Prednisone and ulcerative colitis

Side effects57,61

Early toxicity from methotrexate is primarily gastrointestinal (nausea, vomiting, diarrhoea, and stomatitis) and this may be limited by co-prescription of folic acid 5 mg two or three days apart from the MTX. Treatment is discontinued in 10–18% of patients because of side effects. The principal concerns are hepatotoxicity and pneumonitis. A study of liver biopsies in IBD patients taking MTX showed mild histological abnormalities, despite cumulative doses of up to 5410 mg. Surveillance liver biopsy is not warranted, but if the AST doubles then it is sensible to withhold MTX until it returns to normal, before a rechallenge. The prevalence of pneumonitis has been estimated at two to three cases per 100 patient years of exposure, but large series have not reported any cases.

4.8.5 Ciclosporin62

(Oral or intravenous, unlicensed therapy for UC.) Ciclosporin (CsA) is an inhibitor of calcineurin, preventing clonal expansion of T-cell subsets. It has a rapid onset of action and is effective in the management of severe UC.

Role of CsA62–68

Intravenous CsA is rapidly effective as a salvage therapy for patients with refractory colitis, who would otherwise face colectomy, but its use is controversial because of toxicity and long term failure rate. Toxicity can be reduced by using lower doses (2 mg/kg/day intravenously), by oral microemulsion ciclosporin, or by monotherapy without corticosteroids. The drug should rarely be continued for more than 3–6 months and its main role is a bridge to thiopurine therapy. A meta-analysis of four randomised controlled trials showed that CsA has no therapeutic value in CD.

Monitoring therapy62

Measurement of blood pressure, full blood count, renal function, and CsA concentration (aim 100–200 ng/ml) are advisable at 0, 1, and 2 weeks, then monthly. Measurement of blood cholesterol and magnesium are appropriate before starting therapy (below).

Side effects62,64,65

Minor side effects occur in 31–51%, including tremor, paraesthesiae, malaise, headache, abnormal liver function, gingival hyperplasia, and hirsutism. Major complications are reported in 0–17%, including renal impairment, infections, and neurotoxicity. The risk of seizures is increased in patients with a low cholesterol (<3.0 mmol/l) or magnesium (<0.50 mmol/l). Oral therapy is an alternative in these circumstances. Prophylaxis against Pneumocystis carinii pneumonia is an individual decision dependent on nutritional state, concomitant immunomodulator therapy, and duration of therapy, but other opportunistic infections (for example, Aspergillus sp.) may be as common.

4.8.6 Infliximab69

Infliximab (IFX) (Remicade) is a chimeric anti-TNF monoclonal antibody with potent anti-inflammatory effects, possibly dependent on apoptosis of inflammatory cells. Numerous controlled trials have demonstrated efficacy in both active and fistulating CD. Guidelines for the use of infliximab have been produced by the National Institute of Clinical Excellence (www.nice.org.uk, guideline no 40).

Efficacy for inflammatory CD69–71

A multicentre, double blind study in 108 patients with moderate to severe CD refractory to 5-ASA, corticosteroids, and/or immunomodulators, demonstrated an 81% response rate at 4 weeks after 5 mg/kg IFX compared with 17% given placebo. The duration of response varied, but 48% who had received 5 mg/kg still had a response at week 12. The ACCENT-1 study was the definitive retreatment trial. Maintenance of remission in 335 responders to a single infusion of IFX 5 mg/kg for active CD (out of an initial 573) was examined. The protocol was complex. In broad terms, patients were treated with placebo, 5 mg/kg or 10 mg/kg every 8 weeks until week 46. At week 30, 21% of the placebo treated patients were in remission compared with 39% of the patients treated with 5 mg/kg infusions (p = 0.003) and 45% of those treated with 10 mg/kg infusions (p = 0.0002). IFX is licensed but not yet approved by NICE for maintenance therapy of CD in the UK.

Evidence for fistulising CD72,73

IFX is the first agent to show a therapeutic effect for fistulising CD in a controlled trial. Ninety four patients with draining abdominal or perianal fistulas of at least 3 months’ duration were treated. 68% in the 5 mg/kg group and 56% in the 10 mg/kg group experienced a 50% reduction in the number of draining fistulas at two or more consecutive visits compared with 26% given placebo (p = 0.002 and p = 0.02, respectively). The problem is that the duration of this effect was in most cases limited to only 3 or 4 months. A large retreatment trial for fistulating CD (ACCENT-II) has been conducted. A total of 306 patients with actively draining enterocutaneous fistulae were treated with three induction infusions of IFX 5 mg/kg at weeks 0, 2, and 6. Of the 306, 195 (69%) responded and these were randomised to 5 mg/kg maintenance infusions or placebo every 8 weeks. Patients who lost response were switched from placebo to active treatment at 5 mg/kg, or the retreatment dose increased from 5 to 10 mg/kg. At the end of the 12 month trial, 46% of the patients on active retreatment had a fistula response versus 23% on placebo (p = 0.001). Complete response (all fistulae closed) was observed in 36% of patients on active treatment, compared with 19% on placebo (p = 0.009). Treatment of fistulising CD with IFX is not currently approved by NICE unless criteria for severe active disease are also met.

Selection69

National guidelines govern its use. In the UK, it is limited to patients with severe active CD (Harvey Bradshaw index >8, CD activity index >300) refractory to or intolerant of steroids and immunosuppression, for whom surgery is inappropriate. Retreatment is often necessary, after a variable interval (most commonly 8–16 weeks). All patients should receive an immunomodulator (AZA, MP, or MTX) unless these cannot be tolerated, as these probably extend the interval and reduce development of antibodies to IFX that in turn reduce efficacy and increase side effects. Because IFX is associated with a four- or fivefold increase in risk of tuberculosis, all patients should have a chest x ray to exclude past or present infection and be asked about previous BCG vaccination before IFX infusion. Tuberculin testing can be limited to those who have not had BCG and who are not on immunomodulators. Patients with evidence of previous tuberculosis should be seen by a thoracic physician. Guidelines for chemoprophylaxis are being produced by the British Thoracic Society (2004).

Side effects74,75

Treatment with IFX is relatively safe if used for appropriate indications. Infusion reactions (during or shortly after infusion) are rare and respond to slowing the infusion rate or treatment with antihistamines, paracetamol, and sometimes corticosteroids. Anaphylactic reactions have been reported. A delayed reaction of joint pain and stiffness, fever, myalgia, and malaise may occur if there has been an interval >1 year following a previous infusion and can be limited by pretreatment with hydrocortisone. Infection is the main concern. Active sepsis (for example, an abscess) is an absolute contraindication, as this risks overwhelming septicaemia. Reactivation or development of tuberculosis has been reported in 24/100 000 patients with rheumatoid arthritis given anti-TNF therapy, compared with 6/100 000 not given such treatment. IFX may exacerbate existing cardiac failure. The theoretical risk of lymphoproliferative disorders or malignancy (in view of the role of endogenous TNF in tumour suppression) has not been confirmed in post-marketing surveillance, but follow up is short. IFX is best avoided in those with a history of malignancy.

