Use Of Thiopurines Research Articles

Sa1937 Predictive Factors of Disease Relapse Following Thiopurine Withdrawal for Sustained Clinical Remission of IBD

Introduction Thiopurine therapy is effective in maintaining clinical remission in IBD. However, long-term therapy is associated with an increased risk of lymphoma; therefore in clinical practice we aim to withdraw therapy after 4–5 years. Nevertheless, many patients will experience disease relapse within 12 months of drug withdrawal. 1 Methods The aim of the present study was to retrospectively determine the relapse rate in ulcerative colitis (UC) and Crohn9s disease (CD) following azathioprine (AZA) or mercaptopurine (MP) withdrawal and to determine factors predictive of relapse. Patients were identified by electronic case note review of an IBD research database in Edinburgh. Major inclusion criteria were AZA and/or MP therapy for a minimum of 3 years, AZA/MP withdrawn due to sustained clinical remission no steroid therapy for 6 months prior to drug withdrawal, and minimum 12 months follow-up. The primary outcome was disease relapse requiring AZA reinitiation, steroids or colectomy within 12 months of AZA/MP withdrawal, with secondary outcome assessed at 24 months. Clinical/laboratory predictors of relapse were sought. 1826 electronic records were reviewed (865 CD and 961 UC). 634 were treated with a thiopurine (348 CD and 286 UC). 74 met the strict study inclusion criteria (45 CD and 29 UC). Results CD was associated with a significantly higher risk of relapse than UC on Kaplan–Meier analysis (Abstract OC-166 figure 1, p=0.026). The moderate-severe relapse rate for 12 months was 44% for CD and 14% for UC. For 24 months, relapse rates were 60% for CD and 48% for UC. Elevated platelet count (p=0.03) and elevated white cell count (p=0.03) were predictive of relapse for UC, while no predictive factors were identified for CD. Median (range) duration of thiopurine use was 6.2 (3.4–18.7) years for CD and 6.0 (3.1–18.0) years for UC. Median duration of follow-up was 32 months for CD and 45 months for UC. Retreatment with a thiopurine after relapse was successful in 7/7 cases for UC and 18/24 for CD. Conclusion Relapse rates after withdrawal of a thiopurine are high, particularly for CD, and predicting this remains difficult. To help increase the power of this study, we are now expanding it across the UK. Competing interests None declared. Reference 1. Treton . Clin Gastroenterol Hepatol 2009; 7 :80.

Does Smoking Influence Crohnʼs Disease in the Biologic Era? The TABACROHN Study

While most studies have found a negative effect of smoking on Crohn's disease (CD) phenotype, more recent data have failed to reproduce this association, which might be due to a current wider use of thiopurines and biologic therapy. The TABACROHN study aimed at defining the impact of smoking on CD in the largest published series. This multicenter cross-sectional study included 1170 CD patients. Patients were classified as nonsmokers, current smokers, or former smokers according to their present smoking status. Clinical data regarding disease characteristics, treatment, and complications were collected. Smokers were more frequently under maintenance treatment when compared to nonsmokers. In addition, current smokers presented higher use of biologic drugs compared to nonsmokers. Tobacco exposure and a higher tobacco load were independent predictors of need for maintenance treatment and stenosing phenotype, respectively. In the era of early and widespread use of immunosuppressants and biologics, tobacco exposure is an independent predictor of need for maintenance treatment, specifically biologic therapy. The wider use of biologics and immunosuppressants could account for the existence of no major differences in disease behavior and complications between nonsmokers and current smokers.

