Randomised clinical trial: deep remission in biologic and immunomodulator naïve patients with Crohn's disease - a SONIC post hoc analysis.

BACKGROUND: As treatment goals in Crohn's disease (CD) evolve, targets now include clinical remission (CR), mucosal healing (MH) and biological remission [C-reactive protein normalisation (CRPnorm )]. AIMS: To evaluate the association of baseline factors and treatment with the achievement of different composite remission parameters at week 26. METHODS: This post hoc analysis of the SONIC trial evaluated different composite remission measures at week 26 in a subgroup of patients with Crohn's disease activity index (CDAI) scores, CRP, and endoscopic data available at baseline and week 26 (N = 188). Assessed composite remission measures were: CR (CDAI < 150) and MH (absence of any mucosal ulcerations), previously referred to as 'deep remission;' and alternative composite endpoints: CR + CRPnorm (CRP < 0.8 mg/dL); CRPnorm  + MH; and CR + CRPnorm  + MH. RESULTS: Among analysed patients, 136/188 (72.3%) achieved CR and 90/188 (47.9%) achieved MH at week 26. All composite outcomes were significantly greater (Bonferroni significance level, P ≤ 0.016) with combination therapy (i.e. infliximab and azathioprine; 52.3-63.6%) vs. azathioprine monotherapy (12.9-29.0%; p ≤ 0.005 for all comparisons). Composite remission rates including MH were significantly greater with combination therapy (52.3-56.9%) vs. infliximab (25.6-32.3%; P ≤ 0.015 for all comparisons except CRPnorm  + MH, P = 0.017) and vs. azathioprine monotherapy (12.9-20.4%; P ≤ 0.002 for all comparisons). Median serum trough infliximab concentrations among patients who achieved MH or CR + MH were greater when compared with those among patients who did not achieve MH (P = 0.018) or CR + MH (P = 0.053). Among the subgroup of patients with early Crohn's disease, MH alone or in combination with composite remission criteria significantly improved clinical outcomes of patients who received combination therapy. CONCLUSIONS: Combination therapy was more effective in achieving various composite remission measures vs. azathioprine or infliximab monotherapy. These data illustrate that 'deep remission' is achievable with combination therapy in a high percentage of patients with early Crohn's disease. ClinicalTrials.gov number: NCT00094458.

Use of video capsule endoscopy in Crohn's disease.

Capsule endoscopy has been available since 2001 to image the small intestine, a boon to practitioners managing patients with inflammatory bowel disease. During the last ten years, new technologies have been developed, including computed tomographic enterography, magnetic resonance enterography, in addition to our standard small bowel follow through, all of which image the small bowel. This has created a situation in which multiple options are available to the gastroenterologist to image the small bowel, each with strengths. This review focuses on capsule endoscopy as it pertains to the imaging of the small bowel in patients with known or suspected Crohn's disease. We will focus on comparative imaging data, how capsule endoscopy may aid in the prediction of disease type and course, the avoidance and meaning of capsule retention, along with cost considerations, and directions for the future.

Inflammatory bowel disease related osteonecrosis: report of a large series with a review of the literature.

BACKGROUND: Osteonecrosis is a major complication of inflammatory bowel disease usually associated with steroid use. There are few large series available detailing the specifics of affected patients. AIM: To identify any specific characteristics of osteonecrosis in this cohort. A major focus was placed on steroid dose, the average time between diagnosis of IBD and appearance of osteonecrosis and the frequency of multiple joint involvement. METHODS: Our study identified 23 patients in the practices of five gastroenterologists at the Mount Sinai Medical Center. We retrospectively reviewed their clinical history, as well as imaging studies. We classified osteonecrosis according to the Association Research Circulation Osseous (ARCO) staging system. RESULTS: Although our prednisone dosing data could not be used as an accurate predictor of onset or joint distribution, there was a tendency for correlation between the average daily dosing and the ARCO score. The ARCO scoring system was consistent for patients with bilateral hip involvement. The distribution of affected joints in IBD is similar to other conditions associated with osteonecrosis, with hips being the most frequently involved joints. Data showed bilateral involvement in most hips, but usually unilateral disease in the shoulders and knees. Treatment options include core decompression for early stages, whereas joint replacement surgery is required for stages 3 and 4. CONCLUSION: IBD predisposes patients to corticosteroid induced osteonecrosis. An exact threshold dose has not been determined. The data suggests that either long term therapy or short term high dose treatment increases the risk of osteonecrosis. Even if symptoms are limited to one joint, multiple joints are often involved and comprehensive testing with MRI is indicated in all cases.

