the management of steroid dependency in ulcerative colitis

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Apr 3, 2007 - sing⁄intermittent clinical course.1, 2 Its prognosis has changed over the decades ... defined as CS dependent (steroid-dependent or SD-UC).9.
Alimentary Pharmacology & Therapeutics

Review article: the management of steroid dependency in ulcerative colitis G. BIANCHI PORRO, A. CASSINOTTI, E. FERRARA, G. MACONI & S. ARDIZZONE

Department of Clinical Science, Chair of Gastroenterology, ‘‘L. Sacco’’ University Hospital, Milan, Italy Correspondence to: Prof. G. Bianchi Porro, Ospedale ‘‘L. Sacco’’, Azienda Ospedaliera – Polo Universitario, Via G.B. Grassi 74, 20157 Milan, Italy. E-mail: [email protected]

Publication data Submitted 2 January 2007 First decision 19 January 2007 Resubmitted 30 March 2007 Second decision 1 April 2007 Resubmitted 1 April 2007 Accepted 3 April 2007

SUMMARY Background Approximately 20% of patients with ulcerative colitis have a chronic active disease often requiring several courses of systemic steroids in order to achieve remission, but followed by relapse of symptoms during steroid tapering or soon after their discontinuation. Although short term control of symptoms can be achieved with steroid treatment, this pattern of drug response, known as steroid-dependency, leads to important complications of the treatment, while a significant proportion of patients requires colectomy. Aim To review the studies currently available specifically evaluating the management of steroid-dependent ulcerative colitis. Results The clinical and biological mechanisms of steroid-dependency are not well understood compared with those determining steroid-refractoriness. Very few evidence-based data are available concerning the management of patients with steroid-dependent ulcerative colitis. The therapeutic role of aminosalicylates, thiopurines, methotrexate, infliximab, leukocyte apheresis and other drugs in the treatment of steroid-dependent ulcerative colitis are evaluated. Conclusions Outcomes of studies in steroid-refractory patients may not be applicable to steroid-dependency. Trials are needed to define the correct approaches and new strategies to ameliorate the therapy of steroid-dependent ulcerative colitis. Aliment Pharmacol Ther 26, 779–794

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2007.03334.x

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INTRODUCTION Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease (IBD) characterized by a chronic relapsing ⁄ intermittent clinical course.1, 2 Its prognosis has changed over the decades since the first descriptions of significant mortality 50 years ago.3 The introduction of safe and effective therapies and better surgical procedures has improved the clinical course of the disease. Despite these recent successes, a significant proportion of patients continues to suffer from particularly resistant forms of disease leading to the need for repeated therapies with significant toxicity and even colectomy, which is potentially curative but often unacceptable in the patient’s eyes. Systemic corticosteroids (CS) have been used to treat patients with active IBD for over 50 years. In 1955, Truelove and Witts showed that oral cortisone effectively induced remission in patients with active UC.4 CS are rapidly active and highly effective, making them the drug of choice for the initial management of moderate to severe active UC.5, 6 Nevertheless, steroidtreated active patients may show different patterns of response to this therapy. One group will have good results, achieving symptom-free periods of satisfactory length; another group will respond well initially but lose benefit as the treatment is tapered or stopped. A third group will show complete refractoriness to the drugs despite high doses or prolonged therapies, experiencing only their side effects and finally needing colectomy. The purpose of this report was to describe the available data about the management of the specific subset of steroid-dependent UC patients, in whom clinicians can again obtain some good response with systemic CS (unlike steroid refractory patients), but the relapse will occur, as the dose is decreased or a few weeks or months after discontinuation, making it necessary to increase the dosage again or resume treatment to achieve short-term control of symptoms. No specific reviews are currently available directly addressing this topic.7, 8 In this paper, we gave prominence to controlled studies, stressing the need to consider only evidence-based results from studies that specifically described this particular subset of patients, in order not to generalize data referring to steroid refractoriness, rather than dependency. To be considered effective in this clinical scenario, a drug should be able to establish remission, prevent relapse and limit exposure to CS.

SEARCH STRATEGY AND SELECTION CRITERIA Electronic searches were conducted using the PubMed database from the earliest records to September 2006. The search terms used were ‘steroids’, ‘steroid-dependence’, ‘steroid-dependency’, ‘therapy’, ‘glucocorticoids’, ‘outcome’, ‘inflammatory bowel disease’, ‘ulcerative colitis’ and ‘IBD’. Reference lists of all relevant articles were searched for further studies. Of the identified studies only articles published in the English language and analysing steroid-dependent patients in their population were selected.

EPIDEMIOLOGY AND DEFINITIONS OF STEROID-DEPENDENT ULCERATIVE COLITIS If we analyse the population studied in various works describing the outcome of steroid therapy, it is not difficult to understand what the authors mean by response and refractoriness: the definitions of these two terms are generally consistent, leading to substantial reproducibility across studies. On the other hand, we are assailed by a jungle of terms to define steroiddependency, with each study giving its own definition. This leads to various problems in analysing therapeutic outcomes. Nevertheless, a few definitions frequently recur in various studies, such as those by Munkholm and Truelove.9, 10 Thus, response to CS has been defined as clinical improvement after treatment with high-dose oral CS (40–60 mg prednisone or equivalent) within 30 days or clinical improvement after treatment with high-dose intravenous CS within 7–10 days. Conversely, patients who fail to respond to CS within this timeframe have been defined as CS refractory. Patients who initially respond to CS but then relapse during tapering or shortly after drug discontinuation of CS, and require re-introduction of CS therapy to maintain symptoms control, have been defined as CS dependent (steroid-dependent or SD-UC).9 Some authors use the term steroid-resistance to include both steroid-dependent and refractory disease, while others use it as a synonym for steroid-refractoriness. Very few articles have been published on the clinical course and prognosis of UC. Most of these have a retrospective design, with the relative disadvantages. In the largest epidemiological study on the clinical course of UC, an inception cohort study on 1161 patients in Copenhagen County, Langholz et al.11 showed that the cumulative probability of a relapsing ª 2007 The Authors, Aliment Pharmacol Ther 26, 779–794 Journal compilation ª 2007 Blackwell Publishing Ltd

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course is 90% after 25 years of follow-up. There are no significant predictors of the type of clinical course in individual patients, although the same authors showed that the presence of active disease in the first 2 years after diagnosis significantly predicts for an intermittent course in the following 5 years. The few other studies on predictors of poor response to therapy do not specifically analyse steroid-dependency as an outcome but rather surrogates such as the colectomy rate, for which the suggested predictive factors are young age at diagnosis (