What is the Optimal Therapy for Crohn's Disease: Step-up or Top-down?

Ming Valerie Lin; Wojciech Blonski; Gary R Lichtenstein

Disclosures

Expert Rev Gastroenterol Hepatol. 2010;4(2):167-180. 

In This Article

What is the Rationale for Early Use of Biological Therapy in CD?

Anti-TNF-α agents have been shown to be highly effective for the management of fistulas.[80,81,83–85] If a treatment induces profound and long-lasting mucosal healing, which in turn reduces complications and the need for surgical interventions, it could potentially slow down or even stop the progression and change the natural course of the disease.

Early treatment was shown to be associated with longer-sustained remission in children with early CD[123,124] and recent advancement in rheumatology (Behandel Strategieen [BeST] trial[125]) demonstrated that early aggressive treatment in patients with rheumatoid arthritis slowed down the disease progression, with earlier functional improvement and less radiographic damage after 1 year. AZA, despite its ability to induce mucosal healing, did not change the outcome of the disease.[116] This was in contrast to the trials on infliximab, with early mucosal healing associated with a better outcome. These data support the notion that time of initiation of therapy is of crucial importance if one takes into consideration that longer disease duration inevitably leads to more irreversible damage.

Several clinical trials on adalimumab have demonstrated the efficacy of this drug as an induction, remission and mucosal healing agent.[91,93,95] The CLASSIC I trial evaluating the efficacy of adalimumab induction therapy in patients with CD showed that the rates of remission at week 4 in the adalimumab group were as high as 36% in patients who received 160 mg compared with 12% in the placebo group (p = 0.001).[91] The extension study in the CLASSIC II trial showed that adalimumab administered weekly or biweekly was superior to placebo (79 vs 44%; p ≤ 0.05 and 83 vs 44%; p ≤ 0.05, respectively) in maintaining remission (83 vs 44% for placebo; p ≤ 0.05). A study performed by Colombel et al. showed that patients who received adalimumab had significantly lower numbers of draining fistulas than the placebo group during the treatment period of 56 weeks.[95] Of the patients with healed fistulas, 90% had sustained fistula healing for up to an additional year of open-label adalimumab.[95]

Efficacy of certolizumab pegol as a maintenance agent in CD was assessed in a randomized double-blind placebo controlled trial – the PRECISE II trial.[98] The patients who responded to certolizumab pegol as induction therapy (i.e., reduction in CDAI ≥100 points from baseline) were randomized to receive either certolizumab pegol 400 mg or placebo administered every 4 weeks through to week 26.[98] The sustained clinical remission (CDAI ≤150) rates and clinical response maintenance rate were significantly higher in patients treated with certolizumab pegol when compared with the placebo arm at week 26 (48 vs 29%; p ≤ 0.001 and 63 vs 36%; p ≤ 0.001, respectively).[98] From this study, certolizumab pegol was shown to be more efficacious than placebo in maintaining clinical remission (RR: 1.68; 95%CI: 1.30–2.16) and clinical response (RR: 1.74; 95%CI: 1.41–2.13) through to the end of the PRECISE II trial.[98] A similar approach to the BeST Trial, investigating the early biological treatment effect on CD, was undertaken by D'Haens et al., comparing top-down and step-up therapy in a controlled, randomized fashion.[126] The study population consisted of 133 patients with CD, who were treatment-naive to glucocorticoids, immunomodulators or infliximab, had a CD diagnosis of less than 4 years and had active disease (as indicated by CDAI ≥220 points). They were randomized into receiving either early combination immunosuppression (top-down) or conventional (step-up) treatment. The conventional therapy consisted of an initial treatment with budesonide or methylprednisolone, followed by AZA if patients became steroid-dependant or steroid-refractory, followed by infliximab if immunosuppression failed to control the symptoms. The early combination immunosuppression therapy consists of initial treatment of infliximab and AZA, with repeat infliximab infusion as needed (episodic) for patients with disease relapse and failure to respond to corticosteroids or infliximab. They were able to demonstrate that patients who received early combination therapy (top-down) had a significantly higher proportion in early induction of remission, a lower relapse rate, a lower mean number of days of corticosteroid use and complete mucosal healing in 75% of the early combination immunosuppression (top-down) group, compared with 21% in the conventional (step-up) treatment group at 2 years. By assessing some of the proposed surrogate end points, the top-down therapy could potentially alter the natural history of CD. We may be able to prevent stricturing and penetrating disease or extraintestinal complications, avoid corticosteroid and related complications, decrease hospitalization and surgery and ultimately decrease the healthcare cost.

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