Standardizing Scoring Conventions for Crohn's Disease Endoscopy: An International RAND/UCLA Appropriateness Study.

BACKGROUND AND AIMS: Endoscopic assessment of disease activity is integral for evaluating treatment response in patients with Crohn's disease (CD). We aimed to define appropriate items for evaluating endoscopic activity and conventions for consistent endoscopic scoring rules in CD. METHODS: A 2-round modified RAND/University of California at Los Angeles Appropriateness Method study was conducted. A panel of 15 gastroenterologists used a 9-point Likert scale to rate the appropriateness of statements pertaining to the Simple Endoscopic Score for CD, Crohn's Disease Endoscopic Index of Severity, and additional items relevant to endoscopy scoring in CD. Each statement was voted as appropriate, uncertain, or inappropriate based on the median panel rating and presence of disagreement. RESULTS: Panelists voted that it is appropriate for all ulcers to contribute to endoscopic scoring in CD, including aphthous ulcers, ulcerations at a surgical anastomosis, and anal canal ulcers (scored in the rectum). Endoscopic healing should reflect an absence of ulcers. Narrowing should be defined as a clear decrease in luminal diameter; stenosis should be defined by an impassable narrowing, and if occurring at the junction of 2 segments, scored in the distal segment. Scarring and inflammatory polyps were considered inappropriate for including in the affected area score. The optimal method for defining ulcer depth remains uncertain. CONCLUSIONS: We outlined scoring conventions for the Simple Endoscopic Score for CD and Crohn's Disease Endoscopic Index of Severity, noting that both scores have limitations. Therefore, we identified priorities for future research and steps for developing and validating a more representative endoscopic index in CD.

Existing Bowel Preparation Quality Scales Are Reliable in the Setting of Centralized Endoscopy Reading.

BACKGROUND: Development of bowel preparation products has been based upon colon cleansing rating by a local endoscopist. It is unclear how bowel preparation scales perform when centrally evaluated. AIMS: To evaluate the reliability of bowel preparation quality scales when assessed by central readers. METHODS: Four central readers evaluated 52 videos in triplicate, 2 weeks apart, during the entire endoscopic procedure (insertion/withdrawal of the colonoscope) and exclusively on colonoscope withdrawal using the Boston Bowel Preparation Scale (BBPS), Chicago Bowel Preparation scale, Harefield Cleansing Scale, Ottawa Bowel Preparation Quality Scale (OBPQS), Aronchick score, a visual analogue scale, and additional items proposed in a modified Research and Development/University of California Los Angeles appropriateness process. Reliability was assessed with intraclass correlation coefficients. RESULTS: Intraclass correlation coefficients (95% confidence interval) for inter-rater reliability of the quality scales ranged from 0.51 to 0.65 (consistent with moderate to substantial inter-rater reliability) during the entire procedure. Corresponding intraclass correlation coefficients for intra-rater reliability ranged from 0.69 to 0.77 (consistent with substantial intra-rater reliability). Reliability was highest in the right colon and lowest in the left colon. No differences were observed in reliability when assessed for the procedure overall (insertion/withdrawal) relative to assessment on withdrawal alone. CONCLUSION: All five bowel preparation quality scales had moderate to substantial inter-rater reliability. Panelists considered the Aronchick score too simplistic for clinical trials and recognized that assessment of residual fluid in the Ottawa Bowel Preparation Quality Scale was not amenable to central assessment.

Responsiveness of Endoscopic Indices of Disease Activity for Crohn's Disease.