Difficult differential diagnoses in IBD: ileitis and indeterminate colitis.

When considered in the appropriate clinical scenarios, the diagnoses of Crohn's disease or ulcerative colitis are usually straightforward. Most cases can be definitively diagnosed by the typical subacute or chronic history of symptoms, and radiographic, endoscopic, and histologic confirmation in the presence of negative stool studies; newer serologic assays are now available and are of value if the diagnosis remains uncertain. In this paper, we review distinguishing features in the diagnosis of ileitis and the distinction to be made in conclusively diagnosing ulcerative vs. Crohn's colitis.

Treatment responses in collagenous colitis.

OBJECTIVE: In the nearly 20 yr since collagenous colitis was first recognized, the results of therapies have not been systematically described in substantial numbers of patients. We have therefore conducted a retrospective analysis of 26 patients treated in this institution during the years 1991-1994. METHODS: Twenty-nine cases of collagenous colitis were obtained by review of biopsy specimens collected between 1991 and 1994 at The Mount Sinai Hospital. Each chart was reviewed for patient demographics, symptoms, coexisting conditions, specific therapies, and therapeutic outcomes. Additional data were obtained from telephone calls to patients when deemed necessary. Three patients were exeluded from the study because of lack of follow-up. Therapeutic outcomes were defined as follows: Complete Remission (CR): normalization of bowel function; Partial Remission (PR): 50% reduction in frequency of bowel movements; Failure: <50% reduction in frequency of bowel movements; or Relapse: return of symptoms after cessation of treatment. Median follow-up was 58 wk from time of diagnosis, with a range of 22-376 wk. RESULTS: The 26 patients (25 women, one man) had a mean age of 62 yr (range, 22-85 yr) at diagnosis. Of 26 patients, 22 responded to some form of therapy and one had spontaneous remission. Six of the responders ultimately remained in CR with no therapy. Twelve are maintained on 5-aminosalicylic acid (5-ASA) and or antidiarrheals to control symptoms. An additional six required prednisone throughout the follow-up period to remain in CR or PR. Two patients failed all therapy. CONCLUSION: Collagenous colitis is a treatable condition in most patients. We recommend initial therapy with antidiarrheals, followed by a trial of 5-ASA agent. A trial of 5-ASA in combination with prednisone should be attempted in patients refractory to 5-ASA alone, with subsequent attempts in the responders to taper prednisone and maintain remission with no therapy, if possible, or with 5-ASA and/or antidiarrheal agents if necessary.

Cyclosporine in inflammatory bowel disease.

For the past decade, the use of oral and intravenous cyclosporine has been examined for patients with inflammatory bowel disease who have demonstrated resistance to steroid treatment. Updated and new results from a number of studies offer short-term and long-term data on cyclosporine and its effectiveness in achieving and maintaining remission from disease. Short-term and long-term toxicity associated with cyclosporine is reviewed here, as well as quality of life among patients who have been treated successfully. Also discussed are practice patterns among clinicians using cyclosporine in its varied formulations and the appropriate settings for its use.

Ulcerative colitis practice guidelines in adults. American College of Gastroenterology, Practice Parameters Committee.

Guidelines for clinical practice are intended to indicate preferred approaches to medical problems as established by scientifically valid research. Double-blind placebo controlled studies are preferable, but compassionate use reports and expert review articles are utilized in a through review of the literature conducted through Medline with the National Library of Medicine. When only data that will not withstand objective scrutiny are available, a recommendation is identified as a consensus of experts. Guidelines are applicable to all physicians who address the subject without regard to specialty training or interests and are intended to indicate the preferable but not necessarily the only acceptable approach to a specific problem. Guidelines are intended to be flexible and must be distinguished from standard of care, which are inflexible and rarely violated. Given the wide range of specifies in any health care problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision. Guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the Board of Trustees. Each has been intensely reviewed and revised by the Committee, other experts in the field, physicians who will use them, and specialists in the science of decision of analysis. The recommendations of each guideline are therefore considered valid at the time of their production based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at a time established and indicated at publication to assure continued validity.

Sialosyl-Tn antigen: initial report of a new marker of malignant progression in long-standing ulcerative colitis.

