Review Article Optimal use of in and

Xavier Verhelst, Martine De Vos, Hans Van Vlierberghe Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium

Abstract Although they have been introduced a long time ago, corticosteroids are still extensively used for the treatment of several gastroenterological and hepatological diseases. The goal of this review is to provide an overview of current indications for the optimal use of corticosteroids in this field. For a growing number of indications, can be an interesting alternative for systemic corticosteroids due to its rapid first-pass hepatic metabolism. Furthermore, topical corticosteroids are increasingly used, e.g., for the treatment of eosinophilic and selected patients with inflammatory bowel disease. We conclude that corticosteroids remain of great importance in gastroenterology and hepatology, but the balance between benefit and side-effects use should be evaluated cautiously.”

Key words: corticosteroids, gastroenterology, hepatology, optimal

INTRODUCTION choice for many patients. Recommendations are mainly based upon the evidence-based Although, many new molecules have emerged guidelines from the European Crohn’s and for the treatment of gastroenterological and Organization.[1,2] hepatologic diseases, corticosteroids are currently still extensively used. The goal of Crohn’s disease this paper was to provide an overview of In mildly active localized ileocecal CD, current indications for corticosteroids in the budesonide (9 mg daily) is the treatment of choice[1] and induces remission in 50-70% field of gastroenterology and hepatology. [3-6] Corticosteroids include conventional of patients over 8-10 weeks. Budesonide with controlled ileal release (CIR) is preferred systemic corticosteroids (e.g., prednisone, due to the high first-pass metabolism in methylprednisolone), nonsystemic the liver via the cytochrome P450-3A4 corticosteroids (e.g., budesonide) and (CYP3A4) pathway, which enables maximal topical corticosteroids (e.g., budesonide Address for Correspondence: antiinflammatory effects in the ileocecal Dr. Xavier Verhelst, ). Department of Gastroenterology and region and minimizes (but not excludes) Hepatology, Ghent University Hospital, systemic steroid-related side-effects.[7] Gent, Belgium. GASTROENTEROLOGY E-mail: [email protected] However, it should be kept in mind that budesonide can inhibit the hypothalamic- Access this article online Inflammatory bowel disease pituitary-adrenal axis.[3,7] In moderately Website: Crohn’s disease (CD) and www.intern-med.com active localized ileocecal CD, budesonide (UC) are inflammatory diseases of the (9 mg daily) or systemic corticosteroids can DOI: [1] 10.4103/2224-4018.135601 . CD can affect any be used. Although corticosteroids are the [8,9] Quick Response Code: portion of the gastrointestinal tract, while mainstay for induction of remission, they UC is confined to the colon. The choice are a bad choice for maintaining remission of treatment should be guided by the due to a lack of an efficiency[10,11] and the severity and the site of the disease and the well-known multiple side-effects. Other balance between potency and potential immunomodulatory drugs like azathioprin side-effects. Although a variety of drugs is or antitumor necrosis factor agents will need available, conventional, and nonsystemic to be introduced early to minimize steroid remain an appropriate exposure.[1] For severely active localized

