Emergence of Inflammatory Bowel Disease During Treatment With Secukinumab

Emergence of Inflammatory Bowel Disease During Treatment With Secukinumab Abstract Secukinumab is an anti-IL 17A monoclonal antibody currently licensed for the treatment of plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. However, although inflammatory bowel disease is a disorder with related immune characteristics, secukinumab has not proved to be effective in these diseases. In fact, negative results in a clinical trial designed to assess the efficacy of secukinumab in patients with Crohn’s disease have been published. On the other hand, the drug fact sheet states that secukinumab should be used with caution in patients with inflammatory bowel disease. Although the drug has shown to worsen these pathologies, there are no published data of cases in which the patient is first diagnosed with inflammatory bowel disease during secukinumab treatment. We present two cases of emergence of inflammatory bowel disease in patients with plaque psoriasis and ankylosing spondylitis, treated with secukinumab. Secukinumab, IBD, adverse effects; clinical trials, epidemiology, pathology 1. Introduction Secukinumab is a human monoclonal anti-interleukin-17 (IL17) antibody approved in Europe in 2015 for the treatment of psoriasis, psoriatic arthropathy, and ankylosing spondylitis (AS). However for inflammatory bowel disease (IBD), which is associated with the above diseases, indication for secukinumab is not authorised; and the medication fact sheet notifies that it should be used cautiously in patients with IBD.1 In 2012, Hueber et al.2 published the results of a clinical trial about the efficacy and safety of secukinumab versus placebo in the treatment of patients with moderate to severe Crohn’s disease (CD); the results were unexpected, considering that secukinumab increased disease-worsening more than placebo, leading to early completion of the clinical trial. Regarding ulcerative colitis (UC), no studies have been conducted with this drug for the moment. On the other hand, the safety results of clinical trials carried out with secukinumab for dermatological and rheumatic diseases describe exacerbations or new cases of IBD, with a low incidence.3,4 It should be mentioned that as the first drug in this new therapeutic group, long-term safety data of secukinumab are limited. Therefore, some safety issues remain unresolved and should be addressed in the post-marketing period through the results of ongoing studies and the recording of reported adverse reactions (ADRs). Additionally, there are no published clinical cases of IBD development after the commercialisation and use of secukinumab in actual clinical practice. We present two clinical cases of debut IBD in patients treated with this anti-IL17 antibody; ethical responsibilities have been taken into account. 2. Case report 2.1. First case This is the case of a 19-year-old female patient with penicillin allergy and smoking habit, who was diagnosed with generalised plaque psoriasis 3 years earlier. The patient had started methotrexate treatment with a good clinical response in the past year, but this was suspended due to intolerance (asthenia and arthromyalgia) and recurrence of the skin lesions. Subsequently subcutaneous (SC) secukinumab 300 mg/4 weeks was started, with a previous induction regimen. Two months after treatment the response was satisfactory, but nausea (without vomiting), abdominal pain (predominantly mesogastric), and soft stools appeared in the past 3 weeks, with progressive worsening leading to hospital admission. The patient referred to presenting in the past 4 years episodes of abdominal pain of similar characteristics but with slight intensity and brief duration. The pains spontaneously subsided, and the patient hadnot consulted for this reason. At physical examination, absence of psoriatic lesions and presence of pain on the abdominal palpation were observed, predominantly in the mesogastrium and right flank. Analytical data collected leukocytes 17180 cells/µL, haemoglobin (Hb) 12.7 g/dL, C-reactive protein (CRP) 170 mg/L, normal remainder. Microbiological stool examination: culture, parasites, and Clostridium difficile toxin were negative. Abdominal ultrasound resulted without alterations. At ileo-colonoscopy, presence of aphtoid ulcers from sigmodes with predominance in the right colon and ileum were noted. The histology examination revealed inflammatory alterations compatible with CD. AT magnetic resonance enterography, a slight thickening of the distal ileum wall and ileocaecal valve was observed, in an extension of 5 cm with enhancement after administration of contrast, without extramural involvement, inflammatory collections, or fistula trajectories. The patient was diagnosed as having ileocolic CD, with an inflammatory pattern. Treatment with corticosteroids was indicated and the digestive symptoms and analytical alterations reported remitted. Secukinumab was discontinued and ustekinumab was indicated for psoriasis control. 