Issue 04

Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that now includes an annual national meeting, regional satellites in both official languages, a website, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the issue editor, Dr Shomron Ben-Horin, at the annual national meeting, Mentoring in IBD XV: The Master Class, held November 7, 2014 in Toronto, Ontario.

An important part of optimizing the management of patients treated with a tumour necrosis factor-α (TNF-α) inhibitor is therapeutic drug monitoring (TDM), or measuring drug and antidrug antibody (ADA) levels.

Correlation between drug and antibody levels and clinical outcome

Numerous studies have demonstrated that higher TNF-α inhibitor trough levels are associated with better clinical outcomes. A study of 168 patients with Crohn’s disease (CD) treated with adalimumab after infliximab failure, with a median 2-year follow-up, found that treatment discontinuation was correlated with low adalimumab trough levels, which were more common if ADAs were present.(1) Similarly, a study of 115 patients with ulcerative colitis (UC) treated with infliximab found detectable trough drug levels were associated with clinical remission, endoscopic improvement, and decreased risk for colectomy, whereas undetectable trough drug levels were associated with poorer outcomes, regardless of antibody status.(2)

Evidence also supports a relation between TNF-α inhibitor drug levels and control of inflammation, as demonstrated by mucosal healing. A prospective study of 82 patients with inflammatory bowel disease (IBD) who experienced a disease flare on adalimumab therapy measured drug and ADA levels before treatment optimization with weekly adalimumab.(3) The study found patients with subtherapeutic drug levels and undetectable ADAs had the most durable response after dose intensification, whereas treatment failure was associated with subtherapeutic drug levels and detectable ADAs before optimization. During the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) data were collected on infliximab drug levels and outcomes in 728 patients with moderate-to-severe UC.(4) Analysis of this data found better clinical and mucosal healing outcomes and a lower rate of ADAs in patients with infliximab levels >3.7 μg/mL during maintenance therapy.

A population pharmacokinetic study that measured infliximab concentrations in 169 samples of patients with UC or CD found low albumin, low body weight, and ADAs to be significantly associated with high infliximab clearance (P≤.001).(5) This pharmacokinetic modelling predicted dose intensification based on TDM would result in substantially improved drug levels.

TDM in management of primary nonresponse

Infliximab

In the situation of primary nonresponse to TNF-α inhibitor induction, research indicates that TDM–guided interventions are unlikely to benefit patients treated with infliximab. In a cohort of TNF-α inhibitor-naive patients with CD, no significant difference was found in infliximab trough levels between 67 nonresponders and 191 responders.(6) In addition, retrospective evaluation of trough infliximab levels in 33 patients with CD found high drug levels among patients with primary nonresponse.(7) Similar results have been demonstrated in patients with UC. These results suggest no benefit to measuring trough levels in primary nonresponse to infliximab.

A pilot study investigating fecal drug concentrations in 9 patients found substantial fecal infliximab loss in patients with severe IBD, with the greatest loss occurring shortly after infusion.(8) Significantly greater fecal infliximab loss occurred in nonresponding than in responding patients on the first day after infusion (P=.024). In addition, a retrospective analysis of 50 patients with acute severe corticosteroid-refractory UC that compared clinical outcomes with standard and accelerated (3 induction doses within a median 24 days) induction dosing found a significantly reduced rate of early colectomy with accelerated dosing induction (6.7 vs. 40%, P=.039).(9)

Adalimumab

In contrast with infliximab, a growing body of evidence implicates low drug levels as an important cause of some adalimumab induction failures and suggests a possible benefit of individually intensified induction dosing. The Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn´s Disease (CLASSIC) I trial, a dose-ranging study, demonstrated a linear dose-response relation.(10) Optimal Week 4 remission rates were seen with the highest induction dose evaluated (160 mg at Week 0 and 80 mg at Week 2). In addition, analysis of adalimumab trough data collected during the Ulcerative colitis Long-Term Remission and maintenance with Adalimumab (ULTRA) 2 trial correlated trough concentration quartiles at Week 8 with clinical remission and response using the full Mayo score for 518 enrolled patients with moderate-to-severe UC.(11) The analysis demonstrated a relation between adalimumab trough levels and response and remission during induction, suggesting that dosing regimens providing higher trough levels could increase efficacy in some patients. Providing somewhat of a contradiction to these data, molecular fluorescent antibody imaging has found that low tissue TNF-α levels predict a lack of response to adalimumab, indicating that, in some patients, adalimumab failure may be caused by inflammation not mediated by TNF-α.(12)

TDM in management of loss of response

For patients with secondary loss of response, TDM offers a noninvasive test which, when coupled with C-reactive protein (CRP) levels and/or fecal calprotectin test results, may be useful in diagnosing the underlying etiology of a clinical flare and guiding management decisions.

