Crohn's disease is an idiopathic, chronic inflammatory disorder of the digestive tract with heterogeneous clinical presentations. Crohn's is currently not a curable disease, and patients are faced with a lifetime of recurrent disease flare-ups and remissions. Management strategies for Crohn's must therefore be targeted toward lifelong management, taking into consideration not only the short-term but also the long-term aspects of the disease. With this in mind, here we review the classifications and natural history of Crohn's disease and discuss possible predictive factors for the disease evolution in a patient. Here we also evaluate the current preferable treatment practices, based on scientifically valid research and collective clinical experience, for the management of mild to moderate Crohn's disease.
Patients with ulcerative colitis (UC) who achieve remission with corticosteroids often relapse after tapering or discontinuation; alternative treatments limiting steroid exposure and UC relapse would be beneficial. It remains uncertain whether patients with corticosteroid-induced remission experience benefit with mesalamine granules (MG), a locally acting aminosalicylate extended-release capsule formulation for maintenance of UC remission in adults. Efficacy and safety of MG 1.5 g once daily was evaluated in patients with UC in corticosteroid-induced remission. Data from patients with previous corticosteroid use to achieve baseline UC remission were analyzed from two 6-month randomized, double-blind, placebo-controlled trials and a 24-month open-label extension (OLE). Six-month relapse-free rates were assessed using the revised Sutherland Disease Activity Index. UC-related adverse events (AEs) were recorded during the 30 months. Included were 158 steroid-treated patients in UC remission (MG, n = 105; placebo, n = 53) and 74/105 MG-treated patients who continued MG in the OLE. A significantly larger percentage of patients remained relapse-free at 6 months with MG (77.1 %) versus placebo (54.7 %; P = 0.006), with a 55 % reduction in relapse risk (hazard ratio [HR] 0.45; 95 % CI 0.25–0.79). There was a similar (49.2 %) reduction in risk of UC-related AEs at 6 months (HR 0.51; 95 % CI 0.31–0.84; P = 0.009) that was sustained during the OLE. MG 1.5 g once daily administered for maintenance of corticosteroid-induced remission was associated with low risk of relapse and UC-related AEs. NCT00744016, NCT00767728, and NCT00326209.
Many patients with ulcerative colitis (UC) respond to mesalamine therapy within 8 weeks. Those not achieving remission after 8 weeks are often treated with steroids or other immunosuppressive therapies. This study aimed to determine the effect of 8 weeks' high-dose MMX mesalamine extension therapy in patients with active, mild-to-moderate UC who had previously failed to achieve complete remission in 2 phase III, double-blind, placebo-controlled studies of MMX mesalamine (SPD476-301 and -302).Patients with active, mild-to-moderate UC who did not achieve clinical and endoscopic remission after or=1 point reduction from baseline in sigmoidoscopy score.Overall, 304 patients who entered this acute extension study were evaluated; 59.5% achieved remission at week 8. Remission rates were similar irrespective of prior treatment in the initial acute phase III studies.Most patients with mild-to-moderate UC who fail to achieve remission with up to 8 weeks' initial mesalamine therapy can achieve clinical and endoscopic remission following a further 8 weeks' treatment with high-dose MMX mesalamine therapy, thereby avoiding step-up therapy.
