Tofacitinib

The guideline is of relevance to adults aged 16 years and over and was developed according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology,2 (link) in accordance with the principles of the AGREE II tool,3 (link) and in compliance with the BSG Guidelines Advice Document.4 The completed document was formally peer reviewed by the BSG CSSC and BSG Council prior to submission for publication. The guideline writing process was supported by regular consultation from Professor Cathy Bennett (Systematic Research Ltd and Royal College of Surgeons in Ireland (RCSI)) and used a bespoke online platform developed by Dr Stuart Gittens (ECD Solutions: https://www.guideline.pub/bsg-ibd/) to develop clinical questions structured by Population, Intervention, Comparator and Outcome (PICO) or Population, Exposure, Outcome (PEO) development, to assimilate evidence and to facilitate voting of draft statements and recommendations using a modified eDelphi process.
After commissioning of the guideline by the BSG CSSC, a Guideline Development Group (GDG) was convened by the Chair of the IBD Section Committee of the BSG (ABH). A GDG Lead (CAL) and conflicts of interest Chair (TI) were appointed. Key Stakeholders from the following groups were represented: British Society of Gastroenterology (BSG), Association of Coloproctology of Great Britain and Ireland (ACPGBI), Royal College of Nursing (RCN), British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN), British Dietetic Association (BDA), British Society of Gastrointestinal and Abdominal Radiology (BSGAR), and the Primary Care Society for Gastroenterology (PCSG). Patient representation was provided by Crohn’s and Colitis UK.
Members of the BSG IBD Section Committee were invited to take part in the GDG along with external clinicians with relevant experience. The GDG and all conflicts of interest for 12 months preceding GDG formation were vetted and approved by the BSG CSSC.
Clinical priorities to be covered by the guideline were set by the GDG including:

Definitions, clinical features and diagnosis

Investigations including imaging

Treatment of active UC including surgery and acute severe UC (ASUC)

Pouchitis management

Treatment of active Crohn’s disease (ileal, ileocolonic, colonic, jejunal, upper GI, perianal)

Maintenance treatment of Crohn’s disease

Surgery for Crohn’s disease (including non-perianal fistulising disease)

Common considerations for drug groups to include mesalazines, corticosteroids, thiopurines, methotrexate, ciclosporin, anti-TNF, vedolizumab, ustekinumab, tofacitinib and antibiotics

Therapeutic monitoring including drug levels and drug toxicity/immunogenicity, and pre-treatment infection screening and vaccination

