European Journal of Clinical Pharmacology

, Volume 69, Issue 3, pp 431–438

Influence of polymorphisms and TNF and IL1β serum concentration on the infliximab response in Crohn’s disease and ulcerative colitis

  • Diana Lacruz-Guzmán
  • Daniel Torres-Moreno
  • Francisco Pedrero
  • Patricia Romero-Cara
  • Iván García-Tercero
  • Javier Trujillo-Santos
  • Pablo Conesa-Zamora



Inflammatory bowel diseases (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC), are partially attributable to an increased secretion of proinflamatory cytokines, such as tumour necrosis factor (TNF) and interleukin-1β (IL1β), which play essential roles in the disease pathogenesis and are target molecules for specific therapy. Given the inter-individual variability in the response to the anti-TNF monoclonal antibody infliximab, the aim of our study was to explore the predictive value of TNF and/or IL1β as surrogate markers of infliximab response.


Serial serum concentrations of TNF and IL1β and TNF promoter region and IL1B polymorphisms were determined in 47 patients (29 CD and 18 UC) receiving infliximab and correlated with treatment response.


Baseline serum concentrations of TNF and IL1β were higher in UC patients than in CD patients (p = 0.0097 and 0.0024, respectively). CD patients showing <0.64 pg/ml IL1β at baseline were more frequently responders than non-responders (p = 0.036), and the C allele of the IL1B polymorphism was associated with higher IL1β serum concentrations (p = 0.026) and with poorer clinical remission after 14 weeks of infliximab treatment. No significant association was found between serum TNF concentration or TNF polymorphism and patient response to infliximab.


This is the first study evaluating the pharmacogenetic role of the rs1143634 polymorphism of IL1B and TNF polymorphisms in infliximab-treated IBD patients. We found an association between the rs1143634 C allele and higher serum IL1β concentrations and a lower response to infliximab treatment in CD patients that warrants the interest of future studies in larger and independent series.


Tumour necrosis factor Interleukin-1 Infliximab Crohn’s disease Pharmacogenetics Ulcerative colitis 


