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 are the Current Available Therapies for Treatment of Patients with CD?

The first-line therapies are 5-ASA (not approved by the US FDA for treatment of CD), antibiotics (not FDA approved for treatment of CD) and the controlled-release corticosteroid budesonide (currently FDA approved for treatment of CD). These are used for mild-to-moderate disease. Oral prednisone is considered the second-line therapy. Immunomodulators, such as azathioprine (AZA), 6-mercaptopurine (6-MP) or methotrexate, represent third-line therapy for those patients who failed the previous therapy or who are steroid-dependent or steroid-refractory. Biologic agents, such as infliximab, adalimumab or certolizumab pegol, have traditionally been reserved for patients who failed the first three lines of drug therapy. Natalizumab, an anti-α4 integrin antibody, was recently approved by the FDA for moderate-to-severe Crohn's disease.[9,10] Owing to concern over the rare, but potentially disabling neurological side effect of progressive multifocal leukoencephalopathy (PML), natalizumab is only indicated for patients who did not respond to anti-TNF therapy and who are enrolled in a Tysabri Outreach Unified Commitment to Health (TOUCH) prescribing program.[10,11]

First-line Therapy (5-ASA, Antibiotics & Budesonide)

These medications are used in mild-to-moderate active CD. 5-ASA agents exert their therapeutic effect topically within the lumen of the intestine.[12] Since the oral route of drug administration results in rapid absorption in the proximal small bowel, different oral formulations have been developed to allow the release of the specific active moiety in different locations of the GI tract. These include the slow-release formulations (coated with an ethylcellulose), pH-dependent delayed release formulations (coated with Eudragit® L or S resins) and azo-bound prodrugs, such as olsalazine and balsalazide.[12,13] Mesalamine, when given as 3–6 g daily, was demonstrated to be effective in treating active CD.[14–16] However, recent randomized, double-blind, placebo controlled multicenter trials failed to show any evidence that 5-ASA formulations were more effective than placebo in maintaining medically induced remission in patients with CD[17–24] or any significant risk reductions in CD relapses.[17–19,21–23,25–28] The observed pooled risk difference between 5-ASA and controls was −4.7% (95% CI: −9.6–2.8).[26] A Cochrane systematic review of six randomized placebo controlled trials with 12-month follow-up and one placebo controlled study with 24-month follow-up demonstrated no superiority of 5-ASA over placebo in maintaining remission of CD with odds ratio (OR) of 1.00 (95% CI: 0.80–1.24) and 0.98 (95% CI: 0.51–1.90), respectively.[24] Therefore, there is currently insufficient evidence to recommend therapy with 5-ASA for maintaining medically achieved remission of CD.[29]

Luminal bacterial floras have been hypothesized to be a putative etiological factor in CD and this has led to the use of antibiotics for treating patients with mild-to-moderate luminal and perianal diseases.[30–33] Metronidazole and ciprofloxacin are the most widely used antibiotics. They can be used alone or in combination.[34] Metronidazole has been compared with placebo in a double-blinded randomized controlled trial and it was found that metronidazole was more effective in reducing clinical symptoms, especially in patients with diseases confined to the large intestine or both small and large intestines.[35] Metronidazole was also compared with sulfasalazine in a Scandinavian trial[36] and was found to be equally efficacious to sulfasalazine in the treatment of CD. Despite several clinical trials demonstrating the efficacy of metronidazole and/or ciprofloxacin for the treatment of active CD,[30,37–40] data are limited on the efficacy of antibiotics as maintenance therapy of nonsurgically[40,41] or surgically induced remission.[42,43] The potentially serious side effects (peripheral neuropathy[43,44] and tendinitis or tendon rupture[45,46]) associated with these drugs and the possibility of drug resistance also precluded their long-term use.

There has been speculation of a causative association between Mycobacterium avium and Mycobactrium paratuberculosis infections and CD. A meta-analysis of seven randomized placebo controlled trials observed no beneficial effect and produced insufficient evidence to support the use of antituberculosis therapy in patients with CD, with a pooled OR of 1.36 (95% CI: 0.87–2.13) and a number-needed-to-treat of 15.[47]

