Thiopurine Initiation Research Articles

Thiopurines Have Sustained Long-term Effectiveness in Patients with Inflammatory Bowel Disease, Which is Independent of Disease Duration at Initiation: A Propensity Score Matched Analysis.

Thiopurines are viable option for the treatment of inflammatory bowel disease [IBD] in resource-limited countries. However, data on the effect of disease duration at thiopurines initiation on long-term effectiveness are limited. We performed a propensity matched analysis of a retrospective cohort of patients with ulcerative colitis [UC] and Crohn's disease [CD]. Patients initiated on thiopurines early in the disease course [≤2 years] were compared with those started late [>2 years]. Effectiveness was defined as no requirement for hospitalisation, anti-tumour necrosis factor [TNF] agents, or surgery, and minimum steroid requirement [≤1 steroid course in 2 years] during follow-up. A total of 988 [UC: 720, CD: 268] patients were included (male: 665 [60.8%], median age: 40 [32-51] years, median follow-up: 40 [19-81] months). Overall effectiveness at 5 and 10 years was 79% and 72% in UC, and 69% and 63% in CD, respectively. After propensity score matching, there was no difference in 5- and 10-year effectiveness between early and late thiopurine initiation groups either for UC [81% and 80% vs 82% and 74%; p = 0.92] or CD [76% and 66% vs 72% and 51%, p = 0.32]. Male sex for UC (negative: hazard ratio [HR]: 0.67, 95% confidence interval [CI): 0.45-0.97; p = 0.03), and ileal involvement [positive: HR: 3.03, 95% CI: 1.32-6.71; p = 0.008], steroid-dependent disease [positive: HR: 2.70, 95% CI: 1.26-5.68; p = 0.01] and adverse events [negative: HR: 0.47, 95% CI:0.27-0.80; p = 0.005] for CD were predictors of thiopurine effectiveness. Thiopurines have sustained long-term effectiveness in both UC and CD. However, early thiopurine initiation had no better effect on long-term disease outcome compared with late initiation.

Patients with elderly onset inflammatory bowel disease have a decreased chance of initiation of all types of medications and increased risk of surgeries-A nationwide cohort study.

In patients with elderly (≥60 years) onset inflammatory bowel disease (IBD), we studied initiation of medications, drug persistency and surgeries. A nationwide cohort study based on Danish registries, comprising incident IBD patients ≥18 years from 1995 to 2020 (N = 69,039). Patients were divided into elderly (N = 19,187) and adult onset (N = 49,852). Outcomes were initiation of thiopurines, 5-ASA, biologics and corticosteroids within 1 and 5 years after diagnosis, and for those who initiated medications, we estimated drug persistency. Surgeries were examined within 1 and 5 years. We used regression models controlling for covariates. In elderly patients, the adjusted hazard ratios (aHR) for initiating thiopurines, 5-ASA and biologics within 1 year were 0.44 (95% CI 0.42-0.47), 0.77 (95% CI 0.75-0.79) and 0.29 (95% CI 0.26-0.31) respectively. The results were similar within 5 years. In elderly patients, drug persistency for thiopurines, 5-ASA and biologics was not impaired within 5 years. The aHR of stopping steroids within 1 and 5 years were 0.80 (95% CI 0.76-0.84) and 0.77 (95% CI 0.74-0.80) respectively. The risk of surgeries was increased in the elderly patients (in ulcerative colitis, within 5 years, aHR 1.39 [95% CI 1.27-1.52], and in Crohn's disease 1.13 [95% CI 1.04-1.23]). We found significantly low chance of initiation of IBD medications in elderly patients, the reason may not be due to mild disease course. In elderly patients, drug persistency was comparable to adults. Clinicians should carefully consider whether they underuse IBD-specific medications in elderly patients, and special attention should be applied to timely discontinuation of corticosteroids.

