In contrast to sulfasalazine, other aminosalicylate formulations are well tolerated. In most clinical trials, the frequency of drug adverse events is similar to that in patients treated with placebo. For unclear reasons, olsalazine may stimulate a secretory diarrhea—which should not be confused with active IBD—in 10% of patients. Rare hypersensitivity reactions may occur with all aminosalicylates but are much less common than with sulfasalazine. Careful studies have documented subtle changes indicative of renal tubular damage in patients receiving high doses of aminosalicylates. Rare cases of interstitial nephritis are reported, particularly in association with high doses of mesalamine formulations; this may be attributable to the higher serum 5-ASA levels attained with these drugs. Sulfasalazine and other aminosalicylates rarely cause worsening of colitis, which may be misinterpreted as refractory colitis.
In gastrointestinal practice, prednisone and prednisolone are the most commonly used oral glucocorticoids. These drugs have an intermediate duration of biologic activity allowing once-daily dosing.
Hydrocortisone enemas, foam, or suppositories are used to maximize colonic tissue effects and minimize systemic absorption via topical treatment of active IBD in the rectum and sigmoid colon. Absorption of hydrocortisone is reduced with rectal administration, although 15–30% of the administered dosage is still absorbed.
Budesonide is a potent synthetic analog of prednisolone that has high affinity for the glucocorticoid receptor but is subject to rapid first-pass hepatic metabolism (in part by CYP3A4), resulting in low oral bioavailability. Two pH-controlled delayed-release oral formulations of budesonide are available that release the drug either in the distal ileum and colon (pH > 5.5, Entocort) or in the colon (pH > 7, Uceris), where it is absorbed. The bioavailability of controlled-release budesonide capsules is approximately 10%.
As in other tissues, glucocorticoids inhibit production of inflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1) and chemokines (IL-8); reduce expression of inflammatory cell adhesion molecules; and inhibit gene transcription of nitric oxide synthase, phospholipase A2, cyclooxygenase-2, and NF-κB.
Glucocorticoids are commonly used in the treatment of patients with moderate to severe active IBD. Active disease is commonly treated with an initial oral dosage of 40–60 mg/d of prednisone or prednisolone. Higher doses have not been shown to be more efficacious but have significantly greater adverse effects. Once a patient responds to initial therapy (usually within 1–2 weeks), the dosage is tapered to minimize development of adverse effects. In severely ill patients, the drugs are usually administered intravenously.
For the treatment of IBD involving the rectum or sigmoid colon, rectally administered glucocorticoids are preferred because of their lower systemic absorption.
The oral controlled-release budesonide (9 mg/d) formulations described above are used in the treatment of mild to moderate Crohn’s disease involving the ileum and proximal colon (Entocort) and ulcerative colitis (Uceris). They are slightly less effective than prednisolone in achieving clinical remission but have significantly less adverse systemic effects.
Corticosteroids are not useful for maintaining disease remission. Other medications such as aminosalicylates or immunosuppressive agents should be used for this purpose.