OBJECTIVES: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however neither instrument is fully validated. We evaluated the responsiveness to change of the SES-CD and CDEIS using data from a trial of adalimumab, a drug therapy of known efficacy. METHODS: Paired video recordings (N=112) of colonoscopies (baseline and week 8-12) obtained from patients with CD who participated in a trial of adalimumab therapy were reviewed in random order, in duplicate, by four central readers (56 pairs of videos by 2 groups of readers). Responsiveness of the SES-CD and the CDEIS was evaluated by comparing correlations between the observed and pre-specified predictions of change scores for these endoscopic indices with a global endoscopic evaluation of severity (GELS), a patient reported outcome (PRO2), and the Crohn's disease activity index (CDAI), and by calculation of the standardized effect size, and Guyatt's Responsiveness statistic (GRS) using 2 definitions of change; (1) treatment assignment and (2) an absolute change in total PRO2 of 50. The potential application of effect size estimates was demonstrated by calculating hypothetical sample sizes for comparing two independent groups. The impact of removing stenosis as an index item and adjusting for the number of segments observed was also assessed. RESULTS: Changes in both endoscopic instruments and the GELS were highly correlated. The SES-CD displayed numerically higher effect sizes for both definitions of change. The standardized effect size and GRS estimates (95% confidence interval) for the SES-CD based on treatment assignment were 0.84 (0.53, 1.15) and 0.79 (0.48, 1.09). Corresponding values for the CDEIS were 0.72 (0.42, 1.02) and 0.75 (0.45, 1.06). The standardized effect size and GRS estimates for the SES-CD based on an absolute change in total PRO2 of 50 points or greater were 0.76 (0.49, 1.02) and 0.93 (0.64, 1.21). Corresponding values for CDEIS were 0.70 (0.44, 0.97), 0.83 (0.55, 1.10). Removal of stenosis as an index item and adjusting for observed segments did not improve responsiveness estimates. CONCLUSIONS: Although both the SES-CD and CDEIS are valid measures of endoscopic disease activity that are moderately responsive to changes in endoscopic disease activity, the SES-CD displayed numerically greater responsiveness in this data set.

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.

BACKGROUND: Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial. OBJECTIVES: To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis. SEARCH METHODS: The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included. SELECTION CRITERIA: Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes. MAIN RESULTS: Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported. AUTHORS' CONCLUSIONS: Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (September 2012).

Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease.

BACKGROUND & AIMS: Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone. METHODS: In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50. RESULTS: Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated. CONCLUSIONS: The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.

The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis.

BACKGROUND & AIMS: Interobserver differences in endoscopic assessments contribute to variations in rates of response to placebo in ulcerative colitis (UC) trials. We investigated whether centralized review of images could reduce these variations. METHODS: We performed a 10-week, randomized, double-blind, placebo-controlled study of 281 patients with mildly to moderately active UC, defined by an Ulcerative Colitis Disease Activity Index (UCDAI) sigmoidoscopy score ≥2, that evaluated the efficacy of delayed-release mesalamine (Asacol 800-mg tablet) 4.8 g/day. Endoscopic images were reviewed by a single expert central reader. The primary outcome was clinical remission (UCDAI, stool frequency and bleeding scores of 0, and no fecal urgency) at week 6. RESULTS: The primary outcome was achieved by 30.0% of patients treated with mesalamine and 20.6% of those given placebo, a difference of 9.4% (95% confidence interval [CI], -0.7% to 19.4%; P = .069). Significant differences in results from secondary analyses indicated the efficacy of mesalamine. Thirty-one percent of participants, all of whom had a UCDAI sigmoidoscopy score ≥2 as read by the site investigator, were considered ineligible by the central reader. After exclusion of these patients, the remission rates were 29.0% and 13.8% in the mesalamine and placebo groups, respectively (difference of 15%; 95% CI, 3.5%-26.0%; P = .011). CONCLUSIONS: Although mesalamine 4.8 g/day was not statistically different from placebo for induction of remission in patients with mildly to moderately active UC, based on an intent-to-treat analysis, the totality of the data supports a benefit of treatment. Central review of endoscopic images is critical to the conduct of induction studies in UC; ClinicalTrials.gov Number, NCT01059344.

Co-grafting of neural stem cells with olfactory en sheathing cells promotes neuronal restoration in traumatic brain injury with an anti-inflammatory mechanism.

