Kinggaard, Glerup, Henning, Andersen, Vibeke, Fredberg, Ulrich, Kristiansen, Karsten, Christensen, Robin, Ellingsen, Torkell, Kragsnæs, Maja Skov, Kjeldsen, Jens, Horn, Hans Christian, Munk, Heidi Lausten, Pedersen, Finn Møller, Holt, Hanne Marie, Pedersen, Jens Kristian, Holm, Dorte Kinggaard, Glerup, Henning, Andersen, Vibeke, Fredberg, Ulrich, Kristiansen, Karsten, Christensen, Robin, and Ellingsen, Torkell
Published: 2018

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