2.2. Second case In this case, a 60-year-old male patient, ex-smoker for 20 years, was diagnosed 21 years ago with positive HLA-B27 AS. No other interesting background information was detected. He was in treatment with naproxen, but due to poor control of the disease it was necessary to add sulphasalazine 500 mg/8 h, tramadol 50 mg/8 h and SC secukinumab 150 mg/4 weeks (with a previous induction regimen). At the third induction dose, the patient reported abdominal pain in the hypogastrium, diarrhoea of 10–12 bowel movements daily, and rectal bleeding. His medication was stopped without improvement, and he had to be admitted to the hospital. Outstanding analytical data at admission comprised Hb 14 g/dL and CRP 128 mg/L. After abdominal computed tomography and colonoscopy, he was diagnosed as having ulcerative colitis with severe endoscopic activity, at least up to 40 cm from the anal margin. Full-dose intravenous (IV) steroid treatment, mesalazine enemas, and initiation of a biologic drug (infliximab) for corticosteroid refractoriness were indicated. After the second dose of infliximab, the patient followed a favourable course, and the symptoms completely remitted. 3. Discussion The association between different immune-mediated inflammatory pathologies such as rheumatoid arthritis, AS, IBD, psoriasis, hidradenitis suppurativa, and uveitis, is widely known. These diseases share pathogenic immune-based mechanisms and some pharmacological treatments, which require multidisciplinary collaboration among dermatologists, rheumatologists, and gastroenterologists. Therefore, it is necessary for all of these to know the different treatments used in these types of patients. Secukinumab is a biologic drug licensed for the treatment of psoriasis, psoriatic arthropathy, and AS, but not for IBD.1 In fact, a multicentre phase II study has been published comparing secukinumab with placebo in 59 patients with CD, and it had to stop before the appointed date because of a statistically significant difference in the mean disease activity index in favour of placebo.2 On the other hand, the safety profile from secukinumab studies in patients with dermatological and rheumatological pathology showed a low incidence of adverse events in the digestive tract. Thus, Van de Kerkhof et al.3 performed a safety analysis of secukinumab in 10 phase II and phase III clinical studies of patients with plaque psoriasis. A total of 3993 patients were included, with an incidence of 0.33 cases of IBD per 100 patient/years. They considered there was not significant relationship between secukinumab and IBD. Regarding patients with AS, two phase III clinical trials were conducted (patients with this pathology treated with secukinumab). In the safety results, exacerbations or new cases of IBD occurred with an incidence of 0.7 per 100 patient/years.4 In our case, since the incorporation of secukinumab into the hospital’s Pharmacotherapeutic Guide, the total number of patients treated with this drug until February 2018 was 53 (25 from dermatology, 28 from rheumatology). Following the information on the first appearance of CD related to secukinumab, the hospital Pharmacy Service carried out an active search for all patients who had been undergoing treatment with the drug at some point, thus finding the second clinical case that we report. Both ADRs have been notified to the Andalusian Centre of Pharmacovigilance. We must remark that ustekinumab, a human monoclonal antibody against interleukins 12/23 (IL12/23), is effective in the treatment of both psoriasis and CD.5 It has been speculated that IL17, unlike IL12/23, may have a protective role on the intestinal mucosa.6–12 The cases presented illustrate the negative relationship between secukinumab and IBD, as it may not only worsen the progression of this disease in patients with psoriasis or AS, but also may put in evidence cases of subclinical or latent disease. In conclusion, in addition to the warning against the use of secukinumab in IBD, in view of the two clinical cases detected, the need for an anamnesis and close monitoring of possible digestive manifestations should be considered in all patients treated with this drug. Ustekinumab, infliximab, or adalimumab would be safer therapeutic options in these cases. Funding None. Conflict of Interest Authors declare no conflict of interest Author Contributions ML: concept and design of study, acquisition, analysis, and interpretation of data, draft and revision of article. RG: concept and design of study, acquisition, analysis, and interpretation of data, draft of article. MF: concept and design of study, analysis and interpretation of data, draft and revision of article. References 1. Agencia Española de Medicamentos y Productos Sanitarios . CIMA (Centro de Información de Medicamentos). Ficha Técnica de Secukinumab . (Spanish Agency of Medicines and Health Products. CIMA [Drug Information Center]). Secukinumab Technical Data Sheet . https://cima.aemps.es/cima/pdfs/es/ft/114980003/FT_114980003.pdf. Accessed March 29, 2018. 