Journal of Gastroenterology

, Volume 52, Issue 5, pp 535–554

Systematic review with meta-analysis: loss of response and requirement of anti-TNFα dose intensification in Crohn’s disease

  • Yun Qiu
  • Bai-li Chen
  • Ren Mao
  • Sheng-hong Zhang
  • Yao He
  • Zhi-rong Zeng
  • Shomron Ben-Horin
  • Min-hu Chen



To review the frequency with which anti-TNF-α loses its effect and dose “intensification” is required for Crohn’s disease (CD) treatment.


Electronic databases were searched for eligible studies. Raw data from studies meeting inclusion criteria were pooled for effect estimates. Subgroup analyses were performed for exploration of heterogeneity regarding all outcomes.


Eighty-six eligible studies were included. Estimates of loss of response (LOR) incidence ranged from 8 to 71%. The random effects pooled incidence of LOR with a median follow-up of 1-year was 33% (95% CI 29–38, 55 studies, n = 6135). The effect estimate based on data from patients with infliximab was 33% (95% CI 27-40), 30% (95% CI 22–39) for adalimumab, and 41% (95% CI 30–53) for certolizumabpegol. Overall, the mean percentage of patients’ LOR to anti-TNFs was 38.5%. The annual risk for LOR was 20.9% per patient-year. The random-effects pooled rate of need for dose intensification with a median follow-up of 1 year was 34% (95% CI 28–41, 38 studies, n = 10,690). The effect estimate for infliximab was 38% (95% CI 28–50), 36% (95% CI 30–43) for adalimumab, and 2% (95% CI 2–3) for certolizumab-pegol. The mean percentage of patients who needed an anti-TNF dose escalation was 23% with an annual risk of 18.5% per patient-year. There was no evidence of publication bias for incidence of LOR but not for the dose intensification (p = 0.001).


Overall, around one-third of CD patients experience a LOR and required dose intensification in primary anti-TNF-α responders.


Loss of response Anti-TNFα Dose intensification Crohn’s disease 

Supplementary material

535_2017_1324_MOESM1_ESM.tif (591 kb)
Supplementary Fig. 1. Assessment of quality of randomized controlled trials using Cochrane risk of bias tool (TIFF 591 kb)
535_2017_1324_MOESM2_ESM.docx (20 kb)
Supplementary Table 1. Assessment of quality of observational studies using Newcastle Ottawa Quality Assessment Scale (NOS) (DOCX 19 kb)
535_2017_1324_MOESM3_ESM.docx (18 kb)
Supplementary Table 2. Summary of subgroup analysis of anti-TNFs dose intensification among primary responders (DOCX 17 kb)


