William Connell

Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease

The incidence of various cancers, especially non-Hodgkin lymphoma (NHL), is higher among patients who receive azathioprine for immunosuppression after organ transplants than in the general population. We have studied the risk of neoplasia after azathioprine in 755 patients treated for inflammatory bowel disease. The patients received 2 mg/kg daily for a median of 12.5 months (range 2 days to 15 years) between 1962 and 1991; median follow-up was 9 years (range 2 weeks to 29 years). Overall there was no significant excess of cancer: 31 azathioprine-treated patients developed cancer before age 85 compared with 24.3 expected from rates in the general population (observed/expected ratio 1.27, p = 0.186). There was a difference in the frequency of colorectal (13) and anal (2) carcinomas (expected 2.27; ratio 6.7, p = 0.00001); these tumours are recognised complications of chronic inflammatory bowel disease. There were 2 cases of invasive cervical cancer (expected 0.5), but no case of NHL. Among patients with extensive chronic ulcerative colitis there was no difference in cancer frequency between 86 who had received azathioprine and 180 matched patients who had never received it. Thus, azathioprine treatment does not substantially increase the risk of cancer in inflammatory bowel disease.

Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience.

Myelosuppression is an important and potentially lethal complication of azathioprine treatment. The blood count has been reviewed in all patients treated with azathioprine for inflammatory bowel disease over 27 years in one hospital. Altogether 739 patients (422 with Crohns disease, 284 with ulcerative colitis, and 33 with indeterminate colitis) were treated with 2 mg/kg/day azathioprine for a median of 12.5 months (range 0.5-132) between 1964 and 1991. Full blood counts were performed monthly for the duration of treatment. In 37 patients (5%) who developed bone marrow toxicity, the drug was withdrawn or the dose reduced. Thirty two of these patients were asymptomatic and five developed symptoms. Leucopenia (white blood count less than 3.0 x 10g/l) occurred in 28 (3.8%) patients, in nine of whom it was severe (white blood count < 2.0 x 10(9)/l). Of these nine patients, three were pancytopenic: two died from sepsis and the other had pneumonia but recovered. A further two patients with severe leucopenia developed a mild upper respiratory infection only. Thrombocytopenia (platelet count < 100,000 x 10(6)/l) in 15 patients was associated with leucopenia in six and developed in isolation in a further nine (total 2%). Isolated thrombocytopenia was never clinically severe. Myelotoxicity from azathioprine developed at any time during drug treatment (range 2 weeks-11 years after starting the drug) and occurred either suddenly or over several months. Bone marrow suppression as a result of azathioprine treatment is uncommon when a moderate dose is used, but is potentially severe. Leucopenia is the commonest and most important haematological complication. Regular monitoring of the full blood count is recommended during treatment.

Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis

BACKGROUND/AIMS Cancer surveillance in patients with ulcerative colitis is of unproven benefit. This study assesses the efficacy and analyzes factors limiting the success of a surveillance program during a 21-year period in 332 patients with ulcerative colitis to the hepatic flexure and disease duration exceeding 10 years. METHODS Clinical assessment and sigmoidoscopy with biopsy was undertaken yearly. Colonoscopy and biopsy every 10 cm throughout the colon was performed every 2 years or more often if dysplasia was found. Only biopsy specimens reported as showing dysplasia were reviewed. RESULTS Surveillance contributed to detection of 11 symptomless carcinomas (8 Dukes A, 1 Dukes B, and 2 Dukes C), but 6 symptomatic tumors (4 Dukes C and 2 disseminated) presented 10-43 months after a negative colonoscopy. Dysplasia without carcinoma was confirmed in 12 symptomless patients who underwent colectomy. The 5-year predictive value of low-grade dysplasia for either cancer or high-grade dysplasia was 54% using current criteria. CONCLUSIONS Surveillance identified some patients at a curable stage of cancer or with dysplasia. Limiting factors were failure to include patients with presumed distal colitis, biennial colonoscopy, the number of biopsy specimens at each colonoscopy, and variation in histological identification and grading of dysplasia.

Crohn's disease management after intestinal resection: a randomised trial.

BACKGROUND Most patients with Crohns disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. METHODS In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohns disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patients study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. FINDINGS Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0.03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0.03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2.4, 95% CI 1.2-4.8, p=0.02) and the presence of two or more clinical risk factors including smoking (OR 2.8, 95% CI 1.01-7.7, p=0.05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0.51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0.36), respectively. INTERPRETATION Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohns disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. FUNDING AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohns Colitis Australia, and the National Health and Medical Research Council.

