Keywords

Introduction

Glucocorticosteroids have been around for about 60 years as a first-line treatment to induce remission in Crohn disease and ulcerative colitis in children and adults. The first randomized trial demonstrating their efficacy in active IBD was conducted in 1965 by Truelove et al. [1]. Systemic corticosteroid treatment may cause disfiguring cosmetic side effects during short-term use and bone demineralization as well as growth failure in long-term treatment, therefore limiting its use in children and adolescents. In addition to the side effects, corticosteroid resistance and dependence are common. The current trend is to minimize or even avoid corticosteroid use in pediatric as well as adult inflammatory bowel disease (IBD). In pediatric Crohn disease, enteral nutrition as primary therapy is a safe and effective alternative to prednisolone, whereas introduction of immune modulating therapy and biological treatment early in the course of disease is a successful steroid-sparing strategy [2]. In this chapter, the working mechanism, efficacy, side effects, and pharmacokinetics of “classic” (systemic) as well as topical corticosteroids such as budesonide will be reviewed.

The Working Mechanism of Corticosteroids

Under homeostatic conditions, activation of the innate and adaptive immune system is counteracted by endogenous glucocorticoids [3, 4]. At lower dosages, steroids may well follow these physiological pathways, whereas at higher concentrations other mechanisms may be involved.

Upon binding of the high-affinity glucocorticoid receptor, a cascade of events takes place starting with the dissociation of molecular chaperones followed by nuclear translocation. At this location, specific DNA sequences in the promoter region of steroid-responsive genes (glucocorticoid response elements) are bound leading to suppression of the genes encoding for the transcription of inflammatory proteins such as those involved in the mitogen-activated protein kinase (MAPK) pathway. Subsequently, the production of inflammatory mediators such as prostaglandins is reduced. The major anti-inflammatory effects of glucocorticoids appear to be due largely to interaction between the activated glucocorticoid receptor and transcription factors, notably nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1), that mediate the expression of inflammatory genes [5]. Inflammation may also become suppressed by increasing the synthesis of the anti-inflammatory mediators such as interleukin 10 and of inhibitor of kappa Ba (IĸBa), which is regarded as an inhibitor of the key inflammatory transcription factor NF-ĸB. Inhibition of nongenomic mechanisms may also be involved. An example is the activation of endothelial nitric oxide synthase by glucocorticoids leading to the production of nitric oxide (NO). NO is an important modulator of the inflammatory cascade in IBD by affecting leukocyte-endothelial interactions, leukocyte infiltration, and vasodilatation. In summary, it has become clear that glucocorticoids interact with a wide range of molecules and therefore exert their immunosuppression by affecting various inflammatory pathways.

Systemic Corticosteroids

Placebo-controlled trials on the safety and efficacy of prednisolone have not been performed in children with Crohn disease or ulcerative colitis. Multiple studies, however, as reviewed by Heuschkel et al. [6], have compared the results of enteral nutrition versus a course of steroids in the treatment of active Crohn disease in children and reported clinical remission in 85% of children treated with predniso(lo)ne. In children with severe acute ulcerative colitis, current guidelines recommend intravenous methylprednisolone as first-line treatment [7], with response rates of 71% as reported from a prospective trial in this group of patients [8].

One of the major drawbacks of corticosteroids is the range of side effects that may emerge during treatment, being cosmetic (acne, moon face, weight gain), psychological (mood swings, insomnia, depression), metabolic (bone demineralization, diabetes), or a risk of infections as a result of immune suppression. In children, the effect of systemic corticosteroids on growth is a special concern [9]. Moreover, it has long been known that corticosteroids do not heal the mucosa in IBD [10] and are not effective for the maintenance of remission [11–13]. From recent excellent data, drawn from a multicenter observational registry in the USA, we are now informed about the natural history of corticosteroid therapy in children with Crohn disease [14] as well as ulcerative colitis [15]. Despite the use of immunomodulators, 31% of children with CD and 45% of children with UC were found to be corticosteroid dependent at 1 year after diagnosis [14, 15]. This is in accordance with data from adults [16–18].

Topical Corticosteroids

Targeting local and systemic inflammatory processes in IBD therapeutic agents of first choice (e.g., aminosalicylates, corticosteroids) have been developed in special galenic forms to accomplish the topical delivery of the active compounds to the terminal ileum (Crohn disease) and/or the colon (Crohn disease and ulcerative colitis).

For over 10 years, nonsystemic corticosteroids such as budesonide, beclomethasone dipropionate, fluticasone, and hydrocortisone thiopivalate have been of interest for the targeted therapy of IBD. Budesonide is a glucocorticosteroid with a weak mineralocorticosteroid activity. It has a favorable ratio between anti-inflammatory activity and systemic glucocorticosteroid effect. This is explained by a high local glucocorticosteroid activity and an extensive first-pass hepatic degradation to metabolites with very low glucocorticosteroid activity. Due to these circumstances, the well-known glucocorticosteroid adverse effects are less frequent than with the conventional corticosteroids.