Oral budesonide for treatment of people with active ulcerative colitis

What did the researchers find?

We found six studies that included a total of 1808 participants. One study (343 participants) compared standard budesonide to mesalamine (an anti-inflammatory drug composed of 5-aminosalicylic acid), one study (72 participants) compared standard budesonide to conventional corticosteroids, four studies (1393 participants) compared budesonide-MMX® to placebo (a fake medicine with no active ingredients such as a sugar pill) or active comparators including Entocort (standard budesonide), prednisolone (a conventional steroid drug) or mesalamine. Four studies were judged to be of high quality and two studies were judged to be of low quality.

Evidence from three studies including 900 participants indicates that the newer formulation, budesonide-MMX® at a dose of 9 mg/day was superior to placebo for induction of remission irrespective of mesalamine use. There is evidence to suggest that budesonide-MMX® at a dose of 9 mg/day is particularly effective in patients with left-sided disease as opposed to patients with more extensive disease. One small study (32 participants) comparing standard budesonide to placebo found no difference in remission rates. Evidence from one study (343 participants) comparing standard budesonide to mesalamine suggests that standard budesonide was significantly less effective than mesalamine for induction of remission. However, another study (247 participants) found no difference in remission rates between patients treated with budesonide-MMX® and mesalamine. One study (212 participants) found no difference in remission rates between patients treated with budesonide-MMX® 9 mg/day and standard budesonide 9 mg/day. One small study (72 participants) found no difference in endoscopic remission rates between patients treated with standard budesonide and prednisolone, however budesonide patients were less likely than prednisolone patients to experience adrenal suppression, a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. Commonly reported side-effects in the studies include worsening ulcerative colitis, headache, pyrexia (raised body temperature), insomnia (difficulty sleeping), back pain, nausea, abdominal pain, diarrhoea, flatulence and nasopharyngitis (common cold). More studies with larger numbers of participants are needed to allow conclusions regarding the comparative effectiveness of budesonide versus conventional steroid drugs, budesonide-MMX® versus standard budesonide and budesonide versus mesalamine.

Intravenous corticosteroids in moderately active ulcerative colitis refractory to oral corticosteroids

Abstract

Background: Oral corticosteroids remain the mainstay of treatment for moderately active ulcerative colitis (UC). In patients who fail to respond to oral corticosteroids, attempting the intravenous route before starting rescue therapies is an alternative, although no evidence supports this strategy.

Aim: To evaluate clinical outcomes after a course of intravenous corticosteroids for moderate attacks of UC according to the failed oral corticosteroids or not.

Methods: All episodes of active UC admitted to three university hospitals between January 2005 and December 2011 were identified and retrospectively reviewed. Only moderately active episodes treated with intravenous corticosteroids were included. Treatment outcome was compared between episodes which failed to outpatient oral corticosteroids for the index flare and those directly treated by intravenous corticosteroids.

Results: 110 episodes were included, 45% of which failed to outpatient oral corticosteroids (median dose 60 mg/day , median length of course 10 days ). Initial response (defined as mild severity or inactive disease at day 7 after starting intravenous corticosteroids, without rescue therapy) was achieved in 75%, with no between-group differences (78% vs. 75%). After a median follow-up of 12 months (IQR 4–24), 35% of the initial responders developed steroid-dependency and up to 13% required colectomy. Unsuccessful response to oral corticosteroids was the only factor associated with steroid-dependency in the long term (P = 0.001).

Conclusions: Intravenous corticosteroids are efficient for inducing remission in moderately active UC unresponsive to oral corticosteroids, but almost half of these patients develop early steroid-dependency. Alternative therapeutic strategies should be assessed in this clinical setting.

1 Introduction

Ulcerative colitis (UC) is a chronic inflammatory condition of the colon that usually follows a relapsing-remitting course1. Within 5 years of diagnosis, most patients will have experienced several relapses regardless of disease extent, as reported in the recent population-based studies assessing the natural history of the disease 2. Medical therapy of acute UC flares depends mainly on their severity. Thus, mild flares are usually managed with oral and/or topical aminosalicylates, whereas intravenous corticosteroids (CSs) remain as the first-line therapy for severe attacks 3. To optimize clinical outcomes in these patients, response to any treatment should be assessed in a timely manner; in this sense, it is widely accepted that response to aminosalicylates should be evaluated in 2 to 4 weeks, whereas response to intravenous CS in severe attacks should be assessed in 3 to 5 days 4.

The approach to moderate flares is not so clear. Although oral aminosalicylates are also considered as the treatment of choice in this clinical setting3, many patients use these agents for maintenance treatment, and dose escalation in this situation has been poorly evaluated. An accepted alternative in these patients and in those not responding to oral aminosalicylates is oral CS therapy3. The use of oral CS in moderately active UC is supported by the early British trials 5–7, carried out in small samples and more than 60 years ago. We now know that almost half of UC patients will require at least one course of CS in their lives (mainly for moderate flares), and that this has not changed in the last six decades 2. We also know that CS requirements do not depend on the time from disease diagnosis or disease extent, and that the yearly proportion of patients treated with CS remains stable over time in a given UC cohort8. Unlike in mild and severe flares, there is no established timing for the assessment of response to oral CS 4, although prospective data suggest that it can be predicted as simply and early as in severe flares9.

Despite the widespread use of oral CS in clinical practice, few RCTs including conventional oral CS for the treatment of moderately active UC have been performed 10,11. These trials reported clinical remission rates of 60-65% after 4 weeks of treatment. Therefore, an appreciable proportion of patients treated with oral CS will require “rescue” therapy, a clinical scenario where no specific RCTs have been done to date. Current recommendations advise initiation of anti-TNF agents, although tacrolimus or intravenous CSs are also considered potential alternatives to colectomy3. The aim of our study was to evaluate the utility of intravenous CS in patients who failed to respond to oral CS for a moderate flare of UC.

2 Materials and methods

Between January 2005 and December 2011, all patients admitted for UC flares who received intravenous corticosteroids (CSs) were identified from the electronic records of three referral university hospitals. Patients were only included in the study if they had moderately active UC according to the Montreal classification of severity12 at the time intravenous CSs were started, and patients with ulcerative proctitis were excluded. Episodes of patients with more than one episode were only included if they did not meet steroid-dependency criteria (defined by a clinical relapse during corticosteroid therapy or within the first 3 months after corticosteroid discontinuation). Patients were grouped according to whether they had received oral prednisone for the same flare before admission. For IV therapy, methyl-prednisolone at a dose of 1 mg/kg/day was used in the three centres. In the case of clinical response, CS tapering was started at discharge and the dose was reduced by 10 mg weekly until reaching 20 mg, and by 5 mg weekly thereafter until complete withdrawal.

