Author names: Kelly Chatten 1 Jimmy K. Limdi 1, 3 Christian P. Selinger 2
1 Department of Gastroenterology, Section of Inflammatory Bowel Diseases, The Northern Care Alliance NHS Foundation Trust, Manchester, United Kingdom
2 Department of Gastroenterology, Leeds Teaching Hospital NHS Trust, Leeds, United Kingdom
3 Manchester Academic Health Sciences, Faculty of Biology, Medicine & Health, University of Manchester, United Kingdom
- Corticosteroids when used judiciously have a decisive role in the induction of remission in active IBD, but are ineffective for the maintenance of remission. Planning ahead of the next steps when steroid therapy finishes is crucial.
- Improved referral pathways for newly diagnosed and symptomatic patients in primary and within secondary care: “Right patient, right clinic, at the right time” and utilisation of IBD specialist clinics and multidisciplinary meetings to explore steroid sparing options as appropriate. Regular audit of steroid use is a useful quality improvement exercise.
- Timely recognition of steroid refractoriness and/or steroid dependency with appropriate early treatment escalation.
- Inflammatory bowel disease
Abbreviations (with definitions)
IBD – Inflammatory Bowel Disease
CD – Crohn’s disease
UC – Ulcerative colitis
QIP – Quality Improvement Project
BSG – British Society of Gastroenterology
ECCO – European Crohn’s and Colitis Organisation
MMX – Multimatrix
Inflammatory bowel disease (IBD) comprises of ulcerative colitis (UC) and Crohn’s disease (CD) which are chronic, relapsing, progressive and potentially disabling immune-mediated diseases affecting the gastro-intestinal tract. Ever since the first demonstration of efficacy for the induction of remission for UC in 1955, and in 1966 for CD, corticosteroids have remained a cornerstone for the decisive induction of remission of active IBD. Despite high rates of efficacy for induction of remission, both inflammation and symptoms frequently return upon their discontinuation, and they do not have a role in the maintenance of remission. Furthermore, their use is associated with a plethora of adverse effects including (but not limited to) insomnia, weight gain, hypertension, hyperglycaemia, cataracts, glaucoma, mood disturbances, psychosis, venous thromboembolism, serious infections, and an increased risk of mortality.
Meanwhile, there has been a wider appreciation of the “disconnect” between symptoms and objective measures of disease activity in recent years. Evidence that uncontrolled inflammation leads to progressive intestinal injury, irreversible bowel damage, and complications, with multidimensional negative effects on quality of life, has redefined our paradigms with meaningful disease control.
The principle behind “treat to target”, is to treat inflammatory activity early and effectively, before intestinal damage and disability occurs. The initial target of treatment is resolution of abdominal pain and normalisation of bowel habit, cessation of rectal bleeding (implying resolution of clinical symptoms), followed by biomarker and then endoscopic remission, with the aim of reducing disease-related complications, disability ,and normalising quality of life. Accordingly, international guidelines recommend reduction of steroids and the early and effective use of corticosteroid-sparing disease-modifying therapies[1,7,8].
Steroid use and misuse
We aim to highlight misuse of steroids in clinical practice through clinical case scenarios, and highlight how timely recognition and intervention with steroid-sparing strategies can reduce the need for steroids and their unwanted side effects in people living with IBD.
Definitions of steroid use
The British Society of Gastroenterology (BSG) and European Crohn’s and Colitis Organisation (ECCO) have defined steroid use in IBD as follows [1,7,8]:
Steroid relapse – disease relapse within 3 months of stopping steroids.
Steroid refractory – active disease despite prednisolone 1 mg /kg/day for a period of 4 weeks.
Steroid dependent – unable to reduce steroids below the equivalent of prednisolone.
10 mg/day or budesonide 3 mg/day within 3 months of starting steroids without recurrent active disease.
