Update on the Management of Crohn’s Disease
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- Buchner, A.M., Blonski, W. & Lichtenstein, G.R. Curr Gastroenterol Rep (2011) 13: 465. doi:10.1007/s11894-011-0220-x
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Crohn’s disease (CD) is a chronic inflammatory disorder characterized by focal, asymmetric, transmural inflammation of any part of the luminal gastrointestinal tract of uncertain etiology and an unpredictable course. The available treatment options include aminosalicylates, budesonide and systemic corticosteroids, antibiotics, immunomodulators,methotrexate and anti-TNF agents. This review discusses recent developments in the treatment of CD and provides a comprehensive update on management of patients with CD based on the data from randomized controlled trials. Pique
Key wordsCrohn’s diseaseMesalamineCorticosteroidsBudesonideAzathioprine6-mercaptopurineAnti-TNF antibodiesInfliximabAdalimumabCertolizumab pegolNatalizumab
Crohn’s disease (CD) is a chronic inflammatory disorder characterized by focal, asymmetric, transmural inflammation of any part of the luminal gastrointestinal tract of uncertain etiology and an unpredictable course. The prevalence and incidence of CD in the United States is estimated to be 50 per 100,000 and 5 per 100,000 annually, respectively . The appropriate treatment regimen for a patient with CD is based on disease activity, disease distribution, and phenotypic behavior, taking into account the balance between medications and their potential adverse effects and prevention of disease-related complications. Since the etiology of CD remains undefined, the treatment remains empirical and not curative. Our present ability to predict the future disease course in patients with CD is not well defined. A large cohort study from Scandinavia  demonstrated that among all patients treated with 5-ASA agents and corticosteroids, 13% of patients will achieve complete remission, 20% of patients will experience annual relapse and 67% will have a combination of relapse and remission within the first 8 years after initial diagnosis. Fewer than 5% of patients will have a continuous course of active disease.
The 5-ASA agents are used frequently to manage mild to moderately active CD, exerting their therapeutic effect within the lumen of the intestine . There are various oral formulations of 5-ASA agents that have been introduced to allow the release of their specific moiety in different location of the GI tract, depending on disease location. These include slow release formulations (coated with ethylcellulose), pH-dependent delayed release formulations and azo-bound prodrugs, such as olsalazine and balsalazide [4, 5]. Until recently, mesalamine was considered to be effective treatment of active CD [6–8]. However, subsequent randomized double blind, placebo controlled multicenter studies did not demonstrate any advantage of using 5-ASA over placebo in maintaining medically induced remission in patients with CD or any significant risk reductions in CD relapses [9–17]. The pooled risk difference between 5-ASA and controls was −4.7% (95% CI:−9.6–2.8) . The most recent Cochrane systematic review of all available 19 trials evaluating the efficacy of 5-ASA for the treatment of mildly to moderately active CD concluded that sulfasalazine had modest efficacy compared to placebo in the treatment of mild to moderate active CD . Furthermore olsalazine and low dose and high dose mesalamine were not found to be more effective than placebo . These results were confirmed in the most recent systematic review and meta-analysis of efficacy of 5-ASA in CD. In this review there was trend toward a benefit with sulfasalazine over placebo (two RCTs, RR of failure to achieve remission = 0.83; 95% CI 0.77–1.06) but no definite benefit of mesalamine over placebo (four RTCs, RR = 0.91; 95% CI = 0.77–1.06) [20••]. Furthermore, neither sulfasalazine nor mesalamine were effective at preventing quiescent CD relapse in the intention to treat analysis, though a per protocol analysis showed that mesalamine appeared to reduce the risk of relapse (R = 0.79; 95% CI = 0.66–0.95, number needed to treat [NNT] = 13) [20••]. In the most recent systematic review of nine randomized controlled trials analyzing the role of 5-ASA for maintenance of surgically induced remission in CD, pooled analyses suggested that 5-ASA agents may be superior to placebo, though the results should be interpreted cautiously as adequately powered studies did not confirm these observations and publication bias with the lack of published, negative studies may be playing a role [21••].
