Corticosteroids

Introduction

Corticosteroids have been an important therapeutic option in the treatment of ulcerative colitis (UC) since the pivotal trial by Truelove and Witts in 1954. Even after newer treatments emerged, steroids have remained an important therapeutic option due to their rapid onset (with most patients experiencing improvements in symptoms within days) and well-established efficacy. Their mechanism of action is a result of their ability to modulate the immune response through interaction with glucocorticoid receptors, which inhibits the expression of adhesion molecules and trafficking of inflammatory cells in the intestine, thus inhibiting inflammatory processes. Although very effective for the short-term control of flare-ups, they are not recommended for long-term or maintenance use due to adverse events and their lack of efficacy to maintain remission. Therefore, it is important to consider the place of corticosteroids within treatment regimens for UC, balancing effective induction of remission with the risk for serious adverse events.

Usage and Formulations

Aminosalicylate (5-ASA) drugs are the first-line therapy option for patients with mild to moderate disease. In patients with proctitis or left-sided UC who do not achieve response or remission with 5-ASA drugs, topical corticosteroids can be initiated as a second-line add-on therapy. Although 5-ASA drugs are superior to topical corticosteroids at inducing remission, clinical and endoscopic improvement can be improved further when combining 5-ASA drugs and corticosteroids. Foam corticosteroid formulations are often better tolerated than enemas in patients with active distal UC.

A short-term course of oral corticosteroids is frequently used as the next option in patients with mild to moderate UC who do not respond to combination 5-ASA therapy, or in those patients where a more rapid response is desired. A recommended starting dose is 40 mg to 60 mg prednisone or equivalent daily. Once a response is seen, typically within 2 weeks, steroids should be tapered by 5 mg to 10 mg per week until reaching 20 mg daily, then tapered by 2.5 mg to 5 mg per week until completion. In addition to traditional corticosteroids (e.g., prednisone), corticosteroids with minimal systemic activity have been developed to improve the adverse event profiles of these oral agents. Such agents include budesonide and prolonged-release beclomethasone dipropionate, both of which have been shown to be effective at inducing remission in UC. At present, only prolonged release budesonide is available commercially in the United States. Due to extensive first-pass hepatic metabolism, the majority of budesonide is metabolized by the cytochrome P450 system in the liver to inactive metabolites and only 10% to 15% of the drug reaches the systemic circulation. Due to the lower risk for systemic adverse events, these drugs should be considered as alternative first-line options in patients with mild to moderate UC who have failed 5-ASA therapy.

Oral corticosteroids are often the first-choice treatment options for moderate to severe UC, followed by a transition to thiopurines and/or biologics or tofacitinib in those who respond. If symptoms fail to respond to oral corticosteroids, then anti-tumor necrosis factor (TNF) therapy or hospitalization for intravenous (IV) steroids is warranted. IV steroids are effective at inducing remission in up to 70% of patients.

All patients treated with corticosteroids as inductive therapy should be bridged to medical therapy which has been demonstrated to be effective at maintaining remission. Steroids are not effective for maintenance of remission in patients with UC and prolonged use of steroids is associated with potential development of a serious adverse event. In general, although they are very effective at inducing remission, corticosteroids are typically given at the lowest possible dose for the shortest period of time. Frequent short-term use is also inadvisable.

Safety

Approximately 50% of patients receiving steroids experience adverse events (Table 9-1). The risk for adverse events increases with prolonged use, and due to the development of steroid dependence, tapering is required to avoid withdrawal symptoms. In some patients, the adverse events of steroids may outweigh their anti-inflammatory benefit. Early adverse events include acne, edema, glucose intolerance and sleep and mood disturbance. More serious adverse events occur with prolonged use (i.e., >12 weeks), including osteoporosis, cataracts, myopathy, infection and development of diabetes. Additionally. osteonecrosis is an uncommon side effect that may occur years after initial use of steroids.

Some physicians may choose to avoid corticosteroid use, but there are several ways to reduce the risk for adverse events:

• Rapid tapering
• Alternate-day dosing
• Use of topical corticosteroids
• Use of rapidly-metabolized corticosteroids, such as budesonide.

Because of their significant short- and long-term adverse events, use of corticosteroids should be monitored. In the clinical practice, calcium and vitamin D supplementation, periodic bone mineral density assessment and glucose intolerance monitoring are important to consider. Caution is warranted in the elderly population, which have a higher incidence of steroid dependence and experience more frequent and severe adverse events, including osteoporotic-related fractures, precipitating or worsening diabetes mellitus, altered mental status and longer hospitalizations.

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Uceris (Budesonide)

Budesonide was approved by the FDA as extended-released tablets and rectal foam formulations for the treatment of UC, with the following therapeutic indications:

• Extended-release tablets: Indicated for the induction of remission in patients with active, mild to moderate UC.
• Rectal foam: Indicated for the induction of remission in patients with active mild to moderate distal UC extending up to 40 cm from the anal verge.

Extended-release tablets contain budesonide (Budesonide MMX or Uceris) within an enteric-coated core, protecting against dissolution in gastric contents and delaying budesonide release until exposure to a pH ≥7 in the small intestine. Upon disintegration of the protective coating, the core matrix provides extended release of budesonide in a time-dependent manner. The efficacy of budesonide extended-release tablets in the induction of remission in active mild to moderate UC was assessed in a pair of two randomized clinical trials enrolling 970 adult patients. The primary analysis population consisted of 899 patients with histology consistent with active UC. Both studies compared 9 mg and 6 mg budesonide extended-release tablets with placebo and an active reference arm. The primary endpoint was induction of remission after 8 weeks of treatment, defined as an Ulcerative Colitis Disease Activity Index (UCDAI) score of ≤1, with subscores of 0 for rectal bleeding, stool frequency and mucosal appearance and with a ≥1 point reduction in an endoscopy-only score. In both studies, 9 mg budesonide extended-release tablets demonstrated superiority to placebo in inducing remission (Table 9-2).

Two replicate clinical trials were conducted to assess the efficacy of budesonide rectal foam in the treatment of UC. These trials enrolled adult patients with active mild to moderate distal UC with disease extending at least 5 cm but no further than 40 cm from the anal verge, confirmed by endoscopy. Eligible patients were also required to have a Modified Mayo Disease Activity Index (MMDAI) score between 5 and 10, inclusive, a rectal bleeding subscore of 2 or 3 and an endoscopy subscore of 2 or 3. Oral and rectal corticosteroids and rectal 5-ASA products were prohibited during the trials but were permitted as rescue therapy; oral 5-ASA products were permitted at doses ≤4.8 g/day. In total, 546 patients were randomized to receive either 2 mg budesonide rectal foam or placebo twice daily for 2 weeks followed by once daily for 4 weeks. The primary endpoint of each trial was the proportion of subjects who were in remission after 6 weeks of treatment, defined as a decrease or no change in the stool frequency subscore from baseline, a rectal bleeding subscore of 0, and an endoscopy score of 0 or 1. In both trials, a greater proportion of patients in the budesonide rectal foam group were in remission at Week 6 and had a rectal bleeding subscore of 0 at Week 6 compared to placebo (Table 9-3).

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