Mark A. Peppercorn

Mesalamine capsules for the treatment of active Crohn's disease: Results of a 16-week trial

BACKGROUND Mesalamine is released from sulfasalazine in the colon and benefits colonic Crohns disease. The mesalamine used in this study releases the drug throughout the small bowel and colon. Therefore, this study was designed to detect benefit for Crohns disease involving the small bowel alone or both the colon and small bowel. METHODS This double-blind, randomized, multicenter prospective controlled trial compared placebo and three daily doses of mesalamine in 310 patients. The primary outcome criterion was change in the Crohns Disease Activity Index (CDAI) from baseline to final study visit. RESULTS Patients taking 4 g/day mesalamine experienced a decrease of 72 CDAI points compared with 21 points in the placebo group (P < 0.01). Remission occurred in 43% of the 4-g group and 18% of the placebo group. Patients with ileum-only disease showed a 93-point improvement on 4 g mesalamine, compared with a 2-point improvement in similar patients on placebo. Mesalamine in this trial was not associated with clinically significant toxicity. CONCLUSIONS This controlled-release mesalamine preparation is safe and effective at 4 g/day as a single agent in treatment of active Crohns disease of the ileum and colon.

Tumor necrosis factor-α, interleukin-1β, and interleukin-6 expression in inflammatory bowel disease

The etiology of ulcerative colitis (UC) and Crohns disease (CD) remains enigmatic. Infiltrating intestinal macrophages are capable of producing the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). We investigated the presence of IL-6, TNF-α and IL-1β mRNA transcripts in inflammatory bowel disease (IBD), normal, and other inflammatory intestinal specimens utilizing the polymerase chain reaction (PCR). TNF-α mRNA levels did not vary between inflammatory bowel disease and control specimens. IL-1β mRNA levels were highest in active UC and noninflammatory bowel disease inflammatory specimens while IL-6 mRNA levels were highest in active IBD specimens. Infiltrating T cells, macrophages, and B cells were identified as sources of IL-6 protein in inflammatory bowel disease specimens by immunofluorescent staining. IL-6 transcripts were elevated only in active inflammatory bowel disease specimens, suggesting that IL-6-mediated immune processes are ongoing in the inflammatory mucosal environment of CD and UC.

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.

Distribution Studies of Salicylazosulfapyridine and its Metabolites

Abstract Previous studies in the rat have indicated that the initial reaction of salicylazosulfapyridine (SAS) metabolism, reduction of the azo bond, can be attributed exclusively to the action of the intestinal bacteria. This finding raises questions concerning the amount of intact SAS that reaches its possible site of action within the lumen in inflammatory disease of the lower intestine. Accordingly, a study of the distribution of SAS and its metabolites in the rat and in man has been undertaken. In both species only small amounts of SAS were recovered in the urine. The drug was not recovered in the feces of rats but small amounts were found in the feces of 4 of 11 human subjects. In both species a consistent finding was high levels of sulfapyridine in the urine and high levels of 5-aminosalicylate in the feces. Indeed the level of 5aminosalicylate in rat feces greatly exceeded that found when an equimolar amount of 5-aminosalicylate itself was fed orally to the rats. These studies indicate that SAS is almost completely metabolized in both human subjects and rats and that there is a tendency for its metabolite 5-aminosalicylate to reach relatively high levels in the feces.

Sulfasalazine: Pharmacology, Clinical Use, Toxicity, and Related New Drug Development

Sulfasalazine is metabolized by intestinal bacteria, resulting in the release of sulfapyridine and 5-aminosalicylate. The drug is useful in the treatment of active ulcerative colitis as well as in preventing relapses of the disease in remission. Although effective in active Crohns disease as well, sulfasalazine appears to be of greater benefit to patients with colitis and ileocolitis than those with ileitis alone. 5-Aminosalicylate itself is efficacious when given in enema and suppository form; oral agents capable of delivering 5-aminosalicylate to distal disease sites are now under study. The drugs mechanism of action may relate to its effects on prostaglandin synthesis or interference with arachidonic acid metabolism by the lipoxygenase pathway. Common adverse reactions of sulfasalazine, including nausea, headache, and anorexia, as well as hemolysis, are associated with high serum sulfapyridine levels and often can be avoided by lowering the dose of sulfasalazine. Mild allergic reactions, such as rash and fever, may be overcome by gradual desensitization.