BACKGROUND: We sought to investigate the effects of co-grafting neural stem cells (NSCs) with olfactory ensheathing cells (OECs) on neurological behavior in rats subjected to traumatic brain injury (TBI) and explore underlying molecular mechanisms. METHODS: TBI was established by percussion device made through a weight drop (50 g) from a 30 cm height. Cultured NSCs and OECs isolated from rats were labeled by Hoechst 33342 (blue) and chloromethyl-benzamidodialkyl carbocyanine (CM-Dil) (red), respectively. Then, NSCs and/or OECs, separately or combined, were transplanted into the area surrounding the injury site. Fourteen days after transplantation, neurological severity score (NSS) were recorded. The brain tissue was harvested and processed for immunocytochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Significant neurological function improvement was observed in the three transplant groups, compared to the TBI group, and co-transplantation gave rise to the best improvement. Morphological evaluation showed that the number of neurons in cortex from combination implantation was more than for other groups (P <0.05); conversely, the number of apoptotic cells showed a significant decrease by TUNEL staining. Transplanted NSCs and OECs could survive and migrate in the brain, and the number of neurons differentiating from NSCs in the co-transplantation group was significantly greater than in the NSCs group. At the molecular level, the expressions of IL-6 and BAD in the co-graft group were found to be down regulated significantly, when compared to either the NSC or OEC alone groups. CONCLUSION: The present study demonstrates for the first time the optimal effects of co-grafting NSCs and OECs as a new strategy for the treatment of TBI via an anti-inflammation mechanism.

Role of neuregulin-1/ErbB signaling in stem cell therapy for spinal cord injury-induced chronic neuropathic pain.

Chronic neuropathic pain is a common and debilitating consequence of spinal cord injury (SCI). In a rat contusion injury model, we observed that chronic neuropathic pain is present on day 7 after SCI and persists for the entire 56-day observation period. However, currently available pain therapies are inadequate for SCI-induced neuropathic pain. In this study, we show that spinal transplantation of mouse embryonic stem cell-derived oligodendrocyte progenitor cells (OPCs) enhances remyelination in the injured spinal cord and reduces SCI-induced chronic neuropathic pain. Moreover, we found that SCI reduces the protein level of neuregulin-1 and ErbB4 in the injured spinal cord and that OPC transplantation enhances the spinal expression of both proteins after SCI. Finally, intrathecal injection of neuregulin-1 small interfering RNA, but not the control nontarget RNA, diminishes OPC transplantation-produced remyelination and reverses the antinociceptive effect of OPC transplantation. Our findings suggest that the transplantation of embryonic stem cell-derived OPCs is an appropriate therapeutic intervention for treatment of SCI-induced chronic neuropathic pain, and that neuregulin-1/ErbB signaling plays an important role in central remyelination under pathological conditions and contributes to the alleviation of such pain.

Methotrexate for induction of remission in ulcerative colitis.

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.

Methotrexate for maintenance of remission in Crohn's disease.

BACKGROUND: Safe and effective long-term treatments that reduce the need for corticosteroids are needed for Crohn's disease. Although purine antimetabolites are moderately effective for maintenance of remission patients often relapse despite treatment with these agents. Methotrexate may provide a safe and effective alternative to more expensive maintenance treatment with TNF-α antagonists. This review is an update of a previously published Cochrane review. OBJECTIVES: To conduct a systematic review of randomized trials examining the efficacy and safety of methotrexate for maintenance of remission in Crohn's disease. SEARCH METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED, EMBASE, and the Cochrane IBD/FBD Group Specialized Trials Register were searched from inception to June 9, 2014. Study references and review papers were also searched for additional trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared methotrexate to placebo or any other active intervention for maintenance of remission in Crohn's disease were eligible 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 maintaining clinical remission as defined by the studies and expressed as a percentage of the total number of patients randomized (intention-to-treat analysis). We calculated the pooled 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: Five studies (n = 333 patients) were included in the review. Three studies were judged to be at low risk of bias. Two studies were judged to be at high risk of bias due to blinding. Intramuscular methotrexate was superior to placebo for maintenance of remission at 40 weeks follow-up. Sixty-five per cent of patients in the intramuscular methotrexate group maintained remission compared to 39% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 76 patients).The number needed to treat to prevent one relapse was four. A GRADE analysis indicated that the overall quality of evidence supporting this outcome was moderate due to sparse data (40 events). There was no statistically significant difference in maintenance of remission at 36 weeks follow-up between oral methotrexate (12.5 mg/week) and placebo. Ninety per cent of patients in the oral methotrexate group maintained remission compared to 67% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 22 patients). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to very sparse data (17 events). A pooled analysis of two small studies (n = 50) showed no statistically significant difference in continued remission between oral methotrexate (12.5 mg to 15 mg/week) and 6-mercaptopurine (1 mg/kg/day) for maintenance of remission. Seventy-seven per cent of methotrexate patients maintained remission compared to 57% of 6-mercaptopurine patients (RR 1.36, 95% CI 0.92 to 2.00). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was very low due to high risk of bias in one study (no blinding) and very sparse data (33 events). One small (13 patients) poor quality study found no difference in continued remission between methotrexate and 5-aminosalicylic acid (RR 2.62, 95% CI 0.23 to 29.79). A pooled analysis of two studies (n = 145) including one high quality trial (n = 126) found no statistically significant difference in maintenance of remission at 36 to 48 weeks between combination therapy (methotrexate and infliximab) and infliximab monotherapy. Fifty-four percent of patients in the combination therapy group maintained remission compared to 53% of monotherapy patients (RR 1.02, 95% CI 0.76 to 1.38, P = 0.95). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to high risk of bias in one study (no blinding) and sparse data (78 events). Adverse events were generally mild in nature and resolved upon discontinuation or with folic acid supplementation. Common adverse events included nausea and vomiting, symptoms of a cold, abdominal pain, headache, joint pain or arthralgia, and fatigue. AUTHORS' CONCLUSIONS: Moderate quality evidence indicates that intramuscular methotrexate at a dose of 15 mg/week is superior to placebo for maintenance of remission in Crohn's disease. Intramuscular methotrexate appears to be safe. Low dose oral methotrexate (12.5 to 15 mg/week) does not appear to be effective for maintenance of remission in Crohn's disease. Combination therapy (methotrexate and infliximab) does not appear to be any more effective for maintenance of remission than infliximab monotherapy. The results for efficacy outcomes between methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Large-scale studies of methotrexate given orally at higher doses for maintenance of remission in Crohn's disease may provide stronger evidence for the use of methotrexate in this manner.

