Lloyd R. Sutherland

A Simple Classification of Crohn's Disease: Report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998

Summary: Crohns disease is a heterogeneous entity. Previous attempts of classification have been based primarily on anatomic location and behavior of disease. However, no uniform definition of patient subgroups has yet achieved broad acceptance. The aim of this international Working Party was to develop a simple classification of Crohns disease based on objective variables. Eight outcome‐related variables relevant to Crohns disease were identified and stepwise evaluated in 413 consecutive cases, a database survey, and by clinical considerations. Allocation of variables was conducted with well‐defined Crohns disease populations from Europe and North America. Cross‐table analyses were performed by chi‐square testing. Three variables were finally elected: Age at Diagnosis [below 40 years (A1), equal to or above 40 years (A2)], Location [terminal ileum (L1), colon (L2), ileocolon (L3), upper gastrointestinal (L4)], and Behavior [nonstricturing nonpenetrating (B1), stricturing (B2), penetrating (B3)]. The allocation of patients to these 24 subgroups proved feasible and resulted in specific disease clusters. Cross‐table analyses revealed associations between Age at Diagnosis and Location, and between Behavior and Location (all p < 0.001). The Vienna classification of Crohns disease provides distinct definitions to categorize Crohns patients into 24 subgroups. Operational guidelines should be used for the characterization of patients in clinical trials as well as for correlation of particular phenotypes with putative biologic markers or environmental factors.

Methotrexate for the Treatment of Crohn's Disease

BACKGROUND Although corticosteroids are highly effective in improving symptoms of Crohns disease, they may have substantial toxicity. In some patients, attempts to discontinue corticosteroids are unsuccessful. METHODS We conducted a double-blind, placebo-controlled multicenter study of weekly injections of methotrexate in patients who had chronically active Crohns disease despite a minimum of three months of prednisone therapy. Patients were randomly assigned to treatment with intramuscular methotrexate (25 mg once weekly) or placebo for 16 weeks. The patients also received prednisone (20 mg once a day), which was tapered over 10 weeks unless their condition worsened. The primary outcome measure was clinical remission at the end of the 16-week trial. Remission was defined by the discontinuation of prednisone and a score of < or = 150 points on the Crohns Disease Activity Index. RESULTS A total of 141 patients were randomly assigned in a 2:1 ratio to methotrexate (94 patients) or placebo (47 patients). After 16 weeks, 37 patients (39.4 percent) were in clinical remission in the methotrexate group, as compared with 9 patients (19.1 percent) in the placebo group (P = 0.025; relative risk, 1.95; 95 percent confidence interval, 1.09 to 3.48). The patients in the methotrexate group received less prednisone overall than those in the placebo group (P = 0.026). The mean (+/- SE) score on the Crohns Disease Activity Index after 16 weeks of treatment was significantly lower in the methotrexate group (162 +/- 12) than in the placebo group (204 +/- 17, P = 0.002). The changes in quality-of-life scores and serum orosomucoid concentrations were similar. In the methotrexate group, 16 patients (17 percent) withdrew from treatment because of adverse events (including asymptomatic elevation of serum aminotransferase in 7 and nausea in 6), as compared with 1 patient (2 percent) in the placebo group. CONCLUSIONS In a group of patients with chronically active Crohns disease, methotrexate was more effective than placebo in improving symptoms and reducing requirements for prednisone.

Oral Budesonide for Active Crohn's Disease

Background Corticosteroids are the most efficacious drugs for inducing remission in active Crohns disease, but their benefits are frequently offset by serious side effects. Budesonide is a corticosteroid with high topical antiinflammatory activity but low systemic activity because of extensive hepatic metabolism. We investigated the efficacy and safety of an oral controlled-ileal-release preparation of budesonide in patients with active Crohns disease involving the ileum or ileum and proximal colon. Methods In a double-blind, multicenter trial, 258 patients were randomly assigned to receive placebo or one of three doses of budesonide -- 3, 9, or 15 mg daily. The primary outcome measure was clinical remission, as defined by a score of 150 or less on the Crohns disease activity index. Results After eight weeks of treatment, remission occurred in 51 percent of the patients in the group receiving 9 mg of budesonide (95 percent confidence interval, 39 to 63 percent), 43 percent of those receiving 15 mg (95 ...

