Issue 02

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. Edward V. Loftus Jr., at the annual national meeting, Mentoring in IBD XVI: The Master Class, held November 6, 2015 in Toronto, Ontario.

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The biologics approved for Crohn’s disease (CD) and ulcerative colitis (UC) in North America include the tumour necrosis factor-α (TNF-α) inhibitors infliximab, adalimumab, and golimumab and the anti-integrin agent vedolizumab. There is no doubt that these agents have favorably altered the natural history and improved the quality of life of many patients with inflammatory bowel disease (IBD). However, the variability in pharmacokinetics of TNF-α inhibitors, their potential for immunogenicity, and discrepancies between objective measures of bowel inflammation and clinical symptoms complicate their use in clinical practice.

Treatment principles

Several principles apply to the treatment of IBD with biologics.

Loss of response

Ensure that apparent loss of response is truly loss of response before switching therapy.

Symptoms may also be due to concurrent celiac disease; bacterial overgrowth; bile salt diarrhea; irritable bowel syndrome; hypersensitivity colitis; short bowel syndrome; or malabsorption of carbohydrates, such as lactose or fructose. Bacterial overgrowth is relatively common in CD. A study of 150 patients with symptomatic CD found 38 had positive hydrogen glucose breath tests.(1) Risk factors for positive tests included multiple resections, partial colonic resection, and ileocolonic disease.

Objective evidence of inflammation

Base treatment decisions on objective data, rather than just symptoms.

Poor correlation exists between the symptom-based Crohn’s Disease Activity Index (CDAI) and the inflammation-based Crohn’s Disease Endoscopic Index of Severity (CDEIS).(2) Although symptoms alert the clinician to the presence of a problem, they are insensitive and nonspecific for bowel inflammation. C-reactive protein (CRP), fecal calprotectin (FCP), and fecal lactoferrin significantly correlate with the Simple Endoscopic Score for Crohn’s Disease (SES-CD) (P<0.05), but not with the CDAI.(3)

Treatment based on serologic (reduction in CRP), endoscopic (mucosal healing), or radiographic (computed tomography enterography [CTE] or magnetic resonance enterography [MRE]) endpoints allows treatment to a target of mucosal healing or reduction in inflammation and provides an opportunity to alter the natural history of CD.

Early combination therapy

Implement combination therapy early.

The Study of Immunomodulator Naïve Patients in Crohn’s Disease (SONIC) found 96 of 169 patients receiving combination therapy (56.8%) achieved corticosteroid-free clinical remission compared with 75 of 169 patients (44.4%) receiving infliximab monotherapy (P=0.02) and 51 of 170 patients (30.0%) receiving azathioprine monotherapy.(4) Both combination therapy (P<0.001) and monotherapy with infliximab (P=0.006) were significantly more effective than monotherapy with azathioprine.

The traditional step-up approach to therapy in CD is less likely to improve long-term outcomes or avert bowel damage. A study comparing top-down and step-up therapy found that early initiation of combination immunosuppression was significantly more effective (P=0.003) than traditional therapy in inducing remission and reducing use of corticosteroids in patients with CD (Figure 1).(5) Endoscopic follow-up of a representative subset (n=49) of the initial cohort of this study, a secondary analysis, found that complete mucosal healing predicted sustained, steroid-free remission 3 and 4 years after therapy was initiated (Figure 1).(6)

Treatment optimization

Ensure that each treatment is fully optimized before switching therapies.

Treatment optimization and drug levels

Azathioprine

Although individual studies of the relation between 6-thioguanine nucleotide (6-TGN) levels and IBD activity in patients treated with azathioprine or mercaptopurine showed variable results, a meta-analysis of 12 studies strongly supported the conclusion that higher 6-TGN levels are associated with clinical remission.(7)

Infliximab

The SONIC study found significantly (P<.001) higher levels of infliximab in patients receiving combined immunosuppression than in those receiving infliximab monotherapy, and a higher proportion of patients with serum infliximab concentrations >1 mg/mL achieved corticosteroid-free remission.(8)

A study evaluating the relation between infliximab trough levels, clinical remission, and endoscopic improvement enrolled a cohort of 115 patients with UC.(9) Significantly higher rates of remission (69% vs. 15%; P<.001) and endoscopic improvement (76% vs. 28%, P<.001) were seen in patients with detectable trough infliximab levels than in those with undetectable trough levels. Patients with undetectable infliximab trough levels had an increased risk of colectomy (55% vs. 7%, P<.001). Not all patients with undetectable infliximab levels had antidrug antibodies (ADAs). Clinical outcomes were not associated with concurrent immunosuppression.

