The pharmacologic management of Crohn's disease

• Abstract

Crohn's disease (CD) is a discontinuous transmural chronic inflammatory disorder involving any part of the lining of the gastrointestinal tract (GIT). In the majority of cases, the small intestine is primarily affected; however, inflammation can occur anywhere from the oral cavity to the anal canal. The most common patient complaints include abdominal pain, frequent bowel movements with or without the presence of blood, anorexia, fatigue, and fevers. The primary goal of therapy is to improve symptoms, resolve acute GIT inflammation, and induce and maintain remission. Current pharmacologic treatment options for CD include aminosalicylates, corticosteroids, and immunosuppressant agents; biologic agents may be initiated if patients do not respond to traditional interventions. (Formulary. 2008;43:93–104.)

Crohn's disease (CD) is a chronic discontinuous transmural inflammatory disorder involving any part of the lining of the gastrointestinal tract (GIT), with the majority of cases affecting the small intestine. CD is usually diagnosed during late adolescence or early adulthood but may also be observed from the fifth to eighth decade of life.^1–3 The incidence and prevalence of CD are reported to be highest in the United Kingdom, northern Europe, and North America.¹ The incidence of the disease ranges from 3.1 to 14.6 cases per 100,000 person-years in North America, which equals approximately 10,000 to 47,000 new diagnoses per year.¹ Caucasian and African American individuals are more likely to have CD than Hispanic or Asian individuals.^1,2,4 Women may be affected slightly more often than men.^1–4

The pathogenesis of CD is not fully understood but appears to be associated with genetic, environmental, and immune factors.^1,2,8 The strongest evidence of a genetic etiology comes from concordance studies in dizygotic and monozygotic twins.⁸ In recent research related to inflammatory bowel disease (IBD), investigators have linked mutations in the CARD15 (NOD2) gene to CD, with this gene mutation occurring in approximately 10% to 15% of patients with CD.⁸ Moreover, it has been demonstrated that developed regions have a higher prevalence of individuals with CD compared with developing regions.^1,2,8 This difference may be explained in part by the developed countries' quality of sanitation and personal hygiene. Another environmental factor associated with CD is tobacco use; smokers are 2 times more likely to develop GIT symptoms than nonsmokers and are more likely to relapse after surgery-induced remission.^1,8 Dietary intake of carbohydrates and foods containing high amounts of lactose or fructose may also be a risk factor for CD.^1,2,8

The Crohn's Disease Activity Index (CDAI) may be used to determine the severity of the disease in adults.^5,6 The CDAI evaluates 8 specific variables (number of liquid or soft stools, severity of abdominal pain, general well-being, number of extraintestinal manifestations, presence of abdominal mass, hematocrit levels, antidiarrheal use, and body weight). In most studies, CDAI scores <150 indicate clinical remission, and scores >450 indicate severe disease.^9,10 In comparison, the Harvey-Bradshaw Index (HBI) focuses on 5 clinical parameters (general well-being, abdominal pain, abdominal mass, number of loose stools, and presence of extraintestinal manifestations). HBI scores range from 0 to 25; a score <5 indicates clinical remission.^9,10

Today, most treatments available for IBD target and suppress the immune system. Patients with active CD are more likely to have a dysfunctional immune system, in which the luminal lining is infiltrated with lymphocytes and mast cells. Pro-inflammatory cytokines such as interferon (IFN)-gamma, CD4+ T cells, interleukin (IL)-2, and tumor necrosis factor (TNF)-alpha may be overproduced, thus stimulating a cascade to activate mediators of the inflammatory process.^8,11

PHARMACOLOGIC TREATMENT AGENTS

Treatment options for CD include anti-inflammatory agents (eg, sulfasalazine, mesalamine) and corticosteroids for the induction of response in patients with mild-to-moderate CD. Immunomodulators, antibiotics, and biologic agents may be used for the maintenance of remission.^5,6,12–15 These treatment options are summarized in Table 1.^16–21

Aminosalicylates and their derivatives. Despite having an indication for ulcerative colitis (UC) only, aminosalicylates, including sulfasalazine and 5-aminosalicylic acid (mesalamine), are commonly used off-label to treat, induce, and maintain remission in patients with mild-to-moderate CD. The first aminosalicylate to be used for IBD was sulfasalazine, which is composed of 2 compounds, sulfapyridine and mesalamine, linked by an azo bond. Once sulfasalazine reaches the colon, colonic bacterial azo-reductase cleaves the azo-bond, separating the sulfapyridine component from the mesalamine molecule.^16,22 Sulfasalazine in divided doses of 3 to 6 g/d has demonstrated efficacy in inducing remission in patients with mild-to-moderate colonic or ileocolonic CD.^5,6,16 However, sulfapyridine is associated with several dose-related adverse events, including headaches, nausea, vomiting, anorexia, and dyspepsia.^6,22 In rare cases, hypersensitivity reactions such as fever, rash, hepatotoxicity, bone marrow suppression, and change in sperm morphology may occur.²²

Several formulations containing mesalamine without the sulfapyridine molecule have been developed; these newer formulations have a more favorable side-effect profile.^6,16 The determination of which mesalamine product should be prescribed is based primarily on the site of GIT inflammation, as each formulation is unique as to where active drug is released.^5,16

In several randomized, double-blind, placebo-controlled trials, mesalamine has demonstrated a minimal effect in inducing clinical response compared with placebo; however, these trials had small sample sizes and used low mesalamine doses.^6,22–24 It has been suggested that higher doses of mesalamine may lead to a dose-response effect; however, the accuracy of this theory has yet to be determined.^22,25–27

In clinical practice, patients with CD are often prescribed sulfasalazine or mesalamine for the maintenance of medically induced remission. However, meta-analyses evaluating mesalamine for this indication have not demonstrated efficacy for this agent versus placebo.^28,29 Akobeng et al²⁸ performed a meta-analysis evaluating 7 randomized, controlled trials that compared mesalamine with placebo; there was no significant difference in efficacy between mesalamine and placebo.

