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Published in: Gut Pathogens 1/2020

01-12-2020 | Infliximab | Research

Profound remission in Crohn’s disease requiring no further treatment for 3–23 years: a case series

Authors: Gaurav Agrawal, Annabel Clancy, Roy Huynh, Thomas Borody

Published in: Gut Pathogens | Issue 1/2020

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Abstract

Background

Crohn’s disease (CD) is rising in incidence and has a high morbidity and increased mortality. Current treatment use immunosuppressives but efficacy is suboptimal, and relapse is common. It has been shown that there is an imbalance present in the gut microbiome (dysbiosis) in CD with a possible infective aetiology—Mycobacterium avium subsp. paratuberculosis (MAP) being the most proposed. Antibacterial therapy and Faecal Microbiota Transplantation (FMT) are emerging treatments which can result in clinical and endoscopic remission, if employed correctly. The objective of this study was to report on the treatment and clinical outcomes of patients with CD in prolonged remission.

Results

Ten patients were identified to have achieved prolonged remission for 3–23 years (median 8.5 years). Of these, 7/10 took targeted Anti-MAP therapy (AMAT) for a median 36 months and then ceased AMAT treatment. After stopping AMAT five patients underwent Faecal Microbiota Transplantation (FMT) (average four infusions). In 4/7, AMAT was combined with infliximab (mean of six infusions) that was withdrawn within 6 months after fistulae resolution. One patient achieved deep mucosal healing with AMAT alone. Of the 3/10 patients not prescribed AMAT, one had a combination of anti-inflammatory agents and a single antibiotic (metronidazole) followed by FMT. The other two received only FMT for Clostridioides difficile Infection.

