Glucocorticoid therapy for gastrointestinal diseases.

Review

Glucocorticoid therapy for gastrointestinal diseases George Triadafilopoulos 1.

Introduction

Stanford University School of Medicine, Gastroenterology, Stanford, CA, USA

2.

Mechanisms of action of glucocorticoids

3.

General principles of

Introduction: Glucocorticoids are widely used as anti-inflammatory and immunosuppressive agents in many immune-mediated gastrointestinal diseases. However, a number of undesirable side effects may occur and dictate continuous surveillance and monitoring to prevent complications. Areas covered: This review of the English language literature identified on PubMed focuses on key aspects of glucocorticoid therapy in patients with gastrointestinal diseases, highlighting specific aspects of recognition and management of its secondary effects. Expert opinion: Long-term cohort studies as well as placebo- and sham-controlled trials have evaluated the clinical efficacy, safety and tolerability of glucocorticoid therapy in many gastrointestinal diseases. Other immunosuppressive and biological therapies have made glucocorticoid therapy part of a broader arsenal of therapies. Newer compounds that carry less systemic toxicity and improved tolerability are increasingly used. For several gastrointestinal diseases, the role of the mucosal immunity is currently being explored and microscopic inflammation of the intestinal mucosa may have an important pathogenetic role. Glucocorticoid therapy, particularly with newer, safer compounds, may play an important new role in patients with altered motility and visceral hypersensitivity. The interplay of the gut microbiota and the host that contributes to the development of gut-associated lymphoid tissues and gut-specific immune responses will also undoubtedly be explored.

glucocorticoid therapy for

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by Universitat de Girona on 03/24/15 For personal use only.

gastrointestinal diseases 4.

Specific aspects of glucocorticoid therapy in gastrointestinal diseases

5.

Complications of glucocorticoid therapy and their prevention

6.

Conclusion

7.

Expert opinion

Keywords: corticosteroids, drug safety, intestinal inflammation, pharmacovigilance Expert Opin. Drug Saf. (2014) 13(5):563-572

1.

Introduction

Glucocorticoids have been used as anti-inflammatory and immunosuppressive agents for several decades but their exact mechanism(s) of action are still incompletely understood. Extensively used either as a short course or long-term therapy across many specialties and for many systemic diseases, glucocorticoids offer unquestionable clinical benefits but, at the same time, may be associated with unwanted adverse effects [1]. The first step to improve the benefit-to-risk ratio of these compounds involved the synthesis of new glucocorticoids (e.g., prednisolone and methylprednisolone), which differ from the original cortisone by exhibiting less mineralocorticoid activity but considerably greater glucocorticoid potency [2]. Drug delivery direct to the site of inflammation by inhalation, topical or intralesional application, has improved their anti-inflammatory and immunosuppressive effects while minimizing side effects [3]. The initiation of glucocorticoid therapy should always take into account the risks of the disease to be treated and the risks of therapy as they pertain to each patient. Since the introduction of many new therapies for systemic diseases, clinicians today are able to reduce the dose and duration of glucocorticoid therapy, minimizing the cumulative dose administered to patients [4]. The appropriate prescription of glucocorticoid therapy and the monitoring, prevention and treatment of its possible 10.1517/14740338.2014.904852 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

563

G. Triadafilopoulos

endothelial cells, and suppression of the production and action of humoral factors involved in inflammation [6].

Article highlights. .

.

.


.

.

.

Glucocorticoids are used as anti-inflammatory and immunosuppressive agents in the treatment of many immune-mediated gastrointestinal diseases. In the course of glucocorticoid therapy, several undesirable side effects may occur and dictate a continuous surveillance, monitoring and patient education to prevent complications. An important rule in clinical practice is to prescribe as little amount of glucocorticoids as necessary, locally if possible, and for the shortest time period. Newer glucocorticoid compounds, less likely to cause systemic adverse effects, as well as intralesional and topical preparations are increasingly used. Combination glucocorticoid therapy with other agents, such as biologics and immunosuppressants, is widely practiced but not well standardized. As newer, safer molecules are developed, the prospect of a long-term glucocorticoid therapy that carries minimal systemic toxicity and better tolerability will play an important in an expanded arena of gastrointestinal diseases.

This box summarizes key points contained in the article.

adverse events is a critical endeavor and, if done correctly, minimizes morbidity and mortality, while restoring life expectancy and quality. An important general rule in routine clinical practice is to prescribe as little amount as necessary, locally if possible, and for the shortest time period. This review focuses on key aspects of glucocorticoid therapy in patients with gastrointestinal diseases, highlighting specific aspects of recognition and management of its secondary effects.

2.

Mechanisms of action of glucocorticoids

Several major mechanisms of action of glucocorticoids have been characterized [2]. The strong anti-inflammatory and immunosuppressive effects of glucocorticoids are mediated primarily by the cytosolic glucocorticoid receptors. These receptors are members of a superfamily of ligand-inducible transcription factors and exert genomic effects that can result in increased expression of regulatory proteins or decreased production of proinflammatory proteins. Many of the desirable anti-inflammatory and immunosuppressive effects of glucocorticoids are induced by suppression of synthesis of proinflammatory mediators, such as cytokines (e.g., IL-1, IL-2, TNF and interferon) and prostaglandins [5]. Glucocorticoids also exert their effects via rapid, nongenomic mechanisms that can be classified as involving nonspecific interactions with cellular membranes, or mediated by cytosolic or membrane-bound glucocorticoid receptors. The resulting clinical effects include inhibition of leukocyte trafficking, interference with the function of leukocytes, fibroblasts and 564

General principles of glucocorticoid therapy for gastrointestinal diseases

3.

