Issue 05

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 contributing editor, Dr Subrata Ghosh, at the annual national meeting, Mentoring in IBD XV: The Master Class, held November 7, 2014 in Toronto, Ontario.

Treat-to-target is an established concept in several chronic inflammatory diseases and an evolving one in inflammatory bowel disease (IBD). Judging treatment success and failure only by symptoms may leave a considerable reservoir of subtle untreated inflammation that may lead to tissue damage and disability. An international group, under the auspices of the International Organization for the Study of Inflammatory Bowel Diseases, is working to finalize the treatment targets for IBD, with the objective of changing the disease course. The time to achieve the target is thought to be as important as reaching the target itself, and trials are now underway to test whether a time-sensitive treat-to-target approach is superior to more conventional approaches.

Evolution of treatment goals to improve outcomes

Advances in IBD therapeutics have allowed better disease control (Figure 1).(1–4) Rigorous treatment goals can be set to modify the disease course, but this approach requires more complex treatment algorithms involving risk stratification and objective monitoring of disease activity. A treat-to-target approach also must consider the timing of interval and final endpoint assessment (Table 1).

Early diagnosis

Early diagnosis is critical, as the duration of disease before effective treatment is implemented can affect efficacy. The Crohn’s trial of the fully Human antibody Adalimumab for Remission Maintenance (CHARM) randomized 854 patients with moderately to severely active Crohn’s disease (Crohn’s disease activity index [CDAI] score 220–450) to adalimumab or placebo.(5) At Week 4, responding patients (n=499) were randomized to two different doses of adalimumab or placebo. A sub-analysis of CHARM assessed efficacy by disease duration before adalimumab treatment.(6) At Week 56, response rates were 51.3% for patients with disease duration <2 years (P=.014 vs. placebo), 43.9% for those with disease duration between 2 and 5 years (P=.001 vs. placebo), and 35.2% for patients with disease duration ³5 years (P=.001 vs. placebo).

Prediction of outcomes

Extensive research has identified predictors of poor outcome in patients with Crohn’s disease (CD).(7) These include young age at diagnosis and disease severity and extent. An observational study of 102 patients with active ileocolonic disease assessed the risk of colectomy in patients with severe endoscopic lesions, defined as extensive and deep ulcerations covering more than 10% of the surface area of at least one colonic segment.(8) The presence of severe endoscopic lesions at the index colonoscopy independently predicted colectomy with a relative risk (RR) of 6.72 (95% confidence interval [CI] 2.26–20.03).

Early effective therapy

A 2-year open-label randomized trial that included 133 patients with Crohn’s disease compared the benefits of early combined immunosuppression with conventional therapy.(9) The primary outcome, steroid-independent remission without bowel resection at Weeks 26 and 52, was achieved in significantly more patients in the combined immunosuppression group. At Week 26, the primary outcome was achieved in 60.0% (39/65) of patients in the combined immunosuppression group and 35.9% (23/64) of controls (P=.0062). At Week 52, the corresponding rates were 61.5% (40/65) for combined immunosuppression and 42.2% (27/64) for controls (P=.0278). These results demonstrate the benefit of early effective therapy.

The EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing (EXTEND) trial (10) randomized patients with moderate-to-severe ileocolonic CD and active mucosal ulceration to adalimumab (n=62) or placebo (n=61). Patients with early CD (<5 years duration) had higher rates of mucosal healing (40%, 4/10) with adalimumab than those who had CD ≥5 years (21%, 9/43, P=.029).

Furthermore, a retrospective, registry-based study that included 425 patients with CD assessed phenotypic factors that predicted the need for surgery.(11) Complications associated with longstanding disease, such as strictures (adjusted hazard ratio [HR] 6.17, 95% CI 2.81–13.54) and fistulas (adjusted HR 3.39, 95% CI 1.45–7.92), were significantly associated with the need for surgery. These data support the concept that early treatment during the inflammatory stages of CD results in better outcomes than treatment later in the disease course.

