BACKGROUND:

Methotrexate, a folate antagonist, is an immunosuppressant drug that is effective for treating several inflammatory disorders including Crohn's disease. Ulcerative colitis, a related chronic inflammatory bowel disease, can be challenging to treat. T his updated systematic review summarizes the current evidence on the use of methotrexate for induction maintenance of remission in ulcerative colitis.

OBJECTIVES:

The objectives of this review were to assess the efficacy and safety of methotrexate for maintenance of remission in patients with ulcerative colitis.

SEARCH METHODS:

We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized trials register from inception to June 26, 2014. Study references and review papers were also searched for additional trials. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only.

SELECTION CRITERIA:

Randomized controlled trials in which methotrexate was compared to placebo or an active comparator in patients with quiescent ulcerative were considered for inclusion.

DATA COLLECTION AND ANALYSIS:

Two authors independently extracted data and assessed the risk of bias for each study. The primary outcome was the occurrence of clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included frequency and nature of adverse events, change of disease activity score and steroid-sparing effect. We calculated the risk ratio and corresponding 95% confidence interval for dichotomous outcomes. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria.

MAIN RESULTS:

Three trials (165 patients) fulfilled the inclusion criteria. One study compared oral methotrexate (12.5 mg/week) to placebo, another compared oral methotrexate (15 mg/week) to 6-mercaptopurine (6-MP, 1.5 mg/kg/day) or 5-aminosalicylic acid (5-ASA, 3 g/day) and the other compared methotrexate (15 mg/week) in combination sulfasalazine (3 g/day) to sulfasalazine. The placebo-controlled study was rated as low risk of bias. The study comparing methotrexate to 6-MP and 5-ASA was rated as high risk of bias and the study assessing methotrexate and sulfasalazine was rated as unclear risk of bias for sequence generation, allocation concealment and blinding. The placebo-controlled study found no statistically significant differences in the proportion of patients who maintained remission. At nine months, 36% (5/14) of methotrexate patients maintained remission compared to 54% (10/18) of placebo patients (RR 0.64, 95% CI 0.28 to 1.45). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (15 events). The study comparing combination therapy to sulfasalazine found no statistically significant difference in the proportion of patients who maintained remission. At 12 months, 100% (14/14) of patients in the combination group maintained remission compared to 75% (9/12) of sulfasalazine patients (RR 1.32, 95% CI 0.94 to 0.86), A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to unknown risk of bias and very sparse data (23 events). There were no statistically significant differences in maintenance of remission rates between methotrexate and 6-MP or between methotrexate and 5-ASA. At 76 weeks, 14% (1/7) of methotrexate patients maintained remission compared to 64% (7/11) of 6-MP patients (RR 0.22, 95% CI 0.03 to 1.45) and 0% (0/2) of 5-ASA patients (RR 1.13, 95% CI 0.06 to 20.71). A GRADE analysis indicated that the overall quality of the evidence from this study was very low due to high risk of bias and very sparse data. Adverse events reported in these studies included transient leucopenia, migraine, nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia

AUTHORS' CONCLUSIONS:

The results for efficacy and safety outcomes between methotrexate and placebo, methotrexate and sulfasalazine, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration of methotrexate would be effective in quiescent ulcerative colitis is unknown. At present there is no evidence supporting the use of methotrexate for maintenance of remission in ulcerative colitis. More studies are needed to determine the efficacy and safety of methotrexate maintenance therapy in patients with quiescent ulcerative colitis. Large scale methodologically rigorous randomized controlled trials are needed. These studies should investigate higher doses of methotrexate (e.g. 15 to 25 mg/week) and parenteral administration.

Microscopic colitis (MC) is diagnosed in up to 13% of patients investigated for chronic diarrhea, particularly in middle-aged and elderly patients. Recent studies have suggested an etiological role for various drugs, including nonsteroidal anti-inflammatory drugs and proton pump inhibitors. To ascertain the potential role for drug exposure in the development of MC, we performed a systematic review based on a MEDLINE search and conducted a meta-analyses on the available data. We also give an overview of the case reports and studies illustrating the role of drugs in inducing MC. A number of hypotheses are formulated with regard to the potential pathophysiological mechanisms in drug-induced MC. However, confirmative evidence is still largely lacking. Considering the high number of drug users and the relatively low incidence of MC, it is more likely that drug-induced cases of MC are the result of an idiosyncratic reaction.