Double blind, placebo controlled trial of metronidazole in Crohn's disease.

A double blind study compared the efficacy of metronidazole in two doses (20 mg/kg, 10 mg/kg) with placebo in patients with Crohns disease. One hundred and five patients participated but only 56 completed the 16 week study -21 were withdrawn for deterioration of symptoms, 17 for adverse experiences, and 11 for protocol violation. Significant improvement in disease activity as measured by the Crohns disease activity index (metronidazole 20 mg/kg, 97 units; metronidazole 10 mg/kg, 67 units; placebo -1 unit, p = 0.002) and serum orosomucoid (metronidazole 20 mg/kg/day, 49; 10 mg/kg/day, 38; placebo, -9, p = 0.001)) were detected. Changes in C reactive protein concentrations did not achieve significance when all three groups were considered but were significant when all metronidazole treated patients were grouped and compared with the placebo treated patients (0.8 v -0.9, p less than 0.05). Although patients receiving metronidazole 20 mg/kg/day had a greater improvement in disease activity than those receiving 10 mg/kg/day (difference 30 units (95% confidence intervals -27-87), the small sample size may have precluded the detection of statistical significance. Preliminary analysis suggests that metronidazole was more effective in patients with disease confined to the large intestine or affecting both small and large bowel than in those with small bowel disease only. There were no differences in remission rates between metronidazole and placebo treated patients. We conclude that metronidazole warrants further assessment in the treatment of patients with active Crohns disease.

Meta-analysis of Enteral Nutrition as a Primary Treatment of Active Crohn's Disease

BACKGROUND/AIMS The efficacy of enteral nutrition as primary therapy of active Crohns disease is controversial. The aim of the study was to compare by meta-analysis the likelihood of clinical response to liquid diet therapy vs. corticosteroids and to assess the importance of formula composition to efficacy. METHODS Randomized controlled trials comparing exclusive enteral nutrition with corticosteroids and elemental with nonelemental formulas were identified through a combination of computerized and hand-searching techniques. Rates of clinical remission of active Crohns disease, based on the intention-to-treat principle, were extracted from the studies by two independent reviewers. Odds ratios for likelihood of clinical response were calculated. RESULTS In eight trials comprising 413 patients, enteral nutrition was inferior to corticosteroids (pooled odds ratio, 0.35; 95% confidence interval, 0.23-0.53). In five trials comprising 134 patients, there was no difference in the efficacy of elemental versus nonelemental formulas (pooled odds ratio, 0.87; 95% confidence interval, 0.41-1.83). CONCLUSIONS Corticosteroids are more effective than enteral nutrition in the treatment of active Crohns disease. Limited sample size precludes definitive conclusions about the importance of formula composition in the efficacy of enteral nutrition; however, data analyzed in this study do not support an advantage to elemental feedings compared with a polymeric formulation.

Effect of cigarette smoking on recurrence of Crohn's disease.

The effect of cigarette smoking on recurrence (defined in this study as the need for repeat surgery) in patients who had previously required surgery for Crohns disease was assessed in a historical cohort of 174 patients. Mean follow-up was 10.8 yr. The 5- and 10-yr recurrence rates were 28% and 56%, respectively. Five- and 10-yr rates were significantly different for smokers (36%, 70%) and nonsmokers (20%, 41%). When patients were stratified by gender, the increased risk was more apparent in women (odds ratio 4.2, 95% confidence interval 2.0-4.2) than in men (odds ratio 1.5, 95% confidence interval 0.8-6.0). Evidence for a dose-response relationship could be identified in women but not men. Cigarette smoking may not only be a risk factor for development of Crohns disease but also may influence disease activity following surgery.