P268 A survey about the use of thiopurines for inflammatory bowel diseases among Italian gastroenterologists

P268 A survey about the use of thiopurines for inflammatory bowel diseases among Italian gastroenterologists

P112 The natural history of Crohn's disease (CD): A long-term (>10 years) follow-up study

Background: Most of the studies on the natural history of CD include small cohorts with less than 5 years of follow-up. Aims: To study the natural history of CD in a cohort with more than 10 years of evolution. To identify predictive factors of bad outcome. Methods: A retrospective study including CD patients with more than 10 years of evolution was performed. The study population was divided into 3 groups by year of diagnosis (Group A = 1985 1991, Group B = 1992 1997, Group C = 1998 2001). Survival curves were compared with the Kaplan Meier test. Cox regression analysis was performed to identify predictive factors of surgery in these patients. Results: 133 patients with CD were included. Mean followup was 17 years (range 3 51). 29% presented changes in disease behaviour. At baseline, the proportion of patients with stricturing behaviour was 11%, while 9% had penetrating behaviour. At the end of follow-up, these figures were 23% and 24% respectively. 43% of these changes occurred within the first 5 years of follow-up. There was an increasing and earlier use of thiopurines over time: 10 years after diagnosis the proportion of patients on thiopurines was 40% in group A, 59% in group B, and 82% in group C (p < 0.001), and the median time to start of thiopurines was 130, 83 and 39 months respectively.

P113 Calprotectin for relapse risk assessment in teenagers with inflammatory bowel disease who claim to have full disease control

Background: Most of the studies on the natural history of CD include small cohorts with less than 5 years of follow-up. Aims: To study the natural history of CD in a cohort with more than 10 years of evolution. To identify predictive factors of bad outcome. Methods: A retrospective study including CD patients with more than 10 years of evolution was performed. The study population was divided into 3 groups by year of diagnosis (Group A = 1985 1991, Group B = 1992 1997, Group C = 1998 2001). Survival curves were compared with the Kaplan Meier test. Cox regression analysis was performed to identify predictive factors of surgery in these patients. Results: 133 patients with CD were included. Mean followup was 17 years (range 3 51). 29% presented changes in disease behaviour. At baseline, the proportion of patients with stricturing behaviour was 11%, while 9% had penetrating behaviour. At the end of follow-up, these figures were 23% and 24% respectively. 43% of these changes occurred within the first 5 years of follow-up. There was an increasing and earlier use of thiopurines over time: 10 years after diagnosis the proportion of patients on thiopurines was 40% in group A, 59% in group B, and 82% in group C (p < 0.001), and the median time to start of thiopurines was 130, 83 and 39 months respectively.

Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non‐melanoma skin cancer in an at‐risk population: A cohort study

The thiopurines azathioprine and 6-mercaptopurine are effective in the management of patients with inflammatory bowel disease (IBD) in whom aminosalicylates, antibiotics and corticosteroids have failed to induce or maintain remission. Long-term use of these agents has been linked to a greatly increased risk of non-melanoma skin cancer and lymphatic cancer in organ transplant recipients. There is some evidence to suggest that IBD patients receiving thiopurines might be at increased risk of cancer. Our aim was to determine the incidence of cancer in a cohort of patients with IBD managed in our clinic, and to relate this to thiopurine exposure. We conducted a retrospective study based on the clinical and pathology records of patients attending a specialist IBD clinic at Groote Schuur Hospital, Cape Town, South Africa between 1960 and 2007. We analyzed the records of 1084 patients. A total of 123 subjects (11.5%) had received thiopurine therapy. Cancer was identified in 51 patients (4.7%), including colorectal cancer (15 patients), melanoma (two patients), non-melanoma skin cancer (seven patients) and non-Hodgkin's lymphoma (five patients). A diagnosis of non-melanoma skin cancer was significantly associated with thiopurine exposure (odds ratio 5.0, 95% confidence interval 1.1-22.8). Six of seven non-melanoma skin cancers occurred in Caucasian patients, with a highly significant association with thiopurine use (odds ratio 12.4, 95% confidence interval 2.3-67.4). Patients with IBD who receive thiopurines are at increased risk of non-melanoma skin cancer. The risk is highest in Caucasian patients, and is negligible in other groups.

Risk of non‐melanoma skin cancer with thiopurine use in inflammatory bowel disease

See article in J. Gastroenterol. Hepatol. 2012; 27: 385–389.