  1. 1.
    Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132:52–65.PubMedCrossRefGoogle Scholar
  3. 3.
    Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007;357:239–50.PubMedCrossRefGoogle Scholar
  4. 4.
    Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med. 1999;340:1398–405.PubMedCrossRefGoogle Scholar
  5. 5.
    Lichtenstein GR, Yan S, Bala M, et al. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn’s disease. Gastroenterology. 2005;128:862–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Allez M, Karmiris K, Louis E, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects. J Crohns Colitis. 2010;4:355–66.PubMedCrossRefGoogle Scholar
  7. 7.
    Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336–41.PubMedCrossRefGoogle Scholar
  8. 8.
    Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(96–109):e1.Google Scholar
  9. 9.
    Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Freeman MF, Tukey JW. Transformations related to the angular and the square root. Ann Math Stat. 1950:607–611.Google Scholar
  12. 12.
    Wilson EB. Probable inference, the law of succession, and statistical inference. J Am Stat Assoc. 1927;22(158):209–12.CrossRefGoogle Scholar
  13. 13.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.PubMedCrossRefGoogle Scholar
  14. 14.
    Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ Br Med J. 2003;327:557.CrossRefGoogle Scholar
  15. 15.
    Fleiss JL. The statistical basis of meta-analysis. Stat Methods Med Res. 1993;2:121–45.PubMedCrossRefGoogle Scholar
  16. 16.
    Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med. 2002;21:1559–73.PubMedCrossRefGoogle Scholar
  17. 17.
    Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Schwarzer G. Meta: An R package for meta-analysis. SpherWave: an R package for analyzing scattered spherical data by Spherical Wavelets 2007:40.Google Scholar
  19. 19.
    Rutgeerts P, D’Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology. 1999;117:761–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Hommes DW, van de Heisteeg BH, van der Spek M, et al. Infliximab treatment for Crohn’s disease: one-year experience in a Dutch academic hospital. Inflamm Bowel Dis. 2002;8:81–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology. 2003;124:917–24.PubMedCrossRefGoogle Scholar
  22. 22.
    Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876–85.PubMedCrossRefGoogle Scholar
  23. 23.
    Candon S, Mosca A, Ruemmele F, et al. Clinical and biological consequences of immunization to infliximab in pediatric Crohn’s disease. Clin Immunol. 2006;118:11–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Corman S, Issa M, Beaulieu DB, et al. Escalation of infliximab maintenance therapy in Crohn’s disease. Am J Gastroenterol. 2006;101:S470.CrossRefGoogle Scholar
  25. 25.
    Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007;132:863–73 (quiz 1165–1166).PubMedCrossRefGoogle Scholar
  26. 26.
    Ainsworth MA, Bendtzen K, Brynskov J. Tumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn’s disease. Am J Gastroenterol. 2008;103:944–8.PubMedCrossRefGoogle Scholar
  27. 27.
    de Ridder L, Rings EH, Damen GM, et al. Infliximab dependency in pediatric Crohn’s disease: long-term follow-up of an unselected cohort. Inflamm Bowel Dis. 2008;14:353–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Gonzaga JE, Issa M, Skaros S, et al. W1255 Durability of infliximab in Crohn’s disease patients treated with maintenance infusions beyond one year. Gastroenterology. 2008;A-134:A-665–6.Google Scholar
  29. 29.
    Gonzalez-Lama Y, Lopez-San Roman A, Marin-Jimenez I, et al. Open-label infliximab therapy in Crohn’s disease: a long-term multicenter study of efficacy, safety and predictors of response. Gastroenterol Hepatol. 2008;31:421–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Milestone AN, Bullas DC, Hart AL, et al. M1146 Long-term outcome and adverse events in Crohn’s disease patients treated with infliximab at a single tertiary referral center over 9 years. Gastroenterology. 2008;134:A-348.CrossRefGoogle Scholar
  31. 31.
    Rudolph SJ, Weinberg DI, McCabe RP. Long-term durability of Crohn’s disease treatment with infliximab. Dig Dis Sci. 2008;53:1033–41.PubMedCrossRefGoogle Scholar
  32. 32.
