Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high-risk patients - a POCER study analysis.

BACKGROUND: Crohn's disease recurs in the majority of patients after intestinal resection. AIM: To compare the relative efficacy of thiopurines and anti-TNF therapy in patients at high risk of disease recurrence. METHODS: As part of a larger study comparing post-operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine-intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment. RESULTS: A total of 101 patients [50% male; median (IQR) age 36 (25-46) years] were included. There were no differences in disease history between thiopurine- and adalimumab-treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2-i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab-treated patients [intention-to-treat (ITT); P = 0.028] or 24 of 62 (39%) vs. 3 of 24 (13%) respectively [per-protocol analysis (PPA); P = 0.020]. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab). CONCLUSIONS: In Crohn's disease patients at high risk of post-operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.

Changing face of care for patients with moderate to severe inflammatory bowel disease: the role of specialist nurses in the governance of anti-TNF prescribing.

BACKGROUND: Anti-tumour necrosis factor (TNF) therapy is highly effective for inflammatory bowel disease (IBD), but expensive and potentially toxic. Meticulous supervision prior to and during anti-TNF treatment is required to screen and monitor patients for adverse clinical events. In addition, a systematic administrative process is necessary to comply with Australian Medicare requirements and ensure ongoing therapy is uninterrupted. IBD nurses are essential components of multidisciplinary IBD services, but their role in facilitating the safe and timely delivery of anti-TNF drugs is unacknowledged. AIM: The aim of the study was to calculate time spent by IBD nurses on anti-TNF drug governance and its indirect cost. METHODS: Time spent on activities related to anti-TNF governance was retrospectively assessed by questionnaire among IBD nurses employed at Melbourne hospitals. The capacity of IBD clinics at these hospitals was separately evaluated by surveying medical heads of clinics. RESULTS: On average, each Melbourne IBD service handled 150 existing and 40 new anti-TNF referrals in 2013. The average annual time spent by nurses supervising an existing and newly referred anti-TNF patient was 3.5 and 5.25 h respectively, or a minimum of two full working days per week. If clinicians undertook this activity during normal clinic time, the organisational opportunity cost was at least 58%. CONCLUSIONS: Anti-TNF therapy governance is an essential quality component of IBD care that is associated with a definite, indirect cost for every patient treated. IBD nurses are best positioned to undertake this role, but an activity-based funding model is urgently required to resource this element of their work.

Perspectives of paediatric and adult gastroenterologists on transfer and transition care of adolescents with inflammatory bowel disease.

BACKGROUND: Programmes specific to inflammatory bowel disease (IBD) that facilitate transition from paediatric to adult care are currently lacking. AIM: We aimed to explore the perceived needs of adolescents with IBD among paediatric and adult gastroenterologists and to identify barriers to effective transition. METHODS: A web-based survey of paediatric and adult gastroenterologists in Australia and New Zealand employed both ranked items (Likert scale; from 1 not important to 5 very important) and forced choice items regarding the importance of various factors in facilitating effective transition of adolescents from paediatric to adult care. RESULTS: Response rate among 178 clinicians was 41%. Only 23% of respondents felt that adolescents with IBD were adequately prepared for transition to adult care. Psychological maturity (Mean = 4.3, standard deviation (SD) = 0.70) and readiness as assessed by adult caregiver (Mean = 4, SD = 0.72) were prioritised as the most important factors in determining timing of transfer. Self-efficacy and readiness as assessed by adult caregiver were considered the two most important factors to determine timing of transition by both groups of gastroenterologists. Poor medical and surgical handover (Mean = 4.10, SD = 0.8) and patients' lack of responsibility for their own care (Mean= 4.10, SD = 0.82) were perceived as major barriers to successful transition by both paediatric and adult gastroenterologists. CONCLUSIONS: Deficiencies exist in current transition care of adolescents with IBD in Australia and New Zealand. Standardising transition care practices with strategies aimed at optimising communication, patient education, self-efficacy and adherence may improve outcomes.

Development and validation of a patient-reported disability measurement tool for patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease can impact on a patient's ability to maintain normal physical and mental function, and fulfil their social, family and work roles. Aspects of disability in IBD have received little attention. AIM: To develop, validate and apply a questionnaire directed towards evaluating these disease aspects. METHODS: A literature review on disability in IBD was undertaken, and opinion about aspects of disability to measure was sought from six IBD-specialised gastroenterologists. A questionnaire was developed, and IBD patients completed the new disability questionnaire, the SF-36 and the short-IBD (SIBDQ - 10 point). A subgroup of patients completed the questionnaire again 4 weeks later. Healthy volunteers were studied as a control group. RESULTS: A total of 116 IBD out-patients were approached, of whom 81 (52 Crohn's disease and 28 ulcerative colitis) participated. Nineteen patients were re-evaluated at 4 weeks. Twenty-five controls were studied. All subscales demonstrated good Cronbach's alpha reliability and reproducibility. There was a significant inverse correlation between the disability score and the SIBDQ and between the disability score and the SF36 and a positive correlation with the Crohn's Disease Activity Index (CDAI) (all P < 0.001). Disability differed between ulcerative colitis and controls, but not between active and inactive disease. CONCLUSIONS: The new disability questionnaire is sensitive for detecting disability, is reliable and reproducible, and correlates with disease activity in Crohn's disease, but not ulcerative colitis. Further prospective testing is now needed in the longer term, larger patient populations and in different countries and ethnicities.

Postoperative recurrence of Crohn's disease: impact of endoscopic monitoring and treatment step-up.