Glucocorticoid type Of the many commercially available agents, oral prednisone and prednisolone are considered the standards of oral administration, whereas hydrocortisone and methylprednisolone are used mostly intravenously (i.v.). Fluticasone and budesonide are also used as oral agents and are considered as less likely to cause systemic adverse effects [7]. Triamcinolone is used intralesionally; hydrocortisone is the main ingredient of topical agents, such as enemas, suppositories and creams. 3.1

Mode of administration Oral administration is the simplest and most convenient way for long-term therapy. In contrast, injection therapy is either used as a pulse therapy at high doses over a short time or as intermediate-term therapy, if patients cannot tolerate oral administration. Intravenous pulse therapy may be associated with headaches, a ‘flush’ feeling, nausea, visual disturbances, arthralgias and/or myalgias or more serious complications, such as life-threatening infections, arrhythmias or acute neuropsychiatric syndromes. For this reason, it is important to initiate pulse therapy in a controlled hospital setting with hemodynamic monitoring, correction of glucose and electrolyte disturbances and slow infusion [8]. 3.2

Dosage The amount of corticosteroid used varies, depending on the disease to be treated, its severity, other available therapeutic options and the preference of the physician. It is generally preferable to start with a high dose and then to reduce the dose as the inflammation subsides. Neutrophilic pleocytosis due to demargination of neutrophils and a reduction of eosinophilic and basophilic counts are usually seen. 3.3

Treatment initiation and monitoring Treating with glucocorticoids requires careful consideration, planning and patient understanding of its risks and benefits. Continuous monitoring of the clinical efficacy, tolerability and side effects, then allows for a balanced decision to continuation or not of such therapy, or dose adjustment. In patients treated long-term, the risk of adrenal suppression has to weigh in the decision of termination of therapy. Rapid tapering may be associated with worse symptoms than those seen initially. Reappearance of the disease symptoms after treatment discontinuation usually requires restitution of glucocorticoid therapy, possibly with adjunctive use of other immunosuppressants. Consensus-based recommendations on monitoring for adverse events of low-dose glucocorticoid therapy in clinical trials and daily practice have been recently published [9]. 3.4

Expert Opin. Drug Saf. (2014) 13(5)

Glucocorticoid therapy for gastrointestinal diseases

3.5

Duration of therapy

The duration of glucocorticoid therapy depends on the individual’s therapeutic response, the development of dependence or resistance and the concomitant use of other agents, such as anti-TNF inhibitors or immunosuppressants. In most cases, treatment consists of low-dose glucocorticoids for 2 -- 6 months. Treatment is stopped if the underlying disease is considered cured or other adjunctive treatments have been implemented in order to maintain it in remission.

Specific aspects of glucocorticoid therapy in gastrointestinal diseases


4.

Eosinophilic esophagitis Most patients with eosinophilic esophagitis respond to topical or oral glucocorticoids, exhibiting a decrease in esophageal tissue eosinophilia and sometimes improvement in dysphagia [10]. Fluticasone is administered as two 220 mcg sprays swallowed twice daily (b.i.d.) [11], although response rates are better with a higher dose. Treatment is generally well tolerated and patients tend to respond within several days. If they respond, treatment is continued for 8 weeks [12]. Approximately 15% of patients relapse when treatment is stopped and maintenance therapy may be needed [13]. Nonresponsive patients may benefit from a higher dose of fluticasone or a change to oral viscous budesonide. Side effects include dry mouth, esophageal candidiasis and, rarely, herpes esophagitis [14,15]. Budesonide, 1 mg b.i.d., is administered using a nebulizer, with patients swallowing the liquid or as a viscous suspension of compounded budesonide with sucralose that may facilitate better mucosal contact. In a placebo-controlled, randomized trial, patients who received budesonide had significantly improved dysphagia and histological improvement compared with those who received placebo [16]. Ciclesonide is a topical glucocorticoid that has less systemic absorption than fluticasone. At a dose of 80 or 160 mcg, two sprays b.i.d., for 2 months, ciclesonide improves symptoms and decreases esophageal eosinophil counts [17]. Prednisone, 40 -- 60 mg orally per day, is slightly more effective than fluticasone but with more frequent side effects. In a randomized trial of oral prednisone or fluticasone almost all patients became asymptomatic by 4 weeks but the prednisone group showed a better histologic response. Glucocorticoid side effects occurred in 40% of prednisone users, whereas esophageal candidiasis was seen in 15% of those treated with fluticasone [18]. Maintenance therapy with topical steroids (fluticasone 880 mcg daily or budesonide 1 mg daily) and relevant dietary restriction is recommended in patients presenting with dysphagia, episodic food impaction or esophageal stricture. In a placebo-controlled maintenance trial, patients who received budesonide were more likely to be in clinical remission (64 vs 36%) and exhibit decreased esophageal mucosal 4.1

thickness [19]. In adults with glucocorticoid-dependent eosinophilic esophagitis, immunomodulatory treatment with purine analogues is a promising approach for inducing and maintaining long-term remission without the need for further glucocorticoids [20]. Esophageal strictures Intralesional glucocorticoid injections increase the effectiveness of endoscopic dilation of strictures at various sites because they inhibit stricture formation by interfering with collagen synthesis and chronic fibrosis thereby reducing stricture recurrence. Intralesional glucocorticoid injection combined with dilation, endoscopic incisional therapy with or without dilation, and placement of self-expanding metallic stents (SEMS), Polyflex or biodegradable stents, self-bougienage, and endoscopic surgery have all been used in the management of refractory strictures [3]. A sham-controlled trial of patients with a peptic stricture showed a significant reduction in the need for repeat dilation in those patients who received glucocorticoid injection [21]. Prior to dilation with balloon or mechanical (bougie) dilators, a standard sclerotherapy needle is used to inject triamcinolone into four quadrants of the stricture. Intralesional glucocorticoids have also been combined with systemic glucocorticoids. Glucocorticoid therapy also reduced the need for periodic dilation in patients with caustic-induced esophageal strictures [22]. One randomized trial compared triamcinolone injection with saline injection. A larger luminal diameter was achieved in the glucocorticoid group in comparison with those in the control group [23]. Glucocorticoids have been used in the prevention of stricture formation from esophageal caustic injury. However, a meta-analysis of studies from 1991 to 2004, and another analysis of the literature from 1956 to 2006 did not find any benefit. Therefore, the use of glucocorticoids in the management of corrosive ingestions should be abandoned as they do not prevent the development of strictures and may lead to the development of serious adverse effects [24,25]. 4.2