Budesonide and Systemic Corticosteroids
Controlled-release oral budesonide is recommended for the management of mild to moderately active ileocecal CD as one of the first line treatment options [22, 23]. It is known to have a reduced risk of systemic corticosteroid related complications in view of its high topical activity and low-systemic bioavailability (10%). A Cochrane systemic review of randomized trials evaluating the efficacy of budesonide at a dose of 9 mg daily demonstrated budesonide to be more effective than placebo (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 moderately active ileocecal CD after 8 weeks of treatment . In addition, budesonide was inferior to conventional corticosteroids in inducing remission of CD (RR 0.85, 95% CI 0.75–0.97) . On the other hand, a safety analysis of six trials revealed that budesonide was associated with a significant reduction in adverse events related to corticosteroid use with a relative risk of 0.64 (95% CI 0.54–0.76) .
Recently, a predetermined pooled analysis of four randomized, placebo controlled trials assessing the efficacy of budesonide in maintaining remission of CD revealed that budesonide at a daily dose of 6 mg was effective only in maintaining remission for up to 9 months and did not prevent relapse over 9 months, whereas budesonide administered at a lower daily dose of 3 mg was not superior to placebo at any time of study period . In addition, a Cochrane meta-analysis of eight randomized, placebo controlled trials confirmed that budesonide administered at a 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) . On the other hand, a lower maintenance dose of budesonide (3 mg daily) was demonstrated 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 . Furthermore, budesonide was shown to have fewer corticosteroid-associated side effects and less suppression of the pituitary-adrenal function compared to prednisolone . Despite these results, budesonide has a limited role in the treatment of active CD. It is not effective in approximately 20% of patients with active CD (in particular, patients with extensive disease who do not have ileocecal involvement or those with left-sided colitis) . There is also no supportive evidence for the use of budesonide in fistulizing disease since all patients with fistulas were excluded from entering the budesonide efficacy trials. A comparison between budesonide 9 mg daily and weaning doses of prednisolone 40 mg daily in maintaining remission of CD by Schoon et al.  showed no superiority of budesonide over traditional corticosteroids at 3 months (RR 0.81, 95% CI 0.60–1.0), 6 (RR 0.79, 95% CI 0.56–1.12) or 12 months (RR 0.79, 95% CI 0.55–1.13) of treatment. Therefore, in light of the most recent data, budesonide is not recommended as a maintenance treatment of CD.
Systemic corticosteroids, considered to be a second line therapy, 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 first line therapy. A population-based inception cohort study confirmed that among patients with CD who received corticosteroids, 84% had either complete or partial response while 16% did not respond to treatment over the first 30 days . However, within 1 year of initial use of corticosteroids, 28% of patients with CD became corticosteroid-dependent, and 38% underwent surgery . Studies evaluating the optimal corticosteroid dosage or dose schedules for CD are lacking. However, it has been shown that approximately 50% to 70% of patients achieve clinical remission over 8–17 weeks with a dosage equivalent of prednisone 40 mg daily [29–31]. In addition, data from several clinical trials [6, 29] have clearly demonstrated that systemic corticosteroids in low doses are not effective in maintaining remission of CD. The most recent systemic review and meta-analysis of glucorticosteroid therapy in inflammatory bowel disease that included trials of standard glucocorticosteroids in CD remission reported a statistically significant effect, but because of heterogeneity between studies, the overall effect was not significant (RR = 0.46; 95% CI 0.17–1.28)  . Standard gluocorticosteroids were superior to budesonide for CD remission (RR = 0.82; 95% CI 0.68–0.98),but glucocorticosteroid related adverse events were more frequent (RR = 1.64; 95% CI 1.43–2.00) .
High dose corticosteroids have not been evaluated as a potential maintenance treatment due to the increased risk of significant side effects and long term use of systemic corticosteroids is not recommended for the same reason.