AIM: Eighty per cent of patients with Crohn's disease require surgery, of whom 70% will require a further operation. Recurrence occurs at the anastomosis. Although often recommended, the impact of postoperative colonoscopy and treatment adjustment is unknown. METHOD: Patients with a bowel resection over a 10-year period were reviewed and comparison made between those who did and did not have a postoperative colonoscopy within 1 year of surgery, and those who did or did not have a step-up in drug therapy. RESULTS: Of 222 patients operated on, 136 (65 men, mean age 33 years, mean disease duration 8 years, median follow-up 4 years) were studied. Of 70 patients with and 66 without postoperative colonoscopy, clinical recurrence occurred in 49% and 48% (NS) and further surgery in 9% and 5% (NS). Eighty-nine per cent of colonoscoped patients had a decision based on the colonoscopic findings: of these, 24% had a step-up of drug therapy [antibiotics (n =10), aminosalicylates (n=2), thiopurine (n=5), methotrexate (n=1)] and 76% had no step-up in drug therapy. In colonoscoped patients clinical recurrence occurred in 9 (60%) of 15 patients with, and 23 (49%) of 47 without step-up and surgical recurrence in 2 (13%) of 15 and 4 (9%) of 47 (NS). CONCLUSION: Clinical recurrence occurs in a majority of patients soon after surgery. In this cohort, there was no clinical benefit from colonoscopy or increased drug therapy within 1 year after operation. However, the response to the endoscopic findings was not standardized and immunosuppressive therapy was uncommon. Standardizing timing of colonoscopy and drug therapy, including more intense therapy, may improve outcome, although this remains to be proven.

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 individual's 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 patient's 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 Crohn's 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 Crohn's 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 (χ(2) (7) = 10.42, P = 0.17, χ(2) /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 (ß = 51, P < 0.001). In turn, illness perceptions had a significant direct influence on depression and anxiety (ß = 41, P < 0.001, ß = 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.

Cerebral venous thrombosis associated with ulcerative colitis.

Thromboembolic complications, such as deep venous thrombosis and pulmonary embolism, are well recognized in patients with inflammatory bowel disease (IBD). We describe three cases of cerebral venous thrombosis complicating ulcerative colitis. Cerebral venous thrombosis is a rare but potentially devastating complication of IBD, and the diagnosis needs to be considered in any patient with IBD presenting with neurological symptoms.

Oral cyclosporin in refractory inflammatory bowel disease.

BACKGROUND: The role of cyclosporin in patients with severe, refractory inflammatory bowel disease is unclear. METHODS: A seven year retrospective review of patients treated with oral cyclosporin for inflammatory bowel disease refractory to conventional medical therapy was undertaken. RESULTS: Twenty-eight patients (13 ulcerative colitis and 15 Crohn's disease) received oral cyclosporin for a mean of nine months (range 0.25-27 months). Within four weeks of starting cyclosporin, a complete clinical response occurred in 15 patients (nine with ulcerative colitis and six with Crohn's colitis), in whom conventional maintenance treatment was instituted concurrently. The clinical response was sustained during cyclosporin treatment in ten, but maintained after cyclosporin withdrawal in only five patients (18% of entire study group). Four of the five patients who relapsed after cyclosporin withdrawal had failed previously to respond to azathioprine. None of the five patients with continuing remission after cyclosporin withdrawal had received azathioprine in the past. There were three clinically significant infections and 14 cases of impaired renal function during treatment. CONCLUSIONS: Oral cyclosporin induces remission in some patients with severe ulcerative colitis or Crohn's colitis, but its benefits in cases refractory to azathioprine are over-shadowed by a high frequency of relapse after drug withdrawal.

Safety of corticosteroids and immunosuppressive agents in ulcerative colitis.

For many years, corticosteroids have been the mainstay for treating acute ulcerative colitis. In patients with refractory disease, immunosuppressive therapy may be indicated, including azathioprine or its metabolite 6-mercaptopurine, cyclosporin and possibly methotrexate. Their benefits in ulcerative colitis must be weighed up against their possible adverse effects, the availability of surgical cure for this condition, and the long-term risk of carcinoma complicating colitis that applies in patients with chronic extensive disease. Information about the safety of corticosteroids and immunosuppressive agents has accumulated as a result of their extensive use in inflammatory bowel disease, organ transplantation and various other disorders.

Safety of drug therapy for inflammatory bowel disease in pregnant and nursing women.

: Drug therapy is justified in pregnant patients with active inflammatory bowel disease. Selection of medical treatment depends on disease severity and the potential for fetal toxicity. Preferably, pregnancy should be planned to coincide with periods of disease quiescence, so that drug requirements can be minimized. Sulphasalazine and prednisolone are clearly safe in pregnancy and lactation. Preliminary studies suggest that lowto-moderate-dose mesalazine is well tolerated in pregnant and nursing mothers. Immunosuppressive therapy during pregnancy in transplant and nontransplant recipients may be associated with an increased risk of fetal growth retardation and prematurity. The risk of congenital malformations from azathioprine and cyclosporin is not markedly increased, although exposure to methotrexate during the first trimester may cause fetal loss and characteristic anomalies. Short-term therapy with metronidazole in the first trimester is not associated with an increased risk of teratogenicity, although the safety of this drug in pregnancy as primary therapy for Crohn's disease using higher doses for prolonged periods has not been confirmed.

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 Mark's 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 Dukes's 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 Dukes's stage: about 90% of patients with Dukes's 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).

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.

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.

Lower gastrointestinal malignancy in Crohn's disease.

An increased incidence of carcinoma of the small bowel and colon has been described in patients with Crohn's disease. Tumours arising in the rectum and anus are reported less often. Between 1940 and 1992, of some 2500 patients with Crohn's 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 Crohn's 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 Crohn's disease may apply particularly to those with chronic complicated anorectal 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 Crohn's 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.