Case History 1
A 32 year-old lady with a 12-month history of diarrhoea with bleeding, abdominal pain, and 8 kg weight loss, was diagnosed with ileo-colonic CD at her local hospital and prescribed a tapering course of prednisolone 40mg daily along with a calcium and vitamin D supplement with instructions that she would receive a follow-up appointment in clinic in “due course”. Her symptoms flared upon reducing her prednisolone dose to 10mg and her GP increased this to 40mg daily awaiting hospital review. Her clinic review is postponed by 2 months due to “unavoidable circumstances” and she presents to the A&E department with abdominal pain , worsening diarrhoea, and bleeding, having recently completed her second course of prednisolone. She is discharged from A&E with another course of steroids and arrangements to be seen in either the IBD nurse or consultant clinic in 6-8 weeks.
This lady is steroid dependent and should be escalated to effective immunomodulatory and/or biologic therapy having demonstrated steroid dependence. Improved education in primary care/A+E and clear referral pathways to the appropriate secondary care clinic (eg. IBD flare line, rapid access clinic) could prevent unnecessary steroids in this scenario.
Case History 2
A 24-year-old man with a 3-year history of left sided ulcerative colitis presents to the emergency department with diarrhoea and bleeding. He has taken his 5-ASA medication inconsistently over the years and required a “few courses” of steroids over the years to control his colitis. He is prescribed a course of prednisolone 40mg daily along with a calcium and vitamin D supplement with a hospital follow up in 6-8 weeks. His symptoms improve and he does not attend his follow-up appointment with the IBD nurse. Two weeks after completing his prednisolone course, he has another flare up and is prescribed prednisolone again by the out-of-hours GP services with “improvement” in symptoms. At his telephone appointment with the IBD nurse 6 weeks later, he says he feels improved with 3-4 bowel motions with minimal bleeding and mucus per rectum. He is on 5mg prednisolone and asks to “increase it back up” to 40mg daily.
This man has also demonstrated steroid dependence and needs an exit strategy to prevent further steroids courses and treat his ulcerative colitis more effectively. First line therapy for left sided UC would be with 5ASA (ideally oral and enema in combination). Once daily dosing for oral preparations may improve treatment adherence. This gentleman should be counselled on the side effects of prolonged and repeated steroids and advised regarding treatment adherence. If there is ongoing need for steroids despite 5ASA therapy, escalation to immunomodulatory and/or biological would be appropriate.
Both these cases are a sobering reminder that steroid use and indeed misuse are common in real-world practice. They highlight deficiencies in care, access to specialist clinics, poor disease education of the patient, and reactive care rather than thinking ahead beyond the next step. This underscores the importance of improvement in quality of care at various levels to achieve better outcomes for our patients.
Corticosteroids for the induction of remission
In the seminal double-blind randomised placebo-controlled trial by Truelove and Witts in 210 patients with ulcerative colitis, treated with 100mg cortisone, 41.3% of patients achieved remission at 6 weeks compared to 15.8% in the placebo arm2. Subsequent studies, including the meta-analysis of 5 randomised controlled trials, reported that corticosteroids are more effective than placebo for inducing remission in active UC [RR of no remission 0.65; 95% CI (0.45-0.93)]. Second generation corticosteroids including various preparation of Budesonide MMX as well as multimatrix system enabling targeted release in the colon and beclomethasone dipropionate (BDP) have emerged as alternatives. In a pooled analysis of the CORE I &II studies, Budesonide MMX 9mg/day demonstrated a combined clinical and endoscopic remission rate of 17.7% versus 6.2% for placebo. Both clinical and endoscopic remission were significantly better with Budesonide MMX in left-sided but not extensive disease. While budesonide MMX still has glucocorticoid side effects (most frequent were mood changes, sleep changes, and insomnia), there are lower rates of side effects and no association with adrenal suppression or significant reduction in bone mineral density. BDP was demonstrated to be non-inferior to tapered prednisolone (starting at 40mg daily), achieving clinical response in 64.6% for BDP vs. 66.2% for prednisolone. However, there was also no difference in the co-primary end-point of steroid-related adverse events and reduction in morning cortisol below 150nmol/L.
The BSG recommends systemic corticosteroids in patients with moderate to severe UC and in mild UC that does not respond to 5ASA1. Budesonide MMX is a suggested alternative for those with mild to moderate disease and wishing to avoid corticosteroids.