2. Hueber W , Sands BE , Lewitzky S et al. ; Secukinumab in Crohn’s Disease Study Group . Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial . Gut 2012 ; 61 : 1693 – 700 . Google Scholar CrossRef Search ADS PubMed 3. Van de Kerkhof PC , Griffiths CE , Reich K et al. Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis . J Am Acad Dermatol 2016 ; 75 : 83 – 98.e4 . Google Scholar CrossRef Search ADS PubMed 4. Baeten D , Sieper J , Braun J et al. ; MEASURE 1 Study Group; MEASURE 2 Study Group . Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis . N Engl J Med 2015 ; 373 : 2534 – 48 . Google Scholar CrossRef Search ADS PubMed 5. Agencia Española de Medicamentos y Productos Sanitarios . CIMA (Centro de Información de Medicamentos). Ficha Técnica De Ustekinumab . (Spanish Agency of Medicines and Health Products. CIMA [Drug Information Center]). Ustekinumab Technical Data Sheet . https://cima.aemps.es/cima/pdfs/es/ft/08494001/FT_08494001.pdf. Accessed March 30, 2018. 6. Targan SR , Feagan BG , Vermeire S et al. A Randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of AMG 827 in subjects with moderate to severe Crohn’s disease . Gastroenterology 2012 ; 143 : E26 – 6 . Google Scholar CrossRef Search ADS 7. Poulain D , Sendid B , Standaert-Vitse A et al. Yeasts: neglected pathogens . Dig Dis 2009 ; 27 ( Suppl 1 ): 104 – 10 . Google Scholar CrossRef Search ADS PubMed 8. Strober W , Zhang F , Kitani A , Fuss I , Fichtner-Feigl S . Proinflammatory cytokines underlying the inflammation of Crohn’s disease . Curr Opin Gastroenterol 2010 ; 26 : 310 – 7 . Google Scholar CrossRef Search ADS PubMed 9. Puel A , Döffinger R , Natividad A et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I . J Exp Med 2010 ; 207 : 291 – 7 . Google Scholar CrossRef Search ADS PubMed 10. Liu L , Okada S , Kong XF et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis . J Exp Med 2011 ; 208 : 1635 – 48 . Google Scholar CrossRef Search ADS PubMed 11. Fragoulis GE , Siebert S , McInnes IB . Therapeutic targeting of IL-17 and IL-23 cytokines in immune-mediated diseases . Annu Rev Med 2016 ; 67 : 337 – 53 . Google Scholar CrossRef Search ADS PubMed 12. Dige A , Støy S , Rasmussen TK et al. Increased levels of circulating Th17 cells in quiescent versus active Crohn’s disease . J Crohns Colitis 2013 ; 7 : 248 – 55 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Emergence of Inflammatory Bowel Disease During Treatment With Secukinumab

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Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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Abstract

Abstract Secukinumab is an anti-IL 17A monoclonal antibody currently licensed for the treatment of plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. However, although inflammatory bowel disease is a disorder with related immune characteristics, secukinumab has not proved to be effective in these diseases. In fact, negative results in a clinical trial designed to assess the efficacy of secukinumab in patients with Crohn’s disease have been published. On the other hand, the drug fact sheet states that secukinumab should be used with caution in patients with inflammatory bowel disease. Although the drug has shown to worsen these pathologies, there are no published data of cases in which the patient is first diagnosed with inflammatory bowel disease during secukinumab treatment. We present two cases of emergence of inflammatory bowel disease in patients with plaque psoriasis and ankylosing spondylitis, treated with secukinumab. Secukinumab, IBD, adverse effects; clinical trials, epidemiology, pathology 1. Introduction Secukinumab is a human monoclonal anti-interleukin-17 (IL17) antibody approved in Europe in 2015 for the treatment of psoriasis, psoriatic arthropathy, and ankylosing spondylitis (AS). However for inflammatory bowel disease (IBD), which is associated with the above diseases, indication for secukinumab is not authorised; and the medication fact sheet notifies that it should be used cautiously in patients with IBD.1 In 2012, Hueber et al.2 published the results of a clinical trial about the efficacy and safety of secukinumab versus placebo in the treatment of patients with moderate to severe Crohn’s disease (CD); the results were unexpected, considering that secukinumab increased disease-worsening more than placebo, leading to early completion of the clinical trial. Regarding ulcerative colitis (UC), no studies have been conducted with this drug for the moment. On the other hand, the safety results of clinical trials carried out with secukinumab for dermatological and rheumatic diseases describe exacerbations or new cases of IBD, with a low incidence.3,4 It should be mentioned that as the first drug in this new therapeutic group, long-term safety data of secukinumab are limited. Therefore, some safety issues remain unresolved and should be addressed in the post-marketing period through the results of ongoing studies and the recording of reported adverse reactions (ADRs). Additionally, there are no published clinical cases of IBD development after the commercialisation and use of secukinumab in actual clinical practice. We present two clinical cases of debut IBD in patients treated with this anti-IL17 antibody; ethical responsibilities have been taken into account. 