Crohn Disease: Zachos M

Panaccione R, Fedorak RN, Aumais G, Bernstein CN, Bitton A, Croitoru K, Enns R, Feagan B, Fishman M, Greenberg G, Griffiths A, Marshall JK, Rasul I, Sadowski D, Seidman E, Steinhart H, Sutherland L, Walli E, Wild G, Williams CN, Zachos M, Anonymous00234. · University of Calgary, Calgary, Canada. · Can J Gastroenterol. · Pubmed #15372114 links to  free full text

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Zachos M, Tondeur M, Griffiths AM. · Hospital for Sick Children, Division of Gastroenterology, Hepatology and Nutrition, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8. · Cochrane Database Syst Rev. · Pubmed #17253452 No free full text.

Abstract: BACKGROUND: The role of enteral nutrition in Crohn's disease is controversial. Increasing research on the mechanisms by which nutritional therapy improves the clinical well being of patients with Crohn's disease has led to novel formula design and trials comparing two different forms of enteral nutrition. This meta-analysis aims to provide an update on the existing effectiveness data for both corticosteroids versus enteral nutrition and for one form of enteral nutrition versus another for inducing remission of active Crohn's disease. OBJECTIVES: To evaluate the effectiveness of exclusive enteral nutrition (EN) as primary therapy to induce remission in Crohn's disease and to examine the importance of formula composition on effectiveness. SEARCH STRATEGY: Studies were selected using a computer-assisted search of the on-line bibliographic databases MEDLINE (1966-2006) and EMBASE (1984-2006), as well as the Science Citation Index on Web of Science. Additional citations were sought by manual search of references of articles retrieved from the computerized search, abstracts submitted to major gastroenterologic meetings and published in the journals: American Journal of Gastroenterology, Gut, Gastroenterology, Journal of Pediatric Gastroenterology and Nutrition, and Journal of Parenteral and Enteral Nutrition, and from the reviewers' personal files or contact with leaders in the field. SELECTION CRITERIA: All randomized and quasi-randomized controlled trials involving patients with active Crohn's disease defined by a clinical disease activity index were considered for review. Studies evaluating the administration of one type of enteral nutrition to one group of patients and another type of enteral nutrition or conventional corticosteroids to the other group were selected for review. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two authors and any discrepancies were resolved by rereading and discussion. For the dichotomous variable, achievement of remission, individual and pooled trial statistics were calculated as odds ratios (OR) with 95% confidence intervals (CI); both fixed and random effect models were used. The results for each analysis were tested for heterogeneity using the chi square statistic. The studies were separated into two groups: A. one form of enteral nutrition compared with another form of enteral nutrition and B. one form of enteral nutrition compared with corticosteroids. Subgroup analyses were conducted on the basis of clinical or disease criteria and formula composition. Sensitivity analyses were conducted on the basis of the inclusion of abstract publications, methodologic quality and by random or fixed effects models. MAIN RESULTS: In part A, of the 15 included eligible trials (one abstract) comparing different formulations of EN for the treatment of active CD, 11 compared one (or more) elemental formula to a non-elemental one, three compared enteral diets of similar protein composition but different fat composition, and one compared non-elemental diets differing only in glutamine enrichment. Meta-analysis of ten trials comprising 334 patients demonstrated no difference in the efficacy of elemental versus non-elemental formulas (OR 1.10; 95% CI 0.69 to 1.75). Subgroup analyses performed to evaluate the different types of elemental and non-elemental diets (elemental, semi-elemental and polymeric) showed no statistically significant differences. Further analysis of seven trials including 209 patients treated with EN formulas of differing fat content (low fat: < 20 g/1000 kCal versus high fat: > 20 g/1000 kCal) demonstrated no statistically significant difference in efficacy (OR 1.13; 95% CI 0.63 to 2.01). Similarly, the effect of very low fat content (< 3 g/1000 kCal) or type of fat (long chain triglycerides) were investigated, but did not demonstrate a difference in efficacy in the treatment of active CD, although a non significant trend was demonstrated favoring very low fat and very low long chain triglyceride content. This result should be interpreted with caution due to statistically significant heterogeneity and small sample size. Sensitivity analyses had no significant effects on the results. The role of specific fatty acids or disease characteristics on response to therapy could not be evaluated. In part B, eight trials (including two abstracts) comparing enteral nutrition to steroid therapy met the inclusion criteria for review. Meta-analysis of six trials that included 192 patients treated with enteral nutrition and 160 treated with steroids yielded a pooled OR of 0.33 favouring steroid therapy (95% CI 0.21 to 0.53). A sensitivity analysis including the abstracts resulted in an increase in the number of participants to 212 in the enteral nutrition group and 179 in the steroid group but the meta-analysis yielded a similar result (OR 0.36; 95% CI 0.23 to 0.56). There were inadequate data from full publications to perform further subgroup analyses by age, disease duration and disease location. AUTHORS' CONCLUSIONS: Corticosteroid therapy is more effective than enteral nutrition for inducing remission of active Crohn's disease as was found in previous systematic reviews. Protein composition does not influence the effectiveness of EN in the treatment of active CD. A non significant trend favouring very low fat and/or very low long chain triglyceride content exists but larger trials are required to explore the significance of this finding.

