Glucocorticoids are highly effective for the short- term control of Crohn’s disease-related symptoms, but they are less effective for maintenance of remission, and have significant adverse effects that preclude safe long-term administration.

They work by interacting with glucocorticoid receptors in the cell nucleus to alter expression of inflammatory genes,  inhibit the expression of adhesion molecules, and inhibit the migration of inflammatory cells into tissues.

In a 23-year population-based study of the natural history of Crohn’s disease, the short-term benefit of steroids was substantial with 84 % of patients demonstrating complete or partial response at 30 days. However, only 32 % of these patients were able to maintain remission at the end of a year without ongoing steroid use.

Another 28 % were steroid dependent and 39 % required surgery by 1 year. This study highlights the excellent short-term efficacy of steroids but also underscores the need for steroid-sparing therapy to maintain the initial response to steroids.
Several other studies have confirmed the efficacy of Medical Therapy for systemic glucocorticoids for induction of remission in active Crohn’s disease.

Despite their benefit for induction of remission,  systemic glucocorticoids have numerous adverse effects that prohibit sustained administration.  Short-term side effects can include psychiatric disturbances such as anxiety, emotional lability,  psychosis,  and insomnia.

Other potential effects can include hypertension, hyperglycemia, acne, fungal, viral, and bacterial infections,  and weight gain.  Long-term effects can include cataracts,  glaucoma,  osteoporosis, avascular necrosis,  diabetes mellitus,  steroid induced myopathy, and adrenal insufficiency. In a safety registry of Crohn’s disease patients, corticosteroid use was independently associated with higher risk of mortality (HR 2.14)  and serious infection (HR 1.57).

  Because of the multiple side effects associated with these medications,  budesonide has been studied as an alternative glucocorticoid treatment.

Budesonide is a topical glucocorticoid with high affinity for the glucocorticoid receptors (200 times that of prednisolone)  that delivers steroid locally to the distal ileum and proximal colon. Because of extensive first pass metabolism in the liver, only 10- 15 % of the oral dose is systemically active,  leading to fewer side effects compared with traditional glucocorticoids.

Abnormal responses to ACTH tests were less common in budesonide-treated patients compared to those receiving systemic glucocorticoids,  but still more common than in patients receiving placebo, confirming there is a small degree of systemic activity with budesonide. Budesonide is more effective than placebo but less effective than prednisone in inducing remission in patients with active luminal Crohn’s disease,  and the greatest benefit appears to be in patients with ileal or proximal colonic disease.  Budesonide is not effective for the prevention of relapse in patients with quiescent Crohn’s disease.

With regard to maintenance therapy,  a 2003 meta-analysis of corticosteroids showed no benefit as maintenance therapy at 6,  12,  and 24 months when compared with placebo. Meta- analyses of budesonide have similarly demonstrated a lack of improvement over placebo in maintenance of remission at 3, 6, and 12 months. Because of their potential side effects and lack of maintenance efficacy data,  corticosteroids are typically only used for short-term treatment of an acute disease exacerbation,  or as a bridge to maintenance therapy with a steroidsparing agent. 

### R. A. Fausel , MD
T. L. Zisman , MD, MPH
Division of Gastroenterology, University of Washington Medical Center , 1959 NE Pacific Street, Box 356424 , Seattle , WA 98195 , USA