Treatment optimization

One way to optimize treatment in patients with CD is to combine a tumour necrosis factor-α (TNF-α) inhibitor with an immunomodulator. The Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease (SONIC) compared the rates of mucosal healing achieved with treatment with azathioprine, infliximab, and the combination at 26 weeks.(1) SONIC found a 43.9% rate of mucosal healing in the group receiving combination therapy (n=107), significantly higher (P≤.001) than in the group receiving azathioprine (16.5%, n=109) and higher (P=.055) than in the group receiving infliximab (30.1%, n=93). The benefit of combination therapy likely reflects both reduced immunogenicity and synergistic efficacy.

Treatment optimization also requires early and effective management of loss of response, using therapeutic drug monitoring. Measuring drug levels can clarify the reason for loss of response and is more cost effective than empiric dose intensification.(12) Measuring thiopurine metabolites can also help to optimize the safety and effectiveness of that therapeutic class.

Treatment to target

It is well known that persistent inflammation results in tissue damage. The concept of treat-to-target rests on treating residual inflammation in patients who may be in clinical remission to prevent tissue remodelling. Treating clinically silent inflammation represents a paradigm shift in practice, and requires greater use of objective monitoring tools to assess whether treatment goals are achieved.

A prospective patient registry included 181 patients with CD with good quality of life, measured by the short inflammatory bowel disease questionnaire (SIBDQ) and same-day C-reactive protein (CRP) results.(13) CRP was elevated in 24% (n=43) of patients. Over 24 months, hospitalization rates were 37% (16/43) among those with elevated CRP and 7% (9/138, P<.001) among those with normal CRP. Multivariate analysis found CRP elevation to be significantly associated with hospitalization (odds ratio [OR] 6.82, 95% CI 2.50–18.58, P<.0001) after adjusting for covariates. This 6-fold greater risk of hospitalization indicated that patients with CD who are clinically well could benefit from closer monitoring to prevent disease-related complications.

A study to correlate endoscopic activity, CDAI scores, and CRP in CD with fecal calprotectin and lactoferrin enrolled 77 patients.(14) The Crohn’s disease index of severity (CDEIS) was scored during ileocolonoscopy. The study found a significant correlation between CDEIS and fecal calprotectin and lactoferrin (P<.001). These measures were more sensitive for endoscopic disease activity than was the CDAI.

A retrospective study of 252 patients with IBD evaluated rates of deep remission (clinical remission with mucosal healing) with TNF-α inhibitor therapy.(15) After a median of 23 months of maintenance therapy, 168 (67%) patients were in clinical remission, and 122 (48%) were in deep remission, of whom 99 (81%) were also in histologic remission. Median CRP and fecal calprotectin levels were significantly lower in patients in deep remission.

A subanalysis of the infliximab diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors (STORI) trial evaluated the utility of close monitoring of CRP and fecal calprotectin to predict relapse in 113 patients, 51 of whom relapsed after infliximab discontinuation.(16) Values linked to short-term relapse were CRP >5 mg/L (HR 4.2, 95% CI 1.9–9.2, P=.001) and fecal calprotectin levels >250 μg/g (HR 6.5, 95% CI 2.7–15.6, P<.001).

A 1-year study evaluated the ability of fecal calprotectin levels to predict relapse in 43 patients with CD and 37 with ulcerative colitis (UC) in clinical remission.(17) The median calprotectin levels in the 25 (58%) patients with CD (122 mg/L) and the 19 (51%) with UC (123 mg/L) who relapsed were significantly (P<.0001) higher than those in patients who did not relapse (41.5 mg/L for CD, 29.0 mg/L for UC, normal <10 mg/L), demonstrating the ability of this biomarker to predict relapse.

