Burton I. Korelitz

Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study

OBJECTIVE:The aim of this study was to determine whether a relationship exists between the use of nonsteroidal antiinflammatory drugs (NSAIDs) and exacerbation or onset of inflammatory bowel disease (IBD).METHODS:Sixty consecutive IBD patients admitted to the hospital were carefully interviewed to ascertain whether they used NSAIDs and the relationship in time and duration to the exacerbation (or onset) of the IBD; 62 patients with irritable bowel syndrome were similarly interviewed and served as controls.RESULTS:In 31% of our IBD population there was a correlation between use of NSAIDs and IBD activity, whereas in only 2% of the irritable bowel syndrome population who used NSAIDs did this relationship exist.CONCLUSIONS:NSAIDs provoke disease activity in both ulcerative colitis and Crohns disease and should be avoided in patients with a history of IBD whenever possible.

Carcinoma arising in anorectal fistulas of Crohn's disease

PURPOSE: Anorectal fistulas are commonly associated with Crohns disease. Carcinoma arising in an anal fistula in the absence of Crohns disease occurs rarely. Carcinoma arising in an anorectal fistula of Crohns disease is likewise rare and is the subject of this article. METHODS: We have seen eight cases in seven patients. Four of these were squamous carcinoma and three were adenocarcinoma. Details of these seven patients are presented. RESULTS: Two deaths in the four patients with squamous carcinoma and one in the two patients with adenocarcinoma with adequate follow-up suggest a poorer prognosis in both types of malignancy than when these lesions occur without Crohns disease. CONCLUSION: Carcinoma does arise in the midst of the anorectal fistulas and abscesses of Crohns disease. Carcinoma arising in a Crohns disease fistula can be very difficult to diagnose. Examination may be limited by pain, stricture, or induration of the perianal and perineal tissues. Examination under anesthesia can also overlook the lesion. Diagnostic examination under anesthesia yields increases with biopsies or curettage of the fistulous tracts.

Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine.

Objective:Most complications of 6-mercaptopurine (6MP) used in the treatment of inflammatory bowel disease (IBD) occur early, whereas neoplasms occur late in the course. Concern persists that the risk is increased when 6MP is used. We report our experience with malignant tumors developing over 27 yr of treating IBD patients with 6MP.Methods:A total of 591 patients with IBD treated with 6MP between 1969 and 1997 were followed or traced until present to identify all malignant tumors and blood dyscrasias that had developed to determine the type, distribution, and duration of the IBD, the dose and duration of 6MP therapy, the concurrent versus previous use of 6MP, the incidence and probable relationship of 6MP to specific neoplasms, and whether the 6MP had been effective in treatment.Results:A total of 550 patients (93%) fulfilled the criteria for follow-up; these included 380 with Crohns disease (CD) and 170 with ulcerative colitis (UC). Twenty-five patients had developed neoplasms (16 of 380 CD and nine of 170 UC) (p= 0.66). In half of the cases, the goal of therapy had been achieved with 6MP. In 10 patients, the neoplasm was diagnosed while the patients were taking 6MP (40%) and in 15, many years after the 6MP had been terminated (60%). The incidence of neoplasms (25 of 550) was 2.7/1000 patient-years of follow-up. The most common neoplasms were found in the bowel (eight of 550, 1.6%; five CD, and three UC), and breast (three, 0.5%; two CD, and one UC). Non-Hodgkins lymphomas occurred in two patients with CD; one was cerebral and the other abdominal. One patient with CD developed leukemia. The duration of 6MP therapy ranged from 5 months to 22 yr, with a mean of 5 yr. The dose of 6MP ranged from a quarter of a tablet/day (12.5 mg) to 100 mg/day, with the majority in a range from 50 to 75 mg/day.Conclusion:In no instance could a neoplasm be attributed to the use of 6MP. The incidence of colon cancer is not greater than that with long standing colitis. Suspicion of a relationship between 6MP and leukemia/lymphoma persists, but the incidence is low. This must be weighed against the improved quality of life due to 6MP for patients with IBD.

Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease.

OBJECTIVE:The outcomes of pregnancies after maternal use of 6-mercaptopurine (6-MP) for inflammatory bowel disease (IBD) during pregnancy have been reported, but data are lacking for outcomes when the fathers use this drug.METHODS:Subjects were male patients with IBD seen at one center between 1970 and 1997. Patients and their wives were interviewed. Group 1 comprised pregnancies fathered by men who were taking 6-MP. This group was further subdivided into those conceived within 3 months of 6-MP use and those conceived at least 3 months after 6-MP was stopped. Group 2 comprised pregnancies fathered by men with IBD, similar in characteristics to group 1, who had not taken 6-MP before fertilization. Information was collected regarding the fathers, the mothers, and the pregnancies, as well as the health of the children, in a historical cohort study.RESULTS:There were 50 pregnancies in group 1 (13 in 1A and 37 in 1B) and 90 pregnancies in group 2. Four of the 13 pregnancies in group 1A were associated with complications. There were two spontaneous abortions, and two congenital anomalies including a missing thumb in one and acrania with multiple digital and limb abnormalities in the other. Risk of complications was significantly increased when compared with group 1B (p < 0.013) and group 2 (p < 0.002).CONCLUSION:The incidence of pregnancy-related complications was significantly increased when the fathers used 6-MP within 3 months of conception.