Corticosteroids. Corticosteroids are effective (off-label) in inducing remission and reducing symptoms in patients with moderate-to-severe disease and in those with mild-to-moderate disease in whom first-line regimens such as sulfasalazine or mesalamine have failed.^{5,12,16,30,31} In the National Cooperative Crohn's Disease Study (NCCDS), 569 patients were randomized to 1 of 4 treatment regimens: prednisone 0.5 to 0.75 mg/kg/d (maximum dose, 60 mg), sulfasalazine 1 g/15 kg, azathioprine (AZA) 2.5 mg/kg, or placebo.³⁰ Remission was defined as a CDAI score <150. A total of 47%, 38%, and 36% of patients treated with prednisone, sulfasalazine, or AZA, respectively, achieved remission versus 26% of patients who received placebo.

In other clinical studies, approximately 45% to 80% of patients receiving either prednisone 40 to 60 mg/d or prednisolone 1 mg/kg/d achieved complete remission, defined as a total regression of clinical symptoms; <2 bowel movements/d with no blood or pus in the stool; and an absence of abdominal pain, weight loss, fever, and extraintestinal symptoms within 30 days of initiating corticosteroids.^12,16,31,32

Short-term therapy with corticosteroids is recommended for inducing remission in patients with moderate-to-severe CD.¹² However, corticosteroids are not recommended for prolonged durations in maintaining remission, as corticosteroid therapy has not been demonstrated to be beneficial for this indication.^6,12,31,32

Prednisone, prednisolone, hydrocortisone, and methylprednisolone are commonly prescribed off-label for their immediate anti-inflammatory effects and should be dosed to provide an equivalent of prednisone 40 to 60 mg.^6,12,16 Although the response to corticosteroids is generally favorable in patients with CD, long-term maintenance therapy with corticosteroids is not recommended, as approximately 25% to 50% of patients will relapse once the corticosteroid dose is decreased or discontinued.^30–33 Also, these agents are associated with a multitude of adverse effects, including weight gain, edema, increased appetite, irritability, osteopenia, and osteoporosis.^12,16

Budesonide is a glucocorticoid that primarily undergoes first-pass hepatic metabolism, resulting in a more favorable toxicity profile compared with conventional corticosteroids.^12,16 This agent is approved for the treatment of mild-to-moderate active CD involving the ileum and/or the ascending colon and for the maintenance of clinical remission of mild-to-moderate CD involving the ileum and/or the ascending colon for up to 3 months.¹⁸ Budesonide is available as a capsule that contains acid-stable, slow-release microgranules, which release active drug when the pH environment is >5.5.^34–36 Because of its unique formulation, controlled-release budesonide has been demonstrated to be effective in the treatment of mild-to-moderate ileal and proximal colonic CD.^{12–14,34,35} In a double-blind, multicenter trial, 51% of patients with active CD (CDAI score >200) localized to the ileum or with ileocolonic disease achieved remission (CDAI score <150) during treatment with budesonide 9 mg/d compared with patients who received budesonide 3 mg/d (33%) or 15 mg/d (43%) or placebo (20%).³⁴ A significant mean decrease in CDAI score of 121 points was observed at Week 8 with budesonide 9 mg/d compared with a 21-point decrease in the placebo arm (P<.001). Immediate remission response was observed as early as Week 2 with budesonide 9 mg/d (P<.001). Another trial demonstrated similar remission rates with budesonide 9 mg/d compared with prednisolone 40 mg/d, with a scheduled taper of the treatment regimens over 10 weeks.³⁵ The prednisolone group demonstrated a higher remission rate (56%–67%) than the budesonide group (40%–53%). However, systemic side effects were more common with prednisolone than with budesonide (55% vs 33%; P=.003). In another trial, budesonide was demonstrated to be more effective than mesalamine 2 g twice daily after 16 weeks of therapy (P<.001).³⁶ Meta-analysis has confirmed the therapeutic benefit of budesonide in inducing remission in patients with mild-to-moderate active ileal or right-sided CD.³⁷

Immunomodulators. The agents AZA and 6-mercaptopurine (6-MP) are commonly used off-label as maintenance therapy after corticosteroid-induced remission; the steroid-sparing effects of these agents may allow corticosteroid-dependent patients with CD to taper off corticosteroids.^12–15 The most effective oral dose of AZA ranges from 2 to 3 mg/kg/d; the most effective dose of 6-MP ranges from 1 to 1.5 mg/kg/d.^6,12 Several well-controlled trials and meta-analyses have demonstrated that these immunosuppressive therapies are effective in maintaining remission in patients with mild quiescent CD.^38,39 Candy et al³⁸ compared AZA 2.5 mg/kg/d plus prednisolone 1 mg/kg/d with prednisolone 1 mg/kg/d plus placebo. Patients with active disease (CDAI $200) were enrolled in the first phase of the trial to determine the efficacy of these regimens in inducing remission; in the second phase of the trial, patients continued treatment with AZA or placebo without corticosteroids to determine the efficacy of AZA in maintaining remission. At the end of Week 12 in the first study phase, there was no statistical difference in induction of remission between the 2 groups. In the second phase of the study, there was a significant difference in maintenance of remission between the AZA group and the placebo group (42% vs 7%; P=.001). A meta-analysis of 5 well-designed trials indicated an overall remission maintenance rate of 67% in patients treated with AZA versus 52% in those treated with placebo.³⁹

The use of AZA and 6-MP for inducing remission in patients with active CD is still controversial.^12,30,38,40 Similar to the trial by Candy et al,³⁸ the NCCDS study demonstrated no difference between AZA 2.5 mg/kg/d and placebo at the end of the 4-month study period.^30,38 However, a meta-analysis by Sandborn et al⁴⁰ suggested that these agents are effective for the induction of remission, albeit not immediately. In a 52-week, randomized, double-blind, placebo-controlled trial, 72% of patients treated with 6-MP 1.5 mg/kg/d demonstrated significant clinical improvement (based on a grading scale of 0 for no change, +3 for excellent improvement, and –3 for severe worsening) compared with 14% of patients in the placebo group (P<.01). The average time to response was 3.1 months.⁴¹