Pharmacokinetics

The absolute bioavailability of budesonide is very low, which results from gastrointestinal afflux mediated by P-glycoprotein, the product of the multidrug resistance 1 (MDR1) gene, and from biotransformation via cytochrome p450 3A (CYP3A) in the gut and liver. After this extensive first-pass metabolism, the metabolites 6β-hydroxybudesonide and 16α-hydroxyprednisolone are formed. Glucocorticoid activity of these metabolites amounts to only 1–10% of the parent drug.

Two pharmacokinetic studies have been performed in children with Crohn disease [19, 20]. Absolute bioavailability of budesonide (Entocort®) was found to be similar in children (9 ± 5%) compared to healthy adults (11 ± 7%) [20]. Consistently, overall systemic elimination of budesonide (Budenofalk®) reflected by clearance and half-life was not different in children and adults [19]. Conversion to 6β-hydroxybudesonide was shown to be 1.5-fold higher in children than in adults, suggesting enhanced biotransformation via CYP3A enzymes in children [19]. Corrections in dosing of budesonide based on body weight or body surface may not adequately reflect differences in pharmacodynamics. Therefore, the dose of budesonide (9 mg, once daily) decided on in both pediatric clinical trials [21, 22] was the same as used in adults with Crohn disease.

Topical Steroid Formulations

There are two oral formulations of budesonide used for treatment of Crohn disease: controlled ileal release (Entocort®) and pH-dependent release (Budenofalk®). Budenofalk is available in the EU but not in the USA. The controlled ileal release capsules contain 3 mg of budesonide distributed in approximately 100 pellets that have an outer coating of Eudragit L100–55 that dissolves at pH of 5.5 or higher. Absorption of Entocort® in the ileocaecal region ranges from 52 to 79%. The pH-dependent Budenofalk® capsules also contain 3 mg of budesonide in 400 pellets of 1 mm diameter and are coated with Eudragit, resistant to pH below 6.

For rectal treatment of left-sided ulcerative colitis, budesonide is available as enemas containing 2 mg per 100 ml of enema (Entocort® enema), and recently a new budesonide foam containing 2 mg per 25 ml of enema (Uceris® enema) has been developed with a goal of optimizing drug retention and providing uniform drug delivery to the rectum and distal colon with a mean spread of 25 cm [23]. Also, an oral controlled release system, MMX® extended-release budesonide 9 mg tablets (Uceris®; Cortiment®), characterized by a multi-matrix structure, has been developed. This new formulation has a gastric-resistant outer layer that dissolves as the luminal pH increases over 7.0 [24, 25]. It aims at a homogenous distribution of budesonide through the ascending, transverse, and descending colon, in order to treat colonic IBD, more specifically ulcerative colitis.

Efficacy of Oral Budesonide Treatment in Crohn Disease

Two randomized clinical trials have been performed comparing safety and efficacy of budesonide versus prednisolone in children with active ileocecal Crohn disease [21, 22]. In the non-blinded study by Levine et al., 33 patients (mean age 14.3 years) with active mild-to-moderate pediatric Crohn disease were randomized to 12 weeks of treatment with pH-modified release budesonide (Budenofalk® 9 mg, once daily) or prednisone (40 mg, once daily) [26]. The groups treated with budesonide and prednisone did not differ by age, onset of disease, location of disease, or disease activity. Remission (defined as Pediatric Crohn Disease Activity Index PCDAI ≤ 10) at 12 weeks was reported in 9/19 patients (47%) of the budesonide treatment group and in 7/14 patients (50%) of the prednisone treatment group (difference not statistically significant). Side effects occurred in 32% and 71% of patients treated with budesonide and prednisone, respectively (p < 0.05). Severity of cosmetic side effects was significantly lower in patients treated with budesonide (p < 0.01).

The study by Escher et al. was a randomized, double-blind, double-dummy, controlled multicenter clinical trial. In a joined effort by the IBD working group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), 36 centers located in eight European countries took part [22]. Planned sample size was 120, but the study was terminated prematurely due to low enrolment numbers, with 48 patients (mostly new patients) with active Crohn disease involving ileum and/or ascending colon completing the 12-week study. Patients (mean age 13 years) were randomized to budesonide (Entocort 9 mg, once daily for 8 weeks, tapered to 6 mg for 4 weeks) or prednisolone (1 mg per kg bodyweight, once daily for 4 weeks, followed by 4 week tapering down to a 2.5 mg daily dose). Primary outcome parameter was clinical remission (modified Crohn’s Disease Activity Index (CDAI ≤ 150)) at 8 weeks. Clinical remission was reported within 2 weeks of treatment in about 50% of the patients in both groups. At week 8, 12/22 patients in the budesonide group (55%) and 17/24 patients in the prednisolone group (71%) were in clinical remission (p = 0.25). The observed 16% difference in remission rate in favor of prednisone was statistically not significant. In case of planned enrolment of 120 patients, the extrapolated difference in remission rates would still not have reached significance. Mean CDAI of the patients was 239 (budesonide group) and 268 (prednisolone), representing mild-to-moderate disease. It is unknown whether prednisolone may be more effective than budesonide in patients with severe disease. Data from the North American prospective Pediatric IBD Collaborative Research Group Registry show that oral budesonide was used in 13% of children with newly diagnosed Crohn disease, mostly combined with 5-ASA (in 77%) or immunomodulators (43%). Despite the fact that oral budesonide is designed for controlled ileal release, less than 50% of these patients had disease located in the terminal ileum and/or ascending colon [27].