Akobeng AK, Zachos M. · Department of Paediatric Gastroenterology, Central Manchester and Manchester Children's University Hospitals, Booth Hall Children's Hospital, Charlestown Road, Blackley, Manchester, UK, M9 7AA. · Cochrane Database Syst Rev. · Pubmed #14974022 No free full text.

Abstract: BACKGROUND: Crohn's disease may be refractory to conventional treatments such as corticosteroids, enteral nutrition and immuno-suppressive agents. A number of patients with the disease may also become steroid-dependent leading to increased risk of developing steroid-related adverse effects. Recent studies suggest that TNF-a blocking agents may be effective in inducing remission in Crohn's disease. OBJECTIVES: To conduct a systematic review to evaluate the effectiveness of TNF-a blocking agents in inducing remission in patients with active Crohn's disease. SEARCH STRATEGY: We searched MEDLINE (1966-June 2003), EMBASE (1984-June 2003), the Cochrane Central Register of Controlled Trials from the Cochrane Library (Issue 2, 2003) and the IBD Review Group Specialized Trials Register. We hand-searched the articles cited in each publication obtained. SELECTION CRITERIA: We included only randomised controlled trials in which patients with active Crohn's disease (defined by a validated Crohn's disease activity index) were randomly allocated to receive a TNF-a blocking agent in the treatment arm, or to receive placebo or another treatment in the comparison arm. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of the methodological quality of each trial were independently performed by two reviewers. Any disagreement among reviewers was resolved by consensus. Outcome measures reported in the primary studies included clinical remission, clinical response and changes in disease activity index. MAIN RESULTS: Ten studies were identified of which 4 met the inclusion criteria. The included studies either differed in the type of TNF-a blocking agent used or in the way outcomes were assessed to such an extent that we considered it inappropriate to combine the data statistically. There is evidence from one randomised controlled trial that suggests that a single intravenous infusion of the monoclonal antibody cA2, infliximab, may be effective for induction of remission in Crohn's disease. There was no difference in response rates among infliximab doses of 5, 10 or 20 mg/kg. The results of two other trials suggested that CDP571, the genetically engineered human TNF monoclonal antibody, may also be effective in reducing disease activity index at 2 weeks after an infusion. We did not find any evidence to support the use of etanercept in Crohn's disease. REVIEWER'S CONCLUSIONS: Evidence from one randomized controlled trial suggests that a single infusion of infliximab may be effective for induction of remission in Crohn's disease. Based on this study, we can recommend a dose of 5 mg/kg. There is also some evidence that CDP571 may be effective in inducing remission in Crohn's disease. We did not find any evidence that supports the use of etanercept in Crohn's disease. The period of follow up for the patients in these studies was probably too short to allow adequate assessment of recently reported serious adverse effects such as tuberculosis and lymphoma.

Zachos M, Tondeur M, Griffiths AM. · GI/Nutrition, Clinical Epidemiology, Hospital for Sick Children, University of Toronto, 555 Universtiy Ave., Toronto, Ontario, Canada, M5G 1X8. · Cochrane Database Syst Rev. · Pubmed #11686966 No free full text.