Effect of Topical 5-aminosalicylic Acid (5-asa) Therapy on Rectal Musocal Biopsy Morphology in Chronic Ulcerative Colitis

Classic teaching emphasizes that chronic ulcerative colitis is characterized morphologically by the presence of fixed architectural and cellular mucosal changes that categorize the process as chronic. To examine the effect of topical 5-aminosalicylic acid (5-ASA) enemas on the presence of six histological features of chronicity in established chronic ulcerative colitis, 123 mucosal biopsies were taken prospectively at 1-month intervals, all from the same anatomic location (10 cm), from 14 patients treated with either 5-ASA or placebo enemas. The biopsies were evaluated for the presence of mixed inflammation in the lamina propria, crypt architectural abnormalities, basally located lymphoid aggregates, basal plasmacytosis, villiform surface epithelial configuration, and Paneth cell metaplasia. Overall, 29% of biopsies from 64% of patients were histologically normal (no chronic features, no active disease). Compared with patients treated with placebo enemas, patients treated with 5-ASA enemas showed a significantly higher percentage of normal biopsies (36% ASA group vs. 12% placebo group; p = 0.005) and a lower percentage occurrence of each individual histological feature of chronicity. In addition, patients treated with 5-ASA had a higher average number of normal biopsies per patient (3.0) than those treated with placebo enemas (1.3). Therefore, histologically normal-appearing mucosal biopsies do occur in established cases of chronic ulcerative colitis, and this finding is enhanced by treatment with 5-ASA enemas. Awareness of these results should prevent the presence of normal rectal mucosal biopsy findings in chronic ulcerative colitis patients from being misinterpreted as either evidence against this diagnosis or as representing focal skip areas characteristic of Crohns disease.

Risk of early surgery for Crohn's disease: implications for early treatment strategies.

OBJECTIVES:In this study we aimed to define the rate of early surgery for Crohns disease and to identify risk factors associated with early surgery as a basis for subsequent studies of early intervention in Crohns disease.METHODS:We assembled a retrospective cohort of patients with Crohns disease diagnosed between 1991 and 1997 and followed for at least 3 yr, who were identified in 16 community and referral-based practices in New England. Chart review was performed for each patient. Details of baseline demographic and disease features were recorded. Surgical history including date of surgery, indication, and procedure were also noted. Risk factors for early surgery (defined as major surgery for Crohns disease within 3 yr of diagnosis, exclusive of major surgery at time of diagnosis) were identified by univariate analysis. Multiple logistic regression was used to identify independent risk factors.RESULTS:Of 345 eligible patients, 69 (20.1%) required surgery within 3 yr of diagnosis, excluding the 14 patients (4.1%) who had major surgery at the time of diagnosis. Overall, the interval between diagnosis and surgery was short; one half of all patients who required surgery underwent operation within 6 months of diagnosis. Risk factors identified by univariate analysis as significantly associated with early surgery included the following: smoking; disease of small bowel without colonic involvement; nausea and vomiting or abdominal pain on presentation; neutrophil count; and steroid use in the first 6 months. Disease localized to the colon only, blood in the stool, use of 5-aminosalicylate, and lymphocyte count were inversely associated with risk of early surgery. Logistic regression confirmed independent associations with smoking as a positive risk factor and involvement of colon without small bowel as a negative risk factor for early surgery.CONCLUSIONS:The rate of surgery is high in the first 3 yr after diagnosis of Crohns disease, particularly in the first 6 months. These results suggest that improved risk stratification and potent therapies with rapid onset of action are needed to modify the natural history of Crohns disease.

