Geert R. D'Haens

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.

Efficacy and Safety of Retreatment With Anti-Tumor Necrosis Factor Antibody (Infliximab) to Maintain Remission in Crohn's Disease

BACKGROUND & AIMS Infliximab, an anti-tumor necrosis factor monoclonal antibody, rapidly reduces signs and symptoms of active Crohns disease. The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit. METHODS The efficacy, safety, pharmacokinetics, and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a randomized, double-blind, placebo-controlled, parallel group trial. Seventy-three patients with active Crohns disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response (>/=70-point decrease in the Crohns Disease Activity Index) to an initial infusion of infliximab (or placebo) were studied. RESULTS Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab. Median values for Crohns Disease Activity Index, inflammatory bowel disease questionnaire (a quality of life measurement), and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment, but not with placebo retreatment. Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity. One case of lymphoma and 1 case of suspected lupus were reported; the complete long-term safety profile of infliximab requires additional clinical investigation. CONCLUSIONS Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohns disease not responding to conventional treatments.

Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial

BACKGROUND Most patients who have active Crohns disease are treated initially with corticosteroids. Although this approach usually controls symptoms, many patients become resistant to or dependent on corticosteroids, and long exposure is associated with an increased risk of mortality. We aimed to compare the effectiveness of early use of combined immunosuppression with conventional management in patients with active Crohns disease who had not previously received glucocorticoids, antimetabolites, or infliximab. METHODS We did a 2-year open-label randomised trial at 18 centres in Belgium, Holland, and Germany between May, 2001, and January, 2004. We randomly assigned 133 patients to either early combined immunosuppression or conventional treatment. The 67 patients assigned to combined immunosuppression received three infusions of infliximab (5 mg/kg of bodyweight) at weeks 0, 2, and 6, with azathioprine. We gave additional treatment with infliximab and, if necessary, corticosteroids, to control disease activity. 66 patients assigned to conventional management received corticosteroids, followed, in sequence, by azathioprine and infliximab. The primary outcome measures were remission without corticosteroids and without bowel resection at weeks 26 and 52. Analysis was by modified intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00554710. FINDINGS Four patients (two in each group) did not receive treatment as per protocol. At week 26, 39 (60.0%) of 65 patients in the combined immunosuppression group were in remission without corticosteroids and without surgical resection, compared with 23 (35.9%) of 64 controls, for an absolute difference of 24.1% (95% CI 7.3-40.8, p=0.0062). Corresponding rates at week 52 were 40/65 (61.5%) and 27/64 (42.2%) (absolute difference 19.3%, 95% CI 2.4-36.3, p=0.0278). 20 of the 65 patients (30.8%) in the early combined immunosuppression group had serious adverse events, compared with 19 of 64 (25.3%) controls (p=1.0). INTERPRETATION Combined immunosuppression was more effective than conventional management for induction of remission and reduction of corticosteroid use in patients who had been recently diagnosed with Crohns disease. Initiation of more intensive treatment early in the course of the disease could result in better outcomes.

The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations.

Principal changes with respect to the 2004 ECCO guidelines Ileocolonoscopy is recommended within the first year after surgery where treatment decisions may be affected (Statement 8C). Thiopurines are more effective than mesalazine or imidazole antibiotics alone in post-operative prophylaxis (Statement 8F). ### 8.1 Epidemiology of post-operative Crohns disease In the natural history of CD, intestinal resection is almost unavoidable since about 80% of patients require surgery at some stage. Surgery is unfortunately not curative as the disease inexorably recurs in many patients. The post-operative recurrence rate varies according to the definition used: clinical, endoscopic, radiological, or surgical. It is lowest when the repeat resection rate is considered, intermediate when clinical indices are used and highest when endoscopy is employed as the diagnostic tool.1–10 Data from endoscopic follow-up of patients after resection of ileo-caecal disease have shown that in the absence of treatment, the post-operative recurrence rate is around 65–90% within 12 months and 80–100% within 3 years of the operation. The clinical recurrence without therapy is about 20–25%/year.1,10 It has been demonstrated that the post-operative clinical course of CD is best predicted by the severity of endoscopic lesions. Symptoms, in fact, appear only when severe lesions are present and it is not uncommon to observe patients with fairly advanced recurrent lesions at endoscopy who remain asymptomatic.1 For these reasons, clinical indices such as the CDAI have low sensitivity at discriminating between patients with or without post-operative recurrence.11 These data mandate strategies aimed at interrupting or delaying the natural course of post-operative recurrence. Several medications have been tried in an attempt to prevent post-operative recurrence, mostly with disappointing results. The aim of this Consensus was therefore critically to evaluate the optimal strategies for the management of post-operative recurrence in CD. Most, if not all, of the evidence available deals with …

Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial.

Context Can adalimumab, an antitumor necrosis factor (anti-TNF) agent, induce remission in patients with Crohn disease who do not respond to or cannot tolerate another anti-TNF agent? Contribution This double-blind, placebo-controlled trial included 325 adults with Crohn disease who had symptoms despite treatment with infliximab or who could not tolerate infliximab because of adverse events. At 4 weeks, more patients randomly assigned to the adalimumab group achieved remission than did those in the placebo group (21% vs. 7%). Cautions The trial did not directly compare efficacy of different anti-TNF agents and did not assess maintenance of response or the long-term immunogenicity of adalimumab. The Editors Tumor necrosis factor (TNF) is an important proinflammatory cytokine in treating Crohn disease (1). Infliximab is a chimeric, anti-TNF monoclonal antibody effective in inducing and maintaining response and remission in patients with moderate to severe Crohn disease (2, 3). Some patients treated with infliximab experience a loss of efficacy over time or become intolerant of infliximab (47). Adalimumab, a human anti-TNF monoclonal antibody, is effective for inducing and maintaining remission in patients with Crohn disease who are naive to infliximab (810). Both adalimumab and certolizumab pegol (a pegylated humanized antibody fragment [Fab] to TNF) are effective for maintaining remission in a broad population of patients with Crohn disease who are naive to infliximab or who have responded to infliximab and then electively discontinued treatment despite continued response or because of lost response, intolerance, or both (10, 11). To our knowledge, no controlled trials have been conducted with these agents in a sample restricted to patients with lost response or intolerance to infliximab. We conducted a 4-week, placebo-controlled trial (GAIN [Gauging Adalimumab Efficacy in Infliximab Nonresponders]), in which adult patients with moderate to severe Crohn disease who had symptoms despite infliximab therapy or who could not take infliximab because of adverse events received adalimumab induction therapy. The Appendix shows the list of investigators for the GAIN trial group. Methods Design Overview This randomized, double-blind, placebo-controlled trial was conducted at 52 centers from November 2004 to December 2005 (last patient contact was on 26 June 2006). The protocol was approved by the institutional review board at each center. All patients provided written informed consent. Setting and Participants Fifty-two sites in the United States, Canada, Belgium, and France enrolled patients, with 1 to 29 patients at each site. We recruited patients from tertiary care centers, academic medical institutions, and independent research organizations. Eligible patients included men and women 18 to 75 years of age with Crohn disease for at least 4 months that was moderately to severely active at baseline, defined by a Crohns Disease Activity Index (CDAI) (12) score of 220 to 450 points (range, 0 to 600 points; greater scores indicate more severe disease activity). We required radiologic or endoscopic evidence to confirm the presence of Crohn disease. To be included, patients must have been intolerant of infliximab or must have previously responded to infliximab and then lost response. We excluded patients who had a primary nonresponse to infliximab as defined by the investigator, received infliximab or another TNF antagonist within the past 8 weeks, previously received adalimumab (Humira, Abbott Laboratories, Abbott Park, Illinois), or participated in an adalimumab clinical trial. Concurrent therapies, including stable dosages of 5-aminosalicylates, prednisone (40 mg/d), budesonide (9 mg/d), azathioprine, 6-mercaptopurine, methotrexate, and antibiotics, were permitted. We excluded patients who changed dosages or discontinued azathioprine, 6-mercaptopurine, or methotrexate treatment within 12 weeks of screening. Similarly, we excluded patients who changed dosages or discontinued 5-aminosalicylates, mesalamine, or sulfasalazine treatment within 4 weeks of screening. Prednisone (40 mg/d) and budesonide (9 mg/d) dosages must have been stable for 2 weeks or more before screening. Dosages of all these medications were required to remain stable during the study. We excluded patients with the short bowel syndrome, a symptomatic stricture, or bowel resection within the past 6 months; those who had undergone ostomy or ileoanal pouch; and those receiving total parenteral nutrition. We also excluded patients who had received antibiotic treatment for infections not related to Crohn disease within 3 weeks of the study and those with untreated tuberculosis or demyelinating disorders. We excluded female patients who were pregnant or were breast-feeding. We also excluded patients with a history of clinically significant drug or alcohol abuse in the past year; abnormal results on electrocardiography; or elevated