Anal skin tags in inflammatory bowel disease: New observations and a clinical review

Background: The association between intestinal Crohns disease (CD) and specific perianal abnormalities called anal skin tags (AST) has been recognized but not well defined. Skin tags have been classified into 2 types: 1) raised, broad, or narrow, single or multiple, soft or firm, and painless, often referred to as “elephant ears”; or 2) edematous, hard, often cyanotic, tender or not, and typically arising from a healed anal fissure, ulcer, or hemorrhoid. The aims of this study were to i) better characterize those skin tags identified by the term “elephant ears” and differentiate them from other types of AST; ii) compare their prevalence in patients with CD and ulcerative colitis (UC); iii) observe the relationship of the skin tags to the location of the primary bowel disease; and iv) to discuss the value of these typical AST in making an early diagnosis of CD. Methods: Photographs of all AST were taken when present at lower endoscopy in 170 consecutive patients with inflammatory bowel disease (IBD) seen in the private office of the senior investigator and Lenox Hill Hospital. Data was gathered with respect to major differences between the 2 types of AST. The location of the primary bowel disease for these patients was obtained from an extensive IBD computer database and review of details from charts. Results: Specific features of AST were described and served to favor type 1 versus type 2. AST were found more frequently in patients with CD (75.4%) as compared to patients with UC (24.6%), confirming previous observations that they are more diagnostic of CD (P = 0.005). Subset analysis revealed a trend with a greater incidence of AST in patients with colitis (46.9%) as compared to patients with ileitis (36.7%) and ileocolitis (16.3%) (P = 0.067). Conclusions: We provide photographs with the most characteristic features of AST and attempt to separate elephant ears (type 1) from less typical AST (type 2) in CD. Our study confirms previous reports that AST are more commonly found in association with CD as compared with UC and more so in the presence of disease limited to the colon as compared to disease elsewhere in the bowel. Our observations support the diagnostic significance of AST heralding the diagnosis of CD when they are discovered on physical exam, especially in young people with diarrhea, abdominal pain, and/or growth retardation.

Intravenous corticotrophin vs. Hydrocortisone in the treatment of hospitalized patients with Crohn's disease: A randomized double-blind study and follow-up

Summary: Adrenocorticotrophic hormone (ACTH) and corti‐costeroids have no maintenance values for inflammatory bowel disease but serve to reduce the severity of disease. The effec‐tiveness of intravenous corticotrophin versus hydrocortisone in ulcerative colitis has been determined including whether previous steroid therapy influenced the better response to one rather than the other, but no such studies have ever been done in Crohns disease. Eighty‐eight patients hospitalized with moderate‐to‐severe Crohns disease (Present‐Korelitz [P‐K] Index ‐3 to ‐2 and the International Organisation for the Study of Inflammatory Bowel Disease‐Crohns & Colitis Foundation of America [IOIBD‐CCFA] Index, mean 14, range 5‐23) were treated in a prospective, randomized, double‐blind clinical trial to receive either continuous intravenous infusion of 120 U/day of ACTH (44 patients) or hydrocortisone 300 mg/day (44 patients). Patients were also subdivided into those who received oral steroids during the 30 days prior to intravenous therapy and those who had not. Response was followed on a daily basis and tabulated at 3, 5, and 10 days. Patients were followed from 1‐3 years to determine the later status. After 10 days of intravenous therapy 36 of 44 patients (82%) who received ACTH and 41 of 44 patients (93%) who received hydrocortisone fully responded (P‐K index +3 and IOIBD‐CCFA Index mean of 3). At the end of the study, response to intravenous ACTH and hydrocortisone was not statistically different whether or not patients received oral steroids during the 30 days prior to admission, although the response to IV ACTH tended to be faster at 3 days in those who had received previous steroid therapy. Intravenous ACTH and hydrocortisone are equally effective in achieving therapeutic goals in patients with Crohns disease who have not achieved results with oral medications. Moreover the response rate was high (mean 88%), serving to buy time for establishment of successful maintenance programs of treatment with oral 5‐ASA and immunosuppressive drugs for 69% of patients at 1‐3 years.