The National Cooperative Crohn’s Disease Study in 1979 from the USA demonstrated superiority of prednisone (60%) over placebo (30%) for the induction of remission in 295 patients with active CD; and the European Cooperative Crohn’s Disease Study also demonstrated superiority of methylprednisolone over placebo by week 6, in 215 patients with active CD[11,12]. Subsequent studies, including a Cochrane review of 2 placebo-controlled trials and six 5-aminosalicylate (5-ASA) controlled trials demonstrated superiority of corticosteroids in achieving clinical remission over placebo [RR 1.99; 95% CI (1-51-2.64;p <0.00001)] and 5-ASA [RR 1.65; 95% CI (1-33-2.03;p <0.00001)]. In a double-blind randomised trial, ileal release budesonide was as effective at inducing remission in patients with mild to moderately active CD with significantly fewer side-effects, but Budesonide proved inferior to prednisolone for severe CD. While budesonide has fewer side effects than prednisolone, it does still suppress adrenal function and affect bone metabolism.
The BSG recommends that mild to moderately active ileo-caecal CD can be treated with ileal release Budesonide but that for patients with moderate to severely active CD, following initial treatment with prednisolone, early introduction of biological therapy should be considered, especially with adverse prognostic features such as structuring, penetrating, or perianal disease.
Long term steroid use has substantial side effects including increased infection rates, osteoporosis, diabetes, cardiovascular events, mood disorders, and all cause mortality.
Patients should be co-prescribed calcium and vitamin D to prevent corticosteroid induced bone loss and counselled on the risk secondary adrenal insufficiency and adrenal crisis on omission of steroids. They should be provided with a steroid alert care to carry for the duration of steroid treatment.
Out-patient use of corticosteroids
Despite the increasing armamentarium of effective immunomodulatory and biological therapies, clinician reliance on corticosteroids has not reduced. In a recent European prospective population-based inception cohort study (488 CD and 717 UC patients), 60% of CD and 52% UC patients had been exposed to corticosteroids after 5 years. Concerningly, 14% of UC and 9% of CD patients received corticosteroids for more than 6 consecutive months during follow-up. A UK study trend looking at 23,509 incident IBD cases reassuringly showed reduction of prolonged (>3 months) corticosteroid exposure in CD, over time (36.5% between 1990-97 vs. 26.8% between 2002-2010, p<0.001). Alarmingly however, despite a similar increase in thiopurine use, corticosteroid prescriptions within 5 years of diagnosis in UC increased (29.9% between 1990-93 vs. 48.5% between 2002-2005), as did recurrent prescriptions (15.3% between 1990-93 vs. 17.8% between 2002-2005) and “very prolonged” corticosteroid use (> 6 months) exposure (11.0% between 1990-97 vs. 13.0% between 2002-2010, p=0.03). An inherent limitation of this retrospective study however, is the confounding introduced by variables not studied or included in the analysis.
Multicentre UK Audit of steroid use
Our group conducted a prospective multicentre audit of corticosteroid use in previous 12 months among 1176 patients with IBD in 2016. Steroid dependency or “excess” were defined as per BSG and ECCO guidelines[1,7,8]. Corticosteroid exposure was noted in 30% of patients with 14.9% meeting criteria for steroid dependency/excess and 49.1% patients were judged to have inappropriate steroid dependency. The decision to commence steroids was made in primary care in 17% patients; 91.3% of these cases classed as avoidable steroid excess vs. 42% of cases initiated in secondary care. In CD, an established IBD multidisciplinary team was protective [OR 0.62; 95% CI 0.46-0.91], whereas treatment with 5-ASA was associated with dependency or excess [OR 1.87; 95% CI 1.01-3.91]. Treatment at a centre with dedicated IBD clinics was protective in UC [OR 0.64; 95% CI 0.21-0.94].
In a follow-up study with 2385 patients across 19 centres, we noted a 14.8% rate of steroid excess or dependency, 50.7% of which was deemed avoidable. Seven centres that had introduced quality improvement achieved reduction in steroid exposure (23.8% vs. 31%, p<0.001) and excess (11.5% vs. 17.1%, p<0.001), an effect that remained true on multivariate analysis. Treatment at a centre with an IBD MDT was associated with a lower risk of steroid excess/dependency and in UC use of a thiopurine without a biologic for more than 3 months was independently associated with an increased risk of steroid excess.
