Milan Lukas

Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial

Background: Adalimumab induced clinical remission after four weeks in patients with active Crohn’s disease in the CLASSIC I trial. Objective: To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn’s disease in a follow-on randomised controlled trial (CLASSIC II). Methods: In the preceding CLASSIC I trial, 299 patients with moderate to severe Crohn’s disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg, or placebo, at weeks 0 and 2. In all, 276 patients from CLASSIC I enrolled in CLASSIC II and received open-label adalimumab 40 mg at weeks 0 (week 4 of CLASSIC I) and 2; 55 patients in remission at both weeks 0 and 4 were re-randomised to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. Patients not in remission at both weeks 0 and 4 were enrolled in an open-label arm and received adalimumab 40 mg every other week. With non-response or flare, these patients could have their dosages increased to 40 mg weekly. Patients in the randomised arm with continued non-response or disease flare could switch to open-label adalimumab 40 mg every other week and again to 40 mg weekly. The primary end point was maintenance of remission (CDAI <150) in randomised patients through week 56. Results: Of 55 patients randomised at week 4, 79% who received adalimumab 40 mg every other week and 83% who received 40 mg weekly were in remission at week 56, v 44% for placebo (p<0.05). In all, 204 patients entered the open-label arm. Of these, 93 (46%) were in clinical remission at week 56. Adalimumab was generally well-tolerated in all patients. Conclusions: Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn’s disease naive to anti-TNF treatment.

Vedolizumab as induction and maintenance therapy for Crohn's disease

BACKGROUND The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohns disease is unknown. METHODS In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohns disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohns Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS Vedolizumab-treated patients with active Crohns disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).

The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations.

Principal changes with respect to the 2004 ECCO guidelines Ileocolonoscopy is recommended within the first year after surgery where treatment decisions may be affected (Statement 8C). Thiopurines are more effective than mesalazine or imidazole antibiotics alone in post-operative prophylaxis (Statement 8F). ### 8.1 Epidemiology of post-operative Crohns disease In the natural history of CD, intestinal resection is almost unavoidable since about 80% of patients require surgery at some stage. Surgery is unfortunately not curative as the disease inexorably recurs in many patients. The post-operative recurrence rate varies according to the definition used: clinical, endoscopic, radiological, or surgical. It is lowest when the repeat resection rate is considered, intermediate when clinical indices are used and highest when endoscopy is employed as the diagnostic tool.1–10 Data from endoscopic follow-up of patients after resection of ileo-caecal disease have shown that in the absence of treatment, the post-operative recurrence rate is around 65–90% within 12 months and 80–100% within 3 years of the operation. The clinical recurrence without therapy is about 20–25%/year.1,10 It has been demonstrated that the post-operative clinical course of CD is best predicted by the severity of endoscopic lesions. Symptoms, in fact, appear only when severe lesions are present and it is not uncommon to observe patients with fairly advanced recurrent lesions at endoscopy who remain asymptomatic.1 For these reasons, clinical indices such as the CDAI have low sensitivity at discriminating between patients with or without post-operative recurrence.11 These data mandate strategies aimed at interrupting or delaying the natural course of post-operative recurrence. Several medications have been tried in an attempt to prevent post-operative recurrence, mostly with disappointing results. The aim of this Consensus was therefore critically to evaluate the optimal strategies for the management of post-operative recurrence in CD. Most, if not all, of the evidence available deals with …

European evidence based consensus on the diagnosis and management of Crohn’s disease: special situations

This third section of the European Crohn’s and Colitis Organisation (ECCO) Consensus on the management of Crohn’s disease concerns postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy. The first section on definitions and diagnosis reports on the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn’s disease. The second section on current management addresses treatment of active disease, maintenance of medically induced remission, and surgery of Crohn’s disease.