Relevant information regarding several variables was collected, including epidemiological (sex, age, smoking habits, family history of IBD), clinical (time from UC diagnosis to index flare, previous CS courses, UC extent, failed oral CS for the index flare, extraintestinal manifestations, steroid dependency criteria, and/or colectomy during follow-up), biological (C-reactive protein at baseline, 3, and 7 days, duration of follow-up), and treatment (previous maintenance therapy, disease severity at day 3 and 7 of intravenous CS, need for rescue therapy during the index flare, CS-related major side effects ) parameters. For the purposes of this study, we arbitrarily defined initial efficacy as mild activity or inactive disease according to the Montreal severity score, with no need for rescue treatment at day 7 after starting intravenous CS. Patients were followed up until colectomy, death, or date of data collection (September 2012), and the occurrence of steroid-dependency criteria or colectomy during follow-up was also recorded.

For each episode, every outcome was addressed until the end of follow-up, death or the occurrence of a new flare requiring corticosteroids.

The study was approved by the Institutional Review Board of the coordinating centre (Hospital Universitari Germans Trias i Pujol).

All statistical analyses were performed using SPSS12.0 for Windows (SPSS Inc., Chicago, IL, USA). Data are expressed as median and interquartile range (IQR) or absolute and relative frequencies. Chi-square was used to compare dichotomous variables. For continuous variables, Student’s t-test was used provided that values showed a normal distribution and variances were homogenous. Otherwise, Mann–Whitney U-test was used. Predictive factors of initial efficacy, colectomy, and steroid-dependency were initially univariately screened with the above-mentioned tests. Those variables achieving a P-value ≤0.1, as well as those believed to be clinically meaningful, were included in a logistic regression analysis to identify independent predictors.

3 Results

A total of 172 episodes of intravenous CS therapy in patients with UC were recorded during the study period. Among these, 110 episodes in 89 patients corresponded to moderate flares. Fifty episodes (45%) were initially treated with oral CS with absent or partial clinical response. A similar proportion of episodes were included in each participating centre (29%, 34%, and 36% of the series), with 11 to 16 episodes per year.

Most episodes (62%) corresponded to extensive UC and only 16% occurred in active smokers. Median time from UC diagnosis to the index flare was 38 months (IQR 3–108) and 53% of episodes had received courses of systemic CS in the past. Twenty-three percent of episodes were not on any maintenance therapy before the index flare, whereas 21% were on thiopurines at that time and 35% were on oral mesalazine. No differences were found between patients who were directly treated with intravenous CS for a moderate flare and those who failed to oral CS for the index flare, except for a higher proportion of previous courses of systemic CS, a younger age, a higher proportion of maintenance therapy with mesalazine before the index flare (but the same on thiopurines), and lower C-reactive protein levels among the latter (Table 1). In patients who failed oral CS for the index flare, the median dose of oral prednisone was 60 mg/day (IQR 48–60) for a median course duration of 10 days (IQR 7–17). Methylprednisolone was used in all episodes for intravenous therapy, at a median dose of 60 mg/day (IQR 60–60).

Table 1

Characteristics of episodes according to failed oral corticosteroids for the index flare or directly treatment with intravenous corticosteroids. Data expressed as absolute and relative frequencies and median (interquartile range). UC = ulcerative colitis; IBD = inflammatory bowel disease; CS = corticosteroids; and IV-CS = intravenous corticosteroids.

Table 1

Characteristics of episodes according to failed oral corticosteroids for the index flare or directly treatment with intravenous corticosteroids. Data expressed as absolute and relative frequencies and median (interquartile range). UC = ulcerative colitis; IBD = inflammatory bowel disease; CS = corticosteroids; and IV-CS = intravenous corticosteroids.

According to the Montreal classification of severity, all episodes had moderate activity at the onset of intravenous CS. At day 3, 53% had improved (mild activity) and 3% had worsened (severe activity), in a similar proportion in both study groups (Fig. 1). Both study groups also had similar median levels of C-reactive protein at day 3 (14 vs. 24 mg/L, P = 0.6) and at day 7 (11 vs. 19 mg/L, P = 0.1). This resulted in 76% initial efficacy (as previously defined) in the whole series (84 out of 110 episodes), with no difference between the study groups. We found no baseline factor associated with initial efficacy, and only those patients with a lesser disease activity at day 3 of intravenous CS therapy had a higher probability to achieve initial efficacy criteria (Table 2). Rescue therapy (cyclosporin, infliximab, and/or colectomy) was required in 29 episodes (26%). Three episodes required colectomy during hospital admission after a median time of 28 days from the beginning of intravenous CS (IQR 20–58).

Figure 1

Proportion of episodes achieving mild activity or inactive disease at day 3 or 7 of intravenous corticosteroids, stratified by failure of oral corticosteroids (black bars) or directly treatment with intravenous corticosteroids (grey bars) for the index flare.

Figure 1

Proportion of episodes achieving mild activity or inactive disease at day 3 or 7 of intravenous corticosteroids, stratified by failure of oral corticosteroids (black bars) or directly treatment with intravenous corticosteroids (grey bars) for the index flare.

Table 2

Associated factors to initial efficacy. UC = ulcerative colitis; CS = corticosteroids; IV-CS = intravenous corticosteroids.

Table 2

Associated factors to initial efficacy. UC = ulcerative colitis; CS = corticosteroids; IV-CS = intravenous corticosteroids.

No differences regarding the incidence of short-term CS-related major side effects were found between the study groups. Seven episodes required insulin therapy during CS therapy and infections developed in nine episodes. One patient died because of an infectious complication. She was a 77-year-old former smoker with distal UC who initially received intravenous UC for a moderate flare. She had a clinical response and CSs were discontinued 56 days later. Two months after CS withdrawal, she died of acute pneumonia.