Controlled-release oral budesonide has high topical activity and low-systemic bioavailability (10%), and thus it has a reduced risk of systemic corticosteroid-related complications.[48,49] It is recommended for use in patients with mild-to-moderately active CD involving the ileum and/or right colon. The Cochrane systematic review of randomized trials assessing the efficacy of budesonide at a dose of 9 mg daily showed that it was more effective than placebo (relative risk [RR]: 1.96; 95% CI: 1.19–3.23) or mesalamine (RR: 1.63; 95% CI: 1.23–2.16) in inducing remission of mild-to-moderate active ileocecal CD after 8 weeks of treatment.[50] A predetermined pooled analysis of four randomized, placebo controlled trials evaluating the efficacy of budesonide in maintaining remission of CD found that budesonide administered at the daily dose of 6 mg was only effective in maintaining remission up to 9 months but did not prevent relapse over 9 months, whereas budesonide administered at lower daily dose of 3 mg was not superior to placebo at any time of the study period.[51] However, a recently published Cochrane meta-analysis of eight randomized placebo controlled trials has demonstrated that budesonide given at the daily dose of 6 mg was not more efficacious than placebo in maintaining remission of CD at 3 months (RR: 1.25; 95% CI: 1.00–1.58; p = 0.05), 6 months (RR: 1.15; 95% CI: 0.95–1.39; p = 0.14) or 12 months (RR: 1.13; 95% CI: 0.94–1.35; p = 0.19).[52] On the other hand, a lower maintenance dose of budesonide (3 mg daily) was shown to be superior to placebo only after 3 months of treatment (RR: 1.31; 95% CI: 1.03–1.67; p = 0.03) without sustained benefit after 6 and 12 months.[52]

Although some clinical trials demonstrated comparable efficacy in inducing clinical remission between budesonide and prednisolone,[53] the recent Cochrane systematic review of nine randomized controlled trials demonstrated that budesonide at a daily dose of 9 mg was inferior to conventional corticosteroids in inducing remission of CD (RR: 0.85; 95% CI: 0.75–0.97).[50] On the other hand, the safety analysis in six trials showed that treatment with budesonide was associated with significant reduction in adverse events related to corticosteroid use, with a RR: of 0.64 (95% CI: 0.54–0.76).[50] Rutgeerts et al. found that budesonide had fewer glucocorticoid-associated side effects and less suppression of the pituitary–adrenal function compared with prednisolone.[53] Despite these results, budesonide has a limited treatment population for active CD. It is not effective in approximately 20% of patients with active CD (in particular, patients with extensive diseases who do not have ileocecal involvement or those with left-sided colitis).[54] There is also no evidence for the use of budesonide in fistulizing disease. A comparison between budesonide 9 mg daily and weaning doses of prednisolone 40 mg daily in maintaining remission of CD performed by the authors of a recent Cochrane meta-analysis based on the results obtained by Schoon et al.[55] has shown no superiority of budesonide over a traditional corticosteroid at 3 (RR: 0.81; 95% CI: 0.60–1.09), 6 (RR: 0.79; 95% CI: 0.56–1.12) or 12 months (RR: 0.79; 95% CI: 0.55–1.13) of treatment.[52] Therefore, in light of the recent data, budesonide is not recommended as a maintenance treatment for CD.

Second-line Therapy (Systemic Corticosteroids)

Corticosteroids are highly effective in achieving clinical remission in CD. Systemic corticosteroids (prednisone 40–60 mg daily) have remained the mainstay of treatment to control acute disease that has not responded to the first-line therapy. A population-based inception cohort study observed that among patients with CD who received corticosteroids, 84% of them had either complete or partial response and 16% of them did not respond to treatment over the first 30 days.[56] However, within 1 year of initial use of corticosteroids, 28% of patients with CD became corticosteroid-dependent and 38% of CD patients underwent surgery.[56] There are as yet no studies evaluating the optimal corticosteroid dosage or dose schedules for CD. However, it has been shown that approximately 50–70% of patients achieved clinical remission over 8–17 weeks in a dosage equivalent of prednisone 40 mg daily.[53,57,58] In addition, data from several clinical trials have clearly demonstrated that systemic corticosteroids in low doses are not an effective agent in maintaining remission of CD.[14,57] High-dose corticosteroids have not been evaluated as a potential maintenance treatment owing to increased risk of significant side effects, and long-term use of systemic corticosteroids is not recommended for the same reason.