Clinicopathological characteristics of colorectal carcinoma complicating ulcerative colitis.

This study examined three features associated with colorectal carcinoma complicating ulcerative colitis: (a) the distribution of 157 cancers in 120 patients with ulcerative colitis treated at St Marks Hospital between 1947 and 1992; (b) the frequency at which dysplasia was found at a distance from the tumour in 50 total proctocolectomy specimens in which an average of 27 histology blocks were reviewed, and (c) the five year survival rate according to Dukess stage and participation in a surveillance programme. Of 157 carcinomas, 88 (56%) occurred in the rectosigmoid, 19 (12%) in the descending colon or splenic flexure, and 50 (32%) in the proximal colon. Among the 120 patients, the rectum or sigmoid colon contained cancer in 81 (67.5%). Dysplasia was detected in 41 of 50 reviewed proctocolectomy specimens (82%). Dysplasia distant to a malignancy occurred in 37 (74%); two were classified indefinite, probably positive, 19 were low grade, and 16 were high grade; in 18 specimens there was an elevated dysplastic lesion. Survival was related to the Dukess stage: about 90% of patients with Dukess A or B cancer were alive at five years. The five year survival of 16 patients in whom cancer developed during surveillance was 87% compared with 55% of 104 patients who did not participate in surveillance (p = 0.024).

Lower gastrointestinal malignancy in Crohn's disease.

An increased incidence of carcinoma of the small bowel and colon has been described in patients with Crohns disease. Tumours arising in the rectum and anus are reported less often. Between 1940 and 1992, of some 2500 patients with Crohns disease seen at this hospital, 15 are known to have developed carcinoma of the lower gastrointestinal tract. Malignancy occurred in the colon in two patients, in the upper two thirds of rectum in one, in the lower third of rectum in seven, and in the anus in five. The 12 patients with carcinoma arising in the anus or lower rectum had longstanding severe anorectal Crohns disease, which included a stricture in four, fistula in four, proctitis in one, abscess in two, and enlarged anal skin tags in one. The development of malignancy in patients with Crohns disease may apply particularly to those with chronic complicated anorectal disease.

Capsule endoscopy vs. push enteroscopy and enteroclysis in suspected small-bowel Crohn's disease

BACKGROUND The diagnosis of small-bowel Crohns disease sometimes is difficult and may be missed by conventional imaging studies. Capsule endoscopy might identify small-bowel disease undetected by other investigations. METHODS Patients with or without known Crohns disease who were suspected to have small-bowel Crohns disease were prospectively evaluated with push enteroscopy, enteroclysis, and capsule endoscopy. Each examiner was blinded to results of other investigations. Referring doctors were required to complete questionnaires before and after the investigations. RESULTS Twenty-two patients were known to have Crohns disease (Group 1), and 21 were suspected to have small-bowel Crohns disease (Group 2). In Group 1, capsule endoscopy detected more erosions than the other two investigations (p < 0.001). In Group 2, a new diagnosis of Crohns disease was made in two patients, but there was no significant difference in yield compared with the other two investigations. Referring physicians rated the usefulness of capsule endoscopy as 4.4 on a scale of 5. Capsule endoscopy changed management for 30 patients (70%). CONCLUSIONS Capsule endoscopy has a higher yield than push enteroscopy and enteroclysis in patients with known Crohns disease when small-bowel mucosal disease is suspected, and this leads to a change in management in the majority of these patients.

High incidence of inflammatory bowel disease in Australia: A prospective population-based Australian incidence study

Background: To date, there have been no population‐based epidemiological studies published from Australia concerning the incidence of inflammatory bowel disease (IBD). Our hypothesis was that the incidence of IBD in Australia is at least as high as other industrialized countries, given similar genetic and environmental risk factors. Methods: A prospective, population‐based IBD incidence study was conducted between April 2007 and March 2008 in Greater Geelong, Victoria, Australia. According to 2006 Australian Census data, this comprises an at‐risk population of 259,015. Cases were ascertained from multiple overlapping sources. All local general practitioners, gastroenterologists, surgeons, and pediatricians were contacted every 2 months to identify new IBD cases. The Royal Childrens Hospital in Melbourne, local endoscopy and pathology centers were also searched to ensure completeness of case capture. Standard IBD case definitions were used with clinical, endoscopic, and histological criteria. Results: In all, 76 new cases of IBD were identified during the 1‐year period. There were 45 cases of Crohns disease, 29 of ulcerative colitis, and 2 of indeterminate colitis. The crude annual incidence rates for IBD overall, Crohns disease, ulcerative colitis, and indeterminate colitis were 29.3 per 100,000 (95% confidence interval [CI] 23.5–36.7 per 100,000), 17.4 per 100,000, 11.2 per 100,000, and 0.8 per 100,000, respectively. When directly age‐standardized to the World Health Organization standard population the overall IBD incidence rate was 29.6 per 100,000. Conclusions: This is the first prospective, Australian population‐based IBD incidence study. The incidence rates are among the highest reported in the literature of IBD. (Inflamm Bowel Dis 2009)