JOURNAL OF TRANSLATIONAL INTERNAL MEDICINE / APR-JUN 2014 / VOL 2 | ISSUE 2 53 Verhelst, et al.: Corticosteroids in gastroenterology and hepatology ileocecal CD, the initial treatment will be based upon extensive active UC without systemic side-effects.[17] Severe systemic corticosteroids, administered in oral or intravenous UC is a serious condition that requires hospitalization form. Lack of response will rapidly lead to the introduction and intensive treatment in a multidisciplinary expert of biological agents or even evaluation for surgery.[1] In inflammatory bowel disease center.[2] It includes the use of patients with infrequent relapses, corticosteroids can be high dose intravenous corticosteroids (e.g., prednisolone restarted, in combination with immunomodulatory therapy. 60 mg/24 h) and response should be assessed on the 3rd In active colonic CD, remission can be induced, but not day of treatment. Second line therapies are cyclosporine, maintained with systemic corticosteroids. In patients with or tacrolimus. If these therapies all fail, infrequent relapses, steroids can be restarted in combination can be indicated.[2] with an immunomodulatory agent. For extensive small bowel CD, systemic steroids can be used in combination Similar to CD, corticosteroids are never indicated for the with thiopurines or methotrexate. In esophageal and maintenance of remission in UC.[2] gastroduodenal CD, systemic corticosteroids can be used for induction of remission if proton pump inhibitors have failed. Microscopic colitis is an increasingly recognized disease entity of unknown origin causing chronic watery In Europe, the systemic of choice is without blood loss.[18] Although it is a benign condition, methylprednisolon 32 mg once daily. A response is expected it can dramatically affect the quality of life. Two subtypes in 60-80% of patients within 14 days. A gradual tapering have been described, [19] and lymphocytic of 4 mg/week can be started upon response, in order to colitis.[20] Diagnosis is based upon a history of watery stools, finally discontinue corticosteroids.[12] Calcium and Vitamin the absence of macroscopic abnormalities on endoscopy D suppletion is advocated when the duration of treatment and typical histological findings.[21] The pathophysiology is expected to be longer than 12 weeks.[1] Budesonide with is unknown, but an association has been described with CIR is given at a dose of 9 mg once a day for 8-16 weeks numerous drugs, including nonsteroidal inflammatory and then tapered by 3 mg every 4 weeks.[12] drugs, proton pump inhibitors, selective serotonin reuptake inhibitors.[21,22] A meta-analysis showed that budesonide has Despite the well-known side-effects systemic corticosteroids a beneficial effect in both collagenous and lymphocytic remain the agent of choice for induction of remission, but colitis.[23] A recent placebo controlled phase three clinical are obsolete for long-term use in CD patients. Budesonide trial confirmed a high remission rate after treatment with is a good alternative for mild to moderate localized ileocecal budesonide 9 mg daily during 8 weeks in patients with disease due to less side-effects. collagenous colitis.[24] The major problem is that up to 30% of patients will relapse after cessation of budesonide,[25] Ulcerative colitis implying recurrent courses of budesonide or even long In contrast to CD, UC is limited to the colon. Therefore, term use of low doses of budesonide. However, this has some patients can effectively be treated with topical steroids, not been well-studied so far. including suppositories and enemas. For example, the first choice for UC are suppositories.[2] A Cochrane Eosinophilic oesophagitis systematic review revealed that topical mesazaline is more is a condition of increasing efficient for these patients than topical corticosteroids, prevalence and recognition. It is defined as a chronic, limiting their use to patients intolerant for .[13] immune/antigen mediated with Combination of both (beclomethasone dipropionate 3 symptoms-related to esophageal dysfunction and mg and 5-aminosalicylic acid 2 g) can be indicated[14] and histologically characterized by eosinophil-predominant sometimes systemic corticosteroids are needed to induce inflammation.[26] The first step in the treatment is acid remission.[2] In mild to moderately active left sided and suppression with proton pump inhibitors,[27] but if this extensive UC, corticosteroids are not advised (neither fails topical steroids are beneficial. Specific formulations systemic nor topical) in the first line of treatment. They are not available, but good results have been described should only be introduced when a combination of oral with swallowed fluticasone propionate (e.g., 220 µg and topical mesazaline fails.[2] However, they have proven twice a day). The product is administered using a efficacy for the induction of remission in UC.[15] Budesonide metered dose inhaler and sprayed into the mouth and is less effective than mesazaline and is not indicated for then swallowed. In contrast to treatment for asthma, induction of remission in UC patients.[16] An interesting the patient should not inhale when spraying. Eating and alternative is a preparation of beclometasone dipropionate drinking should be avoided for 30 min.[28] Duration of 5 mg with colonic release. It has shown a powerful effect therapy has not been defined, but experts advocate to equal to mesalazine to induce remission in left sided and treat for 6-8 weeks. Virtually all patients will relapse,

