National Cooperative Crohn's Disease Research Articles

Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

Covering the Cover

Covering the Cover

Use of the tumor necrosis factor-blockers for Crohn's disease.

The use of anti-tumor necrosis factor-α therapy for inflammatory bowel disease represents the most important advance in the care of these patients since the publication of the National Co-operative Crohn's disease study thirty years ago. The recommendations of numerous consensus groups worldwide are now supported by a wealth of clinical trials and several meta-analyses. In general, it is suggested that tumor necrosis factor-α blockers (TNFBs) are indicated (1) for persons with moderately-severe Crohn's disease or ulcerative colitis (UC) who have failed two or more causes of glucocorticosteroids and an acceptably long cause (8 wk to 12 wk) of an immune modulator such as azathioprine or methotrexate; (2) non-responsive perianal disease; and (3) severe UC not responding to a 3-d to 5-d course of steroids. Once TNFBs have been introduced and the patient is responsive, therapy given by the IV and SC rate must be continued. It remains open to definitive evidence if concomitant immune modulators are required with TNFB maintenance therapy, and when or if TNFB may be weaned and discontinued. The supportive evidence from a single study on the role of early versus later introduction of TNFB in the course of a patient's illness needs to be confirmed. The risk/benefit profile of TNFB appears to be acceptable as long as the patient is immunized and tested for tuberculosis and viral hepatitis before the initiation of TNFB, and as long as the long-term adverse effects on the development of lymphoma and other tumors do not prone to be problematic. Because the rates of benefits to TNFB are modest from a population perspective and the cost of therapy is very high, the ultimate application of use of TNFBs will likely be established by cost/benefit studies.

Corticosteroids in Crohn's disease.

Crohn's disease is a lifelong illness characterized by chronic recurrent flares. The precise etiology of Crohn's disease is unknown. However, it appears to involve an enhanced systemic immune response and intensified local intestinal mucosal inflammatory activity, mediated through various inflammatory cells and an array of proinflammatory cytokines. Corticosteroids have been the mainstay of treatment of Crohn's disease. The controlled trials of the National Cooperative Crohn's Disease Study and the European Cooperative Crohn's Disease Study established that corticosteroids were effective for the induction of remission in Crohn's disease for the duration of the studies (6-17 wk). However, corticosteroids have not been shown to have an impact on the maintenance of long term remission in patients with Crohn's disease. In addition, they are associated with a high potential for dependence and serious toxic side effects. Alternative classes of medical therapy for Crohn's disease, including modified corticosteroids and a group of new biological therapies, have proven to be efficacious in the management of active and/or quiescent Crohn's disease.

Progress in treatment for Crohn’s disease

Since the initial description of Crohn's disease as a distinct clinical entity in 1932, the medical treatment has evolved from empiric observations, to the development of biological treatments based on better understandings of the immune abnormalities that occur in Crohn's disease. Sulfasalazine was the first medication that was effective in the treatment of patients with inflammatory bowel disease. However, it was not until 1977 that Azad Kahn et al. determined that such improvement was related to 5-aminosalicylic acid. This discovery led to the manufacturing of different delivery systems of 5-ASA targeted at the site of inflammation. In 1977 the National Cooperative Crohn's Disease Study (NCCDS) showed that sulfasalazine was effective for induction of remission in patients with active Crohn's disease, but not effective for maintenance of remission.

Prevalence of the factor V Leiden mutation in human inflammatory bowel disease with different activity

Background: the developmental mechanism of inflammatory bowel disease (IBD) in patients is unknown, but it may be influenced by different environmental and genetical factors. Aims of this study were: (1) to classify the IBD patients according the disease activity; and (2) to determine the presence of factor V Leiden mutation in IBD patients. Patients and methods: the observation was carried out in 49 patients with Crohn's disease (CD) and 29 patients with ulcerative colitis (UC). None of them had a history of thrombotic episodes. IBD was diagnosed by conventional clinical, endoscopic, radiological and histological criteria. The factor V Leiden mutation was detected by the polymerase chain reaction (PCR) method. Crohn's disease activity index (CDAI) was evaluated using the method of the National Cooperative Crohn's Disease Study. We determined the UC disease activity according to Truelove–Witts classification. Results: The prevalence of factor V Leiden mutation was increased in both populations of the patients to compare it with healthy persons (14.28 and 27.58% vs. 5.26%, n=7/49 and 8/29 vs. 3/57). The statistical analysis did not show a significant relationship between the CDAI or the Truelove–Witts grade in UC and the presence of Leiden mutation. Conclusion: the presence of factor V Leiden mutation probably has a role in the development of IBD. Our results suggest a higher prevalence of this mutation in Central European patients than in Southern, Northern Europe or America, may be due to the genetical differences of these populations.

