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.

Gluten-sensitive enteropathy and systemic lupus erythematosus.

A patient with systemic lupus erythematosus developed gluten-sensitive enteropathy, or celiac sprue. The patient's histocompatibility antigens included HLA-B8 and HLA-DR3, previously found to have a high frequency in gluten-sensitive enteropathy and possibility increased as well in systemic lupus erythematosus. Such histocompatibility antigens are common to a variety of autoimmune disorders. An immune basis for the association is discussed herein.

Effect of topical 5-aminosalicylic acid (5-ASA) therapy on rectal mucosal 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 Crohn's disease.

Enhanced intramucosal cytotoxic lymphocyte gene expression in ulcerative colitis.

: The histopathology of the mucosal lesions in ulcerative colitis suggests that cellular immune hyperactivity plays a role in the pathogenesis of ulcerative colitis. The role of colonic mucosal cytotoxic lymphocytes in ulcerative colitis is highly controversial. In vitro determinations of cytotoxic lymphocyte function vary according to the experimental conditions and target cells employed. Transcription of the cytotoxic molecules granzyme B and perforin are specific for activated cytotoxic lymphocytes. We investigated whether activated cytotoxic lymphocytes are present in ulcerative colitis lesions via identification of granzyme B, perforin, and interleukin 2 transcripts. RNA was extracted from endoscopic colonic biopsies taken from normal and ulcerative colitis patients. An aliquot was reverse transcribed, followed by gene amplification in the polymerase chain reaction. A competitive template was incorporated within the reaction permitting the quantitation of specific mRNA species. Granzyme B and perforin levels of reverse transcribed cDNAs (RT-cDNAs) were significantly elevated in active ulcerative colitis as compared to normal colonic tissues (p = 0.0081 and p = 0.0018, respectively) when calculated as a ratio with the RT-cDNA of the constitutively expressed gene GAPDH. Interleukin 2 mRNA measurements did not vary between normal and UC samples to a statistically significant degree. These data suggest heightened lymphocyte cytotoxic function within ulcerative colitis mucosal lesions.

Granulomatous inflammation of minor salivary gland ducts: a new oral manifestation of Crohn's disease.

Multiple sublingual cystic masses developed in a 27-year-old man with active intestinal Crohn's disease during prednisone therapy. Surgical excision revealed noncaseating granulomatous inflammation involving the walls of minor salivary gland ducts. In some areas, this ductal lesion was associated with rupture and mucocele formation. Three weeks after excision of the salivary gland tissue, the patient experienced an exacerbation of his intestinal disease, accompanied by a recurrent lesion on the floor of his mouth and aphthous ulcerations of the buccal mucosa. The oral lesions and intestinal symptoms resolved only after azathioprine therapy. This salivary gland lesion represents a previously undescribed oral manifestation of Crohn's disease.

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.

Evaluation and medical therapy of acute gastrointestinal bleeding.

Gastrointestinal bleeding is a major reason for hospitalization and an important cause of morbidity and mortality. Diagnosis and treatment of this common clinical problem has changed markedly over the past 40 years. The initial approach to patients with gastrointestinal bleeding should be both therapeutic and diagnostic, with close attention to cardiovascular status and clotting parameters. Once the patient is stabilized, clinical history, physical examination, gastric aspirate, and laboratory data should be assessed to determine if the bleeding site is in the upper or lower gastrointestinal tract. Once that is determined, a more specific diagnosis should be made if possible, as therapy often will depend upon a precise diagnosis. Therapy includes angiographic and pharmacologic techniques, as well as tamponade in the case of esophageal varices. The use of antacids in acute upper gastrointestinal bleeding is well established, while the role of cimetidine is less clear. Newer modalities of treatment, such as the use of laser coagulation, are currently being evaluated.

Enteric diseases of homosexual men.