Is small intestinal permeability really increased in relatives of patients with Crohn's disease?

BACKGROUND Patients with Crohns disease have increased intestinal permeability, which may precede the development of clinical disease and be involved in disease pathogenesis. Subsequent studies have suggested that, as a group, first-degree relatives of patients with Crohns disease do not have significantly increased small intestinal permeability rates. The present study proposes that conventional data analysis, used in these studies, may be inappropriate and has overlooked an important observation. METHODS Lactulose and mannitol permeabilities were defined in healthy controls and in patients with Crohns disease and their first-degree relatives. RESULTS Intestinal permeability in relatives was similar to that in the control group, but a subpopulation had abnormally high permeability rates in the absence of clinical evidence for disease. Raw data from another investigator confirmed this finding in an additional study; consequently, it is concluded that the original hypothesis is still viable. A small proportion of individuals, at high risk of developing Crohns disease, have increased intestinal permeability. CONCLUSIONS Increased intestinal permeability may precede clinical manifestations of Crohns disease.

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease ☆ ☆☆ ★

BACKGROUND & AIMS Azathioprine is effective for Crohns disease but acts slowly. A loading dose may decrease the time to response. METHODS A placebo-controlled study was conducted in patients with active Crohns disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohns Disease Activity Index of </=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. RESULTS At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. CONCLUSIONS A loading dose does not decrease the time to response in patients with steroid-treated Crohns disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Population-Based Study of the Epidemiology of and the Risk Factors for Invasive Staphylococcus aureus Infections

A population-based active-surveillance study of the Calgary Health Region (population, 929,656) was conducted from May 1999 to April 2000, to define the epidemiology of invasive Staphylococcus aureus (ISA) infections. The annual incidence was 28.4 cases/100,000 population; 46% were classified as nosocomial. Infection was most common in people at the extremes of the age spectrum and in males. Several conditions were associated with acquisition of ISA infection, and the highest risk was observed in persons undergoing hemodialysis or peritoneal dialysis and in persons infected with human immunodeficiency virus. Forty-six patients (19%) died. Significant independent risk factors for mortality included positive blood-culture result, respiratory focus, empirical antibiotic therapy, and older age. A higher systolic blood pressure at presentation was associated with reduced case-fatality rate. ISA infections are common, with several definable groups of patients at increased risk for acquisition and death from these infections. This study provides important data on the burden of ISA disease and identifies risk groups that may potentially benefit from preventive efforts.

Sulfasalazine Revisited: A Meta-Analysis of 5-Aminosalicylic Acid in the Treatment of Ulcerative Colitis

