Kenneth R. Falchuk

Clinical experience with infliximab therapy in 100 patients with Crohn's Disease

OBJECTIVE:The aim of this study was to assess our clinical experience with infliximab, a monoclonal antitumor necrosis factor antibody, following its approval for treatment of refractory Crohns disease (CD).METHODS:We followed 100 consecutive patients with CD (53 women and 47 men; mean age, 41 yr) who received a total of 233 infliximab (5 mg/kg) infusions. Adverse events were noted and clinical response assessed every 2 wk for 6 months after each infusion using the Harvey Bradshaw Index (HBI) for active disease, the Perianal Disease Activity Index (PDAI) for fistulous disease, and steroid withdrawal rates for steroid-sparing efficacy.RESULTS:Indications for therapy were active disease (n = 57), perianal fistulous disease (n = 33), and steroid dependency (n = 10). Significant infusion reactions occurred in 16 patients (6.9% of infusions) including anaphylactic shock in one patient. Fourteen patients experienced infectious adverse events, 13 of whom were on concurrent steroids. Sixty percent of patients with active disease experienced ≥50% HBI reduction at 2 wk; mean duration of response, 8.2 wk. Three of 26 first-time nonresponders with active disease (12%) responded to a second infusion. Sixty-nine percent of patients with fistulous disease experienced >50% reduction in their PDAI at 2 wk; mean duration of response, 10.9 wk. Four of 10 steroid-dependent patients (40%) discontinued steroid therapy, one of whom recommenced steroid therapy at 24 wk.CONCLUSIONS:Our clinical response rates mirror the efficacy reported in the controlled trials for active and fistulous disease. Steroid-sparing efficacy was seen in 40% of steroid-dependent patients. Concurrent steroids did not reduce the risk of significant infusion reactions (6.9%), but did increase the risk of infections.

A Multicenter Placebo-controlled Clinical Trial of Oral Metoclopramide in Diabetic Gastroparesis

40 patients with diabetic gastroparesis. Results of a 3-wk double-blind study indicate that metoclopramide at a dosage of one 10-mg tablet four times daily reduced nausea, vomiting, fullness, and early satiety and improved meal tolerance better than placebo. Statistically significant differences were noted for nausea and postprandial fullness. Mean gastric emptying assessed by radionuclide scintigraphy was significantly improved in the metoclopramide-treated group when compared with their baseline result. Metoclopramide is an effective agent for improving the upper gastrointestinal motor function in diabetic patients with gastroparesis.

Serum Lysozyme in Crohn's Disease and Ulcerative Colitis

Serum lysozyme (muramidase) concentrations were determined in patients with different types of inflammatory bowel disease and in normal subjects. The mean (plus or minus S.E.M.) lysozyme concentration for each group was as follows: controls, 8.8 plus or minus 0.3, ulcerative colitis, 9.3 plus or minus 0.6, Crohns disease, 26.3 plus or minus 1.4. a and bacterial and nonbacterial enteritis, 8.9 plus or minus 0.7 mug per milliliter. Thus, mean enzyme levels were significantly greater in Crohns disease than in ulcerative colitis (p smaller than 0.001), bacterial and nonbacterial enteritis (p smaller than 0.001) and healthy volunteers (p smaller than 0.001). The elevation of serum lysozyme in Crohns disease may be related to tissue macrophages because no correlation was found between either the serum lysozyme concentration and the white-cell counts or the absolute numbers of circulating granulocytes or monocytes. Our findings suggest that serum lysozyme may be useful in the differential diagnosis of Crohns disease from other types of bowel inflammation.

Widespread cytomegalovirus gastroenterocolitis in a patient with acquired immunodeficiency syndrome.

This case report documents extensive gastrointestinal cytomegalovirus infection in a patient with acquired immunodeficiency syndrome, presenting as diarrhea and involving stomach, duodenum, and colon. Endoscopic biopsy specimens and cultures were essential to make the diagnosis and to distinguish the illness from inflammatory bowel disease. A careful search for other potential pathogens was made as well. The discussion includes a review of literature regarding cytomegalovirus involvement of the gastrointestinal tract.