Multiple forms of DNA Damage Caused by UVA Photoactivation of DNA 6‐Thioguanine

Thiopurines are prescribed frequently as medication for cancer and for inflammatory disorders. One of them, azathioprine, has been the immunosuppressant of choice for organ transplant recipients for many years. Thiopurine use is associated with elevated sun sensitivity and skin cancer risk. Skin sensitization is selective for UVA. 6-TG integrates into DNA and unlike the canonical DNA bases, it is a strong UVA chromophore with an absorbance maximum at 342 nm. DNA 6-TG is a photosensitizer and a source of reactive oxygen species. Reactive oxygen that is generated from the photochemical activation of DNA 6-TG causes extensive damage to DNA and proteins. This damage is mutagenic and extremely toxic to cultured human cells. Here we describe some of the lesions that are known to be generated from UVA irradiation of DNA 6-TG. We discuss how this photochemical damage might contribute to the toxic effect of thiopurine/UVA treatment on cultured cells and to the high risk of skin cancer in thiopurine-treated patients.

The clinical characteristics at diagnosis and course of Crohnʼs disease: A Korean multicenter study

Hospitalization and Colectomy IRs in M06-826 and M06-827 Trials Hospitalization and Colectomy IRs in M06-826 and M06-827 Trials The incidence and prevalence of Crohn's disease (CD) is increasing in Asian countries including Korea. However, the clinical features and course of Asian CD patients remain unclear. Therefore, this study was performed to elucidate the clinical characteristics at diagnosis and course of Korean CD patients. Patients diagnosed with CD since January 2009 were prospectively registered at the nationwide, multicenter registry of CD in Korea. They were prospectively followed and the data of 204 patients from 26 hospitals who were followed for at least one year were analyzed. One hundred fifty four patients (75.5%) were male and median age at diagnosis was 23 years (12 ∽ 63 years). At diagnosis, abdominal pain was the most common presenting symptom (56.4%) and perianal fistula and/or abscess was the sole presentation in 41 patients (20.1%). Twenty three patients (11.3%) had received anti-tuberculous medication and seven (3.4%) were previously misdiagnosed as ulcerative colitis (UC). Seven patients (3.4%) had a positive first-degree family history of inflammatory bowel disease. One hundred thirty five patients (66.2%) had disease in both small bowel and colon, 49 (24.0%) had isolated small bowel disease, and 20 (9.8%) had isolated colonic disease. The inflammatory, stricturing, and penetrating behaviors defined by the Montreal classification were observed in 141 (69.1%), 29 (14.2%), and 34 (16.7%) patients, respectively. The median duration of follow-up was 19.1 months (range, 12.3 ∽ 26.4 months). The cumulative rate of use of 5-aminosalicylic acids, corticosteroids, thiopurines, and infliximab were 96.1%, 43.1%, 64.2%, and 6.9%, respectively. The one-year cumulative intestinal resection rate was 17.6% and there was no mortality during follow-up. Korean CD patients differed from Western patients in gender distribution and disease location at diagnosis. The more frequent use of thiopurines was observed in our recently diagnosed patients. Further long-term follow-up evaluation is required to investigate the clinical outcomes of CD patients in Asia.

Long-term outcome of ulcerative colitis in patients who achieve clinical remission with a first course of corticosteroids

BackgroundAlthough the early outcomes of ulcerative colitis after a first course of corticosteroids are well known, data on long-term disease evolution in patients responding to a first corticosteroid course are scarce. AimsTo evaluate the long-term clinical evolution in ulcerative colitis patients responding to a first course of corticosteroids and to identify those factors associated with a poorer outcome. MethodsRetrospective review of 114 patients diagnosed with ulcerative colitis who responded to the first corticosteroid course, and did not start thereafter maintenance therapy with thiopurines were included. ResultsCorticosteroids were prescribed because of a moderate (78%) or a severe flare (22%). All but two patients followed maintenance treatment with mesalazine after corticosteroid discontinuation. After a median follow-up of 83 months (7–156), 72% of patients suffered new relapses leading to corticosteroid reintroduction in 65% of patients. The earlier corticosteroids were introduced in the course of ulcerative colitis, the higher the risk of relapse and corticosteroid reintroduction. Thiopurines were started in 51%, and infliximab in 19%. Eleven percent of patients underwent colectomy. No predictors of thiopurine use or colectomy were found. ConclusionsHalf of the ulcerative colitis patients responding to a first course of corticosteroids will require immunosuppressors mainly because of steroid-dependence.

