title: Consumption of gluten with gluten-degrading enzyme by celiac patients: a pilot-study.
abstract: OBJECTIVE
  To assesses the safety and efficacy of Aspergillus niger prolyl endoprotease (AN-PEP) to mitigate the immunogenic effects of gluten in celiac patients.
  
  
  METHODS
  Patients with initial diagnosis of celiac disease as confirmed by positive serology with subtotal or total villous atrophy on duodenal biopsies who adhere to a strict gluten-free diet (GFD) resulting in normalised antibodies and mucosal healing classified as Marsh 0 or I were included. In a randomised double-blind placebo-controlled pilot study, patients consumed toast (approximately 7 g/d gluten) with AN-PEP for 2 wk (safety phase). After a 2-wk washout period with adherence of the usual GFD, 14 patients were randomised to gluten intake with either AN-PEP or placebo for 2 wk (efficacy phase). Measurements at baseline included complaints, quality-of-life, serum antibodies, immunophenotyping of T-cells and duodenal mucosa immunohistology. Furthermore, serum and quality of life questionnaires were collected during and after the safety, washout and efficacy phase. Duodenal biopsies were collected after the safety phase and after the efficacy phase. A change in histological evaluation according to the modified Marsh classification was the primary endpoint.
  
  
  RESULTS
  In total, 16 adults were enrolled in the study. No serious adverse events occurred during the trial and no patients withdrew during the trial. The mean score for the gastrointestinal subcategory of the celiac disease quality (CDQ) was relatively high throughout the study, indicating that AN-PEP was well tolerated. In the efficacy phase, the CDQ scores of patients consuming gluten with placebo or gluten with AN-PEP did not significantly deteriorate and moreover no differences between the groups were observed. During the efficacy phase, neither the placebo nor the AN-PEP group developed significant antibody titers. The IgA-EM concentrations remained negative in both groups. Two patients were excluded from entering the efficacy phase as their mucosa showed an increase of two Marsh steps after the safety phase, yet with undetectable serum antibodies, while 14 patients were considered histologically stable on gluten with AN-PEP. Also after the efficacy phase, no significant deterioration was observed regarding immunohistological and flow cytometric evaluation in the group consuming placebo compared to the group receiving AN-PEP. Furthermore, IgA-tTG deposit staining increased after 2 wk of gluten compared to baseline in four out of seven patients on placebo. In the seven patients receiving AN-PEP, one patient showed increased and one showed decreased IgA-tTG deposits.
  
  
  CONCLUSIONS
  AN-PEP appears to be well tolerated. However, the primary endpoint was not met due to lack of clinical deterioration upon placebo, impeding an effect of AN-PEP.
authors.affiliation: Greetje J Tack, Jolanda MW van de Water, Chris J Mulder, Department of Gastroenterology and Hepatology, VU University Medical Centre, 1007 MB Amsterdam, The Netherlands.
authors.forename: Greetje J
authors.initials: GJ
authors.lastname: Tack
authors.forename: Jolanda M W
authors.initials: JM
authors.lastname: van de Water
authors.forename: Maaike J
authors.initials: MJ
authors.lastname: Bruins
authors.forename: Engelina M C
authors.initials: EM
authors.lastname: Kooy-Winkelaar
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Bergen
authors.forename: Petra
authors.initials: P
authors.lastname: Bonnet
authors.forename: Anita C E
authors.initials: AC
authors.lastname: Vreugdenhil
authors.forename: Ilma
authors.initials: I
authors.lastname: Korponay-Szabo
authors.forename: Luppo
authors.initials: L
authors.lastname: Edens
authors.forename: B Mary E
authors.initials: BM
authors.lastname: von Blomberg
authors.forename: Marco W J
authors.initials: MW
authors.lastname: Schreurs
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Mulder
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood; D001234:Aspergillus niger / Q000201:enzymology*; D001284:Atrophy; D001706:Biopsy; D002446:Celiac Disease / Q000175:diagnosis / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D004311:Double-Blind Method; D004386:Duodenum / Q000187:drug effects / Q000473:pathology; D057487:Enzyme Therapy; D005260:Female; D005656:Fungal Proteins / Q000009:adverse effects / Q000302:isolation & purification / Q000627:therapeutic use*; D005983:Glutens / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010865:Pilot Projects; D000085822:Prolyl Oligopeptidases; D011788:Quality of Life; D012697:Serine Endopeptidases / Q000009:adverse effects / Q000302:isolation & purification / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000906:Antibodies; D005656:Fungal Proteins; D005983:Glutens; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases
keywords: Adverse events; Aspergillus niger prolyl endoprotease; Celiac disease; Enzyme; Gluten; IgA-tTG intestinal deposits; Prolyl endoprotease; Treatment; efficacy