Three brothers with dysphagia caused by eosinophilic esophagitis

Idiopathic eosinophilic esophagitis (EE) is a chronic inflammatory disorder of the esophagus characterized by dense infiltration of eosinophils within the squamous epithelium. It is distinct from the eosinophilic infiltration of the esophagus associated with GERD and eosinophilic gastroenteritis. The pathogenesis of EE is not entirely clear. There is a strong association with allergies, and it may be a response to environmental allergens, particularly food allergens. Personal and family histories of allergic diseases were noted in 62% to 85% of patients. It is more frequently reported in pediatric patients but can be present at any age, and the incidence in adults appears to be increasing. More than three fourths of reported patients are maleda predilection not yet explained. This report describes 3 adult brothers with dysphagia; in all 3 cases, EE was ultimately diagnosed. Although the true prevalence of the EE is unclear, data from an Australian population suggest that it may be approximately 0.01%. If there is no familial component to the disease, the probability that 3 brothers would develop EE is 10 . Given the low probability of such an occurrence, our 3 patients highlight and suggest potential hereditary and genetic features in the pathogenesis of EE. This is an association that has not been reported.

The Incidence and Clinical Spectrum of Refractory Celiac Disease in a North American Referral Center

OBJECTIVES:Refractory celiac disease (RCD) is one of the most serious causes of persistent symptoms in patients with celiac disease (CD). Published reports suggest that approximately half of patients in Europe are RCD type II, which carries a poor prognosis with a 5-year survival rate of ∼50% compared with ∼90% for RCD type I. However, disease patterns may be different in North America. The aim of this study was to explore the clinical spectrum of RCD in a North American population.METHODS:Medical records of patients with biopsy-proven CD presenting to our institution were reviewed for a diagnosis of RCD. Demographic data, clinical characteristics, and mortality were evaluated and compared with our general CD population.RESULTS:In all, 34 out of 844 (4.0%) CD patients had RCD. The cumulative incidence of RCD for patients diagnosed with CD at our center was 1.5%. Unintentional weight loss at diagnosis of RCD was found in 76.5% (n=26) compared with 16.7% (n=141) at diagnosis of CD (P<0.0001) and diarrhea at diagnosis of RCD was found in 79.4% (n=27) compared with 40.5% (342) at diagnosis of CD (P<0.0001). Five patients (14.7%) were diagnosed with RCD type II and of these, two died of enteropathy-associated lymphoma within 24 months of diagnosis of CD (observed mortality rate 5.9%).CONCLUSIONS:Although RCD is a serious condition with significant morbidity; the observed mortality rates are low in our population. This study suggests that RCD may be less severe in North American vs. European populations.

Histologic Markers of Inflammation in Patients With Ulcerative Colitis in Clinical Remission

BACKGROUND & AIMS Mucosal healing, based on histologic analysis, is an end point of maintenance therapy for patients with ulcerative colitis (UC). There are few data on how histologic signs of inflammation correlate with endoscopic and peripheral blood measures of inflammation in these patients. We investigated patterns of histologic features of inflammation in patients with UC in clinical remission, and correlated these with endoscopic and biochemical measures of inflammation. METHODS We performed a prospective observational study of 103 patients with UC in clinical remission undergoing surveillance colonoscopy while receiving maintenance therapy with mesalamine or thiopurines; 2674 biopsy specimens were collected from 708 colonic segments. Each colonic segment was evaluated based on the Mayo endoscopic subscore and the Geboes histology score (range, 0-5.4). Biomarkers were measured in peripheral blood samples. RESULTS Histologic features of inflammation were found in 54% of patients receiving maintenance therapy; 37% had at least moderate inflammation based on histology scores. Of the 52 patients with endoscopic evidence only of left-sided colitis, 34% had histologic features of inflammation in their proximal colon. Histology scores correlated with endoscopic scores for per-segment inflammation (Spearman ρ = 0.65; P < .001). Patients with histology scores greater than 3.1 had a significantly higher mean level of C-reactive protein than those with scores less than 3.1. There were no differences among treatment groups in percentages of patients with histologic scores greater than 3.1. CONCLUSIONS Patients in clinical remission from UC still frequently have histologic features of inflammation, which correlate with endoscopic appearance. Patients with at least moderate levels of inflammation, based on histologic grading (score >3.1), have higher serum levels of C-reactive protein, which could be used as a surrogate marker of histologic inflammation.

