Skip to main content

Advertisement

SpringerLink
Log in

Effectiveness and Tolerability of Methotrexate Combined with Biologics in Patients with Crohn’s Disease: A Multicenter Observational Study

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Methotrexate (MTX) combination therapy with biological agents has gained increasing interest. Here, we assessed the efficacy and tolerability of the MTX combination therapy in patients with Crohn’s disease (CD).

Methods

We performed a multicenter observational study with 185 patients with CD with MTX and biologics combination therapy; the patients were recruited from three IBD Clinics in Korea. We evaluated the outcomes of the MTX combination therapy and examined the predictive factors of clinical and endoscopic remission.

Results

MTX was administered orally to 62.7% of patients; the mean dose was 15.5 mg per week, and the mean treatment duration was 36 months. Of the 169 patients treated with MTX combination therapy for over 6 months, the steroid-free clinical remission rates were 34.3%, 26.0%, 29.8%, and 32.7% at 4, 12, 18, and 24 months, respectively. Previous thiopurine use was a significant negatively associated independent factor (p < 0.001), and a higher dose of MTX (≥ 15 mg/week) was a positively associated independent factor of steroid-free clinical remission (p = 0.035). Ninety-six patients underwent follow-up endoscopy after 28 months, and 36 (37.5%) achieved endoscopic remission. Longer disease duration (p = 0.006), ileocolonic type of Montreal location (p = 0.036), and baseline C-reactive protein (CRP) level of more than 5 mg/L (p = 0.035) were significant negatively associated independent factors and a higher dose of MTX (≥ 15 mg/week) was a positively associated independent factor of endoscopic remission (p = 0.037).

Conclusions

MTX combination therapy with biologics was effective and tolerable in patients with CD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

CD:

Crohn’s disease

TNF:

Tumor necrosis factor

MTX:

Methotrexate

6-MP:

6-Mercaptopurine

FDA:

Food and Drug Administration

ATI:

Antibodies to infliximab

CBC:

Complete blood count

CDAI:

Crohn’s Disease Activity Index

CRP:

C-reactive protein

SES-CD:

Simple Endoscopic Score for Crohn’s Disease

BMI:

Body mass index

OR:

Odds ratio

CI:

Confidence interval

HR:

Hazard ratio

References

  1. Torres J, Bonovas S, Doherty G et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis. 2020;14:4–22.

    Article  PubMed  Google Scholar 

  2. Otake H, Matsumoto S, Mashima H. Long-term clinical and real-world experience with Crohn’s disease treated with anti-tumor necrosis factor-alpha antibodies. Intest Res. 2022;20:464–474.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4:1248–1254.

    Article  CAS  PubMed  Google Scholar 

  4. Kennedy NA, Heap GA, Green HD et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2019;4:341–353.

    Article  PubMed  Google Scholar 

  5. Rosh JR, Gross T, Mamula P, Griffiths A, Hyams J. Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn’s disease: a cautionary tale? Inflamm Bowel Dis. 2007;13:1024–1030.

    Article  PubMed  Google Scholar 

  6. Mackey AC, Green L, Leptak C, Avigan M. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease: update. J Pediatr Gastroenterol Nutr. 2009;48:386–388.

    Article  PubMed  Google Scholar 

  7. Ansari A, Arenas M, Greenfield SM et al. Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2008;28:973–983.

    Article  CAS  PubMed  Google Scholar 

  8. Kim JH, Cheon JH, Kim WH. The frequency and the course of the adverse effects of azathioprine/6-mercaptopurine treatment in patients with inflammatory bowel disease. Korean J Gastroenterol. 2008;51:291–297.

    PubMed  Google Scholar 

  9. Herfarth HH, Kappelman MD, Long MD, Isaacs KL. Use of methotrexate in the treatment of inflammatory bowel diseases. Inflamm Bowel Dis. 2016;22:224–233.

    Article  PubMed  Google Scholar 

  10. Gabbani T, Deiana S, Lunardi S, Manetti N, Annese V. Safety profile of methotrexate in inflammatory bowel disease. Expert Opin Drug Saf. 2016;15:1427–1437.

    Article  CAS  PubMed  Google Scholar 

  11. Feagan BG, McDonald JW, Panaccione R et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn’s disease. Gastroenterology. 2014;146:681–688.

    Article  CAS  PubMed  Google Scholar 

  12. Vermeire S, Noman M, Van Assche G et al. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut. 2007;56:1226–1231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Carbonnel F, Colombel JF, Filippi J et al. Methotrexate is not superior to placebo for inducing steroid-free remission, but induces steroid-free clinical remission in a larger proportion of patients with ulcerative colitis. Gastroenterology. 2016;150:380–388.

    Article  CAS  PubMed  Google Scholar 

  14. Daperno M, D’Haens G, Van Assche G et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc. 2004;60:505–512.

    Article  PubMed  Google Scholar 

  15. Chande N, Wang Y, MacDonald JK, McDonald JW. Methotrexate for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2014;2014:CD006618.

  16. Koh SJ, Hong SN, Park SK et al. Korean clinical practice guidelines on biologics for moderate to severe Crohn’s disease. Intest Res. 2022.

