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Randomized Trial of Ciprofloxacin Doxycycline and Hydroxychloroquine Versus Budesonide in Active Crohn’s Disease

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Abstract

Background

Increased mucosa-associated E. coli are present in Crohn’s disease, but their role in pathogenesis is uncertain.

Aims

To assess efficacy and safety of an antibiotic/hydroxychloroquine combination effective against E. coli inside macrophages.

Methods

Adults with moderately active disease (CDAI > 220–450 plus C reactive protein ≥ 5 mg/l and/or fecal calprotectin > 250 μg/g) were randomized to receive (open-label) oral budesonide (Entocort CR 9 mg/day 8 weeks, 6 mg/day 2 weeks, 3 mg/day 2 weeks) or oral ciprofloxacin 500 mg bd, doxycycline 100 mg bd, hydroxychloroquine 200 mg tds for 4 weeks, followed by doxycycline 100 mg bd and hydroxychloroquine 200 mg tds for 20 weeks. Primary endpoints were remission (CDAI ≤ 150) at 10 weeks, remission maintained to 24 weeks, and remission maintained to 52 weeks. Patients not responding (CDAI fall by > 70) by 10 weeks were invited to crossover onto the alternative therapy.

Results

Fifty-nine patients were recruited across 8 sites. Including crossover, 39 patients received antibiotics/hydroxychloroquine and 39 received budesonide. At 10 weeks, 24 weeks, and 52 weeks on initial therapy, only 2/27, 2/27, and 1/27 were in remission on antibiotics/hydroxychloroquine compared with 8/32, 1/32, and 1/32 on budesonide (P = 0.092 at 10 weeks). Withdrawals by 10 weeks due to adverse events were seen in 15 receiving antibiotics/hydroxychloroquine and 6 budesonide. Results including crossover were more promising with 9/24 patients receiving antibiotics/hydroxychloroquine per protocol in remission by 24 weeks. No correlation was seen between response to antibiotics/hydroxychloroquine and ASCA/OmpC antibody status or disease location.

Conclusion

Overall results with this antibiotic/hydroxychloroquine combination were unimpressive, but long-term remission is seen in some patients and justifies further study.

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Data accessibility statement

Anonymized patient level data can be made available on reasonable request after approval by the Trial Management Committee and after signing a data access agreement. Proposals should be directed to the corresponding author. Full trial protocol is available on journal website.

References

  1. Palmela C, Chevarin C, Xu Z, et al. Adherent-invasive Escherichia coli in inflammatory bowel disease. Gut. 2018;67:574–587.

    Article  CAS  Google Scholar 

  2. Ryan P, Kelly RG, Lee G, et al. Bacterial DNA within granulomas of patients with Crohn’s disease—detection by laser capture microdissection and PCR. Am J Gastroenterol. 2004;99:1539–1543.

    Article  CAS  Google Scholar 

  3. O’Brien CL, Pavli P, Gordon DM, et al. Detection of bacterial DNA in lymph nodes of Crohn’s disease patients using high throughput sequencing. Gut. 2014;63:1596–1606.

    Article  Google Scholar 

  4. Gutiérrez A, Zapater P, Juanola O, et al. Gut bacterial DNA translocation is an independent risk factor of flare at short term in patients with Crohn’s disease. Am J Gastroenterol. 2016;111:529–540.

    Article  Google Scholar 

  5. Keita ÅV, Alkaissi LY, Holm EB, et al. Enhanced E. coli LF82 translocation through follicle-associated epithelium in Crohn’s disease is dependent on long polar fimbriae and CEACAM6-expression, and increases paracellular permeability. J Crohns Colitis. 2020;14:216–229.

    Article  Google Scholar 

  6. Roberts CL, Keita AV, Duncan SH, et al. Translocation of Crohn’s disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers. Gut. 2010;59:1331–1339.

    Article  Google Scholar 

  7. Darfeuille-Michaud A, Boudeau J, Bulois P, et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology. 2004;127:412–421.

    Article  Google Scholar 

  8. Bringer MA, Glasser AL, Tung CH, et al. The Crohn’s disease-associated adherent-invasive Escherichia coli strain LF82 replicates in mature phagolysosomes within J774 macrophages. Cell Microbiol. 2006;8:471–484.

    Article  CAS  Google Scholar 

  9. Meconi S, Vercellone A, Levillain F, et al. Adherent-invasive Escherichia coli isolated from Crohn’s disease patients induce granulomas in vitro. Cell Microbiol. 2007;9:1252–1261.

    Article  CAS  Google Scholar 

  10. O’Brien CL, Bringer MA, Holt KE, et al. Comparative genomics of Crohn’s disease-associated adherent-invasive Escherichia coli. Gut. 2017;66:1382–1389.

    Article  Google Scholar 

  11. Subramanian S, Roberts CL, Hart CA, et al. Replication of colonic Crohn’s disease mucosal Escherichia coli isolates within macrophages and their susceptibility to antibiotics. Antimicrob Agents Chemother. 2008;52:427–434.