In adults, a Cochrane systematic review demonstrated that budesonide is more effective than placebo, though inferior to conventional corticosteroids in mild-to-moderate active Crohn disease in the terminal ileum and/or ascending colon. However, the likelihood of adverse events and adrenal suppression with budesonide is lower [28]. Four trials comparing budesonide versus prednisolone in adults showed less corticosteroid-related adverse events in the budesonide group [29–32]. Based on the above evidence, ECCO guidelines state that oral budesonide (9 mg once daily) for mild-to-moderate ileocaecal Crohn disease is an alternative to systemic corticosteroids for induction of remission in children [33] and a preferred treatment in adults [34].

Side Effects of Budesonide in Children

Glucocorticosteroid (GCS)-associated side effects such as moon face and acne were shown to occur significantly less in children treated with budesonide compared to prednisolone [22]. In the randomized clinical trial by Escher et al., moon face was almost three times as common in the prednisolone group. All short-term GCS-associated side effects of budesonide versus prednisolone are listed in Table 29.1. Adrenal suppression, expressed as a decrease in mean morning plasma cortisol levels, was evident during budesonide remission induction but significantly less compared to prednisolone treatment. Headache was reported in both treatment groups in 4/22 (budesonide group) and 4/26 patients (prednisolone group) and may be associated with benign intracranial hypertension as reported by Levine et al. [35].

Table 29.1 Glucocorticosteroid-associated side effects of budesonide versus prednisolone in children with ileocaecal Crohn disease
Full size table

A retrospective review of six prepubertal children with Crohn disease showed linear growth to be subnormal (2 cm/year) during budesonide maintenance treatment [36]. It remains unclear, however, whether impaired growth in these children (with PCDAI’s of 15–27.5, indicating active disease) was due only to budesonide treatment or to ongoing mucosal inflammation.

Maintenance Treatment in Crohn Disease

Maintenance treatment with budesonide has not been studied prospectively in children. Systemic corticosteroids however have not been shown to be effective in prolonging clinical remission. A Cochrane review based on four placebo-controlled randomized trials in adults with Crohn disease [31, 37–39] concluded that maintenance treatment with oral budesonide at 6 mg/day is not effective in preventing relapses of Crohn disease in adults [40]. In addition, a recent meta-analysis demonstrated that there is no statistically significant benefit of oral budesonide over placebo in the prevention of relapse in adults with quiescent Crohn disease, while glucocorticosteroid-related side effects were significantly more common with budesonide [11]. In light of this evidence, and the concerns on longitudinal growth in children, maintenance treatment with budesonide should not be recommended.

Budesonide in Ulcerative Colitis

No studies have been performed in children. In adults, topical steroid treatment with budesonide foam enemas is more efficacious than placebo in inducing remission in patients with mild-to-moderate left-sided colitis as demonstrated in two randomized, double-blinded studies [41] and has demonstrated a favorable safety profile [42]. However, budesonide enema was less effective in left-sided UC compared to 5-ASA [43]. In adults with mild-to-moderate active left-sided colitis, three studies have each shown a modest effect of budesonide MMX formulation for inducing remission compared to placebo, and the drug is well tolerated [44–47]. The role of these mediations in maintenance of remission in ulcerative colitis has not been studied.

Conclusion

Corticosteroids have been the first-line treatment in Crohn disease for many years. Disfiguring acute and serious long-term side effects, such as growth retardation and bone demineralization, limit their use. The current trend in pediatric as well as adult Crohn disease is to minimize and avoid repeated corticosteroid use by introducing immunomodulators early in the course of disease. In Europe, primary treatment of active Crohn disease by a 6–8 week course of enteral nutrition is favored over remission induction by prednisolone. Systemic or topical corticosteroids are not effective as maintenance treatment.

Adrenal suppression is less severe during budesonide treatment compared to prednisolone, and glucocorticosteroid-associated side effects such as acne and moon face occur less frequently.

Corticosteroids do not heal the mucosa, do not prevent relapse, and do not alter the course of disease. In the current era, confidence with early immunomodulator and biological treatment is growing, with a tendency toward step-down instead of step-up treatment. While this strategy needs to be substantiated by prospective studies, it is clear that corticosteroids are losing their position as first-line treatment of pediatric IBD.