Methotrexate for induction of remission in refractory Crohn's disease.

BACKGROUND: Although corticosteroids are effective for induction of remission of Crohn's disease, many patients relapse when steroids are withdrawn or become steroid dependent. Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine or 6-mercaptopurine therapy. This systematic review is an update of previously published Cochrane reviews. OBJECTIVES: The primary objective was to assess the efficacy and safety of methotrexate for induction of remission in patients with active Crohn's disease in the presence or absence of concomitant steroid therapy. SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized register from inception to June 9, 2014 for relevant studies. Conference proceedings and reference lists were also searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials of methotrexate compared to placebo or an active comparator for treatment of active refractory Crohn's disease in adult patients (> 17 years) were considered for inclusion. DATA COLLECTION AND ANALYSIS: The primary outcome was failure to enter remission and withdraw from steroids. Secondary outcomes included adverse events, withdrawal due to adverse events, serious adverse events and quality of life. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis. The Cochrane risk of bias tool was used to assess the methodological quality of included studies. The GRADE approach was used to assess the overall quality of evidence supporting the primary outcome. MAIN RESULTS: Seven studies (495 patients) were included. Four studies were rated as low risk of bias. Three studies were rated as high risk of bias due to open label or single-blind designs. The seven studies differed with respect to participants, intervention, and outcomes to the extent that meta-analysis was considered to be inappropriate. GRADE analyses indicated that the quality of evidence was very low to low for most outcomes due to sparse data and inadequate blinding. Three small studies which employed low dose oral methotrexate showed no statistically significant difference in failure to induce remission between methotrexate and placebo or between methotrexate and 6-mercaptopurine. For the study using 15 mg/week of oral methotrexate 33% (5/15) of methotrexate patients failed to enter remission compared to 11% (2/18) of placebo patients (RR 3.00, 95% CI 0.68 to 13.31). For the study using 12.5 mg/week of oral methotrexate 81% (21/26) of methotrexate patients failed to enter remission compared to 77% (20/26) of placebo patients (RR 1.05, 95% CI 0.79 to 1.39). This study also had an active comparator arm, 81% (21/26) of methotrexate patients failed to enter remission compared to 59% (19/32) of 6-mercaptopurine patients (RR 1.36, 95% CI 0.97 to 1.92). For the active comparator study using 15 mg/week oral methotrexate, 20% (3/15) of methotrexate patients failed to enter remission compared to 6% of 6-mercaptopurine patients (RR 3.20, 95% CI 0.37 to 27.49). This study also had a 5-ASA arm and found that methotrexate patients were significantly more likely to enter remission than 5-ASA patients. Twenty per cent (3/15) of methotrexate patients failed to enter remission compared to 86% (6/7) of 5-ASA patients (RR 0.23, 95% CI 0.08 to 0.67). One small study which used a higher dose of intravenous or oral methotrexate (25 mg/week) showed no statistically significant difference between methotrexate and azathioprine. Forty-four per cent (12/27) of methotrexate patients failed to enter remission compared to 37% of azathioprine patients (RR 1.20, 95% CI 0.63 to 2.29). Two studies found no statistically significant difference in failure to enter remission between the combination of infliximab and methotrexate and infliximab monotherapy. One small study utilized intravenous methotrexate (20 mg/week) for 5 weeks and then switched to oral (20 mg/week). Forty-five per cent (5/11) of patients in the combination group failed to enter remission