Role of Thiopurine and Anti-TNF Therapy in Lymphoma in Inflammatory Bowel Disease

The objective of this study was to assess inflammatory bowel disease (IBD) medications in relation to lymphoma risk. Information on IBD and relevant medications and other utilization was obtained from the Kaiser Permanente IBD Registry, 1996-2009. Lymphoma cases were ascertained from the Kaiser Permanente Cancer Registry. Lymphoma incidence was compared between the IBD cohort and the general Kaiser Permanente population. Of the 16,023 IBD patients without human immunodeficiency virus followed an average 5.8 years, 43 developed lymphoma. IBD patients with and without lymphoma did not differ with respect to past IBD-related visits, procedures, or tests. The standardized incidence rate ratio (SIRR) for lymphoma among IBD patients with no dispensing of thiopurine or anti-tumor necrosis factor (TNF) was 1.0 (95% confidence interval (CI): 0.96-1.1). Of the 21,282 person-years involving exposure to thiopurine or anti-TNF, 81% involved thiopurine alone; 3%, anti-TNF alone; and 16%, combination therapy. Among patients with thiopurine but not anti-TNF dispensings, the SIRR was 0.3 (95% CI: 0.2-0.4) for past use and 1.4 for current use (95% CI: 1.2-2.7). Among patients with dispensing of anti-TNF (with and without thiopurine), the SIRR was 5.5 for past use (95% CI: 4.5-6.6) and 4.4 for current use (95% CI: 3.4-5.4). The most common lymphoma subtypes were diffuse large B-cell lymphoma (44%), follicular lymphoma (14%), and Hodgkin's disease (12%). Our study provides evidence that IBD alone is not associated with the risk of lymphoma. Use of anti-TNF with thiopurine and current use of thiopurine alone were associated with increased risk, although the effect of disease severity merits further evaluation.

Increased Risk of Nonmelanoma Skin Cancers Among Individuals With Inflammatory Bowel Disease

There are limited data on the risk of nonmelanoma skin cancer (NMSC) among individuals with inflammatory bowel disease (IBD), including those with or without exposure to immunosuppressant medications. Individuals with IBD (n = 9618) were identified from the University of Manitoba IBD Epidemiology Database and matched with randomly selected controls (n = 91,378) based on age, sex, and postal area of residence on the date of IBD diagnosis (index date). Groups were followed up from the index date until a diagnosis of any invasive cancer (including NMSC), death, migration from the province, or the end of the study (December 31, 2009), whichever came first. Cox regression analysis was performed to calculate the relative risk of NMSC among the individuals with IBD, adjusting for frequency of ambulatory care visits and socioeconomic status. Of the individuals followed, 1696 were diagnosed with basal cell skin cancer (BCC) and 341 were diagnosed with squamous cell skin cancer (SCC). Individuals with IBD had an increased risk for BCC, compared with controls (hazard ratio, 1.20; 95% confidence interval [CI], 1.03-1.40). Among patients with IBD, use of thiopurines increased the risk of SCC (hazard ratio, 5.40; 95% CI, 2.00-14.56), compared with controls. Use of thiopurines also was associated with SCC in a case-control, nested analysis of individuals with IBD (odds ratio, 20.52; 95% CI, 2.42-173.81). The risk of BCC could be increased among individuals with IBD. Use of thiopurines increases the risk of SCC among individuals with IBD.

“Tac”kling a Difficult Problem

“Tac”kling a Difficult Problem

Thiopurines prevent advanced colorectal neoplasia in patients with inflammatory bowel disease

Background and aimsPrevious studies have suggested a chemopreventive effect of 5-aminosalicylic acid (5-ASA) therapy in patients with inflammatory bowel disease (IBD). This effect has not been reported in IBD patients...

