Skip to main content
Top
Published in: BMC Gastroenterology 1/2017

Open Access 01-12-2017 | Research article

Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis

Authors: Chelle L. Wheat, Cynthia W. Ko, Kindra Clark-Snustad, David Grembowski, Timothy A. Thornton, Beth Devine

Published in: BMC Gastroenterology | Issue 1/2017

Login to get access

Abstract

Background

The magnitude of risk of serious infections due to available medical therapies of inflammatory bowel disease (IBD) remains controversial. We conducted a systematic review and network meta-analysis of the existing IBD literature to estimate the risk of serious infection in adult IBD patients associated with available medical therapies.

Methods

Studies were identified by a literature search of PubMed, Cochrane Library, Medline, Web of Science, Scopus, EMBASE, and ProQuest Dissertations and Theses. Randomized controlled trials comparing IBD medical therapies with no restrictions on language, country of origin, or publication date were included. A network meta-analysis was used to pool direct between treatment comparisons with indirect trial evidence while preserving randomization.

Results

Thirty-nine articles fulfilled the inclusion criteria; one study was excluded from the analysis due to disconnectedness. We found no evidence of increased odds of serious infection in comparisons of the different treatment strategies against each other, including combination therapy with a biologic and immunomodulator compared to biologic monotherapy. Similar results were seen in the comparisons between the newer biologics (e.g. vedolizumab) and the anti-tumor necrosis factor agents.

Conclusions

No treatment strategy was found to confer a higher risk of serious infection than another, although wide confidence intervals indicate that a clinically significant difference cannot be excluded. These findings provide a better understanding of the risk of serious infection from IBD pharmacotherapy in the adult population.