Circulating antibodies to bovine albumin in ulcerative colitis and Crohn's disease. Characterization of the antibody response.

The presence of antibodies against a dietary protein, bovine serum albumin (BSA), was investigated in the serum of normal subjects and patients with inflammatory bowel disease and celiac disease. Antibodies to BSA were demonstrated in 28 of 30 patients with ulcerative colities (93%), 30 of 35 with Crohns disease (86%), 5 with untreated celiac disease and in 12 of 28 normal subjects (43%). In patients with inflammatory bowel disease, antibodies to BSA were present in greater amounts in those with severe and moderate disease than in those with mild disease. Moreover, in those patients with high titers of circulating antibody, the serum anti-BSA activity was always associated with IgG and sometimes with IgA. These findings suggest that an increased absorption of antigenic material and stimulation of antibody production may occur in association with intestinal mucosal damage, not only in ulcerative colitis and celiac disease, but also in Crohns disease.

A simulator-based curriculum to promote comparative and reflective analysis in an internal medicine clerkship.

Purpose To develop and evaluate a novel curricular framework using high-fidelity patient simulation in an internal medicine clerkship. Method Two 90-minute simulator-based modules of ischemic heart failure and hypoxemic respiratory failure were developed from adult and experiential learning principles. Three short simulated cases focused on each pathophysiologic concept were intermixed with two short teaching sessions and a period of comparative analysis. In 2002–03, the program was piloted among 90 third-year medical students at Harvard Medical School assigned to complete their core internal medicine clerkship. An entry and two follow-up questionnaires were used to assess the process. The instructors conducted quantitative and qualitative data analysis and directly observed students’ performances. Results Instructors consistently noted students’ ability to appropriately extract a history, perform a basic examination, and order appropriate tests. However, students demonstrated repeated errors in the application of knowledge to the clinical circumstance. A final comparative discussion was essential to new learning and students recognized this integrative analysis as the most critical component of the exercise. Every student reported the experience as useful. Ninety-four percent (n = 85) felt the simulator should become a routine part of the clerkship and 68% (n = 71) desired three or more sessions during their internal medicine clerkship. Conclusions Simulator-based curricular modules are feasible in an internal medicine clerkship and can successfully complement existing curricula. By comparing similar cases in a compressed time frame, students may achieve enhanced efficiencies in reflective and meta-cognitive learning. As medical simulation is increasingly available, such a curriculum may represent valuable additions to the internal medicine educational environment.

Predictors of endoscopic inflammation in patients with ulcerative colitis in clinical remission.

Background:Patients with ulcerative colitis (UC) who are in clinical remission may still have underlying endoscopic inflammation, which is associated with inferior clinical outcomes. The goal of this study was to determine the prevalence of active endoscopic disease, and factors associated with it, in patients with UC who are in clinical remission. Methods:Prospective observational study in a single center. Patients with UC in clinical remission (by Simple Clinical Colitis Activity Index) were enrolled prospectively at the time of surveillance colonoscopy. Disease phenotype, endoscopic activity (Mayo subscore), and histologic score (Geboes) were recorded, and blood was drawn for peripheral blood biomarkers. Results:Overall, 149 patients in clinical remission were prospectively enrolled in this cohort; 81% had been in clinical remission for >6 months, and 86% were currently prescribed maintenance medications. At endoscopy, 45% of patients in clinical remission had any endoscopic inflammation (Mayo endoscopy subscore >0), and 13% had scores >1. In a multivariate model, variables independently associated with a Mayo endoscopic score >1 were remission for <6 months (P = 0.001), white blood count (P = 0.01), and C-reactive protein level (P = 0.009). A model combining these 3 variables had a sensitivity of 94% and a specificity of 73% for predicting moderate-to-severe endoscopic activity in patients in clinical remission (area under the curve, 0.86). In an unselected subgroup of patients who had peripheral blood mononuclear cell messenger RNA profiling, GATA3 messenger RNA levels were significantly higher in patients with endoscopic activity. Conclusions:Duration of clinical remission, white blood count, and C-reactive protein level can predict the probability of ongoing endoscopic activity, despite clinical remission in patients with UC. These parameters could be used to identify patients who require intensification of treatment to achieve mucosal healing.