Another study examined mucosal healing and its impact on the disease course in 740 patients with IBD.(18) Factors predictive of mucosal healing in patients with UC were >12 years of education (P=.004) and extensive disease at diagnosis (P=.02). Mucosal healing was significantly (P=.02) associated with a decreased risk of colectomy (Figure 2). Predictive factors in patients with CD were fewer at diagnosis (P=.03) and medical treatment without steroids (P=.01). Mucosal healing was also associated with less inflammation after 5 years (P=.02) and decreased requirement for corticosteroids (P=.02). These data strengthen the case for using mucosal healing as a treatment goal in IBD.

If mucosal healing is to be used as a treatment target, it requires a working definition. Currently, the proposed definition in CD is the absence of ulcers greater than 5 mm in diameter. Quantitative endpoints, such as CDEIS or the simple endoscopic score for Crohn’s disease (SES-CD) are more responsive to change but complex as a treatment goal. Although mucosal healing is associated with relevant long-term outcomes, no evidence supports treating to these goals.

The Randomized Evaluation of an Algorithm for Crohn’s Treatment (REACT), a cluster randomization trial, compared the effectiveness of early combined immunosuppression with conventional management in patients with CD in community gastroenterology practices, using an algorithm to treat-to-target.(19) The trial did not meet the primary endpoint, as the early treatment strategy did not increase the proportion of patients with Harvey-Bradshaw Index (HBI) <5 and no corticosteroid therapy at 12 months. However, early combined immunosuppression was significantly more effective in achieving secondary outcomes (complications, surgery, and the combined secondary outcome of complications, surgery, and hospitalization) with an adjusted HR of .74 (P<.001). These community data demonstrate that short-term symptom changes are not an appropriate treatment target, and that early combined immunosuppression may be effective in preventing CD-related complications.

Realization of remission

In EXTEND, deep remission was defined as clinical remission (CDAI <150) with complete mucosal healing. Deep remission at Week 12 was associated with the following outcomes at Week 52 (P<0.05): better quality of life, less impairment of activity and less hospitalization.(4,20) Of note, these 1-year data are considered exploratory, as the primary endpoint of mucosal healing at Week 12 was not reached (P=.34).

Maintenance of remission

Few data exist on long-term maintenance of remission with TNF-α inhibitors. The Additional Long-Term Dosing With HUMIRA to Evaluate Sustained Remission and Efficacy in CD (ADHERE) study, the long-term open extension of the CHARM study, evaluated maintenance of clinical remission over 4 years with adalimumab, in patients with moderately to severely active CD.(21) Of 329 early responders randomized to adalimumab induction, at least 30% achieved remission (99/329) or response (116/329) at Year 4, with 54% of patients in remission at Year 1 maintaining remission at Year 4.

Monitoring in treat-to-target approach

Symptom-based assessment has now been shown to be inadequate for monitoring and managing disease activity. Objective monitoring is fundamental to a treat-to-target approach (Figure 3). A comprehensive baseline assessment of disease activity, an appropriate individualized monitoring strategy, and a regular monitoring schedule are essential. To ensure accuracy in monitoring, precise and standardized endoscopic content and terminology should be used. The overall objective is to maintain quality of life through tight control of disease activity.

Conclusions

Enough evidence now exists to support adoption of a treat-to-target approach in patients with IBD. Symptom control does not mean control of inflammation. Patients should be stratified for risk, and treatment efficacy should be monitored frequently using objective tools to minimize or eliminate tissue damage (Figure 4). When disease activity is not adequately controlled, treatment should be modified to ensure long-term success.

Clinical case

Case presentation

You are seeing a new referral sent to you by the emergency department because of an abnormal computed tomography (CT) scan that showed thickening of the terminal ileum. The patient is a 27-year-old male with a 7-month history of 3 kg weight loss. He has vague abdominal discomfort with eating and thus has some food avoidance, but there is no change in bowel habits that he can convincingly describe.

Family history identifies a maternal aunt with an ileostomy from an unknown gastrointestinal disorder.