DOP075 -Table 1 Variable/unit/population Anti-TNF naive Anti-TNF non-responder PBO=16 FIL=57 PBO=28 FIL=71 Clinical remission (CDAI<150), %, ITT-NRI 13 60 29 37 100-points clinical response (CDAI improvement with ≥100 points), %, ITT-NRI 44 67 39 54 PRO2 score, mean change from baseline, ITT-LOCF (7×(mean daily number of liquid or very soft stools + 7×(mean daily abdominal pain score)) -19.8 -24.8 -13.2 -19.5 PRO2 remission (PRO2 ≤28), %, ITT-NRI 31 61 29 41 CDAI general well-being score, mean change from baseline, ITT-LOCF -0.78 -1.08 -0.58 -0.90Total IBDQ score, mean change from baseline, ITT-LOCF 19.7 40.8 16.3 28.2 Overall total histopathology score, mean change from baseline, ITT-LOCF -0.3 -3.9 -0.7 -3.2 Anti-TNF naive Anti-TNF non-responder PBO=9 FIL=39 PBO=18 FIL=54 Combined clinical-biological response, %, ITT-NRI (CDAI score <150 points and CRP decrease >50% and/or fecal calprotectin decraese >50% from baseline) 3 6 6 2 0 CDAI: Crohn's Disease Activity Index; ITT: Intent-to-treat; NRI: Non-responder imputation; LOCF: Last observation carried forward; IBDQ: Inflammatory Bowel Disease Questionnaire; ITT population = 172 patients (2 pts without post-baseline assessments).remained on stable doses until Week 10.Patients naïve to anti-TNF therapy as well as patients who were previously exposed to anti-TNF with no response or loss-of-response were included.Endpoints include clinical outcome (CDAI), patient-reported outcomes (PRO: CDAI and IBDQ), histopathology (D'Haens score) and combined clinical-biological response (CDAI and biomarkers).Results: Baseline characteristics were similar in FIL and PBO groups, including mean disease duration (8.3 years), mean CDAI score (293), mean CRP (15.6mg/L, 41%>10mg/L), oral corticosteroids (51%, mean daily dose 20.8 mg/day).42% of the patients were anti-TNF naïve, 58% were anti-TNF non-responder.Clinical remission (CDAI<150) was induced at Week 10 in 47% of FIL patients versus 23% on PBO (p=0.0077).CDAI remission and response were higher in the FIL group versus PBO irrespective of prior anti-TNF therapy.PRO measured by changes from baseline in PRO2 score and general well-being (CDAI component), as well as quality of life assessed by IBDQ improved more in both FIL subgroups compared to PBO.A combined clinicalbiological response endpoint confirmed these findings in the subgroup with elevated CRP or faecal calprotectin at baseline.Histopathology at Week 10 showed numerically greater effects after FIL treatment versus PBO for both subgroups (Table 1).FIL was safe and well tolerated.Similar incidences in SAEs, TEAEs leading to discontinuation and infections were observed in both anti-TNF subgroups, with a somewhat higher incidence of TEAEs in anti-TNF non-responders.Conclusions: Efficacy of filgotinib was shown in CD patients independently of their prior anti-TNF exposure, and was consistent across all endpoints.The safety profile was also similar.These data suggest a favourable risk/benefit profile, in both anti-TNF naives and anti-TNF non-responders.
OBJECTIVES: The ACCENT I study evaluated the long term effects of infliximab as maintenance therapy for patients with Crohn's disease. Health-related quality of life (HRQL) was also assessed in the trial. METHODS: In ACCENT I, a total of 573 patients received a single infusion of 5 mg/kg infliximab at baseline. After assessment of response at wk 2, patients were randomly assigned repeat infusions of placebo at wk 2 and 6 and then every 8 wk thereafter until wk 46 (single dose), repeat infusions of 5 mg/kg of infliximab at the same time points (5 mg/kg maintenance), or 5 mg/kg of infliximab at wk 2 and 6 followed by 10 mg/kg (10 mg/kg maintenance). HRQL analyses presented include the 335 patients classified as wk-2 responders. The treatment regimens were compared with regard to their change from baseline in the IBDQ and Short Form–36 (SF-36) scores. RESULTS: Baseline scores indicated substantial impairment in HRQL. Throughout the study, all IBDQ and SF-36 scores were improved at all time points compared to baseline. After wk 10 and through wk 54, these improvements were greater in the two infliximab maintenance groups than in the single-dose group. The mean change from baseline to wk 54 in total IBDQ was greater in the 5-mg/kg maintenance group (22.1, p < 0.05) and 10-mg/kg maintenance group (30.2, p < 0.001) than in the single-dose group (8.9). Similarly, the mean change from baseline to wk 54 in the PCS of the SF-36 was greater in the 5-mg/kg maintenance group (6.1, p < 0.05) and 10-mg/kg maintenance group (7.2, p < 0.01) than in the single-dose group (2.5). CONCLUSIONS: Infliximab therapy provides substantially improved HRQL as measured by both the disease-specific IBDQ and the generic SF-36. A maintenance regimen of either 5 mg/kg or 10 mg/kg of infliximab is more effective than a single 5-mg/kg infliximab infusion in sustaining this benefit.