compared to 62% of infliximab patients (RR 0.73, 95% CI 0.31 to 1.69). The other study assessing combination therapy utilized subcutaneous methotrexate (maximum dose 25 mg/week). Twenty-four per cent (15/63) of patients in the combination group failed to enter remission compared to 22% (14/63) of infliximab patients (RR 1.07, 95% CI 0.57 to 2.03). A large placebo-controlled study which employed a high dose of methotrexate intramuscularly showed a statistically significant benefit relative to placebo. Sixty-one per cent of methotrexate patients failed to enter remission compared to 81% of placebo patients (RR 0.75, 95% CI 0.61 to 0.93; number needed to treat, NNT=5). Withdrawals due to adverse events were significantly more common in methotrexate patients than placebo in this study. Seventeen per cent of methotrexate patients withdrew due to adverse events compared to 2% of placebo patients (RR 8.00, 95% CI 1.09 to 58.51). The incidence of adverse events was significantly more common in methotrexate patients (63%, 17/27) than azathioprine patients (26%, 7/27) in one small study (RR 2.42, 95% CI 1.21 to 4.89). No other statistically significant differences in adverse events, withdrawals due to adverse events or serious adverse events were reported in any of the other placebo-controlled or active comparator studies. Common adverse events included nausea and vomiting, abdominal pain, diarrhea, skin rash and headache. AUTHORS' CONCLUSIONS: There is evidence from a single large randomized trial which suggests that intramuscular methotrexate (25 mg/week) provides a benefit for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Lower dose oral methotrexate does not appear to provide any significant benefit relative to placebo or active comparator. However, these trials were small and further studies of oral methotrexate may be justified. Comparative studies of methotrexate to drugs such as azathioprine or 6-mercaptopurine would require the randomization of large numbers of patients. The addition of methotrexate to infliximab therapy does not appear to provide any additional benefit over infliximab monotherapy. However these studies were relatively small and further research is needed to determine the role of methotrexate when used in conjunction with infliximab or other biological therapies.

Bone mass in individuals with chronic spinal cord injury: associations with activity-based therapy, neurologic and functional status, a retrospective study.

OBJECTIVE: To describe the prevalence of osteoporosis and its association with functional electrical stimulation (FES) use in individuals with spinal cord injury (SCI)-related paralysis. DESIGN: Retrospective cross-sectional evaluation. SETTING: Clinic. PARTICIPANTS: Consecutive persons with SCI (N=364; 115 women, 249 men) aged between 18 and 80 years who underwent dual-energy x-ray absorptiometry (DXA) examinations. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Prevalence of osteoporosis defined as DXA T score ≤-2.5. RESULTS: The prevalence of osteoporosis was 34.9% (n=127). Use of FES was associated with 31.2% prevalence of osteoporosis compared with 39.5% among persons not using FES. In multivariate adjusted logistic regression analysis, FES use was associated with 42% decreased odds of osteoporosis after adjusting for sex, age, body mass index, type and duration of injury, Lower Extremity Motor Scores, ambulation, previous bone fractures, and use of calcium, vitamin D, and anticonvulsant; (adjusted odds ratio [OR]=.58; 95% confidence interval [CI], .35-.99; P=.039). Duration of injury >1 year was associated with a 3-fold increase in odds of osteoporosis compared with individuals with injury <1 year; (adjusted OR=3.02; 95% CI, 1.60-5.68; P=.001). CONCLUSIONS: FES cycling ergometry may be associated with a decreased loss of bone mass after paralysis. Further prospective examination of the role of FES in preserving bone mass will improve our understanding of this association.