    Teshima CW, Thompson AF, Dhanoa LS, et al. W1243 Concomitant use of immunosuppressive therapy in an outpatient IBD subspecialty clinic results in rates of response higher than those seen in the infliximab randomized controlled trials. Gastroenterology. 2008;134:A-663.CrossRefGoogle Scholar
  33. 33.
    Vera Mendoza I, Calvo M, De la Revilla J, et al. P098 Long-term infliximab in Crohn’s disease. J Crohns Colitis Suppl. 2008;2:34–5.CrossRefGoogle Scholar
  34. 34.
    Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.PubMedCrossRefGoogle Scholar
  35. 35.
    Goldner DL, Shenoy-Bhangle AS, Gee MS, et al. Clinical and radiological response to anti-TNF alpha treatment for perianal fistulizing Crohn’s disease in one institution in pediatric patients. Gastroenterology. 2011;140:S-508–9.CrossRefGoogle Scholar
  36. 36.
    Steenholdt C, Bendtzen K, Brynskov J, et al. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn’s disease. Scand J Gastroenterol. 2011;46:310–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Imaeda H, Andoh A, Fujiyama Y. Development of a new immunoassay for the accurate determination of anti-infliximab antibodies in inflammatory bowel disease. J Gastroenterol. 2012;47:136–43.PubMedCrossRefGoogle Scholar
  38. 38.
    Van Assche G, Vermeire S, Ballet V, et al. Switch to adalimumab in patients with Crohn’s disease controlled by maintenance infliximab: prospective randomised SWITCH trial. Gut. 2012;61:229–34.PubMedCrossRefGoogle Scholar
  39. 39.
    Brandse JF, Peters CP, Gecse KB, et al. Effects of infliximab retreatment after consecutive discontinuation of infliximab and adalimumab in refractory Crohn’s disease. Inflamm Bowel Dis. 2014;20:251–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Cornillie F, Hanauer SB, Diamond RH, et al. Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial. Gut. 2014;63:1721–7.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Hibi T, Sakuraba A, Watanabe M, et al. C-reactive protein is an indicator of serum infliximab level in predicting loss of response in patients with Crohn’s disease. J Gastroenterol. 2014;49:254–62.PubMedCrossRefGoogle Scholar
  42. 42.
    Peyrin-Biroulet L, Laclotte C, Bigard MA. Adalimumab maintenance therapy for Crohn’s disease with intolerance or lost response to infliximab: an open-label study. Aliment Pharmacol Ther. 2007;25:675–80.PubMedCrossRefGoogle Scholar
  43. 43.
    Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007;56:1232–9.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Seiderer J, Brand S, Dambacher J, et al. Adalimumab in patients with Crohn’s disease—safety and efficacy in an open-label single centre study. Aliment Pharmacol Ther. 2007;25:787–96.PubMedCrossRefGoogle Scholar
  45. 45.
    Karmiris K, Paintaud G, Degenne D, et al. P021 Adalimumab trough serum levels and clinical response in a single-center cohort of inflammatory bowel disease patients: can trough serum levels serve as a predictor for future loss of response? J Crohns Colitis Suppl. 2008;2:11.CrossRefGoogle Scholar
  46. 46.
    Lopez Palacios N, Mendoza JL, Taxonera C. Adalimumab induction and maintenance therapy for Crohn’s disease. An open-label study. Rev Esp Enferm Dig. 2008;100:676–81.PubMedCrossRefGoogle Scholar
  47. 47.
    Panaccione R, Sandborn WJ, D’Haens G, et al. 920 Adalimumab maintains long-term remission in moderately to severely active Crohn’s disease after infliximab failure: 1-year follow-up of gain trial. Gastroenterology. 2008;134:A-133–4.Google Scholar
  48. 48.
    Bortlik M, Duricova D, Komarek V, et al. W1225 Adalimumab in a clinical practice—experience with human anti TNF-α therapy in tertiary clinical center. Gastroenterology. 2009;136:A-682.Google Scholar
  49. 49.
    Karmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology. 2009;137:1628–40.PubMedCrossRefGoogle Scholar
  50. 50.
    Oussalah A, Babouri A, Chevaux JB, et al. Adalimumab for Crohn’s disease with intolerance or lost response to infliximab: a 3-year single-centre experience. Aliment Pharmacol Ther. 2009;29:416–23.PubMedCrossRefGoogle Scholar
  51. 51.
    Chaparro M, Panes J, García V, et al. W1275 Long-Term Durability of Response to Adalimumab Treatment in Crohn’s Disease. Gastroenterology. 2010;138:S-689.Google Scholar
  52. 52.
    Russo E, O’Donnell S, Dearden J, et al. W1312 Long-term efficacy of the second biologic in the management of Crohn’s disease. A retrospective survey on an English-Irish cohort. Gastroenterology. 2010;138:S-697.Google Scholar
  53. 53.
