HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease

被引:306
作者
Sazonovs, Aleksejs [1 ]
Kennedy, Nicholas A. [2 ,3 ]
Moutsianas, Loukas [1 ]
Heap, Graham A. [2 ,4 ]
Rice, Daniel L. [1 ]
Reppell, Mark [4 ]
Bewshea, Claire M. [3 ]
Chanchlani, Neil [2 ,3 ]
Walker, Gareth J. [2 ,3 ]
Perry, Mandy H. [5 ]
McDonald, Timothy J. [5 ]
Lees, Charlie W. [6 ]
Cummings, J. R. Fraser [7 ,8 ]
Parkes, Miles [9 ]
Mansfield, John C. [10 ]
Irving, Peter M. [11 ]
Barrett, Jeffrey C. [1 ]
McGovern, Dermot [12 ]
Goodhand, James R. [2 ,3 ]
Anderson, Carl A. [1 ]
Ahmad, Tariq [2 ,3 ]
机构
[1] Wellcome Sanger Inst, Wellcome Genome Campus, Hinxton, England
[2] Royal Devon & Exeter Hosp Natl Hlth Serv Fdn Trus, Dept Gastroenterol, Exeter, Devon, England
[3] Univ Exeter, Exeter Inflammatory Bowel Dis & Pharmacogenet Res, Exeter, Devon, England
[4] AbbVie Inc, N Chicago, IL USA
[5] Royal Devon & Exeter Hosp Natl Hlth Serv Fdn Trus, Dept Blood Sci, Exeter, Devon, England
[6] Western Gen Hosp, Natl Hlth Serv Lothian, Dept Gastroenterol, Edinburgh, Midlothian, Scotland
[7] Univ Hosp Southampton Natl Hlth Serv Fdn Trust, Dept Gastroenterol, Southampton, Hants, England
[8] Univ Southampton, Fac Expt Med, Southampton, Hants, England
[9] Cambridge Univ Hosp Natl Hlth Serv Fdn Trust, Addenbrookes Hosp, Dept Gastroenterol, Cambridge, England
[10] Newcastle Upon Tyne Hosp Natl Hlth Serv Fdn Trust, Dept Gastroenterol, Newcastle Upon Tyne, Tyne & Wear, England
[11] Guys & St Thomas NHS Fdn Trust, Dept Gastroenterol, London, England
[12] Cedars Sinai Med Ctr, F Widjaja Fdn Inflammatory Bowel & Immunobiol Res, Los Angeles, CA 90048 USA
基金
英国惠康基金; 英国医学研究理事会;
关键词
PANTS; GWAS; Loss Of Response; Drug Persistence; GENOME-WIDE ASSOCIATION; COMBINATION THERAPY; AZATHIOPRINE; GENES; MONOTHERAPY; RISK;
D O I
10.1053/j.gastro.2019.09.041
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies. METHODS: We performed a genomewide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naive patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer >= 10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease. RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 x 10(-13)). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 x 10(-4)). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58). CONCLUSIONS: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies.
引用
收藏
页码:189 / 199
页数:11
相关论文
共 28 条
[1]   Immunogenicity to infliximab is associated with HLA-DRB1 [J].
Billiet, Thomas ;
Vande Casteele, Niels ;
Van Stappen, Thomas ;
Princen, Fred ;
Singh, Sharat ;
Gils, Ann ;
Ferrante, Marc ;
Van Assche, Gert ;
Cleynen, Isabelle ;
Vermeire, Severine .
GUT, 2015, 64 (08) :1344-U196
[2]   Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].
Burton, Paul R. ;
Clayton, David G. ;
Cardon, Lon R. ;
Craddock, Nick ;
Deloukas, Panos ;
Duncanson, Audrey ;
Kwiatkowski, Dominic P. ;
McCarthy, Mark I. ;
Ouwehand, Willem H. ;
Samani, Nilesh J. ;
Todd, John A. ;
Donnelly, Peter ;
Barrett, Jeffrey C. ;
Davison, Dan ;
Easton, Doug ;
Evans, David ;
Leung, Hin-Tak ;
Marchini, Jonathan L. ;
Morris, Andrew P. ;
Spencer, Chris C. A. ;
Tobin, Martin D. ;
Attwood, Antony P. ;
Boorman, James P. ;
Cant, Barbara ;
Everson, Ursula ;
Hussey, Judith M. ;
Jolley, Jennifer D. ;
Knight, Alexandra S. ;
Koch, Kerstin ;
Meech, Elizabeth ;
Nutland, Sarah ;
Prowse, Christopher V. ;
Stevens, Helen E. ;
Taylor, Niall C. ;
Walters, Graham R. ;
Walker, Neil M. ;
Watkins, Nicholas A. ;
Winzer, Thilo ;
Jones, Richard W. ;
McArdle, Wendy L. ;
Ring, Susan M. ;
Strachan, David P. ;
Pembrey, Marcus ;
Breen, Gerome ;
St Clair, David ;
Caesar, Sian ;
Gordon-Smith, Katherine ;
Jones, Lisa ;
Fraser, Christine ;
Green, Elain K. .