The rationale for the use of antibiotics in CD is based on the hypotheses that the etiology of CD may be related to unidentified bacterial pathogens and that the bacterial flora of the intestinal lumen may play a role in the development of inflammation [33–35]. This is supported by experimental models of colitis in animal models, confirming that bowel inflammation does not occur without gut bacteria . The most frequently used antibiotics in CD are metronidazole and ciprofloxacin, either as monotherapy or combination therapy. Several trials have evaluated the use of various antibiotics as an induction treatment of active CD. A meta-analysis of six randomized, double blind placebo controlled trials determined that treatment with broad-spectrum antibiotics (metronidazole, ciprofloxacin or cotrimoxazole) was more than twice as effective as placebo at inducing clinical improvement defined as either response, remission, or improvement in clinical and/or laboratory findings in 804 patients with active CD (OR = 2.257, 95% CI 1.678–3.036, P < 0.001) . It has to be noted however, that many of the trials that were included in the meta-analysis enrolled patients receiving concomitant treatment with sulfasalazine, newer 5-ASA agents, prednisone, budesonide, AZA/6-MP, methotrexate (MTX), or infliximab.
There were two randomized, placebo controlled trials that suggested a benefit of metronidazole or ornidazole in maintaining surgically induced remission (ileal or ileocolonic resection) of CD [38, 39]. Treatment with metronidazole for 3 months resulted in significant reduction in severe endoscopic recurrence upon conclusion of treatment (13% vs. 43%, P = 0.02) and significant reduction in clinical recurrence after 1 year of follow-up (4% vs. 25%, P = 0.044) but not after 2 and 3 years of follow-up when compared to placebo . Continuous treatment with ornidazole for a period of 1 year caused significant reduction in clinical (7.9% vs. 37.5%, P = 0.046) and endoscopic (53.6% vs. 79%, P = 0.037) recurrence upon conclusion of treatment when compared to placebo . However, the development of side effects, in particular paresthesias and polyneuropathy, is a significant limitation for the application of these drugs in clinical practice [38, 39].
The most recent systemic review and meta-analysis assessing antibiotic therapy in inflammatory bowel disease (IBD) found that, for active CD management, there were 10 RCTs involving 1,160 patients . A statistically significant benefit of antibiotics compared to placebo (RR of active CD not in remission = 0.85; 95% CI = 0.73–0.99, P = 0.03) was reported . There was moderate heterogeneity between studies (I2 = 48%) and a diverse number of antibiotics were tested (anti-tuberculosis therapy, macrolides, fluroquinolones, 5-nitroimidazoles, and rifaximin) either alone or in combination. Rifamycin derivatives, either alone or in combination with other antibiotics, appeared to have a significant effect at inducing remission in active CD . In perianal CD with fistulas, there were three trials evaluating 123 patients using either ciprofloxacin or metronidazole . There was again a statistically significant effect in reducing fistula drainage (RR = 0.8; 95% CI = 0.66–0.98) with no heterogeneity (I2 = 0%) and a number needed to treat of 5 (95% CI = 3–20) .
Mycobacterium avium and Mycobactrium paratuberculosis infections have been speculated to be associated with the presence of CD, but data from seven randomized placebo controlled trials including 355 patients with CD noted no beneficial effect of anti-tuberculous therapy in maintaining remission of CD with the pooled OR of 1.36 (95% CI 0.87–2.13) and NNT of 15 . Therefore, based on current evidence, we do not advocate for the use of antituberculous agents in CD.
The immunomodulators such as azathioprine (AZA) and 6-mercaptopurine (6-MP) have been demonstrated to be effective at maintaining clinical remission after corticosteroid-inductive therapy or surgery  and in assisting corticosteroid dosage reduction. The corticosteroid-sparing effect was observed among 30 patients treated with AZA when compared to placebo with a pooled OR of 5.22 (95% CI 1.06–25.68) and NNT of 3 . Based on a meta-analysis of four controlled trials, AZA/6-MP was found to be significantly more effective than placebo at 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 . In addition, when compared to placebo, AZA/6MP displayed an overall preventive effect on severe endoscopic recurrence with a mean difference of 15% one year post surgery (P = 0.026) . Conversely, the most recent systematic review and meta-analysis on the efficacy of immunosuppressive therapy for IBD assessed five trials of AZA/6-MP with 390 active CD patients and two trials with 198 inactive CD patients and found no significant effect of therapy in inducing (RR = 0.87; 95% CI 0.71–1.06) and maintaining remission (RR = 0.64; 95% CI0.34–1.23) when compared to placebo [44••]. The downside of immunomodulators therapy is an increased rate of adverse events compared to placebo recipients, leading to withdrawal of the drug (17.2% vs. 9.8%, P = 0.021) .
