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Association of polymorphisms in promoter region of TNF-α -238 and -308 with clinical outcomes in patients with immune-mediated inflammatory diseases on anti-TNF therapy

Rheumatology International volume 41, pages 2195–2203 (2021)Cite this article

Abstract

The hypothesis of the study was that polymorphisms in promoter regions -238 and -308 of TNF-α could be associated with different clinical outcomes in inflammatory bowel diseases (IBD) and immune-mediated rheumatic diseases (IMRD). The aim was to examine the possible association of both polymorphisms with concentration of C-reactive protein (CRP) and fecal calprotectin (fCAL), onset of the remission and development of the ADA in patients on therapy with anti-TNF inhibitors. The prospective study was done in patients with IBD and IMRD on infliximab (IFX) or adalimumab (ADM). Patients were genotyped for TNF-α -238 and -308 polymorphisms. The concentration of CRP, fCAL, IFX or ADM and antibodies to drugs were measured according to manufacturer’s instructions and followed-up for 6 or 12 months. Out of all patients (N = 112), number of patients in remission did not differ according to genotypes (for IBD patients P = 0.509 vs 0.223; for IMRD patients P = 0.541 vs 0.132 for TNF-α -238 and -308, respectively). Initial CRP concentration was higher in IBD patients with TNF-α -308 GG than GA/AA genotypes in patients who failed to achieve remission [11.8 (4.4–39.6) vs 3.1 (1.5–6.5), P = 0.033]. In IBD patients with remission, fCAL concentration after at least 6 months of therapy was higher in TNF-α-308 GG than in GA genotype [52 (25–552) vs 20 (20–20) µg/g, P = 0.041]. Our results showed the association of TNF-α -308 GG genotype with a higher concentration of CRP and fecal calprotectin in patients with inflammatory bowel diseases on IFX or ADM therapy. Clinical remission and development of antibodies to anti-TNF drugs were not associated with TNF-α -238 and -308 polymorphisms.

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References

  1. Blandizzi C, Gionchetti P, Armuzzi A, Caporali R, Chimenti S, Cimaz R et al (2014) The role of tumour necrosis factor in the pathogenesis of immune-mediated diseases. Int J Immunopathol Pharmacol 27(1 Suppl):1–10. https://doi.org/10.1177/03946320140270S101

    Article  CAS  PubMed  Google Scholar 

  2. Kuek A, Hazleman BL, Ostör AJ (2007) Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad Med J 83(978):251–260. https://doi.org/10.1136/pgmj.2006.052688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Roda G, Jharap B, Neeraj N, Colombel JF (2016) Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol 7(1):e135. https://doi.org/10.1038/ctg.2015.63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Johnson KJ, Sanchez HN, Schoenbrunner N (2019) Defining response to TNF-inhibitors in rheumatoid arthritis: the negative impact of anti-TNF cycling and the need for a personalized medicine approach to identify primary non-responders. Clin Rheumatol 38(11):2967–2976. https://doi.org/10.1007/s10067-019-04684-1

    Article  PubMed  Google Scholar 

  5. Aguillón JC, Cruzat A, Aravena O, Salazar L, Llanos C, Cuchacovich M (2006) Could single-nucleotide polymorphisms (SNPs) affecting the tumour necrosis factor promoter be considered as part of rheumatoid arthritis evolution? Immunobiology 211(1–2):75–84. https://doi.org/10.1016/j.imbio.2005.09.005

    Article  CAS  PubMed  Google Scholar 

  6. Burke KE, Khalili H, Garber JJ, Haritunians T, McGovern DPB, Xavier RJ, Ananthakrishnan AN (2018) Genetic markers predict primary nonresponse and durable response to anti-tumor necrosis factor therapy in ulcerative colitis. Inflamm Bowel Dis 24(8):1840–1848. https://doi.org/10.1093/ibd/izy083

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bek S, Bojesen AB, Nielsen JV, Sode J, Bank S, Vogel U, Andersen V (2017) Systematic review and meta-analysis: pharmacogenetics of anti-TNF treatment response in rheumatoid arthritis. Pharmacogenomics J 17(5):403–411. https://doi.org/10.1038/tpj.2017.26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Prieto-Pérez R, Cabaleiro T, Daudén E, Abad-Santos F (2013) Gene polymorphisms that can predict response to anti-TNF therapy in patients with psoriasis and related autoimmune diseases. Pharmacogenomics J 13(4):297–305. https://doi.org/10.1038/tpj.2012.53