The first major therapeutic advance in ulcerative colitis was the discovery of sulfasalazine (sulfapyridine bonded to 5-aminosalicylic acid [5-ASA]) [1], which was the first effective therapeutic agent for active ulcerative colitis [2] and for maintenance of remission [3]. Currently, all patients with ulcerative colitis in remission take sulfasalazine indefinitely [4]. The maximum dose of sulfasalazine is limited by the frequency of adverse drug reactions [5]. Approximately 30% of patients taking sulfasalazine report adverse reactions; many are idiosyncratic but others are dose related. Azad Khan [6] and others [7] showed that 5-ASA was the active moiety of sulfasalazine and that sulfapyridine functioned only as a carrier. Many investigators believed that the development of a new delivery system would allow the use of higher doses of 5-ASA, which might provide additional therapeutic benefits to patients. Currently five new preparations are available. They can be broadly classified into three categories: pH-dependent formulations; microsphere formulations; and those formulations that bind 5-ASA to another carrier, which requires splitting of the diazo bond by bacteria. Although generic names are generally preferable, in this situation proprietary names are required to identify each medication by its release mechanisms. The first 5-ASA delayed-release, pH-sensitive preparation (Asacol) (Proctor & Gamble Pharmaceuticals, Inc., Norwich, New York) is a pellet of 5-ASA coated with a resin (Eudragit S) that dissolves when the pH of the fecal contents is more than 7 [8]. A second pH-dependent, 5-ASA preparation (Claversal, Salofalk, Mesasal, Rowasa) is coated with another resin (Eudragit L) that dissolves at a fecal pH that is more than 6 [9]. The only currently available microsphere preparation of 5-ASA (Pentasa) consists of 5-ASA coated with an ethylcellulose that allows for slow release of the medication beginning in the duodenum and extending into the colon [9]. The alternative-carrier approach includes binding 5-ASA to another 5-ASA molecule, olsalazine (Dipentum, Kabi Pharmacia, Piscataway, New Jersey), or to various benzoic acid derivatives, such as balsalazide [10] or benzalazine [11]. The newer products are more expensive for patients, and their superiority over sulfasalazine has not yet been proven. To better define the role and efficacy of these new 5-ASA-containing medications, we did a meta-analysis of the randomized, controlled trials comparing them with either placebo or sulfasalazine. Methods A literature search was done using the MEDLINE and BIOS data bases for January 1981 to May 1992 and using the MESH headings ulcerative colitis and aminosalicylates. Citations were limited to those published in English. A manual search sought additional citations using references in articles retrieved from the computerized search as well as review articles, proceedings from symposia, and textbooks. Studies of oral 5-ASA preparations for the acute and maintenance treatment of ulcerative colitis were accepted for analysis if they were randomized, controlled, of parallel design, and had a treatment duration of a minimum of 4 weeks for acute therapy and of 6 months for maintenance therapy. Studies accepted for analysis were reviewed independently by two of the authors (LRS and GRM), and the results of each study were recorded. For reports of acute therapy, the numbers of patients with clinical, endoscopic, or histologic remission as defined in each study were recorded. For studies of maintenance therapy, the number of patients remaining in remission clinically or endoscopically were recorded. Results were recorded on an intention-to-treat basis. No uniform definition of a response existed across the studies. Where possible the numbers of patients having adverse effects or withdrawing from therapy because of adverse events were recorded. Original investigators were contacted when necessary to clarify points regarding inclusion criteria or data. We did a blinded quality analysis of each study we selected, using the criteria and methods outlined by Chalmers and colleagues [12] (Appendix Table 1, Appendix Table 2, and Appendix Table 3). Any discrepancies between reviewers about the retrieved data or quality assessment were settled by consensus. Appendix Table 1. Quality Assessment Scoring System: Study Protocol* Appendix Table 2. Quality Assessment Scoring System: Statistical Analysis Appendix Table 3. Quality Assessment Scoring System: Presentation of Results Studies were separated into three groups: 5-ASA compared with placebo for acute therapy, 5-ASA compared with sulfasalazine for acute therapy, and 5-ASA compared with sulfasalazine for maintenance therapy. Each group was analyzed separately. For each group, homogeneity was tested using the method outlined by DerSimonian and Laird [13]. Pooled odds ratios with 95% confidence intervals (CIs) were calculated using a commercially available, computerized biostatistical