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A major goal of the treat-to-target approach is achieving mucosal healing in patients with inflammatory bowel disease (IBD).(1) Appropriate drug levels can facilitate reaching this goal, which can reduce the occurrence of flares and the need for surgery. Early aggressive medical therapy, routine monitoring, and appropriate therapeutic adjustment can help achieve mucosal healing and may improve outcomes.(2) Surgery, despite the development of minimally invasive techniques, does not represent a durable therapeutic option, as it does not affect long-term disease course.(3)

Mucosal healing and drug levels

Mucosal healing has been found to be an independent predictor of sustained clinical remission in patients with ulcerative colitis (UC) receiving infliximab.(1) Higher infliximab levels during induction have been linked to increased rates of short-term mucosal healing. A retrospective, single-centre analysis of data was performed from patients (n=101) with UC, who received infliximab induction therapy at 0, 2, and 6 weeks and endoscopic evaluation at baseline and at 10 to 14 weeks. Infliximab levels were measured at 0, 2, 6, and 14 weeks.

Short-term mucosal healing, which was achieved in 54 patients (53.4%), was associated with higher median infliximab levels at 2, 6, and 14 weeks than seen in patients without short-term mucosal healing.(1) Higher infliximab levels were also associated with female sex and concomitant use of immunomodulators. Multivariate analysis found infliximab levels of ≥15 μg/mL at week 6 (P=.025) and ≥2.1 μg/mL at week 14 (P=.004) were independently associated with short-term mucosal healing. These results agree with the findings of other studies. In addition, patients with a higher initial inflammatory burden, manifested as more extensive (pancolitis) and active disease, and higher levels of antidrug antibodies had the lowest infliximab levels, in agreement with the results of other studies. This study raises the question of whether drug level monitoring during induction may increase rates of mucosal healing.

It has been suggested that patients with a higher inflammatory burden and more rapid drug clearance may require accelerated, rather than standard, tumour necrosis factor-α (TNF-α) regimens to achieve mucosal healing.(1) Such regimens may use 3-dose induction or higher or more frequent maintenance doses. Although the current study found lower infliximab levels in these patients, no differences were seen in the rate of short-term mucosal healing. This finding indicates that standard dosing achieved therapeutic drug levels for the range of inflammatory burden in this patient cohort, but it does not exclude the possibility that patients with a very high inflammatory burden may need higher induction dosing to achieve detectable drug concentrations. In addition, other factors besides pharmacokinetics may be relevant for achieving short-term mucosal healing.

Mucosal healing and early aggressive therapy

In CD, mucosal healing predicts lower rates of complications, hospitalization, and surgery.(2) Early aggressive therapy to achieve mucosal healing rapidly may therefore improve long-term outcomes. Studies have found that mucosal changes occur relatively rapidly after adjusting TNF-α inhibitor levels. As a result, frequent repeated assessment and, in the absence of mucosal healing, adjustment of dosage or change of therapy may facilitate control of inflammation, achievement of mucosal healing, and prevention of irreversible bowel damage that necessitates surgical intervention.

Mucosal healing as a treatment target has been investigated in both UC and CD and is feasible in both. A retrospective cohort study of 60 patients with mild to severe endoscopic UC activity at baseline (mean disease duration 5 years, range 0.7–10.5 years) was performed to determine the feasibility of mucosal healing as a treatment target in UC.(3) Serial endoscopy and adjustment of therapy with findings of continuing disease activity found mucosal healing in 26% at 26 weeks, 52% at 52 weeks and 70% at 76 weeks, demonstrating that mucosal healing is a feasible treatment target in UC. A retrospective cohort study of 67 patients with CD with endoscopic lesions at baseline (median disease duration 9.8 years, range 1.2–21.12 years) was performed to assess the feasibility of using mucosal healing as a treatment target in CD.(4) Serial endoscopy and adjustment of therapy with findings of continuing disease activity found mucosal healing in 12.7% at 24 weeks and 45.0% at 52 weeks, demonstrating the feasibility of mucosal healing as a treatment target in CD.

Minimally invasive surgery

The introduction of highly effective medical therapies has not eliminated the need for surgery in patients with IBD.(5) In fact, up to 80% of patients with CD and 30% of patients with UC ultimately require surgery. In addition, significant numbers of patients with CD require multiple surgeries during their lifetime. The development of minimally invasive surgical techniques for patients with IBD has been hailed as a major advance. Today, minimally invasive surgery is generally accepted as safe and effective, to the point that laparoscopic approaches are included in several clinical guidelines. Potential advantages include reductions in hospital stay, wound infection, and pain.

In CD, the major surgical procedure is ileocolic resection for refractory stricturing disease.(5) Comparison with open ileocolic resection has found laparoscopic surgery to be associated with a non-significant trend towards faster recovery of bowel function and decreased hospital stay and complications. No differences have been found in disease recurrence or long-term morbidity, possibly due to the small populations studied. In addition, a need still exists for open surgery in CD, especially for patients with complicated disease, challenging surgical anatomy, and often for those requiring multiple surgeries.

In UC, refractory disease, malignant transformation risk, and emergency indications in patients with severe medically refractive colitis are the major indications for surgery.(5) In emergency subtotal colectomies, similar results are seen for laparoscopic and open resections, with some studies finding reductions in postoperative morbidity and length of stay and faster return of bowel function. In elective surgery for medically refractory disease, a meta-analysis of 27 studies found reductions in length of stay, wound infection, and intraoperative blood loss with laparoscopic surgery. No difference was seen in pouch failure, with a trend to better pouch function after minimally invasive procedures.

Patient benefits associated with minimally invasive surgical techniques in IBD are limited to the procedure itself and the early postoperative period, as the disease course is unaffected. As a result, avoidance of complications requiring surgery remains an important goal for treating patients with IBD. More frequent achievement of mucosal healing with the treat-to-target strategy may allow this goal to be achieved.  

References

1. Papamichael K, Van Stappen T, Vande Casteele N, et al. Infliximab concentration thresholds during induction therapy are associated with short-term mucosal healing in patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2016;14:543–9.
2. 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.
3. Bouguen G, Levesque BG, Pola S, et al. Feasibility of endoscopic assessment and treating to target to achieve mucosal healing in ulcerative colitis. Inflamm Bowel Dis. 2014;20:231–9.
4. Bouguen G, Levesque BG, Pola S, et al. Endoscopic assessment and treating to target increase the likelihood of mucosal healing in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2014;12:978–85.
5. Neumann PA, Rijcken E. Minimally invasive surgery for inflammatory bowel disease: review of current developments and future perspectives. World J Gastrointest Pharmacol Ther. 2016;7(2):217–26.

Special Edition IBD Dialogue 2016 Volume 02: Treat-to-Target in IBD is made possible by an unrestricted educational grant from…