P423 Azathioprine still remains the first step-up therapy in patients with Inflammatory Bowel Disease in low-middle income countries

Abstract Background Inflammatory bowel disease (IBD) including Ulcerative Colitis (UC) and Crohn’s Disease (CD) is characterized by remitting/relapsing course. A proportion of patients with UC, and almost all patients with CD require long-term immunosuppression to maintain endoscopic and clinical remission and prevent disease progression. The present study aimed to evaluate the long-term efficacy of thiopurines, their predictors, and the effect of the early use of thiopurines on disease outcomes in patients with IBD. Methods A retrospective cohort analysis of patients with IBD following up in IBD clinic at AIIMS, New Delhi, India from, 2004–2020. Efficacy was defined as a state of not requiring hospitalization, anti-TNF agents, surgery, and only minimum (≤, 1 steroid course in, 2 years) steroid requirement during follow-up. Early and late thiopurine initiation was defined as commencement of thiopurines ≤2 and >2 years of disease onset, respectively. Results Of, 1264 consecutive patients on thiopurines (both, 6-MP and azathioprine), 988 (UC:720, CD:268) were considered for efficacy analysis (males-60.8%, mean age at disease onset-31.69±12.34 years and thiopurine initiation-35±13.14 years). Time to event analysis showed a median efficacy rate of, 79%, 72% and, 68%, 61% at, 5 and, 10 years in UC and CD patients respectively after thiopurine initiation. On multivariate analysis, only the male sex was found to be a significant predictor of relapse (HR:, 1.49, 95% CI:, 1.021–2.194; P=0.039) in UC and Ileal involvement (HR:, 0.391, 95% CI:, 0.176–0.86; P=, 0.021) and steroid-dependent disease (HR:, 0.429, 95% CI:, 0.186–0.965; P=, 0.041) were associated with decreased risk of relapse and presence of any adverse event was associated with increased risk of relapse (HR:, 2.37, 95%CI:, 1.39–4.05; P=0.008). Kaplan Meier survival analysis showed no difference between the efficacy of early and late thiopurine groups, both in UC (Log-rank test P = 0.72) and CD (Log-rank test P = 0.76). Figure, 1: Kaplan Meier curve showing relapse-free survival on thiopurine in ulcerative colitis and Crohn’s disease. Figure, 2: Kaplan Meier survival analysis comparing relapse-free survival in early vs late thiopurine initiation group in UC (Log-rank test P = 0.72). Figure, 3: Kaplan Meier survival analysis comparing relapse-free survival in early vs late thiopurine initiation group in CD (Log-rank test P-value:, 0.764). Conclusion Thiopurines still remains a viable long-term option for maintenance of remission in patients with IBD, especially in resource-limited countries. Their use can be further enhanced by optimizing their therapy and regular monitoring for adverse events.

P616 Sustainability of thiopurines monotherapy in ulcerative colitis: a nationwide analysis from the epi-IIRN cohort

Abstract Background Thiopurines have been long used to maintain remission in ulcerative colitis (UC) but are also associated with toxicity and therapeutic failure. We aimed to assess the sustainability rate of thiopurines commenced as monotherapy in UC, and to explore predictors of sustainability. Methods This study was performed on data from four Health Maintenance Organizations (HMOs), covering 98% of the Israeli population. We included all biologic-naïve UC patients diagnosed after 2005 and treated with thiopurines monotherapy for at least three months. Treatment with 5- aminosalicylic acid (ASA) was allowed if initiated prior to or during the first three months from initiation of thiopurines. Sustainability was defined as continued thiopurines treatment without switching therapy, adding biologics or requiring surgery. At most one short steroid course was allowed. Cox regression model was used to explore estimated predictors to sustainability. Results A total of 1,897 (370 [20%] pediatric-onset and 1,527 [80%] adults) thiopurines-treated patients were included with a 15,033 person-years of follow-up. The median time from UC diagnosis to initiation of thiopurines was 12.7 months (IQR 4.6–30.9), and the median treatment duration was 13.0 months (6.3–28.4). Sustainability rate was evident in 92% of patients after 6 months from initiation of thiopurines and 83%, 65% and 42% at one, three and five years, thereafter. Sustainability was associated with early initiation of thiopurines during disease course (HR 0.99 [95%CI 0.985–0.995]) and lack of 5-ASA at initiation of thiopurines (HR 0.7 [95%CI 0.6–0.8]). Conclusion As many as two thirds of biologic-naïve UC patients treated with thiopurines monotherapy sustain this treatment after five years, especially when initiated early and without 5-ASA.

DOP54 Real-world effectiveness of thiopurine monotherapy in Crohn’s Disease: Is there still a place for thiopurines in the biological era?

