Daniel C. Baumgart (ed.)Crohn’s Disease and Ulcerative Colitis10.1007/978-3-319-33703-6_29

29. Steroid Therapy for Crohn’s Disease

A. Hillary Steinhart¹

(1)

IBD Centre, Mount Sinai Hospital and Department of Medicine, University of Toronto, Room 445, 600 University Avenue, Toronto, ON, M5G 1X5, Canada

A. Hillary Steinhart

Email: hsteinhart@mtsinai.on.ca

Steroids are a class of hormones that are normally produced in a variety of organs in the human body. They have a number of different physiologic properties that are determined by the nature of the molecular substitutions at several points around the backbone ring structure that is common to all steroids. The steroid hormone cortisone is produced by the adrenal cortex and, in additional to promoting catabolic metabolism, it also demonstrates several anti-inflammatory properties. It is these properties that provide the potential for therapeutic use of steroids in Crohn’s disease and a variety of other inflammatory and autoimmune disorders. Cortisone is rarely used clinically to treat Crohn’s disease, but a number of synthetically altered forms of steroids are frequently utilized as therapeutic agents. These pharmacologic agents typically have modifications that enhance their potency by increasing their affinity for binding of the steroid receptor, that alter their excretion or elimination, or that change their relative glucocorticoid and mineralocorticoid effect. The most commonly used of the systemically administered and active steroids are prednisone, prednisolone, methylprednisolone, and hydrocortisone. Budesonide, a highly potent and topically active steroid, is also used as one of several controlled release preparations for treating Crohn’s disease, particularly when inflammation is confined to the terminal ileum and the ascending colon.

Induction Therapy

Conventional Steroids

Steroids are very effective at reducing inflammation and alleviating symptoms in patients with active intestinal Crohn’s disease. They have been in use for the treatment of Crohn’s disease for well over half a century and generally have the advantage of being effective in treating active inflammation in a number of different locations throughout the gastrointestinal tract as well as treating some of the extraintestinal manifestations of Crohn’s disease. Despite the widespread use of steroids there have been relatively few randomized controlled trials that have both demonstrated their effectiveness and provided clear guidance with respect to optimal dosing, duration of therapy and tapering regimens. The effectiveness of steroids in treating active Crohn’s disease was confirmed by the first part of the National Cooperative Crohn’s Disease Study (NCCDS) in the USA [1], and by the European Cooperative Crohn’s Disease Study (ECCDS) [2].

In the NCCDS , Part 1, Phase 1 the effectiveness of prednisone, sulfasalazine, and azathioprine were compared to placebo in treating patients with symptoms of active Crohn’s disease over a 17 week study period [1]. In the steroid treated arm the dose of prednisone was based upon the baseline disease activity with 0.5 mg/kg used for those patients with mild to moderate disease activity (Crohn’s disease activity index score between 150 and 300) and 0.75 mg/kg for those with more severe disease activity (Crohn’s disease activity index score greater than 300). The maximum daily dose of prednisone was 60 mg. A complex analysis of outcome rankings demonstrated superiority to placebo for both prednisone and sulfasalazine . Using that analytical method it appeared that prednisone was particularly effective in patients with small intestinal involvement but not terribly effective in patients with only colonic involvement. When the more conventional outcome assessment of the proportion of patients in remission by the end of the 17-week study period was used, only prednisone was found to be superior to placebo with approximately 62 % of patients in remission (Crohn’s disease activity index below 150) compared with approximately 30 % in the placebo arm using life table analysis. Using simple proportional analysis 47 % of prednisone-treated patients and 26 % of placebo-treated patients were in remission at week 17.

In the induction phase of the European Cooperative Crohn’s Disease Study (ECCDS) patients with active Crohn’s disease were randomized to receive 6-methylprednisolone, sulfasalazine, combination 6-methylprednisolone and sulfasalazine, or placebo for 6 weeks [2]. The 6-methylprednisolone was initiated at 48 mg per day and tapered to a dose of 12 mg per day over the 6-week study period. Patients initially randomized to the steroid arm who were in remission at the end of the acute phase (CDAI < 150) were then continued on maintenance 6-methylprednisolone 8 mg per day. Two increases in steroid dose back to 48 mg per day followed by repeated attempts at tapering were permitted in the 6-methylprednisolone-treated patients who were not in remission by the end of 6 weeks. Treatment with 6-methylprednisolone was found to be effective in inducing remission and was superior to sulfasalazine when Crohn’s disease was located in the small intestine or both small and large intestine. In patients with only colonic disease location the combination of 6-methylprednisolone and sulfasalazine was the most effective treatment. Overall, 83 % of patients in the steroid treated arm were in remission at the end of 18 weeks as compared with 32.9 % of patients in the placebo arm.

Pooled analysis of the steroid induction studies demonstrated a twofold increased likelihood of remission induction with steroids as compared with placebo and a number needed to treat of 3.33 [3].

Many potential side effects of prednisone were recognized and described within the context of the induction therapy phase (Part 1, Phase I) of the NCCDS with moon face reported in 47 % of patients, striae in 6 %, ecchymoses in 17 %, acne in 30 %, infection in 27 %, muscle weakness in 9 %, hirsutism in 7 %, and polyuria in 15 % [1]. However, the use of prednisone in that trial was not consistent with what would currently be considered to be standard practice in that no tapering of the dose was permitted over the 17-week trial period. The high cumulative steroid dose, particularly in patients with higher disease activity scores at baseline, may have contributed to the very high rate of steroid associated side effects. Combining the adverse event results of the NCCDS and ECCDS demonstrated an almost fivefold increased risk of adverse events in steroid-treated patients as compared to placebo [3]. Although most of these did not result in patient withdrawal from the studies, the use of steroids was associated with a trend toward greater withdrawal rates in steroid-treated patients.

