Corticosteroids are strong, non-selective, anti-inflammatory agents used to treat many inflammatory disorders, autoimmune conditions and haematological cancers. They inhibit synthesis and transcription of pro-inflammatory proteins, which down-regulates the production of nuclear factor kappa-B and inflammatory cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-alpha. In addition, anti-inflammatory mediators are up-regulated by corticosteroids.
This review aims to evaluate the role of corticosteroids in inflammatory bowel disease (IBD) within clinical practice. The review will focus on both ulcerative colitis (UC) and Crohn's disease (CD) in summarising key recommendations to choosing the correct steroid depending on disease severity. Adverse effects and steroid dependence are covered to ensure early recognition, education and management.
In the 1950s, Truelove and Witts (1955) showed that oral cortisone could be used to induce remission in patients with UC. In the 1970s Summers et al (1979) reported oral prednisolone starting at 60 mg once daily was effective in inducing remission in patients with active CD. Corticosteroids are effective and rapidly active and are therefore deemed the initial therapeutic option for patients with moderately-to-severely active inflammatory bowel disease. First-generation corticosteroids include hydrocortisone, prednisolone and methylprednisolone. They are used in moderate-to-severe disease, where rapid and systemic anti-inflammation is required. Second-generation corticosteroids include budesonide, budesonide multimatrix and beclomethasone diproprionate. These are reserved for mild-to-moderate disease, where local or specific anti-inflammation is required.
Adverse effects
Despite their effectiveness, corticosteroids are characterised by their serious adverse effects, which limit their long-term use. Recognition of their adverse effects is important in their prevention and management. The frequency and severity of adverse effects are dependent on the dose and duration of corticosteroids. In general, adverse effects are more likely to occur when corticosteroids are used daily for over 3 weeks. Approximately 50% of patients will develop short-term adverse effects (Keenan, 1997).
Dermatological features, such as bruising, skin thinning, striae and poor wound healing, are common, even at low doses. Weight gain, intrascapular fat padding and truncal obesity are signs of endogenous Cushing's syndrome (Hopkins and Leinung, 2005). Ophthalmological conditions include cataracts and glaucoma. Long-term steroid use can lead to gut irritation, leading to gastrointestinal bleeding and ulcer formation. Acid-suppression medication, such as omeprazole, lansoprazole and ranitidine, can be co-prescribed with steroids to minimise the risk. Impairment of the heart and kidneys can cause hypertension, fluid retention and atherosclerotic disease. Calcium and vitamin D supplementation should be co-prescribed with steroids to prevent steroid-induced osteoporosis (Buckley et al, 1996). Mood disorders, including depression, insomnia and psychosis, are typically associated with high-dose steroids. Adrenal insufficiency and diabetes mellitus should be recognised early through regular blood glucose monitoring.
Systemic steroids dampen the immune system, leading to increased risk of infection and poor wound healing; this is especially important because patients with IBD commonly require surgical management when medical therapy fails (Wang et al, 2013). The European Crohn's and Colitis Organisation (ECCO) advises a steroid-sparing immunomodulator agent, such as azathioprine or 6-mercaptopurine, in patients who have required two or more courses of corticosteroids within the previous 12 months (O'Connor et al, 2010).
Evidence has emerged linking systemic corticosteroids to increased mortality in IBD. The TREAT registry provided prospective data on outcomes after over 30 000 patient-years of follow-up. Prednisone was found to increase mortality risk on multivariate analysis, while other CD therapies, such as infliximab, did not (Lichtenstein et al, 2012). The ENCORE registry also prospectively followed up CD patients who received infliximab, conventional therapies or a combination of both for 5 years. In this cohort, prednisone was the only agent associated with increased mortality risk (D'Haens et al, 2017).
Induction of remission in severe disease
UC is a chronic, inflammatory condition causing continuous mucosal inflammation of the colon. CD is a chronic, relapsing-remitting, inflammatory disease; it can affect all parts of the gastrointestinal tract, and the full thickness of intestinal wall is inflamed. CD affects the ileum alone in 23% of patients and ileum plus the colon in 41% of patients (Farmer et al, 1975). Intravenous corticosteroids are often used to induce remission in acute severe IBD, especially for hospitalised patients.
Acute severe colitis is a medical emergency and defined by the presence of more than six bloody stools per day along with any one of the following: tachycardia >90 bpm, fever >37.8 °C, haemoglobin <10.5 gm/dl, erythrocyte sedimentation rate (ESR) >30 mm/hr and/or c-reactive protein (CRP) >45 mg/L—known as the Truelove and Witts (1955) criteria. Corticosteroids are given intravenously using methylprednisolone 60 mg every 24 hours or hydrocortisone 100 mg four times daily. Higher doses are no more effective, but lower doses are less effective (Rosenberg et al, 1990). Treatment duration beyond 7–10 days gives no additional benefits (Turner et al, 2007). A systematic review of steroids in acute severe colitis reported the overall response to steroids was 67%. The overall short-term colectomy (removal of the large bowel) rate was 29%, and mortality was 1% (Turner et al, 2007).