    Russo EA, Iacucci M, Lindsay JO, et al. Survey on the use of adalimumab as maintenance therapy in Crohn’s disease in England and Ireland. Eur J Gastroenterol Hepatol. 2010;22:334–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Swoger JM, Loftus EV Jr, Tremaine WJ, et al. Adalimumab for Crohn’s disease in clinical practice at Mayo clinic: the first 118 patients. Inflamm Bowel Dis. 2010;16:1912–21.PubMedCrossRefGoogle Scholar
  55. 55.
    Sprakes MB, Hamlin PJ, Warren L, et al. Adalimumab as second line anti-tumour necrosis factor alpha therapy for Crohn’s disease: a single centre experience. J Crohns Colitis. 2011;5:324–31.PubMedCrossRefGoogle Scholar
  56. 56.
    Molnar T, Farkas K, Nyari T, et al. Frequency and predictors of loss of response to infliximab or adalimumab in Crohn’s disease after one-year treatment period—a single center experience. J Gastrointestin Liver Dis. 2012;21:265–9.PubMedGoogle Scholar
  57. 57.
    Assa A, Hartman C, Weiss B, et al. Long-term outcome of tumor necrosis factor alpha antagonist’s treatment in pediatric Crohn’s disease. J Crohns Colitis. 2013;7:369–76.PubMedCrossRefGoogle Scholar
  58. 58.
    Cozijnsen M, Duif V, Kokke F, et al. Adalimumab therapy in children with Crohn disease previously treated with infliximab. J Pediatr Gastroenterol Nutr. 2015;60:205–10.PubMedCrossRefGoogle Scholar
  59. 59.
    Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007;357:228–38.PubMedCrossRefGoogle Scholar
  60. 60.
    D’Haens G, Mitchev K, Sandborn WJ. T1126 Response and remission at 18 months of certolizumab pegol in patients with active Crohn’s disease is not influenced by rapidity and magnitude of induction: an analysis of PRECISE 2 and 3. Gastroenterology. 2008;134:489.Google Scholar
  61. 61.
    Sandborn WJ, Vermeire S, D’Haens GR, et al. 143 Welcome: a randomized, double-blind, controlled trial comparing certolizumab pegol 400 Mg every 2 weeks with every 4 weeks for maintenance of response and remission in patients with moderate to severe Crohn’s disease with secondary failure to infliximab. Gastroenterology. 2009;136:A-27.Google Scholar
  62. 62.
    Lichtenstein G, Thomsen OO, Schreiber S, et al. S1040 Long-term remission with certolizumab pegol in Crohn’s Disease: efficacy over 4 years in patients with no prior TNF-α inhibitor exposure (PRECiSE 3 Study). Gastroenterology. 2010;138:S-165.CrossRefGoogle Scholar
  63. 63.
    Sandborn WJ, Abreu MT, D’Haens G, et al. Certolizumab pegol in patients with moderate to severe Crohn’s disease and secondary failure to infliximab. Clin Gastroenterol Hepatol. 2010;8(688–695):e2.Google Scholar
  64. 64.
    Sandborn WJ, Schreiber S, Hanauer SB, et al. Reinduction with certolizumab pegol in patients with relapsed Crohn’s disease: results from the PRECiSE 4 study. Clin Gastroenterol Hepatol. 2010;8(696–702):e1.Google Scholar
  65. 65.
    Mocciaro F, Renna S, Orlando A, et al. P.1.125: certolizumab pegol in patients with Crohn’s disease: a long term update of compassionate use. Dig Liver Dis. 2011;43(Supplement 3):S189.CrossRefGoogle Scholar
  66. 66.
    Sandborn WJ, Lee SD, Randall C, et al. Long-term safety and efficacy of certolizumab pegol in the treatment of Crohn’s disease: 7-year results from the PRECiSE 3 study. Aliment Pharmacol Ther. 2014;40:903–16.PubMedCrossRefGoogle Scholar
  67. 67.
    Regueiro M, Siemanowski B, Kip KE, et al. Infliximab dose intensification in Crohn’s disease. Inflamm Bowel Dis. 2007;13:1093–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Schnitzler F, Fidder H, Ferrante M, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort. Gut. 2009;58:492–500.PubMedCrossRefGoogle Scholar
  69. 69.
    Lam MC, Lee T, Atkinson K, et al. Time of infliximab therapy initiation and dose escalation in Crohn’s disease. World J Gastroenterol. 2014;20:214–8.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Taxonera C, Olivares D, Mendoza JL, et al. Need for infliximab dose intensification in Crohn’s disease and ulcerative colitis. World J Gastroenterol. 2014;20:9170–7.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Sandborn WJ, Hanauer S, Loftus EV Jr, et al. An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn’s disease. Am J Gastroenterol. 2004;99:1984–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Papadakis KA, Shaye OA, Vasiliauskas EA, et al. Safety and efficacy of adalimumab (D2E7) in Crohn’s disease patients with an attenuated response to infliximab. Am J Gastroenterol. 2005;100:75–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Ho GT, Smith L, Aitken S, et al. The use of adalimumab in the management of refractory Crohn’s disease. Aliment Pharmacol Ther. 2008;27:308–15.PubMedCrossRefGoogle Scholar
