Although a significant amount of data was uncovered from the published literature, it was apparent that there was significant between-study heterogeneity and a number of evidence gaps (Table 3). Definitions for primary failure and secondary failure varied and were not consistently reported. There was relatively more evidence characterizing the use and outcomes of IFX therapy, and lesser evidence for ADA, with few studies providing evidence on the use of other available biologics such as NAT, GOL and CTZ. Furthermore, there remain gaps in the literature in the reporting of therapeutic rates of primary failure and secondary failure, or the response to treatment failure (such as dose escalation or therapy switching) across treatments, which need to be characterized to fully ascertain the extent of unmet need in patients with UC and CD.
Respondents from both countries had more experience in the treatment of CD than in the treatment of UC. The mean number of patients with CD that a clinician in the UK reported to have treated with biologic therapy was 70, versus 34 patients with UC; by comparison, French clinicians treated a mean of 44 patients with CD using biologic therapies, compared with 27 patients with UC. However, whereas the experience of UK clinicians was restricted to IFX and ADA, French clinicians had experience in the use of IFX, ADA, GOL and CTZ.
In the UK context, fewer CD compared with UC patients were classified as having severe disease, rather than moderate disease, at onset (57 vs. 69% were classified as having severe CD and UC, respectively). However, on average, it was estimated that CD patients were treated with a biologic 8 months sooner than UC patients (15 vs. 23 months from disease onset to first biologic therapy). The experience of UK clinicians was restricted to IFX and ADA, and in this context, clinicians were asked a series of questions related to treatment failure and response with first-line and second-line biologic therapy with these two anti-TNFα agents.
In France, the proportion of patients classified as having severe disease rather than moderate disease were similar among UC and CD patients, with more patients categorized as severe for both (UC: 58% severe vs. 40% moderate; CD: 55% severe vs. 44% moderate). However, consistent with UK clinician experience, it was estimated that CD patients were treated with a biologic 6 months sooner than UC patients (12 vs. 18 months on average from disease onset to administration of first-line anti-TNFα agent). French clinician experience was reported for IFX, ADA, GOL and CTZ, and in this context, clinicians were asked a series of questions related to treatment failure and response with first-line and second-line anti-TNFα agents; clinician experience was predominantly in treatment with IFX and ADA, with clinicians having limited experience with GOL and CTZ.
When asked to estimate treatment failure on the basis of their own experience, UK clinicians estimated that 18–26% of patients fail and discontinue therapy with a first-line anti-TNFα agent during the induction phase (primary failure), and that 22–26% lose response and discontinue that anti-TNFα agent over time – that is, secondary failure of the first-line anti-TNFα agent. Estimates of treatment failure were even higher for second-line treatment with an anti-TNFα agent: 28–37% of patients fail and discontinue treatment during the induction phase, and 31–41% lose response and discontinue their second-line anti-TNFα agent treatment over time (Fig. 2). Among patients who lost response, it was estimated that 68–77% of patients discontinued treatment by the end of the first year, and 82–90% of patients discontinued treatment by the end of the second year of treatment due to loss of response.
French clinicians estimated that up to 26% of patients failed and discontinued first-line biologic therapy during the induction phase, and up to 28% lose response and discontinue therapy with an anti-TNFα agent over time. Estimates of treatment failure were even higher with second-line anti-TNFα agents, where it was estimated that up to 29% of patients failed and discontinued treatment during the induction phase, and up to 40% lose response and discontinue an anti-TNFα agent over time (Fig. 3). Among patients who lose response and discontinue biologic treatment, it was estimated that 45–60% discontinue treatment by the end of their first year of treatment. By the end of the third year of treatment, 73–87% of patients discontinue treatment due to loss of response.
UK clinicians estimated that in patients with first-line treatment failure who showed signs of a reduced response, their response would be to add another (nonbiologic) treatment, such as corticosteroids, in around 25% of cases, increase the dose of the existing biologic therapy in 21–24% of cases, increase the administration frequency in 17–25% of cases, and offer surgery as a treatment option in 20–22% of cases. When treatment alternatives in patients failing first-line biologic therapy were restricted to surgery or a switch to a second-line biologic, UK clinicians estimated that among UC patients failing IFX as a first-line anti-TNFα agent, around 50% would switch to ADA as a second-line anti-TNFα agent and the other 50% would pursue surgery as a treatment option. Similarly among ADA failures, around 50% would switch to IFX as a second-line anti-TNFα agent and 50% would pursue surgery. Among CD patients failing IFX, clinicians estimated that around 70% would switch to ADA as a second-line anti-TNFα agent and the other 30% would pursue surgery as a treatment option. For ADA failures, around 50% would switch to IFX as a second-line anti-TNFα agent and 50% would pursue surgery. French clinicians estimated that among patients with first-line treatment failure or a reduced response, around 18–39% would receive an additional nonbiologic treatment, such as corticosteroids, around 12–33% would be administered an increased dose of the existing anti-TNFα agent, administration frequency would be increased in around 9–27% of patients and surgery would be offered to around 7–23% of patients. When treatment alternatives in patients failing first-line biologic therapy were restricted to surgery or a switch to a second-line anti-TNFα agent, it was estimated that among UC patients, around 20% would switch to surgery from biologic therapy (IFX/ADA/CTZ) and 77%would switch between IFX and ADA (i.e. IFX to ADA or ADA to IFX). Among CD patients failing a first-line anti-TNFα agent, 15% would switch to surgery from IFX/ADA, 26% would switch from CTZ to surgery and 80% would switch between IFX and ADA; clinicians estimated that there was limited switching to GOL or CTZ.