Conclusions

Prolonged remission has been achieved for 3–23 years with individualised treatments, with the majority using AMAT ± infliximab and FMT. Treatment with antibiotics and/or FMT provides a potential new avenue for treatment of CD. These findings should stimulate thinking, investigations and better therapy against MAP and the dysbiosis of the gut flora, to enable higher rates of prolonged remission.
Literature
1.
go back to reference Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG clinical guideline: management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4):481–517.PubMedCrossRef Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG clinical guideline: management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4):481–517.PubMedCrossRef
2.
go back to reference Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s Disease. N Engl J Med. 2016;375(20):1946–60.PubMedCrossRef Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s Disease. N Engl J Med. 2016;375(20):1946–60.PubMedCrossRef
3.
4.
go back to reference Yu H, Maclsaac D, Wong J, et al. Market share and costs of biologic therapies for inflammatory bowel disease in the USA. Aliment Pharmacol Ther. 2018;47(3):364–70.PubMedCrossRef Yu H, Maclsaac D, Wong J, et al. Market share and costs of biologic therapies for inflammatory bowel disease in the USA. Aliment Pharmacol Ther. 2018;47(3):364–70.PubMedCrossRef
5.
go back to reference Davis WC, Kuenstner JT, Singh SV. Resolution of Crohn’s (Johne’s) disease with antibiotics: what are the next steps? Expert Rev Gastroenterol Hepatol. 2017;11(5):393–6.PubMedCrossRef Davis WC, Kuenstner JT, Singh SV. Resolution of Crohn’s (Johne’s) disease with antibiotics: what are the next steps? Expert Rev Gastroenterol Hepatol. 2017;11(5):393–6.PubMedCrossRef
6.
go back to reference Green C, Elliott L, Beaudoin C, et al. A population-based ecologic study of inflammatory bowel disease: searching for etiologic clues. Am J Epidemiol. 2006;164(7):615–23 (Discussion 624–8).PubMedCrossRef Green C, Elliott L, Beaudoin C, et al. A population-based ecologic study of inflammatory bowel disease: searching for etiologic clues. Am J Epidemiol. 2006;164(7):615–23 (Discussion 624–8).PubMedCrossRef
7.
go back to reference Pickup R, Rhodes G, Arnott S, et al. Mycobacterium avium subsp. paratuberculosis in the catchment area and water of the river Taff in South Wales, United Kingdom, and its potential relationship to clustering of Crohn’s Disease Cases in the City of Cradiff. Appl Environ Microbiol. 2005;71(4):2130–9.PubMedPubMedCentralCrossRef Pickup R, Rhodes G, Arnott S, et al. Mycobacterium avium subsp. paratuberculosis in the catchment area and water of the river Taff in South Wales, United Kingdom, and its potential relationship to clustering of Crohn’s Disease Cases in the City of Cradiff. Appl Environ Microbiol. 2005;71(4):2130–9.PubMedPubMedCentralCrossRef
8.
go back to reference Gearry RB, Chb MB, Richardson A, et al. High incidence of Crohn’s disease in Canterbury, New Zealand: results of an epidemiologic study. Inflamm Bowel Dis. 2006;12(10):936–43.PubMedCrossRef Gearry RB, Chb MB, Richardson A, et al. High incidence of Crohn’s disease in Canterbury, New Zealand: results of an epidemiologic study. Inflamm Bowel Dis. 2006;12(10):936–43.PubMedCrossRef
9.
go back to reference Franke A, McGovern DPB, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42(12):1118–25.PubMedPubMedCentralCrossRef Franke A, McGovern DPB, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42(12):1118–25.PubMedPubMedCentralCrossRef
10.
go back to reference Strober W, Asano N, Fuss I, et al. Cellular and molecular mechanisms underlying NOD2 risk-associated polymorphisms in Crohn’s disease. Immunol Rev. 2014;260(1):249–60.PubMedCrossRef Strober W, Asano N, Fuss I, et al. Cellular and molecular mechanisms underlying NOD2 risk-associated polymorphisms in Crohn’s disease. Immunol Rev. 2014;260(1):249–60.PubMedCrossRef
11.
go back to reference Van Kruiningen H, Chiodini R, Thayer W, et al. Experimental disease in infant goats induced by a Mycobacterium isolated from a patient with Crohn’s disease. Dig Dis Sci. 1986;31(12):1351–60.PubMedCrossRef Van Kruiningen H, Chiodini R, Thayer W, et al. Experimental disease in infant goats induced by a Mycobacterium isolated from a patient with Crohn’s disease. Dig Dis Sci. 1986;31(12):1351–60.PubMedCrossRef
12.