Third-line Therapy (Immunomodulators & Methotrexate)

The immunomodulators AZA and 6-MP have been shown to be effective in maintaining clinical remission after corticosteroid-inductive therapy or surgery,[59] and in assisting corticosteroid dosage reduction. The corticosteroid-sparing effect was observed among 30 patients treated with AZA compared with placebo with a pooled Peto OR of 5.22 (95% CI: 1.06–25.68) and a number-needed-to-treat of three.[59] A meta-analysis of four controlled trials found that AZA/6-MP was significantly more efficacious than placebo in preventing clinical relapses in surgically induced remission, with a mean difference of 8% (p = 0.021) and 13% (p = 0.018) after 1 and 2 years, respectively.[60] In addition, when compared with placebo, AZA/6MP displayed an overall preventive effect on severe endoscopic recurrence, with a mean difference of 15% at 1 year post surgery (p = 0.026).[60] However, it needs to be emphasized that patients treated with AZA/6-MP experienced a nearly twofold increased rate of adverse events leading to withdrawal of the drug when compared with placebo recipients (17.2 vs 9.8%, respectively; p = 0.021).[60]

Among the rare but serious side effects[61–63] of immunomodulators is the fear of developing non-Hodgkin lymphoma[64–66] and hepatosplenic T-cell lymphoma[66–70] associated with the prolonged use of these medications. The slow onset of action of 3–6 months precludes their use as inductive agents. The genetic coding for thiopurine methyltransferase can now be identified prior to the use of 6-MP. This allows for a more tailored use of the drug and a decrease in toxicity for 0.3–11% of the population with a thiopurine methyltransferase genetic mutation.[71,72] Despite the risks of lymphoma, some of the authors claimed that the benefits of maintenance therapy with AZA outweigh the risks.[73] We need more evidence to better define the optimal duration of therapy, which will maximize the duration of clinical remission with minimal risks of potential lethal complications.

Methotrexate is a folic acid antagonist that inhibits purine synthesis, DNA and RNA formation, and suppresses inflammation in chronic inflammatory conditions through a complicated cascade.[74] There are fewer published articles on the use of methotrexate in CD compared with other medications. A recent Cochrane database meta-analysis of three randomized placebo-controlled trials has demonstrated that methotrexate, when administered intramusculary at the weekly dose of 15 mg, was three-times more efficacious than placebo in maintaining remission of CD.[75] Given the potential adverse events, such as liver fibrosis, pneumonitis and bone marrow suppression, the optimal duration of maintenance therapy with methotrexate remains unknown.[76,77] Among 20 patients with irritable bowel disease (IBD) who received methotrexate at a mean accumulated dose of 2633 mg over a mean period of 132 weeks, only one patient (5%), with an accompanying diagnosis of obesity and diabetes, had liver fibrosis.[78] Although these results may have implied that patients with IBD are not as high risk for liver fibrosis as patients with psoriasis or rheumatoid arthritis, more data are required on methotrexate-related liver toxicity in patients with IBD to validate these preliminary findings.

The Fourth-line Therapy: Anti-TNF (Infliximab, Adalimumab & Certolizumab Pegol)

The biological therapies for CD are designed to block or neutralize proinflammatory cytokines, which play a major role in the pathogenesis of CD. Infliximab is a murine chimeric antibody directed against TNF-α and it is administered intravenously. It was approved by the FDA[79] for induction and maintenance therapy in patients with moderate-to-severe CD refractory to conventional therapies (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen [ACCENT] I trial).[80] It is also effective in reducing the number of draining enterocutaneous and rectovaginal fistulae, and maintaining fistula closure in adult patients with fistulizing Crohn's disease.[81,82] The recommended maintenance dose of infliximab is 5 mg/kg every 8 weeks with an increase to 10 mg/kg in case of loss of response.[80] Studies have clearly demonstrated that maintenance therapy with infliximab in patients with CD is superior to episodic treatment.[80] Maintenance therapy was associated with higher clinical response and remission rates, significant reduction in hospitalizations and surgical procedures, prolonged mucosal healing, faster steroid weaning, decreased neutralizing antibody formation and better quality of life.[80,81,83–86]

Recent preliminary 1-year data from the Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC) trial have indicated that monotherapy with infliximab or combination therapy consisting of infliximab and AZA are more likely to maintain long-term corticosteroid-free remission than monotherapy with AZA.[87] Immunomodulator-naive patients with active CD were enrolled and randomized into three treatment arms: monotherapy with infliximab given at 5 mg/kg (weeks 0, 2, 6 and then every 8 weeks), montherapy with oral AZA given at 2.5 mg/kg/day or combination therapy of infliximab and AZA at the dose mentioned earlier. It was found that the combination therapy and infliximab monotherapy had a significantly higher proportion of patients who were in corticosteroid-free remissions (46 and 35%, respectively). This was compared with AZA montherapy (24%) at week 50. However, final data from the SONIC trial[87] would be necessary to further assess the efficacy, safety and risk–benefit of infliximab and AZA combination therapy given the recent reports of hepatosplenic natural killer T-cell lymphomas observed in young males receiving the combination therapy.[67,70,88,89]