Among those episodes who avoided colectomy during hospital admission, 47% followed maintenance therapy with thiopurines, 38% with oral mesalazine, and 15% with infliximab. Episodes with initial efficacy were followed up for a median of 12 months (IQR 4–24); 38% were on maintenance therapy with thiopurines (41% in those failing oral CS for the index flare, 36% in those treated directly with intravenous CS). CS could be completely withdrawn in 72 out of the 84 episodes (86%) in which the initial efficacy was achieved; however, 35% of the cases (29 out of 84) met steroid-dependency criteria during follow-up. Although failure of oral CS for the index flare had no impact on the initial efficacy of intravenous corticosteroids, it was associated with a higher likelihood to develop steroid-dependency during follow-up (51% vs. 17%) (Fig. 2). When taking into account only those patients with initial efficacy who received further maintenance therapy with mesalazine, steroid-dependency developed in 39% of those failing to oral CS for the index flare and in 15% of those treated directly with intravenous CS. In fact, failure of oral corticosteroids was the only factor associated with steroid-dependency in the univariate analysis (P = 0.001) and a clear trend in the logistic regression analysis (P = 0.057) (Table 3). Finally, 11 patients were colectomized after a median of 7 months from the index flare (IQR 4–17), but no associated factor was found on both the univariate and logistic regression analyses. One patient died during follow-up. He was a 75-year-old former smoker with longstanding distal UC who achieved response to intravenous CS, which could be successfully withdrawn. The patient relapsed 10 months later and was colectomized. He died of multiple non-infectious postoperative complications.

Figure 2

Outcomes during follow-up, stratified by failure of oral corticosteroids (black bars) or directly treatment with intravenous corticosteroids (grey bars) for the index flare.

Figure 2

Outcomes during follow-up, stratified by failure of oral corticosteroids (black bars) or directly treatment with intravenous corticosteroids (grey bars) for the index flare.

Table 3

Associated factors to development of steroid-dependency during follow-up. UC = ulcerative colitis; CS = corticosteroids; 5ASA = mesalazine.

Table 3

Associated factors to development of steroid-dependency during follow-up. UC = ulcerative colitis; CS = corticosteroids; 5ASA = mesalazine.

4 Discussion

Oral CSs are frequently used in UC. In a recent review of population-based longitudinal cohorts of UC patients, oral CSs were estimated to be prescribed in 24–40% of patients within the first year and in up to 56% within the first 10 years from disease diagnosis 13. As mentioned before, oral prednisolone produces clinical remission at 4 weeks in about two-thirds of patients with moderate UC flares. Although the oral route is recommended for moderate flares, intravenous administration is not unusual in clinical practice. In an early Swedish UC cohort, 29% of patients who were treated with intensive intravenous treatment had moderately active UC at the time intravenous CSs were started 14; of these, 62% received intravenous CS as first-line therapy. In the present series, in a 7-year period and three referral centres, 64% of the intravenous courses of CS were prescribed for moderate flares and in 55% of them the oral route was not previously attempted. Despite this, both routes of administration have never been compared in this clinical setting. Sood et al. published the only comparison of daily oral prednisolone to weekly intramuscular methylprednisolone, in 40 patients with moderately active UC. No advantages of the intramuscular route were demonstrated, and clinical response was actually faster among patients treated via the oral route 15.

Therefore, at least one-third of the patients with moderately active UC treated with oral CS (perhaps more if response to therapy is assessed within the first 3–5 days) are potential candidates for treatment escalation. Few alternatives to colectomy are available in this clinical scenario, and none has been specifically assessed in the controlled trials. Clinical experience and retrospective cohorts suggest that calcineurin inhibitors and anti-TNF agents could be of benefit 3, and their use seems reasonable if patients’ clinical status worsens while on oral CS. It has also been repeatedly advised that the intravenous route should be attempted in this setting, although there is no clinical evidence to support this recommendation 3,16. From a pharmacokinetic point of view, two studies carried out in the 1980s in patients with severe UC reported that prednisolone absorption was delayed as compared with the healthy controls when administered orally 17,18. When given intravenously, no difference was found between patients and controls. In UC patients, plasma levels were persistently higher during the 8-hour study period after 20 mg given intravenously as a bolus or in continuous infusion vs. 40 mg given orally. These findings led the authors to recommend the intravenous route, at least in severe attacks. From this perspective, trialling intravenous CS therapy is a particularly sound option in patients with poor or partial response to oral CS. Järnerot et al. reported their clinical experience with intensive intravenous therapy in 61 patients with moderately severe flares, 23 of whom failed to respond to 40 mg of oral prednisone 14. Remission (as defined by the resolution of symptoms together with a normal endoscopic appearance at sigmoidoscopy) was achieved in 78.3% of them, as compared to 92% in those patients treated initially with intravenous CS. However, this series is hardly comparable to ours as far as remission was not defined by means of time, and long-term outcomes were clearly influenced by the lack of maintenance therapy other than sulfasalazine or the prophylactic use of colectomy in long-lasting UC.

No clear rules are established for decision-making in moderate flares (and even less after failure of oral CS), which is why we arbitrarily decided to use mild or inactive disease and no need for rescue therapy at day 7 of intravenous CS as the main efficacy endpoint. We found that up to 76% of patients with moderate flares presented early clinical response to intravenous CS, regardless of failure of oral CS for the index flare or prior maintenance therapy with thiopurines. This finding should stimulate the use of the intravenous route instead of calcineurin inhibitors or anti-TNF agents in patients failing to respond to oral CS. However, the rate of early steroid-dependency was as high as 51% in this subset of patients (39% in those who received maintenance therapy with mesalazine). Disappointingly, the present investigation does not provide useful tools to improve treatment strategies in this clinical scenario. This is mainly due to the limitations of the study. First, due to its retrospective design, we cannot account for a propensity to use the intravenous route in patients previously treated or not previously treated with oral CS. Second, we did not assess endoscopic findings, and endoscopic remission has demonstrated to be of outstanding relevance to predict better outcomes in patients with clinical response 19. Moreover, faecal calprotectin levels were not available in our centres at the time of the study. The availability of serial faecal markers and endoscopic findings among patients with initial clinical response might have helped conceive an improved treatment algorithm in this clinical setting.

Conversely, the direct use of intravenous CS for moderate flares seemed to produce better outcomes than expected, with initial clinical response rates of up to 75% and a low rate of further steroid dependency — figures slightly better than those historically reported in patients treated with oral CS 10,11,20. Therefore, prospective controlled trials comparing oral and intravenous CS for the treatment of moderate flares of UC are warranted.

Finally, the rate of colectomy during admission was low in our series (3%), but increased considerably when taking into account colectomies performed during follow-up, with an overall colectomy rate of 13% after a median follow-up of 1 year. These figures are in agreement with the two recently reported series in which the use of CS (even for moderate flares) was associated with 10–20% colectomy rates in the mid- and long term 21,22.

In summary, intravenous CSs are highly efficient in inducing clinical response in moderate UC flares, particularly when compared to the reported efficacy of oral CS in RCTs. In patients failing oral CS, attempting intravenous CS may be considered an alternative, with good initial efficacy but a high likelihood of early steroid-dependency. Therefore, in patients with moderate flares, intravenous CS should be evaluated as a first-line treatment. Otherwise, in patients who failed to respond to oral CS, this strategy should be compared to other medical options such as calcineurin inhibitors and anti-TNF agents, particularly with respect to long-term outcomes.