Eosinophilic gastroenteritis Glucocorticoids are the mainstay of therapy for patients with moderate-to-severe symptoms, tissue and peripheral eosinophilia who do not improve after an elimination diet [26]. The usual dose of prednisone is 20 -- 40 mg daily for 2 weeks, with tapering thereafter. Within 2 weeks, the majority of patients improve and do not require further treatment. However, relapses can occur and they are treated with long-term, low-dose glucocorticoid (prednisone 5 -- 10 mg daily) for up to several months. 4.3

Refractory gluten-sensitive enteropathy Glucocorticoids, such as i.v. hydrocortisone 100 mg q6 h or oral prednisone 40 -- 60 mg daily, induce a short-term clinical and mucosal response in refractory gluten-sensitive enteropathy and dermatitis herpetiformis, when used in combination with 4.4


565

G. Triadafilopoulos

a gluten-free diet [27,28]. As a response is achieved, a glucocorticoid-sparing agent, such as azathioprine 2 mg/kg/day orally, is introduced [29]. Alternatively, 6-mercaptopurine (2 mg/kg/day, orally) or methotrexate, 25 mg orally per week may be used. Those who respond undergo gradual tapering of prednisone by 5 mg/week to the lowest dose that keeps the patient asymptomatic and continuation of the immune modulator. Budesonide, 9 mg orally per day, has also been effective [30]. Graft-versus-host disease Glucocorticoid therapy is commonly used in the treatment of acute and chronic graft-versus-host disease (GvHD). However, there has been no systematic analysis of effects of their use on the patients’ survival and quality of life and the dose and length of therapy for acute GvHD are unclear. Typically, methylprednisolone 2 mg/kg per day is used in divided doses for several weeks, followed by a gradual taper. Opportunistic infections and interstitial pneumonitis may occur [31]. For patients with GvHD with gastrointestinal involvement without infection, budesonide or beclomethasone may allow reduction of systemic steroids. In one randomized study, 60 patients with intestinal GvHD and poor oral intake were treated with prednisone (1 mg/kg per day) plus either placebo or beclomethasone (8 mg/day). Beclomethasone therapy was associated with a better initial and durable response [32].


4.5

Crohn’s disease Glucocorticoids are effective for symptom relief but do not induce mucosal healing in Crohn’s disease [33,34]. Glucocorticoid therapy is ineffective as maintenance therapy and does not benefit perforating or fistulizing Crohn’s disease [35,36]. Retrospective studies have identified systemic corticosteroid therapy as a risk factor for increased postoperative sepsis in patients with Crohn’s disease. Prednisone, 40 -- 60 mg orally per day, remains the key therapy for patients with mild-to-moderate disease and most patients respond within 2 weeks [37]. At that point, a gradual tapering by 5 mg/week should be considered. Once remission is achieved and the prednisone is stopped, and other maintenance therapies are initiated. Multivariate logistic regression analysis of a prospective, observational registry of 6273 patients with Crohn’s disease over mean period of 5.2 years, showed that treatment with prednisone was associated with increased mortality risk (hazard ratio [HR] = 2.14; 95% CI: 1.55, 2.95; p < 0.001) and was independently associated with serious infections (HR = 1.57; 95% CI: 1.17, 2.10; p = 0.002) [38]. However, confounding by indication has not been clearly ruled out. Budesonide, in an enteric-coated formulation, is a synthetic glucocorticoid with a strong affinity for glucocorticoid receptors and has preferentially local anti-inflammatory over systemic effects. Controlled ileal release budesonide is a glucocorticoid with a high first-pass hepatic metabolism that may be used as an alternative to prednisone for the induction of remission in patients with active ileitis or right-sided Crohn’s colitis, particularly in those with known intolerance or 4.6

566

contraindications to systemic glucocorticoids. Budesonide is used at a dose of 9 mg/day for 2 -- 4 months and then tapered by 3 mg increments over 1 -- 2 months. Although budesonide is less effective in inducing remission than prednisone, it has significantly fewer side effects; it is not useful in maintenance of remission [39]. Beclomethasone dipropionate significantly reduces the relapse rate in Crohn’s ileitis compared with placebo after induction of remission with a short course of systemic glucocorticoids and is well tolerated. In a study of 84 patients with active Crohn’s disease who achieved remission during a 2-week prednisone run-in period and then randomized to receive beclomethasone dipropionate for 24 weeks or continue prednisone for a further 2 weeks followed by placebo for 22 weeks, the cumulative relapse rate by Kaplan--Meier analysis was 38.0% in the beclomethasone and 56.0% in the placebo groups, respectively (p = 0.025) [40]. Lavy treated 10 patients with Crohn’s colonic strictures with dilation and injection of triamcinolone. Two patients required additional dilation and injection of steroids after 1 year, whereas eight patients remained well over a followup period of 1.5 -- 3 years [41]. Singh et al. have reported 29 stricture dilations in 17 patients with Crohn’s disease with 20 strictures. Technical success was achieved in 28 of the 29 stricture dilations (96.5%). Four-quadrant steroid injections were carried out in 11 strictures. The recurrence rate in this group was 10% and that in the nonsteroid group was 31.3%. Three perforations occurred (all colonic) during the 29 stricture dilations [42]. Another approach is to use a suspension of betamethasone dipropionate preparation [43]. Ulcerative colitis The treatment goals in ulcerative colitis involve control of symptoms and induction and maintenance of clinical, steroid-free remission, mucosal healing, prevention of hospital admission and surgery and improved quality of life. Treatment should be tailored to disease activity and disease extent [44]. Topical 5-aminosalicylic acid (5-ASA) is an established first-line therapy for the induction of remission of active proctitis because it is superior to topical glucocorticoids and oral 5-ASA [45]. The addition of topical beclomethasone carries greater efficacy than rectal 5-ASA alone, with higher rates of clinical, histologic and endoscopic improvements at 4 weeks, compared with single-agent therapy [46]. Oral glucocorticoids should be considered in patients not responding [47]. Prednisolone is most commonly used, usually at a starting dose of 40 mg/day, followed by tapering by 5 mg/week. There is no evidence to support the use of glucocorticoids as a maintenance therapy, and prolonged courses should be avoided due to associated side effects. Glucocorticoid suppositories are preferred in patients with ulcerative proctitis. If the colitis extends beyond the distal rectum, glucocorticoid foam preparations or enemas in combination with glucocorticoid suppositories b.i.d. are used. 4.7