AIM:

The study reviews the literature related to ischaemic colitis (IC) to establish an evidence base for its management and to identify factors predicting severity and mortality.

METHOD:

A systematic review of the English language literature was conducted according to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. MEDLINE, Embase and Cochrane Library databases were searched using the keyword search 'ischaemic colitis OR colon ischaemia OR colonic ischaemia OR management ischaemic colitis'. IC is often misdiagnosed so only studies where the diagnosis was supported by histopathology in every case were included. Critical appraisal was performed of included studies using predefined quality assessment checklists and narrative data synthesis.

RESULTS:

In all, 2610 publications were identified. Of these, eight retrospective case series and three case controlled studies describing 1049 patients were included. Medical management was used in 80.3% patients of whom 6.2% died. Surgery was required in 19.6% of whom 39.3% died. The overall mortality of IC was 12.7%. Lack of rectal bleeding, peritonism and renal dysfunction were commonly quoted predictors of severity; however, right sided IC appeared to be the most significant predictor of outcome.

CONCLUSION:

Most patients with IC can be managed conservatively. Right sided IC may be the most significant predictor of severity.

BACKGROUND:

Ischaemic colitis has been associated with co-morbid conditions, medications, vascular surgery and advanced age in case reports and case series. Few data exist on the baseline incidence in the general population or on the increased risk imposed by these risk factors.

AIM:

To systematically review the literature regarding the incidence, prevalence and risk factors for ischaemic colitis.

METHODS:

Searches of bibliographic databases were performed independently by two investigators. Studies were included if they used population-based samples, disease-specific population samples or case-control population-based samples of adults with ischaemic colitis, and reported the incidence, prevalence or risk factors for ischaemic colitis. Eligible articles were reviewed and data were abstracted in a duplicate, independent manner.

RESULTS:

Four studies were identified that reported the general population incidence and four that reported the disease-specific population incidence. The incidence of ischaemic colitis in general populations ranged from 4.5 to 44 cases per 100 000 person-years. The risk was increased two- to four-fold by either prevalent irritable bowel syndrome or chronic obstructive pulmonary disease. The risk was also increased in females and in subjects of 65 years and older.

CONCLUSIONS:

Ischaemic colitis is uncommon in the general population. The effect sizes of the most commonly reported risk factors have not been adequately quantified in population-based studies.

AIM:

Ischaemic colitis is uncommon. Aetiological factors include abdominal aortic surgery, drugs (especially inotropics) or rheumatoid diseases, such as Takayasu's or Buerger's diseases. However, there is often no triggering factor, and it may be part of multifactorial cardiac, respiratory, renal or metabolic failure.

METHOD:

A systematic review of the current literature on the management of ischaemic colitis was carried out.

RESULTS:

Ten retrospective trials (841 patients) were included. No randomized controlled or prospective trial of the management of ischaemic colitis was found.

CONCLUSION:

There is very little evidence base for the management of this condition.

BACKGROUND:

The prognosis of acute severe ulcerative colitis (ASC) influences therapeutic decisions, but data on prevalence or long-term outcome are few.

METHODS:

A systematic review of all patients with UC diagnosed in Oxford was performed to assess the prevalence of ASC defined by Truelove and Witts' (TW) criteria and determine whether outcome is related to disease activity on admission, likelihood of recurrence and long-term prognosis.

RESULTS:

750 patients (median follow up 12.7 yr, range 0-648 mo) met inclusion criteria out of a total cohort of 1853 patients. 24.8% (186/750) had at least one admission for ASC (294 admissions in 186 patients). Overall, 12% (93/750) had a colectomy, compared to 39.8% (74/186) of patients with one or more episodes of ASC (p<0.0001) and 3.4% (19/564) in those with no admission. The colectomy rate on first admission (37/186, 19.9%) was lower than on the second or subsequent admissions (OR 2.35, 95% CI 1.33-4.14, p=0.003), being 29.0%, 36.6%, 38.2% after two, three, or subsequent episodes respectively. It was 8.5% (11/129) if patients had one TW criterion in addition to ≥6 bloody bowel motions/day, compared to 31% (29/94) if two additional criteria were present and 48% (34/71) if three or more additional criteria were present (p=1.4 × 10⁻⁵; OR 4.35, 95% CI 2.20-8.56 one criterion vs two or more).