An assessment of the relation between infliximab levels and outcome in patients with moderate-to-severe UC used data from the Active Ulcerative Colitis Trials 1 and 2.(10,11) At Weeks 8, 30, and 54, the proportion of patients achieving clinical remission increased with increasing quartiles of infliximab concentration. Patients with clinical response, mucosal healing, and/or clinical remission had significantly higher infliximab concentrations than patients not meeting these criteria (P<.01). Patients in lower infliximab quartiles had lower levels of serum albumin and a higher incidence of ADAs. A steady-state infliximab level of 3.7 μg/mL was associated with optimal outcomes.

Adalimumab

An observational study of patients with CD (N=168) evaluated the long-term efficacy of adalimumab in patients with lack of response to infliximab and assessed the impact of trough levels and ADAs.(12) Of responding patients, 61.5% demonstrated sustained clinical benefit at the end of follow-up, a median of 20.4 (11.7–5 -30.0) months. During the study, 102 patients (65.4%) stepped up to adalimumab, 40 mg weekly, and 60 patients (38.5%) discontinued adalimumab, primarily due to loss of response. Patients who discontinued therapy had significantly lower adalimumab trough levels compared with those who continued therapy. ADAs, which were present in 9.2% of patients, reduced trough levels.

Treat to target

Treat to target.

A treat-to-target approach to therapy in IBD generally uses mucosal healing as the target, although the target may be influenced by comorbidities and risks associated with drug therapy. The treat-to-target approach complements early initiation of combination therapy in high-risk patients. This approach requires regular objective assessment of disease activity, followed by any appropriate therapeutic adjustments, to ensure that the target, once achieved, is maintained indefinitely.(13) Although it has been suggested that mucosal healing should be assessed every 6 months until the target is achieved and then every 1 to 2 years, with the frequency adjusted according to the presence of inflammation (Figure 2), additional studies are needed to determine the optimal interval between target assessment.

Assessment of response to treatment change

Assess response to a change in therapy objectively.

Traditionally, endoscopy is used to assess mucosal healing. The utility of less invasive modalities has been assessed as an alternative to endoscopy. A retrospective study of serial CTE imaging in patients (N=63) with CD evaluated the correlation between radiologic response, endoscopic appearance and CRP.(14) The finding of a poor-to-fair correlation between CTE, endoscopic healing, and CRP indicated that CTE was not a substitute for endoscopy. Another study evaluated pre- and post-therapy CTE and MRE results in 150 patients with small-bowel CD and used outcomes of surgery, hospitalization, and/or corticosteroid therapy.(15) Complete radiologic response was associated with a reduced risk of surgery, hospitalization, and corticosteroid use, compared with nonresponse. Partial radiologic response was associated with a reduced risk of surgery or hospitalization.

The magnetic resonance index of activity (MaRIA) is based on wall thickness, relative contrast enhancement, magnetic resonance imaging (MRI) edema, and MRI ulcers. A study performed to define and validate MaRIA included patients with active (n=29) or inactive (n=19) CD.(16) Patients underwent ileocolonoscopy, with CDEIS as a reference standard, and MRI. Independent predictors of disease severity using CDEIS as a reference were wall thickness, relative contrast enhancement, and presence of edema and ulcers on MRI.

Therapeutic drug monitoring

Factors affecting levels of TNF-α inhibitors

Numerous factors have been shown to affect TNF-α inhibitor pharmacokinetics, including presence of ADAs; sex and/or body size; disease severity, including TNF burden; and albumin levels (Figure 3).(17) As a result, pharmacokinetics of these agents can be highly variable. As empiric adjustment of TNF-α inhibitor dose may not produce an optimal outcome, therapeutic drug monitoring (TDM) is a valuable clinical tool allowing clinicians to optimize therapy by maintaining drug concentration in an effective range.

Clinical impact of optimization based on TDM

A retrospective review (N=155) evaluated clinical outcomes in patients who had infliximab therapy adjusted based on trough and ADA levels.(18) The major rationale for performing TDM was loss of response or partial response, although some patients had possible autoimmune or delayed hypersensitivity reactions. Of the 35 patients positive for ADAs, 11 of the 12 patients (92%) switched to an alternative TNF-α inhibitor had a complete or partial response, whereas only 1 of 6 patients (17%) who had their infliximab dose increased had a complete or partial response (P<.004). Of 63 patients with subtherapeutic infliximab levels, the infliximab dose was increased in 29 patients, 25 of whom (86%) had a clinical or partial response, and 6 patients were switched to an alternative agent, 2 of whom (33%) had a response (P<.016). Routine assessment of trough and ADA levels in patients with loss of response or incomplete response may help optimize therapy (Figure 4).