Dose intensification can produce short-term response in a significant proportion of patients (Figure 1).(13)

Dose intensification is not beneficial for all patients, however. A retrospective study of pediatric and adult patients with IBD and suspected loss of response to TNF-α inhibitors correlated outcomes of different interventions and trough and ADA levels during 330 loss-of-response events.(14) Patients who failed to respond to dose intensification or a switch to another TNF-α inhibitor could be identified by trough levels for adalimumab >4.5 µg/mL or infliximab >3.8 µg/mL (90% specificity). This group of patients did, however, respond to expectant management, mostly when no clear evidence of inflammation was found, or out-of-class interventions, when inflammation was corroborated (>75% specificity). Also, patients who failed to respond to dose intensification could be identified by the presence of high-titre ADAs (>4 µg/mL-equivalent anti-adalimumab ADAs or >9 µg/mL-equivalent anti-infliximab ADAs, 90% specificity) (Figure 2). This group of patients responded better to a switch of TNF-α inhibitor than to dose intensification (P=.03). However, patients with low-titre or undetectable ADAs did respond to dose intensification (P=.02).

In a prospective study of 82 patients with IBD with loss of response to adalimumab, infliximab therapy was initiated if treatment optimization with weekly adalimumab failed.(3) Measurement of ADA and trough drug levels found a better response to adalimumab among patients with low ADA and trough levels and a better response to infliximab among patients with high ADA and low trough levels (Figure 3). Patients with low ADA and high trough levels did not have a good response to either intervention. It can be concluded that the ADA titre, rather than simply the presence or absence of ADAs, can predict response to dose intensification or switch to another TNF-α inhibitor.

If a switch to another TNF-α inhibitor is necessary, the response rate to a second agent may not be as high as to the initial one. Subgroup analysis of data from ULTRA 2 illustrates this point, as clinical response and remission were lower in the 98 adalimumab-treated patients who had previously received TNF-α inhibitor therapy than in the 150 patients who were TNF-α inhibitor naïve.(15)

Possible mechanisms of loss of response

A recent European Crohn’s and Colitis Organisation workshop focused on failure of TNF-α inhibitor therapy in IBD with the objective of better understanding primary nonresponse and secondary loss of response.(16) The workshop publication summarized the variety of mechanisms that may be involved in drug failure (Table 1).

Investigation and clinical decision making

One important but sometimes overlooked factor in evaluating loss of response is adherence. As studies indicate that 15 to 29% of patients treated with infliximab or adalimumab have missed at least one injection or infusion during the past 3 months, it is critical to determine adherence when investigating the cause of the loss of response.(17,18)

Adequate investigation of loss of response involves TDM, endoscopy, imaging, CRP, calprotectin, and additional tests as necessary. Routine use of a TDM-based algorithm, with ADA and trough levels guiding therapeutic decision-making, rather than universal dose intensification, can significantly reduce treatment costs (P<.001) without negatively affecting outcomes.(19) One such algorithm for managing loss of response encompasses investigations and clinical decision-making (Figure 4).(20)

TDM during maintenance therapy in responding patients

In responding patients receiving maintenance TNF-α inhibitor therapy, emerging evidence suggests that TDM can allow dose adjustments to improve both efficacy and cost-effectiveness. The trough level adapted infliximab treatment (TAXIT) trial in patients with CD demonstrated that fine-tuning infliximab dosage to achieve trough levels between 3 and 7 μg/mL improved disease control in patients with subtherapeutic drug levels and reduced both drug exposure and costs in patients with supratherapeutic levels, without affecting clinical outcomes. A 52-week follow-up trial found no additional benefit in ongoing trough level-based dosing, probably because the study design allowed dose optimization in both arms.(21)

Interpretation of drug/ADA results

Interpretation of drug and ADA results, which is not always simple, should consider the clinical context in which the blood test was obtained (Table 2). For instance, several possible reasons exist for a finding of undetectable trough drug levels, depending on the patient’s clinical status. Management strategies may vary considerably, based on differences in the patient’s clinical status at the time of measurement.(19) 

Transient and persistent ADAs

Measurement of infliximab trough and ADA levels in 1,232 serum samples collected from 90 patients with IBD allowed a retrospective study to correlate ADA formation and kinetics with trough drug levels, inflammatory markers, and clinical status.(22) The analysis determined that transient ADAs seldom resulted in loss of response, but sustained high ADA levels led to permanent loss of response. In addition, low trough levels at Week 14 were associated with a risk of ADA formation and infliximab discontinuation. Similarly, a retrospective study of patients with IBD who developed ADAs to infliximab investigated variations in ADA levels and their relation to clinical status. Among patients responding to infliximab, ADAs to infliximab disappeared in two-thirds of patients after 3 to 5 infusions, whereas among patients without clinical response, ADAs persisted.