The rare but serious side effects [45–47] of long term immunomodulator therapy include the development of non-Hodgkins lymphoma [48–50] and hepatosplenic T-cell lymphoma (HSTCL) [50–54, 55••]. In our recent study  analyzing all three available population based studies, the overall incidence of HSTCL was 1.32 cases per 100,000 person-years with a number needed to harm (NNH) of 1:75,488 patients per year.
The slow onset of action of 3–6 months precludes the use of immunomodulators as induction agents. The genetic coding for thiopurine methyltransferase (TPMT) can now be identified prior to the use of 6-MP or AZ and the measurement of TPMT enzyme activity is currently recommended prior to the use of 6-MP or AZA. This leads to a more tailored use of the drug and decreased toxicity in 0.3–11% of the population with TPMT genetic mutations [57, 58] Despite the low risk of lymphoma, investigators have claimed that the benefits of maintenance therapy with AZA outweigh the risks . However, more evidence is needed to better define the optimal duration of therapy, which will maximize the duration of clinical remission while minimizing the risks of developing potential lethal complications.
Methotrexate is a folic acid antagonist that inhibits purine synthesis, DNA and RNA formation, and eventually inhibits of the S phase of the cell cycle. The actual cell targets of methotrexate involved in the suppression of inflammation in chronic inflammatory conditions are not known. It has been speculated that methotrexate may have targets within intestine epithelial cells, lamina propria cells, intraepithelial lymphocytes, leukocytes, and monocytes-macrophages.
A Cochrane meta-analysis of five randomized, controlled trials assessing the role of methotrexate in induction of remission of corticosteroid dependent CD determined that methotrexate given subcutaneously at the weekly dose of 25 mg was significantly superior to placebo (failure to induce remission: OR = 0.40, 95%CI 0.19–0.84, NNT = 5) . Another recent Cochrane meta-analysis of 3 randomized controlled trials confirmed that low dose methotrexate (15 mg/week) administered intramuscularly is threefold more effective than placebo in maintaining remission of CD [OR =3.11; 95% CI 1.31–7.41; P = 0.01] with a NNT of 4 to prevent relapse .
Management of CD with methotrexate at higher dose has been associated with development of adverse events such as myelosuppression or hepatotoxicity. The risk of withdrawal of methotrexate (25 mg/week) due to adverse events was found to be fourfold greater than the risk of withdrawal with placebo (OR = 4.03, 95% CI 1.38–11.78) . Folate supplementation is suggested in order to lessen the possibility of methotrexate-induced toxicity [62, 63]. It has been also recommended that liver biopsy should be performed in patients treated with methotrexate who have elevated values of aspartate aminotransferase or with decreased serum albumin levels despite reduction in methotrexate . Discontinuation of methotrexate is recommended if liver biopsy confirms moderate-to-severe fibrosis or cirrhosis .
Anti–Tumor Necrosis Factor Antibodies (Infliximab, Adalimumab, Certoliuzmab Pegol)
The proinflammatory cytokine tumor necrosis factor (TNF) has been demonstrated to play a role in the inflammatory cascade in patients with CD. Anti-TNF antibodies neutralize this cytokine and thus interrupt the proinflammatory cascade. The three anti-TNF agents that have been approved by the US FDA for the induction and maintenance therapy of CD are infliximab, adalimumab, and certolizumab pegol. Infliximab is recommended for induction and maintenance treatment in patients with moderate to severe active luminal CD who are not responsive or tolerant to conventional therapy and for patients with fistulizing CD. Adalimumab is recommended in patients with moderate to severe active luminal CD who do not respond to conventional therapy or who are either intolerant to or have lost a response to infliximab. Certolizumab pegol is indicated in patients with moderate to severe luminal CD who are not responsive to conventional therapy. While infliximab is administered as an intravenous infusion (5 mg/kg at week 0,2 and 6 followed by every 8 week maintenance schedule ), both adalimumab and certolizumab pegol are administered as subcutaneous injections. Treatment with adalimumab consists of initial injection of 160 mg followed by an 80 mg dose given two weeks later with initiation of maintenance treatment after 2 weeks at dose 40 mg every 2 weeks . Medical management with certolizumab pegol is initiated with a subcutaneous injection of 400 mg at weeks 0, 2 and 4 followed by maintenance treatment every 4 weeks .