The Oxford Criteria for predicting failure to respond to intravenous corticosteroids on the third day of treatment are: stool frequency ≥9 or CRP ≥45 mg/L and a stool frequency of 3–8 per 24 hours (Travis et al, 2011). When these criteria are met, second-line (‘rescue’) therapy is required. Rescue therapy options include infliximab, ciclosporin or colectomy with end ileostomy formation. Those cases that meet the Oxford Third Day Criteria have an 85% chance of coming to colectomy on that admission. Therefore, regular assessment of response to steroids is of paramount importance. In a group of 80 patients who underwent emergency colectomy for severe UC between 1994 and 2000, patients with significantly longer duration of preoperative medical therapy (>8 days) were more likely to have major postoperative complications (Randall et al, 2010). Patients who respond to intravenous steroids should be converted to oral steroids at day 5. Prednisolone 40 mg once daily, reducing by 5 mg every week, is an appropriate regimen. Acid suppression, calcium and vitamin D supplementation should be co-prescribed.
For moderate-to-severely active CD, systemic corticosteroids are required to induce clinical remission. Randomised controlled trials (RCTs) (Summers et al, 1979; Malchow et al, 1984) have looked at the efficacy of both methylprednisolone and prednisolone compared with placebo for the treatment of moderate-to-severely active CD. This data has been summarised in a Cochrane systematic review and meta-analysis (Benchimol et al, 2008). Oral methylprednisolone was given at a dose of 48 mg once daily with weekly stepwise reduction. Oral prednisolone dosages ranged from 0.5 mg/kg to 0.75 mg/kg, with a maximum daily dose of 60 mg. The dose was tapered by 5 mg per week over an 8–12-week period. Both trials showed systemic steroids were superior to placebo (93.6% vs 54%) in inducing clinical remission. Adverse events were five times higher in the corticosteroid group.
Induction of remission in moderate disease
Budesonide is a glucocorticoid that is metabolised in the liver via the cytochrome P450 pathway. Approximately 90% of orally administered budesonide undergoes first-pass metabolism, resulting in low systemic bioavailability. Budesonide gives significantly less hypothalamic–pituitary–adrenal axis suppression and steroid-related adverse effects compared with prednisolone.
Budesonide multimatrix is designed for topical release along the whole colon. This extended-release technology is characterised by a multimatrix structure surrounded by gastro-resistant capsule that dissolves in colonic fluid with pH >7. Budesonide has high topical anti-inflammatory properties and works by depressing the activity of endogenous chemical mediators of inflammation. Protein synthesis is inhibited, leading to down-regulation of the production of inflammatory cytokines present in UC. The recommended daily dosing for induction of remission is 9 mg once daily, for up to 8 weeks. A clinical response is typically observed after 7–10 days of therapy (Sherlock et al, 2010).
Two 8-week RCTs of budesonide multimatrix reported statistically significantly increased rates of combined clinical, endoscopic and histological remission in adults with mild-to-moderate UC compared with placebo (Travis et al, 2014; Abdalla and Herfarth, 2016). As per National Institute Health and Care Excellence (NICE) guidelines, budesonide is licensed for inducing remission in mild-to-moderate active UC in adults for whom aminosalicylate treatment is not sufficient.
There are two formulations of budesonide used to treat CD: the controlled-ileal release Entocort (Tillotts) and the pH-dependent release Budenofalk (Dr Falk). The controlled-ileal release formulation uses a gelatin capsule containing acid-resistant microgranules that dissolve at pH of 5.5 or higher. The pH-dependent formulation contains micropellets that are resistant to a pH below 6 (Fedorak and Bistritz, 2005).
A Cochrane systematic review and meta-analysis (Rezaie et al, 2015) included three RCTs (Greenberg et al, 1994; Tremaine et al, 2002; Suzuki et al, 2013) that compared budesonide 9 mg once daily with placebo. Budesonide was superior to placebo for inducing clinical response and clinical remission. When compared with conventional steroids (prednisolone), budesonide had a better safety profile, owing to its low bioavailability and systemic absorption.
A Cochrane systematic review and meta-analysis (Thomsen et al, 1998) reviewed RCTs (Tromm et al, 2011; Yokoyama et al, 2017) that compared budesonide 9 mg once daily with mesalazine 4.5 g once daily. Budesonide was not superior to mesalazine for inducing clinical remission; however, there was a significant improvement in clinical response.