Typically, hydrocortisone foam, 80 mg 1 -- 2 times/day is initially used for 2 -- 3 weeks and then every other day thereafter. A response is usually seen in 3 -- 4 weeks. In patients who exhibit significant symptom improvement, topical glucocorticoids should be tapered gradually to a once nightly or every-other nightly regimen. Hydrocortisone suspension may also be used as 100 mg enema every night for 3 weeks or until remission. In general, 2 -- 3 months of therapy may be required, followed by a dose tapering. If symptoms of ulcerative colitis do not improve quickly, oral glucocorticoids should be started using prednisone 40 mg per day in order to minimize adverse effects [48]. Nearly 70% of patients respond to the first course of glucocorticoids, but 22% develop glucocorticoid dependency and only 50% maintain glucocorticoid-free remission [49]. No randomized trials have assessed the optimal duration of glucocorticoid therapy, but maximum dose should be maintained until a significant clinical improvement is achieved. The new extended-release formulation of budesonide multi-matrix system (MMX), a novel, once-daily oral formulation of budesonide (9 mg) that uses a MMX technology to extend the release of budesonide throughout the colon is effective for the treatment of mild-to-moderately active ulcerative colitis. Two 8-week randomized, double-blind, placebo-controlled trials in adults with active mild-to-moderate ulcerative colitis demonstrated significant benefit over placebo in achieving clinical and endoscopic remission [50,51]. Neither oral glucocorticoids nor budesonide should be used for maintenance of remission [52]. Glucocorticoids should be tapered by 5 mg weekly after induction of remission. Faster tapering may lead to disease relapse or adrenal insufficiency [53]. If steroids cannot be tapered to < 10 mg daily within 3 months without relapse, or if relapse occurs within 3 months of stopping glucocorticoid therapy, patients are considered to have glucocorticoid-dependent ulcerative colitis [54]. Regimens for i.v. glucocorticoids include methylprednisolone (16 -- 20 mg i.v. every 8 h) or hydrocortisone (100 mg i.v. every 8 h). Methylprednisolone is preferred because it has higher nongenomic activities than other glucocorticoids, is associated with less sodium-retention and potassium wasting and typically leads to clinical improvement in ~ 50 -60% of patients [55,56]. Continuous infusions of i.v. glucocorticoids are not safer or more effective than bolus injection in achieving clinical remission [57]. Patients with ulcerative colitis often require steroid therapy before surgery and often receive perioperative steroids in a variety of doses. Steroids increase postoperative morbidity after total proctocolectomy for ulcerative colitis [58].

was 12.32 (95% CI: 5.53 -- 27.46), and for maintaining clinical response was 8.82 (95% CI: 3.19 -- 24.37), with a number needed to treat of two patients for each outcome. Budesonide also induced and maintained histological response and was well tolerated [59]. In a randomized study of 51 patients of budesonide (9 mg/ day for 6 weeks) or placebo, 87% patients on budesonide were in clinical remission versus 14% of placebo [60]. Clinical remission was observed within 2 weeks in 60% of patients and after 4 -- 6 weeks in 85% of patients [61]. A meta-analysis of eight randomized trials that included 248 patients randomized to glucocorticoids versus placebo found that budesonide was significantly more effective than placebo for short-term clinical response [relative risk (RR): 3.07; 95% CI: 2.06 -4.57] [62]. Prednisolone was not superior to placebo for short-term clinical response (RR: 2.00; 95% CI: 0.38 -10.58). Histologic improvement was seen with both shortand long-term budesonide (RR: 3.76; 95% CI: 2.00 -- 7.06 and RR: 2.50; 95% CI: 1.25 -- 4.98, respectively). Symptom relapse occurred in 46 -- 80% of patients within 6 months of treatment cessation. Withdrawal because of adverse effects occurred in 4.4% of patients, with no difference between study groups. Relapses are common after budesonide discontinuation and long-term maintenance therapy may be needed, albeit at the risk of glucocorticoid-related side effects. Hemorrhoids and anal pruritus In cases of external anal pruritus, topical hydrocortisone may be applied up to 3 -- 4 times per day. Rectal hydrocortisone suppository (30 mg, two to three times a day [t.i.d.] for 2 weeks) is used for irritation and pruritus associated with hemorrhoids and proctitis. 4.9

Chronic radiation proctitis Rectal glucocorticoids have been used in the treatment of chronic radiation proctitis in studies of small sample sizes and short follow-up. Rectal hydrocortisone (90 mg b.i.d.) is superior to rectal betamethasone (5 mg b.i.d.) [63]. In a small randomized controlled trial with a short follow-up of 4 weeks, Kochhar et al. who compared sulfasalazine (500 mg t.i.d.) with rectal prednisolone 20 mg b.i.d. to rectal sucralfate (2 mg b.i.d.) had a clinical improvement in 53% of patients with oral sulfasalazine plus rectal glucocorticoids compared with a 94% improvement with rectal sucralfate alone. Forty seven percent had improved endoscopic findings in the sulfasalazine plus rectal glucocorticoid group as compared with 71% in the rectal sucralfate alone [64]. 4.10