Ultrastructural immunogold localization of subcellular sites of TNF‐α in colonic Crohn's disease

Tumor necrosis factor‐α, a proinflammatory cytokine, might have an important role(s) in initiating, modifying, and/or sustaining chronic inflammatory processes such as those that characterize Crohns disease, an inflammatory bowel disease of unknown etiology. We used an immunogold ultrastructural morphometric approach to localize tumor necrosis factor‐α in colonic Crohns disease biopsies. Tumor necrosis factor‐α was present in seven cell types (fibroblasts, eosinophils, mast cells, macrophages, colonic epithelial absorptive cells, Paneth cells, neutrophils). Tumor necrosis factor‐α‐containing subcellular organelles included lipid bodies (fibroblasts, eosinophils, macrophages, mast cells, colonic epithelial cells, neutrophils), secretory granules (eosinophils, Paneth cells), phagolysosomes (macrophages, colonic epithelial cells), and Golgi structures and vesicle membranes (neutrophils). A gradient of extracellular tumor necrosis factor‐α immunoreactivity surrounded eosinophils, mast cells, and macrophages. P values of gold counts/μm2 were significant for all cells, organelles, and extracellular spaces measured, and all positive structures significantly exceeded the background labeling density/μm2. Specificity controls (normal rabbit serum, tumor necrosis factor‐α‐absorbed primary antibody) either failed to label these sites or gave markedly reduced specific tumor necrosis factor‐α labeling, respectively. These findings represent the first ultrastructural localization of the subcellular sites of TNF‐α in vivo in seven cell lineages in human colonic tissues.

Advances in drug therapy for inflammatory bowel disease.

PURPOSE To identify advances in drug therapy for inflammatory bowel disease, and to evaluate the effectiveness of the new agents in treating both ulcerative colitis and Crohn disease. DATA IDENTIFICATION Studies published from January 1980 through June 1989 were identified using MEDLINE and through extensive hand searching of bibliographies in identified articles. STUDY SELECTION One hundred and ten articles directly related to the topic were found and analyzed. Another 42 articles were relevant to the material reviewed. DATA EXTRACTION Articles were selected on the basis of study quality and their significance with regard to treatment of inflammatory bowel disease. RESULTS OF DATA ANALYSIS The aminosalicylates are emerging as effective and safe therapy for inflammatory bowel disease. Corticotropin can be considered the drug of choice for certain patients with severe ulcerative colitis, and new rapidly metabolized topical steroids appear to be as effective as traditional forms and have fewer side effects. Immunosuppressive agents, including 6-mercaptopurine and azathioprine, may be useful in treating difficult-to-manage patients with either Crohn disease or ulcerative colitis, whereas cyclosporine appears promising but should be reserved for patients in whom other measures have failed. Patients with refractory perineal Crohn disease and those with Crohn colitis may benefit from metronidazole. Many other drugs including clonidine, cromoglycate, chloroquine, fish oil, methotrexate, antituberculous agents, interferon, and superoxide dismutase have shown enough promise in preliminary studies to warrant controlled clinical trials. CONCLUSIONS Drug therapy for inflammatory bowel disease, limited for many years to sulfasalazine and some corticosteroids, has been extended to include the aminosalicylates, rapidly metabolized topical steroids, immunosuppressive agents, and metronidazole. Potentially useful newer drugs await further study.

Is there a role for antibiotics as primary therapy in Crohn's ileitis?

Although their use has been deemed plausible by previous investigators, the role of antibiotics as primary therapy in active Crohns ileitis is still unclear. Here we detail the response of four patients with active ileitis to ciprofloxacin, a quinolone antibiotic. Each patient had a dramatic improvement in abdominal pain and diarrhea coincident with the institution of ciprofloxacin, despite the absence of any obvious enteric infection. It is uncertain whether ciprofloxacin is treating an undetected pathogen, bacterial overgrowth, an unsuspected microperforation, or even if it is having its effect through a mechanism entirely unrelated to its antimicrobial properties. Our experience suggests that there is a need for a prospective controlled trial of ciprofloxacin or other antibiotics in active Crohns ileitis.