2. Case report 2.1. First case This is the case of a 19-year-old female patient with penicillin allergy and smoking habit, who was diagnosed with generalised plaque psoriasis 3 years earlier. The patient had started methotrexate treatment with a good clinical response in the past year, but this was suspended due to intolerance (asthenia and arthromyalgia) and recurrence of the skin lesions. Subsequently subcutaneous (SC) secukinumab 300 mg/4 weeks was started, with a previous induction regimen. Two months after treatment the response was satisfactory, but nausea (without vomiting), abdominal pain (predominantly mesogastric), and soft stools appeared in the past 3 weeks, with progressive worsening leading to hospital admission. The patient referred to presenting in the past 4 years episodes of abdominal pain of similar characteristics but with slight intensity and brief duration. The pains spontaneously subsided, and the patient hadnot consulted for this reason. At physical examination, absence of psoriatic lesions and presence of pain on the abdominal palpation were observed, predominantly in the mesogastrium and right flank. Analytical data collected leukocytes 17180 cells/µL, haemoglobin (Hb) 12.7 g/dL, C-reactive protein (CRP) 170 mg/L, normal remainder. Microbiological stool examination: culture, parasites, and Clostridium difficile toxin were negative. Abdominal ultrasound resulted without alterations. At ileo-colonoscopy, presence of aphtoid ulcers from sigmodes with predominance in the right colon and ileum were noted. The histology examination revealed inflammatory alterations compatible with CD. AT magnetic resonance enterography, a slight thickening of the distal ileum wall and ileocaecal valve was observed, in an extension of 5 cm with enhancement after administration of contrast, without extramural involvement, inflammatory collections, or fistula trajectories. The patient was diagnosed as having ileocolic CD, with an inflammatory pattern. Treatment with corticosteroids was indicated and the digestive symptoms and analytical alterations reported remitted. Secukinumab was discontinued and ustekinumab was indicated for psoriasis control. 2.2. Second case In this case, a 60-year-old male patient, ex-smoker for 20 years, was diagnosed 21 years ago with positive HLA-B27 AS. No other interesting background information was detected. He was in treatment with naproxen, but due to poor control of the disease it was necessary to add sulphasalazine 500 mg/8 h, tramadol 50 mg/8 h and SC secukinumab 150 mg/4 weeks (with a previous induction regimen). At the third induction dose, the patient reported abdominal pain in the hypogastrium, diarrhoea of 10–12 bowel movements daily, and rectal bleeding. His medication was stopped without improvement, and he had to be admitted to the hospital. Outstanding analytical data at admission comprised Hb 14 g/dL and CRP 128 mg/L. After abdominal computed tomography and colonoscopy, he was diagnosed as having ulcerative colitis with severe endoscopic activity, at least up to 40 cm from the anal margin. Full-dose intravenous (IV) steroid treatment, mesalazine enemas, and initiation of a biologic drug (infliximab) for corticosteroid refractoriness were indicated. After the second dose of infliximab, the patient followed a favourable course, and the symptoms completely remitted. 3. Discussion The association between different immune-mediated inflammatory pathologies such as rheumatoid arthritis, AS, IBD, psoriasis, hidradenitis suppurativa, and uveitis, is widely known. These diseases share pathogenic immune-based mechanisms and some pharmacological treatments, which require multidisciplinary collaboration among dermatologists, rheumatologists, and gastroenterologists. Therefore, it is necessary for all of these to know the different treatments used in these types of patients. Secukinumab is a biologic drug licensed for the treatment of psoriasis, psoriatic arthropathy, and AS, but not for IBD.1 In fact, a multicentre phase II study has been published comparing secukinumab with placebo in 59 patients with CD, and it had to stop before the appointed date because of a statistically significant difference in the mean disease activity index in favour of placebo.2 On the other hand, the safety profile from secukinumab studies in patients with dermatological and rheumatological pathology showed a low incidence of adverse events in the digestive tract. Thus, Van de Kerkhof et al.3 performed a safety analysis of secukinumab in 10 phase II and phase III clinical studies of patients with plaque psoriasis. A total of 3993 patients were included, with an incidence of 0.33 cases of IBD per 100 patient/years. They