Steroid assessment Toolkit
The audit process led to the development of a dedicated on-line steroid assessment tool. This practical and simple tool can be used in real-time, even in busy outpatient clinics, to periodically assess and audit steroid use in the secondary/hospital care setting, although capturing steroid use in primary care remains a challenge. The UK IBD Standards recommend that steroid use should be audited regularly (at least annually) and such a tool can monitor steroid use and take measures to reduce misuse.
Top 10 tips to reduce unnecessary steroid use
- Corticosteroids when used judiciously have a decisive role in the induction of remission in active IBD, but are ineffective for the maintenance of remission. Planning the next step when steroid therapy finishes is crucial e.g. escalation to biologic or small molecule treatment.
- Prolonged and often unnecessary steroid use is ineffective and harmful with adverse effects including serious infection risk and increased mortality.
- Education of general practitioners and people living with IBD on the use and consequences of inappropriate use.
- Optimisation of primary care pathways such as 5-ASA optimisation and patient self-management.
- Improved referral pathways for newly diagnosed and symptomatic patients in primary and within secondary care: “Right patient, right clinic, at the right time”. Prompt review and management is key.
- Timely recognition of steroid refractoriness and/or steroid dependency with appropriate early treatment escalation.
- Early risk stratification of patients at risk of adverse outcomes with timely disease modifying and steroid sparing strategies.
- Use of second-generation steroids where possible and appropriate.
- Utilisation of IBD specialist clinics and multidisciplinary meetings to explore steroid sparing options as appropriate.
- Periodic (at least annual) audit of steroid prescribing as a key continuous quality improvement programme, e.g. using the steroid assessment tool.
Conflicts of interest
Kelly Chatten: None
Christian Selinger has received unrestricted research grants from Abbvie and Janssen, has provided consultancy to Arena, Galapagos, Dr Falk, Abbvie, Janssen, Fresenius Kabi and Takeda, and had speaker arrangements with Janssen, Dr Falk, Abbvie, Celltrion, Janssen, Pfizer, and Takeda.
Jimmy Limdi has received research grants from Galapagos and Takeda, has provided consultancy to Arena, Galapagos, Abbvie, Janssen, Pfizer and Takeda, and had speaker arrangements with Janssen, Tillotts, Abbvie, Janssen, Pfizer, and Takeda.
- Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019;68:s1–106. doi:10.1136/GUTJNL-2019-318484
- SC T, LJ W. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;2:1041–8. doi:10.1136/BMJ.2.4947.1041
- Jones JH, Lennard-Jones JE. Corticosteroids and corticotrophin in the treatment of Crohn’s disease. Gut 1966;7:181–7. doi:10.1136/GUT.7.2.181
- Ford AC, Bernstein CN, Khan KJ, et al. Glucocorticosteroid therapy in inflammatory bowel disease: Systematic review and meta-analysis. Am J Gastroenterol 2011;106:590–9. doi:10.1038/AJG.2011.70
- Lewis JD, Scott FI, Brensinger CM, et al. Increased Mortality Rates With Prolonged Corticosteroid Therapy When Compared With Antitumor Necrosis Factor-α-Directed Therapy for Inflammatory Bowel Disease. Am J Gastroenterol 2018;113:405. doi:10.1038/AJG.2017.479
- Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021;160:1570–83. doi:10.1053/J.GASTRO.2020.12.031/ATTACHMENT/F1BB64EB-27CC-4F26-9FE8-91734BCE443B/MMC3.PDF
- Torres J, [ECCO] on behalf of the EC and CO, Bonovas S, et al. ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment. J Crohn’s Colitis 2020;14:4–22. doi:10.1093/ECCO-JCC/JJZ180
- Raine T, Bonovas S, Burisch J, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohn’s Colitis 2022;16:2–17. doi:10.1093/ECCO-JCC/JJAB178
- Travis SPL, Danese S, Kupcinskas L, et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut 2014;63:433–41. doi:10.1136/GUTJNL-2012-304258
- Van Assche G, Manguso F, Zibellini M, et al. Oral prolonged release beclomethasone dipropionate and prednisone in the treatment of active ulcerative colitis: Results from a double-blind, randomized, parallel group study. Am J Gastroenterol 2015;110:708–15. doi:10.1038/AJG.2015.114
- National Cooperative Crohn’s Disease Study: results of drug treatment – PubMed. https://pubmed.ncbi.nlm.nih.gov/38176/ (accessed 25 Mar2022).