Prospero registration

The protocol for this systematic review was registered on PROSPERO (CRD42014013497).
Appendix
Available only for authorised users
Literature
1.
go back to reference Bruzzese V, Lorenzetti R, Zullo A, Hassan C, Campo SM. Anti-TNF therapy and tuberculosis risk in rheumatic diseases, psoriasis, and IBD: A pooled-data analysis of randomized controlled trials. Annals of the Rheumatic Diseases 2013;72(3). Bruzzese V, Lorenzetti R, Zullo A, Hassan C, Campo SM. Anti-TNF therapy and tuberculosis risk in rheumatic diseases, psoriasis, and IBD: A pooled-data analysis of randomized controlled trials. Annals of the Rheumatic Diseases 2013;72(3).
2.
go back to reference Aberra FN, Lichtenstein GR. Methods to avoid infections in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2005;11:685–95.CrossRefPubMed Aberra FN, Lichtenstein GR. Methods to avoid infections in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2005;11:685–95.CrossRefPubMed
3.
go back to reference Colombel JF, Loftus EV, Tremaine WJ, et al. The safety profile of Infliximab in patients with Crohn’s disease: the mayo clinic experience in 500 patients. Gastroenterology. 2004;126:19–31.CrossRefPubMed Colombel JF, Loftus EV, Tremaine WJ, et al. The safety profile of Infliximab in patients with Crohn’s disease: the mayo clinic experience in 500 patients. Gastroenterology. 2004;126:19–31.CrossRefPubMed
4.
go back to reference Toruner M, Loftus Jr EV, Harmsen WS, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008;134:929–36.CrossRefPubMed Toruner M, Loftus Jr EV, Harmsen WS, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008;134:929–36.CrossRefPubMed
5.
go back to reference Colombel J, Sandborn W, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.CrossRefPubMed Colombel J, Sandborn W, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.CrossRefPubMed
6.
go back to reference Lichtenstein G, Cohen R, Feagan B, et al. Safety of infliximab and other Crohn’s disease therapies-TREAT registry data with nearly 24,575 patient years of follow-up. Am J Gastroenterol. 2008;103:1116. Lichtenstein G, Cohen R, Feagan B, et al. Safety of infliximab and other Crohn’s disease therapies-TREAT registry data with nearly 24,575 patient years of follow-up. Am J Gastroenterol. 2008;103:1116.
8.
go back to reference Ardizzone S, Bollani S, Manzionna G, Imbesi V, Colombo E, Bianchi PG. Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn’s disease: a randomised, investigator-blind study. Dig Liver Dis. 2003;35:619–27.CrossRefPubMed Ardizzone S, Bollani S, Manzionna G, Imbesi V, Colombo E, Bianchi PG. Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn’s disease: a randomised, investigator-blind study. Dig Liver Dis. 2003;35:619–27.CrossRefPubMed
9.
go back to reference Ardizzone S, Maconi G, Russo A, Imbesi V, Colombo E, Bianchi PG. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut. 2006;55:47–53.CrossRefPubMedPubMedCentral Ardizzone S, Maconi G, Russo A, Imbesi V, Colombo E, Bianchi PG. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut. 2006;55:47–53.CrossRefPubMedPubMedCentral
10.
go back to reference Arora S, Katkov W, Cooley J, et al. Methotrexate in Crohn’s disease: results of a randomized, double-blind, placebo-controlled trial. Hepatogastroenterology. 1999;46:1724–9.PubMed Arora S, Katkov W, Cooley J, et al. Methotrexate in Crohn’s disease: results of a randomized, double-blind, placebo-controlled trial. Hepatogastroenterology. 1999;46:1724–9.PubMed
11.
go back to reference Bar-Meir S, Chowers Y, Lavy A, et al. Budesonide versus prednisone in the treatment of active Crohn’s disease. The Israeli Budesonide Study Group. Gastroenterology. 1998;115:835–40.CrossRefPubMed Bar-Meir S, Chowers Y, Lavy A, et al. Budesonide versus prednisone in the treatment of active Crohn’s disease. The Israeli Budesonide Study Group. Gastroenterology. 1998;115:835–40.CrossRefPubMed
12.
go back to reference Bar-Meir S, Fidder H, Faszczyk M, et al. Budesonide foam vs. hydrocortisone acetate foam in the treatment of active ulcerative proctosigmoiditis. Dis Colon Rectum. 2003;46:929–36.CrossRefPubMed Bar-Meir S, Fidder H, Faszczyk M, et al. Budesonide foam vs. hydrocortisone acetate foam in the treatment of active ulcerative proctosigmoiditis. Dis Colon Rectum. 2003;46:929–36.CrossRefPubMed
13.
go back to reference Colombel J, Sandborn W, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132:52–65.CrossRefPubMed Colombel J, Sandborn W, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132:52–65.CrossRefPubMed
14.
go back to reference Cortot A, Colombel J, Rutgeerts P, et al. Switch from systemic steroids to budesonide in steroid dependent patients with inactive Crohn’s Disease. Gut. 2001;48:186–90.CrossRefPubMedPubMedCentral Cortot A, Colombel J, Rutgeerts P, et al. Switch from systemic steroids to budesonide in steroid dependent patients with inactive Crohn’s Disease. Gut. 2001;48:186–90.CrossRefPubMedPubMedCentral
15.
go back to reference D’Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet. 2008;371:660–7.CrossRefPubMed D’Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet. 2008;371:660–7.CrossRefPubMed
16.
go back to reference Ewe K, Press A, Singe C, et al. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease. Gastroenterology. 1993;105:367–72.CrossRefPubMed Ewe K, Press A, Singe C, et al. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease. Gastroenterology. 1993;105:367–72.CrossRefPubMed