go back to reference Selby W, Pavli P, Crotty B, et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn’s disease. Gastroenterology. 2007;132(7):2313–9.PubMedCrossRef Selby W, Pavli P, Crotty B, et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn’s disease. Gastroenterology. 2007;132(7):2313–9.PubMedCrossRef
13.
go back to reference Graham D, et al. Phase III randomised, double blind, placebo-controlled, multicenter, paralell group study to assess the efficacy and safety of add-on fixed-dose anti-mycobacterial therapy (RHB-104) in moderately to severely active Crohn’s disease. United Eur Gastroenterol. 2018;6:1586.CrossRef Graham D, et al. Phase III randomised, double blind, placebo-controlled, multicenter, paralell group study to assess the efficacy and safety of add-on fixed-dose anti-mycobacterial therapy (RHB-104) in moderately to severely active Crohn’s disease. United Eur Gastroenterol. 2018;6:1586.CrossRef
14.
go back to reference Gui GPH, Thomas PRS, Tizard MLV, et al. Two-year-outcomes analysis of Crohn’s disease treated with rifabutin and macrolide antibiotics. J Antimicrob Chemother. 1997;39(3):393–400.PubMedCrossRef Gui GPH, Thomas PRS, Tizard MLV, et al. Two-year-outcomes analysis of Crohn’s disease treated with rifabutin and macrolide antibiotics. J Antimicrob Chemother. 1997;39(3):393–400.PubMedCrossRef
15.
go back to reference Abubakar I, Myhill D, Aliyu S, et al. Detection of MAP from patients with CD using nuclei acid-based techniques: a systematic review and meta-analysis. Inflamm Bowel Dis. 2008;14:401–10.PubMedCrossRef Abubakar I, Myhill D, Aliyu S, et al. Detection of MAP from patients with CD using nuclei acid-based techniques: a systematic review and meta-analysis. Inflamm Bowel Dis. 2008;14:401–10.PubMedCrossRef
16.
go back to reference Feller M, Huwiler K, Stephan R, et al. Mycobacterium avium subspecies paratuberculosis and Crohn’s disease: a systematic review and meta-analysis. Lancet Infect Dis. 2007;7(9):607–13.PubMedCrossRef Feller M, Huwiler K, Stephan R, et al. Mycobacterium avium subspecies paratuberculosis and Crohn’s disease: a systematic review and meta-analysis. Lancet Infect Dis. 2007;7(9):607–13.PubMedCrossRef
17.
go back to reference Blevins SM, Bronze MS. Robert Koch and the “golden age” of bacteriology. Int J Infect Dis. 2010;14(9):744–51.CrossRef Blevins SM, Bronze MS. Robert Koch and the “golden age” of bacteriology. Int J Infect Dis. 2010;14(9):744–51.CrossRef
19.
go back to reference Behr MA, Hanley J. Reflection and reaction antimycobacterial therapy for Crohn’ s disease: a reanalysis. Lancet Infect Dis. 2008;8(6):344.PubMedCrossRef Behr MA, Hanley J. Reflection and reaction antimycobacterial therapy for Crohn’ s disease: a reanalysis. Lancet Infect Dis. 2008;8(6):344.PubMedCrossRef
20.
go back to reference Borody TJ, Bilkey S, Wettstein AR, et al. Anti-mycobacterial therapy in Crohn’s disease heals mucosa with longitudinal scars. Dig Liver Dis. 2007;39(5):438–44.PubMedCrossRef Borody TJ, Bilkey S, Wettstein AR, et al. Anti-mycobacterial therapy in Crohn’s disease heals mucosa with longitudinal scars. Dig Liver Dis. 2007;39(5):438–44.PubMedCrossRef
21.
go back to reference Chamberlin W, Borody TJ, Campbell J. Primary treatment of Crohn’s disease: combined antibiotics taking center stage. Expert Rev Clin Immunol. 2011;7(6):751–60.PubMedCrossRef Chamberlin W, Borody TJ, Campbell J. Primary treatment of Crohn’s disease: combined antibiotics taking center stage. Expert Rev Clin Immunol. 2011;7(6):751–60.PubMedCrossRef
22.
go back to reference Joossens M, Huys G, Cnockaert M, et al. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut. 2011;60(5):631–7.PubMedCrossRef Joossens M, Huys G, Cnockaert M, et al. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut. 2011;60(5):631–7.PubMedCrossRef
23.
go back to reference Xiang L, Ding X, Li Q, et al. Efficacy of faecal microbiota transplantation in Crohn’s disease: a new target treatment? Microb Biotechnol. 2020;1751:7915–13536. Xiang L, Ding X, Li Q, et al. Efficacy of faecal microbiota transplantation in Crohn’s disease: a new target treatment? Microb Biotechnol. 2020;1751:7915–13536.
24.
go back to reference Borody TJ, Finlayson S, Paramsothy S. Is Crohn’s disease ready for fecal microbiota transplantation? J Clin Gastroenterol. 2014;48(7):582–3.PubMedCrossRef Borody TJ, Finlayson S, Paramsothy S. Is Crohn’s disease ready for fecal microbiota transplantation? J Clin Gastroenterol. 2014;48(7):582–3.PubMedCrossRef
25.