    Article  CAS  Google Scholar 

  12. Townsend CM, Parker CE, MacDonald JK, et al. Antibiotics for induction and maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2019;2:CD012730. https://doi.org/10.1002/14651858.

    Article  CAS  PubMed  Google Scholar 

  13. Prantera C, Lochs H, Grimaldi M, et al. Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease. Gastroenterology. 2012;142:473–481.

    Article  CAS  Google Scholar 

  14. Arnold GL, Beaves MR, Pryjdun VO, et al. Preliminary study of ciprofloxacin in active Crohn’s disease. Inflamm Bowel Dis. 2002;8:10–15.

    Article  Google Scholar 

  15. Su JW, Ma JJ, Zhang HJ. Use of antibiotics in patients with Crohn’s disease: a systematic review and meta-analysis. J Dig Dis. 2015;16:58–66.

    Article  CAS  Google Scholar 

  16. Levine A, Kori M, Kierkus J, et al. Azithromycin and metronidazole versus metronidazole-based therapy for the induction of remission in mild to moderate paediatric Crohn’s disease: a randomised controlled trial. Gut. 2019;68:239–247.

    Article  CAS  Google Scholar 

  17. Fenollar F, Lagier JC, Raoult D. Tropheryma whipplei and Whipple’s disease. J Infect. 2014;69:103–112.

    Article  Google Scholar 

  18. van Roeden SE, Bleeker-Rovers CP, de Regt MJA, et al. Treatment of chronic Q fever: clinical efficacy and toxicity of antibiotic regimens. Clin Infect Dis. 2018;66:719–726.

    Article  Google Scholar 

  19. Lagier JC, Fenollar F, Lepidi H, et al. Treatment of classic Whipple’s disease: from in vitro results to clinical outcome. J Antimicrob Chemother. 2014;69:219–227.

    Article  CAS  Google Scholar 

  20. Flanagan PK, Chiewchengchol D, Wright HL, et al. Killing of Escherichia coli by Crohn’s disease monocyte-derived macrophages and Its enhancement by hydroxychloroquine and vitamin D. Inflamm Bowel Dis. 2015;21:1499–1510.

    Article  Google Scholar 

  21. Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2011;60:571–607.

    Article  Google Scholar 

  22. Rutgeerts P, Löfberg R, Malchow H, et al. A comparison of budesonide with prednisolone for active Crohn’s disease. N Engl J Med. 1994;331:842–845.

    Article  CAS  Google Scholar 

  23. Subramanian S, Asher R, Weston W, et al. Validation of a simple 0 to 10 numerical score (IBD-10) of patient-reported inflammatory bowel disease activity for routine clinical use. Inflamm Bowel Dis. 2016;22:1902–1907.

    Article  Google Scholar 

  24. Kuenzig ME, Rezaie A, Kaplan GG, et al. Budesonide for the induction and maintenance of remission in Crohn’s disease: systematic review and meta-analysis for the cochrane collaboration. J Can Assoc Gastroenterol. 2018;1:159–173.

    Article  Google Scholar 

  25. Sendid B, Colombel JF, Jacquinot PM, et al. Specific antibody response to oligomannosidic epitopes in Crohn’s disease. Clin Diagn Lab Immunol. 1996;3:219–226.

    Article  CAS  Google Scholar 

  26. Young M, Davies MJ, Bailey D, et al. Characterization of oligosaccharides from an antigenic mannan of Saccharomyces cerevisiae. Glycoconj J. 1998;15:815–822.

    Article  CAS  Google Scholar 

  27. Mpofu CM, Campbell BJ, Subramanian S, et al. Microbial mannan inhibits bacterial killing by macrophages: a possible pathogenic mechanism for Crohn’s disease. Gastroenterology. 2007;133:1487–1498.

    Article  CAS  Google Scholar 

  28. Standaert-Vitse A, Jouault T, Vandewalle P, et al. Candida albicans is an immunogen for anti-Saccharomyces cerevisiae antibody markers of Crohn’s disease. Gastroenterology. 2006;130:1764–1775.

    Article  CAS  Google Scholar 

  29. Hase K, Kawano K, Nochi T, et al. Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature. 2009;462:226–230.

    Article  CAS  Google Scholar 

  30. Roggenbuck D, Reinhold D, Wex T, et al. Autoantibodies to GP2, the major zymogen granule membrane glycoprotein, are new markers in Crohn’s disease. Clin Chim Acta. 2011;412:718–724.

    Article  CAS  Google Scholar 

  31. Schwardt O, Rabbani S, Hartmann M, et al. Design, synthesis and biological evaluation of mannosyl triazoles as FimH antagonists. Bioorg Med Chem. 2011;19:6454–6473.

    Article  CAS  Google Scholar 

  32. Subramanian S, Ekbom A, Rhodes JM. Recent advances in clinical practice: a systematic review of isolated colonic Crohn’s disease: the third IBD? Gut. 2017;66:362–381.

    Article  CAS  Google Scholar 

  33. Dulai PS, Singh S, Vande Casteele N, et al. Should we divide Crohn’s disease into ileum-dominant and isolated colonic diseases? Clin Gastroenterol Hepatol. 2019;17:2634–2643.