Based on a recent meta-analysis of fourteen randomized placebo controlled trials including 3995 patients with luminal CD, anti-TNF antibodies were determined to be significantly more effective than placebo at inducing remission at 4 weeks with a total mean difference in effect between anti-TNF agents and placebo of 11% (95% CI 6%–16%, P < 0.001) . Among patients who responded to an open-label induction with either infliximab, adalimumab, or certolizumab followed by randomized, placebo controlled maintenance treatment, anti-TNF agents were significantly superior to placebo in maintaining remission at weeks 20 through 30 with a total mean difference in effect between active and placebo arms of 23% (95% CI 18%–28%, P < 0.001) . Among patients who were randomized before induction treatment, certolizumab and CDP571 were confirmed to be superior to placebo for maintaining remission at weeks 20 through 30 with a total mean difference between arms of 8% (95% CI 3%–12%, P < 0.001) . Infliximab and adalimumab were determined to be significantly superior to placebo in maintenance of corticosteroid-free remission at weeks 48 through 52 with respective mean differences of 10% (95% CI 4%–16%) and 20% (95% CI 14%–26%) based on the analysis of two randomized trials .
Based on the pooled data from ten trials of 776 patients with fistulizing CD, maintenance treatment with anti-TNF agents was determined to be effective only following an open-label induction treatment with these agents with a total mean difference of 16% [95% CI 8%–25%, P < 0.001] over placebo . The investigators concluded that existing data support only the use of infliximab in fistulizing CD with a number needed to treat of 3–7, whereas the efficacy of adalimumab and certolizumab pegol in this form of CD should be further investigated due to limited data .
A Cochrane meta-analysis of trials assessing maintenance treatment of CD with anti-TNF agents determined that infliximab was twofold more effective than placebo at maintaining clinical remission (RR = 2.50; 95% CI 1.64–3.80), clinical response (RR = 1.66; 95% CI 1.00–2.76) and healing of enteric fistulas (RR = 1.87; 95%CI 1.15–3.04) and threefold more effective than placebo in maintaining corticosteroid-free remission (RR = 3.13; 95%CI 1.25–7.81) . Its effect was not observed to be dose dependent . It was also noted that adalimumab and certolizumab pegol were significantly more effective than placebo as maintenance therapies, though there were not enough studies to perform pooled analyses . Among patients who responded to induction treatment with certolizumab pegol, these agents were nearly twofold more effective than placebo at maintaining clinical remission, with respective relative risks of 1.68 (95% CI 1.30–2.16) and 1.74 (95% CI 1.41–2.13) .
In a recent meta-analysis of 21 anti-TNF antibody trials with a total 5356 patients, there was no increased risk of death (total mean difference 0.04%, 95% CI −0.2%–0.3%, P = 0.74), malignancy (mean difference −0.14%, 95% CI −0.4%–0.2%, P = 0.39) or serious infections (mean difference 0.1%, 95% CI −0.4%–0.6%, P = 0.72) between the active and placebo arms  of these trials.