The impact of UC and CD on the quality of life of patients and on medical expenditure is well understood 59, as is the need for effective treatment options 60. The efficacy of conventional treatments and biologic therapies used to manage cases of UC and CD has been explored in a number of clinical trials 15–26,61–63. Meta-analyses and retrospective analyses of patients receiving the available biologic therapies suggest that their comparative effectiveness is similar, whereas other studies point toward differences between the treatments in terms of patient-relevant outcomes 27–31. The current literature, therefore, does not allow definitive conclusions to be drawn with regard to the comparative outcomes of patients treated with currently available biologic therapies in clinical practice. This research aimed to characterize treatment patterns and outcomes of patients with UC and CD and therein characterize the degree of unmet medical need among patients with these conditions.
The reviewed literature and estimates of treatment failure obtained from clinicians treating patients with biologics in current clinical practice demonstrate that there is significant unmet need among patients with UC and CD. In the significant number of patients who cannot tolerate or who fail their first-prescribed biologic treatment, subsequent pharmacological treatment choices are restricted to the biologic therapies currently available. Data from this study suggest that the outcome for patients who cycle between existing biologic treatment options with similar mechanisms of action (i.e. IFX, ADA, GOL, CTZ) is likely to be suboptimal in around 21–41% of cases.
This study was supported by Cegedim Strategic Data (CSD UK Ltd) and Capita India Pvt. Ltd in the design and implementation of the clinician surveys and systematic literature reviews, respectively. We acknowledge writing support provided by Beverley Jones (HEOR Ltd).
This study was funded by an unrestricted research grant from Takeda Development Centre, Europe. Initial data analyses and writing was undertaken by J.P.G. and P.C.M., who are employees of HEOR Ltd and received funding from Takeda Development Centre, Europe. All named authors contributed to the study design, writing support and interpretation of findings.
J.P.G., P.C.M., A.M. and D.M.S. have served as consultants to and received research funding from Takeda Development Centre, Europe, in relation to this study. J.P.G., P.C.M. and D.M.S. are employees of HEOR Ltd. A.M. is an employee of Oxon Epidemiology. J.P. is an employee of Takeda Development Centre, Europe.
1. Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet 2007; 369:1627–1640.
2. Pithadia AB, Jain S. Treatment of inflammatory bowel disease (IBD). Pharmacol Rep 2011; 63:629–642.
8. Caviglia R, Boskoski I, Cicala M. Long-term treatment with infliximab in inflammatory bowel disease: safety and tolerability issues. Expert Opin Drug Saf 2008; 7:617–632.
9. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al.. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345:1098–1104.
10. Siegel CA, Hur C, Korzenik JR, Gazelle GS, Sands BE. Risks and benefits of infliximab for the treatment of Crohn’s disease
. Clin Gastroenterol Hepatol 2006; 4:1017–1024, quiz 976.
11. Siegel CA, Marden SM, Persing SM, Larson RJ, Sands BE. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn’s disease
: a meta-analysis. Clin Gastroenterol Hepatol 2009; 7:874–881.
15. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al.. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease
: the CHARM trial. Gastroenterology 2007; 132:52–65.
16. Colombel JF, Sandborn WJ, Rutgeerts P, Kamm MA, Yu AP, Wu EQ, et al.. Comparison of two adalimumab treatment schedule strategies for moderate-to-severe Crohn’s disease
: results from the CHARM trial. Am J Gastroenterol 2009; 104:1170–1179.
17. Feagan BG, Panaccione R, Sandborn WJ, D’Haens GR, Schreiber S, Rutgeerts PJ, et al.. Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn’s disease
: results from the CHARM study. Gastroenterology 2008; 135:1493–1499.
18. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al.. Maintenance infliximab for Crohn’s disease
: the ACCENT I randomised trial. Lancet 2002; 359:1541–1549.
19. Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al.. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease
: the CLASSIC-I trial. Gastroenterology 2006; 130:323–333.
20. Lémann M, Mary JY, Duclos B, Veyrac M, Dupas JL, Delchier JC, et al.. Groupe d'Etude Therapeutique des Affections Inflammatoires du Tube Digestif (GETAID). Infliximab plus azathioprine for steroid-dependent Crohn's disease patients: a randomized placebo-controlled trial. Gastroenterology 2006; 130:1054–1061.
21. Probert CS, Hearing SD, Schreiber S, Kühbacher T, Ghosh S, Arnott ID, Forbes A. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis
: a randomised controlled trial. Gut 2003; 52:998–1002.
22. Reinisch W, Sandborn WJ, Hommes DW, D’Haens G, Hanauer S, Schreiber S, et al.. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis
: results of a randomised controlled trial. Gut 2011; 60:780–787.
23. Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al.. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis
. Gastroenterology 2014; 146:85–95, quiz e14-5.
24. Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D’Haens G, Wolf DC, et al.. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis
. Gastroenterology 2012; 142:257.e3–265.e3.
25. Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, et al.. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease
. Gastroenterology 2005; 129:807–818.
26. Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH, et al.. Natalizumab for the treatment of active Crohn’s disease
: results of the ENCORE Trial. Gastroenterology 2007; 132:1672–1683.
27. Dretzke J, Edlin R, Round J, Connock M, Hulme C, Czeczot J, et al.. A systematic review
and economic evaluation of the use of tumour necrosis factor-alpha (TNF-alpha) inhibitors, adalimumab and infliximab, for Crohn’s disease
. Health Technol Assess 2011; 15:1–244.
28. Behm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn’s disease
. Cochrane Database Syst Rev 2008; 1:CD006893.
29. Stidham RW, Lee TC, Higgins PD, Deshpande AR, Sussman DA, Singal AG, et al.. Systematic review
with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn’s disease
. Aliment Pharmacol Ther 2014; 39:1349–1362.
30. Stidham RW, Lee TC, Higgins PD, Deshpande AR, Sussman DA, Singal AG, et al.. Systematic review
with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis
. Aliment Pharmacol Ther 2014; 39:660–671.
31. Patil SA, Rustgi A, Langenberg P, Cross RK. Comparative effectiveness of anti-TNF agents for Crohn’s disease
in a tertiary referral IBD practice. Dig Dis Sci 2013; 58:209–215.
32. Moher D, Liberati A, Tetzlaff J, Altman DG, et al.. Preferred reporting items for systematic
reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009; 151:264–269.
33. National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. 2008. Available at: http://www.nice.org.uk/article/pmg9
. [Accessed 20 March 2014].
34. The Cochrane Collaboration. Cochrane Handbook for Systematic
Reviews of Interventions. Version 5.1.0. 2011. Available at: http://handbook.cochrane.org
. [Accessed 12 August 2014].
36. Microsoft Corporation. Microsoft Excel 2013: Microsoft Corporation, Redmond, Washington, USA.
37. StataCorp. Stata statistical software: release 11. StataCorp LP, College Station, Texas, USA; 2009.
38. Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol 2011; 106:685–698.
39. Alzafiri R, Holcroft CA, Malolepszy P, Cohen A, Szilagyi A. Infliximab therapy for moderately severe Crohn’s disease
and ulcerative colitis
: a retrospective comparison over 6 years. Clin Exp Gastroenterol 2011; 4:9–17.
40. Herrlinger KR, Barthel DN, Schmidt KJ, Büning J, Barthel CS, Wehkamp J, et al.. Infliximab as rescue medication for patients with severe ulcerative/indeterminate colitis refractory to tacrolimus. Aliment Pharmacol Ther 2010; 31:1036–1041.
41. Gies N, Kroeker KI, Wong K, Fedorak RN. Treatment of ulcerative colitis
with adalimumab or infliximab: long term follow-up of a single centre cohort. Aliment Pharmacol Ther 2010; 32:522–528.
42. Oussalah A, Evesque L, Laharie D, Roblin X, Boschetti G, Nancey S, et al.. A multicenter experience with infliximab for ulcerative colitis
: outcomes and predictors of response, optimization, colectomy, and hospitalization. Am J Gastroenterol 2010; 105:2617–2625.
43. Ho GT, Mowat A, Potts L, Cahill A, Mowat C, Lees CW, 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; 29:527–534.
44. Taxonera C, Estellés J, Fernández-Blanco I, Merino O, Marín-Jiménez I, Barreiro-de Acosta M, et al.. Adalimumab induction and maintenance therapy for patients with ulcerative colitis
previously treated with infliximab. Aliment Pharmacol Ther 2011; 33:340–348.