Authorship statement

Guarantor of article: Eugeni Domènech is acting as the submission’s guarantor.

Specific author contributions: Jordina Llaó and Juan E. Naves designed the study, collected and analysed the data, and wrote the paper. Eugeni Domènech, designed the study, analysed data, and wrote the paper. Alexandra Ruiz-Cerulla, Laura Marín, Míriam Mañosa, Lorena Rodríguez-Alonso, Eduard Cabré, Esther Garcia-Planella, and Jordi Guardiola collected data and revised the paper. All authors approved the final version of the article, including the authorship list.

Conflict of interests

The authors declare that they have no conflict of interest.

Acknowledgements

Eugeni Domènech received a research grant (Beca d’intensificació 2013) from the Catalonian Society of Gastroenterology (Societat Catalana de Digestologia) that partly supported this study.

1. Henriksen M Jahnsen J Lygren I Sauar J Kjellevold O Schulz T et al. Ulcerative colitis and clinical course: results of a 5-year population-based follow-up study (the IBSEN study). Inflamm Bowel Dis 2006;12:543–50. 2. Jess T Riis L Vind I Winther KV Borg S Binder V et al. Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark. Inflamm Bowel Dis 2007;13:481–9. 3. Dignass A Lindsay JO Sturm A Windsor A Colombel JF Allez M et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis 2012;6:991–1030. 4. Panaccione R Rutgeerts P Sandborn WJ Feagan B Schreiber S Ghosh S . Review article: treatment algorithms to maximize remission and minimize corticosteroid dependence in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008;28:674–88. 5. Truelove SC Witts LJ . Cortisone in ulcerative colitis; preliminary report on a therapeutic trial. Br Med J 1954;2:375–8. 6. Lennard-Jones JE Longmore AJ Newell AC Wilson CW Jones FA . An assessment of prednisone, salazopyrin, and topical hydrocortisone hemisuccinate used as out-patient treatment for ulcerative colitis. Gut 1960;1:217–22. 7. Baron JH Connell AM Kanaghinis TG Lennard-Jones JE Jones AF . Out-patient treatment of ulcerative colitis. Comparison between three doses of oral prednisone. Br Med J 1962;2:441–3. 8. Romberg-Camps MJ Dagnelie PC Kester AD et al. Influence of phenotype at diagnosis and of other potential prognostic factors on the course of inflammatory bowel disease. Am J Gastroenterol 2009;104:371–83. 9. Mañosa M Cabré E Garcia-Planella E et al. Decision tree for early introduction of rescue therapy in active ulcerative colitis treated with steroids. Inflamm Bowel Dis 2011;17:2497–502. 10. Hawthorne AB Record CO Holdsworth CD et al. Double blind trial of oral fluticasone propionate v prednisolone in the treatment of active ulcerative colitis. Gut 1993;34:125–8. 11. Rhodes JM Robinson R Beales I et al. Clinical trial: oral prednisolone metasulfobenzoate (Predocol) vs. oral prednisolone for active ulcerative colitis. Aliment Pharmacol Ther 2008;27:228–40. 12. Silverberg M Satsangi J Ahmad T et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal world congress of gastroenterology. Can J Gastroenterol 2005;19(Suppl A):5A–36A. 13. Magro F Rodrigues A Vieira AI et al. Review of the disease course among adult ulcerative colitis population-based longitudinal cohorts. Inflamm Bowel Dis 2012;18:573–83. 14. Järnerot G Rolny P Sandberg-Gertzén H . Intensive intravenous treatment of ulcerative colitis. Gastroenterology 1985;89:1005–13. 15. Sood A Midha V Sood N Kaushal V Awasthi G . Methylprednisolone acetate versus oral prednisolone in moderately active ulcerative colitis. Indian J Gastroenterol 2002;21:11–3. 16. Travis SP Stange EF Lémann M et al. European evidence-based consensus on the management of ulcerative colitis: current management. J Crohns Colitis 2008;2:24–62. 17. Elliott PR Powell-Tuck J Gillespie PE et al. Prednisolone absorption in acute colitis. Gut 1980;21:49–51. 18. Berghouse LM Elliott PR Lennard-Jones JE English J Marks V . Plasma prednisolone levels during intravenous therapy in acute colitis. Gut 1982;23:980–3. 19. Ardizzone S Cassinotti A Duca P et al. Mucosal healing predicts late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis. Clin Gastroenterol Hepatol 2011;9:483–9. 20. Faubion Jr WA Loftus Jr EV Harmsen WS Zinsmeister AR Sandborn WJ . The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001;121:255–60. 21. Garcia-Planella E Mañosa M Van Domselaar M et al. Long-term outcome of ulcerative colitis in patients who achieve clinical remission with a first course of corticosteroids. Dig Liver Dis 2012;44:206–10. 22. Bello C Belaiche J Louis E Reenaers C . Evolution and predictive factors of relapse in ulcerative colitis patients treated with mesalazine after a first course of corticosteroids. J Crohns Colitis 2011;5:196–202. © 2014 European Crohn’s and Colitis Organisation

Anabolic steroids

Who uses anabolic steroids and why?

The majority of people who use anabolic steroids for non-medical purposes identify as male, typically in their mid to late 30’s.5

A study completed by the National Drug and Alcohol Research Centre found the following people typically use anabolic steroids:6

  • Competitive athletes – who are motivated by their desire to succeed.
  • People concerned about their body image – recreational weight trainers and body builders and people working in the fashion and entertainment industries.
  • Body building professionals – people involved in body building as a competitive sport.
  • People who need muscle strength to do their job – bodyguards, security personal, construction workers, police and members of the armed services.
  • Young men – who want to increase their athletic performance or who are striving to reach the same physical appearance that is often portrayed in the media.6

How do they work?

Anabolic steroids work by imitating the properties of naturally occurring hormones.3 They have a similar chemical composition to testosterone and are therefore able to activate testosterone receptors. Once the receptors are stimulated, a domino effect of metabolic reactions takes place as the drug instructs the body to increase muscle tissue production.3

There are different ways for people to use anabolic steroids non-medically. This can include three different methods, including:

  • Cycling – periods of use followed by equivalent periods of abstinence.
  • Pyramiding – periods of use where the amount is gradually increased to a peak, and then tapered down.