    Article  CAS  PubMed  Google Scholar 

  9. Lee YH, Ji JD, Bae SC, Song GG (2010) Associations between tumor necrosis factor-α (TNF-α) -308 and -238 G/A polymorphisms and shared epitope status and responsiveness to TNF-α blockers in rheumatoid arthritis: a metaanalysis update. J Rheumatol 37(4):740–746. https://doi.org/10.3899/jrheum.090707

    Article  CAS  PubMed  Google Scholar 

  10. Miceli-Richard C, Comets E, Verstuyft C, Tamouza R, Loiseau P, Ravaud P et al (2008) A single tumour necrosis factor haplotype influences the response to adalimumab in rheumatoid arthritis. Ann Rheum Dis 67(4):478–484. https://doi.org/10.1136/ard.2007.074104

    Article  CAS  PubMed  Google Scholar 

  11. Netz U, Carter JV, Eichenberger MR, Dryden GW, Pan J, Rai SN, Galandiuk S (2017) Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn’s disease. World J Gastroenterol 23(27):4958–4967. https://doi.org/10.3748/wjg.v23.i27.4958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mitrović J, Morović-Vergles J, Martinović Kaliterna D, Anić B, Babić-Naglić Đ, Grazio S et al (2017) 2017 Recommendation proposal of the Croatian Society of rheumatology for the treatment of patients with rheumatoid arthritis with biologic drugs and targeted synthetic drugs. Reumatizam 64(2):65–70 ((in Croatian))

    Google Scholar 

  13. Grazio S, Novak S, Laktašić-Žerjavić N, Anić B, Babić-Naglić Đ, Grubišić F et al (2017) 2017 Recommendation proposal of the Croatian Society of Rheumatology for the treatment of adults with axial spondyloarthritis and psoriatic arthritis with biologic drugs and targated synthetic drugs. Reumatizam 64(2):71–87 ((in Croatian))

    Google Scholar 

  14. Vucelić B, Čuković-Čavka S, Banić M, Bilić A, Borzan V, Duvnjak M et al (2013) Croatian consensus on the treatment of inflammatory bowel diseases with biologic therapy. Acta Med Croatica 67(2):75–86

    PubMed  Google Scholar 

  15. Gomollón F, Dignass A, Annese V, Tilg H, Van Assche G, Lindsay JO et al (2017) ECCO. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: Part 1: Diagnosis and medical management. J Crohns Colitis 11(1):3–25. https://doi.org/10.1093/ecco-jcc/jjw168

    Article  PubMed  Google Scholar 

  16. Torres J, Bonovas S, Doherty G, Kucharzik T, Gisbert JP, Raine T et al (2020) ECCO guidelines on therapeutics in Crohn’s Disease: medical treatment. J Crohns Colitis 14(1):4–22. https://doi.org/10.1093/ecco-jcc/jjz180

    Article  PubMed  Google Scholar 

  17. Lin X, Qiu Y, Feng R, Chen B, He Y, Zeng Z, Zhang S, Chen M, Mao R (2020) Normalization of C-reactive protein predicts better outcome in patients with Crohn’s disease with mucosal healing and deep remission. Clin Transl Gastroenterol. https://doi.org/10.14309/ctg.0000000000000135

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zaghlol HM, Abdelshafy S, Mohamed RA, Abdelaleem EA (2019) Tumour necrosis factor gene polymorphisms in Egyptian patients with rheumatoid arthritis and their relation to disease activity and severity. Cent Eur J Immunol 44(3):277–284. https://doi.org/10.5114/ceji.2019.89602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gheita TA, Azkalany GS, Gaber W, Mohey A (2015) Clinical significance of serum TNFα and -308 G/A promoter polymorphism in rheumatoid arthritis. Egypt Rheumatol 37(2):49–54. https://doi.org/10.1016/j.ejr.2014.07.001

    Article  Google Scholar 

  20. Orr CK, Najm A, Young F, McGarry T, Biniecka M, Fearon U, Veale DJ (2018) The utility and limitations of CRP, ESR and DAS28-CRP in appraising disease activity in rheumatoid arthritis. Front Med (Lausanne) 5:185. https://doi.org/10.3389/fmed.2018.00185