Abstract Background In current guidelines, thiopurines are still recommended as first-line maintenance therapy for patients with Crohn’s disease (CD). Due to their lack of immunogenicity, oral administration route and low costs, thiopurines are an attractive first-line treatment option. However, in recent studies the position of thiopurine monotherapy in CD has been questioned as a result of relatively lower overall effectiveness rates compared to ulcerative colitis. Real-world long-term effectiveness data substantiating the use and position of thiopurines in CD management remain sparse. We assessed long-term effectiveness of thiopurine monotherapy in CD using the population-based IBD South-Limburg (IBDSL) cohort. Methods All CD patients in the IBDSL cohort starting thiopurine monotherapy as first-line maintenance therapy between 1991–2014 were included. Thiopurine monotherapy was defined effective if either: (1) no escalation to biological treatment, (2) no course of corticosteroids, (3) no resective surgery or, (4) no hospitalization for active disease was required whilst on thiopurine treatment. Patients with early treatment discontinuation (i.e. <3 months) were identified, including reason of discontinuation. Long-term effectiveness was assessed adjusting for differences in follow-up between patients using Kaplan-Meier analysis. Potential risk factors for therapy failure were identified using Cox regression. Results In total, 643/1162 (55.3%) CD patients (median follow-up: 8.5 years IQR 5.0–13.2) received first-line thiopurine monotherapy after a median of 9.7 months (IQR 3.2–31.3) after diagnosis. Therapy was discontinued within three months in 164 patients (25.5%), mainly due to adverse events [Figure 1]. Thiopurine monotherapy was effective for the duration of treatment in 229/479 (35.6%) patients, corresponding to estimated effectiveness rates of 62.9%, 43.9% and 31.2% after 1, 5 and 10 years, respectively [Figure 1–2]. No significant difference in effectiveness was observed after stratifying for era of thiopurine initiation (pre-biological (1991–1998) vs. biological (>1999) era, p=0.84). Factors associated with thiopurine failure were stricturing disease (aHR 1.41, 95%CI 1.01–1.96) and upper GI involvement (aHR 1.52, 95%CI 1.02–2.28) at diagnosis. During follow-up, 40/229 patients with a durable response discontinued treatment due to quiescent disease. Of these, 35 patients (87.5%) remained without treatment 24 months after discontinuation. Conclusion Real-world data from this population-based study demonstrate that thiopurine monotherapy remains an effective and durable first-line treatment option for CD, even in the biological era. These results should be considered in the ongoing discussion regarding the position of thiopurine therapy.

Thiopurine Monotherapy Is Effective in Maintenance of Mild-Moderate Inflammatory Bowel Disease.

Crohn's disease (CD) and ulcerative colitis (UC) are complex, inflammatory bowel diseases (IBD) with debilitating complications. While severe IBD typically requires biologic agents, the optimal therapy for mild-moderate IBD is less clear. To assess the efficacy of thiopurine monotherapy for maintenance of mild-moderate IBD and clinical variables associated with treatment outcome. This retrospective study included adults with mild-moderate IBD who were started on thiopurines without biologic therapy. The primary outcome was therapy failure, defined by disease progression based on clinical, endoscopic, and radiologic criteria. Clinical variables were extracted at time of thiopurine initiation. Univariable and multivariable Cox proportional hazards models were used to examine the independent contribution of the clinical variables on treatment response. From 230 CD patients, 64 (72%) were free of treatment failure with mean follow-up of 3.3years. In our multivariable model, thiopurine failure was associated with concomitant systemic steroid administration (aHR 2.43, p = 0.001), whereas protective factors included concomitant oral 5-aminosalicylic acid (5-ASA) therapy (aHR 0.54, p = 0.02) and non-fistulizing, non-stricturing disease (aHR 0.57, p = 0.047). From 173 UC patients, 50 (71%) were free from treatment failure with mean follow-up of 3.3years. On multivariable analysis, concomitant oral steroids were associated with thiopurine failure (aHR 2.71, p = 0.001). Only 13 (4%) discontinued thiopurines from adverse effects. In mild-moderate uncomplicated IBD, thiopurine monotherapy was associated with longitudinal maintenance of remission and may represent a lower-cost, convenient, and effective alternative to biologics. Multiple clinical variables were predictive of treatment response.

Early thiopurine maintenance is associated with reduced proximal disease progression and colectomy rate in ulcerative colitis.