Stacking – where different steroids are used at the same time, also following a use/abstinence approach.3

Side effects

There is no safe level of drug use

The overall evidence to demonstrate the benefits of anabolic steroids to significantly improve athletic performance is limited.7 Generally speaking however, some research has investigated peoples’ experiences after using anabolic steroids or other performance and image enhancing drugs. This research shows that people who use anabolic steroids experience an increase in muscle strength.8

People may use anabolic steroids in what they believe to be a healthy lifestyle context. They may not see themselves as injecting drug users. However, there are risks associated with using steroids without a prescription or medical supervision, even as part of a fitness training program.

In the worst case, long-term heavy steroid use can lead to heart attack, stroke and death9, especially among men aged in their early 30s who combine steroids with stimulant drugs, such as speed and ecstasy.3, 10, 11

Anabolic steroids affect everyone differently. The following may be experienced:

  • water retention – leading to facial bloating
  • acne – leading to permanent scarring
  • irritability and mood swings
  • more frequent colds
  • aggression and violence
  • increased sex drive
  • sleeping difficulties.3,12

Longer-term effects may include:

  • liver damage
  • kidney or prostate cancer
  • high blood pressure
  • depression
  • cardiovascular complications
  • tendon/ ligament damage.3

Men

Effects include:

  • reduced sperm count and fertility
  • shrunken testicles
  • baldness
  • gynaecomastia (developing breasts)
  • involuntarily and long-lasting erection.3

Women

Effects include:

  • facial hair growth
  • irregular periods
  • deepened voice
  • smaller breasts
  • enlarged clitoris.3

Pregnant women who use steroids risk passing on male traits to unborn daughters due to the increased male hormones in their bloodstream. The only way to avoid the risk of fetal damage is to stop using steroids at least 4 months before falling pregnant, as well as during pregnancy.13

Young people

Young men are more likely than young women to use steroids to gain weight and muscle mass.14

The risks of the following side effects are higher if steroids are injected by young men in their late teens/ early 20s, before they have stopped growing:

  • stunted growth
  • premature balding
  • acne scarring
  • stretch marks on chest and arms
  • prematurely-aged, ‘leathery’ skin
  • injuries from excessively intense gym workouts.15

Injecting risks

Injecting steroids can cause permanent nerve damage, which can lead to sciatica.16 Injecting in unhygienic environments or sharing equipment with others also increases the risk of contracting blood-borne viruses such as HIV/AIDS, tetanus or Hepatitis C or B.3

Withdrawal

Anabolic steroids do not cause physical dependence but people can find themselves relying on them to build confidence and self-esteem.17 This reliance can make it difficult to stop using them in the longer term. Fear of losing muscle size or definition can lead to depression and the pressure to continue use.12

The following symptoms may be experienced after completing an anabolic steroid cycle:

  • extreme tiredness
  • weight loss due to decreased appetite
  • decreased strength
  • depression.18

It can take up to four months to restore the body’s natural testosterone levels (if taking high doses for an extended period of time).

Are Steroids Worth the Risk?

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What Are Steroids?

Steroids (sometimes referred to as “roids” or “juice”) are the same as, or similar to, certain hormones in the body. The body makes steroids naturally to support such functions as fighting stress and promoting growth and development.

But some people use steroid pills, gels, creams, or injections because they think steroids can improve their sports performance or the way they look.

Anabolic steroids are artificially produced hormones that are the same as, or similar to, androgens, the male-type sex hormones in the body. There are more than 100 variations of anabolic steroids. The most powerful androgen is testosterone (pronounced: tess-TOSS-tuh-rone). Although testosterone is mainly a mature male hormone, girls’ bodies produce smaller amounts. Testosterone helps build muscle and promotes the masculine traits that guys develop during puberty, such as deepening of the voice and growth of body hair. Testosterone levels can also affect how aggressive a person is.

Athletes sometimes take anabolic steroids because of their testosterone-like effects.

Other steroids, sometimes called steroidal supplements, contain dehydroepiandrosterone (DHEA) and/or androstenedione (also known as andro). For the most part, steroidal supplements, which used to be found at health food stores or gyms, are now illegal and require a prescription. DHEA is one of the few exceptions and can still be bought over the counter.

Steroid supplements are weaker forms of androgen. Their effects aren’t well known, but it’s thought that, when taken in large doses, they cause effects similar to other androgens like testosterone. But research studies suggest that they do very little or nothing to improve athletic performance.

Here’s what is known about steroidal supplements: Companies that make them often use false claims, and very little is known about the long-term effects some of these substances have on the body. That’s one reason why the government took action to protect citizens by passing laws controlling steroid distribution.

How Do Anabolic Steroids Work?

Anabolic steroids stimulate muscle tissue to grow and “bulk up” in response to training by mimicking the effect of naturally produced testosterone on the body. Anabolic steroids can remain in the body anywhere from a couple of days to about a year. Steroids have become popular because they may improve endurance, strength, and muscle mass. However, research has not shown that steroids improve skill, agility, or athletic performance.

Dangers of Steroids

Anabolic steroids cause many different types of problems. Some of the common side effects are:

  • acne
  • premature balding or hair loss
  • weight gain
  • mood swings
  • aggression
  • problems sleeping
  • high blood pressure
  • greater chance of injuring muscles and tendons
  • jaundice (yellowing of the skin); liver damage
  • stunted growth
  • increased risk of developing heart disease, blood clots, stroke, and some types of cancer

Risks for Girls

Specific risks for girls associated with anabolic steroids include:

  • increased facial and body hair growth
  • development of masculine traits, such as deepening of the voice, and loss of feminine body characteristics, such as shrinking of the breasts
  • enlargement of the clitoris
  • menstrual cycle changes

Risks for Guys

Specific risks for guys include:

  • testicular shrinkage
  • pain when urinating
  • breast development
  • impotence (inability to get an erection)
  • reduced sperm count and infertility

Other Problems

Steroids can also have serious psychological side effects. Some users may become aggressive or combative, believe things that aren’t true (delusions), or have extreme feelings of mistrust or fear (paranoia). And people who use steroids also appear to be at higher risk for using other drugs, such as alcohol or cocaine, often to counteract some of the negative effects of steroids.

Steroid users who inject the drugs with a needle are at risk for infection with HIV (human immunodeficiency virus), the virus that causes AIDS, if they share needles with other users. People who use dirty needles are also at risk for contracting hepatitis, a liver disease, or bacterial endocarditis, an infection of the inner lining of the heart.

Steroids: Stacking and Addiction

Some people “cycle” their steroid doses. This means they take multiple doses of steroids over a period of time, stop for a period, then start up again. “Stacking” means taking two or more different anabolic steroids. Other steroid users may “pyramid” their steroids, starting with a low dose and gradually increasing the dose, frequency, or number of anabolic steroids taken, then tapering off to complete a cycle. Users believe that stacking enhances the effects of each individual drug, pyramiding allows the body to get used to high doses of steroids, and steroid-free periods help the body recuperate from the drugs. There is no scientific evidence to support any of these claims.