54 JOURNAL OF TRANSLATIONAL INTERNAL MEDICINE / APR-JUN 2014 / VOL 2 | ISSUE 2 Verhelst, et al.: Corticosteroids in gastroenterology and hepatology but can be helped with repeated courses of swallowed drug withdrawal can be attempted. This can be done by fluticasone propionate.[29] tapering prednisone to 10 mg/day by 5 mg/week followed by tapering by 2.5 mg/week until the drug is withdrawn. Serum HEPATOLOGY transaminase levels should be monitored every 3 weeks until 3-month after withdrawal, then every 6-month for 1-year and Auto-immune yearly thereafter. In some relapsers, corticosteroid maintenance Auto-immune hepatitis (AIH) is a chronic hepatitis of therapy will be necessary at the lowest possible dose.[30,31] unknown origin leading to a progressive necroinflammatory and fibrotic process in the liver. The diagnosis is based on An interesting alternative for prednisone could be histologic abnormalities, clinical and laboratory findings, budesonide due to its first past hepatic metabolism, including high levels of serum globulins and the presence minimizing corticosteroid related side-effects. In a pivotal of characteristic autoantibodies.[30] Criteria for treatment trial,[32] patients with AIH were randomized to azathioprin have been defined by the American Association for the combined with prednisone 40 mg daily versus budesonide study of Liver Diseases (AASLD)[30] and are summarized in 6-9 mg daily for 6-month. Complete remission was obtained Table 1. Glucocorticoids are the first choice for induction in 60% of patients treated with budesonide, versus 39% of remission. According to AASLD guidelines, treatment in the prednisone group. Although the remission rate in should be started with prednisone (starting with 30 mg the prednisone group was lower than expected, this trial daily and tapering down to 10 mg daily within 4 weeks) in showed that budesonide could be an interesting alternative. combination with (1-2 mg/kg body weight) However, these data still need to be confirmed in larger trials. or a higher dose of prednisolone alone (40-60 mg daily and It is important to note that budesonide is contraindicated in tapering down to 20 mg daily within 4 weeks). The first or in patients with a poor liver function. choice is preferred due to fewer corticosteroid related side- effects. Prednisolone in equivalent dosage can be used. Close Primary biliary cirrhosis monitoring for side-effects is recommended. On an average, Primary biliary cirrhosis (PBC) is an auto-immune disease 65-80% of patients will experience remission between 18 of the small bile ducts and is defined by abnormal serum and 24 months after initiation of treatment. This remission liver enzymes, presence of antimitochondrial antibodies is defined by resolution of symptoms, normalization of (at least 1:40), which are highly specific for the disease serum aninotransferase, bilirubin and gamma globulin levels and histologic features of florid lesions. The and improvement in liver histology to normal or mild portal cornerstone of treatment in PBC is ursodeoxycholic acid hepatitis.[30] Once remission is achieved for at least 24-month, (UDCA). Although systemic corticosteroids can improve liver enzymes in these patients, they have no proven impact on long-term survival and are not indicated.[33] Table 1: Indications for treatment of AIH Three small randomized[34-36] trials showed improvement Treatment attidude Level of evidence of liver enzymes and two[35,36] showed improvement of Start treatment Serum AST/ALT >10 fold ULN Class I, Level A liver histology in PBC Stage I–III patients treated with Serum AST/ALT >5 fold ULN and serum Class I, Level A budesonide in combination with UDCA. A large European gamma-globulin >2 fold ULN and trial is currently ongoing (NCT00746486). As long as Histological features of bridging necrosis or these data are not confirmed, budesonide is not routinely multilobular necrosis indicated in PBC patients. Immunosuppressive treatment should be Class I, Level C instituted in children at the time of diagnosis regardless of symptom status Primary sclerosing cholangitis Incapacitating symptoms Primary sclerosing cholangitis (PSC) is a chronic, cholestatic Consider treatment characterized by inflammation and fibrosis Symptoms and mild laboratory and histological Class IIa, Level C changes balanced against risk of therapy of both intrahepatic and extrahepatic bile ducts leading Do not start treatment, close follow-up to the formation of multifocal bile duct strictures. PSC is Minimal or no disease activity or inactive Class IIa, Level C an immune mediated, progressive disorder that eventually cirrhosis develops into cirrhosis, and hepatic Serious preexistent comorbid conditions Class III, Level C decompensation, in the majority of patients.[37] A long- (vertebral compression, psychosis, brittle [38] diabetes, uncontrolled hypertension), or term beneficial effect for systemic corticosteroid therapy [39] previous known intolerances to prednisone or budesonide has not been proven. Furthermore, unless the disease is severe and progressive it will increase bone loss in patients already prone to and adequate control measures for the [40] comorbid conditions can be instituted osteoporosis. Hence, corticosteroids are not indicated AIH: Auto-immune hepatitis, ALT: Alanine aminotranferease, AST: for the treatment of PSC, unless there is evidence of an Aspartate aminotransferase, ULN: Upper limit of normal overlap syndrome with AIH.[37,41]

