Safety and efficacy of granulocyte/monocyte apheresis in steroid-dependent active ulcerative colitis with insufficient response or intolerance to immunosuppressants and/or biologics (ART trial): 12-week interim results

International audienceBACKGROUND AND AIMS: Patients with active, steroid-dependent ulcerative colitis with insufficient response or intolerance to immunosuppressants and/or biologic therapies have limited treatment options. Adacolumn, a granulocyte/monocyte adsorptive apheresis device, has shown clinical benefit in these patients. This study aimed to provide additional clinical data regarding the safety and efficacy of Adacolumn in this patient subgroup.METHODS: This single arm, open-label, multicentre trial (ART) was conducted at 18 centres across the UK, France and Germany. Eligible patients were 18-75 years old with moderate-to-severe, steroid-dependent active ulcerative colitis with insufficient response or intolerance to immunosuppressants and/or biologics. Patients received ≥5 weekly apheresis sessions with Adacolumn. The primary endpoint was clinical remission rate (clinical activity index ≤4) at Week 12.RESULTS: Eighty-six patients were enrolled. At Week 12, 33/84 (39.3%) of patients in the intention-to-treat population achieved clinical remission, with 47/84 (56.0%) achieving a clinical response (clinical activity index reduction of ≥3). Clinical remission was achieved in 30.0% of patients with prior immunosuppressant and biologic failure; steroid-free clinical remission and response were observed in 22.6% and 35.7% of these patients, respectively. Quality of life (Short Health Scale) significantly improved at Week 12 (p\textless0.0001). The majority of adverse events were of mild/moderate intensity.CONCLUSIONS: At Week 12, Adacolumn provided significant clinical benefit in a large cohort of steroid-dependent ulcerative colitis patients with previous failure to immunosuppressant and/or biologic treatment, with a favourable safety profile. These results are consistent with previous studies and support Adacolumn use in this difficult-to-treat patient subgrou

Tailoring Crohn's disease treatment : the impact of small bowel capsule endoscopy

"Article in Press"; "Epub 2014 Mar 14"BACKGROUND AND AIMS: Small bowel capsule endoscopy (SBCE) may detect proximal small bowel lesions that have been previously missed by ileocolonoscopy and small bowel imaging in patients with known ileal and/or colonic Crohn's disease (CD). We aimed to evaluate whether the therapeutic management is influenced by SBCE findings. METHODS: Retrospective single center study. Inclusion of consecutive patients with known non-stricturing and non-penetrating ileal and/or colonic CD, submitted to SBCE to evaluate disease extension and activity, with ≥ 1year follow-up. Lesions were classified with the Lewis score (LS) as non-significant (LS790). Therapeutic changes were assessed three months after SBCE. RESULTS: Fifty consecutive patients (35±13years, 52% females) were included. At ileocolonoscopy, disease location was ileal (L1) in 60%, colonic (L2) in 10% and ileocolonic (L3) in 30% of the patients. In 33 patients (66%) SBCE detected significant proximal lesions previously missed by other modalities. The proportion of patients on thiopurines and/or biologics before SBCE was 2/50 (4%); this was significantly higher three months after SBCE, 15/50 (30%), p=0.023. Treatment with thiopurines and/or biologics was started more often in patients with proximal small bowel lesions [13/33 (39%) vs. 1/17 (6%), p=0.011, relative risk (RR) 6.5], particularly when severe (6%, 36% and 45% of patients with non-significant, mild and moderate-to-severe inflammation, respectively). CONCLUSIONS: SBCE diagnoses previously undetected lesions and it influences therapeutic management of CD, triggering an earlier introduction of immunomodulators and/or biological therapy

Environmental Factors in the Relapse and Recurrence of Inflammatory Bowel Disease:A Review of the Literature

The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability

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

Developing a Standard Set of Patient-Centred Outcomes for Inflammatory Bowel Disease—an International, Cross-disciplinary Consensus