Role of genetic and environmental factors in British twins with inflammatory bowel disease

Twin studies provide insight into the complex interaction between genetic and environmental factors in the development of inflammatory bowel disease (IBD). We assessed associations between childhood environmental factors and development of Crohn's disease (CD) and ulcerative colitis (UC) in twins. Questionnaires on clinical demographics and exposure to environmental factors were sent to twins with IBD, their healthy co-twins, and their doctors. Kappa statistics were used to examine agreement between twin pairs and odds ratios were calculated by conditional logistic regression. In all, 250 IBD twin pairs (122 CD; 125 UC; 3 CD/UC; 28 concordant pairs) were analyzed. Concordant monozygotic twins with CD showed good agreement for disease location (κ 0.88; 95% confidence interval [CI]: 0.45-1.00), disease behavior (κ 1.00; 95% CI: 0.43-1.00), and moderate agreement for age at diagnosis and need for medical and surgical therapy. Concordant monozygotic twins with UC showed good agreement for disease extent (κ 0.60; CI 0.13-1.00) and use of thiopurines (κ 0.73; CI 0.10-1.00). In discordant twins, symptomatic childhood mumps infection (odds ratio [OR], 3.8; 95% CI, 1.2-11.3) and oral contraceptives (OR, 4.0; 1.1-14.2) were associated with CD. Smoking was associated with CD (OR, 4.3; 95% CI, 1.9-9.8) but inversely associated with UC (OR, 0.3; 95% CI, 0.1-0.9). Both CD and UC twins had suffered more "gastroenteritis" and spent more time with animals than their co-twins. Disease phenotype in CD and disease extent in UC appeared to be genetically influenced. Smoking is a risk factor for CD but is protective for UC. Early exposure to "infections" during childhood may be associated with the development of IBD.

A Distinct Mechanism for Reflux in Patients With Cystic Fibrosis: A Study Using High Resolution Manometry-Impedance

neoplasia. Cox proportional hazard regression analysis was used to calculate the risk of advanced neoplasia in patients with and without thiopurine or 5-ASA use. Results: A total of 2605 patients with a confirmed IBD diagnosis were included in this study. Of these, 981 patients (38%) used 5-ASA, 315 patients (12%) used thiopurines, 459 patients (18%) used both 5-ASA and thiopurines and 850 patients (33%) used none of these drugs. No statistically significant differences were found for type of IBD, gender, age, duration of IBD and extent of IBD between these groups. Thirty-one patients (1%) developed advanced neoplasia during 16,568 person years of follow-up. Of these, 12 patients (39%) had used 5-ASA, 2 (7%) thiopurines and 1 (3%) both drugs. Increasing age and disease involvement of more than 50% of the colon were associated with an increased risk of developing advanced neoplasia (adjusted hazard ratio (HR) 1.07, 95% confidence interval (CI) 1.04-1.11 and adjusted HR 5.88, 95% CI 2.00-17.3, respectively). Thiopurine use was associated with a significantly decreased risk of developing advanced neoplasia (adjusted HR 0.10, 95% CI 0.01-0.73). 5ASA therapy had also a protective effect on developing advanced neoplasia, but this was not statistically significant (adjusted HR 0.51, 95% CI 0.20-1.26). Conclusion: Thiopurine use protects colitis patients against the development of advanced neoplasia. The effect of 5ASA appeared to be less pronounced.

Tolerability and Safety of Conventional Thiopurines Concomitantly With Allopurinol in IBD-Patients With a Skewed Thiopurine Metabolism

was linked to the Dutch nationwide pathology archive (PALGA) to verify the IBD diagnosis and to determinewhether a patient had developed NMSC. Cox proportional hazard regression analysis was used to calculate the risk of NMSC in patients with and without thiopurine use, adjusted for type of IBD, gender, age and duration of IBD. Results: A total of 2887 patients with a confirmed IBD diagnosis were included in this study. Of these, 819 patients (28%) used thiopurines. No statistically significant differences were found for type of IBD, gender, age and extent of IBD between thiopurine users and non-users. Disease duration was significantly shorter in users compared to non-users (34 months (SD 45) versus 38 months (SD 48), p=0.03). Eighty-six patients (3%) developed NMSC during 18,727 person years of follow-up. Of these patients, 24 (28%) had used thiopurines. Mean age at NMSC diagnosis was 64 years (SD 12) in thiopurine users compared to 63 years (SD 13) in nonusers (p=0.68). Increasing age and duration of IBD were associated with a higher risk of developing NMSC (adjusted hazard ratio (HR) 1.06, 95% Confidence Interval (CI) 1.041.08 and adjusted HR 1.007, 95% CI 1.002-1.011, respectively). A diagnosis of ulcerative colitis and female gender were associated with a decreased risk of NMSC (adjusted HR 0.62, 95% CI 0.40-0.98) and adjusted HR 0.47, 95% CI 0.30-0.74). Thiopurine use was not associated with an increased risk of developing NMSC (adjusted HR 0.85, 95% CI 0.511.41). Conclusion: In contrast to transplant recipients, thiopurine use in IBD patients is not associated with an increased risk of developing NMSC.