    Article  Google Scholar 

  21. Chang S, Malter L, Hudesman D (2015) Disease monitoring in inflammatory bowel disease. World J Gastroenterol 21(40):11246–11259. https://doi.org/10.3748/wjg.v21.i40.11246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sun MH, Sun LQ, Guo GL, Zhang S (2019) Tumour necrosis factor-α gene -308 G > A and -238 G > A polymorphisms are associated with susceptibility to irritable bowel syndrome and drug efficacy in children. J Clin Pharm Ther 44(2):180–187. https://doi.org/10.1111/jcpt.12775

    Article  CAS  PubMed  Google Scholar 

  23. Sashio H, Tamura K, Ito R, Yamamoto Y, Bamba H, Kosaka T et al (2002) Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn’s disease, respectively. Immunogenetics 53(12):1020–1027. https://doi.org/10.1007/s00251-001-0423-7

    Article  CAS  PubMed  Google Scholar 

  24. Bouma G, Crusius JB, Garcia-Gonzalez MA, Meijer BU, Hellemans HP, Hakvoort RJ et al (1999) Genetic markers in clinically well defined patients with ulcerative colitis (UC). Clin Exp Immunol 115:294–300. https://doi.org/10.1046/j.1365-2249.1999.00797.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Matsuoka K, Hamada S, Shimizu M, Nanki K, Mizuno S, Kiyohara H et al (2018) Factors predicting the therapeutic response to infliximab during maintenance therapy in Japanese patients with Crohn’s disease. PLoS ONE 13(10):e0204632. https://doi.org/10.1371/journal.pone.0204632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Song GG, Seo YH, Kim JH, Choi SJ, Ji JD, Lee YH (2015) Association between TNF-α (-308 A/G, -238 A/G, -857 C/T) polymorphisms and responsiveness to TNF-α blockers in spondyloarthropathy, psoriasis and Crohn’s disease: a meta-analysis. Pharmacogenomics 16(12):1427–1437. https://doi.org/10.2217/pgs.15.90

    Article  CAS  PubMed  Google Scholar 

  27. Pallio G, Mannino F, Irrera N, Eid AH, Squadrito F, Bitto A (2020) Polymorphisms involved in response to biological agents used in rheumatoid arthritis. Biomolecules 10(9):1203. https://doi.org/10.3390/biom10091203

    Article  CAS  PubMed Central  Google Scholar 

  28. Barber GE, Yajnik V, Khalili H, Giallourakis C, Garber J, Xavier R, Ananthakrishnan AN (2016) Genetic markers predict primary non-response and durable response to anti-TNF biologic therapies in Crohn’s disease. Am J Gastroenterol 111(12):1816–1822. https://doi.org/10.1038/ajg.2016.408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Massey J, Plant D, Hyrich K, Morgan AW, Wilson AG, Spiliopoulou A, Colombo M, McKeigue P, Isaacs J, Cordell H, Pitzalis C, Barton A, BRAGGSS, MATURA Consortium (2018) Genome-wide association study of response to tumour necrosis factor inhibitor therapy in rheumatoid arthritis. Pharmacogenomics J 18(5):657–664. https://doi.org/10.1038/s41397-018-0040-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Steenholdt C, Al-khalaf M, Brynskov J, Bendtzen K, Thomsen OØ, Ainsworth MA (2012) Clinical implications of variations in anti-infliximab antibody levels in patients with inflammatory bowel disease. Inflamm Bowel Dis 18(12):2209–2217. https://doi.org/10.1002/ibd.22910

    Article  PubMed  Google Scholar 

  31. 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):818–824

    Article  CAS  Google Scholar 

  32. Hadinedoushan H, Noorbakhsh P, Soleymani-Salehabadi H (2016) Tumor necrosis factor alpha gene polymorphism and association with its serum level in Iranian population with rheumatoid arthritis. Arch Rheumatol 31(4):306–313. https://doi.org/10.5606/ArchRheumatol.2016.5907

    Article  PubMed  PubMed Central  Google Scholar 

  33. Avdagić N, Babić N, Šeremet M, Delić-Šarac M, Drače Z, Denjalić A, Nakaš-Ićindić E (2013) Tumor necrosis factor-alpha serum level in assessment of disease activity in inflammatory bowel diseases. Med Glas (Zenica) 10(2):211–216