Complications of glucocorticoid therapy and their prevention

5. 4.8

Lymphocytic and collagenous (microscopic) colitis

Although studies assessing the treatment of microscopic colitis have had relatively small sample sizes, budesonide has been effective in improving quality of life in controlled trials. In a systematic review of 10 randomized trials, the pooled odds ratio (OR) for inducing clinical response with budesonide

Nutritional issues Glucocorticoid therapy is a powerful appetite stimulant, causes major alterations in fat, protein and carbohydrate metabolism and may lead to weight gain, fluid retention 5.1


567

G. Triadafilopoulos

and hypokalemia. Because of this, dietary measures need to be implemented upon initiation and for the duration of therapy and should take into account the underlying impact of the gastrointestinal disease to be treated, the patient’s pre-existing nutritional status and lifestyle. In general, low-calorie, lowsalt, high-protein diet is recommended. Depending on regular monitoring of potassium levels, oral potassium may be needed. Dyspepsia and peptic ulcer disease Glucocorticoid therapy has not been conclusively shown to cause ulcers or complications. In a retrospective study of all the randomized, double-blind, controlled trials, 9 of 3267 patients in the placebo group (0.3%) and 13 of 3335 patients in the glucocorticoid group (0.4%) were reported to develop peptic ulcer (p > 0.05) [65]. However, a nested case-control analysis identified 2105 cases of upper gastrointestinal complications and 11,500 controls. The adjusted OR associated with current use of oral glucocorticoids were 1.8 (95% CI: 1.3, 2.4) for upper gastrointestinal complications overall and 2.4 (95% CI: 1.7, 3.4) for gastric and 1.2 (95% CI: 0.8, 1.9) for duodenal damage. Steroids were similarly associated with bleeding (OR = 1.8; 95% CI: 1.3, 2.4) and perforations (OR = 1.6; 95% CI: 0.9, 3.1) [66]. Simultaneous use of steroids with low-medium and high NSAID doses, produced OR of 4.0 (95% CI: 1.3, 12.0) and 12.7 (95% CI: 6.2, 26.1) respectively, compared with non-users. In order to reduce the risk of upper gastrointestinal complications, those treated concomitantly with nonsteroidal anti-inflammatory drugs and those with dyspepsia or prior history of peptic ulcer disease should benefit by daily proton pump inhibition therapy.


5.2

Infections Prolonged use of glucocorticoids may increase the incidence of secondary infection, mask acute infection (including fungal infections), prolong or exacerbate viral infections, or limit the immunological response to vaccines. Exposure to chickenpox should be avoided. Close observation is required in patients with latent tuberculosis and/or tuberculin reactivity and should be used only in conjunction with anti-tuberculosis treatment in patients with active tuberculosis.

to cardiovascular disease [69]. Chronic inflammatory diseases also increase the risk of cardiovascular disease [70] and glucocorticoids may lower this inflammation-mediated risk because they reduce the disease activity. However, glucocorticoids per se are also assumed to represent an independent determinant of greater cardiovascular risk in patients suffering from chronic inflammatory diseases. Disentangling such risk in a quantitative manner from the cardiovascular risk mediated by the underlying disease is necessary. Glucocorticoid therapy should be used with caution in patients with heart failure because long-term use has been associated with fluid retention and hypertension. Myopathy Acute myopathy has been reported with high-dose glucocorticoids and can occur with any of the glucocorticoid preparations usually in older, malnourished patients. Typically, it occurs upon initiation of therapy but it may also happen with chronic maintenance therapy particularly at high doses. Patients typically present with proximal muscle weakness and wasting. Muscle strength improves several weeks after dose reduction and eventually resolves after therapy discontinuation. 5.6

Skin Bruising, facial erythema, petechiae, thin fragile skin, urticaria and impaired wound healing have been described with glucocorticoid therapy. Skin changes were seen in 46% of patients treated for 3 months with prednisone (> 20 mg daily) [71]. Cushingoid features and weight gain are both dose and duration dependent and may occur as early as within 2 months of therapy. 5.7

5.3

Osteoporosis Because it increases bone resorption and reduces bone formation, glucocorticoid therapy should be used with caution in patients with or who are at risk for osteoporosis. High doses and/or long-term use of glucocorticoids have been associated with increased bone loss and osteoporotic fractures [67]. The incidence of glucocorticoid-associated osteonecrosis varies among different underlying diseases [68]. 5.4

Cardiovascular effects Glucocorticoids have adverse systemic effects, including obesity, hypertension and hyperglycemia, that may predispose 5.5

568

Eye manifestations Prolonged glucocorticoid therapy may cause posterior exophthalmos, subcapsular cataracts, glaucoma and may increase the risk for ocular infections. The risk of both cataracts and glaucoma is dose-related [72,73]. 5.8

Psychiatric issues Glucocorticoid use may cause or exacerbate psychiatric disturbances, including depression, euphoria, insomnia, mood swings and personality changes. Psychiatric symptoms appear to be dose-dependent and generally occur during the first few weeks of therapy [74]. 5.9

Adrenal insufficiency Patients who are treated with long-term glucocorticoids should be monitored carefully in the perioperative and early postoperative periods for signs of adrenal insufficiency, regardless of the steroid regimen used, and stress dose glucocorticoids should be administered perioperatively in order to prevent complications of secondary hypoadrenalism. 5.10



6.

Conclusion


Glucocorticoid therapy is widely used in the treatment of gastrointestinal diseases, mostly in short term and plays an important therapeutic role for many patients. However, a number of undesirable side effects may occur and dictate a continuous surveillance, monitoring and patient education to prevent complications. The advent of other immunosuppressive and biological therapies has made glucocorticoid therapy part of a broader arsenal of therapies and has limited the long-term use, but it has added complexity for physicians and patients. 7.