Infliximab trough levels may predict sustained response to infliximab in patients with Crohn's disease

BACKGROUND AND AIMS Over 10% of Crohns disease (CD) patients annually lose response to infliximab. Infliximab trough levels (TL), concomitant immunosuppressants and endoscopic healing were proposed as predictors of favourable infliximab outcome. We assessed infliximab TL measured after induction therapy as predictors of sustained clinical response. Furthermore, we tried to identify other predictors of long-term benefit of infliximab therapy. METHODS We included CD patients treated with infliximab between October 2007 and March 2010 who responded to 3-dose induction followed by maintenance therapy and in whom blood samples taken at treatment week 14 or 22 were available in blood bank. Sustained response to infliximab was defined as absence of treatment failure due to loss of response or drug intolerance. RESULTS Eighty four patients were included. Sustained response to infliximab was observed in 47 (56%) patients during a median follow-up of 25 months (14-37). Infliximab TL>3μg/ml were associated with a decreased risk of treatment failure (HR 0.34; 95% CI: 0.16-0.75), whereas the presence of antibodies against infliximab and need for corticosteroids increased this risk (HR 4.34; 95% CI: 1.51-12.5 and HR 2.49, 95% CI: 1.08-5.73, respectively). No impact of concomitant thiopurines was observed, although patients receiving thiopurines had higher infliximab TL than those without immunomodulators (5.51 vs. 0.71μg/ml; p=0.01). CONCLUSION During a median follow up of 2 years sustained response to infliximab was observed in slightly more than half of CD patients. Infliximab TL>3μg/ml at the start of maintenance regime were predicative of sustained response to infliximab.

Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: results from the IBDchip European Project

Objective Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohns disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course. Design This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied. Results Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02×10-06, OR=1.90), stenosing (p=3.16×10-06, OR=1.82) and penetrating (p=1.26×10-02, OR=1.25) CD behaviours, and need for surgery (p=2.28×e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86×10-06, OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48×10-06, OR=0.35) and surgical rate (p=1.71×10-07, OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12×10-03, HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01×10-02, HR=1.29) among patients with low and high score. Conclusions This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.

Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn's disease with endoscopic recurrence: efficacy and safety results of a randomised, double-blind, double-dummy, multicentre trial

Objective The aim of the study was to compare azathioprine versus mesalazine tablets for the prevention of clinical recurrence in patients with postoperative Crohns disease (CD) with moderate or severe endoscopic recurrence. Methods This was a 1 year, double-blind, double-dummy, randomised study which took place in 21 gastroenterology centres in Austria, the Czech Republic, Germany and Israel. The study participants were 78 adults with CD who had undergone resection with ileocolonic anastomosis in the preceding 6–24 months without subsequent clinical recurrence and with a Crohns disease activity index (CDAI) score <200, but with moderate or severe endoscopic recurrence. The study drugs were azathioprine 2.0–2.5 mg/kg/day or mesalazine 4 g/day over 1 year. The primary end point was therapeutic failure during 1 year, defined as a CDAI score ≥200 and an increase of ≥60 points from baseline, or study drug discontinuation due to lack of efficacy or intolerable adverse drug reaction. Results Treatment failure occurred in 22.0% (9/41) of azathioprine-treated patients and 10.8% (4/37) of mesalazine-treated patients, a difference of 11.1% (95% CI −5.0% to 27.3%, p=0.19). Clinical recurrence was significantly less frequent with azathioprine versus mesalazine (0/41 (0%) vs 4/37 (10.8%), p=0.031), whereas study drug discontinuation due to adverse drug reactions only occurred in azathioprine-treated patients (9/41 (22.0%) vs 0%, p=0.002). The proportion of patients showing ≥1 point reduction in Rutgeerts score between baseline and month 12 was 63.3% (19/30) and 34.4% (11/32) in the azathioprine and mesalazine groups, respectively (p=0.023). Conclusions In this population of patients with postoperative CD at high risk of clinical recurrence, superiority for azathioprine versus mesalazine could not be demonstrated for therapeutic failure. Clinical trial registration number NCT00946946.