Success in delivering value-based healthcare involves measuring outcomes that matter most to patients. Our aim was to develop a minimum Standard Set of patient-centred outcome measures for inflammatory bowel disease (IBD), for use in different healthcare settings.An international working group (n=25) representing patients, patient associations, gastroenterologists, surgeons, specialist nurses, IBD registries and patient-reported outcome measure (PROM) methodologists participated in a series of teleconferences incorporating a modified Delphi process. Systematic review of existing literature, registry data, patient focus groups and open review periods were used to reach consensus on a minimum set of standard outcome measures and risk adjustment variables. Similar methodology has been used in 21 other disease areas (www.ichom.org).A minimum Standard Set of outcomes was developed for patients (aged ≥16) with IBD. Outcome domains included survival and disease control (survival, disease activity/remission, colorectal cancer, anaemia), disutility of care (treatment-related complications), healthcare utilisation (IBD-related admissions, emergency room visits) and patient-reported outcomes (including quality of life, nutritional status and impact of fistulae) measured at baseline and at 6 or 12 month intervals. A single PROM (IBD-Control questionnaire) was recommended in the Standard Set and minimum risk adjustment data collected at baseline and annually were included: demographics, basic clinical information and treatment factors.A Standard Set of outcome measures for IBD has been developed based on evidence, patient input and specialist consensus. It provides an international template for meaningful, comparable and easy-to-interpret measures as a step towards achieving value-based healthcare in IBD

Systematic review with meta-analysis: Endoscopic balloon dilatation for Crohn's disease strictures

Background: Endoscopic balloon dilatation (EBD) is recognised treatment for symptomatic Crohn's strictures. Several case series report its efficacy. A systematic analysis for overall efficacy can inform the design of future studies. Aim: To examine symptomatic (SR) and technical response (TR) and adverse events (AE) of EBD. Stricture characteristics were also explored. Methods: A systematic search strategy of COCHRANE, MEDLINE and EMBASE was performed. All original studies reporting outcomes of EBD for Crohn's strictures were included. SR was defined as obstructive symptom-free outcome at the end of follow-up, TR as post-dilatation passage of the endoscope through a stricture, and adverse event as the presence of complication (perforation and/or bleeding). Pooled event rates across studies were expressed with summative statistics. Results: Twenty-five studies included 1089 patients and 2664 dilatations. Pooled event rates for SR, TR, complications and perforations were 70.2% (95% CI: 60-78.8%), 90.6% (95% CI: 87.8-92.8%), 6.4% (95% CI: 5.0-8.2) and 3% (95% CI: 2.2-4.0%) respectively. Cumulative surgery rate at 5 year follow-up was 75%. Pooled unweighted TR, SR, complication, perforation and surgery rates were 84%, 45%, 15%, 9% and 21% for de novo and 84%, 58%, 22%, 5% and 32% for anastomotic strictures. Outcomes between two stricture types were no different on subgroup meta-analysis. Conclusions: Efficacy and complication rates for endoscopic balloon dilatation were higher than previously reported. From the few studies with 5 year follow-up the majority required surgery. Future studies are needed to determine whether endoscopic balloon dilatation has significant long-term benefits

The management of iron deficiency in inflammatory bowel disease

__Background__ Iron deficiency is a common and undertreated problem in inflammatory bowel disease (IBD). __Aim__ To develop an online tool to support treatment choice at the patient-specific level. __Methods__ Using the RAND/UCLA Appropriateness Method (RUAM), a European expert panel assessed the appropriateness of treatment regimens for a variety of clinical scenarios in patients with non-anaemic iron deficiency (NAID) and iron deficiency anaemia (IDA). Treatment options included adjustment of IBD medication only, oral iron supplementation, high-/low-dose intravenous (IV) regimens, IV iron plus erythropoietin-stimulating agent (ESA), and blood transfusion. The panel process consisted of two individual rating rounds and three plenary discussion meetings. __Results__ The panel reached agreement on 71% of treatment indications. 'No treatment' was never considered appropriate, and repeat treatment after previous failure was generally discouraged. For 98% of scenarios, at least one treatment was appropriate. Adjustment of IBD medication was deemed appropriate in all patients with active disease. Use of oral iron was mainly considered an option in NAID and mildly anaemic patients without disease activity. IV regimens were often judged appropriate, with high-dose IV iron being the preferred option in 77% of IDA scenarios. Blood transfusion and IV+ESA were indicated in exceptional cases only. __Conclusions__ The RUAM revealed high agreement amongst experts on the management of iron deficiency in patients with IBD. High-dose IV iron was more often considered appropriate than other options. To facilitate dissemination of the recommendations, panel outcomes were embedded in an online tool, accessible via http://ferroscope.com/