  17. Hawthorne AB. Methotrexate: a useful alternative in Crohn’s disease? Gut. 2001;49:9–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rampton DS. Methotrexate in Crohn’s disease. Gut. 2001;48:790–791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rosh JR. The current role of methotrexate in patients with inflammatory bowel disease. Gastroenterol Hepatol. 2020;16:43–46.

    Google Scholar 

  20. Narula N, Peyrin-Biroulet L, Colombel JF. Combination therapy with methotrexate in inflammatory bowel disease: time to COMMIT? Gastroenterology. 2014;146:608–611.

    Article  CAS  PubMed  Google Scholar 

  21. Colman RJ, Rubin DT. Optimal doses of methotrexate combined with anti-TNF therapy to maintain clinical remission in inflammatory bowel disease. J Crohns Colitis. 2015;9:312–317.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Borren NZ, Luther J, Colizzo FP et al. Low-dose methotrexate has similar outcomes to high-dose methotrexate in combination with anti-TNF therapy in inflammatory bowel diseases. J Crohns Colitis. 2019;13:990–995.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Henriksen M, Jahnsen J, Lygren I et al. C-reactive protein: a predictive factor and marker of inflammation in inflammatory bowel disease. Results from a prospective population-based study. Gut. 2008;57:1518–1523.

    Article  CAS  PubMed  Google Scholar 

  24. Colombel JF, Sandborn WJ, Reinisch W et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–1395.

    Article  CAS  PubMed  Google Scholar 

  25. Armuzzi A, Pugliese D, Danese S et al. Long-term combination therapy with infliximab plus azathioprine predicts sustained steroid-free clinical benefit in steroid-dependent ulcerative colitis. Inflamm Bowel Dis. 2014;20:1368–1374.

    Article  PubMed  Google Scholar 

  26. Maeda T, Sakuraba H, Hiraga H et al. Long-term efficacy and tolerability of dose-adjusted thiopurine treatment in maintaining remission in inflammatory bowel disease patients with NUDT15 heterozygosity. Intest Res. 2022;20:90–100.

    Article  PubMed  Google Scholar 

  27. Kim YZ, Kang B, Kim ES, et al. Efficacy of combined initial treatment of methotrexate with infliximab in pediatric Crohn’s disease: a pilot study. Biomedicines. 2023;11.

  28. Shea B, Swinden MV, Tanjong Ghogomu E et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013;2013:CD000951.

  29. Reich K, Langley RG, Papp KA et al. A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis. N Engl J Med. 2011;365:1586–1596.

    Article  CAS  PubMed  Google Scholar 

  30. Fournier MR, Klein J, Minuk GY, Bernstein CN. Changes in liver biochemistry during methotrexate use for inflammatory bowel disease. Am J Gastroenterol. 2010;105:1620–1626.

    Article  CAS  PubMed  Google Scholar 

  31. Saibeni S, Bollani S, Losco A et al. The use of methotrexate for treatment of inflammatory bowel disease in clinical practice. Dig Liver Dis. 2012;44:123–127.

    Article  CAS  PubMed  Google Scholar 

  32. Wahed M, Louis-Auguste JR, Baxter LM et al. Efficacy of methotrexate in Crohn’s disease and ulcerative colitis patients unresponsive or intolerant to azathioprine/mercaptopurine. Aliment Pharmacol Ther. 2009;30:614–620.

    Article  CAS  PubMed  Google Scholar 

  33. Seinen ML, Ponsioen CY, de Boer NK et al. Sustained clinical benefit and tolerability of methotrexate monotherapy after thiopurine therapy in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2013;11:667–672.

    Article  CAS  PubMed  Google Scholar 

  34. Park JJ, Yang SK, Ye BD et al. Second Korean guidelines for the management of Crohn’s disease. Intest Res. 2017;15:38–67.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Carter MJ, Lobo AJ, Travis SP, Ibd Section BSoG. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2004;53:V1–V16.

  36. Dignass A, Eliakim R, Magro F et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. J Crohns Colitis. 2012;6:965–990.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

None.

Funding

None.

Author information

Author notes

  1. Jihye Park, Jaeyoung Chun, Hyuk Yoon, and Jae Hee Cheon have contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea

    Jihye Park, Soo Jung Park, Jae Jun Park, Tae Il Kim & Jae Hee Cheon

  2. Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

    Jihye Park, Soo Jung Park, Jae Jun Park, Tae Il Kim & Jae Hee Cheon

  3. Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

    Jaeyoung Chun

  4. Department of Internal Medicine, Seoul National University Bundang Hospital, 166 Gumin-ro, Bundang-gu, Seongnam-si, Gyunggi-do, 463-707, Korea

    Hyuk Yoon

  5. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea

    Hyuk Yoon

Authors
  1. Jihye Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaeyoung Chun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Soo Jung Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jae Jun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tae Il Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hyuk Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jae Hee Cheon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jae Hee Cheon.

Ethics declarations

Conflict of interest

The author declare that they have no competing interest.

Ethical considerations

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, J., Chun, J., Park, S.J. et al. Effectiveness and Tolerability of Methotrexate Combined with Biologics in Patients with Crohn’s Disease: A Multicenter Observational Study. Dig Dis Sci 69, 901–910 (2024). https://doi.org/10.1007/s10620-023-08237-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-023-08237-0

Keywords

Search

Navigation