Azathioprine combined with prednisolone was more effective than prednisolone alone for active Crohn disease

TherapeuticsJanuary 1, 1994Azathioprine combined with prednisolone was more effective than prednisolone alone for active Crohn diseaseJohn R. Saltzman, MDJohn R. Saltzman, MDUniversity of Massachusetts Medical Center, Worcester, Massachusetts, USA (J.R.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-1994-120-1-013 SectionsAboutFull Text ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinkedInRedditEmail Source CitationEwe K, Press AG, Singe CC, et al. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn's disease. Gastroenterology. 1993 Aug;105:367-72.References1 Summers RW, Switz DM, Session JT Jr, et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology. 1979;77:847-69. Google Scholar2 Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study.N Engl J Med. 1980;302:981-7. Google Scholar3 Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989;111:641-9. Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Massachusetts Medical Center, Worcester, Massachusetts, USA (J.R.S.) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails January 1, 1994Volume 120, Issue 1Page: 13KeywordsAbscessesAntibioticsAttentionBlood countsBody weightC-reactive proteinsCrohn's diseaseFistulasImmunosuppressivesLaboratory testsLife expectancyLipasesResearch laboratoriesSerum albuminSurgeryToxicity ePublished: 9 March 2020 Issue Published: January 1, 1994 Copyright & PermissionsCopyright © 1994 by American College of Physicians. All Rights Reserved.Loading ...

Crohn's Disease in Arabs

Crohn's disease is widely described in the Western literature, but it has not been widely observed in the Middle Eastern community. We diagnosed Crohn's disease in seven Arabs, three whom were Saudi Nationals. Their mean age was 32.4 years (range, 18-40 years) and duration of symptoms varied from three months to ten years. The site of the disease was ileocolic in five patients and colonic in two. Mass lesions in the abdomen were seen in three patients. Four cases were diagnosed from histological specimens obtained at laparotomy and resection and the other three were diagnosed from colonoscopic biopsy specimens. Extraintestinal manifestations were found in three patients. Surgery alone was the treatment in two patients, whereas the remaining required medical therapy, mainly steroids, with or without surgery. We conclude that Crohn's disease does occur in the Arab population, but with milder systemic effects.

Immunosuppressant therapy of inflammatory bowel disease. Pharmacologic and clinical aspects.

The history of immunosuppressant drug use, both azathioprine (Aza) and 6-mercaptopurine (6-MP), in inflammatory bowel disease (IBD) over the past 20 years is briefly reviewed. The two drugs appear identical in their pharmacologic and biologic effects. Azathioprine is converted to 6-MP while in the body. Conflicting reports on the effectiveness of Aza have been published. The major National Cooperative Crohn's Disease Study (NCCDS) has found no advantage in Aza over placebo. In contrast, 6-MP was found to be effective in a large randomized trial. The shortcomings of the NCCDS reports are discussed with possible explanations for their negative findings. Our own studies, dating from 1968, are reviewed with 38 patients having been treated for up to 18 years, always in combination with small doses of steroids. Our results with Aza are similar to those of Present and Korelitz with 6-MP; about 70% of previously intractable patients improved substantially. Both Aza and 6-MP bring about healing and closure of most fistulas. Side effects can be serious but are usually manageable and, to some extent, preventable by appropriate dosage schedules. Since Aza has been approved for another benign, presumably autoimmune disease--rheumatoid arthritis--and because of its extensive use in other autoimmune diseases, we prefer to use Aza in selected patients with Crohn's disease who have failed to respond to more conventional modes of therapy. The use of immunosuppressants in ulcerative colitis is less clearly indicated.

Vitamin A therapy in patients with Crohn's disease

Vitamin A therapy has been claimed in isolated reports to be of benefit to patients with Crohn's disease. To investigate this further, 86 patients were entered into a long-term double-blind study of vitamin A, 50,000 U twice daily, as compared with placebo. After a mean of 14.1 mo of treatment there was no significant difference between the groups as measured by a variety of activity indices (including the National Cooperative Crohn's Disease Activity Index), the number of acute attacks, and the surgical rate. No toxic effects of vitamin A were observed during the study. In this study vitamin A has not been shown to be of benefit to patients with Crohn's disease who are in remission.