Expert opinion

Corticosteroids have been widely used as anti-inflammatory and immunosuppressive agents in the treatment of many immune-mediated gastrointestinal diseases for decades. Prednisone and prednisolone are most commonly used orally, whereas hydrocortisone and methylprednisolone are used intravenously. Newer compounds, less likely to cause systemic adverse effects, such as fluticasone and budesonide, are increasingly used orally. Intralesional and topical preparations are also commonly used. Long-term cohort studies, as well as placebo- and shamcontrolled trials have evaluated the clinical efficacy, safety and tolerability of corticotherapy in many gastrointestinal diseases and have identified the limitations associated with its use, particularly in the long-term. Continuous monitoring of the clinical efficacy, tolerability and side effects of corticotherapy is essential in order to minimize side effects. Newer compounds that carry less systemic toxicity and improved tolerability have been introduced and are increasingly used with favorable results. Nevertheless, improved local delivery with minimum, if any, systemic bioavailability is a key desirable goal in the future. Combination therapy with Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

2.

3.

..

Buttgereit F, Burmester GR, Lipworth BJ. Optimised glucocorticoid therapy: the sharpening of an old spear. Lancet 2005;365:801-3 Buttgereit F, Burmester GR, Straub RH, et al. Exogenous and endogenous glucocorticoids in rheumatic diseases. Arthritis Rheum 2011;63(1):1-9 Kochhar R, Poornachandra KS. Intralesional steroid injection therapy in the management of resistant

4.

5.

other agents, such as biologics and immunosuppressants, is widely practiced but not well standardized. For several gastrointestinal diseases, the role of the mucosal immunity is currently being explored. Immune activation is currently considered as an important pathophysiological mechanism of irritable bowel syndrome, and increased baseline serum levels of IL-6 and IL-8 and increased release of proinflammatory cytokines like TNF-a, IL-1b and IL-6 by peripheral blood mononuclear cells have indeed been reported in such patients. Hence, microscopic inflammation of the intestinal mucosa may have an important pathogenetic role but data on the number of immune cells in the intestinal mucosa and the relationship between stress response, microscopic inflammation, and visceral sensitivity are inconsistent. As more evidence accumulates, corticotherapy, particularly with newer, safer compounds, may play an important new role in patients with altered motility and visceral hypersensitivity. The interplay of the gut microbiota and the host that contributes to the development of gut-associated lymphoid tissues and gut-specific immune responses will also undoubtedly be explored. In the coming years, it is unlikely that traditional steroid compounds will be further tested in a controlled fashion. However, as newer, safer molecules are developed, the prospect of a long-term steroid therapy that carries minimal systemic toxicity and better tolerability will become reality in an expanded arena of gastrointestinal applications.

Declaration of interest The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

gastrointestinal strictures. World J Gastrointest Endosc 2010;2(2):61-8 This review discusses the indications, technique, results and complications of the use of intralesional steroid injections in refractory esophageal strictures. Schwiebert LA, Beck LA, Stellato C, et al. Glucocorticosteroid inhibition of cytokine production: relevance to antiallergic actions. J Allergy Clin Immunol 1996;97(1):143-52 Zen M, Canova M, Campana C, et al. The kaleidoscope of glucorticoid effects on immune system. Autoimmun Rev 2011;Apr;10(6):305-10


6.

Buttgereit F, Straub RH, Wehling M, Burmester GR. Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action [review]. Arthritis Rheum 2004;50:3408-17

7.

Lucendo AJ, Molina-Infante J. Emerging Therapeutic Strategies for Eosinophilic Esophagitis. Curr Treat Options Gastroenterol 2013;12(1):1-17

8.

van der Goes MC, Jacobs JW, Boers M, et al. Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice. Ann Rheum Dis 2010;69(11):1913-19

569

G. Triadafilopoulos

9.

10.


11.

12.

13.

14.

15.

16.

..

17.

18.

570

Clin Gastroenterol Hepatol 2008;6(2):165-73

Fardet L, Kassar A, Cabane J, Flahault A. Corticosteroid-induced adverse events in adults: frequency, screening and prevention. Drug Saf 2007;30(10):861-81

19.

Schaefer ET, Fitzgerald JF, Molleston JP, et al. Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children. Clin Gastroenterol Hepatol 2008;6:165-73

20.

Remedios M, Campbell C, Jones DM, Kerlin P. Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointest Endosc 2006;63(1):3-12

21.

Arora AS, Perrault J, Smyrk TC. Topical corticosteroid treatment of dysphagia due to eosinophilic esophagitis in adults. Mayo Clin Proc 2003;78:830-5 Helou EF, Simonson J, Arora AS. 3-yr-follow-up of topical corticosteroid treatment for eosinophilic esophagitis in adults. Am J Gastroenterol 2008;103(9):2194-9 Noel RJ, Putnam PE, Collins MH, et al. Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis. Clin Gastroenterol Hepatol 2004;2:568-75 Lindberg GM, Van Eldik R, Saboorian MH. A case of herpes esophagitis after fluticasone propionate for eosinophilic esophagitis. Nat Clin Pract Gastroenterol Hepatol 2008;5(9):527-30 Straumann A, Conus S, Degen L, et al. Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis. Gastroenterology 2010;139(5):1526-37.1537.e1 A 15-day course of treatment with budesonide is well tolerated and highly effective in inducing a histologic and clinical remission in patients with eosinophilic esophagitis. Schroeder S, Fleischer DM, Masterson JC, et al. Successful treatment of eosinophilic esophagitis with ciclesonide. J Allergy Clin Immunol 2012;129(5):1419-21 Schaefer ET, Fitzgerald JF, Molleston JP, et al. Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children.

Straumann A, Conus S, Degen L, et al. Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2011;9(5):400-9.e1 Netzer P, Gschossmann JM, Straumann A, et al. Corticosteroid-dependent eosinophilic oesophagitis: azathioprine and 6-mercaptopurine can induce and maintain long-term remission. Eur J Gastroenterol Hepatol 2007;19(10):865-9 Ramage JI Jr, Rumalla A, Baron TH, et al. A prospective, randomized, double-blind, placebo-controlled trial of endoscopic steroid injection therapy for recalcitrant esophageal peptic strictures. Am J Gastroenterol 2005;100:2419-25

22.