Because of the slow onset of action of AZA and 6-MP (range, 9–26 weeks), these agents are not recommended for inducing remission in patients with active CD.^5,6,12–14

AZA and 6-MP are associated with several adverse effects, including blood dyscrasias, severe infections, gastrointestinal symptoms, hypersensitivity reactions, hepatotoxicities, dermatologic disorders, and neoplasm.^12,40 It has been estimated that approximately 10% to 30% of patients cannot tolerate AZA or 6-MP.⁴² Several rare but potentially life-threatening adverse effects are associated with immunosuppressant therapy. Many of these toxicities are dose related and include bone marrow suppression, pancreatitis, and hepatotoxicity.^12,40 Most of these events are reversible upon discontinuation of therapy.⁴² To minimize the side effects, clinicians may initiate therapy at a low dose and escalate to the desired dose with frequent complete blood count (CBC) monitoring and liver function tests (LFTs).⁴³ Further trials are needed to determine if this method of initiating immunosuppressive therapy decreases the risk of adverse effects compared with initiating therapy at the full weight-based dose.

Therapeutic response and adverse effects associated with AZA and 6-MP are largely related to the metabolism of these agents.^12,42,43 AZA is a prodrug of 6-MP. 6-MP requires either thiopurine methotransferase (TPMT) to metabolize to an inactive metabolite, 6-methylmercaptopurine (6-MMP), or hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to metabolize to 6-thiosonine 5'-monophosphate, which then eventually metabolizes to the active metabolite 6-thioguanine (6-TGN).^12,42,43 6-TGN concentrations >235 pmol/8310⁸ erythrocytes have been associated with greater therapeutic response.^12,42 The risk of developing hepatotoxicity may be associated with 6-MMP concentrations >5,700 pmol/8310⁸ erythrocytes.⁴³ Additionally, low levels of TPMT have been associated with an increased incidence of leukopenia.^42,43 In the general population, approximately 89% of individuals have normal-to-high levels of TPMT activity, and 11% have intermediate levels.¹² The TPMT enzyme is lacking in 0.3% of the population; therefore, these patients are at greater risk of developing leukopenia.¹² Despite a lack of clinical trials confirming the benefits of measuring TPMT, 6-TGN, and 6-MMP levels, the product labels for 6-MP and AZA recommend genetic testing for TPMT deficiency with TPMT gene mutation assays or TPMT phenotypic assays before initiation of 6-MP or AZA therapy.¹² Obtaining these genetic tests should not replace frequent laboratory monitoring when AZA or 6-MP regimens are initiated.^12,42,43

Intramuscular (IM) methotrexate (MTX) 25 mg is effective (off-label) in inducing remission of active CD and maintaining remission.^5,6,12 Feagan et al⁴⁴ compared IM MTX 25 mg administered once weekly versus placebo in patients with active CD who were corticosteroid dependent. The patients were required to have a history of unsuccessful prednisone taper and also must have been taking prednisone $12.5 mg for >3 months to be enrolled in the trial. A total of 39% of MTX-treated patients achieved clinical remission (defined as CDAI score <150) and successfully tapered off prednisone compared with 19% of placebo-treated patients (P=.025). The trial was continued to determine if lower doses of MTX were effective for the maintenance of remission in patients with CD.^44,45 Patients with a CDAI score <150 who were not taking corticosteroids were enrolled in the second part of the study. IM MTX 15 mg or placebo was administered weekly for 40 weeks; the primary outcome was relapse, defined as an increase in CDAI score >100 points from baseline or the addition of prednisone and/or antimetabolite to the treatment regimen. Patients in the MTX group had a higher maintenance remission rate at Week 40 compared with patients in the placebo group (65% vs 39%). More patients in the placebo arm relapsed and required prednisone to induce remission compared with patients in the MTX arm (58% vs 28%).⁴⁵

Subcutaneous (SC) and oral routes of MTX administration have also been evaluated and have resulted in variable therapeutic response; thus, only IM injections are currently recommended for the treatment of CD.¹² Side effects, including nausea, abnormal LFTs, and bone marrow suppression, may occur with MTX treatment. Because MTX is considered a teratogenic agent, women who are pregnant or breastfeeding should avoid use of this drug.^6,12 Folate supplementation is recommended during treatment, as MTX is a folic acid antagonist.^5,6,12

Tacrolimus, a macrolide antibiotic with immunomodulatory properties that is primarily used for the prevention of organ transplant rejection, has been demonstrated to be effective (off-label) in patients with CD who are resistant to steroid therapy and in whom infliximab therapy has failed. Recommended initial doses of oral tacrolimus range from 0.1 to 0.2 mg/kg/d in 2 divided doses to achieve a serum trough level of 4 to 10 ng/mL.^46–48 Several retrospective studies have demonstrated a clinical response after 4 weeks of treatment with oral tacrolimus in 65% to 90% of enrolled patients with moderate-to-severe chronic active disease who were steroid dependent or in whom AZA, 6-MP, or infliximab therapy had failed.^46,48,49

Tacrolimus is associated with several adverse effects, including paresthesias, tremors, headaches, and nephrotoxicity.¹² Therapeutic drug level monitoring is recommended to minimize these effects. Tacrolimus may be a promising agent for CD; however, long-term follow-up prospective trials comparing tacrolimus with other immunosuppressant therapies and with biologic agents are needed to confirm these results.

