What are the benefits and risks of the treat-to-target strategy in IBD?

By John K. Marshall, MD Volume 2 - Issue 4

Runs 2:00

Treat-to-target recommendations

The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program developed consensus recommendations for treatment targets for ulcerative colitis (UC) and Crohn’s disease (CD).(1) Regulatory agencies have advocated treatment targets for patients with inflammatory bowel disease (IBD) that consider patient-reported outcomes (PRO) in combination with objective measures of disease activity, such as endoscopy. In UC, STRIDE considered adjunctive targets to be histologic remission in UC and normalization of C-reactive protein and fecal calprotectin in CD. Insufficient evidence exists to recommend treating to these adjunctive targets. Randomized clinical trial data indicate that intensive therapy should achieve PRO and endoscopic success in one-third to two-thirds of patients with IBD, depending on individual factors, such as disease duration and prior therapy.

Thiopurines

A Canadian Association of Gastroenterology position paper on the use of thiopurines in IBD highlighted the importance of individualizing therapy and ensuring that the risks and benefits of treatment options are discussed with patients.(2) Thiopurines, along with other common IBD therapies, such as prednisone and methotrexate, have not been approved by Health Canada for use in IBD. Nevertheless, they are an important part of the therapeutic armamentarium for these patients. Azathioprine combined with a tumour necrosis factor-α (TNF-α) inhibitor has been found to be superior to either agent alone for induction and maintenance therapy in IBD. Adverse effects of thiopurines include bone marrow suppression, hepatotoxicity, pancreatitis, allergic reactions, and opportunistic infections, especially in combination when these agents are given with infliximab or a corticosteroid. In addition, an increased relative risk of lymphoproliferative disorders including hepatosplenic T-cell lymphoma (HSTCL) has been identified in patients with IBD, although the absolute risk is very low. (3) Any cases of HSTCL should be reported to the manufacturer or Health Canada.

A meta-analysis of 11 randomized controlled trials (N=881) evaluated the efficacy of 6-mercaptopurine (6-MP) and azathioprine for maintenance of remission in CD.(4) Assessment of the studies using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) found overall low and very low quality of evidence, due to sparse or very sparse data and unclear or high risk of bias. Although the analysis found azathioprine to be more effective than placebo and possibly more effective than budesonide for maintenance of remission in CD, use is limited by adverse effects. No conclusions could be drawn about studies with other active comparators due to low and very low evidence quality. High-quality studies are needed to better quantify the risk-benefit trade-off of azathioprine and 6-mercaptopurine in comparison with active maintenance therapies.

CD has a heterogeneous course with high rates of complications.(5) Recent data from retrospective studies and post-hoc analyses, including a meta-analysis, indicated that azathioprine or a TNF-α inhibitor given early in the disease course (within a few years of diagnosis), or for a prolonged duration, could reduce the risk of surgery in both adults and children with CD. The findings may also indicate possible differences in the pathophysiology between early and longstanding CD or an impact of cumulative bowel damage on treatment responsiveness.

TNF-α inhibitors

TNF-α inhibitors have demonstrated significant efficacy for induction and maintenance of remission in moderate-to-severe CD and UC, and as rescue therapy for hospitalized UC.(6) Infliximab is the most-studied TNF-α inhibitor in IBD, but good efficacy data also exist for other TNF-α inhibitors, including adalimumab and golimumab. Over time, TNF-α inhibitors have been used more widely and earlier in the disease course. The recent cluster-randomized REACT trial demonstrated that early introduction of combined immunosuppression led to reduced rates of surgery, hospitalization and serious disease-related complications.(7) As increases in mucosal healing have been linked to higher TNF-α inhibitor trough levels, therapeutic drug monitoring (TDM) has become more widely used to maximize the TNF-α inhibitor treatment benefit. Prospective studies using TDM are still lacking, as are trials comparing TNF-α inhibitors.

A systematic review and meta-analysis of combination therapy with infliximab and an immunosuppressant compared with infliximab monotherapy in UC identified 4 controlled trials (N=765).(8) Similar numbers of patients were treated with combination therapy (n=376) and infliximab monotherapy (n=389). The clinical remission rate was significantly (P<.001) higher with combination therapy at 4 to 6 months, but no significant difference was seen at 12 months, possibly due to the 2 studies with 12-month results having opposite results. Differences in patient populations (disease duration, prior therapy) could account for this finding. Objective outcomes were not measured in the trials in this analysis.