Abstract: BACKGROUND: The role of enteral nutrition in Crohn's disease is controversial. Increasing research on the mechanisms by which nutritional therapy improves the clinical well being of patients with Crohn's disease has led to novel formula design and trials comparing two different forms of enteral nutrition. This systematic review aims to provide an update on the existing efficacy data for both corticosteroids versus enteral nutrition and for one form of enteral nutrition versus another for inducing remission of active Crohn's disease. OBJECTIVES: To evaluate the efficacy of exclusive enteral nutrition as primary therapy to induce remission in Crohn's disease and to examine the importance of formula composition on efficacy. SEARCH STRATEGY: Studies were selected using a computer-assisted search of the on-line bibliographic databases MEDLINE (1966-2000) and EMBASE (1984-2000), as well as the Science Citation Index on Web of Science. Additional citations were sought by manual search of references of articles retrieved from the computerized search, abstracts submitted to major gastroenterologic meetings and published in the journals: Gut, Gastroenterology, Journal of Pediatric Gastroenterology and Nutrition, and Journal of Parenteral and Enteral Nutrition, and from the reviewers' personal files or contact with leaders in the field. SELECTION CRITERIA: All randomized and quasi-randomized controlled trials involving patients with active Crohn's disease defined by a clinical disease activity index were considered for review. Studies evaluating the administration of one type of enteral nutrition to one group of patients and another type of enteral nutrition or conventional corticosteroids to the other group were selected for review. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers and any discrepancies were resolved by rereading and discussion. For the dichotomous variable, achievement of remission, individual and pooled trial statistics were calculated as odds ratios (OR) with 95% confidence intervals (CI); both fixed and random effect models were used. The results for each analysis were tested for heterogeneity using the chi square statistic. The studies were separated into two groups: A. one form of enteral nutrition compared with another form of enteral nutrition and B. one form of enteral nutrition compared with corticosteroids. Subgroup analyses were conducted on the basis of clinical or disease criteria and formula composition. Sensitivity analyses were conducted on the basis of the inclusion of abstracts of studies not yet fully published, methodologic quality and by random or fixed effects models. MAIN RESULTS: In part A, of the 11 trials (one abstract) comparing different formulations of enteral nutrition ten compared one [or more (Middleton (a)1995)] elemental formulas to a non-elemental diet. The eleventh study (Akobeng 2000) compared two non-elemental diets differing only by glutamine enrichment in one group. This study was therefore not included in the primary analysis but was part of the subgroup analyses. Meta-analysis of nine studies which included 170 patients treated with an elemental diet and 128 patients treated with a non-elemental diet for active Crohn's disease demonstrated no significant difference among diet formulations [OR 1.15 (95% CI: 0.64, 2.08)]. Significant heterogeneity was not present [chi-square 9.77 (df=8)]. Subgroup and sensitivity analyses had no significant effect on the results. In part B, six trials (two abstracts) comparing enteral nutrition to steroid therapy met the inclusion criteria for review. Meta-analysis of four trials that included 130 patients treated with enteral nutrition and 123 treated with steroids yielded a pooled OR of 0.30 favouring steroid therapy (95% CI: 0.17, 0.52). Heterogeneity was not demonstrated [chi-square 0.43 (df=3)]. The risk difference calculated from this meta-analysis was 0.26, and the NNT (number of patients needed to treat with steroids rather than enteral nutrition to achieve one remission) was four. The same result was found in a sensitivity analysis that included abstracts. The inclusion of abstracts resulted in an increase in the number of participants to 150 in the enteral nutrition group and 142 in the steroid group but the meta-analysis yielded a similar result [OR 0.34 (95% CI: 0.20, 0.56)]. There were inadequate data from full publications to perform further subgroup analyses by age, disease duration and disease location. REVIEWER'S CONCLUSIONS: Corticosteroid therapy is more effective than enteral nutrition for inducing remission of active Crohn's disease as was found in past meta-analyses. There is no significant difference in the efficacy of elemental and non-elemental diets for induction of remission of Crohn's disease.

Kundhal PS, Critch JN, Zachos M, Otley AR, Stephens D, Griffiths AM. · Divisions of Gastroenterology and Nutrition, Deparment of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada. · J Pediatr Gastroenterol Nutr. · Pubmed #12500001 No free full text.

