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

So What are the Long-term Considerations for Patients with CD?

Mucosal ulcerations in CD lead to fistula formation, translocation of microbes, toxic megacolon, perforation and bleeding. It thus seems logical that effective treatment should imply complete mucosal healing in parallel with clinical remission. Cosnes et al. have shown that most patients with CD will eventually develop stricturing or perforating complications, with a proportion of 40 and 70% at 5 and 20 years after the initial diagnosis, respectively.[105] A retrospective study from Belgium assessed the 25-year course of CD according to the Vienna classification, and observed that there are statistically significant changes in disease behavior, from nonstricturing and nonpenetrating to structuring or penetrating in 27 and 29.4% of patients after a median duration of 5.5 and 6 years, respectively.[106]

With these results in mind, researchers attempted to advance the treatment options over the past years and have made our treatment goals more ambitious with modification of the natural course of the disease as the ultimate end point. The current potential medical therapy for CD modification consists of corticosteroids, immunomodulators and biological therapy.

Corticosteroids are effective induction agents, but they do not modify the natural course of disease. Modigliani et al. demonstrated that, in patients with CD who were treated with prednisolone (1 mg/kg/day) for up to 7 weeks, 92% of patients underwent clinical remissions within 7 weeks of treatment.[107] However, only 29% of patients in clinical remissions were also in endoscopic remission. In the National Cooperative Crohn's Disease Study (NCCDS) assessing patients receiving prednisone as an induction therapy, nine patients were excluded from further participation because of worsening diseases on their barium radiographs, suggesting disease progression despite clinical improvement in patients who received corticosteroids.[57] A small study from Sweden also demonstrated that early clinical remission in patients treated with prednisone (20–30 mg daily for 6–9 weeks) was poorly correlated with improvement of endoscopic ileal inflammation.[108] Corticosteroids may effectively downregulate mucosal inflammation, but their inability to heal the deep ulcers may be due to their deleterious effects on tissue restitution.[109]

Beaugerie et al. highlighted that among the predictors of disabling disease, patients who required an initial corticosteroid treatment were associated with increased risks of subsequent 5-year disabling clinical course.[8] Faubion et al. demonstrated in a population-based study that 38% of patients with CD who initiated therapy with corticosteroids required operation within 1 year.[56] It was reported that only approximately one third of patients have prolonged response 1 year after their first course.[110] These studies highlighted that the need for corticosteroid treatment is a marker of poor prognosis. Thus, it can be concluded that in addition to the undesirable toxicity and potential for dependency in long-term use, corticosteroids are not beneficial in maintaining remission or preventing new flares and it does not alter the natural course of CD.

The use of immunomodulators as induction and remission agents to treat CD has been well recognized. Candy et al. demonstrated in double-blind randomized control trials that AZA had a therapeutic advantage over placebo in the maintenance of corticosteroid-induced clinical remission in CD.[111] They showed that over a period of 15 months, 42% of patients who received AZA were in remission compared with 7% of patients who received placebo. A similar trial was performed in the pediatric population and it demonstrated that early introduction of immunomodulators was associated with a longer duration of remission and lower corticosteroid dosage requirement.[112] In total, 55 children were randomized to receive 6-MP or placebo in addition to prednisone. It was found that the addition of 6-MP to a regimen of corticosteroids resulted in significantly less need for prednisone and a higher rate of maintenance of remission (9% of patient relapse on AZA compared with 47% in placebo group).[112]

A double-blind noninferiority study comparing the use of placebo and AZA demonstrated that there were more CD relapses associated with placebo than AZA within 18 months of the study period in patients who were in clinical remission on AZA for more than 3.5 years.[113] In addition, a recent prospective cohort study showed that AZA withdrawal is associated with a high risk of clinical relapse (up to 62.7%) within 5 years of cessation.[114] These data suggest that if AZA is well tolerated, it should not be interrupted. In contrast to corticosteroids, the long-lasting clinical remission maintained with immunomodulators may be associated with mucosal healing.[113,115] D'Haens et al. found that in patients who were treated with AZA for a mean duration of 2 years complete mucosal healing was seen in up to 70% in the colon and 54% in the ileum, accompanied by the disappearance of the inflammatory infiltrate.[115] However, despite these encouraging findings, Cosnes et al. failed to demonstrate a decrease in the cumulative risk of intestinal resection associated with the use of immunomodulators (AZA and methotrexate) in a 25-year retrospective study.[116] Of the 565 patients enrolled in the study, 190 (34%) were operated on at least once. It may be argued that, since it was a retrospective study, it may not accurately reflect and may have over-reported the need for surgery, especially considering that the study was conducted in a tertiary referral center, treating, in general, more severe disease with delayed initiation of the medication. This also raises the point that perhaps early potent inflammatory suppressive agents are needed to change the outcome of the disease.[116]