CONCLUSIONS:

A quarter of all patients with ulcerative colitis experience at least one episode of ASC; 20% come to colectomy on first admission, but 40% after two admissions. The likelihood of colectomy is related to biological severity on admission.

BACKGROUND:

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Corticosteroids and 5-aminosalicylates are the most commonly used therapies. However, many patients require immunosuppressive therapy for steroid-refractory and steroid-dependent disease. Methotrexate is a medication that is effective for treating a variety of inflammatory diseases, including Crohn's disease. This review was performed to determine the effectiveness of methotrexate treatment in UC patients. This review is an update of a previously published Cochrane review.

OBJECTIVES:

To assess the efficacy and safety of methotrexate for induction of remission in patients with UC.

SEARCH METHODS:

MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized trials register were searched from from inception to June 26, 2014. Study references and review papers were also searched for additional trials. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only.

SELECTION CRITERIA:

Randomized controlled trials comparing methotrexate with placebo or an active comparator in patients with active ulcerative colitis were considered for inclusion.

DATA COLLECTION AND ANALYSIS:

Two authors independently reviewed studies for eligibility, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome measure was the proportion of patients who achieved clinical remission and withdrawal from steroids as defined by the studies and expressed as a percentage of the total number of patients randomized (intention-to-treat analysis). We calculated the risk ratio (RR) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria.

MAIN RESULTS:

Two studies (n = 101 patients) were included in the review. One study (n = 67) compared oral methotrexate 12.5 mg/week) to placebo. The other study (n = 34) compared oral methotrexate (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) and 5-aminosalicylic acid (3 g/day). The placebo-controlled study was judged to be at low risk of bias. The other study was judged to be at high risk of bias due to an open-label design. There was no statistically significant difference in clinical remission rates between methotrexate and placebo patients. Forty-seven per cent (14/30) of methotrexate patients achieved clinical remission and complete withdrawal from steroids during the study period compared to 49% (18/37) of placebo patients (RR 0.96, 95% CI 0.58 to 1.59. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (32 events). There were no statistically significant differences in the proportion of patients who achieved clinical remission and withdrawal from steroids in the study comparing oral methotrexate to 6-mercaptopurine and 5-aminosalicylic acid. At 30 weeks, 58% (7/12) of methotrexate patients achieved clinical remission and withdrawal from steroids compared to 79% (11/14) of 6-mercaptopurine patients (RR 0.74, 95% CI 0.43 to 1.29) and 25% of 5-aminosalicylic acid patients (RR 2.33, 95% CI 0.64 to 8.49). GRADE analyses indicated that the overall quality of the evidence was very low due to very sparse data (18 and 9 events respectively) and and high risk of bias. In the placebo-controlled trial two patients (7%) were withdrawn from the methotrexate group due to adverse events (leucopenia, migraine) compared to one patient (3%) who had a rash in the placebo group (RR 2.47, 95% CI 0.23 to 25.91). Adverse events experienced by methotrexate patients in the active comparator study included nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia.

AUTHORS' CONCLUSIONS:

Although methotrexate was well-tolerated, the studies showed no benefit for methotrexate over placebo or active comparators. The results for efficacy outcomes between methotrexate and placebo, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration would be effective for induction therapy is unknown. At present there is no evidence supporting the use of methotrexate for induction of remission in active ulcerative colitis. A trial in which larger numbers of patients receive a higher dose of oral methotrexate should be considered. Currently there are two large ongoing placebo-controlled trials (METEOR and MERIT-UC) assessing the efficacy and safety of intramuscular or subcutaneous methotrexate in patients with active UC which may help resolve the evidence supporting the use of methotrexate as therapy for active of ulcerative colitis.

BACKGROUND:

Ulcerative colitis (UC) is a chronic inflammatory condition of the colon characterized by episodes of disease activity and symptom-free remission.There is paucity of evidence regarding the efficacy and safety of complementary or alternative medicines for the management of UC. Curcumin, an anti-inflammatory agent, has been used in many chronic inflammatory conditions such as rheumatoid arthritis, esophagitis and post-surgical inflammation. The efficacy of this agent for maintenance of remission in patients with UC has not been systematically evaluated.

OBJECTIVES:

The primary objective was to systematically review the efficacy and safety of curcumin for maintenance of remission in UC.