Adalimumab is an Ig-G1 monoclonal anti-TNF antibody of fully human origin that is administered subcutaneously and binds with high affinity and specificity to the soluble TNF. It was approved by the FDA in 2007[90] as an induction agent (Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn's Disease [CLASSIC] I trial[91]) and a maintenance agent (CLASSIC II and Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance [CHARM] trials[92,93]) for moderately to severely active CD in adult patients unresponsive to conventional therapy and in those who are intolerant to or lost response to infliximab (Gauging Adalimumab Effectiveness in Infliximab Nonresponders [GAIN] trial[94]). In the CHARM trial, patients with fistulizing CD treated with adalimumab had a significantly decreased number of draining fistulae per day compared with placebo (1.34 vs 0.88; p = 0.002) during a 56-week period.[95] An open-label extension Additional Long-Term Dosing with Humira to Evaluate Sustained Remission and Efficacy in Crohn's Disease (ADHERE) study of the aforementioned subgroup of patients treated with adalimumab observed that 90% of patients with healed fistulas at the end of the CHARM trial maintained their remissions for an additional year with the treatment of adalimumab.[95] The side effects of adalimumab are similar to those of infliximab.[92,93]

Certolizumab pegol is a humanized Fab' fragment attached to two polyethylene glycol molecules with a high binding affinity for TNF-α. Pegylation is thought to increase the half-life and improve the bioavailability of the drug, allowing it to be administered as a subcutaneous injection once every 4 weeks.[96] Certolizumab pegol was shown to be effective in both inducing (Pegylated Antibody Fragment Evaluation in Crohn's Disease Safety and Efficacy [PRECISE] I trial[97]) and maintaining (PRECISE II trial[98]) clinical response and remission. However, certolizumab was not found to be more efficacious than placebo on fistula closure in either of the aforementioned trials.[97,98] In 2008, this drug received FDA approval as an alternative treatment to reduce signs and symptoms of CD and to maintain clinical responses in adult patients presenting with moderately to severely active disease who had inadequate responses to the conventional therapy.[99]

A recent meta-analysis of placebo controlled trials demonstrated that all three anti-TNF agents were safe in patients with CD refractory to standard medical therapy.[100] Although treatment with infiximab, adalimumab and certoliuzmab pegol is overall well tolerated, administration of these agents was associated with the occurrence of various adverse events.[5] These can manifest acutely as headaches, dizziness, nausea, injection-site erythema, flushing, fever, chills, chest pain, cough, dyspnea and pruritis; or as delayed reactions, such as myalgias, arthralgias, fever, rash, pruritis, dysphagia, urticaria and headaches. Hypersensitivity infusion reactions, development of antibodies to infliximab and anti-dsDNA antibodies were the most frequently observed adverse events after intravenous administration of infliximab.[5] Owing to the fact that adalimumab and certoliuzmab are administered subcutaneously, neither acute nor delayed infusion reactions have been reported.[5] On the other hand, injection-site reactions were observed.[5] All three agents are associated with increased risk of infectious complications, particularly with intracellular pathogens.[5] Physicians should also monitor meticulously for the potential development of lymphoma or other malignancies associated with the use of anti-TNF agents.

The Alternative Medical Therapy for the Nonresponders: Selective Adhesion Molecule Inhibitors (Natalizumab)

Natalizumab is a humanized monoclonal antibody targeted against the α4 subunit of integrin molecules and it belongs to a new class of biologic agents called selective adhesion molecule inhibitors.[101] By binding to the α4 subunit, it reduces inflammation and blocking adhesion and migration of leukocytes in the gut. It was approved by the FDA in 2008 as the treatment to induce (Efficacy of Natalizumab in Crohn's Disease Response and Remission [ENCORE] trial[102]) and maintain (Evaluation of Natalizumab as Continuous Therapy [ENACT] 2 trial[103]) clinical response and remission in adult patients with moderately to severely active CD who had inadequate response or intolerance to conventional CD therapies, including the anti-TNF-α agents.[104]

Owing to an underlying risk of PML, natalizumab is available only to patients enrolled in the risk management program (TOUCH Prescribing Program).[201] This agent is approved for use only as a monotherapy owing to the fact that there were three patients who developed PML while being treated with either IFN-β-1a or AZA.[10]

In the ENCORE trials, 509 patients with moderately to severely active CD were randomized into receiving natalizumab or placebo and their responses were assessed at weeks 4, 8 and 12.[102] It was shown that natalizumab had a higher response rate at week 4 (51 vs 37% in placebo; p = 0.01) and better remission rate than placebo at weeks 4, 8 and 12 (p ≤ 009).[102] The authors reported a similar frequency and types of adverse events between the treatment and placebo groups.[102]

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