A lot of people tell themselves they’ll only use steroids for a season or a school year. Unfortunately, steroids can be addictive, making it hard to stop taking them.

And once users stop taking steroids, they can have withdrawal symptoms such as loss of appetite, tiredness, restlessness, insomnia, mood swings, and depression.

Strong Alternatives to Steroids

Anabolic steroid use is illegal and banned by professional sports organizations and medical associations. In spite of this, some athletes continue to take steroids because they think it gives them a competitive advantage. As seen in high-profile cases, if an athlete is caught using steroids, his or her career can be destroyed. And there are serious health consequences.

When it comes right down to it, harming your body or getting disqualified aren’t smart ways to try to improve your athletic performance. Being a star athlete means working hard and training the healthy way: eating the right foods, practicing, and strength training without the use of drugs.

Reviewed by: Steven Dowshen, MD Date reviewed: February 2017

The Pros and Cons of Taking Steroids for Ulcerative Colitis

Since the 1950s, corticosteroids (steroids) have been helping those with ulcerative colitis (UC) put the disease in remission. But these drugs do come with problems. Roughly 50 percent of patients taking steroids, such as prednisone, for UC experience side effects, according to a study published in January 2013 in the journal Therapeutic Advances in Gastroenterology. In the short term, steroids can cause:

  • Weight gain
  • Moon face
  • Acne
  • Irritability
  • Insomnia

After you’re on them even just three months — even at low dosages — they can affect bone strength, increasing the risk of osteoporosis, especially in your hips. Continued use of steroids can:

  • Impair healing
  • Cause you to bruise easily
  • Increase blood pressure
  • Affect blood glucose, a condition known as steroid-induced diabetes

“Steroids can reduce inflammation but they don’t heal the inside,” says David Hudesman, MD, medical director of the inflammatory bowel disease center at NYU Langone in New York City. “They’re like a Band-Aid.”

Yet even as newer, safer therapies have come along, doctors continue to prescribe steroids because, if used appropriately, they can help manage UC without causing serious side effects.

How Steroids Can Help

If the UC is severe and you’re in significant pain, with bloody stools and diarrhea, your doctor may prescribe prednisone for 4 to 12 weeks to relieve symptoms.

And if the UC is mild to moderate, your doctor may prescribe a milder steroid, such as Entocort (budesonide) to reduce inflammation. It isn’t as strong as prednisone and has fewer side effects. “It’s a pill that opens up and coats your intestine,” Hudesman says. Still, if you’re taking Entocort long term, it can affect bone strength.

Concurrently, you will likely also be prescribed a long-term maintenance medication that’s not a steroid, such as Lialda (mesalamine), which can take time to kick in. As the maintenance medication begins to manage the disease, your doctor will likely taper off your steroid dosage until you’re off it completely.

But because of the potential for dangerous side effects, and because steroids don’t actually halt the course of the disease, Dr. Hudesman says that prednisone should only be used if your symptoms are significant and you have an exit strategy. “You’re using it as a bridge to maintenance therapy,” he adds. The same goes for milder steroids, such as Endocort.

When Not to Take Steroids

But what if symptoms recur months after you’ve tapered off steroids?

“The response shouldn’t be to go back on prednisone,” Hudesman says. “You shouldn’t be on multiple courses of steroids, even two courses, within a year.”

Instead, talk to your doctor about changing your maintenance medication, or adding an immunosuppressant or biologic agent. “Whatever is a reasonable time for maintenance medication, we try to give it,” Hudesman says. “If you’re not getting there, then we consider moving medications, or make sure something else isn’t complicating your disease.”

Healthy From the Inside Out

Hudesman is aware that some people with UC may try to manage the disease by avoiding steroids and maintenance medication altogether. According to a study published in February 2017 in the journal Patient Preference and Adherence, it’s common for patients to ditch their maintenance medication because they feel fine. But doing so increases the risk of relapse.

Although steroids can have dangerous side effects, you should take them as directed if you need them. The same goes for your maintenance medication.

“The most important thing to know with UC is that how you feel doesn’t correlate with what’s happening on the inside,” Hudesman says. “Even if you feel great most of the time without medication, if I did a colonoscopy, it might show severe disease. A lot of patients tolerate little flares until they can’t. Then all of a sudden, you’re talking about surgery or a very complicated disease.”

The bottom line? Every patient is different. But if you’re newly diagnosed with UC, you may need a steroid initially until your maintenance medication can manage your condition. You may also need to experiment with maintenance medication until you find one that works, or switch to immunosuppressant or biologic therapy.

“Ideally, the goal is to find a maintenance medication that you feel well with and that heals you from the inside,” Hudesman says.

Lialda

CLINICAL PHARMACOLOGY

Mechanism Of Action

The mechanism of action of mesalamine is not fully understood, but appears to have a topical antiinflammatory effect on the colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

Mesalamine has the potential to inhibit the activation of nuclear factor kappa B (NF?B) and consequently the production of key pro-inflammatory cytokines. It has been proposed that reduced expression of PPAR? nuclear receptors (?-form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. There is evidence that mesalamine produces pharmacodynamic effects through direct activation of PPAR? receptors in the colonic/rectal epithelium.

Pharmacodynamics

The pharmacodynamic actions of mesalamine occur in the colonic/rectal mucosae local to the delivery of drug from LIALDA into the lumen. There is information suggesting that severity of colonic inflammation in ulcerative colitis patients treated with mesalamine is inversely correlated with mucosal concentrations of mesalamine. Plasma concentrations representing systemically absorbed mesalamine are not believed to contribute extensively to efficacy.

Pharmacokinetics

Absorption

The total absorption of mesalamine from LIALDA 2.4 g or 4.8 g given once daily for 14 days to healthy volunteers was found to be approximately 21-22% of the administered dose.

Gamma-scintigraphy studies have shown that a single dose of LIALDA 1.2 g (one tablet) passed intact through the upper gastrointestinal tract of fasted healthy volunteers. Scintigraphic images showed a trail of radio-labeled tracer in the colon, suggesting that mesalamine had distributed through this region of the gastrointestinal tract.

In a single dose study, LIALDA 1.2 g, 2.4 g and 4.8 g were administered in the fasted state to healthy subjects. Plasma concentrations of mesalamine were detectable after 2 hours and reached a maximum by 9-12 hours on average for the doses studied. The pharmacokinetic parameters are highly variable among subjects (Table 3). Mesalamine systemic exposure in terms of area under the plasma concentration-time curve (AUC) was slightly more than dose proportional between 1.2 g and 4.8 g LIALDA. Maximum plasma concentrations (C ) of mesalamine increased approximately dose proportionately between 1.2 g and 2.4 g and sub-proportionately between 2.4 g and 4.8 g LIALDA, with the dose normalized value at 4.8 g representing, on average, 74% of that at 2.4 g based on geometric means.