Induction of remission in mild disease
Proctitis is defined as inflammation of the rectum. Patients with proctitis or left-sided UC can often be managed with topical corticosteroids. Two meta-analyses have reported topical 5-aminosalicylic acid (5-ASA) is more effective than topical steroids, whether assessing symptomatic, endoscopic or histological remission (Marshall and Irvine, 1997). Topical steroids such as beclomethasone diproprionate (3 mg) should therefore be prescribed for patients who have an inadequate response or who are intolerant to topical 5-ASA. An RCT concluded budesonide rectal foam enema (2 g) is more successful than placebo in inducing remission at week 6 in patients with mild-to-moderate proctosigmoiditis (Regueiro et al, 2006). Refractory proctitis may require treatment with systemic corticosteroids.
Maintenance of remission
The data relating to maintenance of remission are disappointing. Prednisone 15 mg once daily was no different to placebo with regard to UC clinical relapse and remission after 6 months (Lennard-Jones et al, 1965). With respect to mucosal healing in UC, a trial involving patients treated with a 3-month tapered course of systemic corticosteroids within a year of initial diagnosis reported that 61.8% had persistent endoscopic activity at 3 months (Ardizzone et al, 2011).
In the NCCDS study, CD patients in clinical remission were given prednisolone 20 mg once daily; this did not reduce flare-ups or disease recurrence after surgery (Summers et al, 1979). A 2014 Cochrane systematic review concluded budesonide use beyond 3 months was ineffective at maintaining remission in CD (Kuenzig et al, 2014). In one study, CD patients who had achieved clinical remission after oral corticosteroids for a duration of 3–7 weeks underwent colonoscopy; 71% still had active endoscopic lesions (Kuenzig et al, 2018).
Steroid-dependent and steroid-refractory disease
Steroid-dependent IBD is defined as disease that initially responds to corticosteroids, but relapses without corticosteroids. Unfortunately, these patients require low-dose corticosteroids to remain symptom free (Porro et al, 2007). Retrospective data has reported that steroid dependency ranges between 11% and 38%. Patients requiring corticosteroids earlier in their disease course have a higher likelihood of developing steroid dependency (Khan et al, 2014). Steroid-refractory IBD is defined as a lack of meaningful response to steroids. Up to 40% of patients do not respond to high-dose steroid therapy. It is important to recognise and prevent long-term steroid use by introducing a steroid-sparing agent.
Starting a steroid-sparing agent is of paramount importance in reducing corticosteroid-related side effects. Many options are available, and choosing the right therapeutic agent depends on several factors: clinical symptoms; endoscopic and histological findings; disease location and progression; extra-intestinal manifestations; past therapy; and patient choice. The importance of achieving steroid-free mucosal healing is being increasingly recognised, and, with more aggressive therapy and the advent of newer agents, the rates of colectomy, steroid-dependent and steroid-refractory disease should decrease over time.
Strategies to prevent corticosteroid excess
ECCO consensus guidelines on the diagnosis and management of IBD emphasise the goal of maintenance therapy is to maintain steroid-free remission (Harbord et al, 2017). This has also been highlighted as a top priority by patient representative bodies (Westwood and Travis, 2008). The 2019 IBD standards released by Crohn's and Colitis UK (2019) advise that steroid treatment should be audited by individual IBD units on a routine basis. This can reduce the rate of inappropriate and prolonged corticosteroid prescribing.
Primary care education may also reduce inappropriate corticosteroid prescribing within the community setting. When surveyed in 2017, half of GPs in the UK stated that they lacked confidence in managing IBD, and two-thirds requested further education (Barrett et al, 2018). Providing GPs with better knowledge of 5-ASA optimisation can prevent unnecessary corticosteroid exposure and empower patients with 5-ASA self-management strategies.
The use of an IBD helpline led by specialist nurses should be encouraged for both patients and their GPs, especially during a flare-up. Second-generation corticosteroids should be encouraged to prevent adverse effects. Rapid diagnosis and management of new IBD is crucial to commence steroid-sparing agents in a timely fashion. Similar pathways should be in place for patients with newly diagnosed IBD at endoscopy. Dedicated IBD clinics led by clinicians and specialist nurses are preferred to general gastroenterology clinics. Regular IBD multidisciplinary team meetings can identify patients with steroid-dependent and steroid-refractory IBD (Selinger et al, 2017). Therapeutic options, such as immunosuppressive therapy and surgery, can be appropriately arranged.
Conclusion
Corticosteroids are effective at inducing remission in IBD. They can be given intravenously, orally or topically and used in mild-to-severe disease. Long-term use should be limited to prevent commonly associated adverse effects. Blood pressure, body mass index and blood glucose monitoring are crucial while on steroids. Acid suppression along with calcium and vitamin D supplementation should be co-prescribed to all patients on long-term corticosteroids. Bridging these patients to a steroid-sparing agent early prevents steroid-refractory and steroid-dependent disease.