The optimal form of systemically acting steroid therapy has not been determined and the choice of specific steroid preparation typically depends upon local experience. Steroids can also be administered intravenously (e.g., hydrocortisone , 6-methylprednisolone ) to hospitalized patients with more severe disease or more acute presentations but the superiority of intravenous administration has not been proven. Its main advantage is that it can be given to patients who are not able to tolerate oral intake.

The optimal dose of steroids for the treatment of active Crohn’s disease has not been established. In the National Cooperative Crohn’s Disease Study , where a dose of prednisone of 0.5 mg/kg per day was used in patients with mild to moderate disease activity and 0.75 mg/kg per day (up to a maximum of 60 mg) was used in patients with moderate to severe disease activity, remission was achieved in 62 % of patients over 17 weeks of treatment [1]. However, in an unblinded single arm study from France, prednisolone was used at a dose of 1 mg/kg for between 3 and 7 weeks with induction of remission observed in 92 % [4]. This raises the possibility that the upper ranges of the steroid dose–response relationship has not been completely elucidated and that doses greater than the usual 40–60 mg per day of prednisone, or its equivalent, may provide additional benefit. Despite this possibility daily doses of steroid higher than the equivalent of 60 mg of prednisone are usually not recommended in the current environment when alternative induction therapies are available for Crohn’s disease patients.

In the acutely ill patient it is important to sufficiently exclude the presence of an abscess or systemic sepsis before initiating any form of systemic steroid. In the European Cooperative Crohn’s Disease Study, of the five deaths that occurred during or shortly after the study period, three occurred in patients treated with steroids who had a palpable abdominal mass prior to initiation of therapy [2]. No routine imaging was performed prior to study entry and, as a result, it is quite likely that these masses could have represented Crohn’s related abscesses or collections that were not properly managed with drainage and antibiotic therapy prior to initiation of prednisolone.

Topical rectally administered steroids, in the form of liquid or foam enemas, can also be used as adjuvant therapy in controlling local symptoms in patients with distal colonic or rectal Crohn’s disease. However, there is no evidence that this is an effective strategy and their use is based upon extension of the data from ulcerative colitis .

Budesonide

For patients with ileal or ileocolonic Crohn’s disease the use of the controlled ileal release preparation of the topically active steroid budesonide is an effective treatment for controlling symptoms of active disease. When administered at a dose of 9 mg per day budesonide was shown to be more effective than placebo [5] and mesalamine [6]. Another placebo controlled trial demonstrated a trended towards higher remission rates on budesonide 9 mg once daily (46.2 %) and 4.5 mg twice daily (51.9 %) as compared with placebo (31.7 %) but this was not statistically significant [7]. A small Japanese trial showed a trend toward higher rate of clinical remission in patients receiving budesonide 9 mg per day compared with placebo (23.1 % versus 11.5 %) after 8 weeks of therapy in patients with ileal, ileocecal, or ascending colon involvement [8].

Doses greater than 9 mg per day do not appear to have any further therapeutic gain and may be associated with a greater incidence of steroid associated side effects and adrenal suppression [5, 8].

Another trial compared 16 weeks of budesonide 9 mg daily to mesalamine 2 g twice daily for control of active ileal or ileocolic Crohn’s disease and demonstrated clear superiority for budesonide with 62 % of budesonide-treated patients and 36 % of mesalamine-treated patients in remission at the end of the study period [6]. Severe and serious adverse events were observed less often in budesonide-treated patients. Ten percent of budesonide-treated patients had abnormal ACTH stimulated cortisol testing at the end of 16 weeks of treatment.

Budesonide that is absorbed from the intestinal lumen into the portal circulation undergoes high first pass metabolism through the liver leading to the production of inactive metabolites. It is this high first pass metabolism that likely results in the favorable short term safety profile with steroid associated side effects seen no more frequently on a 9 mg daily dose as compared with patients receiving placebo. However, the 9 mg daily dose of budesonide resulted in a lowering of basal plasma cortisol levels in two trials [5, 6] and in another trial a smaller proportion of patients receiving budesonide had normal adrenal function after 8 weeks (53 % versus 83 %) [7]. Both placebo controlled trials demonstrated a reduction in ACTH stimulated plasma cortisol levels in patients treated with budesonide [5, 7]. Given the demonstrated subclinical degree of adrenal suppression the use of adrenal replacement therapy for patients undergoing surgery or other severe physiologic stresses should be considered in patients currently or recently on budesonide at a dose of 9 mg per day.

When compared directly to the use of conventional systemic steroids in patients with ileal and ileocolic Crohn’s disease it appears that budesonide controlled ileal release formulation may produce somewhat less reduction in disease activity [9], although another study showed roughly equivalent efficacy [10]. In both studies, induction of remission was slightly less frequent with budesonide than with prednisolone , although the differences were not statistically significant [9, 10]. In the study of Rutgeerts and colleagues, fewer steroid associated side effects and less suppression of morning cortisol levels were observed on budesonide as compared with conventional steroids [9]. In the study of Campieri, steroid associated side effects were observed at similar frequencies in patients treated with budesonide and those treated with conventional steroids, although moon face was observed much more frequently on prednisolone [10]. Adrenal suppression, as measured by short ACTH stimulation test, was more frequent in patients treated with conventional systemic steroids [10].

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