concentrations of aspartate or alanine aminotransferase (>1.75 times the upper limit of the reference range), total bilirubin (51.3 mol/L [3 mg/dL]), or serum creatinine (>141.4 mol/L [>1.6 mg/dL]). Randomization and Intervention We randomly assigned eligible patients to receive subcutaneous injections of adalimumab, 160 mg at week 0 and 80 mg at week 2, or placebo at weeks 0 and 2 and followed patients through week 4. Patients, investigators, study site personnel, and Abbott Laboratories were unaware of treatment assignments. Randomization was completed through a central computer-generated scheme stratified by site, with block sizes of 4. Patient numbers were centrally assigned by an interactive voice-response system in consecutive order. The system provided access to blinded patient treatment information for medical emergencies only. Patients who successfully completed week 4 were eligible to enter an open-label extension study of the long-term safety of repeated administration of adalimumab. Outcomes and Measurements We classified patients as having a loss of response if they had a history of an initial response to infliximab, as defined by the investigator; had received at least 2 doses of infliximab of 5 mg/kg of body weight or more every 8 weeks; and had lacked improvement or had worsening in at least 1 of the following signs or symptoms related to Crohn disease at least 2 weeks after receiving the last dose of infliximab: stool frequency, daily abdominal pain, fever, recurring drainage from a previously nondraining fistula or development of a new draining fistula, rectal bleeding, or change in use of antidiarrheal medication. We classified patients as having intolerance of infliximab if they had a history of discontinuing infliximab treatment because of a clinically significant acute or delayed infusion reaction. We defined a clinically significant acute infusion reaction as an adverse reaction that occurred during or within 24 hours of an infliximab infusion, was considered to be related to the infusion by the physician, and manifested as at least 1 of the following symptoms: temperature greater than 100F; chills or rigors; itching; rash; flushing; urticaria or angioedema; breathing difficulties (dyspnea, chest paint or tightness, shortness of breath, wheezing, or stridor); and clinical hypotension (pallor, diaphoresis, faintness, or syncope), blood pressure less than 90/60 mm Hg, or orthostatic decrease in systolic blood pressure greater than 20 mm Hg. We defined a clinically significant delayed infusion reaction as an adverse reaction that occurred more than 24 hours and fewer than 15 days after an infliximab infusion; was considered to be related to the infusion by the physician; and was manifested through at least 1 of the following symptoms: myalgias, arthralgias, temperature greater than 100F, malaise, and rash. The primary efficacy end point was the proportion of patients with remission at week 4. Remission was defined as a CDAI score less than 150 points (12). Response was defined as a decrease from baseline in CDAI score of 70 points or more (70-point response) or of 100 points or more (100-point response) at week 4. Follow-up Procedures Patients were assessed 2 weeks before randomly assigned treatment began; on day 0; and at 1, 2, and 4 weeks. At each visit, the CDAI score was determined, adverse events and concomitant medications were recorded, and samples were collected for laboratory evaluations. The Inflammatory Bowel Disease Questionnaire (IBDQ) was administered to assess patient-reported outcomes at weeks 0 and 4 (total score range, 32 to 224; greater scores indicate better quality of life) (13). Safety evaluations included physical examinations. Laboratory evaluations included hematologic analysis; serum biochemical analysis; urinalysis; and determination of concentrations of C-reactive protein, adalimumab and antibodies to adalimumab, and infliximab and antibodies to infliximab. Adverse events were recorded through queries, observations by site personnel, and spontaneous patient reports. Investigators assessed and recorded any adverse event, including date of onset, description, severity, time course, duration, outcome, relationship of event to the study drug, alternate causes for events not considered to be probably related to the study drug, final diagnosis (if known), and any actions taken. Investigators rated the severity of each event (mild, moderate, or severe) and the relationship to study drug (probably related, possibly related, probably not related, or not related) on the basis of standard definitions. Serious adverse events were recorded through scheduled telephone contacts, study visits, and spontaneous patient reports from the time informed consent was signed until 70 days after withdrawal of study drug treatment. A data monitoring committee met every 4 to 6 months to discuss unblinded data and recommend either continuing or amending the study. A sponsor steering committee of senior executives w

Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum

BACKGROUND & AIMS Postoperative recurrence of Crohns disease may be triggered by agents in the fecal stream. The aim of this study was to examine intestinal mucosal inflammation induced by contact with intestinal fluids in surgically excluded ileum. METHODS The effects of infusion of intestinal luminal contents into excluded ileum in 3 patients with Crohns disease who had undergone a curative ileocolonic resection with ileocolonic anastomosis and temporary protective proximal loop ileostomy were studied by histopathology and electron microscopy. RESULTS Contact with intestinal fluids for 8 days induced focal infiltration of mononuclear cells, eosinophils, and polymorphonuclear cells in the lamina propria, small vessels, and epithelium in the excluded neoterminal ileum that was previously normal. Epithelial HLA-DR expression increased, and mononuclear cells expressed the KP-1 antigen associated with activation. Marked up-regulation of RFD-7, RFD-9, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 1 was observed after infusion, reflecting epithelioid transformation and transendothelial lymphocyte recruitment. At the ultrastructural level, dilatation of the endoplasmic reticulum and Golgi apparatus occurred in epithelial cells, where also basally located transport vesicles were identified. CONCLUSIONS Intestinal contents trigger postoperative recurrence of Crohns disease in the terminal ileum proximal to the ileocolonic anastomosis in the first days after surgery.

Endoscopic and histological healing with infliximab anti–tumor necrosis factor antibodies in Crohn's disease: A European multicenter trial

BACKGROUND & AIMS Tumor necrosis factor (TNF) is a pivotal cytokine in intestinal inflammation. Controlled trials using a chimeric anti-TNF antibody (infliximab) have shown its efficacy in refractory Crohns disease. METHODS Endoscopic and histological response to infliximab was investigated in a multicenter, randomized, double-blind, and placebo-controlled trial including 30 patients with active Crohns disease undergoing ileocolonoscopy before and 4 weeks after intravenous administration of 5, 10, or 20 mg/kg of infliximab or placebo as a single infusion. Lesions were scored by means of the validated Crohns Disease Endoscopic Index of Severity (CDEIS). Endoscopic biopsy specimens were taken during both procedures from 9 of 30 patients and scored by a single gastrointestinal pathologist. RESULTS CDEIS scores decreased significantly in most infliximab-treated patients without an apparent dose response. No endoscopic improvement was observed in the placebo group. The changes in CDEIS correlated highly with those of the Crohns Disease Activity Index. At a histological level, disappearance of the inflammatory infiltrate was observed in infliximab-treated patients but not in placebo-treated ones; however, architectural changes persisted in most patients. Strictures developed in several patients. CONCLUSIONS Clinical improvement after infliximab therapy in active Crohns disease is accompanied by significant healing of endoscopic lesions and disappearance of the mucosal inflammatory infiltrate.