  74. 74.
    Sheridan JA KD, Slattery E. Adalimumab in Crohn’s disease. Gut 2008;Suppl 2:A2564.Google Scholar
  75. 75.
    West RL, Zelinkova Z, Wolbink GJ, et al. Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn’s disease. Aliment Pharmacol Ther. 2008;28(9):1122–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Cohen RD, Lewis JR, Turner H, et al. W1093 Predictors and timing of adalimumab (ADA) dose escalation in patients with Crohn’s disease (CD). Gastroenterology. 2009;136:A-652.CrossRefGoogle Scholar
  77. 77.
    Ho GT, Mowat A, Potts L, et al. Efficacy and complications of adalimumab treatment for medically-refractory Crohn’s disease: analysis of nationwide experience in Scotland (2004–2008). Aliment Pharmacol Ther. 2009;29:527–34.PubMedCrossRefGoogle Scholar
  78. 78.
    Kemp K, Dibb M, Makin A, et al. 2 year follow-up of adalimumab therapy in patients with Crohn’s disease. J Crohns Colitis. 2009;3:S27–8.CrossRefGoogle Scholar
  79. 79.
    Lees C, Ali A, Thompson A, et al. The safety profile of anti-tumour necrosis factor therapy in inflammatory bowel disease in clinical practice: analysis of 620 patient-years follow-up. Aliment Pharmacol Ther. 2009;29:286–97.PubMedCrossRefGoogle Scholar
  80. 80.
    Loftus Jr E, Pan X, Zurawski P. Dosage pattern of adalimumab in real-world clinical practice and predictors of dosage increase in patients with Crohn’s disease in the United States. Gastroenterology 2009;5.Google Scholar
  81. 81.
    Swaminath A, Ullman T, Rosen M, et al. Early clinical experience with adalimumab in treatment of inflammatory bowel disease with infliximab-treated and naïve patients. Aliment Pharmacol Ther. 2009;29(3):273–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Bultman E, West RL, van Liere-Baron A, et al. W1335 Previous non-response to infliximab predicts early dose-escalation in adalimumab treated Crohn’s disease patients. Gastroenterology. 2010;138:S-701–2.CrossRefGoogle Scholar
  83. 83.
    Nichita C, Stelle M, Vavricka S, et al. Clinical experience with adalimumab in a multicenter Swiss cohort of patients with Crohn’s disease. Digestion. 2010;81:78–85.PubMedCrossRefGoogle Scholar
  84. 84.
    Panaccione R, Colombel JF, Sandborn WJ, et al. Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn’s disease. Aliment Pharmacol Ther. 2010;31:1296–309.PubMedCrossRefGoogle Scholar
  85. 85.
    Wolf DC, Wolf CH. W1325 Persistency equals efficacy in adalimumab patients: preliminary report of a large single site experience. Gastroenterology. 2010;138:S-699.CrossRefGoogle Scholar
  86. 86.
    Cordero Ruiz P, Castro Marquez C, Mendez Rufian V, et al. Efficacy of adalimumab in patients with Crohn’s disease and failure to infliximab therapy: a clinical series. Rev Esp Enferm Dig. 2011;103:294–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Fortea-Ormaechea JI, González-Lama Y, Casis B, et al. Adalimumab is effective in long-term real life clinical practice in both luminal and perianal Crohn’s disease. The Madrid experience. Gastroenterología y Hepatología. 2011;34:443–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Issa M, Zadvornova Y, Naik AS, et al. High rates of escalation and termination of adalimumab therapy and patients exposed to infliximab. Gastroenterology. 2011;140:588.Google Scholar
  89. 89.
    Kiss LS, Szamosi T, Molnar T, et al. Early clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn’s disease. Aliment Pharmacol Ther. 2011;34:911–22.PubMedCrossRefGoogle Scholar
  90. 90.
    Sandborn WJ, Colombel JF, Lomax KG, et al. Achievement of early deep remission is associated with lower rates of weekly dosing for adalimumab-treated patients with Crohn’s disease: data from EXTEND. Gut. 2011;60:A136–7.CrossRefGoogle Scholar
  91. 91.
    Bultman E, de Haar C, van Liere-Baron A, et al. Predictors of dose escalation of adalimumab in a prospective cohort of Crohn’s disease patients. Aliment Pharmacol Ther. 2012;35:335–41.PubMedCrossRefGoogle Scholar
  92. 92.
    Cohen RD, Lewis JR, Turner H, et al. Predictors of adalimumab dose escalation in patients with Crohn’s disease at a tertiary referral center. Inflamm Bowel Dis. 2012;18:10–6.PubMedCrossRefGoogle Scholar
  93. 93.
