Therapeutic Drug Monitoring to Guide Clinical Decision Making in Inflammatory Bowel Disease Patients with Loss of Response to Anti-TNF: A Delphi Technique-Based Consensus.

BACKGROUND: Loss of response is frequently encountered in patients with inflammatory bowel disease (IBD) treated with antitumor necrosis factor (TNF) agents. Therapeutic drug monitoring (TDM) and antidrug antibody measurement are increasingly used in this setting. METHODS: To establish a consensus on the use of TDM in the context of loss of response to anti-TNFs, we performed a vote using a Delphi-style process followed by an expert panel discussion among 8 IBD specialists practicing in Switzerland, Europe. Statements were rated on an even Likert-scale ranging from 1 (strong disagreement) to 4 (strong agreement), based on expert opinion and the available literature. RESULTS: The experts agreed on the following statements: (i) loss of response is associated with inadequate drug levels in both Crohn's disease and ulcerative colitis; (ii) best timepoint for measuring drug levels is prior to the next application (= trough levels) with different thresholds for anti-TNF agents (infliximab 5 µg/mL, adalimumab 8 µg/mL, certolizumab pegol 10 µg/mL); (iii) antidrug antibodies are predictive for loss of response; and (iv) antidrug-antibody titers and drug trough levels are key determinants in the treatment algorithm. Data about non-anti-TNF biologics were considered too limited to propose recommendations. CONCLUSION: A Delphi-style consensus among 8 IBD experts shows that TDM and measurement of antidrug-antibody titers are useful in the context of loss of response to anti-TNF. Optimal cutoff levels depend on the type of anti-TNF. These values are critical in the decision making process. More studies are needed to address the value of such measurements for non-anti-TNF biologics.

Swiss expert opinion: current approaches in faecal microbiota transplantation in daily practice.

INTRODUCTION: Faecal microbiota transplantation (FMT) is an established therapy for recurrent C. difficile infection, and recent studies have reported encouraging results of FMT in patients with ulcerative colitis. Few international consensus guidelines exist for this therapy, and thus FMT policies and practices differ among European countries. As of 2019, stool transplants are considered a non-standardised medicinal product in Switzerland, and a standardised production process requires authorisation by the Swiss Agency for Therapeutic Products. This authorisation leads to prolonged administrative procedures and increasing costs, which reduces treatment accessibility. In particular, patients with ulcerative colitis in Switzerland can only benefit from FMT off-label, even though it is a valid therapeutic option. Therefore, this study summarised the available data on FMT and established a framework for the standardised use of FMT. METHODS: A panel of Swiss gastroenterologists with a special interest in inflammatory bowel disease was established to identify the current key issues of FMT. After a comprehensive review of the literature, statements were formulated about FMT indications, donor screening, stool transplant preparation and administration, and safety aspects. The panel then voted on the statements following the Delphi process; the statements were reformulated and revoted until a consensus was reached. The manuscript was then reviewed by an infectiologist (the head of Lausanne's FMT centre). RESULTS: The established statements are summarised in the supplementary tables in the appendix to this paper. The working group hopes these will help standardise FMT practice in Switzerland and contribute to making faecal microbiota transplantation a safe and accessible treatment for patients with recurrent C. difficile infections and selected patients with ulcerative colitis, as well as other indications in the future.

Position statement on the use of biosimilars in inflammatory bowel disease.

Biologics are effective and have a good safety profile in the treatment of inflammatory bowel disease. Biosimilars have recently become available as treatment option. They are biological agents that are highly similar to the original biologic compound in their structure, biological activity, efficacy and safety. This position paper summarises current knowledge on biosimilars and presents its statements on regulatory issues and clinical situation in order to provide clinicians adequate information for them to reach informed and appropriate shared decision-making with their patients.

Can the CalproQuest predict a positive Calprotectin test? A prospective diagnostic study.