- European Cooperative Crohn’s Disease Study (ECCDS): results of drug treatment – PubMed. https://pubmed.ncbi.nlm.nih.gov/6140202/ (accessed 25 Mar2022).
- Benchimol EI, Seow CH, Steinhart AH, et al. Traditional corticosteroids for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2008;2008. doi:10.1002/14651858.CD006792.PUB2
- 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. doi:10.1016/S0016-5085(98)70254-9
- Coward S, Kuenzig ME, Hazlewood G, et al. Comparative Effectiveness of Mesalamine, Sulfasalazine, Corticosteroids, and Budesonide for the Induction of Remission in Crohn’s Disease: A Bayesian Network Meta-analysis. Inflamm Bowel Dis 2017;23:461–72. doi:10.1097/MIB.0000000000001023
- Homik J, Suarez-Almazor ME, Shea B, et al. Calcium and vitamin D for corticosteroid-induced osteoporosis. Cochrane Database Syst Rev Published Online First: 27 April 1998. doi:10.1002/14651858.CD000952/MEDIA/CDSR/CD000952/IMAGE_N/NCD000952-CMP-001-06.PNG
- National Patient Safety Alert. Steroid Emergency Card to support early recognition and treatment of adrenal crisis in adults. Natl Patient Saf Alert 2020;:1–2.https://www.england.nhs.uk/wp-content/uploads/2020/08/NPSA-Emergency-Steroid-Card-FINAL-2.3.pdf
- Burisch J, Kiudelis G, Kupcinskas L, et al. Natural disease course of Crohn’s disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study. Gut 2019;68:423–33. doi:10.1136/GUTJNL-2017-315568
- Chhaya V, Saxena S, Cecil E, et al. Steroid dependency and trends in prescribing for inflammatory bowel disease – a 20-year national population-based study. Aliment Pharmacol Ther 2016;44:482–94. doi:10.1111/APT.13700
- Selinger CP, Parkes GC, Bassi A, et al. A multi-centre audit of excess steroid use in 1176 patients with inflammatory bowel disease. Aliment Pharmacol Ther 2017;46:964–73. doi:10.1111/APT.14334
- Selinger CP, Parkes GC, Bassi A, et al. Assessment of steroid use as a key performance indicator in inflammatory bowel disease-analysis of data from 2385 UK patients. Aliment Pharmacol Ther 2019;50:1009–18. doi:10.1111/APT.15497
- Kapasi R, Glatter J, Lamb CA, et al. Consensus standards of healthcare for adults and children with inflammatory bowel disease in the UK. Frontline Gastroenterol 2019;11:178–87. doi:10.1136/FLGASTRO-2019-101260
Dr Kelly Chatten is a senior gastroenterology trainee in the North-Western Deanery with an interest in IBD and research. She is currently undertaking an Advanced IBD fellow post at the Northern Care Alliance and is investigator and sub investigator for a number of clinical studies and trials.
Jimmy Limdi is Consultant Gastroenterologist and Head of the IBD section at the Northern Care Alliance Foundation Trust and Deputy Director of Research at the NCA. He is also Honorary Clinical Professor of Gastroenterology at the University of Manchester (Manchester Academic Health Sciences) and Visiting Professor at the Manchester Metropolitan University. He is Chief and principal investigator for numerous IBD clinical trials and has wide research interests in IBD including diet, neuro-motility in ulcerative colitis, women’s health issues and novel therapies. Jimmy is an active researcher and widely published with over 100 peer-reviewed publications in international journals and reviewer and associate editor roles with international journals.
Dr Christian Selinger, MD MSc FRCP Edin, is a Consultant Gastroenterologist in Leeds. Following undergraduate training in Germany and New Zealand Christian trained in Gastroenterology in Manchester from 2006 and spent 18 months of advanced training in Inflammatory Bowel Disease during his fellowship in Sydney, Australia. Christian is the current chair of the BSG IBD section. Christian is an active researcher and widely published with over 100 peer-reviewed publications in international journals.
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