Safety of infliximab in Crohn's disease: a large single-center experience.

BACKGROUND: The aim of this study was to evaluate the short- and long-term safety experience of infliximab treatment in patients with Crohn's disease (CD) in clinical practice. METHODS: The medical records of 297 consecutive patients with CD treated with infliximab at the Beth Israel Deaconess Medical Center were reviewed for demographic features and adverse events. RESULTS: The 297 patients received a total of 1794 infusions. Patients received a median of four infusions and had a median follow-up of 14.3 months. Forty-four patients (15%) experienced a serious adverse event, requiring the infusion to be stopped in 33 patients (11%). Acute infusion reactions occurred in 18 patients (6%) including respiratory problems in 10 patients (3%) and an anaphylactoid reaction in 1 patient (0.3%). Serum sickness-like disease occurred in one patient (0.3%) and three patients (1%) developed drug-induced lupus. One patient developed a probable new demyelination disorder. Eight patients (2.7%), all of whom were on concurrent immunosuppressants, developed a serious infection, one resulting in fatal sepsis. Six patients (2%) developed malignancies including two lymphomas and two skin cancers. A total of four (1.3%) deaths were observed (median age 72.5 years); two due to gastrointestinal bleeding, one due to sepsis, and one due to malignancy. CONCLUSIONS: While short- and long-term infliximab therapy was generally well tolerated, serious adverse events occurred in 15% of patients including drug-induced lupus, fatal sepsis, and malignancy. Concomitant immunosuppressants were significantly associated with infections and deaths, particularly among elderly patients.

Recent advances in inflammatory bowel disease.

The last decade has seen tremendous advances in our knowledge, which has led to genuine improvements in our understanding of the pathogenesis and management of inflammatory bowel disease (IBD). The combined power of cellular and molecular biology has begun to unveil the enigmas of IBD, and, consequently, substantial gains have been made in the treatment of IBD. Refinements in drug formulation have provided the ability to target distinct sites of delivery, while enhancing the safety and efficacy of older agents. Simultaneous progress in biotechnology has fostered the development of new agents that strategically target pivotal processes in disease pathogenesis. This article addresses our current understanding of the pathogenesis of IBD, including the latest developments in animal models and covers agents currently used in the treatment of IBD as well as emerging therapies.

Clinical, biological, and histologic parameters as predictors of relapse in ulcerative colitis.

BACKGROUND & AIMS: Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease. We aimed to assess whether clinical, biological, and histologic parameters in quiescent UC predict time to clinical relapse. METHODS: Seventy-four patients with clinically and endoscopically determined inactive UC were followed up for 1 year or for a shorter period if they had a relapse. Serum erythrocyte sedimentation rate; C-reactive protein, interleukin (IL)-1beta, IL-6, and IL-15 values; anti-neutrophil cytoplasmic antibody titers; and rectal biopsy specimens were obtained at baseline, at 6 and 12 months, and/or at relapse. Multivariate survival analysis was performed to determine independent predictors of clinical relapse. RESULTS: Twenty-seven patients relapsed (19/42 women; 8/32 men). Multivariate Cox regression analysis retained younger age (P = 0.003; hazard ratio, 0.4 per decade), greater number of prior relapses in women (P < 0.001; hazard ratio, 1.6 per prior relapse), and basal plasmacytosis (P = 0.003; hazard ratio, 4.5) on rectal biopsy specimens as predictors of shorter time to clinical relapse. Kaplan-Meier survival curves showed the 20-30-year-old age group and women with more than 5 prior relapses to be groups with shorter times to relapse. CONCLUSIONS: Younger age, multiple previous relapses (for women), and basal plasmacytosis on rectal biopsy specimens were independent predictors of earlier relapse. These findings may help identify patients with inactive UC who will require optimal maintenance medical therapy.

Laparoscopically assisted ileocolectomy for Crohn's disease through a pfannenstiel incision.