Toxicity of infliximab in the course of treatment of Crohn's disease

Infliximab is a monoclonal antibody directed against the pro-inflammatory mediator TNF-α, which was approved in the US in 1998 for treatment-resistant Crohn’s disease. Since that time, the indications have dramatically expanded to include rheumatoid arthritis, ankylosing spondylitis, psoriasis and most recently, active ulcerative colitis. Although the safety profile in the initial studies was quite favourable, subsequent studies have shown that a small percentage of patients reported severe side effects, including pneumonia, tuberculosis, lymphoma, drug-induced lupus and hepatotoxicity. Although these complications are rare, it is important to properly screen patients for predisposing conditions before beginning treatment. Furthermore, concurrent use of other immunosuppresive agents, such as 6-mercaptopurine, may reduce the incidence of less serious side effects, such as arthralgias, myopathies and other antibody-associated diseases. Since its approval, infliximab has revolutionised the treatment of Crohn’s disease and has shown benefit in a variety of other inflammatory conditions, but significant toxicities can occur that necessitate thorough screening protocols and periodic clinical evaluation.

Diffuse alveolar hemorrhage after infliximab treatment of Crohn's disease

Infliximab (Remicade), a chimeric monoclonal antibody to tumor necrosis factor-alpha (anti–TNF-α), is being used with increasing frequency in the treatment of Crohns disease. Infliximabs safety profile to date has been good with reported adverse events being mild to moderate. We report a case of diffuse alveolar hemorrhage after the second infliximab infusion in a patient with Crohns disease. The mechanism by which infliximab may have caused the observed pulmonary insult remains unknown. Physicians should be aware of the possible association between infliximab treatment and the development of alveolar hemorrhage. Future cases should be reported.

Rectal strictures in Crohn's disease and coexisting perirectal complications

Background: The significance of the presence of rectal strictures in Crohns disease has not been well studied. The aim of this study was to examine patients diagnosed with Crohns disease associated with rectal strictures and to describe co‐existing manifestations of perianal disease (abscesses, fistulae, or skin tags) and strictures located elsewhere in the colon or small intestine. Methods: A cohort of 70 Crohns disease patients with rectal strictures were compared with controls without rectal strictures matched for age, gender, and duration of disease. Analysis was done to better elucidate the association of rectal strictures with location of disease and other perirectal complications. Results: The average age of both groups of our Crohns disease patients was 54 years and the average duration of disease since diagnosis was 315 months for the patients and 314 months for the controls. 54% of patients were women and 46% were men. 61.4% of the study population had Crohns colitis, whereas the remaining 38.6% of patients had ileo‐colonic involvement. In contrast, the majority of the control population had ileo‐colonic involvement (74.3%). Perirectal fistulae were present in 61% of patients with rectal strictures versus 34.3% of controls (p value = 0.001). Perirectal abscesses were present in 50% of rectal stricture patients vs. 17.1% of controls (p value < 0.001). Anal skin tags were observed in 23% of study patients vs. 15.7% of controls (p value = 0.275). 37% of patients with rectal strictures also had strictures more proximal in the colon as compared to 54% of controls (p value = 0.07). Only 10% of the study population had small bowel strictures vs. 55.7% of the controls (p value < 0.001). Conclusions: This observational study of Crohns disease patients suggests that the majority of patients with rectal strictures have colonic involvement and increased perianal fistulae and abscesses. Only a minority of patients was observed to have ileal or ileo‐colonic disease, perianal skin tags, or strictures elsewhere. A future study will examine whether the severity of stricturing disease can tell us anything about the disease distribution, prognosis, or response to treatment. Patients with rectal strictures and associated perirectal disease may represent a specific phenotypic presentation of Crohns disease that warrants further study and correlation with serological markers so as to better aid this subgroup of patients.

Prolonged remission of severe Crohn's disease after fever and leukopenia caused by 6-mercaptopurine.

-Mercaptopurine (6MP) and azathioprine (AZA) have been shown to be effective for the treatment and maintenance of remission of Crohn’s disease (1). One of the common side effects of 6MP is leukopenia, which occurs in 8–15% of patients (2). We describe a phenomenon that occurred in four patients who were maintained on 6MP, after a prolonged and severe course of Crohn’s disease with fistulizing complications and many exacerbations, and one additional patient with ulcerative colitis. At one point while on 6MP they all experienced a sudden drop in their white blood count accompanied by high fever leading to prolonged hospitalization. Once they recovered from the acute illness and the total white blood count increased, they remained in prolonged remission. The degree of neutropenia or other sequelae did not appear to be dose related. The following cases have in common a febrile reaction with leukopenia attributable to 6MP in the four young women with severe Crohn’s disease and one young man with ulcerative colitis.