The use of oral topically acting glucocorticosteroids in the treatment of inflammatory bowel disease.

Glucocorticosteroids are the mainstay of treatment of active Crohn's disease and ulcerative colitis. These drugs however carry important cosmetic short-term side effects and when used long-term they induce severe irreversible complications. Topically acting glucocorticosteroids, especially budesonide, have been designed to achieve local effect at the site of inflammation without systemic effects of the drug. The first results of clinical trials are promising and budesonide has been shown to have an improved safety with almost comparable efficacy in comparison with prednisolone. The optimal enema dose seems to be 2 mg/100 ml at night whereas 9 mg o.m. is the optimal dose to treat ileal or right ileocolonic Crohn's disease. Topically acting GCS, like standard GCS are not effective for maintenance of remission of Crohn's disease or recurrence prevention after resection of the involved Crohn's segment

The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice.

The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model. The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression. Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo. These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice

Adalimumab for the treatment of fistulas in patients with Crohn’s disease

To evaluate the efficacy of adalimumab in the healing of draining fistulas in patients with active Crohn's disease (CD). A phase III, multicentre, randomised, double-blind, placebo controlled study with an open-label extension was conducted in 92 sites. A subgroup of adults with moderate to severely active CD (CD activity index 220-450) for >or=4 months who had draining fistulas at baseline. All patients received initial open-label adalimumab induction therapy (80 mg/40 mg at weeks 0/2). At week 4, all patients were randomly assigned to receive double-blind placebo or adalimumab 40 mg every other week or weekly to week 56 (irrespective of fistula status). Patients completing week 56 of therapy were then eligible to enroll in an open-label extension. Complete fistula healing/closure (assessed at every visit) was defined as no drainage, either spontaneous or with gentle compression. Of 854 patients enrolled, 117 had draining fistulas at both screening and baseline (70 randomly assigned to adalimumab and 47 to placebo). The mean number of draining fistulas per day was significantly decreased in adalimumab-treated patients compared with placebo-treated patients during the double-blind treatment period. Of all patients with healed fistulas at week 56 (both adalimumab and placebo groups), 90% (28/31) maintained healing following 1 year of open-label adalimumab therapy (observed analysis). In patients with active CD, adalimumab therapy was more effective than placebo for inducing fistula healing. Complete fistula healing was sustained for up to 2 years by most patients in an open-label extension tria

Serological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn's disease

peer reviewedOBJECTIVES: The use of monoclonal anti-tumor necrosis factor (TNF) antibodies (infliximab, Remicade) is a new therapeutic approach for severe refractory luminal or fistulizing, Crohn's disease (CD). However, up to 30% of patients do not respond to this treatment. So far, no parameters predictive of response to anti-TNT have been identified. Our aim was to determine whether serological markers ASCA (anti-Saccharomyces cerevisiae antibodies) or pANCA (perinuclear antineutrophil cytoplasmic antibodies) could identify Crohn's patients likely to benefit from anti-TNF therapy. METHODS: Serum samples of 279 CID patients were analyzed for ASCA and pANCA before anti-TNF therapy. A blinded physician determined clinical response at week 4 (refractory luminal CD) or week 10 (fistulizing CD) after the first infusion of infliximab (5 mg/kg). RESULTS: Overall, there was no relationship between ASCA or pANCA and response to therapy. However, lower response rates were observed for patients with refractory intestinal disease carrying the pANCA+/ASCA- combination, although this lacked significance (p = 0.067). CONCLUSIONS: In this cohort of infliximab-treated patients, neither ASCA nor pANCA could predict response to treatment. However, the combination pANCA+/ASCA- might warrant further investigation for its value in predicting nonresponse in patients with refractory luminal disease

6-thioguanine treatment in inflammatory bowel disease: A critical appraisal by a European 6-TG working party

Recently, the suggestion to use 6-thioguanine (6-TG) as an alternative thiopurine in patients with inflammatory bowel disease (IBD) has been discarded due to reports about possible (hepato) toxicity. During meetings arranged in Vienna and Prague in 2004, European experts applying 6-TG further on in IBD patients presented data on safety and efficacy of 6-TG. After thorough evaluation of its risk-benefit ratio, the group consented that 6-TG may still be considered as a rescue drug in stringently defined indications in IBD, albeit restricted to a clinical research setting. As a potential indication for administering 6-TG, we delineated the requirement for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Furthermore, indications are preferred in which surgery is thought to be inappropriate. The standard 6-TG dosage should not exceed 25 mg daily. Routine laboratory controls are mandatory in short intervals. Liver biopsies should be performed after 6-12 months, three years and then three-yearly accompanied by gastroduodenoscopy, to monitor for potential hepatotoxicity, including nodular regenerative hyperplasia (NRH) and veno-occlusive disease (VOD). Treatment with 6-TG must be discontinued in case of overt or histologically proven hepatotoxicity. Copyright (c) 2006 S. Karger AG, Basel

A national survey on the patterns of treatment of inflammatory bowel disease in Canada