Methotrexate has been shown to induce histological remission and mucosal healing.[76] It is also effective in maintaining remission,[117] and in some of the retrospective studies it was reported to have up to 90% maintenance of remission rate after 1 year.[118–120]

There is currently not enough evidence that immunomodulators change the natural history of CD, and prospective studies are necessary to answer this important question.

Infliximab has been shown to be a rapid induction and long-term maintenance agent with the ability to heal mucosal ulceration and reduce fistulae.

In the ACCENT l trial, 573 patients with active CD were randomly assigned to receive placebo, infliximab 5 mg/kg or infliximab 10 mg/kg with scheduled repeat infusions.[80] This study successfully demonstrated that infliximab is efficacious in inducing early remission with 58% of patients responding to a single infusion of infliximab within 2 weeks.[80] The clinical remission sustainability rate was also higher in the infliximab-treated group, with 39% for lower and 45% for higher maintenance dose of infliximab compared with 21% of the placebo-treated group (p = 0.003 and p = 0.0002, respectively).[80] It was also observed that patients who responded to the initial infliximab treatment were more likely to discontinue corticosteroids (29% in combined infliximab group vs 9% in placebo group; p = 0.004) and maintain their response for a longer period of time if treatment with infliximab is administered every 8 weeks.[80] A multicenter trial conducted in Europe demonstrated that patients with active CD who were treated with infliximab, irrespective of the dosage, had clinical improvement that was accompanied by significant healing of endoscopic lesions and disappearance of the mucosal inflammatory infiltrate.[121] Present et al. found that 68 and 56% of patients who received infliximab 5 or 10 mg/kg, respectively, achieved a significantly greater reduction (p = 0.002 and p = 0.02, respectively) in the number of draining fistulae from baseline compared with the placebo group (26%).[82] Among patients treated with infliximab 5 and 10 mg/kg, complete fistula closure was observed in 55 and 38% of them, respectively, compared with 13% of the patients assigned to placebo (p = 0.001 and p = 0.04, respectively).[82] It was concluded that infliximab is an efficacious treatment for fistulas in patients with Crohn's disease.[82]

In the ACCENT 2 trial, 306 patients with active CD and draining fistulae were treated with infliximab and those who had a response by week 14 were then randomly assigned to receive placebo or infliximab 5 mg/kg every 8 weeks and to be followed to week 54.[81] The time to loss of response (≥40 weeks vs 14 weeks; p ≤ 0.001) and complete fistula healing at week 54 (36 vs 19%; p = 0.009) was significantly higher for patients who received infliximab maintenance therapy than for those who received placebo maintenance.[81] It was concluded that patients with fistulizing CD who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.[81]

A study comparing scheduled and episodic infliximab treatment strategies found that the efficacy of scheduled infliximab therapy (infusions at week 2 and 6 followed by infusions every 8 weeks) was superior to episodic infusions (infusions at week 2 and 6 followed by infusions every 8 weeks through to week 46).[122] Patients treated with a scheduled program had significantly lower Crohn's Disease Activity Index (CDAI) scores, higher responses and remission rates between weeks 10 and 30, significant rates of mucosal healing (44 vs 18%; p = 0.041) and fewer hospitalizations (p = 0.014) and surgical interventions (p = 0.01) than those receiving episodic treatment.[122] A strong correlation between clinical improvement and improvement of endoscopically viewed bowel ulcerations was successfully demonstrated.[121] The notion that mucosal healing predicts a better long-term outcome was further supported by a study conducted by Schnitzler et al..[84] The authors analyzed mucosal healing during long-term treatment with infliximab in 214 CD patients and assessed whether it had a better outcome in terms of the need for major abdominal surgery.[84] In their study, endoscopic mucosal healing was found in 67.8% of the 183 initial responders to induction with infliximab, with 83 patients having complete healing (45.4%) and 41 having partial healing (22.4%).[84] This was associated with a significantly lower need for major abdominal surgery during long-term median follow-up of 22 months (14.1% of patients with mucosal healing compared with 38.4% of patients without mucosal healing; p ≤ 0.0001).[84]

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