Certain enteric ailments are particularly common among homosexual men. They are primarily infectious diseases and include not only such common venereal diseases as gonorrhea and syphilis but also infections not usually regarded as being sexually transmitted. Among the latter are shigellosis, salmonellosis, giardiasis, and amebiasis. Patients' symptoms are non-specific and seldom helpful in diagnosing particular diseases. The practitioner must be prepared to identify a number of infections with similar presentations that may occur singly or together in gay men. Gonorrhea is probably the most common bacterial infection in gay men. Carriage rates as high as 50% have been reported, and extra-genital carriage is common; this necessitates culturing the urethra, rectum, and pharynx. Procaine penicillin G is the treatment of choice for most patients; spectinomycin is probably the drug of choice in penicillin-sensitive patients. In contrast to other venereal diseases, syphilis may have a characteristic protoscopic presentation. Benzathine penicillin G is the treatment of choice for most patients. Lymphogranuloma venereum causes penile lesions and inguinal lymphadenitis in heterosexual men, whereas homosexual men are more prone to proctitis. The disease may mimic Crohn's disease. Recommended treatment includes tetracycline or sulfamethoxazole-trimethoprim. Shigellosis usually presents as an acute diarrheal illness. Patients generally require only supportive treatment with fluids. Herpes simplex viral infection is difficult to diagnose and has several different presentations, including lumbosacral radiculomyelopathy. Symptomatic treatment with sitz baths, anesthetic ointment, and analgesics is recommended. Venereal warts are believed to be caused by the same virus that causes verrucous warts; they are usually found in the anal canal or around the anal orifice. They are commonly treated with 25% podophyllin solution. Parasitic infections include giardiasis, amebiasis, and pinworm infections. Metronidazole may be used in the treatment of symptomatic giardiasis and amebiasis, but it is not approved for the former indication; quinacrine is approved for giardiasis. Pinworm infestation may be treated with pyrantel pamoate or mebendazole. Cure of enteric diseases in homosexual men must be documented.

Drug therapy of inflammatory bowel disease.

Although the etiology of inflammatory bowel disease is unknown and specific therapy is unavailable, enough information on existing empiric agents is available to allow rational therapy. These agents include sulfasalazine, steroids, immunosuppressive drugs, metronidazole and cholestyramine. Sulfasalazine is a two-part molecule that depends on bacterial cleavage in the colon to deliver locally acting 5-aminosalicylate, whose mechanism of action may relate to inhibition of prostaglandin synthesis. The other half of the molecule, sulfapyridine, is responsible for most of the side effects of the drug. While the efficacy of sulfasalazine in the treatment and prevention of attacks of ulcerative colitis is well established, its use in Crohn's disease appears to be limited to patients with active colitis and ileo-colitis. Sulfasalazine is of major benefit in preventing relapses in patients with ulcerative colitis in remission. New formulations of 5-aminosalicylate may allow delivery of the apparently active moiety to the small bowel and colon without concomitant sulfapyridine toxicity. Corticosteroids are highly effective in acute attacks of ulcerative colitis and Crohn's ileitis and ileo-colitis; the mechanism of antiinflammatory action remains speculative. However, maintenance therapy with steroids is ineffective in preventing relapses or recurrent attacks of either ulcerative colitis or Crohn's disease. Steroid enemas allow topical administration to patients with distal colitis and proctitis with few systemic side effects. In children with growth failure associated with active Crohn's disease, amelioration by steroid therapy may actually restore normal growth. Immunosuppressive agents such as azathioprine and 6-mercaptopurine are of little value in active Crohn's disease when administered alone; however, in combination with other agents they may help diminish steroid dose, close fistulae and prevent relapse. Their mode of action likely depends on long-term cytostatic effects on immune effector cells. Concern for leukopenia and the development of late malignancy has limited their use to patients not responding to other therapies. Metronidazole, an antimicrobial agent that is effective against anaerobes, has recently been shown useful in Crohn's disease involving the colon and perianal area. Its mechanism of action is uncertain, but may be related to its antibacterial actions on anaerobes. Cholestyramine can be successfully used to control bile salt-induced diarrhea in Crohn's patients with terminal ileal resections. Effective drug therapy of inflammatory bowel disease is only part of a total program of management including reassurance, frequent explanation, well-timed use of surgery, and an understanding physician.

Drug therapy for inflammatory bowel disease: Part I.

In a two-part series, recent improvements in drug therapy for inflammatory bowel disease are reviewed. Part I summarizes aminosalicylates and corticosteroids. The active moiety of sulfasalazine, which is 5-aminosalicylic acid (mesalamine), in topical or oral form is as effective as sulfasalazine for treatment and prophylaxis of ulcerative colitis and is tolerated by 80% of sulfasalazine-intolerant patients. Coated forms of mesalamine have a potential advantage in the treatment of Crohn's ileitis in that these forms do not require bacterial cleavage for activity. New rapidly metabolized corticosteroids (budesonide, tixocortol pivalate, beclomethasone dipropionate) in topical and oral forms are emerging as equivalent therapy to standard corticosteroids but are associated with less adrenal suppression.

Drug therapy for inflammatory bowel disease: Part II.