Table 3: Mean (SD) PK Parameters for Mesalamine Following Single Dose Administration of LIALDA Under Fasting Conditions

Administration of a single dose of LIALDA 4.8 g with a high fat meal resulted in further delay in absorption, and plasma concentrations of mesalamine were detectable 4 hours following dosing. However, a high fat meal increased systemic exposure of mesalamine (mean C : 91%; mean AUC: 16%) compared to results in the fasted state. LIALDA was administered with food in the controlled clinical trials that supported its approval.

In a single and multiple dose pharmacokinetic study of LIALDA, 2.4 g or 4.8 g was administered once daily with standard meals to 28 healthy volunteers per dose group. Plasma concentrations of mesalamine were detectable after 4 hours and were maximal by 8 hours after the single dose. Steady state was achieved generally by 2 days after dosing. Mean AUC at steady state was only modestly greater (1.1- to 1.4-fold) than predictable from single dose pharmacokinetics.

In a single dose pharmacokinetic study of LIALDA, 4.8 g was administered in the fasted state to 71 healthy male and female volunteers (28 young (18-35yrs); 28 elderly (65-75yrs); 15 elderly (>75yrs)). Increased age resulted in increased systemic exposure (approximately 2-fold in C ), to mesalamine and its metabolite N-acetyl-5-aminosalicylic acid. Increased age resulted in a slower apparent elimination of mesalamine, though there was high between-subject variability. Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance.

Table 4: Mean (SD) PK Parameters for Mesalamine Following Single Dose Administration of LIALDA 4.8 g under Fasting Conditions to Young and Elderly Subjects

Distribution

Mesalamine is approximately 43% bound to plasma proteins at the concentration of 2.5 µg/mL.

Metabolism

The only major metabolite of mesalamine (5-aminosalicylic acid) is N-acetyl-5-aminosalicylic acid. Its formation is brought about by N-acetyltransferase (NAT) activity in the liver and intestinal mucosa cells, principally by NAT-1.

Elimination

Elimination of mesalamine is mainly via the renal route following metabolism to N-acetyl-5- aminosalicylic acid (acetylation). However, there is also limited excretion of the parent drug in urine. Of the approximately 21-22% of the dose absorbed, less than 8% of the dose was excreted unchanged in the urine after 24 hours, compared with greater than 13% for N-acetyl-5-aminosalicylic acid. The apparent terminal half-lives for mesalamine and its major metabolite after administration of LIALDA 2.4 g and 4.8 g were, on average, 7-9 hours and 8-12 hours, respectively.

Drug Interactions:

The potential effect of Lialda (4.8 g given once daily) on the pharmacokinetics of four commonly used antibiotics were evaluated in healthy subjects. The four antibiotics studied and their dosing regimens were as follows: amoxicillin (single 500 mg dose), ciprofloxacin XR (single 500 mg dose), metronidazole (750 mg twice daily for 3.5 days), and sulfamethoxazole/trimethoprim (800 mg/160 mg twice daily for 3.5 days). Coadministration of Lialda did not result in clinically significant changes in the pharmacokinetics of any of the four antibiotics. The change in Cmax and AUC of amoxicillin, ciprofloxacin and metronidazole when they were co-administered with Lialda were all ≤ 3%. There was an increase of 12% in Cmax and an increase of 15% in AUC of sulfamethoxazole when sulfamethoxazole/trimethoprim was coadministered with Lialda .

Animal Toxicology And/Or Pharmacology

In animal studies with mesalamine, a 13-week oral toxicity study in mice and 13-week and 52-week oral toxicity studies in rats and cynomolgus monkeys have shown the kidney to be the major target organ of mesalamine toxicity. Oral daily doses of 2400 mg/kg in mice and 1150 mg/kg in rats produced renal lesions including granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary necrosis, tubular necrosis, and interstitial nephritis. In cynomolgus monkeys, oral daily doses of 250 mg/kg or higher produced nephrosis, papillary edema, and interstitial fibrosis.

Clinical Studies

Active, Mild To Moderate Ulcerative Colitis

Two similarly designed, randomized, double blind, placebo-controlled trials were conducted in 517 adult patients with active, mild to moderate ulcerative colitis. The study population was primarily Caucasian (80%), had a mean age of 42 years (6% age 65 years or older), and was approximately 50% male. Both studies used LIALDA doses of 2.4 g/day and 4.8 g/day administered once daily for 8 weeks except for the 2.4 g/day group in Study 1, which was given in two divided doses (1.2 g twice daily). The primary efficacy end-point in both trials was to compare the percentage of patients in remission after 8 weeks of treatment for the LIALDA treatment groups versus placebo. Remission was defined as an Ulcerative Colitis Disease Activity Index (UC-DAI) of ≤ 1, with scores of zero for rectal bleeding and for stool frequency, and a sigmoidoscopy score reduction of 1 point or more from baseline.

In both studies, the LIALDA doses of 2.4 g/day and 4.8 g/day demonstrated superiority over placebo in the primary efficacy endpoint (Table 5). Both LIALDA doses also provided consistent benefit in secondary efficacy parameters, including clinical improvement, treatment failure, clinical remission, and sigmoidoscopic improvement. LIALDA 2.4 g/day and 4.8 g/day had similar efficacy profiles.

Table 5: Patients in Remission at Week 8

Maintenance Of Remission In Patients With Ulcerative Colitis

A multicenter, randomized, double-blind, active comparator study was conducted in a total of 826 adult patients in remission from ulcerative colitis. The study population had a mean age of 45 years (8% age 65 years or older), were 52% male, and were primarily Caucasian (64%).

Maintenance of remission was assessed using a modified Ulcerative Colitis Disease Activity Index (UC-DAI). For this trial, maintenance of remission was based on maintaining endoscopic remission defined as a modified UC-DAI endoscopy subscore of ≤1. An endoscopy subscore of 0 represented normal mucosal appearance with intact vascular pattern and no friability or granulation. For this trial the endoscopy score definition of 1 (mild disease) was modified such that it could include erythema, decreased vascular pattern, and minimal granularity; however, it could not include friability.

Subjects were randomized in a 1:1 ratio to receive either LIALDA 2.4 g/day administered once daily or mesalamine delayed release 1.6 g/day administered as 0.8 g twice daily. The proportion of patients who maintained remission at Month 6 in this study using LIALDA 2.4 g once daily (83.7%) was similar to that seen using the comparator (mesalamine delayed release) 1.6 g/day (81.5%).

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