The prospective randomized controlled Trial of Trough Level Adapted Infliximab Treatment (TAXIT) compared the impact on outcomes of TDM-based infliximab dosing with clinically based dosing in patients (N=263) with IBD.(19) Algorithm-based dosing targeted a trough level of 3 to 7 μg/mL. The primary end point was clinical and biochemical remission 1 year after optimization. TDM-based dose augmentation increased the proportion of patients with CD in remission (88% vs. 65%, P=.020) and decreased CRP (3.2 vs. 4.3 mg/L, P<.001), but did not affect remission in patients with UC. TDM-based dose reductions lowered drug costs by 28% (P<.001). Remission was achieved in 66% of patients receiving clinically based dosing and 69% of patients receiving TDM-based dosing (P=.686). Relapse was seen in 21 patients (17%) on the clinically based regimen and 9 patients (7%) on the TDM-based regimen (P=.018). Although TDM-based dosing was better than clinically based dosing in reducing relapse and in using infliximab more efficiently, it did not prove superior in improving remission rates.

A retrospective observational pilot study assessed the impact of proactive TDM-based dose adjustments (n=48) to target levels on outcomes and compared this approach with conventional dosing (n=78).(20) Infliximab dose was increased in 12 patients (25%) and decreased in 7 patients (15%). The probability of continuing infliximab treatment was higher in patients receiving TDM-based dosing than in those receiving conventional dosing (hazard ratio [HR]=0.3; 95% confidence interval [CI]=0.1–0.6; P=.0006) and was highest for patients with infliximab trough levels >5 μg/mL (HR=0.03; 95% CI=0.01–0.1; P<.0001). Discontinuation was lower in the TDM-based dosing group (10%) than in the conventional dosing group (31%, P=.009).

Challenges to achieving mucosal healing

Although mucosal healing is gaining acceptance both as a measure of disease activity in IBD and a clinical trial endpoint, no validated definition exists for mucosal healing in IBD.(21) In addition, full mucosal healing cannot be achieved in many patients, and the degree of healing required to affect outcomes is unknown. Also unknown is the incremental degree of healing that can be achieved by dose escalation or by switching therapies. Finally, the appropriate time interval between changes in therapy and reassessment by endoscopy has not been determined. Biomarkers, such as FCP, lactoferrin, CRP, and fecal S1 00A1 2, show promise as surrogate markers for endoscopic healing.

The community-based Randomized Evaluation of an Algorithm for Crohn’s Treatment (REACT) trial, which followed patients (N=1982) for 2 years, had a primary endpoint of clinical remission, defined as a Harvey-Bradshaw Index (HBI) <5 and no corticosteroid therapy at 12 months. The primary endpoint was not met, possibly because the mean baseline HBI was only 4.1.(22) REACT did, however, determine that algorithm-based treatment with early combined immunosuppression reduced surgeries, hospitalizations, and complications in CD.

Conclusions

The principles of treating IBD with biologics are a useful guide to therapy, including fully optimizing an agent using TDM before switching, using objective markers of inflammation as the basis of treatment decisions, and implementing early combination immunosuppression.

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Clinical Case

Case presentation

Ryan is a 24-year-old law student with 25 cm of ileal and nearly pancolonic Crohn’s disease. You diagnosed him at 22 years of age, and he has been on adalimumab monotherapy for the last 12 months. As he was negative for the Epstein-Barr virus (EBV), you did not start azathioprine. Initially, he did well clinically on adalimumab monotherapy with normalization of his Harvey-Bradshaw Index scores, CRP, and FCP, and mucosal healing after 6 months of therapy. He complains of increasing diarrhea that began about 2 months ago and occurs up to 4 days before his next injection of adalimumab.

Commentary

Therapeutic drug monitoring is appropriate in this situation. As the risks associated with azathioprine therapy in EBV-negative patients are often perceived to be more significant than they actually are, combination therapy may have averted this situation.

Case evolution

You order a complete blood count (CBC), CRP, ferritin, iron, total iron-binding capacity (TIBC), FCP, adalimumab trough levels, and ADAs. Results are as follows:

– Hemoglobin (Hb) is low at 110 g/L

– CRP is elevated at 32 mg/L

– Iron is low at 3 μmol/L

– FCP is elevated at 665 μg/g

– Adalimumab trough levels are slightly low at 2 μg/mL

– Adalimumab ADAs are slightly high at 8 U/mL

Commentary

Target trough levels for adalimumab are 4 to 9 μg/mL, and an increased adalimumab dose may be able to override the low ADA levels, although the sensitization threshold for adalimumab has not been conclusively determined. Three optimization strategies could be used for Ryan: increase the adalimumab dose, decrease the dosing interval, or add an immunosuppressive.