Part II of this two-part article (See The American Journal of Surgery 1992; 164: 85-9) reviews the current definition of the role of immunosuppressive therapy in inflammatory bowel disease (IBD) and the use of antibiotics in IBD, as well as summarizes the uses of the new agents on the horizon for the treatment of IBD. Azathioprine and 6-mercaptopurine have steroid-sparing effects in patients with refractory Crohn's disease and ulcerative colitis, treat Crohn's disease-associated fistulas, and are the first agents to demonstrate efficacy in the prophylaxis of Crohn's disease. Their low risk for the development of lymphoreticular malignancy remains a factor in decisions regarding their long-term use. Cyclosporine is steroid sparing in active chronic Crohn's disease and, given intravenously, may help treat severe, refractory ulcerative colitis. Antibiotics have expanding roles: metronidazole is effective for the primary treatment of Crohn's disease, fistulas, abscess, bacterial overgrowth, and pouchitis (after ileoanal anastomosis). Other potential agents show promise in pilot studies but await controlled trials.

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.

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.

Emergencies in inflammatory bowel disease.

Ulcerative colitis and Crohn's disease, the principal IBDs, are characterized most often by a chronic relapsing course. Despite the protracted nature of these disorders they can present in an acute manner as gastrointestinal emergencies. The urgent manifestations include both intestinal and extraintestinal disease. Extraintestinal emergencies can be ocular, rheumatologic, hematologic, and urologic. Intestinal emergencies often are more severe and can be life-threatening. These may include obstruction, abscesses, perforation, and hemorrhage. The successful management of such complications depends on early diagnosis and the judicious and timely use of both medical and surgical therapies.

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.

Current status of drug therapy for inflammatory bowel disease.

Both topical steroids and sulfasalazine are useful for patients with ulcerative proctitis and distal colitis. For patients with more extensive ulcerative colitis with moderate symptoms, prednisone and/or sulfasalazine will result in improvement in about 80% of patients. Parenteral corticosteroids or ACTH should be used in the setting of severe colitis and antibiotics added if the patient appears toxic. Sulfasalazine is of proven efficacy as maintenance therapy in ulcerative colitis. Prednisone and sulfasalazine are useful in Crohn's disease, although the latter is of limited use in patients with ileitis alone. Immunosuppressive agents such as azathioprine and 6-mercaptopurine may be especially helpful in Crohn's patients refractory to other drugs or dependent on high doses of steroids. Azathioprine is of proven usefulness as maintenance treatment of Crohn's disease. Metronidazole is as effective as sulfasalazine in Crohn's disease involving the colon and has an important role in severe perineal disease. New forms of steroid enemas and topical and oral forms of 5-aminosalicylate based on sulfasalazine should be available soon for patients with both ulcerative colitis and Crohn's disease.

Drug therapy of peptic ulcer disease.

Most patients with peptic ulcer disease can be treated successfully and safely with an intensive antacid regimen. A high-potency liquid antacid given at a dose of from 15 to 30 mL one and three hours after meals and at bedtime for a period of six to eight weeks is the recommended regimen. For patients who cannot tolerate this regimen, who will not comply with the antacids, or who are not responding, H2 receptor blockers are effective alternative choices. Most patients will respond to a regimen of either cimetidine 300 mg with meals and at bedtime, or ranitidine 150 mg b.i.d. over a six to eight week period. The addition of an anticholinergic agent before bedtime can be useful, particularly for patients who continue to have nocturnal symptoms. In addition, in the absence of contraindications, an anticholinergic agent may be added one-half hour before meals in patients who are not responding fully to an antacid or H2 blocker regimen. The efficacy of combining all three agents has not been well established clinically, although there is evidence that in this fashion gastric acidity can be further reduced. An attractive new alternative as a primary therapy of peptic ulcer disease is sucralfate. Certainly, in patients who are known to be intolerant to antacids and who cannot take cimetidine or ranitidine due to adverse effects, sucralfate should be considered as initial therapy. It should be given one-half hour before meals and at bedtime for a six to eight week period.

Inflammatory bowel disease therapy: an update.

The armamentarium for the treatment of IBD has grown considerably within the last decade. Sulfasalazine and corticosteroids, the two cornerstones of past therapy, are now joined by the 5-ASA drugs, antibiotics, immunosuppressive agents, and newer corticosteroids. In addition, several novel therapies with promising initial results are being investigated. As the mechanisms by which these agents work are elucidated, further insight into the pathogenesis of IBD will be gained. Based on the nature and extent of disease, physicians and patients will be able to select the optimal agent or therapeutic combination for control of this enigmatic and morbid disease.

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.