Recently, laparoscopically assisted bowel resections have been shown to be less morbid than the traditional laparotomy, especially for benign conditions such as Crohn's disease. While reports describing laparoscopically assisted bowel resections use a small midline or right transverse incision, we describe a novel laparoscopically assisted approach employing a Pfannenstiel incision for Crohn's patients. We attempted the Pfannenstiel incision since it is well known to be associated with less postoperative pain, decreased ileus and hospital stay, and low rates of wound infection and incisional hernia, compared with midline or right transverse incisions. Furthermore, we found that the Pfannenstiel incision offers additional advantages that may be uniquely suited for Crohn's patients. First, the cosmetic position of the incision is particularly attractive to the young population affected by Crohn's. Second, the Pfannenstiel incision preserves fresh tissue in the midline, right, and left lower quadrants in the event that reoperation or stoma placement are required in the future owing to recurrent disease. We describe our technique in 10 consecutive patients undergoing ileocolectomy for Crohn's disease. Our patients experienced minimal morbidity and were pleased with the cosmetic results of their incisions.

Ileoanal pouch operation: long-term outcome with or without diverting ileostomy.

HYPOTHESIS: Avoiding a diverting ileostomy does not influence the long-term overall morbidity and functional outcome of patients after ileoanal pouch operation (IAP). DESIGN: All patients undergoing IAP were prospectively entered into a database, and those undergoing operation from October 1, 1989, through January 31, 1996, were contacted by mail questionnaire. SETTING: Tertiary referral center. PATIENTS: One hundred thirty unselected sequential patients. INTERVENTIONS: The IAP was completed by a stapled method without diverting ileostomy, provided the patient agreed, and there were no other complicating factors. MAIN OUTCOME MEASURES: Need for reoperation, fecal leakage, pouch frequency, ability to defer evacuation, pouchitis, and overall quality of life. RESULTS: Of 102 patients (78.5%) who initially underwent IAP without diverting ileostomy, 10 (9.8%) developed an anastomotic leak and required a diverting ileostomy. Additional surgery was required in 12 (9.2%) of the 130 patients for bowel obstruction and in 3 (2.3%) for pouch excision. Two patients died of unrelated causes, leaving 125 functioning pouches (96.2%). Questionnaires were completed in 111 (88.8%) of the 125; 75 patients (67.6%) reported perfect continence for gas and stool, 10 patients (9.0%), regular nighttime leakage, and 24 patients (21.6%), occasional fecal leakage. Pouch evacuation frequency (+/-SD) per 24 hours was 7.8+/-2.4 (range, 4-12), and 95.5% of patients could defer pouch evacuation. Of the 111 patients, 42.3% reported pouchitis, with 7.2% receiving long-term antibiotic therapy. Of the patients, 74.8% reported total satisfaction, and 84.7% regarded themselves as being in perfect health. CONCLUSION: Long-term outcome after IAP remains favorable with or without diverting ileostomy.

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 Crohn's 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 > or = 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.

Promising new agents for the treatment of inflammatory bowel disorders.

A groundswell of therapeutic modalities is presently sweeping through the field of inflammatory bowel disease (IBD), revolutionising the treatment and management of these disorders. At the forefront of newer agents are biological therapies, also referred to as 'biologics'. These include infliximab (cA2), CDP 571, rhIL-10, ICAM-1 antisense oligonucleotide (ISIS 2302) and opreleukin (rhIL-11). Among these, infliximab and CDP 571 are perhaps the most promising, particularly in Crohn's disease. Both are anti-TNF alpha monoclonal antibody formulations with proven efficacy at doses of 5 mg/kg for inducing remission in patients with moderate to severe refractory Crohn's disease. Infliximab is beneficial in the treatment of fistulous Crohn's disease as well. Anti-inflammatory cytokines such as rhIL-10 and opreleukin (rhIL-11) in early reports appear efficacious in Crohn's disease but not in ulcerative colitis. Budesonide, a second generation glucocorticoid, in an oral controlled ileal release capsule, is an attractive alternative to prednisone for treating active Crohn's disease of the distal ileum and proximal colon. Also available as an enema, budesonide's efficacy approximates that of prednisolone for inducing remission in active distal ulcerative colitis. Postoperative recurrences of Crohn's disease are a common clinical scenario. Recently, mesalazine, metronidazole and mercaptopurine have been re-evaluated in the postoperative setting. In the largest postoperative prophylaxis trial, mercaptopurine was superior to both placebo and mesalazine in preventing clinical, endoscopic and radiographic relapses. Finally, miscellaneous therapies such as transdermal nicotine, nicotine tartrate enemas and topical lidocaine used in pilot studies for ulcerative colitis have shown promise. Case reports of thalidomide and tacrolimus (FK 506) have reported beneficial effects in treating complicated, refractory Crohn's disease.

Mesalamine-associated thrombocytopenia.

We describe a case of a 25-yr-old woman with ulcerative colitis who developed marked thrombocytopenia during treatment and upon rechallenge with oral mesalamine. In contrast to its parent drug, sulfasalazine, which has often been reported to cause serious blood disorders, particularly agranulocytosis, mesalamine has rately been implicated as a cause of serious blood disorders. Although previous cases of hematological toxicity have been described in patients taking mesalamine, none of these patients were rechallenged in an effort to prove causality between 5-aminosalicyclic acid and the hematological abnormality as well as outrule the possible "autoimmune" contribution of inflammatory bowel disease to the hematological toxicity of these agents. This report demonstrates that mesalamine has the potential, like sulphasalazine, to cause marked thrombocytopenia in an idiosyncratic fashion. All patients receiving mesalamine therapy, either orally or topically should have regular, complete blood profiles.

Medical therapy of specific clinical presentations.

A pluridisciplinary approach that integrates medical therapy with surgery and other aspects of patient care, such as nutritional and psychosocial support, is essential to the management of patients with inflammatory bowel disease (IBD). Despite new medical therapies, such as 5-amino-salicylic acid compounds, steroids, and immunomodulators, the treatment of patients with IBD remains challenging. Success depends on the appropriate use of the available medications in relation to the severity and localization of the disease. The introduction of novel immunomodulating agents such as antitumor necrosis factor alpha is likely to have a major influence on the current therapeutic strategies. This article describes the use of the available medications in the most common clinical presentations of IBD.

Inflammatory bowel disease and pregnancy: a review.

Inflammatory bowel disease often occurs during peak reproductive years. Rates of conception, pregnancy outcome and disease course during pregnancy should be discussed prior to attempted conception. The majority of patients whose disease is well controlled prior to pregnancy should expect a fertility rate comparable to the general population, and an uncomplicated pregnancy with a favorable outcome. The disease should continue to be pharmacologically or surgically controlled as necesssary during pregnancy; the majority of drug options available to pregnant patients being without detriment to the fetus. No predictable inheritance pattern has been established and, at this time, there is no ability to screen prenatally.

Antibiotics in inflammatory bowel disease.

The use of antibiotics as primary therapy in inflammatory bowel disease (IBD) has been an issue of great controversy among the experts in the field. Although the utility of certain antimicrobial agents in managing secondary complications, such as abscess formation, toxic megacolon and pouchitis, has been substantiated by clinical trials, clear evidence to support or undermine their use as primary therapeutic agents in IBD is lacking. This may be secondary to the fact that the etiology of IBD remains unknown, and, despite much speculation and research in the area, no infectious agent has been found to cause or contribute to the pathogenesis of these disorders. The dearth of data, in turn, has resulted in widely varying treatment strategies and a lack of a clear standard of care with regard to the use of antibiotics.

Autoimmune (Hashimoto's) thyroiditis associated with Crohn's disease.

We report the occurrence of autoimmune (Hashimoto's) thyroiditis in three patients with Crohn's disease. Previously, thyroid disease has been described only in association with ulcerative colitis. We review the pertinent literature on thyroid disease in inflammatory bowel disease (IBD) and suggest that this association supports the hypothesis that autoimmunity is involved in the pathogenesis of IBD. Early diagnosis and treatment of thyroid dysfunction in patients with IBD is desirable because thyroid dysfunction worsens the symptoms and course of IBD.

Inflammatory bowel disease and colon cancer: a review.

Extensive and long-standing colitis due to Crohn's disease and ulcerative colitis is associated with an increased incidence of colorectal cancer. Colonoscopy with biopsies for mucosal dysplasia can help stratify those patients who are at increased risk. However, the effectiveness of surveillance programs has been questioned. Newer molecular techniques may eventually lead to the development of more accurate screening tools, but at this time there is not enough evidence to support their widespread use.

Inflammatory bowel disease in the elderly. Practical treatment guidelines.