Thiopurines effectively maintain remission in ulcerative colitis patients. Whether early initiation of thiopurines after ulcerative colitis diagnosis decreases proximal disease progression and colectomy rates is not known. We conducted a cohort study of ulcerative colitis subjects recruited from 1970 to 2009. Early thiopurine maintenance was defined as commencement of azathioprine or mercaptopurine within 5 years of diagnosis and maintenance for at least 6 months. Propensity score matching was conducted to correct for confounders influencing early thiopurine introduction. Outcomes of interest were colectomy rate and endoscopic proximal disease extension. 982 consecutive ulcerative colitis subjects (12 879 patient-years) were recruited with 116 requiring colectomy. Thiopurines initiation and maintenance increased over time with median time to thiopurine commencement decreasing from 23 years in the first decade to 2 years in the last decade (P < 0.0001). Multivariate analysis showed that early thiopurine maintenance significantly decreased the need for colectomy [hazard ratio, 0.13; 95% confidence interval (CI):0.03-0.55; P = 0.006]. The number of subjects needed to be treated to reduce one colectomy at 5 and 10 years was 18 (95% CI, 16- 36) and 12 (95% CI, 11-25). After propensity score matching, early thiopurine maintenance was significantly associated with decreased colectomy (hazard ratio, 0.10; 95% CI, 0.03-0.43; P = 0.002) and proximal progression of disease extent (hazard ratio, 0.26; 95% CI, 0.10-0.78; P = 0.015). Early thiopurine maintenance for >6 months is significantly associated with reduced colectomy and proximal progression of disease extent in ulcerative colitis.

P753 Elevation of liver enzymes in a large cohort of patients with inflammatory bowel disease

Abstract Background Elevation in liver enzymes (ELE) is often seen in patients with inflammatory bowel disease (IBD). The aim of this study is to assess the incidence, character, chronicity, degree, and etiology of ELE in within the validated epiIIRN cohort which includes all IBD patients in Israel (n = 45,074). Methods We current analysis was performed on data from three of four Health Maintenance Organisations (HMOs), covering 48% of the Israeli population. The identification of Crohn’s disease (CD) and ulcerative colitis (UC) utilised previously validated algorithms. Retrieved data included demographics, anthropometric measures, liver enzymes, medications and other diagnoses codes. Mild ELE was defined from upper normal limit (UNL) to X2 UNL, moderate X3 UNL and severe elevation ≥X4 UNL). The pattern of elevation was defined as hepatocellular (isolated elevation of ALT and/or AST), cholestatic (elevated GGT and/or ALK and bilirubin) and mixed pattern. Chronicity of ELE was defined as brief (&amp;lt;30 days) to chronic (&amp;gt;180 days). Results The total incidence (ever) of ELE in CD patients was 33% (3098/9421) and 28% in UC (2001/7040); p &amp;lt; 0.001. The mean age at ELE was 29.9 years (IQR 17.2–47.5) in CD and 37.9 years (23.2–53.8) in UC (p &amp;lt; 0.001). Hepatocellular pattern had more commonly in UC (54% vs. 47%, p &amp;lt; 0.001) as mixed pattern (22% vs. 20%, p = 0.01), while cholestatic pattern had more commonly in CD (31% vs. 26%, p &amp;lt; 0.001). The ELE was transient in 609 (9%) patients, while 4054 (62%) had chronic ELE. Mild ELE was recorded in 860 (22%) CD patients and 460 (19%) UC, and severe in 328 (8%) CD and 253 (10%) UC. ELE was recorded during the first three months after initiation of thiopurines in 604 (15%) CD and 201 (8%) UC patients (p &amp;lt; 0.001), after biologics in 346 (9%) CD and 62 (3%) UC (p &amp;lt; 0.001), after steroids in 538 (14%) and 272 (11%), respectively (p = 0.01) and after methotrexate in 76 (2%) and 15 (0.6%), respectively (p = 0.001). The incidence of fatty liver was most common in UC (5% vs. 3%, p = 0.006). Conclusion ELE is common complication in IBD patients, more so in UC. When enzymes do increase in CD they tend to reach higher levels. Drug induced liver injury was more common in CD. This study was supported by a grant from the Leona M. and Harry B. Helmsley Charitable Trust.