Nonadherence in inflammatory bowel disease: Results of factor analysis

Background: The purpose of the study was to assess overall nonadherence to treatment among patients with Crohns disease (CD) and ulcerative colitis (UC) in a single tertiary center. Methods: A total of 177 patients were enrolled in this study (84 males, 93 females; 117 CD, 60 UC). Patients were interviewed about their nonadherent behavior and their answers were analyzed using factor analysis. Urine samples were collected from a subcohort of 47 patients treated by mesalamine to verify the presence of 5‐ASA or its metabolites. Results: Overall intentional nonadherence was reported by 38.9% of patients; 18.6% of the patients discontinued the treatment at least once. Intentional dose reduction was reported by 18% of patients; 14.7% of patients occasionally did not refill their medications on time. There were no differences in adherence between males and females, disease type, previous bowel surgery, or marital, smoking, and nonsmoking status. More than 38% of patients reported unintentional nonadherence. Factor analysis proved that nonadherence increased with a higher education level of the patients and decreased with older age. Adverse drug effects strongly contributed to nonadherence. Nonadherent patients were more likely to be chronically active or in relapse (&tgr; = 0.212; P = 0.002). In the group of 47 patients whose urine was analyzed, 6 cases (12.7%) were negative for mesalamine or its metabolite. Conclusions: The overall intentional nonadherence with medical therapy is relatively high among IBD patients and should be taken into account when a patients response to treatment is unsatisfactory. Therefore, problems of nonadherence should be discussed with all IBD patients. (Inflamm Bowel Dis 2007)

Delayed-Release Oral Mesalamine 4.8 g/day (800-mg Tablet) Is Effective for Patients With Moderately Active Ulcerative Colitis

BACKGROUND AND AIMS It is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted to determine the efficacy and safety of mesalamine 4.8 g/day compared with 2.4 g/day for the treatment of moderately active UC. METHODS A multicenter, randomized, double-blind, 6-week, active-control study (ASCEND III) was conducted to assess the noninferiority of delayed-release mesalamine 4.8 g/day (Asacol HD, 800-mg tablet; Procter & Gamble, Pharmaceuticals, Inc, Mason, Ohio) with 2.4 g/day (Asacol, 400-mg tablet; Procter & Gamble Pharmaceuticals, Inc) in 772 patients with moderately active UC. The primary endpoint was treatment success (overall improvement) at week 6, defined as improvement in the Physicians Global Assessment (based on clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy), with no worsening in any individual clinical assessment. RESULTS The primary objective of noninferiority was met. Seventy percent (273 of 389) of patients who received 4.8 g/day of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/day (95% confidence interval for 2.4 g/day minus 4.8 g/day, -11.2 to 1.9). In addition, 43% of patients who received 4.8 g/day mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/day (P = .04). A therapeutic advantage for the 4.8 g/day dose was observed among patients previously treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications. Both regimens were well-tolerated with similar adverse events. CONCLUSIONS Delayed-release mesalamine 4.8 g/day (800-mg tablet) is efficacious and well-tolerated in patients with moderately active UC.

Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study

Objective Interleukin-13 (IL-13) has been implicated as a key driver of UC. This trial evaluates the efficacy and safety of tralokinumab, an IL-13-neutralising antibody, as add-on therapy in adults with moderate-to-severe UC despite standard treatments. Design Non-hospitalised adults with UC (total Mayo score ≥6) were randomised to receive tralokinumab 300 mg or placebo subcutaneously every 2 weeks for 12 weeks. The primary end point was the rate of clinical response at week 8. Secondary efficacy end points included clinical remission and mucosal healing rates at week 8 and changes in total Mayo score, total modified Riley score, partial Mayo score and disease activity markers. Results Clinical response rate was 38% (21/56) for tralokinumab vs 33% (18/55) for placebo (p=0.406). Clinical remission rate was 18% (10/56) vs 6% (3/55) (p=0.033) and mucosal healing rate was 32% (18/56) vs 20% (11/55) (p=0.104) for tralokinumab vs placebo. Changes to week 8 in total Mayo score and total modified Riley score were similar for tralokinumab and placebo (least-squares mean difference between groups: −0.49 (p=0.394) and 0.25 (p=0.449), respectively). Partial Mayo score at week 4 was lower with tralokinumab than placebo (least-squares mean difference between groups: −0.90 (p=0.041)). No consistent patterns were observed for disease activity markers. Tralokinumab had an acceptable safety profile. Conclusions Add-on therapy with tralokinumab did not significantly improve clinical response. However, the higher clinical remission rate with tralokinumab than placebo suggests that tralokinumab may benefit some patients with UC. Tralokinumab was well tolerated. Trial registration number ClinicalTrials.gov number: NCT01482884.