Biologics recommendations in the ECCO guidelines on therapeutics in Crohn's disease: medical treatment

Abstract

In 2019, the European Crohn’s and Colitis Organisation released guidelines for the medical management of Crohn’s disease, concerning the induction of remission, the maintenance of remission and the treatment of fistulising perianal disease. This review summarises the key recommendations regarding the use of biologics in these settings.

Commentary

Background

Crohn’s disease (CD) is a potentially debilitating inflammatory bowel disease (IBD) characterised by transmural inflammation affecting any part of the gastrointestinal tract, requiring closely monitored, nuanced therapy to minimise long-term disease complications. This review summarises the key recommendations regarding biologics made by the 2019 European Crohn’s and Colitis Organisation guidelines for the medical management of Crohn’s disease.¹

Induction therapy

For induction of remission, the introduction of biologics in moderate–severe CD is recommended. The highest level of evidence is present for monoclonal antibodies including the anti-TNFα agents infliximab, adalimumab and certolizumab, the anti-IL-12/32 p40 subunit antibody ustekinumab, and anti-α4β7 integrin vedolizumab; all of which induced remission in randomised placebo-controlled trials. The thiopurines azathioprine and mercaptopurine were not recommended as induction agents as monotherapy, but azathioprine in combination with infliximab was shown to be superior to either agent alone in the sentinel SONIC trial.²

Interestingly, the consensus group recommended the use of adalimumab as monotherapy rather than in combination with a thiopurine. This recommendation was based on the DIAMOND study,³ which compared adalimumab monotherapy to combination of adalimumab with azathioprine dosed between 25 and 100 mg in Japanese patients. Though no significant difference in the primary endpoint of clinical remission was noted between the two arms, secondary endpoints of endoscopic response at week 26 was higher, and rate of antidrug antibodies lower, in the combination arm. Subsequent studies have shown that though rates of antidrug antibody formation are lower with adalimumab than infliximab monotherapy, immunomodulator use reduced the rate of antiadalimumab antibody formation by at least twofold.^{4 5} Hence, the use of immunomodulators in combination with adalimumab remains a legitimate part of an induction strategy.

In the absence of head-to-head prospective clinical trials published to date, a recommendation regarding choice of specific biologic agent was unable to be made. Nonetheless, the highest level of evidence for patients with perianal fistulising disease is for infliximab,⁶ with posthoc analysis of the CHARM study supporting use of adalimumab.⁷ The anti-TNFα drugs also have greater evidence in the treatment of most extraintestinal manifestations.⁸ In patients with intolerance or failure of anti-TNFα agents, recent retrospective data from propensity matched cohorts support the efficacy of ustekinumab over vedolizumab.⁹

The safety profiles of medical therapies used for induction must be considered in an individualised approach. Steroids have multiple adverse effects which limit their use in patients in the short-term, as well as predictable long-term metabolic effects for which minimisation of repeated courses is warranted. Vedolizumab and ustekinumab had safety profiles similar to placebo in their sentinel induction and maintenance studies.^{10 11}

Maintenance therapy

Given the chronic, incurable nature of intestinal inflammation in CD, maintenance therapy is recommended for all but the mildest cases, in whom there is little robust evidence to guide a strategy, but close monitoring without therapy may be performed. Following induction of remission, maintenance with the monoclonal antibodies to TNFα, vedolizumab and ustekinumab is recommended. Focussing on anti-TNFα agents, a meta-analysis of five studies showed no significant difference between infliximab, adalimumab or certolizumab pegol in maintaining remission.¹² The guidelines recommend withdrawal of an immunosuppressant in patients treated with combination therapy with either infliximab or adalimumab for the induction of remission. This strategy is currently supported by studies with relatively short-term follow-up where no statistically significant differences noted for the maintenance of clinical and endoscopic remission at 18–24 months.^{13 14} However, a clear reduction in serum infliximab levels in the withdrawal arm and rise in rates of antibodies to infliximab were demonstrated. It is, hence, feasible that thiopurine withdrawal may lead to a higher rate of clinical relapse in a subsequent follow-up period. A strategy to reduce the dose of azathioprine may offer an alternative strategy, which showed no significant reduction in infliximab level or antidrug antibody formation.¹⁴ Whether this translates to reduction in the risk of long-term adverse effects including lymphoma and skin cancers is uncertain.

The role of reactive (following loss of response) or proactive (during induction or when disease in remission) therapeutic drug monitoring (TDM) for anti-TNFα agents was felt to have insufficient evidence to guide a definitive recommendation. The statement regarding reactive TDM is in contrast with other guidelines.¹⁵ Previous retrospective studies have indicated that TDM-guided adjustment of therapies (dose intensification, switch out of class) may be superior to empirical therapy in the management of patients with CD.¹⁵ Fewer prospective data enable a strong recommendation for proactive TDM in CD, with the only prospective studies published at the time of these guidelines, TAXITand TAILORIX¹⁴ failing to show clear benefit of targeting specific levels of infliximab in patients with CD. More recently, a prospective study in children by Assa et al showed superiority of a proactive TDM approach, when an adalimumab level of at least 5 ug/mL was targeted, over a reactive approach.¹⁶ Hence, this area remains one of active research, with recommendations likely to evolve over time.

Ustekinumab and vedolizumab remain other biologic agents with efficacy demonstrated in moderate to severe CD. Though no prospective head-to-head randomised clinical trials that compare the different biological therapies have so far been published, retrospective data indicate that ustekinumab may have greater effectiveness than vedolizumab,⁹ with both agents having a good safety profile.

Therapy of perianal fistulising disease

Based on the sentinel ACCENT I and ACCENT II studies,^{6 17} infliximab was strongly recommended by the guidelines for induction and maintenance of remission in patients with complex perianal fistulising disease. Subsequent retrospective studies have shown that patients with healed fistulas had higher trough infliximab levels than those with active fistulas (15.8 vs 4.4 µg/mL, p<0.0001), suggesting a role for TDM if confirmed in prospective studies.¹⁵ The efficacy of adalimumab was shown by post-hoc analysis of the subgroup of patients with fistulising disease in the CHARM study and open-label extension ADHERE study,⁷ resulting in the guidelines giving a weak recommendation for its use in this setting, limited to patients who fail infliximab. Though little doubt exists regarding the efficacy of combination infliximab and azathioprine therapy over infliximab monotherapy in luminal CD, the guideline authors concluded that there was insufficient data to guide a specific recommendation in patients with fistulising perianal disease. Nonetheless, the approach of combination therapy is frequently adopted in clinical practice, given that perianal fistulising disease is an adverse prognostic marker in patients with CD. There remain insufficient data to guide recommendations for the use of ustekinumab and vedolizumab, which were suggested as options in the presence of contraindications or failure of anti-TNFa therapy and ‘no other treatment options’.

Conclusion

The European Crohn’s and Colitis Organisation Guidelines on Therapeutics in CD: Medical Treatment provide a strong foundation for review of the evidence base of medical therapies currently available for CD. The recommendations are consistent with most evidence available at the time of publication of these guidelines, with areas of controversy including the role of combination therapy with immunomodulators and adalimumab, and TDM. It is expected that these guidelines will continue to evolve with emerging evidence, along with the expanding therapeutic armamentarium arising from the extensive clinical trial pipeline in IBD. Regardless of novel therapies, multidisciplinary biopsychosocial management shall remain central and essential for patients with CD.

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