Reliability and Responsiveness of Clinical and Endoscopic Outcome Measures in Crohn's Disease.

BACKGROUND: Regulatory guidance for Crohn's disease trials recommends coprimary efficacy end points that evaluate both symptoms and mucosal inflammation. We aimed to characterize the operating properties of commonly used disease activity assessments alone and in combination. METHODS: Endoscopic and clinical data were available for 129 participants from the Study of Biologic and Immunomodulator Naïve Patients in Crohn's Disease trial. Readers scored the Simple Endoscopic Score for Crohn's Disease and the Crohn's Disease Endoscopic Index of Severity using standardized conventions. Index reliability was determined using intraclass correlation coefficients. Index responsiveness was assessed using standardized effect sizes based upon treatment assignment. Outcomes were evaluated for optimal sensitivity to treatment effect. RESULTS: Substantial inter-rater reliability was observed when the Simple Endoscopic Score for Crohn's Disease and Crohn's Disease Endoscopic Index of Severity were used as continuous measures (intraclass correlation coefficient, 0.64; 95% confidence interval [CI], 0.50-0.73; and 0.62 95% CI, 0.36-0.77) compared with moderate reliability when dichotomized (0.46; 95% CI, 0.26-0.65; and 0.51; 95% CI, 0.00-0.78). The Simple Endoscopic Score for Crohn's Disease, Crohn's Disease Endoscopic Index of Severity, patient-reported outcome-2, and Crohn's Disease Activity Index were similarly responsive (standardized effect size, 0.43, 95% CI, 0.05-0.81; 0.38, 95% CI, 0.0-0.76; 0.53, 95% CI, 0.15-0.91). A composite outcome of Crohn's Disease Activity Index score <150 and Crohn's Disease Endoscopic Index of Severity score <6 was most sensitive to treatment effect (28.9%; 95% CI, 11.0%-46.8%; P = .003). CONCLUSION: Endoscopic indices were more reliable as continuous measures. Composite outcomes including endoscopy improved sensitivity to treatment effect.

This study largely supports current regulatory guidance for Crohn's disease trials recommending coprimary efficacy end points evaluating both symptoms and mucosal inflammation. Continuous endoscopic measures are most reliable and improve sensitivity to treatment effect when employed in composite outcomes.

Potential role of stem cells for neuropathic pain disorders.

Chronic neuropathic pain is a debilitating disease process associated with several medical disorders. Different from pain caused by inflammation, neuropathic pain is a diffuse pain disorder often found to be recalcitrant to the limited medical treatments available. Intractable nerve pain may benefit from other therapies capable of longer-lasting pain coverage or greater efficacy. A growing number of reports have emerged suggesting a role for stem cells as a cellular delivery source with neuroprotective agents opposing the effects of nerve damage. Here, the authors review the current experimental therapies examining the use of stem cells for the treatment of neuropathic pain disorders.

Lower extremity functional electrical stimulation cycling promotes physical and functional recovery in chronic spinal cord injury.

OBJECTIVE: To examine the effect of long-term lower extremity functional electrical stimulation (FES) cycling on the physical integrity and functional recovery in people with chronic spinal cord injury (SCI). DESIGN: Retrospective cohort, mean follow-up 29.1 months, and cross-sectional evaluation. SETTING: Washington University Spinal Cord Injury Neurorehabilitation Center, referral center. PARTICIPANTS: Twenty-five people with chronic SCI who received FES during cycling were matched by age, gender, injury level, and severity, and duration of injury to 20 people with SCI who received range of motion and stretching. INTERVENTION: Lower extremity FES during cycling as part of an activity-based restorative treatment regimen. MAIN OUTCOME MEASURE: Change in neurological function: motor, sensory, and combined motor-sensory scores (CMSS) assessed by the American Spinal Injury Association Impairment scale. Response was defined as ≥ 1 point improvement. RESULTS: FES was associated with an 80% CMSS responder rate compared to 40% in controls. An average 9.6 CMSS point loss among controls was offset by an average 20-point gain among FES subjects. Quadriceps muscle mass was on average 36% higher and intra/inter-muscular fat 44% lower, in the FES group. Hamstring and quadriceps muscle strength was 30 and 35% greater, respectively, in the FES group. Quality of life and daily function measures were significantly higher in FES group. CONCLUSION: FES during cycling in chronic SCI may provide substantial physical integrity benefits, including enhanced neurological and functional performance, increased muscle size and force-generation potential, reduced spasticity, and improved quality of life.