  1. 1.
    Shih DQ, Targan SR, McGovern D (2008) Recent advances in IBD pathogenesis: genetics and immunobiology. Curr Gastroenterol Rep 10(6):568–575PubMedCrossRefGoogle Scholar
  2. 2.
    Tsianos EV, Katsanos KH, Tsianos VE (2012) Role of genetics in the diagnosis and prognosis of Crohn’s disease. World J Gastroenterol 18(2):105–118PubMedCrossRefGoogle Scholar
  3. 3.
    Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP, Raedler A (1993) Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol 94(1):174–181PubMedCrossRefGoogle Scholar
  4. 4.
    Reenaers C, Louis E, Belaiche J (2010) Current directions of biologic therapies in inflammatory bowel disease. Ther Adv Gastroenterol 3(2):99–106CrossRefGoogle Scholar
  5. 5.
    González S, Rodrigo L, Martínez-Borra J, López-Vázquez A, Fuentes D, Niño P, Cadahía V, Saro C, Dieguez MA, López-Larrea C (2003) TNF-alpha -308A promoter polymorphism is associated with enhanced TNF-alpha production and inflammatory activity in Crohn’s patients with fistulizing disease. Am J Gastroenterol 98(5):1101–1106PubMedGoogle Scholar
  6. 6.
    Louis E, Vermeire S, Rutgeerts P, De Vos M, Van Gossum A, Pescatore P, Fiasse R, Pelckmans P, Reynaert H, D'Haens G, Malaise M, Belaiche J (2002) A positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with -308 TNF gene polymorphism. Scand J Gastroenterol 37(7):818–824PubMedGoogle Scholar
  7. 7.
    Mascheretti S, Hampe J, Kühbacher T, Herfarth H, Krawczak M, Fölsch UR, Schreiber S (2002) Pharmacogenetic investigation of the TNF/TNF-receptor system in patients with chronic active Crohn’s disease treated with infliximab. Pharmacogenomics J 2(2):127–136PubMedCrossRefGoogle Scholar
  8. 8.
    Tomita K, Chiba T, Sugai T, Habano W (2010) Association between tumor necrosis factor-alpha and Fc-gamma receptor polymorphisms with infliximab in Crohn’s disease. Hepatogastroenterology 57(99–100):535–539PubMedGoogle Scholar
  9. 9.
    Matsukura H, Ikeda S, Yoshimura N, Takazoe M, Muramatsu M (2008) Genetic polymorphisms of tumour necrosis factor receptor superfamily 1A and 1B affect responses to infliximab in Japanese patients with Crohn’s disease. Aliment Pharmacol Ther 27(9):765–770PubMedCrossRefGoogle Scholar
  10. 10.
    Pierik M, Vermeire S, Steen KV, Joossens S, Claessens G, Vlietinck R, Rutgeerts P (2004) Tumour necrosis factor-alpha receptor 1 and 2 polymorphisms in inflammatory bowel disease and their association with response to infliximab. Aliment Pharmacol Ther 20(3):303–310PubMedCrossRefGoogle Scholar
  11. 11.
    Louis EJ, Watier HE, Schreiber S, Hampe J, Taillard F, Olson A, Thorne N, Zhang H, Colombel JF (2006) Polymorphism in IgG Fc receptor gene FCGR3A and response to infliximab in Crohn’s disease: a subanalysis of the ACCENT I study. Pharmacogenet Genomics 16(12):911–914PubMedCrossRefGoogle Scholar
  12. 12.
    Satsangi J, Silverberg MS, Vermeire S, Colombel JF (2006) The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 55(6):749–753PubMedCrossRefGoogle Scholar
  13. 13.
    Lichtiger S, Present DH, Kornbluth A et al (1994) Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 330:1841–1845PubMedCrossRefGoogle Scholar
  14. 14.
    Mata M, Morcillo E, Gimeno C, Cortijo J (2011) N-acetyl-l-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type II epithelial cells infected with influenza virus A and B and with respiratory syncytial virus (RSV). Biochem Pharmacol 82(5):548–555PubMedCrossRefGoogle Scholar
  15. 15.
    Morales-Lara MJ, Cañete JD, Torres-Moreno D, Hernández MV, Pedrero F, Celis R, García-Simón MS, Conesa-Zamora P (2012) Effects of polymorphisms in TRAILR1 and TNFR1A on the response to anti-TNF therapies in patients with rheumatoid and psoriatic arthritis. Joint Bone Spine. doi:10.1016/j.jbspin.2012.02.003
  16. 16.
    Fenoglio-Preiser CM, Noffsinger AE, Stemmermann GN, Lantz PE, Isaacson PG (2008) Inflammatory bowel diseases. In: Fenoglio-Preiser CM, Noffsinger AE, Stemmermann GN, Lantz PE, Isaacson PG (eds) Gastrointestinal pathology: an atlas and text. Lippincott Williams & Wilkins, Philadelphia, pp 593–689Google Scholar