go back to reference Cui B, Feng Q, Wang H, et al. Fecal microbiota transplantation through mid-gut for refractory Crohn’s disease: safety, feasibility, and efficacy trial results. J Gastroenterol Hepatol. 2015;30(1):51–8.PubMedCrossRef Cui B, Feng Q, Wang H, et al. Fecal microbiota transplantation through mid-gut for refractory Crohn’s disease: safety, feasibility, and efficacy trial results. J Gastroenterol Hepatol. 2015;30(1):51–8.PubMedCrossRef
26.
go back to reference Agrawal G, Borody T, Turner R, et al. Combining infliximab, anti-MAP and hyperbaric oxygen therapy for resistant fistulizing Crohn’s disease. Futur Sci OA. 2015;1(4):FS077. Agrawal G, Borody T, Turner R, et al. Combining infliximab, anti-MAP and hyperbaric oxygen therapy for resistant fistulizing Crohn’s disease. Futur Sci OA. 2015;1(4):FS077.
27.
go back to reference Laharie D, Reffet A, Belleannée G, et al. Mucosal healing with methotrexate in Crohns disease: a prospective comparative study with azathioprine and infliximab. Aliment Pharmacol Ther. 2011;33(6):714–21.PubMedCrossRef Laharie D, Reffet A, Belleannée G, et al. Mucosal healing with methotrexate in Crohns disease: a prospective comparative study with azathioprine and infliximab. Aliment Pharmacol Ther. 2011;33(6):714–21.PubMedCrossRef
28.
go back to reference Kakkar A, Wasan S, Farraye F. Targeting mucosal healing in Crohn’s disease. Gastroenterol Hepatol. 2011;7(6):374–80. Kakkar A, Wasan S, Farraye F. Targeting mucosal healing in Crohn’s disease. Gastroenterol Hepatol. 2011;7(6):374–80.
29.
go back to reference D’Haens GR, Baert F. Endoscopic healing after infliximab treatment for Crohn’s disease provides a longer time to relapse. Gastroenterology. 2002;122:A100. D’Haens GR, Baert F. Endoscopic healing after infliximab treatment for Crohn’s disease provides a longer time to relapse. Gastroenterology. 2002;122:A100.
30.
go back to reference Rutgeerts P, Van Assche G, Sandborn WJ, et al. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology. 2012;12(142):1102–11.CrossRef Rutgeerts P, Van Assche G, Sandborn WJ, et al. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology. 2012;12(142):1102–11.CrossRef
31.
go back to reference Schnitzler F, Fidder H, Ferrante M, et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease. Inflamm Bowel Dis. 2009;15:1295–301.PubMedCrossRef Schnitzler F, Fidder H, Ferrante M, et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease. Inflamm Bowel Dis. 2009;15:1295–301.PubMedCrossRef
33.
go back to reference Economou M, Trikalinos TA, Loizou KT, et al. Differential effects of NOD2 variants on Crohn’s disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol. 2004;99(12):2393–404.PubMedCrossRef Economou M, Trikalinos TA, Loizou KT, et al. Differential effects of NOD2 variants on Crohn’s disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol. 2004;99(12):2393–404.PubMedCrossRef
34.
go back to reference Pan H, Dai Y, Tang S, et al. Polymorphisms of NOD2 and the risk of tuberculosis: a validation study in the Chinese population. Int J Immunogenet. 2012;39(3):233–40.PubMedCrossRef Pan H, Dai Y, Tang S, et al. Polymorphisms of NOD2 and the risk of tuberculosis: a validation study in the Chinese population. Int J Immunogenet. 2012;39(3):233–40.PubMedCrossRef
35.
go back to reference Arrazuria R, Elguezabal N, Juste RA, et al. Mycobacterium avium subspecies paratuberculosis infection modifies gut microbiota under different dietary conditions in a rabbit model. Front Microbiol. 2016;7:1–14.CrossRef Arrazuria R, Elguezabal N, Juste RA, et al. Mycobacterium avium subspecies paratuberculosis infection modifies gut microbiota under different dietary conditions in a rabbit model. Front Microbiol. 2016;7:1–14.CrossRef
36.
go back to reference Greenstein RJ, Su L, Shahidi A, et al. On the action of 5-amino-salicylic acid and sulfapyridine on M. avium including subspecies paratuberculosis. PLoS ONE. 2007;2(6):3–7.CrossRef Greenstein RJ, Su L, Shahidi A, et al. On the action of 5-amino-salicylic acid and sulfapyridine on M. avium including subspecies paratuberculosis. PLoS ONE. 2007;2(6):3–7.CrossRef
37.
go back to reference Greenstein RJ, Su L, Juste RA, et al. On the action of cyclosporine A, rapamycin and tacrolimus on M avium including subspecies paratuberculosis. PLoS ONE. 2008;3(6):1–6.CrossRef Greenstein RJ, Su L, Juste RA, et al. On the action of cyclosporine A, rapamycin and tacrolimus on M avium including subspecies paratuberculosis. PLoS ONE. 2008;3(6):1–6.CrossRef
38.