17.
go back to reference Feagan B, Rochon J, Fedorak R, et al. Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators. N Engl J Med. 1995;332:292–7.CrossRefPubMed Feagan B, Rochon J, Fedorak R, et al. Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators. N Engl J Med. 1995;332:292–7.CrossRefPubMed
18.
go back to reference Feagan B, Fedorak R, Irvine E, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. North American Crohn’s Study Group Investigators. N Engl J Med. 2000;342:1627–32.CrossRefPubMed Feagan B, Fedorak R, Irvine E, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. North American Crohn’s Study Group Investigators. N Engl J Med. 2000;342:1627–32.CrossRefPubMed
19.
go back to reference Feagan B, McDonald J, Panaccione R, et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn’s disease. Gastroenterology. 2014;146:681–8.CrossRefPubMed Feagan B, McDonald J, Panaccione R, et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn’s disease. Gastroenterology. 2014;146:681–8.CrossRefPubMed
20.
go back to reference Hanauer S, Korelitz B, Rutgeerts P, et al. Postoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology. 2004;127:723–9.CrossRefPubMed Hanauer S, Korelitz B, Rutgeerts P, et al. Postoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology. 2004;127:723–9.CrossRefPubMed
22.
go back to reference Lémann M, Mary J, Duclos B, et al. Infliximab plus azathioprine for steroid-dependent Crohn’s disease patients: a randomized placebo-controlled trial. Gastroenterology. 2006;130:1054–61.CrossRefPubMed Lémann M, Mary J, Duclos B, et al. Infliximab plus azathioprine for steroid-dependent Crohn’s disease patients: a randomized placebo-controlled trial. Gastroenterology. 2006;130:1054–61.CrossRefPubMed
23.
go back to reference Mantzaris G, Sfakianakis M, Archavlis E, et al. A prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and olsalazine for the maintenance of remission of steroid-dependent ulcerative colitis. Am J Gastroenterol. 2004;99:1122–8.CrossRefPubMed Mantzaris G, Sfakianakis M, Archavlis E, et al. A prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and olsalazine for the maintenance of remission of steroid-dependent ulcerative colitis. Am J Gastroenterol. 2004;99:1122–8.CrossRefPubMed
24.
go back to reference Neurath M, Wanitschke R, Peters M, Krummenauer F, Meyer Zum Büschenfelde K, Schlaak J. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease. Gut. 1999;44:625–8.CrossRefPubMedPubMedCentral Neurath M, Wanitschke R, Peters M, Krummenauer F, Meyer Zum Büschenfelde K, Schlaak J. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease. Gut. 1999;44:625–8.CrossRefPubMedPubMedCentral
25.
go back to reference Ochsenkun T, Sackman M, Goeke B. Infliximab for acute severe ulcerative colitis: a randomized pilot study in non steroid refractory patients. Gastroenterology. 2003;124:A62.CrossRef Ochsenkun T, Sackman M, Goeke B. Infliximab for acute severe ulcerative colitis: a randomized pilot study in non steroid refractory patients. Gastroenterology. 2003;124:A62.CrossRef
26.
go back to reference Odonnell LJD, Arvind AS, Hoang P, et al. Double-blind, Controlled Trial of 4-Aminosalicylic Acid and Prednisolone Enemas in Distal Ulcerative-Colitis. Gut. 1992;33:947–9.CrossRef Odonnell LJD, Arvind AS, Hoang P, et al. Double-blind, Controlled Trial of 4-Aminosalicylic Acid and Prednisolone Enemas in Distal Ulcerative-Colitis. Gut. 1992;33:947–9.CrossRef
27.
go back to reference Oren R, Arber N, Odes S, et al. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial. Gastroenterology. 1996;110:1416–21.CrossRefPubMed Oren R, Arber N, Odes S, et al. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial. Gastroenterology. 1996;110:1416–21.CrossRefPubMed
28.
go back to reference Orth T, Peters M, Schlaak J, et al. Mycophenolate mofetil versus azathioprine in patients with chronic active ulcerative colitis: a 12 month pilot study. Am J Gastroenterol. 2000;95:1201–7.CrossRefPubMed Orth T, Peters M, Schlaak J, et al. Mycophenolate mofetil versus azathioprine in patients with chronic active ulcerative colitis: a 12 month pilot study. Am J Gastroenterol. 2000;95:1201–7.CrossRefPubMed
29.
go back to reference Prantera C, Lochs H, Grimaldi M, Danese S, Scribano M, et al. Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease. Gastroenterology. 2012;142:473–81.CrossRefPubMed Prantera C, Lochs H, Grimaldi M, Danese S, Scribano M, et al. Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease. Gastroenterology. 2012;142:473–81.CrossRefPubMed
30.
go back to reference Present D, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med. 1999;340:1398–405.CrossRefPubMed Present D, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med. 1999;340:1398–405.CrossRefPubMed
31.
go back to reference Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology. 1995;108:1617–21.CrossRefPubMed Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology. 1995;108:1617–21.CrossRefPubMed
32.
go back to reference Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.CrossRefPubMed Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.CrossRefPubMed
33.
go back to reference Rutgeerts P, Van Assche G, Vermeire S, et al. Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2005;128:856–61.CrossRefPubMed Rutgeerts P, Van Assche G, Vermeire S, et al. Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2005;128:856–61.CrossRefPubMed
