Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.

BACKGROUND: Inflammatory bowel disease (IBD) is commonly treated with immunomodulators such as azathioprine and 6-mercaptopurine (6-MP). Studies examining lymphoma risk in IBD patients treated with these medications have been underpowered and have yielded conflicting conclusions. AIMS: The purpose of this meta-analysis was to provide a more precise estimate of the relative risk of lymphoma among IBD patients treated with azathioprine or 6-MP. METHODS: Studies were included if they were English language, full article, cohort studies specifically designed to evaluate cancer as an adverse outcome of treatment with azathioprine or 6-MP. Pooled standardised incidence ratios were calculated to estimate the relative risk of lymphoma associated with therapy. Heterogeneity was assessed using Poisson regression. Sensitivity analyses examined the influence of individual studies on risk estimate and heterogeneity statistics. RESULTS: Six studies were identified that met our inclusion criteria. When the data were combined across all studies, the pooled relative risk was 4.18 (95% confidence interval 2.07-7.51; 11 observed cases, 2.63 expected). Sensitivity analysis showed that exclusion of any one study had a relatively small effect on the pooled relative risk estimate (range 3.49-5.21) but excluding either the study with the highest or lowest estimated relative risk eliminated the statistically significant heterogeneity. CONCLUSIONS: Our data suggest an approximate fourfold increased risk of lymphoma in IBD patients treated with azathioprine/6-MP. The increased risk of lymphoma could be a result of the medications, the severity of the underlying disease, or a combination of the two.

Colchicine for persistent constipation after total abdominal colectomy with ileorectostomy for colonic inertia.

Severe constipation caused by colonic inertia may be associated with a generalized gastrointestinal dysmotility syndrome. Patients with severe constipation pose a significant challenge in terms of management. Failure of medical therapy usually leads to surgery in the form of a subtotal colectomy. Most patients develop diarrhea after the surgery, but a subgroup of patients continue to experience constipation. We report the case of such a patient who underwent a total abdominal colectomy and ileorectostomy for intractable constipation. He continued to have constipation after the surgery that was responsive only to a gallon of bowel-cleansing solution. A treatment trial of colchicine was partially unsuccessful when used on its own, but a combination of colchicine and a lesser dose of Colyte was found to be effective in maintaining regular bowel movements.

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 Crohn's disease and should be avoided in patients with a history of IBD whenever possible.

A history of immunosuppressive drugs in the treatment of inflammatory bowel disease: origins at The Mount Sinai Hospital.

Much of what we know about the role of immunopathologic mechanisms in causing Crohn's disease and ulcerative colitis originated from research at The Mount Sinai Hospital. The authors were privileged to have been able to share in this undertaking, along with many others, including Moschcowitz, Klemperer, Otani, Crohn, Ginzburg, Oppenheimer, Garlock, Lyons, Marshak, Janowitz, Aufses, Waye, Greenstein, Sachar, Meyers, Gelernt, Mayer, Lichtiger and Kornbluth. In medical history, elucidation of disease processes is often serendipitous. Transplant surgery was successful because of the discovery by Hitchings and Elion of 6-mercaptopurine (6-MP) and azathioprine, which inhibited rejection. And the concept of immunosuppression slowly evolved into possible treatment of any disease thought to be caused by autoimmunity. This includes those diseases of the bowel seen so frequently at The Mount Sinai Hospital: ileitis, granulomatous colitis, ileocolitis, and ulcerative colitis. This paper depicts the progressive role of immunosuppressive drugs, from corticosteroids to 6-mercaptopurine, cyclosporine and anti-tumor necrosis factor, in both the treatment and understanding of the pathogenesis of Crohn's disease and ulcerative colitis. Major contributions to these treatments have come from physicians and surgeons with roots at The Mount Sinai Hospital.

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.

Anorectal Crohn's disease: surgical and medical management.

In some patients with Crohn's disease the anorectal complications are the major cause of symptoms and morbidity. Anorectal Crohn's disease may be present in patients with intestinal Crohn's disease, may be the initial manifestation of the disease, or rarely occurs without involvement of Crohn's disease elsewhere in the intestinal tract. The pathogenesis of these anorectal complications remains to be clarified. The anorectal examination is very important in the assessment of patients with suspected or documented inflammatory bowel disease. Meticulous physical examination, examination under anaesthesia and radiological imaging modalities may be utilised to specifically identify the location of abscesses and fistulae. Treatment strategy should be directed toward symptomatic relief; the most important symptom is pain. In most patients this pain will be attributable to an incompletely drained rectal abscess. Simple incision and drainage procedures are often all that is required as initial treatment of anorectal abscesses. Treatment of the anorectal fistulae that occur secondary to Crohn's disease requires combined medical and surgical therapy. Drug therapy is more often initiated for Crohn's disease that involves other areas of the gastrointestinal tract. The anorectal manifestations often respond to these same medications. Lay-open procedures (fistulotomies) are often all that is required surgically for simple (low) anorectal fistulae. High (complex) fistulae that involve large portions of the anorectal muscular ring are more difficult to treat. Patients with these fistulae must be treated on an individual basis, usually local surgical therapy combined with a medical regimen. Many surgical procedures are performed and many classes of medications are utilised on patients with these complex anorectal fistulae. Choosing the appropriate surgical and medical interventions is often quite difficult. Although sulfasalazine, mesalazine and corticosteroids have no lasting or maintenance value for fistulae, the immunosuppressive agents mercaptopurine, azathioprine and cyclosporin, the antibacterial metronidazole and the anti-tumour necrosis factor-alpha monoclonal antibody infliximab have varying degrees of effect. The goal of the combined regimen is to cure the fistula, or at least make it minimally symptomatic, without altering the patient's continence.