Physical examination demonstrates tenderness in the right lower quadrant with fullness but no distinct mass. Perianal examination reveals at least 6 fistula sites with one identifiable opening 5 cm from the anus. Investigations reveal the following:

–  Hemoglobin: 110 g/L

–  Mean corpuscular volume: 75 fL

–  White blood cell count: 9.8 X 10⁹/L

–  Platelet count: 678 X 10⁹/L

–  Ferritin: 80 pmol/L

–  Iron: 1 μmol/L

–  C-reactive protein (CRP): 96 mg/L

CT enterography (CTE) demonstrates two 5 cm segments of active inflammation in the midjejunum, a 50 cm segment of active disease in the ileum approximately 10 cm from the Ileocecal valve, and thickening of the transverse colon. Adjacent to the ileal segment is a phlegmon (5 x 4 x 3 cm). Colonoscopy shows deep fissuring ulceration in the rectum and the sigmoid and transverse colon. Magnetic resonance imaging (MRI) demonstrates a complex perianal fistula with multiple trans-sphincteric fistula tracts but no abscess.

Commentary

This very high-risk patient has multiple risk factors and requires early aggressive therapy, including surgical fistula management with placement of setons if possible, and drainage of the phlegmon, if it turns out to be an early abscess. With complex fistulizing disease, this patient has a high risk of sphincter damage. Initiation of combination therapy is also appropriate. Inpatient treatment initiation would be ideal, to allow close monitoring of his progress.

Case evolution

The patient is unable to take time away from his job for inpatient treatment so you begin outpatient treatment with the following:

–  Prednisone, 40 mg daily, tapered

–  Ciprofloxacin, 500 bid x 14 days

–  Metronidazole, 500 bid x 14 days

–  Azathioprine, 150 mg daily

–  Tumour necrosis factor-α (TNF-α) inhibitor induction

–  Iron sucrose infusions (1200 mg)

Commentary

Prednisone may not have a role in patients with fistulizing disease. Antibiotics are important to cover the patient when the TNF-α inhibitor is initiated, as use of biologics in the presence of a phlegmon is a concern, due to the risk of abscess. A longer course of metronidazole may be needed in a patient with draining fistulas.

Case evolution

You set into place the objective monitoring protocol you learned at Mentoring in IBD XV. It is now 12 weeks into the induction phase of your treatment, and you are seeing the patient in your office to assess his response and determine your maintenance therapeutic strategy. He is feeling better, but the fistulae are still draining. Ultrasound demonstrates the phlegmon is still there, although it is smaller (2 x 2 x 2 cm). His CRP is 21.

Commentary

This patient may not achieve remission by 12 weeks. Azathioprine and TNF-α inhibitor drug levels at the end of induction would be useful to indicate whether therapeutic levels were present.

Case evolution

Based on the results of your investigations you escalate therapy by doubling the TNF-α inhibitor dose.

Commentary

This high-risk patient needs frequent follow-up. Objective monitoring should include a complete blood count, liver function tests and CRP, weekly for the first 6 weeks, then monthly for 6 months, then based on the clinical response. Baseline fecal calprotectin would also be useful. Imaging with MRI, low-dose CT, or ultrasound a few weeks after treatment initiation would provide objective information about the status of the phlegmon. Pelvic MRI and colonoscopy at 4 to 6 months can confirm clinical status.

Case evolution

Following your objective monitoring plan, you see the patient again 8 months after the start of his therapy. He is now feeling great. He ranks his well-being as 9 out of 10 and has a HBI of 3 indicating full clinical remission. His fistulae have not drained for the last month. You proceed to colonoscopy and repeat the CTE. Colonoscopy demonstrates residual ulceration in the transverse colon, with the rest of the colonic mucosa healed. CTE demonstrates hyperemia at the site of the jejunal lesions. The ileum is healed and the phlegmon is resolved.