Electrical stimulation promotes the survival of oligodendrocytes in mixed cortical cultures.

Oligodendrocyte (OLG) death plays a major role in white matter dysfunction and demyelination following injury to the CNS. Axonal contact, communication, and neuronal activity appear to promote OLG survival and function in cell culture and during development. The application of electrical stimulation to mixed neural cultures has been shown to promote OLG differentiation and the formation of myelin in vitro. Here we show that OLG viability can be significantly enhanced in mixed cortical cultures by applying biphasic pulses of electrical stimulation (ESTIM). Enhanced survival via ESTIM requires the presence of neurons and is suppressed by inhibition of voltage-gated sodium channels. Additionally, contact between the axon and OLG is necessary for ESTIM to promote OLG survival. This report suggests that patterned neuronal activity could repress delayed progression of white matter injury and promote CNS repair in neurological conditions that involve white matter damage.

Methotrexate for induction of remission in refractory Crohn's disease.

BACKGROUND: Although corticosteroids are effective for induction of remission of Crohn's disease, many patients relapse when steroids are withdrawn or become steroid dependent. Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine or 6-mercaptopurine therapy. This systematic review is an update of a previously published Cochrane review. OBJECTIVES: The primary objective was to assess the efficacy and safety of methotrexate for induction of remission in patients with active Crohn's disease in the presence or absence of concomitant steroid therapy. SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized register from inception to June 27, 2012 for relevant studies. Conference proceedings and reference lists were also searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials of methotrexate compared to placebo or an active comparator for treatment of active refractory Crohn's disease in adult patients (> 17 years) were considered for inclusion. DATA COLLECTION AND ANALYSIS: The primary outcome was failure to failure to enter remission and withdrawal from steroids. Secondary outcomes included adverse events, withdrawal due to adverse events, serious adverse events and quality of life. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention to treat basis. The Cochrane risk of bias tool was used to assess the methodological quality of included studies. The GRADE approach was used to assess the overall quality of evidence supporting the primary outcome. MAIN RESULTS: Seven studies (495 patients) were included. Four studies were rated as low risk of bias. Three studies were rated as high risk of bias due to open label or single-blind designs. The seven studies differed with respect to participants, intervention, and outcomes to the extent that it was considered to be inappropriate to pool the data for meta-analysis. Three small studies which employed low doses of oral methotrexate showed no statistically significant difference in failure to induce remission between methotrexate and placebo or between methotrexate and 6-mercaptopurine. For the study using 15 mg/week of oral methotrexate 33% (5/15) of methotrexate patients failed to enter remission compared to 11% (2/18) of placebo patients (RR 3.00, 95% CI 0.68 to 13.31). For the study using 12.5 mg/week of oral methotrexate 81% (21/26) of methotrexate patients failed to enter remission compared to 77% (20/26) of placebo patients (RR 1.05, 95% CI 0.79 to 1.39). This study also had an active comparator arm, 81% (21/26) of methotrexate patients failed to enter remission compared to 59% (19/32) of 6-mercaptopurine patients (RR 1.36, 95% CI 0.97 to 1.92). For the active comparator study using 15 mg/week oral methotrexate, 20% (3/15) of methotrexate patients failed to enter remission compared to 6% of 6-mercaptopurine patients (RR 3.20, 95% CI 0.37 to 27.49). This study also had a 5-ASA arm and found that methotrexate patients were significantly more likely to enter remission than 5-ASA patients. Twenty per cent (3/15) of methotrexate patients failed to enter remission compared to 86% (6/7) of 5-ASA patients (RR 0.23, 95% CI 0.08 to 0.67). One small study which used a higher dose of intravenous or oral methotrexate (25 mg/week) showed no statistically significant difference between methotrexate and azathioprine. Forty-four per cent (12/27) of methotrexate patients failed to enter remission compared to 37% of azathioprine patients (RR 1.20, 95% CI 0.63 to 2.29). Two studies found no statistically significant difference in failure to enter remission between the combination of infliximab and methotrexate and infliximab monotherapy. One small study utilized intravenous methotrexate (20 mg/week) for 5 weeks and then switched to oral (20 mg/week). Forty-five per cent (5/11) of patients in the combination group failed to enter remission compared to 62% of infliximab patients (RR 0.73, 95% CI 0.31 to 1.69) The other study assessing combination therapy utilized subcutaneous methotrexate (maximum dose 25 mg/week). Twenty-four per cent (15/63) of patients in the combination group failed to enter remission compared to 22% (14/63) of infliximab patients (RR 1.07, 95% CI 0.57 to 2.03). A large placebo-controlled study which employed a high dose of methotrexate intramuscularly showed a statistically significant benefit relative to placebo. Sixty-one per cent of methotrexate patients failed to enter remission compared to 81% of placebo patients (RR 0.75, 95% CI 0.61 to 0.93; number needed to treat, NNT=5). Withdrawals due to adverse events were significantly more common in methotrexate patients than placebo in this study. Seventeen per cent of methotrexate patients withdrew due to adverse events compared to 2% of placebo patients (RR 8.00, 95% CI 1.09 to 58.51). The incidence of adverse events was significantly more common in methotrexate patients (63%, 17/27) than azathioprine patients (26%, 7/27) in one small study (RR 2.42, 95% CI 1.21 to 4.89). No other statistically significant differences in adverse events, withdrawals due to adverse events or serious adverse events were reported in any of the other placebo-controlled or active comparator studies. Common adverse events included nausea and vomiting, abdominal pain, diarrhea, skin rash and headache. AUTHORS' CONCLUSIONS: There is evidence from a single large randomized trial which suggests that intramuscular methotrexate (25 mg/week) provides a benefit for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Lower dose oral methotrexate does not appear to provide any significant benefit relative to placebo or active comparator. However, these trials were small and further studies of oral methotrexate may be justified. Comparative studies of methotrexate to drugs such as azathioprine or 6-mercaptopurine would require the randomization of large numbers of patients. The addition of methotrexate to infliximab therapy does not appear to provide any additional benefit over infiximab monotherapy. However these studies were relatively small and further research is needed to determine the role of methotrexate when used in conjunction with infliximab or other biological therapies.