SEARCH METHODS:

A computer-assisted literature search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Inflammatory Bowel Disease Specialized Trial Register was performed on July 11, 2012 to identify relevant publications. Proceedings from major gastroenterology meetings and references from published articles were also searched to identify additional studies.

SELECTION CRITERIA:

Randomized placebo-controlled trials (RCT) of curcumin for maintenance of remission in UC were included. Studies included patients (of any age) who were in remission at the time of recruitment. Co-interventions were allowed.

DATA COLLECTION AND ANALYSIS:

Two authors independently extracted data and assessed the methodological quality of the included studies using the Cochrane risk of bias tool. Data were analyzed using Review Manager (RevMan 5.1). We calculated the relative risk (RR) and 95% confidence interval (95% CI) for each dichotomous outcome. For continuous outcomes we calculated the mean difference (MD) and 95% CI.

MAIN RESULTS:

Only one trial (89 patients) fulfilled the inclusion criteria. This trial randomized 45 patients to curcumin and 44 patients to placebo. All patients received treatment with sulfasalazine or mesalamine. The study was rated as low risk of bias. Curcumin was administered orally in a dose of 2 g/day for six months. Fewer patients relapsed in the curcumin group than the placebo group at six months. Four per cent of patients in the curcumin group relapsed at six months compared to 18% of patients in the placebo group (RR 0.24, 95% CI 0.05 to 1.09; P = 0.06). There was no statistically significant difference in relapse rates at 12 months. Twenty-two per cent of curcumin patients relapsed at 12 months compared to 32% of placebo patients (RR 0.70, 95% CI 0.35 to 1.40; P = 0.31). A total of nine adverse events were reported in seven patients. These adverse events included sensation of abdominal bulging, nausea, transient hypertension, and transient increase in the number of stools. The authors did not report which treatment group the patients who experienced adverse events belonged to. The clinical activity index (CAI) at six months was significantly lower in the curcumin group compared to the placebo group (1.0 + 2.0 versus 2.2 + 2.3; MD -1.20, 95% CI -2.14 to -0.26). The endoscopic index (EI) at six months was significantly lower in the curcumin group than in the placebo group (0.8 + 0.6 versus 1.6 + 1.6; MD -0.80, 95% CI -1.33 to -0.27).

AUTHORS' CONCLUSIONS:

Curcumin may be a safe and effective therapy for maintenance of remission in quiescent UC when given as adjunctive therapy along with mesalamine or sulfasalazine. However, further research in the form of a large scale methodologically rigorous randomized controlled trial is needed to confirm any possible benefit of curcumin in quiescent UC.