BACKGROUND & AIMS: Expression of the mucin-associated carbohydrate antigen sialosyl-Tn (STn) correlates with malignant transformation in sporadic colonic neoplasms. The aim of this study was to analyze STn antigen expression in patients with long-standing ulcerative colitis (UC). METHODS: STn antigen was assessed by immunohistochemistry in archival tissues. Study A was a retrospective chronological case-control study. Serial surveillance colonoscopic biopsy specimens without inflammation or dysplasia were analyzed in 7 patients who developed colon cancer and in 8 controls who did not develop colon cancer. Study B analyzed the anatomic distribution of STn expression in 17 cancer-bearing (case) and 6 cancer-free (control) colectomy specimens from patients with UC. In some colectomy specimens, STn was compared with aneuploidy, which was determined by flow cytometry. RESULTS: In study A, among the 7 patients with UC who developed cancer, 6 patients (86%) expressed STn in at least one prior nondysplastic surveillance biopsy specimen from the same site. Only 3 of 8 control patients (38%) expressed STn. In study B, STn was expressed in 40 of 82 specimens (49%) from cancer-bearing colons but only 8 of 62 specimens (13%) from cancer-free colons. STn was expressed in most aneuploid areas but was also found in diploid, nondysplastic mucosa. CONCLUSIONS: STn antigen seems to be a promising marker of cancer risk in patients with UC.

How effective is current medical therapy for severe ulcerative and Crohn's colitis? An analytic review of selected trials.

To determine the efficacy of current medical therapies in the treatment of severe ulcerative and Crohn's colitis, we conducted a MEDLINE computer-assisted literature search using the terms "severe ulcerative colitis," "severe Crohn's colitis," "drugs," and "therapy." Studies were compared and then selected based, in decreasing order of importance, on the use of standard criteria to assess disease severity, uniform entrance criteria with prospective drug protocols using defined end points; prospective placebo-controlled trials; and retrospective studies. We then conducted an analytic review of those studies selected. For severe ulcerative colitis, we identified seven studies comprising 319 treatment episodes in 306 patients. Clinical remission was achieved on average in 62% of subjects (range, 43-80%); 38% (25-57%) came to prompt colectomy. Remission was maintained in 38-71% of patients achieving success in the acute phase. For severe Crohn's colitis, we identified five studies comprising 68 patients. Clinical remission was achieved on average in 65% of patients (range, 55-94%). Remission was maintained in 54-69% of those achieving success in the acute phase. Current medical therapies have improved the outlook for severe ulcerative colitis; however, physicians cannot predict response to therapy based upon individual's clinical features or previous presentations. Current medical therapy for severe Crohn's colitis appears to spare many patients early colectomy, but the current dearth of clinical trials postpones any further advances in the medical management of these patients.

Immunosuppressive drugs in Crohn's disease.

We review clinical experience with the immunosuppressive drugs 6-mercaptopurine (6-MP) and azathioprine, cyclosporine, and methotrexate in the management of patients with Crohn's disease. 6-MP and azathioprine are closely related structurally. Their exact mechanism of action is unknown, but both cause immunosuppression by interfering with nucleic acid metabolism in the immunological sequence that follows antigenic stimulation. 6-MP and azathioprine have proved most useful for two indications: reducing steroid requirements and healing fistulas. Among patients who are dependent on steroids for control of active inflammatory Crohn's disease, approximately 50% can be completely weaned from prednisone, and an additional 25% can tolerate a substantial dose reduction when treated with 6-MP or azathioprine. Likewise, 6-MP is effective in closing fistulas in approximately one third of patients and in reducing fistula drainage in an additional one third. However, the onset of action is slow and the results may be dose dependent. Cyclosporine, a selective immunosuppressant drug, inhibits T lymphocytes by inhibiting expression of interleukin-2 and its receptors. Its principal usefulness may be in patients with disabling fistulas or active steroid-refractory colitis who cannot tolerate the several months required for a remission induced by 6-MP or azathioprine. Methotrexate, a dihydrofolate reductase inhibitor, has antimetabolite and antiinflammatory properties. Methotrexate is only slightly, if at all, faster acting than 6-MP or azathioprine. Its principal usefulness may therefore be in cases when these other drugs have not been tolerated or are ineffective.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine in severe ulcerative colitis refractory to steroid therapy.