Kochhar R, Makharia GK. Usefulness of intralesional triamcinolone in treatment of benign esophageal strictures. Gastrointest Endosc 2002;56:829-34

23.

Pelclova´ D, Navra´til T. Do corticosteroids prevent oesophageal stricture after corrosive ingestion? Toxicol Rev 2005;24:125-9

24.

Fulton JA, Hoffman RS. Steroids in second degree caustic burns of the esophagus: a systematic pooled analysis of fifty years of human data: 1956-2006. Clin Toxicol (Phila) 2007;45:402-8

25.

26.

Camargo MA, Lopes LR, Grangeia Tde A, et al. Use of corticosteroids after esophageal dilations on patients with corrosive stenosis: prospective, randomized and double-blind study. Rev Assoc Med Bras 2003;49:286-92 Mori A, Enweluzo C, Grier D, Badireddy M. Eosinophilic gastroenteritis: review of a rare and treatable disease of the gastrointestinal tract. Case Rep Gastroenterol 2013;7(2):293-8

27.

Wall AJ, Douglas AP, Booth CC, Pearse AG. Response of the jejunal mucosa in adult coeliac disease to oral prednisolone. Gut 1970;11:7-14

28.

Kumar PJ, Silk DB, Marks R, et al. Treatment of dermatitis herpetiformis with corticosteroids and gluten free diet: a study of jejunal morphology and function. Gut 1973;14:280-3


29.

Vaidya A, Bolanos J, Berkelhammer C. Azathioprine in refractory sprue. Am J Gastroenterol 1999;94:1967-9

30.

Brar P, Lee S, Lewis S, et al. Budesonide in the treatment of refractory celiac disease. Am J Gastroenterol 2007;102(10):2265-9

31.

Salmasian H, Rohanizadegan M, Banihosseini S, et al. Corticosteroid regimens for treatment of acute and chronic graft versus host disease (GvHD) after allogenic stem cell transplantation. Cochrane Database Syst Rev 2010;(1):CD005565

32.

McDonald GB, Bouvier M, Hockenbery DM, et al. Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial. Gastroenterology 1998;115(1):28-35

33.

Gorard DA, Hunt JB, Payne-James JJ, et al. Initial response and subsequent course of Crohn’s disease treated with elemental diet or prednisolone. Gut 1993;34:1198-202

34.

Modigliani R, Mary JY, Simon JF, et al. Clinical, biological and endoscopic picture of attacks of Crohn’s disease: evaluation of prednisolone. Groupe d’Etude Therapeutique des Affectations Inflammatories Digestives. Gastroenterology 1990;98:811-18

35.

Benchimol EI, Seow CH, Steinhart AH, Griffiths AM. Traditional corticosteroids for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2008;(2):CD006792 Important systematic review on glucocorticoid therapy for induction of remission in Crohn’s disease.

..

36.

Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn’s disease. Gut 1994;35:360-2

37.

Gelbmann CM, Rogler G, Gross V, et al. Prior bowel resections, perianal disease, and a high initial Crohn’s disease activity index are associated with corticosteroid resistance in active Crohn’s disease. Am J Gastroenterol 2002;97:1438-45

38.

Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol 2012;107(9):1409-22



39.

Papi C, Luchetti R, Gili L, et al. Budesonide in the treatment of Crohn’s disease: a meta-analysis. Aliment Pharmacol Ther 2000;14(11):1419

40.

Prantera C, Rizzi M, Cottone M, et al. Beclomethasone dipropionate in Crohn’s ileitis: a randomised, double-blind trial. Dig Liver Dis 2011;43(6):459-64

41.

Lavy A. Triamcinolone improves outcome in Crohn’s disease strictures. Dis Colon Rectum 1997;40:184-6

42.

Singh VV, Draganov P, Valentine J. Efficacy and safety of endoscopic balloon dilation of symptomatic upper and lower gastrointestinal Crohn’s disease strictures. J Clin Gastroenterol 2005;39:284-90

43.

44.

45.

46.

Ramboer C, Verhamme M, Dhondt E, et al. Endoscopic treatment of stenosis in recurrent Crohn’s disease with balloon dilation combined with local corticosteroid injection. Gastrointest Endosc 1995;42:252-5 Kornbluth A, Sachar DB, The Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: american College Of Gastroenterology, practice parameters committee. Am J Gastroenterol 2010;105:501-23 Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative treatments in ulcerative colitis: a meta-analysis. Gut 1997;40(6):775-81 Mulder CJ, Fockens P, Meijer JW, et al. Beclomethasone dipropionate (3 mg) versus 5-aminosalicylic acid (2 g) versus the combination of both (3 mg/2 g) as retention enemas in active ulcerative proctitis. Eur J Gastroenterol Hepatol 1996;Jun;8(6):549-53

47.

Dignass A, Lindsay JO, Sturm A, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis: current management. J Crohns Colitis 2012;6:991-1030

48.

Travis SP, Stange EF, Le´mann M, et al. European Crohn’s and Colitis Organization (ECCO). European evidence-based Consensus on the management of ulcerative colitis: current management. J Crohn’s Colitis 2008;2(1):24-62 European evidence-based consensus on the current management of ulcerative colitis.

..

58.

Aytac E, Londono JM, Erem HH, et al. Impact of stress dose steroids on the outcomes of restorative proctocolectomy in patients with ulcerative colitis. Dis Colon Rectum 2013;56(11):1253-8

59.

Chande N, MacDonald JK, McDonald JW. Interventions for treating microscopic colitis: a Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group systematic review of randomized trials. Am J Gastroenterol 2009;104(1):235-41; quiz 234, 242

Travis SP, Danese S, Kupcinskas L, et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomized CORE II study. Gut 2013;63(3):433-41

60.