Case evolution

You double the dose of adalimumab and add methotrexate and a short course of prednisone, tapering down from 20 mg by 5 mg per week to provide immediate symptomatic relief. His clinical symptoms improve for almost 4 months, but then they rapidly decline with worsening of his diarrhea.

Commentary

Ryan’s improvement is most likely due to the corticosteroid. TDM is again indicated.

Case evolution

You order CBC, CRP, ferritin, iron, TIBC, FCP, adalimumab trough levels, and ADAs. Results are as follows:

– Hb is low at 120 g/L

– CRP is elevated at 18 mg/L

– Iron is low at 8 μmol/L

– FCP is elevated at 333 μg/g

– Adalimumab trough levels are low at 1 μg/mL

– Adalimumab ADAs are high at 50 U/mL

Commentary

With low adalimumab trough levels and high ADAs, it is now appropriate to switch Ryan to an alternative tumour necrosis factor-α inhibitor.

Case evolution

You switch Ryan from adalimumab to infliximab. He does amazingly well during infliximab induction with full clinical remission. During his second maintenance infusion, however, he has a severe infusion reaction and returns to your office for advice on next steps.

Commentary

It is necessary to learn more about the infusion reaction before deciding whether to bring Ryan in to premedicate and observe him during the next infusion or switch out of class to an alternative therapy.

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References

1. Klaus J, Spaniol U, Adler G, et al. Small intestinal bacterial overgrowth mimicking acute flare as a pitfall in patients with Crohn’s disease. BMC Gastroenterol. 2009;9:61.
2. Modigliani R, Mary JY, Simon JF, et al. Clinical, biological, and endoscopic picture of attacks of Crohn’s disease. Evolution on prednisolone. Groupe d’Etude Thérapeutique des Affections Inflammatoires Digestives. Gastroenterology. 1990;98(4):811–8.
3. Jones J, Loftus EV Jr, Panaccione R, et al. Relationships between disease activity and serum and fecal biomarkers in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2008;6(11):1218–24.
4. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383–95.
5. D’Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet. 2008;371(9613):660–7.
6. Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology. 2010;138(2):463–8.
7. Osterman MT, Kundu R, Lichtenstein GR, et al. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology. 2006;130(4):1047–53.
8. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383–95.
9. 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.
10. Reinisch W, Feagan BG, Rutgeerts PJ, et al. Infliximab concentration and clinical outcome in patients with ulcerative colitis. Gastroenterology. 2012;5(Suppl 1):S-114. Abstract 566.
11. 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.e5.
12. 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.
13. Bouguen G, Levesque BG, Feagan BG, et al. Treat to target: a proposed new paradigm for the management of Crohn’s disease. Clin Gastroenterol Hepatol. 2015;13(6):1042–50.e2.
14. Bruining DH, Loftus EV Jr, Ehman EC, et al. Computed tomography enterography detects intestinal wall changes and effects of treatment in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2011;9(8):679–83.e1.
15. Deepak P, Fletcher J, Fidler J, et al. Radiological response is associated with better long-term outcomes and is a potential treatment target in patients with small bowel Crohn’s disease. Am J Gastroenterol. 2015;110(Suppl 1):S786. Abstract 1849.
16. Rimola J, Ordás I, Rodriguez S, et al. Magnetic resonance imaging for evaluation of Crohn’s disease: validation of parameters of severity and quantitative index of activity. Inflamm Bowel Dis. 2011;17(8):1759–68.
17. Ordás I, Feagan BG, Sandborn WJ. Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2012;10(10):1079–87.
18. Afif W, Loftus EV Jr, Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105(5):1133–9.
19. 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):1320–9.e3.
20. Vaughn BP, Martínez-Vazquez M, Patwardhan V, et al. Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study. Inflamm Bowel Dis. 2014;20:1996–2003.
21. Dave M, Loftus EV Jr. Mucosal healing in inflammatory bowel disease-a true paradigm of success? Gastroenterol Hepatol (N Y). 2012;8(1):29–38.
22. Khanna R, Bressler B, Levesque BG, et al. Early combined immunosuppression for the management of Crohn’s disease (REACT): a cluster randomized controlled trial. Lancet. 2015;386(10006):1825–34.

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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

Edward V Loftus Jr, MD AGAF FACG FACP, Professor of Medicine, Director, Inflammatory Bowel Disease Interest Group, Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN

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

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IBD Dialogue 2016·Volume 12 is made possible by unrestricted educational grants from…

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