Rectal biopsy in Crohn's disease.

Rectal biopsies from a series of 35 patients with radiologic evidence of Crohn's disease were assessed histologically and classified according to the type of lesions identified. These were then correlated with the sigmoidoscopic findings and site of radiologic involvement. Overall, 40% of the biopsies were abnormal, and in 28% the changes were highly suggestive of Crohn's disease. Granulomas were identified in 15%. Differences between sigmoidoscopic interpretation and histologic diagnosis were present in 11% of cases. This yield of positive biopsies is similar to earlier reports but is approximately double the numbers recorded by the National Cooperative Crohn's Disease Survey. It is concluded that rectal biopsy may confirm the diagnosis in unselected cases of Crohn's disease and provide useful information in patients where the diagnosis was not previously established. In our hands rectal biopsy was an extremely safe diagnostic procedure.

Gastroenterology: An Annotated Bibliography of Recent Literature

Gastroenterology: An Annotated Bibliography of Recent Literature

National Cooperative Crohn's Disease Study: Adverse reactions to study drugs

Adverse reactions to the drugs employed in the National Cooperative Crohn's Disease Study were sought prospectively at each patient visit and by retrospective review of all patient charts. Prednisone caused evident side effects in over 50% of patients on high-dose suppressive therapy and in approximately one-third of patients on prophylactic doses. Thirty-two percent of patients on high-dose, and 26% on prophylactic-dose prednisone required dose reduction or withdrawal because of side effects. Comparable figures for sulfasalazine were 14% and 12%, and for azathioprine 32% and 20%. The incidence of nausea, vomiting, or anorexia among patients taking sulfasalazine was 46% and 34%, on high and low dose, respectively; however, this incidence was no different than that observed among patients taking placebo. These symptoms occasioned withdrawal from the study of only 4% and 3% of patients on high and low doses of sulfasalazine, respectively. Azathioprine produced leukopenia at a dose of 2.5 mg/kg body weight in 15% of patients and the mean white cell count, lymphocyte count, granulocyte count, and hematocrit all fell significantly in patients on this dose. Pancreatitis occurred in 5% of patients taking azathioprine but in no other patients. Sulfasalazine proved to be the safest effective suppressive drug for Crohn's disease. Prednisone toxicity, though substantial, is acceptable in view of its demonstrated suppressive efficacy. Azathioprine was approximately as toxic as prednisone but no more effective than placebo in suppressing active disease. None of the drugs was effective prophylactically, and all showed appreciable long-term toxicity.

National Cooperative Crohn's Disease Study: Factors determining recurrence of Crohn's disease after surgery

Records of the 569 patients in the National Cooperative Crohn's Disease Study (NCCDS) were analyzed to determine the interval from onset of symptoms to surgery, the incidence of reoperation after each surgery for Crohn's disease, and the influence of surgical intervention, type of surgery, and site of disease upon recurrence of Crohn's disease. Life-table methods were used to calculate recurrence intervals and rates. Reoperation was accepted as indicating recurrence. The cumulative probability of surgery for Crohn's disease in this group of patients was 78% at 20 yr after onset of symptoms. Although comparisons of recurrence rate after first and after second complete resection yielded no statistically significant difference, the data suggest a higher recurrence rate after the second surgery. Bypass surgery was followed by the highest reoperation rate. The time from onset of symptoms to the first operation for Crohn's disease was shortest for patients with ileocolitis, longer for those with disease involving only small bowel, and longest for those with colon-only disease. These differences were statistically significant. Thus, the site of involvement of Crohn's disease is a major determinant of outcome after surgical intervention. Seventy-three patients (13%) underwent abdominal operations for Crohn's disease during their participation in the NCCDS. They were equally divided among the four treatment groups, indicating that none of the drug regimens tested altered the incidence of surgery.