34.
go back to reference Sandborn W, Present D, Isaacs K, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology. 2003;125:380–8.CrossRefPubMed Sandborn W, Present D, Isaacs K, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology. 2003;125:380–8.CrossRefPubMed
35.
go back to reference Sandborn W, Colombel J, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353:1912–25.CrossRefPubMed Sandborn W, Colombel J, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353:1912–25.CrossRefPubMed
36.
go back to reference Sandborn W, Hanauer S, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007;56:1232–9.CrossRefPubMedPubMedCentral Sandborn W, Hanauer S, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007;56:1232–9.CrossRefPubMedPubMedCentral
37.
go back to reference Sandborn W, Feagan B, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007;357:228–38.CrossRefPubMed Sandborn W, Feagan B, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007;357:228–38.CrossRefPubMed
38.
go back to reference Sandborn W, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142:257–65.CrossRefPubMed Sandborn W, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142:257–65.CrossRefPubMed
39.
go back to reference Sandborn W, Gasink C, Gao L, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med. 2012;367:1519–28.CrossRefPubMed Sandborn W, Gasink C, Gao L, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med. 2012;367:1519–28.CrossRefPubMed
40.
go back to reference Sandborn W, Feagan B, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–21.CrossRefPubMed Sandborn W, Feagan B, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–21.CrossRefPubMed
41.
go back to reference Sandborn WJ, Feagan BJ, Marano C, et al. Subcutaneous Golimumab Maintains Clinical Response in Patients with Moderate to Severe Ulcerative Colitis. Gastro 2013;In press. Sandborn WJ, Feagan BJ, Marano C, et al. Subcutaneous Golimumab Maintains Clinical Response in Patients with Moderate to Severe Ulcerative Colitis. Gastro 2013;In press.
42.
go back to reference Sands B, Kozarek R, Spainhour J, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm Bowel Dis. 2007;13:2–11.CrossRefPubMed Sands B, Kozarek R, Spainhour J, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm Bowel Dis. 2007;13:2–11.CrossRefPubMed
43.
go back to reference Schreiber S, Khaliq-Kareemi M, Lawrance I, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007;357:239–50.CrossRefPubMed Schreiber S, Khaliq-Kareemi M, Lawrance I, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007;357:239–50.CrossRefPubMed
44.
go back to reference Schreiber S, Rutgeerts P, Fedorak R, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology. 2005;129:807–18.CrossRefPubMed Schreiber S, Rutgeerts P, Fedorak R, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology. 2005;129:807–18.CrossRefPubMed
45.
go back to reference Targan S, Feagan B, Fedorak R, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology. 2007;132:1672–83.CrossRefPubMed Targan S, Feagan B, Fedorak R, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology. 2007;132:1672–83.CrossRefPubMed
46.
go back to reference Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. 2011. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. 2011.
47.
48.
49.
50.
go back to reference Lu G, Ades A. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med. 2004;23:3105–24.CrossRefPubMed Lu G, Ades A. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med. 2004;23:3105–24.CrossRefPubMed
51.
go back to reference White I. Network-Suite of Commands for Network Meta-Analysis. Cambridge: MRC Biostatistics Unit; 2015. White I. Network-Suite of Commands for Network Meta-Analysis. Cambridge: MRC Biostatistics Unit; 2015.
52.
53.
go back to reference Higgins J, Jackson D, Barrett J, Lu G, Ades A, White I. Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods. 2012;3:98–110.CrossRefPubMedPubMedCentral Higgins J, Jackson D, Barrett J, Lu G, Ades A, White I. Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods. 2012;3:98–110.CrossRefPubMedPubMedCentral
54.
go back to reference Cipriani A, Higgins J, Geddes J, Salanti G. Conceptual and technical challenges in network meta-analysis. Ann Intern Med. 2013;159:130–7.CrossRefPubMed Cipriani A, Higgins J, Geddes J, Salanti G. Conceptual and technical challenges in network meta-analysis. Ann Intern Med. 2013;159:130–7.CrossRefPubMed
56.
go back to reference D’Haens G, Reinisch W, Colombel JF, et al. Five-year Safety Data From ENCORE, a European Observational Safety Registry for Adults With Crohn’s Disease Treated With Infliximab [Remicade(R)] or Conventional Therapy. J Crohns Colitis. 2016. doi:10.1093/ecco-jcc/jjw221. [Epub ahead of print]. D’Haens G, Reinisch W, Colombel JF, et al. Five-year Safety Data From ENCORE, a European Observational Safety Registry for Adults With Crohn’s Disease Treated With Infliximab [Remicade(R)] or Conventional Therapy. J Crohns Colitis. 2016. doi:10.​1093/​ecco-jcc/​jjw221. [Epub ahead of print].
Metadata
Title
Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis
Authors
Chelle L. Wheat
Cynthia W. Ko
Kindra Clark-Snustad
David Grembowski
Timothy A. Thornton
Beth Devine
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Gastroenterology / Issue 1/2017
Electronic ISSN: 1471-230X
DOI
https://doi.org/10.1186/s12876-017-0602-0

Other articles of this Issue 1/2017

BMC Gastroenterology 1/2017 Go to the issue