    Article  Google Scholar 

  34. Buisson A, Vazeille E, Hébuterne X, et al. Non-invasive identification of adherent-invasive E. coli in patients with Crohn’s disease. J Crohn’s Colitis. 2020;14:S044–S045.

    Article  Google Scholar 

  35. Palm NW, de Zoete MR, Cullen TW, et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell. 2014;158:1000–1010.

    Article  CAS  Google Scholar 

  36. Oka A, Sartor RB. Microbial-Based and microbial-targeted therapies for inflammatory bowel diseases. Dig Dis Sci. 2020;65:757–788. https://doi.org/10.1007/s10620-020-06090-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

We are extremely grateful to the patients and clinical and research support staff who contributed to this trial; to the independent members of our Trial Steering Committee: Professor John Williams (Chair), Catherine Charles, and Ian Finnie; to our independent Data Monitoring Committee: Professor John McLaughlin (Chair), Ash Bassi, Jimmy Limdi, Graeme MacLennan, and Emma Wesley; to David Tyrer and Marc Williamson for data management and meeting coordination; to Debbie Atkinson for assistance with governance; and to our co-sponsors the University of Liverpool and the R and D Department of the Royal Liverpool and Broadgreen University Hospitals Trust. We are also very grateful to Prometheus® Laboratories Inc., San Diego, for performing the serological assays for ASCA and anti-bacterial antibodies.

Funding

This study was supported by a grant M/12/3 from Crohn’s and Colitis UK plus support from the National Institute of Health Research Clinical Research Network.

Author information

Authors and Affiliations

  1. Henry Wellcome Laboratory, Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, Royal Liverpool University Hospital, University of Liverpool, Nuffield Building, Crown Street, Liverpool, L69 3GE, UK

    Jonathan M. Rhodes, Sreedhar Subramanian, Kate Martin & Christopher Probert

  2. Wirral University Teaching Hospital, Birkenhead, UK

    Paul K. Flanagan

  3. Biomathematics and Statistics Scotland, Aberdeen, UK

    Graham W. Horgan

  4. Newcastle upon Tyne Hospitals, Newcastle upon Tyne, UK

    John Mansfield

  5. Cambridge University Hospitals, Cambridge, UK

    Miles Parkes

  6. St Mark’s Hospital, Harrow, UK

    Ailsa Hart

  7. James Cook University Hospital, Middlesbrough, UK

    Helen Dallal

  8. Queen Elizabeth Hospital Birmingham, Birmingham, UK

    Tariq Iqbal

  9. Shrewsbury and Telford Hospital, Shrewsbury, UK

    Jeffrey Butterworth

  10. Liverpool Cancer Trials Unit, Liverpool, UK

    Kate Culshaw

Authors
  1. Jonathan M. Rhodes
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  2. Sreedhar Subramanian
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Contributions

JMR, PF, and GH designed the trial. JMR and then CP were Chief Investigators. SS, PF, JM, MP, AH, HD, TI, JB, and CP all recruited and treated patients. KM and KC collected and monitored the data. GH and JMR analyzed the data. JMR, CP, and GH drafted the manuscript. All authors critically revised the manuscript for important intellectual content.

Corresponding author

Correspondence to Jonathan M. Rhodes.

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Conflicts of interest

JMR has been a member of advisory boards for Atlantic, Pharmacosmos, Procter and Gamble, and Vifor and Falk, has received speaking honoraria from Abbott, Allergan, Falk, Ferring, Glaxo Smith Kline, Merck, Procter and Gamble, Schering Plough, Shire, and Wyeth, and with the University of Liverpool and Provexis UK, holds a patent for use of a soluble fiber preparation as maintenance therapy for Crohn’s disease plus a patent for its use in antibiotic-associated diarrhea. The patent also held with the University of Liverpool and others in relation to use of modified heparins in cancer therapy. SS has received speaker fee from MSD, Actavis, Abbvie, Dr Falk pharmaceuticals, Shire, and received educational grant from MSD, Abbvie, and Actavis, and is an advisory board member for Abbvie, Dr Falk Pharma, and Vifor. PKF received a Shire Innovation Fund award and has received funded conference travel from Shire and Tillotts. GWH has provided consultancy for Provexis, Nutricia, and 4DPharma. AH has served as a consultant, advisory board member, or speaker for AbbVie, Arena, Atlantic, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire, and Takeda. She also serves on the Global Steering Committee for Genentech. CP has received speaker fees from Vifor, payment for advisory board attendance from Dr Falk Pharma, and support for attendance to other meetings from Dr Falk Pharma and Vifor. The other authors have no competing interests.

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Rhodes, J.M., Subramanian, S., Flanagan, P.K. et al. Randomized Trial of Ciprofloxacin Doxycycline and Hydroxychloroquine Versus Budesonide in Active Crohn’s Disease. Dig Dis Sci 66, 2700–2711 (2021). https://doi.org/10.1007/s10620-020-06477-y

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  • DOI: https://doi.org/10.1007/s10620-020-06477-y

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