Miehlke S, Heymer P, Bethke B, et al. Budesonide treatment for collagenous colitis: a randomized, double-blind, placebo-controlled, multicenter trial. Gastroenterology 2002;123(4):978-84

Steinhart AH, Ewe K, Griffiths AM, et al. Corticosteroids for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2003;(4):CD000301 Neither oral glucocorticoids nor budesonide should be used for maintenance of remission.

61.

Miehlke S, Madisch A, Voss C, et al. Long-term follow-up of collagenous colitis after induction of clinical remission with budesonide. Aliment Pharmacol Ther 2005;22(11-12):1115-19

62.

Stewart MJ, Seow CH, Storr MA. Prednisolone and budesonide for shortand long-term treatment of microscopic colitis: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2011;9(10):881-90 Budesonide is effective and well tolerated in the short- and long-term treatment microscopic colitis but has a high rate of symptom relapse once it is discontinued.

49.

Faubion WA Jr, Loftus EV Jr, Harmsen WS, et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001;121:255-60

50.

Sandborn WJ, Travis S, Moro L, et al. Once-daily budesonide MMX extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study. Gastroenterology 2012;143:1218-26

51.

52.

..

53.

54.

Carter MJ, Lobo AJ, Travis SP, IBD Section, British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004;53(Suppl 5):V1-16

..

Buttgereit F, Brand MD, Burmester GR. Equivalent doses and relative drug potencies for non-genomic glucocorticoid effects: a novel glucocorticoid hierarchy. Biochem Pharmacol 1999;58(2):363-8

63.

Denton A, Forbes A, Andreyev J, Maher EJ. Nonsurgical interventions for late radiation proctitis in patients who have received radical radiotherapy to the pelvis. Cochrane Database Syst Rev 2002;(1):CD003455

64.

Kochhar R, Patel F, Scharma SC, et al. Radiation-induced proctosigmoiditis: prospective, randomized, double-blind controlled trial of oral sulfasalazine plus rectal steroids versus rectal sucralfate. Dig Dis Sci 1991;36(1):103-7

65.

Conn HO, Poynard T. Corticosteroids and peptic ulcer: meta-analysis of adverse events during steroid therapy. J Intern Med 1994;236:619-32

66.

Herna´ndez-Dı´az S, Rodrı´guez LA. Steroids and risk of upper gastrointestinal complications. Am J Epidemiol 2001;Jun;1;153(11):1089-93

67.

Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced

55.

Lipworth BJ. Therapeutic implications of non-genomic glucocorticoid activity. Lancet 2000;356(9224):87-9

56.

Stange EF, Travis SP, Vermeire S, European Crohn’s and Colitis Organisation (ECCO). European evidence-based Consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohns Colitis 2008;2(1):1-23

57.

.

Bossa F, Fiorella S, Caruso N, et al. Continuous infusion versus bolus administration of steroids in severe attacks of ulcerative colitis: a randomized, double-blind trial. Am J Gastroenterol 2007;102(3):601-8 In severe attacks of ulcerative colitis, continuous infusion of methylprednisolone was safe and effective as bolus administration.


571

G. Triadafilopoulos

osteoporosis: pathophysiology and therapy. Osteoporos Int 2007;18(10):1319-28 68.


69.

572

Shigemura T, Nakamura J, Kishida S, et al. Incidence of osteonecrosis associated with corticosteroid therapy among different underlying diseases: prospective MRI study. Rheumatology (Oxford) 2011;50(11):2023-8 Van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis? Arthritis Rheum 2002;46:862-73

70.

Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004;141(10):764-70

71.

Fardet L, Flahault A, Kettaneh A, et al. Corticosteroid-induced clinical adverse events: frequency, risk factors and patient’s opinion. Br J Dermatol 2007;157(1):142-8

72.

Huscher D, Thiele K, Gromnica-Ihle E, et al. Dose-related patterns of glucocorticoid-induced side effects. Ann Rheum Dis 2009;68(7):1119-24

73.

Da Silva JA, Jacobs JW, Kirwan JR, et al. Safety of low dose glucocorticoid


treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis 2006;65(3):285-93 74.

Brown ES, Chandler PA. Mood and cognitive changes during systemic corticosteroid therapy. Prim Care Companion J Clin Psychiatry 2001;Feb;3(1):17-21

Affiliation George Triadafilopoulos MD Stanford University School of Medicine, Gastroenterology, 300 Pasteur Drive, Stanford, CA 94305, USA E-mail: [email protected]

Glucocorticoid therapy for rheumatic diseases.

Bismuth therapy in gastrointestinal diseases.

Adult tissue stem cell therapy for gastrointestinal diseases.

Special issue on glucocorticoid therapy in rheumatic diseases: introduction.

Serum Resistin Level and Progression of Atherosclerosis during Glucocorticoid Therapy for Systemic Autoimmune Diseases.

Fecal microbiota transplantation for gastrointestinal diseases.

Traditional Persian topical medications for gastrointestinal diseases.

Glucocorticoid therapy for asthma: clinical pharmacology.

Glucocorticoid therapy for severe Pneumocystis carinii pneumonia.

Photodynamic therapy for gastrointestinal tumors.

Mycobiota in gastrointestinal diseases.

The value of glucocorticoid co-therapy in different rheumatic diseases--positive and adverse effects.

Glucocorticoid therapy of Graves' ophthalmopathy.

Glucocorticoid therapy and ocular hypertension.

The effects of glucocorticoid therapy.

Sleep Dysfunction and Gastrointestinal Diseases.

Upper gastrointestinal physiology and diseases.

Immunological Aspects of Gastrointestinal Diseases.

Growth failure in gastrointestinal diseases.

Glucocorticoid Induced Cerebellar Toxicity in the Developing Neonate: Implications for Glucocorticoid Therapy during Bronchopulmonary Dysplasia.

Gene therapy for neurodegenerative diseases.

Gene therapy for retinal diseases.

Thrombolytic therapy for noncoronary diseases.

Helminth therapy for organic diseases?