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Outcome Measures in Coeliac Disease Trials Downloaded from http://gut.bmj.com/ on March 30, 2018 - Published by group.bmj.com Gut Online First, published on February 13, 2018 as 10.1136/gutjnl-2017-314853 Coeliac disease ORIGINAL ARTICLE Outcome measures in coeliac disease trials: the Tampere recommendations Jonas F Ludvigsson,1,2 Carolina Ciacci,3 Peter HR Green,4 Katri Kaukinen,5,6 Ilma R Korponay-Szabo,7,8 Kalle Kurppa,9,10 Joseph A Murray,11 Knut Erik Aslaksen Lundin,12,13 Markku J Maki,14,15 Alina Popp,16,17 Norelle R Reilly,18,19 Alfonso Rodriguez-Herrera,20 David S Sanders,21 Detlef Schuppan,22,23 Sarah Sleet,24 Juha Taavela,25 Kristin Voorhees,26 Marjorie M Walker,27 Daniel A Leffler28 ► Additional material is ABSTRact published online only. To view, Objective A gluten-free diet is the only treatment Significance of this study please visit the journal online option of coeliac disease, but recently an increasing (http:// dx. doi. org/ 10. 1136/ What is already known about this subject? gutjnl- 2017- 314853). number of trials have begun to explore alternative treatment strategies. We aimed to review the literature ► A gluten-free diet is the only treatment option For numbered affiliations see of coeliac disease, but recently an increasing end of article. on coeliac disease therapeutic trials and issue recommendations for outcome measures. number of trials have begun to explore alternative treatment strategies. Correspondence to Design Based on a literature review of 10 062 Dr Jonas F Ludvigsson, references, we (17 researchers and 2 patient ► A large number of trials of non-dietary Department of Medical representatives from 10 countries) reviewed the use treatments for coeliac disease are ongoing or Epidemiology and Biostatistics, and suitability of both clinical and non-clinical outcome under way. Karolinska Institutet, ► There is no consensus on outcome measures in Stockholm 171 77, Sweden; measures. We then made expert-based recommendations jonasludvigsson@ yahoo. com for use of these outcomes in coeliac disease trials and coeliac disease trials. identified areas where research is needed. What are the new findings? Received 14 July 2017 Results We comment on the use of histology, serology, After an extensive literature review, 17 Revised 19 December 2017 clinical outcome assessment (including patient-reported ► Accepted 8 January 2018 researchers and 2 patient representatives from outcomes), quality of life and immunological tools 10 countries reviewed the use and suitability including gluten immunogenic peptides for trials in of histology, serology, clinical outcome coeliac disease. assessment (including patient-reported Conclusion Careful evaluation and reporting of outcomes), quality of life and immunological outcome measures will increase transparency and tools that comprised gluten immunogenic comparability of coeliac disease therapeutic trials, and peptides for trials in coeliac disease. will benefit patients, healthcare and the pharmaceutical In this paper, we make expert-based industry. ► recommendations for use of these outcomes in coeliac disease therapeutic trials. How might it impact on clinical practice in the INTRODUCTION foreseeable future? Coeliac disease (CD) is an immune-mediated disease 1 ► Following the outlined recommendations of triggered by gluten exposure. Although character- this paper, will increase transparency and ised by small intestinal inflammation, consequences comparability of coeliac disease therapeutic are widespread and linked to diverse manifestations 2 3 4 trials with benefit to patients, healthcare and that include osteoporosis, lymphoma, pneu- the pharmaceutical industry. monia5 and increased mortality.6 Symptoms vary, with some patients having diarrhoea and malab- sorption (often termed ‘classical CD’), others suffering from constipation, fatigue and depression with CD is a daily struggle.13 In addition to the (non-classical CD) and some are asymptomatic burden of treatment, patients with CD frequently (subclinical CD).7 The global prevalence of CD is have ongoing symptoms and mucosal healing is about 1%–2%,8 9 but seems to be increasing.10 11 slow and often incomplete. For these reasons, Lifelong adherence to a gluten-free diet (GFD) there is a need for alternative treatments of CD, is the only available treatment for CD.1 For several as suggested by the intensive research efforts reasons, patients find the GFD to be exceedingly undertaken in different laboratories.17 Potential To cite: Ludvigsson JF, burdensome,12 that is, it is socially restrictive13 targets for treatment include glutenases, modi- Ciacci C, Green PHR, et al. 14–16 Gut Epub ahead of print: and more expensive than ordinary food. fied or pretreated gluten, gluten sequestrants, [please include Day Month Patients differ in their ability to adapt psycholog- neutralising antibodies, inhibitors of intestinal Year]. doi:10.1136/ ically to CD. Some people have little difficulty permeability, lymphocyte blockers, including gutjnl-2017-314853 in adopting the GFD, whereas for others, living anti-interleukin-15, tissue transglutaminase Ludvigsson JF, et al. Gut 2018;0:1–15. doi:10.1136/gutjnl-2017-314853 1 Copyright Article author (or their employer) 2018. Produced by BMJ Publishing Group Ltd (& BSG) under licence. Downloaded from http://gut.bmj.com/ on March 30, 2018 - Published by group.bmj.com Coeliac disease (TG2) inhibitors, immune tolerance induction, exposure to Meta-Analyses statement37). We aimed to highlight the state-of- hookworms and DQ2-blocking peptide analogues.17 18 Several the-art of designing intervention trials in CD. of these drugs are now being tested in phase I or phase II trials, and a recent study found that novel therapies attract the interest of patients with CD more than any other disease-re- RESUltS lated topic.19 Histology Of importance is that treatment effects are measured against Clinicopathological correlation is key to the diagnosis of CD robust standards. A recent systematic review20 identified six histo- in adults and children. In adults, confirmation of the diag- 7 38 39 logical CD activity indices,21–26 five patient-reported outcomes nosis by duodenal biopsy is the gold standard. In Europe, (PROs)27–31 and four indices for endoscopic CD activity32–35 that a ‘biopsy-sparing’ protocol (with defined limitations for use) have been used for coeliac trials. has been adopted for symptomatic children defined by an anti- In the present paper, we have explored clinical, serolog- TG2 titre ≥10 times the upper limit of normal, positive endo- ical, histological and immunological outcome measures for mysial antibody (EMA) on a second blood draw and positivity performing clinical trials in CD, and importantly, have included for human leucocyte antigen haplotypes HLA-DQ2 and/or 40 the patient perspectives concerning recommendations for their HLA-DQ8. To evaluate effective treatment for CD, quantita- use. tive histological assessment (morphometry) outperforms qualita- tive histology (eg, the Marsh score) in a trial setting.20 In clinical trials, optimised biopsy protocols should be followed for assess- METHODS ment of mucosal damage or healing. Task force Well-known classifications in histological assessment are Coauthors were invited by JFL and DAL with the aim to obtain described by Marsh and modified by Oberhuber7 38 and Corazza a group with knowledge, experiences and interests that reflect and Villanacci.41 Although grouped classifications are practical the heterogeneity of outcome measures used in trials of CD. in clinical work, recent studies have shown imperfect reproduc- Most of the participating researchers were adult gastroenterol- ibility and reliability.26 42 ogists (PHRG, CC, DSS, KKa, DS, JAM, JT, KEAL, DAL) but Recently published recommendations for biopsy diagnosis of our group also included six paediatricians (JFL, NRR, KKu, CD in adult patients for the number of biopsies and sites are MJM, AP, IRK-S), one pathologist (MMW), one basic scientist available,38 39 with optimal laboratory processing alongside struc- (AR-H) and two representatives of patient organisations (SS and tured reports to include validated morphometric analysis.26 38 KV). Members of this diverse collaboration originated from 10 It is recommended to take at least five duodenal biopsies, one countries. Most of the coauthors participated in the CD meeting or two from the duodenal bulb (D1) and four from the second organised by MJM in Tampere, Finland on 24–25 November part of the duodenum (D2).38 39 These biopsies should be taken 2016 (which provides the motivation for the subtitle of this across circular folds to avoid a crushing artefact.43 Endoscopists paper). should take one biopsy specimen per pass of the forceps in that a single-biopsy technique improves the yield of well-oriented Literature review duodenal biopsy specimens.44 Biopsies from D1 and D2 should Coauthors were divided into seven teams of three to four indi- be reviewed separately by a pathologist.45 viduals who jointly reviewed five domains: serology, histology, When processed in the laboratory, biopsies should be oriented immunology, PROs and other outcome measures. The Karo- correctly and sectioned at three levels. In trial settings it is linska Institutet library carried out literature searches for appropriate to always count intraepithelial lymphocytes (IELs) relevant papers up until 1 December 2016 (see online supple- and state the number present/100 enterocytes (normal counts mentary appendix). This search yielded 10 062 references. After are ≤25/100 enterocytes).7 26 39 45 46 IELs
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