Mucosal Healing in Ulcerative Colitis: A Comprehensive Review

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by periods of remission and periods of relapse. Patients often present with symptoms such as rectal bleeding, diarrhea and weight loss, and may require hospitalization and even colectomy. Long-term complications of UC include decreased quality of life and productivity and an increased risk of colorectal cancer. Mucosal healing (MH) has gained progressive importance in the management of UC patients. In this article, we review the endoscopic findings that define both mucosal injury and MH, and the strengths and limitations of the scoring systems currently available in clinical practice. The basic mechanisms behind colonic injury and MH are covered, highlighting the pathways through which different drugs exert their effect towards reducing inflammation and promoting epithelial repair. A comprehensive review of the evidence for approved drugs for UC to achieve and maintain MH is provided, including a section on the pharmacokinetics of anti-tumor necrosis factor (TNF)-alpha drugs. Currently approved drugs with proven efficacy in achieving MH in UC include salicylates, corticosteroids (induction only), calcineurin inhibitors (induction only), thiopurines, vedolizumab and anti-TNF alpha drugs (infliximab, adalimumab, and golimumab). MH is of crucial relevance in the outcomes of UC, resulting in lower incidences of clinical relapse, the need for hospitalization and surgery, as well as reduced rates of dysplasia and colorectal cancer. Finally, we present recent evidence towards the need for a more strict definition of complete MH as the preferred endpoint for UC patients, using a combination of both endoscopic and histological findings.info:eu-repo/semantics/publishedVersio

Open questions and misconceptions in the diagnosis and management of anemia in patients with gastrointestinal bleeding

Despite high prevalence of iron deficiency anemia (IDA) in patients with acute or chronic gastrointestinal bleeding (GIB), IDA and iron deficiency (ID) are frequently untreated. Reasons may be misconceptions about the impact and diagnosis of IDA and the efficacy of new treatments. Addressing these misconceptions, this article summarizes current evidence for better understanding and management of GIB-associated IDA. Despite only few controlled studies evaluated the efficacy of iron treatment in patients with GIB, there is consistent evidence suggesting that: (a) IDA should be diligently investigated, (b) effective treatment of ID/IDA improves outcomes such as health-related quality of life and can avoid severe cardiovascular consequences, and (c) intravenous iron should be considered as well-tolerated treatment in this setting. Overall, the misconceptions and practices outlined in this article should be replaced with strategies that are more in line with current guidelines and best practice in GIB and other underlying conditions of ID/IDA.A pesar de la alta prevalencia de anemia por déficit de hierro (ADH) en pacientes con hemorragia digestiva (HD) aguda o crónica, la ADH y el déficit de hierro (DH) son frecuentemente infratratados. Diversos conceptos erróneos sobre el impacto, el diagnóstico y la eficacia de los nuevos tratamientos de la ADH probablemente lo justifican. Para abordar estos errores conceptuales, este artículo resume la evidencia actual para una mejor comprensión y manejo de la ADH. A pesar de que existen pocos estudios controlados que hayan evaluado la eficacia del tratamiento con hierro en pacientes con HD, hay evidencia que sugiere que: (a) la ADH debe ser investigada diligentemente; (b) el tratamiento eficaz del DH/ADH mejora la calidad de vida relacionada con la salud y puede evitar relevantes complicaciones cardiovasculares, y (c) el hierro intravenoso debe ser considerado como un tratamiento bien tolerado en este contexto. En general, los conceptos erróneos y las prácticas inadecuadas descritas en este artículo deben ser reemplazados por estrategias que estén más en línea con las directrices actuales y buenas prácticas clínicas en HD y otras condiciones causantes del DH/ADHinfo:eu-repo/semantics/publishedVersio

The role of peptides in bone healing and regeneration: A systematic review

Background: Bone tissue engineering and the research surrounding peptides has expanded significantly over the last few decades. Several peptides have been shown to support and stimulate the bone healing response and have been proposed as therapeutic vehicles for clinical use. The aim of this comprehensive review is to present the clinical and experimental studies analysing the potential role of peptides for bone healing and bone regeneration. Methods: A systematic review according to PRISMA guidelines was conducted. Articles presenting peptides capable of exerting an upregulatory effect on osteoprogenitor cells and bone healing were included in the study. Results: Based on the available literature, a significant amount of experimental in vitro and in vivo evidence exists. Several peptides were found to upregulate the bone healing response in experimental models and could act as potential candidates for future clinical applications. However, from the available peptides that reached the level of clinical trials, the presented results are limited. Conclusion: Further research is desirable to shed more light into the processes governing the osteoprogenitor cellular responses. With further advances in the field of biomimetic materials and scaffolds, new treatment modalities for bone repair will emerge