Background: Etrolizumab (rhuMAb beta7) is an anti-integrin that selectively targets the β7 subunits of the α4β7 and αEβ7 integrins, which are involved in the pathogenesis of ulcerative colitis. Objectives: The objectives of this review were to assess the efficacy and safety of etrolizumab for induction of remission in ulcerative colitis. Search methods: We searched PubMed, MEDLINE, EMBASE, and the Cochrane Library (CENTRAL) from inception to 12 March 2015. References and conference abstracts were searched to identify additional studies. Selection criteria: Randomized controlled trials (RCTs) trials in which etrolizumab was compared to placebo or another active comparator in patients with active ulcerative colitis were included. Data collection and analysis: Two authors independently screened studies for inclusion, assessed methodological quality and extracted data. We assessed methodological quality using the Cochrane risk of bias tool. The primary outcome was failure to induce clinical remission (as defined by the primary studies). Secondary outcomes included failure to induce clinical improvement (as defined by the primary studies), failure to induce endoscopic remission (as defined by the primary studies), adverse events, serious adverse events, withdrawal due to adverse events, and health-related quality of life (as defined by the primary studies). We assessed the overall quality of the evidence using the GRADE criteria. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. Main results: Two RCTs including 172 patients with moderate to severe UC who failed conventional therapy met the inclusion criteria. Both studies were rated as low risk of bias. We did not pool efficacy data from the two included studies due to differences in dose and route of administration. The small phase I study found no statistically significant differences between etrolizumab and placebo in the proportion of patients who failed to enter remission (RR 1.04, 95% CI 1.04 to 1.69; participants = 23) or respond at week 10 (RR 1.67, 95% CI 0.26 to 10.82; participants = 23). The phase II study reported on failure to enter clinical remission at weeks 6 and 10. In the etrolizumab group 91% (71/78) of patients failed to enter remission at week 6 compared to 95% (39/41) of placebo patients (RR 0.96, 95% CI 0.87 to 1.06). Subgroup analysis revealed no statistically significant differences by dose. At week 10, there was a statistically significant difference in clinical remission rates favouring etrolizumab over placebo. Of the patients who received etrolizumab, 85% (66/78) failed to enter remission at week 10 compared to 100% (41/41) patients in the placebo group (RR 0.86, 95% CI 0.77 to 0.95). A subgroup analysis by dose found a statistically significant difference in clinical remission rates favoring 100 mg etrolizumab over placebo (RR 0.81 CI 95% 0.68 to 0.96), but not 300 mg etrolizumab over placebo (RR 0.91, 95% CI 0.80 to 1.03). No significant heterogeneity was detected for this comparison (P = 0.28, I2 = 13.5%). GRADE analyses indicated that the overall quality of evidence for the clinical remission outcomes was moderate due to sparse data. Both of the included studies reported on safety. The outcome adverse events was initially pooled, however this analysis was removed due to high heterogeneity (I2 = 88%). The phase I study found no statistically significant difference between etrolizumab and placebo in the proportion of patients who had at least one adverse event. Ninety-five per cent (36/38) of etrolizumab patients had at least one adverse event compared to 100% (10/10) of placebo patients (RR 0.98, 95% CI 0.84 to 1.14). Common adverse events reported in the phase I study included exacerbation of UC, headache, fatigue, abdominal pain, dizziness, nasopharyngitis, nausea, arthralgia and urinary tract infection. There was a statistically significant difference between etrolizumab and placebo in the proportion of patients who had at least one adverse event. Fifty-six per cent (44/78) of etrolizumab patients had at least one adverse event compared to 79% of placebo patients (RR 0.71, 95% CI 0.55 to 0.91). A GRADE analysis indicates that the overall quality of the evidence for this outcome was moderate due to sparse data. Common adverse events reported in the phase II study included worsening UC, nasopharyngitis, nervous system disorders, headache and arthralgia. A pooled analysis of two studies indicates that there was no statistically significant difference in the proportion of patients who had a serious adverse event. Twelve per cent (14/116) of etrolizumab patients had a serious adverse event compared to 12% of placebo patients (6/49) (RR 0.92, 95% CI 0.36 to 2.34). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (20 events). Common serious adverse events included worsening of UC, impaired wound healing and bacterial peritonitis. Authors' conclusions: Moderate quality evidence suggests that etrolizumab may be an effective induction therapy for some patients with moderate to severe ulcerative colitis who have failed conventional therapy. Due to small numbers of patients in dose subgroups the optimal dosage of etrolizumab is unclear. Due to sparse data we are uncertain regarding the risk of adverse events and serious adverse events. Further studies are needed to determine the efficacy and safety of etrolizumab in this patient population. There are five ongoing phase III etrolizumab trials and two ongoing open-label extension studies that will provide important new information on the efficacy, safety and optimal dose of this drug for the treatment of UC.

BACKGROUND & AIMS:

There is consistently a measurable benefit noted among placebo users in treatment trials of ulcerative colitis (UC). The aim of this study was to define the placebo response in active UC and identify study features that influence the placebo response.

METHODS:

MEDLINE database was searched for placebo-controlled treatment studies of active UC. Data extraction was performed by two reviewers, and one separate investigator reviewed all trials and data extraction before data tabulation. Placebo remission and benefit rates were determined for clinical, endoscopic, and histological outcomes. Synthesis analysis on the weighted proportions from the different studies explored the placebo response as it related to eight study variables.

RESULTS:

Thirty-eight of 44 studies identified were included in the analysis. The clinical remission rate was 9.1% (confidence interval [CI], 6.6-11.6) and the benefit rate was 26.7% (CI, 24.1-29.2). Similar rates were observed endoscopically and histologically. The number of study visits (< or =3 vs. >3) modified placebo response as assessed by clinical benefit (P = 0.05), endoscopic remission (P = 0.02), and histological remission (P = 0.04). Other study variables were not significant placebo response modifiers.

CONCLUSIONS:

In trials of active UC, the placebo remission rate is approximately 10% and the placebo benefit rate is approximately 30%. These rates are consistent regardless of assessment end point. The placebo response is greater in trials with more frequent study visits (more than three).