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Immunoglobulin G4 associated cholangitis might decrease the progression of recurrent .[53] Immunoglobulin G4-associated cholangitis (IAC) is a However, hepatitis C recurrence will probably be overcome rare and recently recognized biliary disease of unknown in the near future by the introduction of newer hepatitis C etiology. In contrast to PSC, it is not related to CD, but treatment regimens.[54] it is often associated with auto-immune and other fibrosing diseases. Biochemical and cholangiographic A well-known problem after liver transplantation is findings can mimic PSC. It is characterized by elevated acute cellular rejection. It will affect 20% to 40% of liver serum IgG4 and infiltration of IgG4 positive plasma cells transplant recipients, mostly during the first 3-month after in bile ducts and liver tissue.[41] Considering that IAC is very transplantation.[55] For severe rejections, treatment is based corticosteroid responsive,[42] the European Association for on high doses of corticosteroids (e.g., methylprednisolone the Study of the Liver recommends first line treatment with 1000 mg boluses for 1-3 days), followed by a gradual systemic steroids, which can be combined with azathioprin. tapering during 6 days.[56] The use of steroid boluses as However, randomized trials are not available.[41] treatment for acute cellular rejection is problematic in HCV patients, since it can cause a more severe HCV Acute recurrence. Acute alcoholic hepatitis is a clinical syndrome with acute onset of jaundice and/or ascites in a patient with CONCLUSION ongoing alcohol abuse.[43] The diagnosis is based upon typical histological findings including steatosis, hepatocyte Corticosteroids remain important in the treatment of ballooning and infiltration with polymorfonuclear numerous gastroenterological and hepatologic diseases. leucocytes.[43] Patients presenting with a Maddrey However, the benefit should cautiously be weighed discriminant function score ≥32 have a limited 1-month against the well-known side-effects. For some indications, survival rate between 50% and 65% in the absence of budesonide can be an interesting alternative for systemic treatment.[44,45] These patients have reduced mortality if corticosteroids due to its fast hepatic metabolism. treated with systemic corticosteroids (prednisolone 40 mg/ day for 28 days).[46] Only so-called corticoid responders REFERENCES with a Lille-score lower than 0.45 after 7 days of treatment should continue treatment to a total of 28 days.[47] Their 1. Dignass A, Van Assche G, Lindsay JO, Lémann M, Söderholm J, Colombel JF, et al. The second European evidence-based Consensus [46,47] 6-month survival rate is estimated at 85%. In these on the diagnosis and management of Crohn’s disease: Current patients, sepsis remains a major concern and infections management. J Crohns Colitis 2010;4:28-62. 2. Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, should be actively searched for and adequately treated et al. 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56. Volpin R, Angeli P, Galioto A, Fasolato S, Neri D, Barbazza F, Verhelst X, Vos MD, Vlierberghe HV. Optimal et al. Comparison between two high-dose methylprednisolone How to cite this article: use of corticosteroids in gastroenterology and hepatology. J Transl schedules in the treatment of acute hepatic cellular rejection in Intern Med 2014;2:53-8. liver transplant recipients: A controlled clinical trial. Liver Transpl Nil, None declared 2002;8:527-34. Source of Support: Conflict of Interest:

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