ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment

Crohn’s disease [CD] is a chronic inflammatory bowel disease [IBD] that can result in progressive bowel damage and disability.1 CD can affect individuals of any age, from children to the elderly,2,3 and may cause significant morbidity and impact on quality of life [QoL]. The precise aetiology of CD remains unknown and a curative therapy is not yet available. Contemporary therapy therefore is focused on control of inflammation, using medications along with timely surgical interventions to alleviate the symptoms of bowel damage. The European Crohn’s and Colitis Organisation [ECCO] produces several guidelines aimed at providing evidence-based guidance on critical aspects of IBD care. In 2020, ECCO published new guidelines on the management of CD in two manuscripts focused on the medical and surgical management of disease.4,5 For the 2020 CD guidelines, ECCO adopted the Grading of Recommendations Assessment, Development, and Evaluation [GRADE] approach, a systematic process for developing guidelines that addresses how to frame the health care questions, summarise the evidence, formulate the recommendations, and grade their strength and quality of associated evidence.6 The present manuscript represents an update to the 2020 guidelines and is focused specifically on medical management of CD, and a companion manuscript developed as part of the same process addresses optimal surgical management.5 We take a drug-by-drug approach to review the evidence for various medical and dietary strategies used in the management of CD. For this iteration of the guidelines, we have introduced several new, clinically relevant questions as chosen by members of the guidelines group, a systematic approach to reviewing and updating previous topics to incorporate any new evidence, and a reappraisal of all evidence in the context of contemporary practice. We have also introduced several ‘practice points’ to summarise evidence, and expert recommendations in certain key areas of practice where the evidence base is limited but where clinicians and patients need to make decisions nonetheless. Here, where application of the GRADE methodology might be impractical, we have used an approach based on systematic literature review, expert discussion, and voting to form consensus recommendations outside the formal GRADE process. It is important to remember that achieving optimal outcomes in CD relies not just on knowledge of the appropriate use of current medical and surgical therapies but also on careful attention to wider aspects of management, including early diagnosis, prompt initial management,7 close monitoring of treatment response, and psychological and dietary support.8 The development of these guidelines followed the GRADE workflow, as adopted in previous ECCO guidelines.9 A panel of 46 experts were selected from an open call according to criteria based on IBD expertise, scientific background, knowledge of GRADE methodology, and prior contribution to ECCO projects. Additionally, six patients with CD selected by the European Federation of Crohn’s and Colitis Associations [EFFCA] were invited to participate in discussions. The group was supported in their work by a team of professional methodologists and librarians. The panellists first agreed on a list of questions using the Population, Intervention, Comparator, Outcomes [PICO] format. PICO questions addressed as part of the 2020 ECCO CD guidelines were reviewed and considered for retention with regards to ongoing relevance, and new PICO questions were formulated, discussed, and added to the list. The relevant outcomes for all PICO questions were graded according to importance using a Delphi consensus process. Note that for PICO questions retained from 2020, the importance of the outcomes was nonetheless revised according to the results of this new consensus. The professional librarians next performed a comprehensive literature search on EMBASE, PubMed/Medline, and Cochrane Central databases, using specific search strings developed for each PICO question [Supplementary files available as Supplementary data at ECCO-JCC online]. For PICO questions retained from the 2020 guidelines, the same search string was used as during the prior literature search, and the start date of database queries set to the same as the end search date for the previous guidelines 1 April 2018. For all new PICO questions, the search start date was unlimited. Two independent consensus group members assessed the relevance of each abstract to the PICO and included or excluded all the relevant papers for the final data extraction and analysis. Subsequently, group members systematically reviewed and summarised the evidence on every outcome voted as ‘important’ or ‘critical’, to compile a Summary of Findings [SoF] table for each question, or updated the prior SoF tables from 2020 [including revision according to any changes to outcomes deemed critical or important]. We adopted a standard hierarchical approach, searching for recent, high-quality systematic reviews and meta-analyses of clinical trials to use in preference to individual randomised clinical trials [RCTs] or observational studies. Results of individual studies were pooled using random-effects meta-analysis as appropriate and when needed. The quality of evidence was then classified and used to inform draft recommendations according to the GRADE methodology.6 GRADE evidence levels for safety data tended to be low, due to downgrading for sparsity of events, reflecting the overall relative safety of the interventions under consideration. Therefore, whereas the evidence for all ‘important’ and ‘critical’ outcomes was considered in the drafting of a recommendation, we decided to base the overall assessment of evidence quality used to inform the strength of each recommendation upon the lowest quality of evidence obtained for the clinical or endoscopic outcomes for each PICO question. Where evidence was not available for an outcome of critical importance, this was reflected in the overall assessment of the quality of the evidence. The assessment of evidence for all individual outcomes was available to all panel members and is presented in the Supplementary materials. During initial discussions and based on feedback from previous ECCO guidelines, we recognised that in certain areas of CD management there are limited high-quality sources of evidence available, but that clinicians and patients must make decisions nonetheless. There are also broad, overarching themes relating to approaches to care that cannot be readily formulated into a PICO question. Use of the GRADE approach in these areas can be resource intensive and lead to recommendations of limited clinical utility. We therefore decided to frame a separate series of ‘practice points’ for such common areas of importance. For these, the systematic literature review and data extraction exercise were followed and the findings used to inform drafting of an expert recommendation. We recognise that the resulting practice points are based upon a different level of evidence compared with the GRADE recommendations, but hope that they will be of practical use to readers nonetheless. These are clearly delineated in the text as distinct from GRADE recommendations. 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