Treating inflammatory bowel disease during pregnancy : Risks and safety of drug therapy

The safety of drug therapy for inflammatory bowel disease during pregnancy is an important clinical concern. Current available information is largely derived from animal studies and clinical experience among patients with inflammatory bowel disease and autoimmune disorders and organ transplant recipients. However, these data are confounded by various factors including difficulty projecting the results of animal studies to humans, methodological deficiencies of some studies, insufficient experience with certain agents, difficulty distinguishing the fetal effects of underlying disease from drug therapy and a need to consider the impact of background rates of adverse fetal outcomes which apply to all pregnancies.In inflammatory bowel disease, the effects of active inflammation on the fetus are believed to be more harmful than those of drug treatment, and therapy is often justified to induce or maintain remission during pregnancy. The choice of appropriate treatment is determined by the severity of the disease and the potential for drug toxicity.No causal relationship has been established between exposure to sulfasalazine or other 5-aminosalicylic acid drugs and the development of congenital malformations. These drugs may be used with relative safety during pregnancy and lactation. Considerable experience with corticosteroids have shown them to pose very small risk to the developing fetus. Current evidence indicates that maternal use of azathioprine is not associated with an increased risk of congenital malformations, though impaired fetal immunity, growth retardation or prematurity is occasionally observed. Preliminary evidence derived from patients with inflammatory bowel disease show no significant fetal toxicity following first trimester exposure to mercaptopurine, though its elective use in pregnancy is controversial. Cyclosporin is not teratogenic, but may be associated with growth retardation and prematurity. Pregnancy should be avoided in women treated with methotrexate because of its known abortifacient effects and risk of causing typical malformations. Although treatment with metronidazole or ciprofloxacin for short durations appear to be devoid of adverse fetal reactions, the effect of prolonged exposure as required in Crohn’s disease remains unknown.

Preliminary examination of the relations between disease activity, illness perceptions, coping strategies, and psychological morbidity in Crohn's disease guided by the common sense model of illness

Background: An individuals psychological adjustment to illness is influenced by disease severity, illness perceptions, and coping strategies. A more precise understanding of the contribution of each of these factors to a patients well‐being may influence the kind of psychological support required by patients. This study therefore aimed to characterize the contributors to psychological well‐being in patients with Crohns disease (CD). The design was a cross‐sectional questionnaire‐based study. Methods: Ninety‐six CD patients (34 males, 62 females, mean age 38 years) attending a tertiary hospital inflammatory bowel disease outpatient clinic were studied. Disease severity was evaluated according to the Crohns Disease Activity Index (CDAI), coping styles assessed with the Carver Brief COPE scale, illness perceptions explored with the Brief Illness Perceptions Questionnaire (BIPQ), and anxiety and depression measured using the Hospital Anxiety and Depression Scale (HADS). Results: Combining the questionnaire data using structural equation modeling resulted in a final model with an excellent fit (χ2 (7) = 10.42, P = 0.17, χ2/N = 1.49, root mean square error of approximation (RMSEA) < 0.07, comparative fit index (CFI) > 0.97, Goodness‐of‐fit index (GFI) > 0.97). Disease activity had a significant direct influence on illness perceptions (&bgr; = 51, P < 0.001). In turn, illness perceptions had a significant direct influence on depression and anxiety (&bgr; = 41, P < 0.001, &bgr; = 0.40, P < 0.001, respectively). Use of emotional coping strategies was associated significantly (P < 0.001) with the presence of anxiety and depression. Conclusions: There is an interrelationship between disease activity, illness perceptions, coping strategies, and depression and anxiety. These aspects of psychological processing provide a framework and direction for the psychological support that patients with CD require.