BACKGROUND: There is a general lack of information on the care of inflammatory bowel disease (IBD) in a broad, geographically diverse, non-clinic population. The purposes of this study were (1) to compare a sample drawn from the membership of a national Crohn's and Colitis Foundation to published clinic-based and population-based IBD samples, (2) to describe current patterns of health care use, and (3) to determine if unexpected variations exist in how and by whom IBD is treated. METHODS: Mailed survey of 4453 members of the Crohn's and Colitis Foundation of Canada. The questionnaire, in members stated language of preference, included items on demographic and disease characteristics, general health behaviors and current and past IBD treatment. Each member received an initial and one reminder mailing. RESULTS: Questionnaires were returned by 1787, 913, and 128 people with Crohn's disease, ulcerative colitis and indeterminate colitis, respectively. At least one operation had been performed on 1159 Crohn's disease patients, with risk increasing with duration of disease. Regional variation in surgical rates in ulcerative colitis patients was identified. 6-Mercaptopurine/Azathioprine was used by 24% of patients with Crohn's disease and 12% of patients with ulcerative colitis (95% CI for the difference: 8.9% – 15%). In patients with Crohn's disease, use was not associated with gender, income or region of residence but was associated with age and markers of disease activity. Infliximab was used by 112 respondents (4%), the majority of whom had Crohn's disease. Variations in infliximab use based on region of residence and income were not seen. Sixty-eight percent of respondents indicated that they depended most on a gastroenterologist for their IBD care. There was significant regional variation in this. However, satisfaction with primary physician did not depend on physician type (for example, gastroenterologist versus general practitioner). CONCLUSION: This study achieved the goal of obtaining a large, geographically diverse sample that is more representative of the general IBD population than a clinic sample would have been. We could find no evidence of significant regional variation in medical treatments due to gender, region of residence or income level. Differences were noted between different age groups, which deserves further attention

Vedolizumab for Treating Moderately to Severely Active Crohn’s Disease After Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe, active Crohn’s disease. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned as the Evidence Review Group (ERG) and produced a critical review of the evidence of the clinical effectiveness and cost effectiveness of the technology, based upon the company’s submission to NICE. The GEMINI II and III trials formed the main supporting evidence for the intervention. Both studies were phase III, randomised, double-blind, placebo-controlled, multicentre trials designed to evaluate the efficacy and safety of vedolizumab. They included patients who were naïve to tumour necrosis factor alpha antagonist (anti-TNF-α) therapy and patients who had an inadequate response to, loss of response to or intolerance of immunomodulators or anti-TNF-α agents. GEMINI II was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment (dosing at weeks 0 and 2, with assessment at week 6) and maintenance treatment (during weeks 6–52). In contrast, GEMINI III was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment only, with doses at weeks 0, 2 and 6, and assessment at weeks 6 and 10. In the absence of any direct head-to-head, randomised, controlled trials comparing vedolizumab with other relevant biologic therapies (adalimumab and infliximab) for the treatment of moderate-to-severe Crohn’s disease, the company conducted a network meta-analysis, which compared vedolizumab, adalimumab, infliximab and placebo for the outcomes of clinical response, enhanced clinical response, clinical remission and discontinuation due to adverse events. The company model estimated the incremental cost-effectiveness ratio (ICER) for vedolizumab compared with the standard of care (consisting of 5-aminosalicylic acids, corticosteroids and immunosuppressants) to be £21,620 per quality-adjusted life-year (QALY) gained within the anti-TNF-α-failure population (which included a confidential patient access scheme for vedolizumab). The ICERs were above £30,000 per QALY gained for the mixed intention-to-treat population (including both anti-TNF-α-naïve and anti-TNF-α-failure populations) and in patients who were anti-TNF-α naïve only. The ERG identified a number of limitations that were believed to limit the robustness of the results presented by the company. These limitations could not be addressed by the ERG without major restructuring of the economic model. Therefore, the ERG concluded that the results from the company’s model needed to be interpreted with caution and that it was unclear whether the ICERs would increase or decrease following amendment of the identified structural issues

Vedolizumab for the Treatment of Adults with Moderate-to-Severe Active Ulcerative Colitis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe active ulcerative colitis (UC). The Evidence Review Group (ERG) produced a critical review of the evidence for the clinical effectiveness and cost effectiveness of the technology, based upon the company's submission to NICE. The evidence was derived mainly from GEMINI 1, a Phase 3, multicentre, randomised, double-blinded, placebo-controlled study of the induction and maintenance of clinical response and remission by vedolizumab (MLN0002) in patients with moderate-to-severe active UC with an inadequate response to, loss of response to or intolerance of conventional therapy or anti-tumour necrosis factor (TNF)-α. The clinical evidence showed that vedolizumab performed significantly better than placebo in both the induction and maintenance phases. In the post hoc subgroup analyses in patients with or without prior anti-TNF-α therapy, vedolizumab performed better then placebo (p value not reported). In addition, a greater improvement in health-related quality of life was observed in patients treated with vedolizumab, and the frequency and types of adverse events were similar in the vedolizumab and placebo groups, but the evidence was limited to short-term follow-up. There were a number of limitations and uncertainties in the clinical evidence base, which warrants caution in its interpretation-in particular, the post hoc subgroup analyses and high dropout rates in the maintenance phase of GEMINI 1. The company also presented a network meta-analysis of vedolizumab versus other biologic therapies indicated for moderate-to-severe UC. However, the ERG considered that the results presented may have underestimated the uncertainty in treatment effects, since fixed-effects models were used, despite clear evidence of heterogeneity among the trials included in the network. Results from the company's economic evaluation (which included price reductions to reflect the proposed patient access scheme for vedolizumab) suggested that vedolizumab is the most effective option compared with surgery and conventional therapy in the following three populations: (1) a mixed intention-to-treat population, including patients who have previously received anti-TNF-α therapy and those who are anti-TNF-α naïve; (2) patients who are anti-TNF-α naïve only; and (3) patients who have previously failed anti-TNF-α therapy only. The ERG concluded that the results of the company's economic evaluation could not be considered robust, because of errors in model implementation, omission of relevant comparators, deviations from the NICE reference case and questionable model assumptions. The ERG amended the company's model and demonstrated that vedolizumab is expected to be dominated by surgery in all three populations