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 Crohn's 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.

Optimum duration of treatment with 6-mercaptopurine for Crohn's disease.

OBJECTIVE: 6-Mercaptopurine (6MP) and azathioprine are immunomodulators used in the treatment of refractory Crohn's disease. Studies have confirmed their efficacy and value in maintenance of remission, but it is our purpose to determine how long 6MP/azathioprine should be continued once remission has been accomplished. METHODS: Careful follow-up was accomplished in patients with Crohn's disease seen at one medical center who were treated with 6MP for > or = 6 months, who achieved remission within 1 yr of initiation of therapy, and who were in prolonged clinical remission (> or = 6 months without steroids). The time-to-relapse was calculated in those who continued treatment, in those who stopped treatment for reasons other than a relapse, and in the whole sample, taking into account that they could be treated with the drug, or could not, as a function of time. The influence of concomitant variables on the time-to-relapse rate was evaluated. RESULTS: A total of 120 patients met the inclusion criteria. The cumulative probabilities of relapse at 1, 2, 3, and 5 yr for those who continued to take 6MP and for those who stopped the therapy for reasons other than a relapse are as follows: Patients maintained on 6MP (n = 84): 1 yr, 29%; 2 yr, 45%; 3 yr, 55%; 5 yr, 61%. Patients who terminated 6MP (n = 36): 1 yr, 36%; 2 yr, 71%; 3 yr, 85%; 5 yr, 85%. Sex, distribution of disease, duration of disease, time to remission on 6MP, and concomitant 5-ASA use did not influence the relapse rates. Younger age was associated with a higher rate of relapse in patients who were maintained on 6MP. A higher daily dose of 6MP was associated with a higher relapse rate. CONCLUSIONS: Discontinuation of 6MP, while Crohn's disease is in remission, leads to higher relapse rates and continuation of 6MP reduces the likelihood of relapse. Therefore, we favor the indefinite use of 6MP once remission has been achieved.

Allergic reactions to 6-mercaptopurine during treatment of inflammatory bowel disease.

Hypersensitivity reactions to 6-mercaptopurine (6-MP) or azathioprine occur during the treatment of inflammatory bowel disease (IBD), raising significant diagnostic and therapeutic challenges. Charts of 591 patient with IBD treated with 6-MP in a single center were retrospectively reviewed. All allergic reactions were recorded along with results of rechallenge, desensitization, and subsequent course of IBD. Sixteen (2.7%) allergic reactions to 6-MP were noted, with fever being the most common (14 cases). Nine of these were rechallenged with 6-MP with recurrence of the same symptoms. Azathioprine was tried in six patients and in five the same symptoms recurred. Four patients underwent successful desensitization to either 6-MP or azathioprine; all four plus another patient who tolerated direct switch to azathioprine entered long-term remission. Among the remaining 11, 5 required surgery, 2 are well on methotrexate, and 4 have chronic symptoms while being treated with other medications. If an allergic reaction to 6-MP occurs during the treatment of IBD, direct switching to azathioprine is probably not justified. Instead, desensitization to either 6-MP or azathioprine should be attempted. Patients who can tolerate these medications after previous allergic reactions have improved outcomes compared with patients who resort to other forms of treatment.

Shingles during the course of treatment with 6-mercaptopurine for inflammatory bowel disease.

OBJECTIVE: Our aim was to study the frequency, severity, and outcome of patients with Crohn's disease and ulcerative colitis treated with 6-mercaptopurine (6MP) who developed shingles during treatment, and to recommend management. While varicella can be severe in young people immunocompromised by steroids, the incidence of herpes zoster in older people with inflammatory bowel disease (IBD) and whether its severity is influenced by 6MP and azathioprine are unknown. METHODS: Data were collected from our IBD Center on 550 patients with IBD to identify those who developed shingles while on 6MP, its severity, the dose and duration of 6MP, and the management of the 6MP. RESULTS: Twelve of 550 patients with IBD treated with 6MP developed shingles. In two with herpes zoster ophthalmicus the pain was prolonged, and one patient developed encephalitis which was brief and uncomplicated; in nine patients the course was benign. Acyclovir should be the treatment of choice even though it was available in only three cases. CONCLUSIONS: Shingles occurs more often in IBD patients treated with 6MP than in those who are not, but the course is usually benign and there has been no mortality. The 6MP should be stopped temporarily until severity is established but if the underlying disease warrants further treatment the 6MP should be restarted.