    Google Scholar 

  34. De Santis IP, Lindenau JD-R, Ramos RB, Silva TR, Casanova G, Oppermann K, Spritzer PM (2020) C-reactive protein gene rs1205 polymorphism is associated with low-grade chronic inflammation in postmenopausal women. Women Midlife Health. https://doi.org/10.1186/s40695-020-00051-2

    Article  Google Scholar 

  35. Polterauer S, Grimm C, Zeillinger R, Heinze G, Tempfer C, Reinthaller A, Hefler L (2011) Association of C-reactive protein (CRP) gene polymorphisms, serum CRP levels and cervical cancer prognosis. Anticancer Res 31(6):2259–2264

    CAS  PubMed  Google Scholar 

  36. Martínez-Calatrava MJ, González-Sánchez JL, Martínez-Larrad MT, Pérez-Barba M, Serrano-Ríos M (2007) Common haplotypes of the C-reactive protein gene and circulating leptin levels influence the interindividual variability in serum C-reactive protein levels. J Thromb Haemost 98(11):1088–1095. https://doi.org/10.1160/th07-03-0231

    Article  Google Scholar 

  37. Hassani M, Dehani M, Zare Rafie M, Esmaeilzadeh E, Davar S, Pakzad B, Mosallaei M, Hoseini SM, Bayat H, Soosanabadi M (2021) Investigation of rs531564 polymorphism in the primary microRNA-124 gene in patients with systemic lupus erythematosus and rheumatoid arthritis: association with disease susceptibility and clinical characteristics. Iran J Allergy Asthma Immunol 20(3):303–313. https://doi.org/10.18502/ijaai.v20i3.6336

    Article  PubMed  Google Scholar 

  38. Miler M, Nikolac Gabaj N, Grazio S, Vahtarić A, Vrtarić A, Grubišić F et al (2020) Lower concentration of vitamin D is associated with lower DAS28 and VAS-pain scores in patients with inflammatory rheumatic diseases treated with infliximab: a pilot study. Rheumatol Int 40(9):1455–1461. https://doi.org/10.1007/s00296-020-04607-3

    Article  CAS  PubMed  Google Scholar 

  39. Chen P, Zhou G, Lin J, Li L, Zeng Z, Chen M, Zhang S (2020) Serum biomarkers for inflammatory bowel disease. Front Med (Lausanne) 7:123. https://doi.org/10.3389/fmed.2020.00123

    Article  Google Scholar 

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Acknowledgements

We thank Assist. Prof. Frane Grubišić, Dr. Ines Doko Vajdić and Dr. Hana Skala Kavanagh for their expert opinion and technical assistance in patients’ assessment.

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There are no financial conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Clinical Chemistry, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia

    Marijana Miler, Nora Nikolac Gabaj, Ivana Ćelap & Mario Štefanović

  2. Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia

    Nora Nikolac Gabaj, Nada Vrkić & Mario Štefanović

  3. Department for Rheumatology, Physical and Rehabilitation Medicine, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia

    Simeon Grazio

  4. Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia

    Vedran Tomašić & Alen Bišćanin

  5. Department of Clinical Immunology, Allergology and Rheumatology, Department of Internal Medicine, School of Medicine, University of Zagreb, University Hospital Dubrava, Zagreb, Croatia

    Joško Mitrović

  6. Clinical Department of Laboratory Diagnostics, University Hospital Dubrava, Zagreb, Croatia

    Lovorka Đerek

  7. Division of Cl Immunology, Allergology and Rheumatology, Department of Internal Medicine, School of Medicine, University of Zagreb, University Hospital Dubrava, Zagreb, Croatia

    Jadranka Morović-Vergles

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  1. Marijana Miler
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Correspondence to Marijana Miler.

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The study was designed in accordance with the Declaration of Helsinki and approved by the Ethical Committees of the Sestre milosrdnice University Hospital Center, Faculty of Pharmacy and University Hospital Dubrava, Zagreb.

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Miler, M., Nikolac Gabaj, N., Ćelap, I. et al. Association of polymorphisms in promoter region of TNF-α -238 and -308 with clinical outcomes in patients with immune-mediated inflammatory diseases on anti-TNF therapy. Rheumatol Int 41, 2195–2203 (2021). https://doi.org/10.1007/s00296-021-05016-w

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Keywords

  • Adalimumab
  • C-reactive protein
  • Fecal calprotectin
  • Immune-mediated rheumatic diseases
  • Infliximab
  • Inflammatory bowel diseases
  • TNF-α polymorphisms