Hark! It’s midnight, children dear –Duck! Here comes another year! Well, readers, when this reaches you perhaps we shall all be in 2026, perhaps not; whichever, the New Year’s Eve couplet above may amuse you as you look backward, or forward, and… but who says that time has to be linear? Very twentieth-century idea, that – we’ve made progress since then. In any case, whenever this is, here we are. ESPGHAN Journal Club isn’t like the seasons, like the years, going around and around and enough to make your head spin. Journal Club instead has one fixed, unmoving point around which everything revolves. Yes: the ultra-stable Dr Jake Mann. What has Ol’ Reliable, as he’s nicknamed, selected for us today? Coeliac disease (CD) is on Jake’s menu – how to diagnose it, how to treat it. Treatment first. In Alimentary Pharmacology & Therapeutics, by Risnes LF et al., writing from a handful of institutions in Oslo: Teriflunomide does not affect gluten-specific T-cell activity in coeliac disease – a randomised, placebo-controlled trial; and then, in a blatant attempt to reduce histopathologists and endoscopists to diagnostic irrelevance and grinding poverty, from Journal of Pediatric Gastroenterology and Nutrition, by Mandile R et al., working in Naples and Rotterdam: A set of serum proteomic biomarkers differentiates celiac children from age- and human leukocyte antigen-matched healthy controls. What, or who, is teriflunomide (“but you can call me Teri”)? Teri is an inhibitor of nuclear factor kappa–light-chain-enhancer of activated B cells (NF-κB), and she’s cytotoxic, albeit not very, which makes her valuable in dampening inflammatory activity. Teri can make activated T cells, in particular, go off the boil, which has won her a rôle in the treatment of multiple sclerosis. Risnes et al. hypothesised that she could usefully be deployed in CD. To test this in 15 children with treated CD, Risnes and co-workers fed Teri to 10 and placebo to 5 for a week, after which a gluten challenge – a slice of white bread daily for three days – was administered, with Teri continued until the end of the second week. Serum levels of interleukin-2, an acute-response indicator, were determined in samples taken four hours after the first slice of white bread was eaten. On Day 15 of the study, eight days from the first day of the challenge, the team counted gluten-specific CD4+ T cells in blood (detected by HLA-DQ2.5:gluten tetramers) that bore the activation marker CD38, a longer-term response indicator, as well as CD103+CD38+ gut-homing CD8+ T cells and γδ T cells. Gluten challenge evoked substantial acute and longer-term inflammatory responses, but Teri administration yielded no difference between cohorts in values for any analyte. Theseus in shadow, patting his way forward; at the end of the corridor, another doorless wall. The darkness, and the stench of the Minotaur, and the sick realisation – I must go back and try again. Risnes et al. have taken the Teri turning, have explored another arm of the labyrinth of how to modulate, how to understand, inflammation in CD, and met with not a doorless wall exactly; instead, a possibility assessed and found wanting. That is something. We learn that one set of ideas about CD is falsifiable. That is even something interesting. But the chagrin of acknowledging that we must go back and try again? We are Theseus. Still in the CD labyrinth with Jake’s other choice; what is that at our feet? Bend, pick up, feel the embossed letters – χτῆμα Ἀριάδνης; “property of Ariadne”. Part-unreeled, a spool of thread! This may actually get us somewhere. Indeed, Mandile et al., our collective daughter of Minos, have sorted through serum biomarkers of inflammation and have given us a clew worth following, perhaps toward light and freedom. That is, toward non-invasive diagnosis in CD that requires neither endoscopy nor mucosal biopsy. Assessments of the proteome in mucosal biopsy specimens have shown certain patterns of increases in inflammation-pathway members; Mandile et al. reviewed relative abundances of 92 such analytes in sera from 100 paediatric patients – 50 with active CD (45 documented by histopathologic study of biopsy specimens, 5 by high titres of anti-tissue transglutaminase antibodies [anti-TTA]) and 50 with HLA-DQ2/DQ8 “at-risk” phenotypes who did not have clinically manifest CD and who did not develop such CD over the nine years after serum sampling. The subjects were age-matched cohort to cohort and of similar ethnic background. Three different statistical sievings yielded seven proteins (CASP8, CXCL9, NT-3, SIRT2, STAMBP, ST1A1, and TNFSF14) that, when present in abundance, distinguished approximately 90% of CD children from non-CD children. Current algorithms for diagnosis of CD, unless anti-TTA titres are very high, require endoscopy and mucosal biopsy with demonstration in the biopsy specimen of certain features. Might demonstration of a serum protein-abundance pattern like that determined to mark CD in the patients of Mandile et al. obviate endoscopy and biopsy in other patients? To answer that question will require confirmation of this study’s findings in other cohorts of other ethnicities. Those are likely already under way. Even now, Theseus is rapidly rolling thread from the labyrinth’s floor onto Ariadne’s spool, following the clew toward a brighter future with many fewer invasive procedures in CD patients. Phlebotomy instead of endoscopy and biopsy; insights from cytokinome work into mechanisms of inflammation in CD; remarkable progress! Even with immiseration looming, paediatric endoscopists and histopathologists must concur in this assessment of what Mandile et al. have contributed with this study. Literature Mandile R et al. A set of serum proteomic biomarkers differentiates celiac children from age- and human leukocyte antigen-matched healthy controls. J Pediatr Gastroenterol Nutr. 2025 Nov 20. doi: 10.1002/jpn3.70261. Online ahead of print. PMID: 41263022. Risnes LF et al. Research communication: Teriflunomide does not affect gluten-specific T-cell activity in coeliac disease – a randomised, placebo-controlled trial. Aliment Pharmacol Ther. 2025 Nov;62(10):1027–1031. doi: 10.1111/apt.70301. Epub 2025 Jul 27. PMID: 41124699.