A Biochemical Mechanism for the Role of Allopurinol in TPMT Inhibition

Introduction Hypermethylation of thiopurines has been associated with drug toxicity and non-response to treatment. In such patients the use of low dose thiopurines with concomitant allopurinol is advocated12. Allopurinol is observed to cause a reduction in methylated metabolites of thiopurines; however the biochemical mechanisms remain incompletely understood. Using an intact erythrocyte model we propose a novel pathway of allopurinol mediated thiopurine- S- methyltransferase (TPMT) inhibition, through the production of 2-hydroxy-6-thiopurine (2OH6MP). Methods EDTA whole blood was obtained from healthy volunteers; the plasma and top 5 th were removed and the red cells washed with 0.9% saline. 150 μL of Earl9s balanced salt solution was added to 100 μL of packed red cells. Cells were incubated with 250 μM of 6-mercaptopurine (6-MP) for 0, 2, 4 and 6 h at 37°C. In the second experiment cells were pre-incubated for 2 h with 280 μM of 2OH6MP prior to the addition of 250 μM 6-MP for either 2 or 4 h. At the end of the incubation period, the media was removed and the red cells lysed with 15% perchloric acid after the addition of dithiotreitol. Methylated thiopurine-metabolites were reduced to the base by boiling at 100°C for 1 h. 75 μL of the red cell lysates and supernatant media were separated by reverse phase HPLC to detect the methylated metabolites of 6-MP. Results In packed red cells there was an increase in the concentration of 6-methylmercaptopurine (6-MeMP) detected at each time point. However, the rate of 6-MeMP production remained constant (mean 0.825 pmol L −1 h −1 , SEM ± 0.038). The concentration of 6-MeMP observed in the media was up to 7-fold lower than the concentration in red cells (mean 0.133 pmol L −1 h −1 , SEM ± 0.009). In red cells pre-incubated with 2OH6MP prior to the addition of 6-MP there was a significant reduction in the rate of 6-MeMP production at both 2 (0.878 pmol L −1 h −1 vs 0.135 pmol L −1 h −1 , p −1 h −1 vs 0.096 pmol L −1 h −1 , p Conclusion The data suggests that 6-MP enters red blood cells, where it undergoes methylation to 6-MeMP. The presence of 2OH6MP leads to a reduction in the rate of 6-MeMP production, most likely through direct inhibition of TPMT. We propose that 6-MP undergoes preferential oxidation via aldehyde oxidase, producing 2OH6MP, which leads to feed-back inhibition of TMPT and thereby a reduction in methylated thiopurine-metabolites. This mechanism may explain why patients treated with a combination of thiopurine and allopurinol have dramatically decreased methylated metabolites.

Monitoring thiopurine methyltransferase (TPMT) activity in inflammatory bowel disease: is it worth it?

IntroductionAzathioprine and 6-mercaptopurine are immunosuppressants used to treat inflammatory bowel disease (IBD). Marrow toxicity occurs in 3% of patients receiving these drugs. Some practitioners propose that checking Thiopurine methyltransferase (TPMT)...

Risk factors and impact of Clostridium difficile infection in acute severe colitis needing hospitalization

IntroductionLimited data is available on the disease specific risk factors and the impact of Clostridium difficile when patients are admitted with a flare up of ulcerative colitis. We aimed to...