Commentary

With clinical remission and endoscopic disease activity, treating to mucosal healing may require a longer duration of the same therapy, dose escalation, or a change in therapy. It is important to discuss these options with the patient. It is appropriate to wait and reassess with repeated colonoscopy before intensifying or changing therapy.

References

1. 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.
2. Baert FJ, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology. 2010;138:463–8.
3. Louis E, Mary JY, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology. 2012;142:63–70.
4. Colombel J-F, Sandborn WJ, Camez A. Deep remission for adalimumab-treated patients with moderate to severe ileocolonic Crohn’s disease: results from EXTEND. Presented at the 5th Congress of the European Crohn’s and Colitis Organisation; February 26, 2010; Prague, Czech Republic.
5. 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(1):52–65.
6. Schreiber S, Reinisch W, Colombel J, et al. Early Crohn’s disease shows high levels of remission to therapy with adalimumab: Sub-analysis of CHARM. Gastroenterology. 2007;132(4 Suppl 1):A147. Abstract 985.
7. Yarur AJ, Strobel SG, Deshpande AR, et al. Predictors of aggressive inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2011;7(10):652–9.
8. Allez M, Lemann M, Bonnet J, et al. Long term outcome of patients with active Crohn’s disease exhibiting extensive and deep ulcerations at colonoscopy. Am J Gastroenterol. 2002;97:947‒953.
9. 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. 2008;371:660–7.
10. Sandborn WJ, Panaccione R, Thakkar R, et al. Crohn’s disease mucosal healing in adalimumab-treated patients is affected by disease duration: results from EXTEND. Gastroenterology. 2010;138(5 Suppl 1):S-164.
11. Moran GW, Dubeau MF, Kaplan GG, et al. Alberta Inflammatory Bowel Disease Consortium. Phenotypic features of Crohn’s disease associated with failure of medical treatment. Clin Gastroenterol Hepatol. 2014;12:434–42.
12. Steenholdt C, Brynskov J, Thomsen OO, 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;63:919–27.
13. Vargas EJ, Ramos Rivers CM, Regueiro M, et al. Silent Crohn’s disease: elevated C-reactive protein in asymptomatic patients and risk of subsequent hospitalization. Gastroenterology. 2014;144(5 Suppl 1):S-102. Abstract 557.
14. Sipponen T, Savilahti E, Kolho KL, et al. Crohn’s disease activity assessed by fecal calprotectin and lactoferrin: correlation with Crohn’s disease activity index and endoscopic findings. Inflamm Bowel Dis. 2008;14:40-6.
15. Molander P, Sipponen T, Kemppainen et al. Achievement of deep remission during scheduled maintenance therapy with TNFα-blocking agents in IBD. J Crohns Colitis. 2013 Oct;7(9):730–5.
16. Lemann M, Colombel JF, Grimaud JC, et al. Fecal calprotectin and high sensitivity C-reactive protein levels to predict mucosal healing in patients with Crohn’s disease. A subanalysis of the STORI study. Gut. 2010;59(Suppl III):A80.
17. Tibble JA, Sigthorsson G, Bridger S, et al. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology. 2000;119:15–22.
18. Frøslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007;133(2):412–422.
19. Khanna R, Levesque BG, Bressler B, et al. Early combined immunosuppression for the management of Crohn’s disease: a community-based cluster randomized trial. Gastroenterology. 2014;146(5 Suppl 1):S-187. Abstract 1053.
20. Colombel JF, Rutgeerts P, Sandborn WJ, et al. Deep remission predicts long-term outcomes for adalimumab-treated patients with Crohn’s disease. Data from EXTEND. 2010;59(Suppl 3):A80.
21. 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.

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

Contributing Editor

Subrata Ghosh, MBBS MD(Edin) FRCPC FRCP FRCPE, Professor and Chair, Department of Medicine, University of Calgary, Zone Clinical Department Head, Alberta Health Services, Calgary, AB

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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© 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.