Cyclosporine 4 mg/kg/d has been demonstrated to be effective (off-label) in patients with UC who are resistant to steroid therapy and who require surgery.¹² The potential efficacy of oral cyclosporine for the treatment of active CD is still under debate.¹² The risk:benefit profile of this agent must be considered if cyclosporine is used to induce a clinical response or to maintain remission.⁵⁰ Relapse occurs frequently after discontinuation of therapy despite an initial induction of response.^50,51 Additionally, as with tacrolimus, therapeutic drug monitoring is required, as several potentially irreversible adverse effects, including nephrotoxicity, paresthesias, and hypertension, may occur.¹² Therefore, cyclosporine is not recommended for the treatment of CD and should be reserved for when all other agents have failed.^12,51

Antibiotics. Antibiotics have been used off-label to treat infections associated with IBD, specifically in patients with fistulas, abscesses, pouchitis, postsurgical CD resection, or perianal disease.^13,14,16,52 It is possible that microorganisms may be a contributing factor to the pathogenesis of CD.^52,53 However, evidence to support the use of antibiotics for mild-to-moderate luminal CD is limited, as most published trials were uncontrolled and used small sample sizes.^6,52,54 Metronidazole and ciprofloxacin are the 2 most studied and commonly used antibiotics for the treatment and maintenance of remission of CD.⁵²

In a randomized, double-blind study, Sutherland et al⁵⁴ evaluated metronidazole 20 mg/kg/d or 10 mg/kg/d in 3 divided doses versus placebo for 16 weeks in patients with active CD (CDAI >180 and <450). Of the 105 patients enrolled, only 56 completed the treatment course. The primary outcome was the change in CDAI score from baseline. Patients treated with the higher dose of metronidazole demonstrated a significant improvement compared with patients who received placebo (P=.002). Patients receiving either dose of metronidazole were more likely to achieve a CDAI score <150 compared with patients who received placebo; however, this difference did not reach statistical significance. Metronidazole-treated patients with small and large intestinal disease involvement were significantly more likely to have a greater change in CDAI score than placebo-treated patients (P=.005), whereas the difference between metronidazole-treated and placebo-treated patients with small bowel disease only was not significant. No significant differences were observed among patients with a history of surgery or prior use of corticosteroids or sulfasalazine.⁵⁴

Colombel et al⁵⁵ conducted a randomized, controlled, nonblinded trial that compared ciprofloxacin 500 mg twice daily versus mesalamine 2 g twice daily in patients with mild-to-moderate CD (CDAI score >150 and <300). Complete remission at 6 weeks was defined as a CDAI score <150 or a decrease in CDAI score from baseline of $75 points. Patients in the ciprofloxacin arm had a complete remission response rate similar to those in the mesalamine arm (56% vs 55%).

Rifaximin, a rifamycin-derived broad-spectrum antibiotic with poor GIT absorption, has been evaluated (off-label) for use in patients with IBD in several small trials.^58,59 In an open-label trial of 29 patients, rifaximin 200 mg 3 times daily for 16 weeks was evaluated to determine the efficacy of this agent for the treatment of active CD. Clinical remission, which was defined as a CDAI score <150, was achieved by 41% of patients at Week 4 and 59% of patients at Week 16.⁵⁸ Prantera et al⁵⁹ conducted a multicenter, randomized, 12-week, double-blind trial in patients with mild-to-moderate active CD (CDAI score >200 and <400). A total of 83 patients were randomized to treatment with either rifaximin gastroresistant granules 800 mg administered once (n=29) or twice (n=29) daily or placebo (n=29). Clinical remission, which was defined as a CDAI score <150, was observed in 32%, 52%, and 33% of patients receiving rifaximin 800 mg once daily, rifaximin 800 mg twice daily, or placebo, respectively (P=not significant). To determine rifaximin's potential role in the treatment of CD, randomized, controlled trials comparing rifaximin with standard treatments such as mesalamine, corticosteroids, and other antibiotics will need to be conducted.

Biologic agents. The treatment of CD has improved significantly over the past decades as more research has focused on the immunopathogenesis of IBD.^5,12 With the advent of biologic agents, more treatment options are now available for patients with CD. Biologic agents are commonly recommended when conventional treatments have failed; however, the risk:benefit profile must be considered before any of these agents are initiated.^{12–15,60,61}

Anti-TNF-alpha agents are monoclonal antibodies (mAbs) that neutralize the inflammatory processes of the gastrointestinal mucosa by inhibiting TNF-alpha. The first anti-TNF-alpha agent approved in the United States for CD was infliximab. This chimeric antibody, which is composed of 75% human and 25% murine components, is indicated for inducing and maintaining clinical remission in patients with moderate-to-severe active CD who have not responded to traditional treatments.¹⁹ Intravenous (IV) infliximab is often initiated at 5 mg/kg at Weeks 0, 2, and 6, and at the same dose every 8 weeks thereafter as a maintenance regimen.

A randomized, placebo-controlled trial evaluated 108 patients with moderate-to-severe CD who did not respond to conventional treatments.⁶² Study patients were evaluated for a clinical response, defined as a decrease of $70 points in the CDAI score compared with baseline values, at Week 4. A total of 81% of patients who received the 5-mg/kg infusion achieved a clinical response compared with 17% of patients who received placebo. However, only 41% of infliximab-treated patients had a clinical response at Week 12. Thus, although it has been demonstrated that infliximab is effective in inducing remission for patients with active CD, a single dose of infliximab does not appear to sustain clinical response.

Repeated doses of infliximab were evaluated in A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen (ACCENT I).⁶³ Of the 573 patients enrolled, 335 (58%) responded (defined as $70-point reduction and $25% decrease in the total baseline CDAI score) to an initial dose of IV infliximab 5 mg/kg at Week 2. These responders were randomized to receive an infusion of either placebo (Group 1) or infliximab 5 mg/kg (Group 2) at Weeks 2 and 6 and every 8 weeks thereafter, or infliximab 5 mg/kg at Weeks 2 and 6 and infliximab 10 mg/kg every 8 weeks thereafter (Group 3), through Week 46. At Week 30, clinical remission, defined as a CDAI score <150, was observed in 21%, 39%, and 45% of patients in Groups 1, 2, and 3, respectively. A total of 29% of the patients in Groups 2 and 3 had achieved clinical remission and were not taking corticosteroids at Week 54 compared with 9% of placebo-treated patients (P=.004).