Adalimumab Induces and Maintains Clinical Remission in Patients With Moderate-to-Severe Ulcerative Colitis

BACKGROUND & AIMS Adalimumab is a fully human monoclonal antibody that binds tumor necrosis factor (TNF)-α. Its efficacy as maintenance therapy for patients with ulcerative colitis has not been studied in a controlled, double-blind trial. METHODS Ulcerative colitis long-term remission and maintenance with adalimumab 2 (ULTRA 2) was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of adalimumab in induction and maintenance of clinical remission in 494 patients with moderate-to-severe ulcerative colitis who received concurrent treatment with oral corticosteroids or immunosuppressants. Patients were stratified based on prior exposure to TNF-α antagonists (either had or had not been previously treated with anti-TNF-α) and randomly assigned to groups given adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every other week or placebo. Primary end points were remission at weeks 8 and 52. RESULTS Overall rates of clinical remission at week 8 were 16.5% on adalimumab and 9.3% on placebo (P = .019); corresponding values for week 52 were 17.3% and 8.5% (P = .004). Among anti-TNF-α naïve patients, rates of remission at week 8 were 21.3% on adalimumab and 11% on placebo (P = .017); corresponding values for week 52 were 22% and 12.4% (P = .029). Among patients who had previously received anti-TNF agents, rates of remission at week 8 were 9.2% on adalimumab and 6.9% on placebo (P = .559); corresponding values for week 52 were 10.2% and 3% (P = .039). Serious adverse events occurred in 12% of patients given adalimumab or placebo. Serious infections developed in 1.6% of patients given adalimumab and 1.9% given placebo. In the group given adalimumab, 1 patient developed squamous cell carcinoma and 1 developed gastric cancer. CONCLUSIONS Adalimumab was safe and more effective than placebo in inducing and maintaining clinical remission in patients with moderate-to-severe ulcerative colitis who did not have an adequate response to conventional therapy with steroids or immunosuppressants.

European evidence based consensus on the diagnosis and management of Crohn's disease: current management.

This second section of the European Crohn’s and Colitis Organisation (ECCO) Consensus on the management of Crohn’s disease concerns treatment of active disease, maintenance of medically induced remission, and surgery. The first section on definitions and diagnosis includes the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn’s disease. The third section on special situations in Crohn’s disease includes postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy for Crohn’s disease.

Mucosal Healing Predicts Sustained Clinical Remission in Patients With Early-Stage Crohn's Disease

BACKGROUND & AIMS Few prospective data are available to support the clinical relevance of mucosal healing in patients with Crohns disease. This study examined whether complete healing, determined by endoscopy, predicts a better outcome in Crohns disease. METHODS One-hundred thirty-three newly diagnosed and treatment-naïve Crohns disease patients were given either a combination of immunosuppressive therapy (azathioprine) and 3 infusions of infliximab or treatment with conventional corticosteroids. Patients given azathioprine were given repeated doses of infliximab for relapses, patients given corticosteroids were given azathioprine in cases of corticosteroid dependency and infliximab only if azathioprine failed. A representative subset of 49 patients from the initially randomized cohort underwent ileocolonoscopy after 2 years of therapy. Correlation analysis was performed between different clinical parameters including endoscopic activity (Simple Endoscopic Score) and clinical outcome 2 years after this endoscopic examination. Data were available from 46 patients 3 and 4 years after therapy began. RESULTS Complete mucosal healing, defined as a simple endoscopic score of 0 after 2 years of therapy, was the only factor that predicted sustained, steroid-free remission 3 and 4 years after therapy was initiated; it was observed in 17 of 24 patients (70.8%) vs 6 of 22 patients with lesions detected by endoscopy (27.3%, Simple Endoscopic Score >0) (P = .036; odds ratio = 4.352; 95% confidence interval, 1.10-17.220). Fifteen of 17 patients with mucosal healing at year 2 maintained in remission without further infliximab infusions during years 3 and 4 (P = .032; odds ratio = 4.883; 95% confidence interval, 1.144-20.844). CONCLUSIONS Complete mucosal healing in patients with early-stage Crohns disease is associated with significantly higher steroid-free remission rates 4 years after therapy began.