References

1. Sands BE, Siegel CA. Chapter 111: Crohn's disease. In: Sleisenger MH, Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger and Fordtran's gastrointestinal and liver disease pathophysiology, diagnosis, management. 9th ed. Philadelphia: Saunders/Elsevier; 2010. p. 1 online resource (2 volumes (xxv, 2299, xc pages)).
2. Summers RW, Switz DM, Sessions Jr JT, Becktel JM, Best WR, Kern Jr F, et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology. 1979;77(4 Pt 2):847- 69.
3. Singleton JW, Hanauer SB, Gitnick GL, Peppercorn MA, Robinson MG, Wruble LD, et al. Mesalamine capsules for the treatment of active Crohn's disease: results of a 16-week trial. Pentasa Crohn's Disease Study Group. Gastroenterology. 1993; 104(5):1293- 301.
4. Hanauer SB, Stromberg U. Oral Pentasa in the treatment of active Crohn's disease: a meta-analysis of double-blind, placebo-controlled trials. Clin Gastroenterol Hepatol. 2004;2(5):379- 88.
5. Lim WC, Hanauer S. Aminosalicylates for induction of remission or response in Crohn's disease. Cochrane Database System Rev. 2010(12):CD008870.
6. Ford AC, Kane SV, Khan KJ, Achkar JP, Talley NJ, Marshall JK, et al. Efficacy of 5-aminosalicylates in Crohn's disease: systematic review and meta- analysis. Am J Gastroenterol. 2011;106(4):617- 29.
7. Box SA, Pullar T. Sulphasalazine in the treatment of rheumatoid arthritis. Br J Rheumatol. 1997;36(3): 382- 6.
8. Navarro F, Hanauer SB. Treatment of inflammatory bowel disease: safety and tolerability issues. Am J Gastroenterol. 2003;98(12 Suppl):S18- 23.
9. Muller AF, Stevens PE, McIntyre AS, Ellison H, Logan RF. Experience of 5-aminosalicylate nephrotoxicity in the United Kingdom. Aliment Pharmacol Ther. 2005;21(10):1217- 24.
10. Sutherland L, Singleton J, Sessions J, Hanauer S, Krawitt E, Rankin G, et al. Double blind, placebo controlled trial of metronidazole in Crohn's disease. Gut. 1991;32(9):1071- 5.
11. Prantera C, Zannoni F, Scribano ML, Berto E, Andreoli A, Kohn A, et al. An antibiotic regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial of metronidazole plus ciprofioxacin. Am J Gastroenterol. 1996;91(2):328- 32.
12. Rutgeerts P, Hiele M, Geboes K, Peeters M, Penninckx F, Aerts R, et al. Controlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal resection. Gastroenterology. 1995;108(6):1617- 21.
13. Bernstein LH, Frank MS, Brandt LJ, Boley SJ. Healing of perineal Crohn's disease with metronidazole. Gastroenterology. 1980;79(2):357- 65.
14. Brandt LJ, Bernstein LH, Boley SJ, Frank MS. Metronidazole therapy for perineal Crohn's disease: a follow-up study. Gastroenterology. 1982;83(2):383- 7.
15. Thia KT, Mahadevan U, Feagan BG, Wong C, Cockeram A, Bitton A, et al. Ciprofioxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn's disease: a randomized, double-blind, placebo-controlled pilot study. Inflamm Bowel Dis. 2009;15(1):17- 24.

16. Dewint P, Hansen BE, Verhey E, Oldenburg B, Hommes DW, Pierik M, et al. Adalimumab combined with ciprofioxacin is superior to adalimumab monotherapy in perianal fistula closure in Crohn's disease: a randomised, double-blind, placebo controlled trial (ADAFI). Gut. 2014;63(2):292- 9.
17. West RL, van der Woude CJ, Hansen BE, Felt- Bersma RJ, van Tilburg AJ, Drapers JA, et al. Clinical and endosonographic effect of ciprofioxacin on the treatment of perianal fistulae in Crohn's disease with infiiximab: a double-blind placebo- controlled study. Aliment Pharmacol Ther. 2004;20(11- 12):1329- 36.
18. Jigaranu AO, Nedelciuc O, Blaj A, Badea M, Mihai C, Diculescu M, et al. Is rifaximin effective in maintaining remission in Crohn's disease? Dig Dis. 2014;32(4):378- 83.
19. Prantera C, Lochs H, Campieri M, Scribano ML, Sturniolo GC, Castiglione F, et al. Antibiotic treatment of Crohn's disease: results of a multicentre, double blind, randomized, placebo-controlled trial with rifaximin. Aliment Pharmacol Ther. 2006;23(8):1117- 25.
20. Prantera C, Lochs H, Grimaldi M, Danese S, Scribano ML, Gionchetti P. Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn's disease. Gastroenterology. 2012;142(3):473- 81.e4.
21. Khan KJ, Ullman TA, Ford AC, Abreu MT, Abadir A, Marshall JK, et al. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta- analysis. Am J Gastroenterol. 2011;106(4):661- 73.
22. Malchow H, Ewe K, Brandes JW, Goebell H, Ehms H, Sommer H, et al. European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment. Gastroenterology. 1984;86(2):249- 66.
23. Hayashi R, Wada H, Ito K, Adcock IM. Effects of glucocorticoids on gene transcription. Eur J Pharmacol. 2004;500(1- 3):51- 62.
24. Faubion Jr WA, Loftus Jr EV, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for infiammatory bowel disease: a population-based study. Gastroenterology. 2001;121(2):255- 60.
25. Benchimol EI, Seow CH, Steinhart AH, Griffiths AM. Traditional corticosteroids for induction of remission in Crohn's disease. Cochrane Database System Rev. 2008(2):CD006792.
26. Ford AC, Bernstein CN, Khan KJ, Abreu MT, Marshall JK, Talley NJ, et al. Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):590- 9. quiz 600.
27. Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, et al. Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol. 2012;107(9):1409- 22.
28. Curkovic I, Egbring M, Kullak-Ublick GA. Risks of infiammatory bowel disease treatment with glucocorticosteroids and aminosalicylates. Dig Dis. 2013;31(3- 4):368- 73.