45. Afif W, Leighton JA, Hanauer SB, Loftus EV Jr, Faubion WA, Pardi DS, et al.. Open-label study of adalimumab in patients with ulcerative colitis
including those with prior loss of response or intolerance to infliximab. Inflamm Bowel Dis 2009; 15:1302–1307.
46. Oussalah A, Laclotte C, Chevaux JB, Bensenane M, Babouri A, Serre AA, et al.. Long-term outcome of adalimumab therapy for ulcerative colitis
with intolerance or lost response to infliximab: a single-centre experience. Aliment Pharmacol Ther 2008; 28:966–972.
47. Lees CW, Ali AI, Thompson AI, Ho GT, Forsythe RO, Marquez L, 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; 29:286–297.
48. Katz L, Gisbert JP, Manoogian B, Lin K, Steenholdt C, Mantzaris GJ, et al.. Doubling the infliximab dose versus halving the infusion intervals in Crohn’s disease
patients with loss of response. Inflamm Bowel Dis 2012; 18:2026–2033.
49. Chaparro M, Panes J, García V, Mañosa M, Esteve M, Merino O, et al.. Long-term durability of infliximab treatment in Crohn's disease and efficacy of dose "escalation" in patients losing response. J Clin Gastroenterol 2011; 45:113–118.
50. Oussalah A, Chevaux JB, Fay R, Sandborn WJ, Bigard MA, Peyrin-Biroulet L. Predictors of infliximab failure after azathioprine withdrawal in Crohn’s disease
treated with combination therapy. Am J Gastroenterol 2010; 105:1142–1149.
51. Russo EA, Iacucci M, Lindsay JO, Campbell S, Hart A, Hamlin J, et al.. Survey on the use of adalimumab as maintenance therapy in Crohn’s disease
in England and Ireland. Eur J Gastroenterol Hepatol 2010; 22:334–339.
52. Ho GT, Smith L, Aitken S, Lee HM, Ting T, Fennell J, et al.. The use of adalimumab in the management of refractory Crohn’s disease
. Aliment Pharmacol Ther 2008; 27:308–315.
53. Swoger JM, Loftus EV Jr, Tremaine WJ, Faubion WA, Pardi DS, Kane SV, et al.. Adalimumab for Crohn’s disease
in clinical practice at Mayo clinic: the first 118 patients. Inflamm Bowel Dis 2010; 16:1912–1921.
54. 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; 25:675–680.
55. Louis E, Löfberg R, Reinisch W, Camez A, Yang M, Pollack PF, et al.. Adalimumab improves patient-reported outcomes and reduces indirect costs in patients with moderate to severe Crohn’s disease
: results from the CARE trial. J Crohns Colitis 2013; 7:34–43.
56. Cordero Ruiz P, Castro Márquez C, Méndez Rufián V, Castro Laria L, Caunedo Álvarez A, Romero Vázquez J, Herrerías Gutiérrez JM. Efficacy of adalimumab in patients with Crohn’s disease
and failure to infliximab therapy: a clinical series. Rev Esp Enferm Dig 2011; 103:294–298.
57. Hoentjen F, Haarhuis BJ, Drenth JP, de Jong DJ. Elective switching from infliximab to adalimumab in stable Crohn’s disease
. Inflamm Bowel Dis 2013; 19:761–766.
58. Van Assche G, Vermeire S, Ballet V, Gabriels F, Noman M, D’Haens G, et al.. Switch to adalimumab in patients with Crohn’s disease
controlled by maintenance infliximab: prospective randomised SWITCH trial. Gut 2012; 61:229–234.
59. Rocchi A, Benchimol EI, Bernstein CN, Bitton A, Feagan B, Panaccione R, et al.. Inflammatory bowel disease: a Canadian burden of illness review
. Can J Gastroenterol 2012; 26:811–817.
60. Lawrance IC. What is left when anti-tumour necrosis factor therapy in inflammatory bowel diseases fails? World J Gastroenterol 2014; 20:1248–1258.
61. Rutgeerts P, Diamond RH, Bala M, Olson A, Lichtenstein GR, Bao W, et al.. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease
. Gastrointest Endosc 2006; 63:433–442.
62. Rutgeerts P, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al.. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease
. Gastroenterology 2004; 126:402–413.
63. D’Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, et al.. Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease
: an open randomised trial. Lancet 2008; 371:660–667.
64. Clinical Effectiveness and Evaluation unit at the Royal College of Physicians. National clinical audit of biological therapies: UK Inflammatory Bowel Disease (IBD) audit. Adult national report. 2013. Available at: https://www.rcplondon.ac.uk/projects/biologics
. [Accessed 13 August 2014].