Influence of polymorphisms and TNF and IL1β serum concentration on the infliximab response in Crohn’s disease and ulcerative colitis
- First Online:
- 762 Downloads
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.
KeywordsTumour necrosis factor Interleukin-1 Infliximab Crohn’s disease Pharmacogenetics Ulcerative colitis
- 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
- 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.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
- 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.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.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.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
- 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.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
- 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
- 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.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