  17. 17.
    Zabaleta J, Camargo MC, Piazuelo MB, Fontham E, Schneider BG, Sicinschi LA, Ferrante W, Balart L, Correa P, Ochoa AC (2006) Association of interleukin-1beta gene polymorphisms with precancerous gastric lesions in African Americans and Caucasians. Am J Gastroenterol 101(1):163–171PubMedCrossRefGoogle Scholar
  18. 18.
    Cimaz R, Cazalis MA, Reynaud C, Gerloni V, Zulian F, Biggioggero M, Martini G, Pontikaki I, Fantini F, Mougin B, Miossec P (2007) IL1 and TNF gene polymorphisms in patients with juvenile idiopathic arthritis treated with TNF inhibitors. Ann Rheum Dis 66(7):900–904PubMedCrossRefGoogle Scholar
  19. 19.
    Carter KW, Hung J, Powell BL, Wiltshire S, Foo BT, Leow YC, McQuillan BM, Jennens M, McCaskie PA, Thompson PL, Beilby JP, Palmer LJ (2008) Association of Interleukin-1 gene polymorphisms with central obesity and metabolic syndrome in a coronary heart disease population. Hum Genet 124(3):199–206PubMedCrossRefGoogle Scholar
  20. 20.
    Solovieva S, Kämäräinen OP, Hirvonen A, Hämäläinen S, Laitala M, Vehmas T, Luoma K, Näkki A, Riihimäki H, Ala-Kokko L, Männikkö M, Leino-Arjas P (2009) Association between interleukin 1 gene cluster polymorphisms and bilateral distal interphalangeal osteoarthritis. J Rheumatol 36(9):1977–1986PubMedCrossRefGoogle Scholar
  21. 21.
    Yilmaz IA, Ozge A, Erdal ME, Edgünlü TG, Cakmak SE, Yalin OO (2010) Cytokine polymorphism in patients with migraine: some suggestive clues of migraine and inflammation. Pain Med 11(4):492–497PubMedCrossRefGoogle Scholar
  22. 22.
    Na KS, Mok JW, Kim JY, Joo CK (2011) Proinflammatory gene polymorphisms are potentially associated with Korean non-Sjogren dry eye patients. Mol Vis 17:2818–2823PubMedGoogle Scholar
  23. 23.
    Camp NJ, Cox A, di Giovine FS, McCabe D, Rich W, Duff GW (2005) Evidence of a pharmacogenomic response to interleukin-l receptor antagonist in rheumatoid arthritis. Genes Immun 6(6):467–471PubMedCrossRefGoogle Scholar
  24. 24.
    Tolusso B, Pietrapertosa D, Morelli A, De Santis M, Gremese E, Farina G, Carniello SG, Del Frate M, Ferraccioli G (2006) IL-1B and IL-1RN gene polymorphisms in rheumatoid arthritis: relationship with protein plasma levels and response to therapy. Pharmacogenomics 7(5):683–695PubMedCrossRefGoogle Scholar
  25. 25.
    Eklund C, Jahan F, Pessi T, Lehtimäki T, Hurme M (2003) Interleukin 1B gene polymorphism is associated with baseline C-reactive protein levels in healthy individuals. Eur Cytokine Netw 14(3):168–171PubMedGoogle Scholar
  26. 26.
    Martínez-Borra J, López-Larrea C, González S, Fuentes D, Dieguez A, Deschamps EM, Pérez-Pariente JM, López-Vázquez A, de Francisco R, Rodrigo L (2002) High serum tumor necrosis factor-alpha levels are associated with lack of response to infliximab in fistulizing Crohn’s disease. Am J Gastroenterol 97(9):2350–2356PubMedGoogle Scholar
  27. 27.
    Ozeki T, Furuya Y, Nagano C, Matsui C, Takayanagi R, Yokoyama H, Yamada Y (2006) Analysis of linkage between lymphotoxin alpha haplotype and polymorphisms in 5′-flanking region of tumor necrosis factor alpha gene associated with efficacy of infliximab for Crohn’s disease patients. Mutat Res 602(1–2):170–174PubMedGoogle Scholar
  28. 28.
    Han Z, Li C, Han S, Han Y, Qiu J, Shi Y, Wang J, Sun A, Ding J, Wu K, Fan D (2010) Meta-analysis: polymorphisms in TNF-alpha gene promoter and Crohn’s disease. Aliment Pharmacol Ther 32(2):159–170PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Diana Lacruz-Guzmán
    • 1
  • Daniel Torres-Moreno
    • 2
  • Francisco Pedrero
    • 3
  • Patricia Romero-Cara
    • 4
  • Iván García-Tercero
    • 4
  • Javier Trujillo-Santos
    • 5
  • Pablo Conesa-Zamora
    • 2
  1. 1.Pharmacy DepartmentSanta Lucía General University Hospital (HGUSL)CartagenaSpain
  2. 2.Molecular Pathology and Pharmacogenetics Group FFIS011, Pathology DepartmentHGUSLCartagenaSpain
  3. 3.Day Hospital HGUSLCartagenaSpain
  4. 4.Gastroenterology Department HUGSLCartagenaSpain
  5. 5.Internal Medicine HUGSLCartagenaSpain

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