The limitations of corticosteroid therapy in Crohn’s disease

Abstract

Corticosteroids are highly effective in inducing clinical remission in patients with active Crohn’s disease. However, the role of corticosteroids in the treatment of this disease is primarily ameliorative because they are ineffective in maintaining remission or healing mucosal lesions. Nearly half of the patients who initially respond to corticosteroid therapy develop a dependency on corticosteroids or have a relapse within 1 year. In addition, use of these agents is often limited by a relatively high risk of serious adverse effects that can involve nearly every major body system. These effects include: bone loss, which can develop with even short‐term and low‐dose corticosteroid therapy; metabolic complications such as glucose intolerance and diabetes mellitus; increased intraocular pressure and glaucoma; and potentially lethal infections. To minimize the risk of toxicity, corticosteroids are increasingly recommended for short‐term use only at the lowest effective dose to induce remission in patients with moderately to severely active Crohn’s disease. Corticosteroid formulations with low systemic bioavailability, such as controlled‐release budesonide, may be associated with a lower rate of dermatologic adverse effects but appear to be somewhat less effective than conventional corticosteroids in inducing remission in patients with active Crohn’s disease. Immunosuppressive agents such as azathioprine, 6‐mercaptopurine, and methotrexate have demon‐ strated corticosteroid‐sparing effects, facilitating the withdrawal of corticosteroids when initiated as maintenance therapy. Infliximab can be used as an alternative to corticosteroids.

NCX-1015, a nitric-oxide derivative of prednisolone, enhances regulatory T cells in the lamina propria and protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice

“…However, mesalamine (23) and the glucocorticoids budesonide (24), dexamethasone (25), and methylprednisolone (25) have proven to be only of limited efficacy in reducing the colitis score, prostaglandin E 2 production, and MPO or matrix metalloproteinase activity associated with this disease model. The poor efficacy of these treatments in TNBS-induced colitis is in line with the weak response of CD patients when compared with patients suffering from ulcerative colitis (1,17). Confirming previous studies, we have now demonstrated that colitis induced in mice by TNBS is generally resistant to steroid administration, because only a very high dose of prednisolone (10 mg͞kg͞day) protected against disease development and͞or induced remission of established disease.…”

“…Although activation of gene expression by glucocorticoids generally requires binding of a GR dimer to a specific DNA site, some effects exerted by glucocorticoids are mediated instead by proteinprotein interactions between the GR and transcription factors such as NF-B͞Rel (12)(13)(14)(15)(16). Glucocorticoids are commonly used to treat IBD patients (11); however, the clinical effects are often transitory, and disease recurs on tapering the drug, whereas high doses are accompanied by serious side effects and dependence (17). Therefore, modified forms of steroids active at lower therapeutic doses would fulfill an urgent clinical need.…”

A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

“…Steroids, such as prednisolone, are powerful drugs that act at the genetic level resulting in the down-regulation of various proinflammatory mediators such as cytokines as well as immune pathways (35). These drugs, with nonspecific actions, possess numerous side effects, and their chronic use must be used with caution in patients (36,37). In our study, prednisolone pretreatment was effective at reducing the majority of parameters measured, consistent with previous findings (38 -40), although treated rats lost considerable body weight attributed to catabolism, a major side effect with steroid therapy (41,42).…”

Granulocyteaphaeresis in steroid‐dependent inflammatory bowel disease: a prospective, open, pilot study

“…1,2 This scenario must be avoided because of the high rate of steroid sideeffects, some of them even irreversible. 3,4 Conventional immunomodulators (mainly azathioprine or methotrexate) or, more recently, infliximab, have demonstrated their efficacy in inducing disease remission and steroid withdrawal. Nevertheless, still a considerable proportion of these patients are refractory or intolerant to these drugs.…”