Abstract: BACKGROUND/AIMS: Despite documented feasibility, reliability, and validity, the Pediatric Crohn's Disease Activity Index (PCDAI) has yet to be demonstrated to be sensitive to change in the time frame of acute treatment trials. We evaluated short-term responsiveness and determined the minimal change in PCDAI score associated with a clinically meaningful improvement in disease activity. METHODS: Standardized effect size (SES) and standardized response mean (SRM) were calculated as measures of responsiveness among pediatric patients being treated for acute exacerbations of Crohn disease 1) in a regular clinical practice setting and 2) as part of a multicenter, randomized controlled trial (RCT). Receiver operating characteristic (ROC) curves were constructed to determine the minimal PCDAI score change associated with significant clinical improvement used as the gold standard in 1) physician global assessment of change and in 2) change in adult Crohn disease activity index (CDAI). RESULTS: Among responders, the SES and SRM of the PCDAI were 1.78 and 1.41 (95% CI: 0.89-1.92) and 2.10 and 1.95 (95% CI: 1.70-2.20) in the clinical practice setting and RCT setting, respectively. The optimal minimal PCDAI change score associated with clinically significant change in physician global assessment was determined to be -12.5 (sensitivity 83.3%, specificity 92.3%). In the RCT setting a change in PCDAI of -10 corresponded to a change in CDAI of not greater-than-or-equal 70 points. CONCLUSIONS: The PCDAI is responsive to improvement in disease activity in Crohn disease patients over a short interval. As such, the PCDAI is an appropriate instrument to use in pediatric acute treatment trials.

Waters AM, Zachos M, Herzenberg AM, Harvey E, Rosenblum ND, Anonymous00052. · Hospital for Sick Children, Toronto, ON, Canada. · Nat Clin Pract Nephrol. · Pubmed #18838984 No free full text.

Abstract: BACKGROUND: A 12-year-old boy presented to hospital with a 6-month history of crampy pre-defecation abdominal pain, non-bloody diarrhea, anorexia and weight loss. Investigations revealed hypochromic microcytic anemia, a low serum iron level, a low serum ferritin level and an elevated serum creatinine level. Histopathological examination of tissue specimens obtained at esophagogastroduodenoscopy and colonoscopy revealed features of Crohn's disease, and a renal biopsy demonstrated tubulointerstitial nephritis. A second case of tubulointerstitial nephritis in a patient with Crohn's disease, is also presented. INVESTIGATIONS: Physical examination, laboratory tests including full blood count, electrolytes, renal function, serum albumin, urinalysis and 24 h urinary protein, esophagogastroduodenoscopy, colonoscopy, abdominal ultrasonography, dimercaptosuccinic acid scan, renal diethylene triamine pentaacetic acid clearance study and renal biopsy. DIAGNOSIS: Tubulointerstitial nephritis secondary to Crohn's disease. MANAGEMENT: Prednisone therapy (60 mg/day) for 1 month followed by a tapering schedule over 3 months.

Kundhal P, Zachos M, Holmes JL, Griffiths AM. · Division of Pediatric Gastroenterology and Nutrition, Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada. · J Pediatr Gastroenterol Nutr. · Pubmed #11479412 No free full text.

Abstract: BACKGROUND: Although the effectiveness of controlled ileal release (CIR) budesonide in children can be extrapolated from adult studies, there are currently no data available concerning the effects of CIR budesonide therapy on linear growth. In the absence of controlled, prospective pediatric clinical trials, we reviewed the outcomes, particularly linear growth, of children and adolescents given CIR budesonide to treat active intestinal inflammation and to maintain remission. METHODS: Thirty-two children (20 males) aged 14.1 +/- 2.7 years with Crohn disease of the distal ileum with or without right colon involvement were treated for active Crohn disease (baseline Pediatric Crohn Disease Activity Index, 34 +/- 14) with 9 mg daily of CIR budesonide through the Hospital for Sick Children, University of Toronto, Inflammatory Bowel Diseases program. RESULTS: At first follow-up visit 8.7 +/- 6.0 weeks later, 19 of 32 (59%) were judged by the physician to have responded. In the subset of 22 patients who had laboratory tests repeated at the first follow-up visit, their Pediatric Crohn Disease Activity Index fell from 33 +/- 14 to 22 +/- 16 (P = 0.001). The Pediatric Crohn Disease Activity Index score fell to less than 15 (cut-off score remission) in 29%. Six prepubertal responders continued to receive 6 mg CIR budesonide for 6 to 13 months. Five of the 6 experienced only mild or no gastrointestinal symptoms and gained weight. Nevertheless, their mean height velocity was only 2.3 +/- 1.0 cm/year, and none grew at a rate of more than 4cm/year whilst receiving CIR budesonide. CONCLUSIONS: These data provide grade III evidence of modest effectiveness of CIR budesonide in children with active Crohn disease confined to the ileum with or without right colon involvement. The subnormal growth observed with continued therapy is concerning and may reflect either inadequately controlled intestinal inflammation or direct suppression of linear growth, as is observed with conventional corticosteroids. Randomized controlled pediatric trials of CIR budesonide must include parameters of linear growth as an outcome variable.