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.

BACKGROUND: Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial. OBJECTIVES: To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis. SEARCH METHODS: The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to June 2012. A manual search was also performed using references from these articles as well as review articles, and proceedings from major gastrointestinal meetings. Authors of maintenance trials were asked about unpublished studies. SELECTION CRITERIA: Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes. MAIN RESULTS: Six studies including 286 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalamine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). All of the studies which used active comparators were open label. When placebo and active comparator studies were pooled to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported. AUTHORS' CONCLUSIONS: Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (Issue 1, 2007).

High-voltage electrical stimulation for the management of stage III and IV pressure ulcers among adults with spinal cord injury: demonstration of its utility for recalcitrant wounds below the level of injury.

CONTEXT: patients with spinal cord injury (SCI) have many factors that are associated with pressure ulcer formation, including paralysis, loss of sensation, poor nutrition, anemia, and skin maceration related to incontinence. Treatment of these ulcers involves relieving pressure, improving nutrition and skin hygiene, treating infections, removing necrotic tissues, and applying the appropriate dressings. However, some cases are not responsive to the above treatment. Electrical stimulation (ES) is thought to enhance soft tissue healing through promotion of protein synthesis, inhibition of bacterial growth, facilitation of epithelial tissue migration, improvement of blood flow, and tensile strength. This data is mainly based on evidence from animal studies and very few rigorously controlled studies conducted in humans. OBJECTIVE: To demonstrate the effectiveness of ES in the treatment of recalcitrant pressure ulcers. METHODS: Retrospective case series describing the care of adults with SCI and recalcitrant pressure ulcers. ES was applied directly into the wound bed: 60 minutes per session, 3-5 times per week; with an intensity of 100 milliamperes and a frequency of 100 pulses per second. Polarity was negative initially and was switched weekly. The amplitude and wave form were maintained throughout. RESULTS: The long-standing (11-14 months) pressure ulcers were completely healed after 7 to 22 weeks of treatment with high-voltage ES. CONCLUSION/CLINICAL RELEVANCE: This case series demonstrates the effectiveness of ES for enhanced healing of Stage III-IV ulcers otherwise unresponsive to standard wound care. Further study is needed to identify the most effective protocol for ES therapy in the treatment of recalcitrant pressure ulcers.