BACKGROUND: There has been no new effective drug therapy for patients with severe ulcerative colitis since corticosteroids were introduced almost 40 years ago. In an uncontrolled study, 80 percent of 32 patients with active ulcerative colitis refractory to corticosteroid therapy had a response to cyclosporine therapy. METHODS: We conducted a randomized, double-blind, controlled trial in which cyclosporine (4 mg per kilogram of body weight per day) or placebo was administered by continuous intravenous infusion to 20 patients with severe ulcerative colitis whose condition had not improved after at least 7 days of intravenous corticosteroid therapy. A response to therapy was defined as an improvement in a numerical symptom score (0 indicated no symptoms, and 21 severe symptoms) leading to discharge from the hospital and treatment with oral medications. Failure to respond to therapy resulted in colectomy, but some patients in the placebo group who had no response and no urgent need for surgery were subsequently treated with cyclosporine. RESULTS: Nine of 11 patients (82 percent) treated with cyclosporine had a response within a mean of seven days, as compared with 0 of 9 patients who received placebo (P < 0.001). The mean clinical-activity score fell from 13 to 6 in the cyclosporine group, as compared with a decrease from 14 to 13 in the placebo group. All five patients in the placebo group who later received cyclosporine therapy had a response. CONCLUSIONS: Intravenous cyclosporine therapy is rapidly effective for patients with severe corticosteroid-resistant ulcerative colitis.

Meta-analysis of the effectiveness of current drug therapy of ulcerative colitis.

We have conducted a meta-analysis of 16 placebo-controlled trials of single drug therapy in ulcerative colitis (UC) for both induction (11 trials) and maintenance of remission (five trials). A total of 468 and 343 patients, respectively, was studied. Various clinical criteria of success were analyzed. The Dersimonian-Laird method for meta-analysis was used to calculate the risk difference. Therapeutic advantage, defined as the difference between drug and placebo response, was also determined. Using various criteria of success, single drug therapy for the induction of remission conferred a therapeutic advantage of 37-48% over placebo. In trials for maintenance of remission, the therapeutic advantage at 6 months was 21%, whereas at 12 months the therapeutic advantage rose to 46% because of a decline in placebo responders with time. In conclusion, meta-analysis has established a standard of reference against which future drug trials can be compared. This standard of reference for drug and placebo rates, as well as the corresponding therapeutic advantages, can help determine the relative value of newer agents in the therapy of UC.

Does hormonal therapy have any benefit for bleeding angiodysplasia?

Sixty-four patients took part in a cohort study measuring the efficacy of daily hormonal therapy in diminishing intestinal bleeding from small bowel angiodysplasia. Thirty patients received 5-10 mg norethynodrel either with mestranol, 0.075-0.15 mg (24 patients) or with conjugated estrogens, 0.625 mg (six patients). The cohort group consisted of 34 patients who either refused hormonal therapy (six patients) or were diagnosed early in our experience, before the resurgence of hormonal therapy (28 patients). Mean follow-up was 15.6 months (range 2-31 months) for the treated group and 13.4 months (range 1-23 months) for the untreated group. In addition, the change in monthly transfusion requirement with therapy was analyzed ("within group" analysis). Fifty percent (15 of 30) of the treated group required no further transfusion during therapy, while 44% (15 of 34) of the untreated group required no further therapy (not significant). During therapy, the mean monthly transfusion requirement of packed red blood cells in the treated group was not significantly different from that found before therapy (1.5 vs. 2.2 units, NS) or from that of the control group (1.5 vs. 1.6 units, NS). The findings do not support the use of hormonal therapy for bleeding from small intestinal angiodysplasia.

How effective are current drugs for Crohn's disease? A meta-analysis.

We have conducted a meta-analysis of 12 placebo controlled trials to determine the efficacy of single drug therapy in Crohn's disease for both induction (seven trials) and maintenance (five trials) of remission. A total of 767 and 796 patients were studied, respectively. Various clinical criteria of success were analyzed. The Dersimonian-Laird method for meta-analysis was used to calculate the risk difference (RD). Therapeutic advantage, defined as the difference between drug and placebo response, was also determined. Using various criteria of success, we found that single drug therapy conferred an 11-29% therapeutic advantage (RD = 0.13-0.33) over placebo for the induction of remission. In trials for maintenance, no therapeutic advantage was found for single drug therapy over placebo. All forms of maintenance therapy followed nearly identical linear rates of relapse over time, showing an approximately 90% maintenance of remission rate at 3 months, which decreased to 25% at 36 months. In conclusion, meta-analysis has established a standard of reference against which future drug trials can be compared. This standard of reference for drug and placebo rates, as well as the corresponding risk differences and therapeutic advantages can help determine the relative value of newer agents in the therapy of Crohn's disease.