P763 Epstein–Barr virus serological status in paediatric patients with inflammatory bowel disease

Abstract Background The impact of Epstein–Barr virus (EBV) infection on the clinical outcomes of children and adolescents with inflammatory bowel disease (IBD) is not well known. The aim of the study is to evaluate the seroprevalence, seroconversion rate and complications associated with EBV infection in a cohort of paediatric IBD (PIBD) patients at a tertiary care hospital. Methods A descriptive study was performed collecting demographic, clinical and treatment data from medical records as well as EBV serological status of paediatric IBD patients from 2012 to 2018. In seronegative patients, seroconversion rate was evaluated. Complications associated with primary EBV infection were described. Since September 2016, EBV serology was included into the initial work-up for PIBD patients. For those patients who did not have EBV study at IBD onset, it was performed during follow-up. Results A total of 307 patients with PIBD were diagnosed between 2012 and 2018. EBV status was available for 131 patients (43%). Of those, 57% had Crohn’s Disease, 41% Ulcerative Colitis, and 2% IBD unclassified (66% males; median age at IBD diagnosis: 13.2 years (IQR: 0.8–17.8)). In 102 patients serological EBV status was determined at IBD onset; while in 17 patients it was performed during the follow-up. Overall, EBV seroprevalence was 67%, and no differences were observed regarding age (over or under 10 years-old). EBV seroprevalence was higher in females than in males (80% vs. 60.5%, p = 0.02). Regarding IBD treatment, 84% had received immunosuppressive treatment [thiopurines (32%), anti-TNF (9%) and combined treatment (59%)], without differences in the seroprevalence rate according to the treatment modality. Forty-three patients were seronegative, and 12 of them had a second determination during follow-up. Overall, 5 patients showed seroconversion (42%) after a mean follow-up of 24 months (IQR: 22–26). All these patients had received treatment with thiopurines: 2 patients presented symptomatic mononucleosis with neutropenia, requiring hospital admission and withdrawal of immunosuppressive treatment and 3 patients had asymptomatic primary infection. Conclusion EBV seroprevalence in our paediatric IBD cohort is similar as previously described in the literature. EBV status study in patients with IBD, especially prior to initiation of thiopurines, may be useful to plan subsequent follow-up since a non-negligible percentage of them could present with complicactions of primary EBV infection under immunosuppressive treatment.

Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine.

A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24months following thiopurine initiation. The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24months. The C/T group developed grade 2-4 leukopenia by 6months, which persisted through 12-24months. The mean MCV in the C/T group became higher than that of the C/C group after 3months. NUDT15 R139C heterozygosity affected the WBC count and MCV for 24months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

OP034 The initiation of thiopurines in elderly patients with inflammatory bowel disease is associated with an increased risk of adverse effects: a case–control study of the ENEIDA registry

OP034 The initiation of thiopurines in elderly patients with inflammatory bowel disease is associated with an increased risk of adverse effects: a case–control study of the ENEIDA registry

Patients' beliefs about medicine are associated with early thiopurine discontinuation in patients with inflammatory bowel diseases.

Patients' beliefs about medicine may either reflect the necessity for treatment or concerns regarding the treatment. We explored the extent to which these beliefs have an effect on thiopurine metabolite levels and premature discontinuation in patients with inflammatory bowel disease (IBD). Patients enrolled in the 'Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory Bowel Disease Clinics' (TOPIC) trial were asked to complete the Beliefs about Medicine Questionnaire (BMQ) 4 weeks after thiopurine initiation. The BMQ measures perceptions about treatment necessity and concerns. On the basis of the necessity and concern scores, patients can be categorized as accepting, ambivalent, indifferent, or skeptical. The thiopurine discontinuation rates for these belief subgroups were compared by Kaplan-Meier curves. Furthermore, clinical response and metabolite levels were compared between the belief subgroups. A total of 767 patients with IBD started thiopurine treatment, of whom 576 (75%) completed the BMQ. Patients could be classified as accepting (34%), indifferent (17%), ambivalent (34%), or skeptical (15%). Compared with patients in the accepting group (discontinuation rate 22%), patients with an indifferent (35%; P=0.02), ambivalent (37%; P<0.01), or skeptical belief (54%; P<0.01) had higher thiopurine discontinuation rates. No differences were observed in the steady-state thiopurine metabolite levels between the different belief subgroups. Patients with a low perceived treatment necessity or high concerns toward IBD treatment were more likely to discontinue thiopurine treatment prematurely. Extra attention toward these patients might prevent premature discontinuation.

Predictive role of NUDT15 variants on thiopurine-induced myelotoxicity in Asian inflammatory bowel disease patients.