program [14]. To confirm the degree of homogeneity, all of the individual trial 95% CIs were also graphed to confirm that a substantial overlap existed for all of the individual CIs (see Figures 1, 2, and 3). (Note that if the CIs for a pooled odds ratio include unity, the evidence supporting an actual difference is weak or inconclusive.) If possible, results were also subgrouped according to the dose of 5-ASA and the specific 5-ASA preparation used; these subgroups were analyzed in a similar manner. Adverse effects and withdrawals were analyzed by pooled odds ratio and by combining the adverse effects for each group; the overall results were analyzed using chi-square tests. The Fisher exact test was used when appropriate for small counts. Figure 1. Randomized, controlled studies of various 5-aminosalicylic acid preparations (all study arms) compared with placebo in active ulcerative colitis. Figure 2. Randomized, controlled studies of various 5-aminosalicylic acid (5-ASA) preparations (all study arms) compared with sulfasalazine in active ulcerative colitis. Figure 3. Randomized, controlled studies of various 5-aminosalicylic acid (5-ASA) preparations (all study arms) compared with sulfasalazine for maintenance of remission of ulcerative colitis. Results From the more than 150 citations collected by the literature search, 59 trials of oral 5-ASA therapy for mild-to-moderate ulcerative colitis as defined by Truelove and Witts [15] were identified. Twenty-seven trials (45.7%) Table 1 and Table 2 met the inclusion criteria and were included in the analysis [11,16-41]. Thirty-two studies were excluded. Fifteen of these studies were open label and were excluded due to lack of randomization [8, 42-55]. Of the remaining 17 studies, the reasons for exclusion included design other than controlled, with parallel design in 3 studies [56-58]; duration less than 4 weeks in 2 studies [59, 60]; single-center reports of patients who were abstracted from larger multicenter trials in 2 [61, 62]; data presented in an inappropriate form for our analysis in 3 abstracts [63-65]; 5 abstracts subsequently published [66-70]; and 2 papers also being published in symposia [71, 72]. Table 1. Characteristics of Each Trial Included in the Meta-Analysis Table 2. Treatment Regimens and Outcome for Each Trial Included in the Meta-Analysis Quality scores, from Chalmers criteria [12], ranged from 0.25 to 0.80, with a median of 0.62 (see Table 1). Scores were normally distributed (Shapiro-Wilks test for normality = 0.920, P = 0.13). Excellent correlation existed between observers, with a correlation coefficient of 0.88 (P < 0.001). Most studies lost points for omissions about study design and use of statistics. No apparent effect of study quality on the results existed within each group. 5-Aminosalicylic Acid Compared with Placebo for Acute Therapy Eight trials, comprising 1007 patients, examined oral 5-ASA compared with placebo for acute mild-to-moderate ulcerative colitis [18, 23-25, 27, 33, 37, 39]. Studies were homogeneous (P > 0.2). The pooled odds ratio for complete remission combining all 5-ASA preparations with all doses was 2.02 (CI, 1.50 to 2.72) (Figure 1). Results were not significantly different if abstracts were excluded from the analysis. If the results were grouped according to the dose of 5-ASA used, a dose-dependent trend was apparent (Table 3). For patients who received less than 2 g of 5-ASA, the response was not different from placebo. The pooled odds ratio, for patients receiving at least 2 g/d of 5-ASA, showed improvement compared with placebo. Table 3. Pooled Odds Ratios for Studies of 5-Aminosalicylic Acid Compared with Placebo by Dose No significant differences in response could be shown between any of the 5-ASA preparations (Table 4). Only three studies [24, 27, 39], all with Dipentum, had sufficient data to determine an endoscopic response to therapy. The pooled odds ratio for endoscopic response was 4.97 (CI, 2.50 to 9.85). Table 4. Pooled Odds Ratios for 5-Aminosalicylic Acid Therapy for Ulcerative Colitis by Preparation 5-Aminosalicylic Acid Compared with Sulfasalazine for Acute Therapy Eight trials, involving 553 patients, compared 5-ASA with sulfasalazine for the acute treatment of ulcerative colitis [11, 16, 19, 29-31, 34, 35]. Studies were homogeneous (P > 0.2). The pooled odds ratio for complete remission, after combining all 5-ASA preparations and comparing them with sulfasalazine, was 1.15 (CI, 0.83 to 1.61) (Figure 2). The result was similar if patients entering into complete remission were combined with those showing improvement; pooled odds ratio was 1.20 (CI, 0.86 to 1.69). The results did not differ significantly when abstracts were excluded. If studies were subgrouped according to the dose of 5-ASA used, no evidence existed for a dose-response relationship. Trials using 2 g/d of 5-ASA had a pooled odds ratio of 1.24 (CI, 0.79 to 1.94), [11, 16, 29, 31, 34, 35], whereas those using less than 2 g/d h