Purpose: Topical mesalamine is widely prescribed for active ulcerative colitis (UC). However, factors predicting topical mesalamine treatment response are poorly characterized. The aim of this study was to evaluate the influence of baseline patient demographics, prior and concomitant medications, and disease severity on treatment outcomes with topical mesalamine therapy in active distal UC. Methods: Primary data from a previously published placebo-controlled, multicenter trial†, comprised of 153 subjects with active distal UC that compared 4g mesalamine rectal suspension to placebo over 6 weeks treatment duration, was reanalyzed. Multivariate analysis was performed to evaluate the effects of baseline demographics (age, gender, disease duration, number of prior flares), prior and concomitant therapies (sulfasalazine, prednisone, AZA-6MP), disease severity (Disease Activity Index (DAI) and subscores— mucosal appearance (MA), rectal bleeding (RB), stool frequency (SF)), and disease extent (5 to 55 cm) on treatment outcome. Mucosal healing (MH) was defined as MA = 0; clinical remission (CR) as a RB = 0 and MH = 0-1 with a 1-pt change; bleeding resolution (BR) as RB = 0; and bleeding cessation as absence of bleeding on 4 consecutive days. Cox proportional hazards model was used to analyze time to bleeding cessation, and logistic regression was employed for other variables. Results: Topical mesalamine therapy had a positive effect on treatment outcome, with hazard ratio (HR) of 3.69 for bleeding cessation, and odds ratios (OR) of 7.94, 4.35, and 8.06 for BR, MH, and CR at Week 3 (p < .01, all variables) and 5.71, 2.57, and 4.42 at Week 6 (p < 0.03, all variables). Prior and concomitant prednisone therapy resulted in a 3.85-fold less chance of achieving MH at Week 6. Prior or concomitant sulfasalazine or AZA-6MP use did not impact outcome, although only two subjects received AZA-6MP therapy. Disease extent had no consistent effect on treatment responsiveness. Stool frequency negatively impacted early outcome, with HR of 0.78 (p < .05) for bleeding cessation, and OR of 0.566 (p < .005) and 0.634 (p < .02) for BR and CR at Week 3, per unit DAI-SF subscore; however, this effect did not persist through Week 6. Male sex adversely affected likelihood of MH at Week 6 (0R 0.4, p < 0.05). No other demographic factors or factors of baseline severity significantly affected treatment responsiveness. Conclusion: Prior and concomitant prednisone represents a significantly negative effect for successful treatment outcome using topical mesalamine in distal active UC. Baseline disease severity and disease extent do not consistently influence the responsiveness of distal active UC to topical mesalamine treatment. †Gastroenterology 1987;92:1894. Disclosure: Dr M. Scott Harris and Dr. Gary Lichtenstein have served as consultants to Meda Pharmaceuticals, Inc. Dr. Harris has also received grant and research funding from Meda Pharmaceuticals. Dr. Gary Lichtenstein has served as a consultant to Shire Pharmaceuticals Inc, Salix Pharmaceuticals Inc, and Warner Chilcott. He also received grant and research funding from Shire Pharmaceuticals Inc., Salix Pharmaceuticals, Inc, and Warner Chilcott. Funding for the statistical re-evaluation of original study reports was provided by Meda Pharmaceuticals. No other funding was provided by Meda.