A network meta-analysis of randomized controlled trials comparing methotrexate, azathioprine/6-MP, infliximab, adalimumab, certolizumab, vedolizumab, or combination therapy with placebo or active therapy for induction and maintenance of remission in patients with CD included 39 trials.(9) The results were as follows:

Induction of remission:(9)

  • Infliximab + azathioprine and adalimumab: superior to certolizumab
  • Infliximab, infliximab + azathioprine, adalimumab, and vedolizumab: superior to placebo
  • Azathioprine/6MP and methotrexate: no difference from placebo

Maintenance of remission:(9)

  • Adalimumab and infliximab + azathioprine: superior to certolizumab
  • Adalimumab, infliximab, and infliximab + azathioprine: superior to azathioprine/6-MP
  • Adalimumab: superior to vedolizumab
  • All treatments (except infliximab + methotrexate): superior to placebo

The network meta-analysis found adalimumab and infliximab + azathioprine to be the most effective therapies for induction and maintenance of remission of CD.

Anti-α4-integrins

A systematic review and meta-analysis of randomized controlled trials assessed the risk-benefit profile of the anti-α4-integrins, natalizumab and vedolizumab, in CD.(10) Literature review identified 5 trials of natalizumab and 3 trials of vedolizumab. Both agents were similarly effective in inducing response and remission and in improving quality of life, in both TNF-α-naïve and -exposed patients. Rates of serious adverse events (6.8% for natalizumab, 8.8% for vedolizumab, and 8.5% for placebo) infusion reactions (9.7% vs. 4.8% for placebo), infections (.6% for natalizumab, .7% for vedolizumab, and 2.3% for placebo), and treatment discontinuation (8.6% for natalizumab, 2.8% for vedolizumab, and 6.9% for placebo) were similar for both agents. Natalizumab is not indicated for treatment of IBD in most jurisdictions because of its association with progressive multifocal leukoencephalopathy (PML). Vedolizumab has not been linked to any cases of PML: this would be expected, as its mechanism of action is more gut specific than that of natalizumab.

Conclusion

The treat-to-target strategy requires highly effective therapy to achieve the endpoint of mucosal healing. Combination biologic therapy may be needed to achieve this, and TDM may have utility in this context.

References

  1. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110:1324–38.
  2. Marshall JK, Otley AR, Afif W, et al. Canadian Association of Gastroenterology position statement regarding the use of thiopurines for the treatment of inflammatory bowel disease. Can J Gastroenterol Hepatol. 2014;28(7):371–2.
  3. Health Canada. Association of Imuran® (azathioprine) or Purinethol® (mercaptopurine) with hepatosplenic T-cell lymphoma (HSTCL). Available at http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/38691a-eng.php. Accessed June 16, 2016.
  4. Chande N, Patton PH, Tsoulis DJ, et al. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2015 Oct 30;(10):CD000067.
  5. Rieder F, Reinisch W. Thiopurines and the natural course of Crohn’s disease: did we finally find the right therapeutic target? Am J Gastroenterol. 2014;109:1037–40.
  6. Samaan MA, Bagi P, Vande Casteele N, et al. An update on anti-TNF agents in ulcerative colitis. Gastroenterol Clin N Am. 2014;43:479–94.
  7. Khanna R, Bressler B, Levesque BG, et al. Early combined immunosuppression for the management of Crohn’s disease (REACT): a cluster randomised controlled trial. Lancet. 2015;386:1825–34.
  8. Christophorou D, Funakoshi N, Duny Y, et al. Systematic review with meta-analysis: infliximab and immunosuppressant therapy vs. infliximab alone for active ulcerative colitis. Aliment Pharmacol Ther. 2015;41:603–12.
  9. Hazlewood GS, Rezaie A, Borman M, et al. Comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in Crohn’s disease: a network meta-analysis. Gastroenterology. 2015;148;344–54.
  10. Chandar AK, Singh S, Murad MH, et al. Efficacy and safety of natalizumab and vedolizumab for the management of Crohn’s disease: a systematic review and meta-analysis. Inflamm Bowel Dis. 2015;21:1695–1708.

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

abbvielogo_coated