National Cooperative Crohn's Disease Study: Study design and conduct of the study

The design and execution of the National Cooperative Crohn's Disease Study are described in this paper. The Study incorporated several noteworthy features developed to meet specific demands of the disease and its therapy. A standard clinical grading system, the Crohn's Disease Activity Index (CDAI) was developed to allow uniform decentralized clinical evaluation and decision-making throughout the 5 yr of the study. All three drugs in widespread clinical use in Crohn's disease were studied both for suppressive and prophylactic efficacy and for toxicity. The study employed a scheme for double-blind evaluation of patient progress which allowed adjustment of prednisone dose according to the degree of illness and ensured continuous monitoring for serious toxicity of any study drug. Results were analyzed primarily by ranking the clinical outcome of every patient according to a uniform and detailed scheme and applying Wilcoxon nonparametric statistics. Outcome was also analyzed by life-table methods. Eleven hundred nineteen patients were entered and 604 patients were randomized at 14 study centers during the 5-yr duration of the study. Twenty patients were eliminated from analysis as not meeting diagnostic criteria for Crohn's disease, and another 15 patients were eliminated as not meeting other preestablished criteria for analysis. Nine percent of randomized patients, equally distributed in the four treatment groups, withdrew as noncompliant. Ninety percent of patients completed all or all but one protocol-specified visits, and 95% completed the final radiologic and sigmoidoscopic evaluation.

Correlations between clinical, blood leukocyte, and skin test data in the National Cooperative Crohn's Disease Study

Peripheral blood leukocyte counts, percentages of lymphocytes and granulocytes, serum albumin levels, and results of skin tests with five antigens were examined in patients randomized in the National Cooperative Crohn's Disease Study. Inspection for differences from normal and correlations with a variety of variables showed no unusual characteristics except for a high incidence of anergy (31%) at randomization, and ranging up to 47.5% after treatment.

Radiographic findings of the National Cooperative Crohn's Disease Study

On-study barium radiographs of 535 patients in the National Cooperative Crohn's Disease Study have been analyzed for the pattern of distribution of bowel disease and the individual features that characterized bowel involvement. On-study and offstudy radiographs of 403 of these patients were compared under code to judge radiographic response to drug treatment and discover correlations of radiographic findings with clinical response. Patients with more clinically active disease had more colonic disease on x-ray. Duodenal abnormalities were recognized in 22% of the patients and radiographically typical Crohn's disease of the duodenum in 8%. Recurrent Crohn's disease and that characterized by small bowel obstruction each displayed a characteristic appearance. Overall there was little evidence of radiographic improvement during the study, and little correlation between clinical response and evidence of radiologic improvement. Only patients treated with prednisone for more than 6 mo showed statistically significant radiologic improvement. Patients with definite radiographic progression or regression were found in each treatment group. Both fistula and stricture with obstruction were associated with a poor clinical response to all therapies. In view of the evidence from this study that radiographic findings do not correlate with clinical symptoms or response, the ritual use of x-ray to follow patients with Crohn's disease is unnecessary.

National Cooperative Crohn's Disease Study: Extraintestinal manifestations and perianal complications

Among 569 patients with Crohn's disease, 24% had a history of at least one extraintestinal manifestation and 36% had a history of perianal disease before randomization. Multiple extraintestinal manifestations occurred in the same patient more frequently than would be expected by chance. Seventy-six percent of patients with ileocolitis had perianal disease, extraintestinal manifestations, or both. This was significantly greater than the 58% incidence in patients with disease confined to the small bowel. Perianal complications alone were significantly more common in patients with colitis or ileocolitis than in those with disease of only the small bowel. This was true also of internal fistulization. There was a significant positive association between perianal disease and the presence of extraintestinal features. Perianal abscess appeared to respond to sulfasalazine and anal fissure to prednisone or azathioprine. These results require confirmation in larger series of patients.

National Cooperative Crohn's Disease Study: Results of drug treatment

The response of active and quiescent Crohn's disease to prednisone, sulfasalazine, or azathioprine has been studied in 569 patients in a placebo-controlled, randomized, multicenter cooperative trial. The response of active symptomatic disease to prednisone or sulfasalazine was significantly better than to placebo. Response to azathioprine was better than to placebo, but the difference did not reach conventional levels of statistical significance. Patients with colonic involvement were especially responsive to sulfasalazine, and those with small bowel involvement were especially responsive to prednisone. Patients' drug therapy immediately before entry to the study significantly affected subsequent response. For patients with quiescent disease, none of the drugs was superior to placebo in prophylaxis against flare-up or recurrence. There is less than a 5% risk that a clinically significant prophylactic effect of any of the drug regimens was missed

Azathioprine-related pancreatitis in patients with Crohn's disease

Pancreatitis developed in 6 patients in the National Cooperative Crohn's Disease Study. In five of these the diagnosis was confirmed by elevated levels of serum amylase or lipase. All cases were in the 113 patients who received azathioprine and occurred within the first 21 days of treatment. This incidence of pancreatitis was significantly greater than in the patients treated with sulfasalazine, prednisone, or placebo (P < 0.01).