This lack of sustained clinical remission may be associated with the development of antibodies to infliximab, also known as human antichimeric antibodies (HACAs). Sporadic infliximab infusions are more likely to result in HACAs than regularly scheduled maintenance therapy. These antibodies often increase the risk of the development of hypersensitivity reactions and may result in a decreased therapeutic response. Hanauer et al⁶⁴ evaluated the data from the ACCENT I trial to assess the possible relationship between the development of antibodies and clinical remission rates. A total of 30% of the patients in Group 1 who received placebo in the maintenance phase developed antibodies compared with 10% of those in Group 2 and 7% of those in Group 3.

Adalimumab, an immunoglobulin G1 (IgG1) fully humanized recombinant mAb, is approved for inducing and maintaining clinical remission in patients with moderate-to-severe active CD in whom traditional treatments have failed.²⁰ This newer biologic agent may also be used in patients who no longer respond to infliximab or in those who developed severe adverse effects. The induction dose of adalimumab was identified in the Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn's Disease (CLASSIC-I) trial.⁶⁵ Patients who received SC adalimumab 160 mg at Week 0 and 80 mg at Week 2 were more likely to be in remission, defined as a CDAI score <150, at Week 4 than those who received placebo (36% vs 12%, respectively). The Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM) evaluated the effect of adalimumab on remission maintenance after an induction regimen of adalimumab 80 mg at Week 0 and 40 mg at Week 2.⁶⁶ A total of 58% of the 854 enrolled patients who had a clinical response, which was defined as a decrease in CDAI score of $70 points at Week 4, were randomized to continued therapy with either adalimumab 40 mg weekly or every other week or placebo for a total of 56 weeks. Clinical remission, defined as a CDAI score <150, was demonstrated in 47%, 40%, and 17% of patients, respectively, at Week 26 and in 41%, 36%, and 12% of patients, respectively, at Week 56.⁶⁶

The Gauging Adalimumab Efficacy in Infliximab Nonresponders (GAIN) trial evaluated 325 patients to determine if an induction dose of adalimumab (160 mg/80 mg at Weeks 0 and 2) versus placebo was effective in inducing remission at Week 4 in patients with moderate-to-severe active CD who did not tolerate or had lost response to infliximab.⁶⁷ Of the 301 patients who completed the 4-week trial, 21% of adalimumab-treated patients achieved remission versus 7% of placebo-treated patients. Several studies have demonstrated that adalimumab is effective for the treatment of CD; however, patients who have previously been treated with infliximab may experience a lower remission rate. In the CHARM trial, patients who had not previously received infliximab demonstrated a 42% remission rate compared with a rate of 31% among patients who had received infliximab within the 12 weeks before study enrollment.⁶⁶

Infliximab and adalimumab have similar adverse-effect profiles. Serious infections have been reported, including sepsis, reactivation of hepatitis B infection, and tuberculosis; some of these infections have resulted in death.¹² Patients with active infections should not begin treatment with these agents until infections have resolved. Before therapy initiation, all patients must be screened for infections, including for latent tuberculosis. Hematologic events, hypersensitivity reactions, hepatotoxicity, serum sickness-like disease, neurologic events, and malignancies are rare yet fatal events that have been associated with infliximab therapy.^12,13,61

Natalizumab is a selective adhesion molecule inhibitor, the first of its class to demonstrate efficacy in treating CD.^68,69 This IV agent is a humanized immunoglobulin mAb that has an affinity for alpha₄-beta₁ and alpha₄-beta₇ integrins.⁷⁰ These specific integrins are found on the surface of leukocytes, which, when stimulated, induce an inflammatory process.⁷⁰ Therefore, natalizumab may be effective in inhibiting the inflammation cascade in the GIT in patients with active CD. In January 2008, natalizumab was approved for the treatment of moderate-to-severe CD in patients with evidence of GIT inflammation in whom conventional therapies, including anti-TNF-alpha agents, have failed and for patients who have not been able to tolerate conventional therapies.²¹

The Evaluation of Natalizumab As Continuous Therapy (ENACT 1) and Efficacy of Natalizumab in Crohn's Disease Response and Remission (ENCORE) trials were developed to determine the efficacy of natalizumab for the induction of response.^68,69 These trials were followed by the ENACT 2 trial to determine the response rate to natalizumab for maintenance treatment.⁶⁸ The ENACT 1 trial did not demonstrate a significant difference in clinical induction response rate (defined as a reduction of $70 points in CDAI score from baseline) or remission rate (CDAI score <150) between patients who received natalizumab 300 mg at Weeks 0, 4, and 8 and patients who received placebo (clinical induction response rate, 56% vs 49%; remission rate, 37% vs 30%). However, in a subgroup analysis, patients with an elevated C-reactive protein (CRP) level (>2.87 mg/L) demonstrated higher response and remission rates with natalizumab treatment than with placebo.⁶⁸ To test this observation, the similarly designed ENCORE trial was developed; in this trial, patients were required to have a CRP level >2.87 mg/L. The primary end point was the proportion of patients who achieved a clinical response, defined as a $70-point decrease in CDAI score, at Weeks 8 and 12. Unlike the ENACT 1 trial, the ENCORE study demonstrated a statistical difference in sustained clinical response at Weeks 8 through 12 among patients treated with natalizumab versus those treated with placebo (48% vs 32%; P<.001).⁶⁹ Patients from the ENACT 1 trial who achieved a response or had gone into remission were considered for the maintenance phase of the ENACT 2 trial. Patients were randomized to receive either natalizumab 300 mg via infusion or placebo every 4 weeks up to Week 56; patients were followed until Week 60. The primary end point was a loss of response, defined as an increase of $70 CDAI points and a total CDAI score of $220 or the need for medical or surgical intervention by Week 12. Loss of remission, defined as an increase in CDAI score to $150 points or the need for medical or surgical intervention by Week 12, was another study end point. At Week 36, 61% of patients who received natalizumab sustained response compared with 28% of patients in the placebo group (P<.001). A higher rate of sustained remission occurred among natalizumab-treated patients than among placebo-treated patients (44% vs 26%; P=.003).⁶⁸