NATURE, 2007, 447 (7145) :661-678
[3]   Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease. [J].
Colombel, Jean Frederic ;
Sandborn, William J. ;
Reinisch, Walter ;
Mantzaris, Gerassimos J. ;
Kornbluth, Asher ;
Rachmilewitz, Daniel ;
Lichtiger, Simon ;
D'Haens, Geert ;
Diamond, Robert H. ;
Broussard, Delma L. ;
Tang, Kezhen L. ;
van der Woude, C. Janneke ;
Rutgeerts, Paul .
NEW ENGLAND JOURNAL OF MEDICINE, 2010, 362 (15) :1383-1395
[4]  
De Groot AS, 2005, DEV BIOLOGICALS, V122, P171
[5]   Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease [J].
de lange, Katrina M. ;
Moutsianas, Loukas ;
Lee, James C. ;
Lamb, Christopher A. ;
Luo, Yang ;
Kennedy, Nicholas A. ;
Jostins, Luke ;
Rice, Daniel L. ;
Gutierrez-Achuryl, Javier ;
Ji, Sun-Gou ;
Heap, Graham ;
Nimmo, Elaine R. ;
Edwards, Cathryn ;
Henderson, Paul ;
Mowat, Craig ;
Sanderson, Jeremy ;
Satsangi, Jack ;
Simmons, Alison ;
Wilson, David C. ;
Tremelling, Mark ;
Hart, Ailsa ;
Mathew, Christopher G. ;
Newman, William G. ;
Parkes, Miles ;
Lees, Charlie W. ;
Uhlig, Holm ;
Hawkey, Chris ;
Prescott, Natalie J. ;
Ahmad, Tariq ;
Mansfield, John C. ;
Anderson, Carl A. ;
Barrett, Jeffrey C. .
NATURE GENETICS, 2017, 49 (02) :256-261
[6]   Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways [J].
Eleftherohorinou, Hariklia ;
Hoggart, Clive J. ;
Wright, Victoria J. ;
Levin, Michael ;
Coin, Lachlan J. M. .
HUMAN MOLECULAR GENETICS, 2011, 20 (17) :3494-3506
[7]   Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations [J].
Gonzalez-Galarza, Faviel F. ;
Takeshita, Louise Y. C. ;
Santos, Eduardo J. M. ;
Kempson, Felicity ;
Thomaz Maia, Maria Helena ;
Soares da Silva, Andrea Luciana ;
Teles e Silva, Andre Luiz ;
Ghattaoraya, Gurpreet S. ;
Alfirevic, Ana ;
Jones, Andrew R. ;
Middleton, Derek .
NUCLEIC ACIDS RESEARCH, 2015, 43 (D1) :D784-D788
[8]   High-density mapping of the MHC identifies a shared role for HLA-DRB1☆01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis [J].
Goyette, Philippe ;
Boucher, Gabrielle ;
Mallon, Dermot ;
Ellinghaust, Eva ;
Jostins, Luke ;
Huang, Hailiang ;
Ripke, Stephan ;
Gusareva, Elena S. ;
Annese, Vito ;
Hauser, Stephen L. ;
Oksenberg, Jorge R. ;
Thomsent, Ingo ;
Leslie, Stephen ;
Daly, Mark J. ;
Van Steen, Kristel ;
Duerr, Richard H. ;
Barrett, Jeffrey C. ;
McGovern, Dermot P. B. ;
Schumm, L. Philip ;
Traherne, James A. ;
Carrington, Mary N. ;
Kosmoliaptsis, Vasilis ;
Karsen, Tom H. ;
Franke, Andre ;
Rioux, John D. .
NATURE GENETICS, 2015, 47 (02) :172-179
[9]  
IQVIA Institute, GLOB US MED 2019 OUT
[10]  
Johnson J. L., 2017, BIORXIV, P164343