Genetic variants ofTPMTand NUDT15have been reported to predict the inter-patient variability in response and toxicity profiles of patients receiving thiopurine therapy. However, the clinical utility of TPMT genotyping in guiding thiopurine doses has been questionable, in part due to underlying differences in the prevalence of TPMT variants in both Caucasian and Asian populations. Several NUDT15 variants have been associated with thiopurine-induced leukopenia, particularly in Asian cohorts. So far, none have been reported in a multiethnic Asian population. To investigate the associations between TPMT and NUDT15 variants with thiopurine-induced myelotoxicity in 129 Asian inflammatory bowel disease patients. Pyrosequencing was performed to screen for TPMT and NUDT15 variants. Intracellular steady-state metabolite concentrations were quantified using liquid chromatography-tandem mass spectrometry. Significant declines in nadir white blood cell, absolute neutrophil count and platelet counts were observed with increasing copy numbers of the risk T allele at NUDT15 c.415C>T locus (overall p < 0.05) within 4, 8 and 12 weeks and 6 months after thiopurine initiation. Patients with low and intermediate NUDT15 activity, as inferred from haplotype pairs, had significantly higher risks of leukopenia (p = 0.000253) and neutropenia (p = 0.002) compared with patients with normal NUDT15 activity. These findings highlight the critical relevance of NUDT15 pharmacogenetics in predicting for thiopurine-induced myelotoxicity and confirm the lack of significance of TPMT variants in Asian inflammatory bowel disease patients.

N797 Therapeutic drug monitoring after thiopurine initiation improves drug efficacy

N797 Therapeutic drug monitoring after thiopurine initiation improves drug efficacy

EBV Status and Thiopurine Use in Pediatric IBD.

Epstein Barr virus (EBV) is a human herpes virus that infects 90% of the world's population and has been linked to the development of lymphoproliferative disorders (LPDs) and immunosuppression. Primary EBV infection in patients with IBD on thiopurines is a risk factor for LPD, including lymphoma. We aimed to describe EBV status in a pediatric population with IBD with an emphasis on those initiating thiopurines. Electronic medical records and EBV serologies were reviewed and categorized into asymptomatic screening versus suspicion for acute infection. EBV status before therapy was described by sex, age, and therapeutic regimen. Descriptive statistics and univariate analysis were employed. Only 150 (22%) of our 688 pediatric patients with IBD had documented EBV status regardless of age or treatment regimen. Only 17% were assessed for suspicion of acute infection and 83% for screening. Sixty-four (52%) screened patients were checked before starting any treatment and only 40% were immunoglobulin (Ig)G positive. There was no difference in mean age between the seronegative and seropositive group. The majority (63%) of thiopurine-treated patients were IgG negative before starting therapy. Eighty percent of primary EBV infections occurred on thiopurines at a mean (SD) of 2 ± 1.5 years after initiating therapy. The majority of our pediatric patients with IBD with documented EBV status were IgG negative at thiopurine initiation. Thiopurines were also associated with primary EBV infection. EBV status may be an important determinate of whether physicians prescribe thiopurines given the risk of primary EBV infections and lymphoproliferative diseases.

Tu1328 Final Thiopurine Metabolite Levels and Shunter Status Can Be Predicted After Six Weeks of Thiopurine Therapy - Biochemical Outcomes From the EATME Study

Background: Dosing of thiopurines [azathioprine (AZA) and mercaptopurine (MP)] in the management of IBD has been based upon patient weight. However, this appears unreliable in predicting final levels of thiopurine metabolites, leading to suboptimal clinical outcomes because of underand over-dosing, and ‘shunting' in 15% where toxic 6-methylmercaptopurine (6MMP) is preferentially produced over the efficacious 6-thioguianine nucleotides (6TGN), with 6MMP:6TGN ratio ≥20. Aims: 1. To determine prospectively the clinical value of timing of measurement of thiopurine metabolites during dose-escalating regimen of thiopurine initiation in a consecutive cohort of IBD patients being initiated on a thiopurine. 2. To determine if the 6MMP:6TGN ratio changes during thiopurine dose escalation. Methods: In this single centre, prospective, open label study patients were commenced on either a daily dose of 50mg AZA or 25mg MP (physician discretion). Doses increased fortnightly by 50mg for AZA or 25mg for MP until target was achieved, aiming for 2-2.5mg/kg for AZA and 1-1.5mg/kg for MP. Hematology, CRP and liver function tests were performed fortnightly to monitor toxicity. Thiopurine metabolites were measured fortnightly until steady-state was achieved, but results were not used for dosing decisions. Clinical and biochemical outcomes were recorded. Landmark analyses of shunter status used logistic regression models. Metabolite levels were analysed using linear regression models. Results: 64 patients (52 Crohn's, 11 ulcerative colitis and 1 IBD-U) were enrolled. Final metabolite outcomes were: 11 (17%) patients were shunters, 27 (42%) were underdosed (6TGN level of 450) and 21 (33%) were therapeutic. 6MMP:6TGN ratios escalated over time in shunters, but not in others. After 2 weeks of therapy, a 6MMP:6TGN ratio above 9 (p=0.058) was suggestive of shunting, while after 6 weeks, a ratio ≥12 (95% CI 7-28, p=0.01) was predictive of shunting. 6TGN levels at week 2 (median 106, range 0-328) predicted final 6TGN outcomes (median282, range 50-746, r=0.681, p .10). Conclusions: 6MMP:6TGN ratios increase during dose escalation in shunters only. Patients with a 6MMP:6TGN ratio 12 or above after 6 weeks should be considered for optimisation with allopurinol rather than waiting until 12 weeks of therapy. Weight-based dosing of thiopurines should no longer be used in standard practice.