Although Crohn's disease and ulcerative colitis were initially described in young adults, it has become increasingly apparent that inflammatory bowel disease (IBD) affects the elderly, with the new onset of disease occurring well into the seventh and eighth decades of life. The diagnosis of IBD in the elderly may be difficult because it can be easily confused with infectious, ischaemic and drug-related processes, as well as with diverticulitis and carcinoma. Although medical treatment for IBD is similar in the young and the elderly, consideration must be given to comorbid illnesses in the older patient. Topical agents should be used as first-line therapy for patients with distal colonic disease. In patients with more proximal involvement, oral mesalazine or sulfasalazine should be used for maintenance therapy, with corticosteroids being reserved for patients with active disease. Metronidazole is particularly efficacious in patients with colonic Crohn's disease. Finally, immunomodulators can be helpful in patients who are steroid-dependent or refractory to the therapies noted above. This article reviews and outlines practical treatment guidelines for the older patient with IBD.

Corticosteroid-associated complications in elderly Crohn's disease patients.

OBJECTIVES: Although complications occur with long-term steroid usage in elderly Crohn's disease patients, there is little information on their short-term risk. This study was designed to assess that risk. METHOD: We reviewed admissions from 1984 to 1995 and found 115 patients over age 50 yr with a confirmed flare of Crohn's disease. Of this group, 55 patients were treated with steroids. We studied potential complications including hypertension (blood pressure > or = 160/90), hyperglycemia (glucose > 200 mg/dl), hypokalemia (K < 3.5 meq/l), mental status changes, nosocomial infections, and heart failure. RESULTS: The mean age was 67 yr (50-90), and 64% were women. There were no differences in baseline characteristics between patients treated with steroids and those not treated with steroids. The relative risk for developing complications are as follows: hypertension 1.46 (95% confidence interval (CI) = 1.09-1.95), hyperglycemia, 1.53 (95% CI = 0.54-4.32), hypokalemia, 1.59 (95% CI = 1.06-2.37), mental status changes, 7.64 (95% CI = 0.97-60.1), nosocomial infection, 1.09 (95% CI = 0.37-3.18), and congestive heart failure, 1.09 (95% CI = 0.16-7.48). Multivariate analyses adjusting for age, severity index, and number of comorbid conditions demonstrated similar findings to the unadjusted analyses. Analyses stratified by patient age demonstrated a similar risk of steroid associated complications for patients < 65 and > or = 65 yr of age. CONCLUSION: Crohn's disease patients over age 50 yr treated with steroids are at significantly increased risk for developing hypertension and hypokalemia and at increased risk for developing mental status changes, but such steroid-effects were not more pronounced with advancing age.

Mesalamine-induced lung toxicity.

Lung toxicity associated with 5-aminosalicylate (5-ASA) agents is a rare entity. We report the case of a 32-yr-old woman with ulcerative colitis who developed progressive shortness of breath while taking one of the 5-ASA drugs, oral mesalamine. Bilateral pulmonary infiltrates, peripheral eosinophilia, and histological findings consistent with acute pneumonitis characterized the lung injury. Although the differential diagnosis is broad, mesalamine-induced lung damage must be considered in patients who develop unexplained respiratory symptoms while taking this agent.

Ultrastructural immunogold localization of subcellular sites of TNF-alpha in colonic Crohn's disease.

Tumor necrosis factor-alpha, a proinflammatory cytokine, might have an important role(s) in initiating, modifying, and/or sustaining chronic inflammatory processes such as those that characterize Crohn's disease, an inflammatory bowel disease of unknown etiology. We used an immunogold ultrastructural morphometric approach to localize tumor necrosis factor-alpha in colonic Crohn's disease biopsies. Tumor necrosis factor-alpha was present in seven cell types (fibroblasts, eosinophils, mast cells, macrophages, colonic epithelial absorptive cells, Paneth cells, neutrophils). Tumor necrosis factor-alpha-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-alpha immunoreactivity surrounded eosinophils, mast cells, and macrophages. P values of gold counts/microns2 were significant for all cells, organelles, and extracellular spaces measured, and all positive structures significantly exceeded the background labeling density/microns2. Specificity controls (normal rabbit serum, tumor necrosis factor-alpha-absorbed primary antibody) either failed to label these sites or gave markedly reduced specific tumor necrosis factor-alpha labeling, respectively. These findings represent the first ultrastructural localization of the subcellular sites of TNF-alpha in vivo in seven cell lineages in human colonic tissues.