go back to reference Krishnan MY, Manning EJB, Collins MT. Effects of interactions of antibacterial drugs with each other and with 6-mercaptopurine on in vitro growth of Mycobacterium avium subspecies paratuberculosis. J Antimicrob Chemother. 2009;64(5):1018–23.PubMedCrossRef Krishnan MY, Manning EJB, Collins MT. Effects of interactions of antibacterial drugs with each other and with 6-mercaptopurine on in vitro growth of Mycobacterium avium subspecies paratuberculosis. J Antimicrob Chemother. 2009;64(5):1018–23.PubMedCrossRef
39.
go back to reference Bach H, Rosenfeld H, Bressler B. Treatment of Crohn’s disease patients with infliximab is detrimental for the survival of MAP. pdf. J Crohns Colitis. 2012;6(5):628–9.PubMedCrossRef Bach H, Rosenfeld H, Bressler B. Treatment of Crohn’s disease patients with infliximab is detrimental for the survival of MAP. pdf. J Crohns Colitis. 2012;6(5):628–9.PubMedCrossRef
40.
go back to reference Qasem A, Naser SA. TNFα inhibitors exacerbate Mycobacterium paratuberculosis infection in tissue culture: a rationale for poor response of patients with Crohn’s disease to current approved therapy. BMJ Open Gastroenterol. 2018;5(1):e000216.PubMedPubMedCentralCrossRef Qasem A, Naser SA. TNFα inhibitors exacerbate Mycobacterium paratuberculosis infection in tissue culture: a rationale for poor response of patients with Crohn’s disease to current approved therapy. BMJ Open Gastroenterol. 2018;5(1):e000216.PubMedPubMedCentralCrossRef
41.
go back to reference Agrawal G, Clancy A, Sharma R, Huynh R, Ramrakha S, Borody T. Targeted combination antibiotic therapy induces remission in treatment-naïve Crohn’s disease: a case series. Microorganisms. 2020;8:371.CrossRefPubMedCentral Agrawal G, Clancy A, Sharma R, Huynh R, Ramrakha S, Borody T. Targeted combination antibiotic therapy induces remission in treatment-naïve Crohn’s disease: a case series. Microorganisms. 2020;8:371.CrossRefPubMedCentral
42.
go back to reference Fecteau ME, Pitta DW, Vecchiarelli B, et al. Dysbiosis of the fecal microbiota in cattle infected with Mycobacterium avium subsp. paratuberculosis. PLoS One. 2016;11(8):e0160353.PubMedPubMedCentralCrossRef Fecteau ME, Pitta DW, Vecchiarelli B, et al. Dysbiosis of the fecal microbiota in cattle infected with Mycobacterium avium subsp. paratuberculosis. PLoS One. 2016;11(8):e0160353.PubMedPubMedCentralCrossRef
44.
go back to reference Rapozo DCM, Bernardazzi C, De Souza HSP. Diet and microbiota in inflammatory bowel disease: the gut in disharmony. World J Gastroenterol. 2017;23(12):2124–40.PubMedPubMedCentralCrossRef Rapozo DCM, Bernardazzi C, De Souza HSP. Diet and microbiota in inflammatory bowel disease: the gut in disharmony. World J Gastroenterol. 2017;23(12):2124–40.PubMedPubMedCentralCrossRef
45.
go back to reference Beckler DR, Elwasila S, Ghobrial G, et al. Correlation between rpoB gene mutation in Mycobacterium avium subspecies paratuberculosis and clinical rifabutin and rifampicin resistance for treatment of Crohn’s disease. World J Gastroenterol. 2008;14(17):2723–30.PubMedPubMedCentralCrossRef Beckler DR, Elwasila S, Ghobrial G, et al. Correlation between rpoB gene mutation in Mycobacterium avium subspecies paratuberculosis and clinical rifabutin and rifampicin resistance for treatment of Crohn’s disease. World J Gastroenterol. 2008;14(17):2723–30.PubMedPubMedCentralCrossRef
46.
go back to reference Zanetti S, Molicotti P, Cannas S, et al. “In vitro” activities of antimycobacterial agents against Mycobacterium avium subsp. paratuberculosis linked to Crohn’s Disease and Paratuberculosis. Ann Clin Microbiol Antimicrob. 2006;5:3–6.CrossRef ​Zanetti S, Molicotti P, Cannas S, et al. “In vitro” activities of antimycobacterial agents against Mycobacterium avium subsp. paratuberculosis linked to Crohn’s Disease and Paratuberculosis. Ann Clin Microbiol Antimicrob. 2006;5:3–6.CrossRef
47.
go back to reference Krishnan MY, Manning EJB, Collins MT. Comparison of three methods for susceptibility testing of Mycobacterium avium subsp. paratuberculosis to 11 antimicrobial drugs. J Antimicrob Chemother. 2009;64(2):310–6.PubMedCrossRef ​Krishnan MY, Manning EJB, Collins MT. Comparison of three methods for susceptibility testing of Mycobacterium avium subsp. paratuberculosis to 11 antimicrobial drugs. J Antimicrob Chemother. 2009;64(2):310–6.PubMedCrossRef
Metadata
Title
Profound remission in Crohn’s disease requiring no further treatment for 3–23 years: a case series
Authors
Gaurav Agrawal
Annabel Clancy
Roy Huynh
Thomas Borody
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Gut Pathogens / Issue 1/2020
Electronic ISSN: 1757-4749
DOI
https://doi.org/10.1186/s13099-020-00355-8

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