Routine use of thiopurines in maintaining remission in pediatric Crohn's disease.

To evaluate the effectiveness of thiopurines in maintaining steroid-free remission in routine clinical practice. The multi-center Pediatric Inflammatory Bowel Disease Network (PIBDNet) cohort study prospectively collected data on thiopurine naïve patients initiating mercaptopurine (6MP) or azathioprine. Patients with a diagnosis of Crohn's disease (CD) were included in our study upon entering remission as determined by physician global assessment (PGA) within 365 d of initiation of thiopurines. The primary outcome of the study was maintenance of steroid-free remission (SFR) at each follow up visit. Patients were considered treatment failures if there had been a change in PGA from remission to mild, moderate or severe disease; disease relapse between visits; need for rescue therapy (biologic therapy, methotrexate, steroids); thiopurine discontinuation, hospitalization or surgical intervention. A secondary outcome defined treatment failure as a change from remission to moderate or severe (not mild) in addition to the previously defined criteria. Sixty-five of 182 patients in the PIBDNet registry met criteria for inclusion in this study. Forty-five of 65 (69%) of included patients achieved remission within 180 d of thiopurine initiation. For the primary outcome, 47% and 23% of patients remained in SFR at 6 and 12 mo. The mean thiopurine dose at initiation for the 65 included patients was 0.89 ± 0.31 mg/kg per day. Metabolite levels were obtained in 48% (31/65) of the included patients with a mean 6TG level of 258 pmole/8 × 10(8) RBC ± 147. For the secondary outcome, 65% and 42% of patients remained in SFR at 6 and 12 mo. Thiopurines were less effective in maintaining remission for pediatric CD in this "real world" cohort than has been previously described. Variation in thiopurine dosing and metabolite measurement was found among practitioners.

Sa1240 LéMann Index Assessment Overtime in Crohn's Disease Patients Treated With Anti TNFs: A Pilot Observational Cohort Study

completing the follow-up period of 8 weeks without any thiopurine dose adjustments. Results: Thirty-two patients with leukopenia and 162 patients without leukopenia were included. Patients with leukopenia were more frequently treated with 6MP than AZA: Odds Ratio (OR) = 7.3 (95%CI 3.1 17.0; p < 0.00001). Additionally, these patients were more often co-treated with anti-TNF agents: OR 5.1 (95%CI 1.6 16.4; p = 0.009). At T1 threshold values of ~213 pmol/8×108 red blood cells (RBC) for 6TGN and ~3525 pmol/8×108 RBC for 6MMPR, patients with elevated T1 6TGN or T1 6MMPR levels were at increased risk of leukopenia between week 1 8: Odds ratios were 6.2 (95%CI: 2.8 13.8; p < 0.001) and 5.9 (95%CI: 2.7 13.3; p < 0.001), respectively. Finally, a logistic regression model was designed including the T1 6TGN and 6MMPR threshold parameters, thiopurine type and concurrent anti-TNF therapy at baseline. The predictive performance measured by Receiver Operating Characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.70 (95%CI: 0.59 0.81; p < 0.001), when either T1 6TGN or 6MMPR threshold values were evaluated. Including all parameters, the AUC was 0.84 (95%CI: 0.76 0.92; p < 0.000001). Conclusions: Both 6TGN and 6MMPR metabolites were independently associated with the occurrence of leukopenia during the first 8 weeks of thiopurine therapy. Assessment of 6TGN and 6MMPR metabolite concentrations one week after thiopurine initiation helps to identify patients at risk of developing leukopenia.