BACKGROUND: Diagnosis of inflammatory bowel disease (IBD) in primary care (PC) is challenging and associated with a considerable diagnostic delay. Using a calprotectin test for any PC patient with abdominal complaints would cause significant costs. The 8-item-questionnaire CalproQuest was developed to increase the pre-test probability for a positive Calprotectin. It is a feasible instrument to assess IBD in PC, but has not yet been evaluated in clinical routine. This study, therefore, aimed to validate whether the CalproQuest increases pretest-probability for a positive fecal Calprotectin. METHODS: Prospective diagnostic trial. The CalproQuest consists of 4 major and 4 minor questions suggestive for IBD. It is considered positive if ≥ 2 major or 1 major and 2 minor criteria are positive. Primary outcome: Sensitivity and specificity of the CalproQuest for Calprotectin levels ≥ 50 µg/g and for positive IBD diagnosis among patients referred to endoscopic evaluation at secondary care level. Secondary finding: Patient-reported diagnostic delay. RESULTS: 156 patients from 7 study centers had a complete CalproQuest and fecal Calprotectin test. The sensitivity and specificity of CalproQuest for Calprotectin ≥ 50 µg/g was 36% and 57%. The sensitivity and specificity of the CalproQuest for positive IBD diagnosis was 37% and 67%. The diagnostic delay was 61 months (SD 125.2). CONCLUSION: In this prospective diagnostic study, the sensitivity and specificity of CalproQuest for Calprotectin levels ≥ 50 µg/g and positive IBD diagnosis were poor. Additional prospective studies concerning the ideal cut-off values, validity and cost-effectiveness of a combined use with the Calprotectin test in the PC setting are necessary.

Feasibility of an 8-item questionnaire for early diagnosis of inflammatory bowel disease in primary care.

AIMS: Diagnosis of inflammatory bowel disease (IBD) is often associated with a diagnostic delay. Although faecal calprotectin is a helpful screening tool, the widespread use in primary care (PC) may not be appropriate due to the low prevalence of IBD in this setting. To increase pretest probability for a positive calprotectin test, an 8-item questionnaire (CalproQuest) was tested for its feasibility and acceptability in PC. METHODS: Population: PC patients with unspecific gastrointestinal complaints for at least 2 weeks. The CalproQuest consists of four major and four minor questions specific for IBD. It is considered positive if greater than or equal to two major or one major and two minor criteria are positive. PRIMARY OUTCOME: feasibility of CalproQuest, secondary outcome: patient's acceptance of stool sampling. RESULTS: Of 95 patients with a complete CalproQuest 52 (54.7%) were positive, 39 (41.1%) fulfilled two major and 13 (13.7%) one major and greater than or equal to two minor criteria. Twenty-seven general practitioners completed 83 (87.4%) questionnaires on feasibility which was assessed positive. Eighty-two patients (86.3%) completed questionnaires on acceptance which was high. CONCLUSION: The CalproQuest is a feasible instrument for assessing IBD in PC. Further prospective studies concerning validity and cost effectiveness of a combined use with the calprotectin test in this setting are necessary.

VAlidation of an 8-item-questionnaire predictive for a positive caLprotectin tEst and Real-life implemenTation in primary care to reduce diagnostic delay in inflammatory bowel disease (ALERT): protocol for a prospective diagnostic study.

INTRODUCTION: Diagnosis of inflammatory bowel disease (IBD) in primary healthcare is challenging and often associated with a considerable diagnostic delay. This delay is associated with worse disease progression and outcomes. Although testing for faecal calprotectin is a useful screening tool to identify patients who need endoscopy for IBD, the widespread use may not be appropriate due to the low prevalence of patients with IBD among all patients attending a general practitioner (GP) with gastrointestinal symptoms. To increase the appropriate application of the faecal calprotectin test, an 8-item questionnaire, the CalproQuest, has been developed to increase pretest probability for a positive test result. METHODS AND ANALYSIS: This is a prospective diagnostic trial. The study consists of two independent and consecutive parts A and B, conducted by gastroenterologists (A) and GPs (B), respectively. Patients included in part A are referred to the gastroenterologist for any endoscopic evaluation. Patients included in part B present at their GP because of ongoing unspecific gastrointestinal symptoms (abdominal pain, bloating, stool irregularities, diarrhoea) for at least 2 weeks. CalproQuest consists of four main and four secondary questions specific for IBD; it is considered positive if ≥2 main criteria are answered positively or one main criterion and two secondary criteria are answered positively. In part A, the sensitivity and specificity of CalproQuest for stool calprotectin levels ≥50 µg/g faeces and for positive IBD diagnosis will be investigated. In part B, the feasibility of CalproQuest in daily primary healthcare practice will be assessed. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Kanton Zurich (reference KEK-ZH-number 2013-0516). The results will be published in a peer-reviewed journal and shared with the worldwide medical community. TRIAL REGISTRATION NUMBER: ISRCTN66310845.