Common adverse effects associated with natalizumab treatment include headache, fatigue, infusion-related reactions, arthralgia, urinary tract infections, and rash; in clinical trials, most of these reported adverse effects were mild in severity.²¹ Serious adverse events associated with natalizumab include hypersensitivity reactions, serious infections, and clinically significant hepatotoxicity.²¹

The labeling for natalizumab includes a boxed warning regarding progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection that affects the brain and can lead to death or severe disability.^21,71 Natalizumab, which was originally approved in November 2004 for the treatment of patients with relapsing forms of multiple sclerosis, was withdrawn from the market in February 2005 after 3 patients developed PML, including 1 patient with CD. Two of these cases resulted in death.⁷² As of June 2006, natalizumab was reintroduced to the market under a strict monitoring plan called the TOUCH Prescribing Program, which was designed to help ensure the safe use of the drug. All patients, prescribers, pharmacies, and infusion centers must be enrolled in the TOUCH Prescribing Program to learn about the risks associated with natalizumab therapy. Only healthcare providers, pharmacies, and infusion centers enrolled in the program may prescribe, distribute, or infuse natalizumab.

Healthcare providers must evaluate the patient's response after 3 months of natalizumab therapy, and the agent should be discontinued if there is no improvement. Patients who are taking corticosteroids should begin a corticosteroid taper during natalizumab treatment; natalizumab should be discontinued if corticosteroids cannot be fully tapered within 6 months.²¹ Natalizumab should not be used in combination with immunosuppressants or anti-TNF-alpha agents.²¹

CURRENT RECOMMENDATIONS FOR THE TREATMENT OF CD

The treatment recommendations for the management of CD are similar in the United States, Asia, and Europe.^{5,6,12–15,73} These guidelines have evolved over the years to include biologic agents. There is an ongoing debate as to whether a "step-down" or "step-up" approach should be used to manage treatment for patients with CD.⁶⁰ Step-down therapy uses biologic agents with or without immunosuppressive treatment as first-line regimens. In contrast, the traditional step-up approach calls for aminosalicylates as the initial treatment, followed by immunosuppressive agents and then by biologic agents.

The drug of choice for the treatment of CD is based on the severity and location of the disease, as many of the agents target specific parts of the GIT. (Editors' note: A treatment algorithm that guides the healthcare practitioner in determining which pharmacologic agents may be use to treat CD based on the patient's disease severity is available at http://www.formularyjournal.com/.)

Mild-to-moderate CD. Patients with mild-to-moderate CD are generally ambulatory patients who are able to tolerate a solid diet and experience only mild abdominal pain or cramps without flu-like symptoms or significant weight loss or dehydration. Treatment is usually based on the location of disease in the GIT. Disease in the ileal, ileocolonic, or colonic segment of the GIT should first be treated with an aminosalicylate agent.^5,6 Several mesalamine preparations are available; all have a similar side-effect profile.¹⁶ The main difference among agents lies in the site of action in the GIT.¹⁶ Budesonide may be recommended for patients with mild-to-moderate disease who have ileocecal and right-sided colonic GIT involvement.^{12–14,34,35} The use of antibiotics is still controversial for mild-to-moderate disease, as most of the published studies have not demonstrated that antibiotics are superior to aminosalicylate agents.^6,52,54,55 However, metronidazole and ciprofloxacin do have a role in treating fistula and abscesses associated with CD.^13,14,16,52

Moderate-to-severe CD. Patients who continue to have symptoms despite being treated with aminosalicylate agents or other agents used for mild-to-moderate disease are considered to have moderate-to-severe CD. These patients usually have significant weight loss, fever, and abdominal tenderness with or without cramping. It is not uncommon to observe laboratory abnormalities, including decreased hematocrit levels and elevated white blood cell counts, in these patients. Oral corticosteroid therapy equivalent to prednisone 40 to 60 mg/d is recommended for the treatment of moderate-to-severe CD; these doses are effective in inducing remission.^6,12,16 Corticosteroids should only be used on a short-term basis until symptoms have resolved. A gradual and slow taper is then recommended to prevent an immediate relapse of CD. Appropriate antibiotics may be needed if an active infection or abscess is present.^13,14,16,52 Biologic agents should be considered for patients who do not respond to corticosteroids or to traditional treatments.^5,12–15

Severe-to-fulminant CD. Patients who continue to have symptoms associated with CD despite the introduction of corticosteroids or who have significant weight loss, fever, and dehydration are considered to have severe-to-fulminant disease. These patients may also experience significant abdominal tenderness and cramping with or without intestinal obstruction. Hospitalization may be required so that IV corticosteroids and bowel rest may be initiated. Surgery may also be needed for patients with intestinal obstruction or an abscess that requires drainage.

Remission and maintenance. Patients who respond to traditional medical interventions or to surgery and are no longer exhibiting symptoms associated with CD are considered to be in remission. Aminosalicylates and immunosuppressive agents are commonly used to maintain remission.^5,6,12–15 Corticosteroids are not used for maintenance because of their poor side-effect profile. If treatment with conventional agents fails and patients cannot be weaned off corticosteroids, biologic agents are recommended.^5,12–15

CONCLUSION

CD is a common condition that may significantly affect a patient's quality of life. Evidence-based literature supports the use of aminosalicylates and immunosuppressive agents to maintain clinical remission and corticosteroids to induce a clinical response. However, patients who are corticosteroid dependent may benefit from treatment with a biologic agent. More research is needed to determine if the step-down approach is more effective than the traditional step-up method for treating CD. Clinicians now have several medical options to choose from and may have even more in the future as agents for the treatment of CD continue to be developed.