A prospective observational study of 125 patients with IBD treated with infliximab measured ADA and trough drug levels in 1,119 serum samples.(23) Serial measurement demonstrated that transient ADAs could develop at any time during therapy, be present at low levels, and disappear spontaneously. In contrast, persistent ADAs tended to appear within the first 12 months of therapy (P<.001), to precede clinical loss of response, and to develop less frequently in patients receiving concomitant immunomodulator therapy.

Conclusions

TDM is an important tool in the management of patients treated with TNF-α inhibitors, but interpretation of TDM findings requires comprehensive evaluation of the clinical situation. Evidence for the benefit of TDM in managing primary nonresponse is beginning to accumulate, but this TDM application has not yet been established. In contrast, measurement of ADA and trough levels has proved useful for diagnosing the etiology of loss of response and determining the most appropriate intervention, in conjunction with determining adherence to treatment and investigating both inflammatory and noninflammatory causes. For patients in remission, TDM may improve efficacy if subtherapeutic drug levels exist and reduce costs if supratherapeutic trough levels are found, without affecting efficacy.

References

1. 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(5):1628–40.
2. Seow CH, Newman A, Irwin SP, et al. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59(1):49–54.
3. Roblin X, Rinaudo M, Del Tedesco E, et al. Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases. Am J Gastroenterol. 2014;109(8):1250–6.
4. Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology. 2014;147(6):1296–1307.
5. Dotan I, Ron Y, Yanai H, et al. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm Bowel Dis. 2014;20(12):2247–59.
6. Van Moerkercke W, Cleynen I, Compernolle G, et al. Trough levels of infliximab in a cohort of primary non-responders. 2009;58 (Suppl II):A70.
7. 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(4):944–8.
8. Brandse JF, van den Brink GR, Wildenberg ME, et al. Loss of infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis. Gastroenterology. 2015;149(2):350–e2.
9. Gibson DJ, Heetun ZS, Redmond CE, et al. An accelerated infliximab induction regimen reduces the need for early colectomy in patients with acute severe ulcerative colitis. Clin Gastroenterol Hepatol. 2015;13(2):330–5.
10. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology. 2006;130(2):323–
11. Mostafa NM, Eckert D, Pradhan RS, et al. Exposure-efficacy relationship (ER) for adalimumab during induction phase of treatment of adult patients with moderate to severe ulcerative colitis. Gastroenterology. 2013;144(5):S-225–S-226.
12. Atreya R, Neumann H, Neufert C, et al. In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn’s disease. Nat Med. 2014;20(3):313–8.
13. Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in Crohn’s disease. Aliment Pharmacol Ther. 2011;33(9):987–95.
14. Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13(3):522–30.
15. Sandborn WJ, Colombel JF, D’Haens G, et al. One-year maintenance outcomes among patients with moderately-to-severely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2. Aliment Pharmacol Ther. 2013;37(2):204–13.
16. 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(4):355–
17. Billioud V, Laharie D, Filippi J, et al. Adherence to adalimumab therapy in Crohn’s disease: a French multicenter experience. Inflamm Bowel Dis. 2011;17(1):152–
18. Lopez A, Billioud V, Peyrin-Biroulet C, Peyrin-Biroulet L. Adherence to anti-TNF therapy in inflammatory bowel diseases: a systematic review. Inflamm Bowel Dis. 2013;19(7):1528–33.
19. Steenholdt C, Brynskov J, Thomsen OØ, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2014;63(6):919–
20. Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nat Rev Gastroenterol Hepatol. 2014;11(4):243–
21. Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148(7):1320–e3.
22. Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108(6):962–
23. Ungar B, Chowers Y, Yavzori M, et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut. 2014;63(8):1258–64.

Editor-in-Chief

John K. Marshall, MD MSc FRCPC AGAF, Chief of Gastroenterology Clinical Service, Hamilton Health Sciences; Professor of Medicine, Division of Gastroenterology, McMaster University , Hamilton, ON

Co-Editor-in-Chief

Richard N. Fedorak, MD FRCPC FRCP (London) FRCS, Dean, Faculty of Medicine & Dentistry; Professor of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB

Issue Editor

Shomron Ben-Horin, MD, Director, Inflammatory Bowel Disease Unit and Gastro-Immunology Laboratory, Sheba Medical Centre, Tel-Aviv University, Tel Aviv, Israel

Mentoring in IBD Curriculum Steering Committee

 Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, ON
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
Craig Render, MD FRPCP, University of British Columbia, University of Alberta, Kelowna, BC
Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON

IBD Dialogue 2015 · Volume 11 is made possible by unrestricted educational grants from…

Published by

1B-391 Berkeley Street, Toronto, ON M5A 2X8

© Catrile & Associates Ltd., 2015. All rights reserved. None of the contents may be reproduced in any form without prior written permission from the publisher. The opinions expressed in this paper are those of the authors and do not necessarily reflect the opinions or recommendations of the sponsors, the grantor, or the publisher.