Improved Outcomes in a Quality Improvement Collaborative for Pediatric Inflammatory Bowel Disease

Unintended variation in the care of patients with Crohn disease (CD) and ulcerative colitis (UC) may prevent achievement of optimal outcomes. We sought to improve chronic care delivery and outcomes for children with inflammatory bowel disease by using network-based quality improvement methods. By using a modified Breakthrough Series collaborative structure, 6 ImproveCareNow Network care centers tested changes in chronic illness care and collected data monthly. We used an interrupted time series design to evaluate the impact of these changes. Data were available for 843 children with CD and 345 with UC. Changes in care delivery were associated with an increase in the proportion of visits with complete disease classification, measurement of thiopurine methyltransferase (TPMT) before initiation of thiopurines, and patients receiving an initial thiopurine dose appropriate to their TPMT status. These were significant in both populations for all process variables (P < .01) except for measurement of TPMT in CD patients (P = .12). There were significant increases in the proportion of CD (55%-68%) and UC (61%-72%) patients with inactive disease. There was also a significant increase in the proportion of CD patients not taking prednisone (86%-90%). Participating centers varied in the success of achieving these changes. Improvements in the outcomes of patients with CD and UC were associated with improvements in the process of chronic illness care. Variation in the success of implementing changes suggests the importance of overcoming organizational factors related to quality improvement success.

Predictors of Therapeutic Remission to Thiopurines in Pediatric Inflammatory Bowel Disease

Background: Variation in thiopurine methyltransferase (TPMT) activity does not fully account for differences in interindividual clinical response to thiopurines in inflammatory bowel disease (IBD). Other genetic and immune biomarkers may also predict therapeutic outcomes with thiopurines. Aims: To test associations of known IBD susceptibility loci and novel “pharmacogenetic” genome-wide association study (GWAS)-identified loci, as well as clinical and immune phenotypes, with thiopurine-induced corticosteroid-free remission in IBD, and develop a predictive model of remission. Methods: Corticosteroid-free remission at 26 weeks after thiopurine initiation was defined using the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and partial Mayo score for ulcerative colitis (UC). Serum was assayed for ASCA IgA and IgG, anti-OmpC, anti-CBir1, I2, and pANCA using ELISA. Clinical phenotypes included age, gender, IBD subtype (CD versus UC), disease duration at thiopurine initiation, and age at diagnosis. Genotyping was performed using Illumina technology. Univariate analyses tested associations of phenotype and genotype with remission. Stepwise logistic regression was performed to build predictive models. Results: Corticosteroid-free remission occurred in 56 of 122 subjects (45.9%) at week 26. Female gender (OR = 0.37; 95% CI: 0.18-0.77; P = 0.011) and pANCA (OR = 0.23; 95% CI: 0.06-0.87; P = 0.049) were negatively associated with corticosteroid-free remission at 26 weeks. Five known IBD susceptibility loci were associated with corticosteroid-free remission (P < 0.05) (Table 1). A single nucleotide polymorphism (SNP) at 15q31 tagging MEF2A (macrophage differentiation) and LYSMD4 (peptidoglycan binding) met the criteria for nominal association at the genome wide level for remission (OR = 9.5; P = 3E-05). The most predictive model of remission included the previously identified HLA-DRB1 locus (rs2516049), 7 novel “pharmacogenetic” GWAS loci, pANCA, disease duration, and a diagnosis of UC with an R-squared of 0.884, area under the curve [AUC] of 0.985, sensitivity of 0.929, specificity of 0.919, accuracy of 0.826, and positive likelihood ratio of 11.45. The probability of remission increased 7.3-fold when the number of predictors increased from 0-4 to 5-7 (95% CI: 2.4321.66; P = 0.0004). Conclusions: The combination of genotype with clinical and immune phenotypes is most predictive of corticosteroid-free remission after thiopurine initiation. Defining predictors of therapeutic efficacy to thiopurines may allow the identification of patients who will benefit most from this class of therapy, contributing to a more individualized approach to therapy. Table 1: SNPs associatedwith corticosteroid-free remissionwith thiopurines atweek 26.