Dr Chan is the assistant director of Pharmacy Clinical Services and a clinical assistant professor, Department of Pharmacy Practice, College of Pharmacy and Department of Medicine, Sections of Digestive Diseases, Liver & Nutrition, University of Illinois at Chicago.

Disclosure Information: The author reports no financial disclosures as related to products discussed in this article.

REFERENCES

1. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–1517.

2. Ekbom A. The epidemiology of IBD: A lot of data but little knowledge. How shall we proceed? Inflamm Bowel Dis. 2004;10(suppl 1):S32–34.

3. Heresbach D, Alexandre JL, Bretagne JF, et al; ABERMAD. Crohn's disease in the over-60 age group: A population based study. Eur J Gastroenterol Hepatol. 2004;16:657–664.

4. Basu D, Lopez I, Kulkarni A, Sellin JH. Impact of race and ethnicity on inflammatory bowel disease. Am J Gastroenterol. 2005;100:2254–2261.

5. Hanauer SB, Sandborn W; Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults. Am J Gastroenterol. 2001;96:635–643.

6. Sandborn WJ, Feagan BG, Lichtenstein GR. Medical management of mild to moderate Crohn's disease: Evidence-based treatment algorithms for induction and maintenance of remission. Aliment Pharmacol Ther. 2007;26:987–1003.

7. Ephgrave K. Extra-intestinal manifestations of Crohn's disease. Surg Clin North Am. 2007;87: 673–680.

8. Baumgart DC , Carding SR. Inflammatory bowel disease: Cause and immunobiology. Lancet. 2007;369:1627–1640.

9. Best WR. Predicting the Crohn's disease activity index from the Harvey-Bradshaw Index. Inflamm Bowel Dis. 2006;12:304–310.

10. Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease. Gastroenterology. 2002;122:512–530.

11. Cobrin GM, Abreu MT. Defects in mucosal immunity leading to Crohn's disease. Immunol Rev. 2005;206:277–295.

12. Lichtenstein GR, Abreu MT, Cohen R, Tremaine W; American Gastroenterological Association. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006; 130:940–987.

13. Travis SP, Stange EF, Lemann M, et al; European Crohn's and Colitis Organisation. European evidence based consensus on the diagnosis and management of Crohn's disease: Current management. Gut. 2006;55(suppl 1):i16–35.

14. Kuhbacher T, Folsch UR . Practical guidelines for the treatment of inflammatory bowel disease. World J Gastroenterol. 2007;13:1149–1155.

15. Ouyang Q, Tandon R, Goh KL, et al. Management consensus of inflammatory bowel disease for the Asia-Pacific region. J Gastroenterol Hepatol. 2006;21:1772–1782.

16. Tamboli CP. Current medical therapy for chronic inflammatory bowel diseases. Surg Clin North Am. 2007;87:697–725.

17. Red Book. 2007 edition. Montvale , NJ : Thompson PDR; 2007.

18. Entocort [package insert]. Wilmington , DE : AstraZeneca; 2005.

19. Remicade [package insert]. Malvern , PA : Centocor Inc; 2007.

20. Humira [package insert]. North Chicago , IL : Abbott Laboratories; 2008.

21. Tysabri [package insert]. Cambridge , MA : Biogen Idec Inc; 2008.

22. Bergman R, Parkes M. Systematic review: The use of mesalazine in inflammatory bowel disease. Aliment Pharmacol Ther. 2006;23:841–855.

23. Tremaine WJ, Schroeder KW, Harrison JM, Zinsmeister AR. A randomized, double-blind, placebo-controlled trial of the oral mesalamine (5-ASA) preparation, Asacol, in the treatment of symptomatic Crohn's colitis and ileocolitis. J Clin Gastroenterol. 1994;19:278–282.

24. Rasmussen SN, Lauritsen K, Tage-Jensen U, et al. 5-Aminosalicylic acid in the treatment of Crohn's disease. A 16-week double-blind, placebo-controlled, multicentre study with Pentasa. Scand J Gastroenterol. 1987;22:877–883.

25. Qasim A, Seery J, O'Morain CA. 5-Aminosalicylates in inflammatory bowel disease: Choosing the right dose. Dig Liver Dis. 2001;33:393–398.

26. Singleton JW, Hanauer SB, Gitnick GL, et al. Mesalamine capsules for the treatment of active Crohn's disease: Results of a 16-week trial. Pentasa Crohn's Disease Study Group. Gastroenterology. 1993;104:1293–1301.

27. Singleton J. Second trial of mesalamine therapy in the treatment of active Crohn's disease. Gastroenterology. 1994;107:632–633.

28. Akobeng AK , Gardener E. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's disease. Cochrane Database Syst Rev. 2005;(1):CD003715.

29. Camma C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn's disease: A meta-analysis adjusted for confounding variables. Gastroenterology. 1997;113:1465–1473.

30. Summers RW, Switz DM, Sessions JT Jr, et al. National Cooperative Crohn's Disease Study: Results of drug treatment. Gastroenterology. 1979;77:847–869.

31. Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn's disease. Gut. 1994;35:360–362.

32. Faubion WA Jr, Loftus EV Jr, Harmsen WS, Zinsmeister AR , Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: A population-based study. Gastroenterology. 2001;121:255–260.

33. Steinhart AH, Ewe K, Griffiths AM, Modigliani R, Thomsen OO. Corticosteroids for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2003;(4):CD000301.

34. Greenberg GR, Feagan BG, Martin F, et al. Oral budesonide for active Crohn's disease. Canadian Inflammatory Bowel Disease Study Group. N Engl J Med. 1994;331:836–841.