Non-drug therapies including leucocyte apheresis and stem cell transplantation

Nutrition and dietary therapy

Lifestyle factors including smoking

Pain and fatigue

Psychological aspects

Service delivery

Primary care management of IBD

Where substantial up-to-date guidance existed on special circumstances—for example, pregnancy, osteoporosis, iron deficiency, immunosuppression in the context of prior malignancy or histology—extensive systematic review would not be performed but summary data would be presented to encourage best practice with referencing to signpost other guidance. Guidance for surgical technique in IBD would not be extensively covered due to a concurrent guideline development process in this area led by the ACPGBI.5 (link) Health economics and costs of drugs would not be assessed as part of the guideline, although cost would be mentioned as an important consideration when there is a choice of treatments.
A clinical framework was then designed to visually map and group patient management decisions and influencing clinical factors, including disease location and severity. Sub-categorisations were made to identify aspects pertinent to pharmacological and non-pharmacological intervention, nutrition, imaging, surgery, primary care and service delivery. Four working groups were formed (led by NAK, TR, PH and PJS alongside CAL and ABH) to draft and develop a list of key thematic and sub-thematic clinical questions grouped into sections defined by the clinical framework that face IBD clinicians in everyday healthcare practice. These clinical questions were circulated to all stakeholder groups for review by members outside the GDG to ensure all relevant areas of clinical practice were covered. Following stakeholder review, the list was further developed producing 54 thematic questions with 360 associated clinical questions grouped around these themes (see online supplementary appendix 1).
Next, the clinical questions were further revised, refined and combined with the thematic questions in order to design the systematic review. Keyword tables derived from these questions and formulated according to PICO or PEO structure were generated on the online platform, and structured searches of electronic literature databases were performed. The literature searches were designed, run in electronic databases and exported to Endnote reference managing software, supported by information specialists at York Health Economics Consortium. Searches of the Medline and EMBASE databases were performed in March 2017 and updated in March 2018. No date or study design limits were incorporated into searches in order to return all available evidence, including conference proceedings (although conference proceeding returns were limited to 5 years preceding the date of search). The search strategy used is presented in online supplementary appendix 2. In this way, systematic literature searches and reviews were undertaken to identify and synthesise evidence to support the creation of statements with supporting narrative syntheses of evidence. A total of 87 959 references were returned after deduplication from these searches. Focused top-up searches using keywords were performed until June 2019 to ensure evidence was up to date at the time of submission for publication. GDG members were able to also propose papers or electronic documents (eg, NICE guidance) for inclusion in the literature databases throughout the guideline development process. In this manner an additional 288 entries were added to the reference library to make a total of 88 247. References were cross-searched both manually using keywords and Boolean operators, and using a bespoke programmatic algorithm (the latter cross-referencing content of abstract, title and keywords with contents of PEO and PICO tables), both facilitated by the online platform. Literature was assessed according to the pre-designed PEO and PICOs, and abstracts±full text assessed for relevance and quality. Evidence-based evaluative text and associated reference lists were developed along with draft statements and grouped/archived in a customised electronic database. Statements considered potential health benefits, side effects and risks of recommendations to patients, as well as cost and service implications. Full economic analyses were not undertaken.
Following statement revision by the GDG according to Delphi methodology, an ‘IBD guidelines eDelphi consensus group’ of 81 clinicians and patients was formed consisting of representatives invited from all stakeholder groups listed above, and all members of the GDG except CB and SG who did not vote. A modified eDelphi mechanism process, employing the online platform, was then used to produce an evidence-based consensus, following a NICE accredited methodology. This consisted of three main rounds of anonymous web-based voting, using a custom-built online voting platform scoring each using a 5-point scale with updated iterations of the statements and evaluative text based on feedback after each round.
Following two rounds of anonymised voting, statements conforming to PICO/PEO which achieved consensus of 80% agreement or higher were categorised according to the GRADE system for grading quality of evidence and strength of recommendations. Assessments were made independently by two members of the GDG (blinded to one another’s assessment) using a custom-built electronic database by NAK in REDCap6 (link) (at https://surveys.exeteribd.org.uk/). All assessments were reviewed and where necessary moderated by CAL and ABH to determine agreement. To assess the quality of evidence for each statement, each member considered study type, risk of bias, inconsistency, indirectness, imprecision, publication bias, effect size, plausible confounding variables and dose–response gradient if applicable. The quality of evidence ranged from ‘high’ (further research is very unlikely to change confidence in the estimate of effect), ‘moderate’ (further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate), ‘low’ (further research is very likely to have important impact on confidence in the estimate of effect and is likely to change the estimate), and ‘very low’ (any estimate of effect is very uncertain). The strength of recommendation was assessed based on considerations of desirable and undesirable anticipated effects, the certainty of the evidence of effects, any important uncertainty about or variability in how much people value the outcome, whether the balance of these effects favours the intervention or comparison, the acceptability of intervention to key stakeholders and feasibility of intervention implementation. The strength of each recommendation was then recorded as ‘strong’ (meaning that benefits clearly outweigh risks and burdens or vice versa) and conditional recommendations as ‘weak’ (where benefits, risks and burdens are conditional, closely balanced or uncertain).
Where statements did not conform to PICO/PEO (such as subjective interventions or where outcomes were multiple) and evidence was indirect or of low quality, recommendations to inform clinical practice were presented as Good Practice Recommendations and listed separately to GRADE recommendations, but still underwent consensus voting.
The GDG voted on all statements and Good Practice Recommendations, and other eDelphi participants voted on one of three subsets of statements and Good Practice Recommendations in order to ensure adequate numbers of responses were obtained for each, that expertise was equally distributed across subject areas and that surgeon members of the group voted on all surgical-related topics. The total number of respondents per statement and recommendation are presented in online supplementary table 3. Statements and recommendations not reaching 80% consensus agreement following three rounds of voting were removed and are presented in online supplementary appendix 3.

Based on the evidence from in vivo experiments demonstrating that baohuoside I inhibits tofacitinib metabolism, we aimed to investigate the inhibitory effects of baohuoside I in vitro. RLMs were prepared and the inhibitory effect of baohuoside I on tofacitinib metabolism was assessed using methods similar to those previously described.15 (link) The volume of incubation system was 200 µL, containing 100 mM pH 7.4 potassium phosphate buffer, 0.5 mg/mL RLMs, and the varying concentration of tofacitinib (1, 2.5, 5, 10, 25, 50, 100, 200 and 400 μM). The system was preincubated at 37 °C for 5 min. The reaction was then initiated by the addition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) at a final concentration of 1 mM, and the incubation was continued for 30 min. To determine the half-maximal inhibitory concentration (IC₅₀) of baohuoside I, various concentrations of baohuoside I (100, 50, 10, 5, 1, 0.1, 0.01, and 0 μM) were selected along with 40 µM of tofacitinib, which is close to its K_m value. In order to investigate the inhibitory mechanism of baohuoside I on tofacitinib, the two drugs were subjected to incubation at various concentration gradients, including 1/4 K_m, 1/2 K_m, K_m, and 2K_m of tofacitinib, as well as 0, 1/4 IC₅₀, 1/2 IC₅₀, IC₅₀, and 2IC₅₀ of baohuoside I. The incubation procedure remained consistent with the afore mentioned method.