A recent randomized trial compared the efficacy of monotherapy with infliximab, AZA and combination therapy with both agents in patients with moderate to severe CD (SONIC: The Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease) [70••]. The study confirmed that patients receiving combination therapy had the greatest corticosteroid-free clinical remission (56.8% vs. 44.4% vs. 30%) and mucosal healing rates (43.9% vs. 30.1% vs. 16.5%) at week 26 when compared with infliximab and AZA monotherapy [70••]. Combination therapy was significantly more effective than infliximab monotherapy (P = 0.02) and AZA monotherapy (P < 0.001) in maintaining corticosteroid-free clinical remission at week 26 [70••]. Likewise, combination therapy was superior to either infliximab (P = 0.006) or AZA monotherapy (P < 0.001) in mucosal healing at week 26 [70••]. Although infliximab monotherapy was inferior to combination therapy, it was still superior to AZA monotherapy in corticosteroid-free remission (P = 0.006) and mucosal healing (P = 0.02) at week 26 [70••]. Safety analysis conducted through week 50 did not reveal any difference in the incidence of adverse events between treatment arms with the exception of a significantly higher incidence of infusion reactions among patients receiving infliximab monotherapy (16.6%) compared to AZA monotherapy (5.6%, P = 0.002) and combination therapy (5%, P < 0.001) [70••]. The development of antibodies to infliximab was observed in 14.6% of patients in infliximab only arm and 0.9% of those in combination arm [70••]. Another recent review identified 36 patients identified with HSTCL among patients with IBD who were treated with either a combination of infliximab and thiopurine (n = 20) or thiopurine alone (n = 16) [55••]. In view of these observations it has been suggested that caution be used when considering thiopurine treatment in patients with IBD, particularly in men younger than 35 years of age as the majority of reported cases of HSTCL occurred in such patients [55••].
Selective Adhesion Molecule Inhibitors (Natalizumab)
Natalizumab, a humanized monoclonal antibody against the α-4 subunit of integrin molecule, belongs to a new class of biologic agents, the selective adhesion molecule inhibitors . This agent is indicated in the medical management of patients with active moderately to severe CD who do not respond to or tolerate conventional treatment with anti-TNF antibodies . Natalizumab is administered as intravenous infusion over a 1 hour interval at the dose of 300 mg every 4 weeks . It should be administered as monotherapy due to previous reports of the development of progressive multifocal leukoencephalopathy (PML) in patients treated with combination therapy with natalizumab and either interferon β-1a or AZA . Natalizumab may be only prescribed to patients enrolled in a TOUCH prescribing program due to a risk of the rare but serious complication of PML [73, 74].
A Cochrane meta-analysis determined that short-term (1 infusion) and longer-term (2 or 3 infusions) treatment with natalizumab had significant advantage over placebo in inducing clinical response and remission in some patients with moderate to severe CD . Due to the limited number of trials, pooled odds ratios for failure to achieve clinical response or remission were not assessed . The incidence of adverse events was similar in natalizumab and placebo arms and occurred in 7% to 11% of patients .
Natalizumab was determined to be more effective than placebo as a maintenance treatment administered to patients who responded to induction treatment with either natalizumab or placebo with sustained response (61% vs. 28%, P < 0.001) and remission (44% vs. 26%, P = 0.003) rates at week 36 .
It has been advocated that before initiation of treatment with this agent, a benefit/risk assessment should be carefully evaluated. It has also been suggested that the level of JC virus in plasma should be measured and subsequent reduction or discontinuation of natalizumab in the event of the detection of this virus might be a preventive measure against the development of PML [75, 77, 78].
Recent data suggest that early initiation of combined treatment with immunomodulators and infliximab is more effective than conventional management with corticosteroids followed by AZA and then infliximab [80••]. Data from the SONIC trial support the rationale for using infliximab or infliximab combined with AZA as an effective maintenance treatment allowing for corticosteroid sparing in immunomodulator naïve patients [70••]. Therefore, inversion of the treatment pyramid (Fig. 1) can represent an effective approach in patients with more severe CD or those who have a high likelihood of having an aggressive course of disease. This approach holds promise for outcomes with fewer strictures, fistulas, complications, surgeries, and hospitalizations. However, identification of the right timing and suitable patients with the right genetic, phenotypic and environmental factors along with more data on the safety and long term benefits of biologics are essential prior to the routine application of the “top-down” strategy.
Gary R. Lichtenstein has worked as a consultant for Abbott Corporation; Alaven; Bristol-Myers Squibb; Centocor Orthobiotech; Elan; Ferring; Meda Pharmaceuticals; Millenium Pharmaceuticals; Pfizer Pharmaceuticals; Proctor and Gamble; Prometheus Laboratories, Inc.; Salix Pharmaceuticals; Santarus; Schering-Plough Corporation; Shire Pharmaceuticals; Warner Chilcotte; UCB; and Wyeth. Anna M. Buchner and Wojciech Blonski reported no potential conflicts of interest relevant to this article.