35. Rutgeerts P, Löfberg R, Malchow H, et al. A comparison of budesonide with prednisolone for active Crohn's disease. N Engl J Med. 1994;331:842–845.

36. Thomsen OO, Cortot A, Jewell D, et al. A comparison of budesonide and mesalamine for active Crohn's disease [erratum in N Engl J Med. 2001;345;1652]. N Engl J Med. 1998;339:370–374.

37. Otley A, Steinhart AH. Budesonide for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2005;(4):CD000296.

38. Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R. A controlled double blind study of azathioprine in the management of Crohn's disease. Gut. 1995;37:674–678.

39. Pearson DC , May GR, Fick G, Sutherland LR. Azathioprine for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 1998;(4):CD000067.

40. Sandborn W, Sutherland L, PearsonD, May G, Modigliani R, Prantera C. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 1998;(3):CD000545.

41. Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med. 1980;302:981–987.

42. Siegel CA , Sands BE. Review article: Practical management of inflammatory bowel disease patients taking immunomodulators. Aliment Pharmacol Ther. 2005;22:1–16.

43. Aberra FN, Lichtenstein GR. Review article: Monitoring of immunomodulators in inflammatory bowel disease. Aliment Pharmacol Ther. 2005;21:307–319.

44. Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. N Engl J Med. 1995; 332:292–297.

45. Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators. N Engl J Med. 2000;342:1627–1632.

46. Ng SC , Arebi N, Kamm MA. Medium-term results of oral tacrolimus treatment in refractory inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:129–134.

47. Ierardi E, Principi M, Francavilla R, et al. Oral tacrolimus long-term therapy in patients with Crohn's disease and steroid resistance. Aliment Pharmacol Ther. 2001;15:371–377.

48. Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease-a long-term follow-up. Am J Gastroenterol. 2006;101:1048–1056.

49. Gonzalez-Lama Y, Gisbert JP, Mate J. The role of tacrolimus in inflammatory bowel disease: A systematic review. Dig Dis Sci. 2006; 51:1833–1840.

50. McDonald JW, Feagan BG, Jewell D, Brynskov J, Stange EF, MacDonald JK. Cyclosporine for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2005;(2):CD000297.

51. Brynskov J, Freund L, NØrby Rasmussen S, et al. Final report on a placebo-controlled, double-blind, randomized, multicentre trial of cyclosporin treatment in active chronic Crohn's disease. Scand J Gastroenterol. 1991;26:689–695.

52. Perencevich M, Burakoff R. Use of antibiotics in the treatment of inflammatory bowel disease. Inflamm Bowel Dis. 2006;12:651–664.

53. Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008;134: 577–594.

54. Sutherland L, Singleton J, Sessions J, et al. Double blind, placebo controlled trial of metronidazole in Crohn's disease. Gut. 1991;32:1071–1075.

55. Colombel JF, Lemann M, Cassagnou M, et al. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn's disease. Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID). Am J Gastroenterol. 1999;94:674–678.

56. Rahimi R, Nikfar S, Rezaie A, Abdollahi M. A meta-analysis of broad-spectrum antibiotic therapy in patients with active Crohn's disease. Clin Ther. 2006;28:1983–1988.

57. Wild GE. The role of antibiotics in the management of Crohn's disease. Inflamm Bowel Dis. 2004; 10:321–323.

58. Shafran I, Johnson LK. An open-label evaluation of rifaximin in the treatment of active Crohn's disease. Curr Med Res Opin. 2005;21:1165–1169.

59. Prantera C, Lochs H, Campieri M, et al. Antibiotic treatment of Crohn's disease: Results of a multicentre, double blind, randomized, placebo-controlled trial with rifaximin. Aliment Pharmacol Ther. 2006;23:1117–1125.

60. Löwenberg M, Peppelenbosch M, Hommes D. Biological therapy in the management of recent-onset Crohn's disease: Why, when and how? Drugs. 2006;66:1431–1439.

61. Kamm MA. Review article: Biological drugs in Crohn's disease. Aliment Pharmacol Ther. 2006;24(suppl 3):80–89.

62. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med. 1997;337:1029–1035.

63. Hanauer SB, Feagan BG, Lichtenstein GR, et al; ACCENT I Study Group. Maintenance infliximab for Crohn's disease: The ACCENT I randomised trial. Lancet. 2002;359:1541–1549.

64. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clin Gastroenterol Hepatol. 2004;2:542–553.

65. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: The CLASSIC-I trial. Gastroenterology. 2006;130:323–333.

66. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: The CHARM trial. Gastroenterology. 2007;132:52–65.

67. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: A randomized trial. Ann Intern Med. 2007;146:829–838.

68. Sandborn WJ, Colombel JF, Enns R, et al; International Efficacy of Natalizumab as Active Crohn's Therapy (ENACT-1) Trial Group; Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med. 2005;353:1912–1925.

69. Targan SR, Feagan BG, Fedorak RN, et al; International Efficacy of Natalizumab in Crohn's Disease Response and Remission (ENCORE) Trial Group. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial. Gastroenterology. 2007;132:1672–1683.

70. von Andrian UH, Engelhardt B. Alpha4 integrins as therapeutic targets in autoimmune disease. N Engl J Med. 2003;348:68–72.

71. FDA approves Tysabri to treat moderate-to-severe Crohn's disease. Drug currently approved for use in treating some forms of multiple sclerosis. FDA website. http://www.fda.gov/bbs/topics/news/2008/new01775.html. Accessed March 3, 2008.

72. FDA approves resumed marketing of Tysabri under a special distribution program. http://www.fda.gov/bbs/topics/news/2006/new01380.html. Accessed March 3, 2008.

73. Chinese Cooperative Group For The Study On IBD; Chinese Society Of Gastroenterology. Consensus on the management of inflammatory bowel disease in China in 2007. J Dig Dis. 2008;9:52-62.