    Baert F, Glorieus E, Reenaers C, et al. Adalimumab dose escalation and dose de-escalation success rate and predictors in a large national cohort of Crohn’s patients. J Crohns Colitis. 2013;7:154–60.PubMedCrossRefGoogle Scholar
  94. 94.
    Hyams J, Walters TD, Crandall W, et al. Safety and efficacy of maintenance infliximab therapy for moderate-to-severe Crohn’s disease in children: rEACH open-label extension. Curr Med Res Opin. 2011;27:651–62.PubMedCrossRefGoogle Scholar
  95. 95.
    Ben-Bassat O, Iacono A, Irwin SP, et al. Tu1327a Golimumab for Treatment of Moderate to Severe Anti-TNF Refaractory Crohn’s Disease: Open Label Experience. Gastroenterology. 2012;142:S-804.CrossRefGoogle Scholar
  96. 96.
    Ma C, Huang V, Fedorak DK, et al. Crohn’s disease outpatients treated with adalimumab have an earlier secondary loss of response and requirement for dose escalation compared to infliximab: a real life cohort study. J Crohns Colitis. 2014;8:1454–63.PubMedCrossRefGoogle Scholar
  97. 97.
    Allez M, Vermeire S, Mozziconacci N, et al. The efficacy and safety of a third anti-TNF monoclonal antibody in Crohn’s disease after failure of two other anti-TNF antibodies. Aliment Pharmacol Ther. 2010;31:92–101.PubMedCrossRefGoogle Scholar
  98. 98.
    Rubin DT, Sederman R. T1324 Administrative claims data analysis of certolizumab pegol in Crohn’s disease PTS demonstrates low rates of dose escalation and high compliance and persistency. Gastroenterology. 2010;138:S-537.CrossRefGoogle Scholar
  99. 99.
    Naik AS, Qumseya B, Ananthakrishnan AN, et al. W1102 Anti-TNF therapy for Crohn’s disease: predictors of dose escalation and early discontinuation by 1 year of therapy. Gastroenterology. 2009;136:654.Google Scholar
  100. 100.
    Rubin DT, Sederman R. 959 Maintenance of response to biologic therapy in Crohn’s disease is improved with “early use” v. “step up” treatment using health claims data. Gastroenterology. 2009;136:A-146.Google Scholar
  101. 101.
    Plevy S, Lu M, Yu A, et al. Observational study of treatment patterns in patients newly initiated with adalimumab or infliximab therapy for Crohn’s disease. Am J Gastroenterol. 2009;104:S479.Google Scholar
  102. 102.
    Van Assche G, Vermeire S, Rutgeerts P. The potential for disease modification in Crohn’s disease. Nat Rev Gastroenterol Hepatol. 2010;7:79–85.PubMedCrossRefGoogle Scholar
  103. 103.
    Gisbert JP, Panes J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol. 2009;104:760–7.PubMedCrossRefGoogle Scholar
  104. 104.
    Billioud V, Sandborn WJ, Peyrin-Biroulet L. Loss of response and need for adalimumab dose intensification in Crohn’s disease: a systematic review. Am J Gastroenterol. 2011;106:674–84.PubMedCrossRefGoogle Scholar
  105. 105.
    Chao J, Mulani P. What is the rate of loss of response to infliximab therapy in Crohn’s disease? Am J Gastroenterol. 2009;104:2353–4 (author reply 2354–2355).PubMedCrossRefGoogle Scholar
  106. 106.
    Kopylov U, Al-Taweel T, Yaghoobi M, et al. Adalimumab monotherapy versus combination therapy with immunomodulators in patients with Crohn’s disease: a systematic review and meta-analysis. J Crohns Colitis. 2014;8:1632–41.PubMedCrossRefGoogle Scholar
  107. 107.
    Moore C, Corbett G, Moss AC. Systematic review and meta-analysis: serum infliximab levels during maintenance therapy and outcomes in inflammatory bowel disease. J Crohns Colitis 2016.Google Scholar
  108. 108.
    Strik AS, Bots SJ, D’Haens G, et al. Optimization of anti-TNF therapy in patients with inflammatory bowel disease. Expert Rev Clin Pharmacol. 2016;9:429–39.PubMedCrossRefGoogle Scholar
  109. 109.
    Panaccione R, Colombel JF, Sandborn WJ, et al. Adalimumab maintains remission of Crohn’s disease after up to 4 years of treatment: data from CHARM and ADHERE. Aliment Pharmacol Ther. 2013;38(10):1236–47.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2017

Authors and Affiliations

  • Yun Qiu
    • 1
  • Bai-li Chen
    • 1
  • Ren Mao
    • 1
  • Sheng-hong Zhang
    • 1
  • Yao He
    • 1
  • Zhi-rong Zeng
    • 1
  • Shomron Ben-Horin
    • 1
    • 2
  • Min-hu Chen
    • 1
  1. 1.Department of GastroenterologyThe First Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouPeople’s Republic of China
  2. 2.IBD Service, Department of Gastroenterology, Sheba Medical Center and Sackler School of MedicineTel-Aviv UniversityTel HashomerIsrael

Personalised recommendations