considered there was not significant relationship between secukinumab and IBD. Regarding patients with AS, two phase III clinical trials were conducted (patients with this pathology treated with secukinumab). In the safety results, exacerbations or new cases of IBD occurred with an incidence of 0.7 per 100 patient/years.4 In our case, since the incorporation of secukinumab into the hospital’s Pharmacotherapeutic Guide, the total number of patients treated with this drug until February 2018 was 53 (25 from dermatology, 28 from rheumatology). Following the information on the first appearance of CD related to secukinumab, the hospital Pharmacy Service carried out an active search for all patients who had been undergoing treatment with the drug at some point, thus finding the second clinical case that we report. Both ADRs have been notified to the Andalusian Centre of Pharmacovigilance. We must remark that ustekinumab, a human monoclonal antibody against interleukins 12/23 (IL12/23), is effective in the treatment of both psoriasis and CD.5 It has been speculated that IL17, unlike IL12/23, may have a protective role on the intestinal mucosa.6–12 The cases presented illustrate the negative relationship between secukinumab and IBD, as it may not only worsen the progression of this disease in patients with psoriasis or AS, but also may put in evidence cases of subclinical or latent disease. In conclusion, in addition to the warning against the use of secukinumab in IBD, in view of the two clinical cases detected, the need for an anamnesis and close monitoring of possible digestive manifestations should be considered in all patients treated with this drug. Ustekinumab, infliximab, or adalimumab would be safer therapeutic options in these cases. Funding None. Conflict of Interest Authors declare no conflict of interest Author Contributions ML: concept and design of study, acquisition, analysis, and interpretation of data, draft and revision of article. RG: concept and design of study, acquisition, analysis, and interpretation of data, draft of article. MF: concept and design of study, analysis and interpretation of data, draft and revision of article. References 1. Agencia Española de Medicamentos y Productos Sanitarios . CIMA (Centro de Información de Medicamentos). Ficha Técnica de Secukinumab . (Spanish Agency of Medicines and Health Products. CIMA [Drug Information Center]). Secukinumab Technical Data Sheet . https://cima.aemps.es/cima/pdfs/es/ft/114980003/FT_114980003.pdf. Accessed March 29, 2018. 2. Hueber W , Sands BE , Lewitzky S et al. ; Secukinumab in Crohn’s Disease Study Group . Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial . Gut 2012 ; 61 : 1693 – 700 . Google Scholar CrossRef Search ADS PubMed 3. Van de Kerkhof PC , Griffiths CE , Reich K et al. Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis . J Am Acad Dermatol 2016 ; 75 : 83 – 98.e4 . Google Scholar CrossRef Search ADS PubMed 4. Baeten D , Sieper J , Braun J et al. ; MEASURE 1 Study Group; MEASURE 2 Study Group . Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis . N Engl J Med 2015 ; 373 : 2534 – 48 . Google Scholar CrossRef Search ADS PubMed 5. Agencia Española de Medicamentos y Productos Sanitarios . CIMA (Centro de Información de Medicamentos). Ficha Técnica De Ustekinumab . (Spanish Agency of Medicines and Health Products. CIMA [Drug Information Center]). Ustekinumab Technical Data Sheet . https://cima.aemps.es/cima/pdfs/es/ft/08494001/FT_08494001.pdf. Accessed March 30, 2018. 6. Targan SR , Feagan BG , Vermeire S et al. A Randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of AMG 827 in subjects with moderate to severe Crohn’s disease . Gastroenterology 2012 ; 143 : E26 – 6 . Google Scholar CrossRef Search ADS 7. Poulain D , Sendid B , Standaert-Vitse A et al. Yeasts: neglected pathogens . Dig Dis 2009 ; 27 ( Suppl 1 ): 104 – 10 . Google Scholar CrossRef Search ADS PubMed 8. Strober W , Zhang F , Kitani A , Fuss I , Fichtner-Feigl S . Proinflammatory cytokines underlying the inflammation of Crohn’s disease . Curr Opin Gastroenterol 2010 ; 26 : 310 – 7 . Google Scholar CrossRef Search ADS PubMed 9. Puel A , Döffinger R , Natividad A et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I . J Exp Med 2010 ; 207 : 291 – 7 . Google Scholar CrossRef Search ADS PubMed 10. Liu L , Okada S , Kong XF et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis . J Exp Med 2011 ; 208 : 1635 – 48 . Google Scholar CrossRef Search ADS PubMed 11. Fragoulis GE , Siebert S , McInnes IB . Therapeutic targeting of IL-17 and IL-23 cytokines in immune-mediated diseases . Annu Rev Med 2016 ; 67 : 337 – 53 . Google Scholar CrossRef Search ADS PubMed 12. Dige A , Støy S , Rasmussen TK et al. Increased levels of circulating Th17 cells in quiescent versus active Crohn’s disease . J Crohns Colitis 2013 ; 7 : 248 – 55 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Journal of Crohn's and ColitisOxford University Press

Published: Sep 1, 2018

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