Use Of Thiopurines Research Articles

Effectiveness of Early Thiopurine Use in Korean Patients With Moderate-to-Severe Ulcerative Colitis: A Prospective Multicenter Cohort (MOSAIK) Study.

Thiopurines play an important role in the management of steroid-refractory and steroid-dependent ulcerative colitis. However, the effectiveness of the early use of thiopurines in ulcerative colitis remains controversial. In this multicenter prospective cohort (MOSAIK) study, we divided patients with ulcerative colitis into those who underwent early (within 6mo of diagnosis) and late (6mo after diagnosis) thiopurine therapy to determine the effectiveness of early thiopurine treatment. The primary outcome was the cumulative rate of clinical relapse (Mayo score >2 points). Multivariate Cox proportional hazards regression was used to identify independent clinical factors associated with the outcomes. Overall, 333 patients with moderate-to-severe ulcerative colitis were included. Of the 118 patients treated with thiopurines, 65 (55.1%) and 53 (44.9%) received thiopurine therapy within and after 6 months of diagnosis. The cumulative use rate of thiopurines was 38.9% at 3 years after diagnosis. The median initial dose of thiopurines was 0.7mg/kg (0.3 to 2.0); the median maintenance dose was 1.1mg/kg (0.3 to 2.4). The cumulative rate of clinical relapse was not significantly different between patients who started thiopurine therapy within 6 months of diagnosis and those who started therapy 6 months after diagnosis (P=0.712). The presence of extraintestinal manifestations (hazard ratio: 4.674, 95% CI: 1.210-18.061, P=0.025) independently predicted an increased risk of clinical relapse. Patients with ulcerative colitis who received early thiopurine therapy did not differ significantly in terms of clinical relapse compared with those who received late therapy.

Safety and Effectiveness of Thiopurines and Small Molecules in Elderly Patients with Inflammatory Bowel Diseases.

The management of inflammatory bowel diseases (IBD) requires weighing an individual patient's therapeutic benefits and therapy-related complication risks. The immunomodulators that have been commonly used so far in IBD therapy are thiopurines, including 6-mercaptopurine and azathioprine. As our understanding of the IBD pathomechanisms is widening, new therapeutic approaches are being introduced, including the Janus kinase (JAK) inhibitors and Sphingosine 1-phosphate receptor (S1PR) modulators' development. Non-selective JAK inhibitors are represented by tofacitinib, while selective JAK inhibitors comprise filgotinib and upadacitinib. As for the S1PR modulators, ozanimod and etrasimod are approved for UC therapy. The number of elderly patients with IBD is growing; therefore, this review aimed to evaluate the effectiveness and safety of the oral immunomodulators among the subjects aged ≥60. Possible complications limit the use of thiopurines in senior patients. Likewise, the promising effectiveness of new drugs in IBD therapy in those with additional risk factors might be confined by the risk of serious adverse events. However, the data regarding this issue are limited.

Mortality of Patients With Inflammatory Bowel Disease in the Faroe Islands From 1966-2020.

Increased mortality rates have been found in patients suffering from inflammatory bowel disease (IBD). The Faroe Islands have the highest occurrence of IBD, mainly ulcerative colitis (UC). This study investigated mortality of patients with IBD compared with the general Faroese population. All patients diagnosed with IBD from 1966-2020 were included, as well as population mortality data. All-cause and cause-specific mortality in the IBD cohort was compared with the population by standardized incidence ratios (SIRs). Risk factors for death within the cohort were assessed by hazard ratios (HRs) using Cox regression. Overall mortality was not increased in patients with Crohn's disease (CD; SIR 0.9; 95% confidence interval [CI], 0.56-1.35) or UC (SIR 1.0; 95% CI, 0.83-1.25). However, patients with UC had an elevated risk of dying from digestive diseases (SIR 4.3; 95% CI, 2.16-7.74). Patients with IBD had lower risk of death of cardiovascular diseases compared with the background population (SIR 0.7; 95% CI, 0.50-0.93). Risk factors for mortality included male gender, age at diagnosis, and use of steroids. Protective factors were use of 5-aminosalicylic acid (5-ASA), thiopurines, and biological treatment. No increased risk of all-cause mortality in patients with CD or UC was found in this nationwide study compared with the entire Faroese population over more than 5 decades. The risk of death due to digestive diseases was, however, increased in patients with UC, while mortality risk of cardiovascular diseases was lower in patients with IBD.

The Complex Relationship between Mechanisms Underlying Inflammatory Bowel Disease, Its Treatment, and the Risk of Lymphomas: A Comprehensive Review.

Patients with inflammatory bowel disease may be at higher risk of developing lymphomas and other cancers of the gastrointestinal tract. In addition, there may be a link between the use of thiopurines or anti-tumor necrosis factor drugs (anti-TNF) and these pathologies. The treatment of patients with Crohn's disease who have previously been diagnosed with lymphoma is a challenge for gastroenterologists. In this report, we examine important clinical issues related to the treatment of patients with inflammatory bowel disease with active lymphoma, as well as of patients with hematological cancer history. In this discussion, we take into account most of the available treatments for inflammatory bowel disease, as well as the impact of chronic inflammation and viral infections. In addition, we try to find common ground for the development of lymphoproliferative disorders and autoimmune diseases. Patients with inflammatory bowel disease may be at higher risk of developing lymphomas and other cancers of the gastrointestinal tract. Chronic inflammatory processes and viral infections play an important role in carcinogenesis. In addition, there may be a link between the use of thiopurines or anti-TNF drugs and these pathologies. A significant risk of the development of lymphoma in people undergoing each therapy should be considered, and it should be estimated how much greater this risk will be in patients with a history of lymphoproliferative disorders. The following review is an attempt to answer which therapy would be the most appropriate for patients with Crohn's disease and a history of lymphoma treatment. A lack of clear guidelines creates great challenges for doctors.

Protocolo diagnóstico y tratamiento del cuadro febril en el paciente con enfermedad inflamatoria intestinal

Fever is a common clinical manifestation of inflammatory bowel disease (IBD). Nevertheless, fever should not be systematically attributed to inflammation. There are multiple diseases that progress with fever and they may be masked by a flare-up of bowel inflammation. Therefore, a differential diagnosis is recommended. One of the main causes of febrile syndrome is infections. Patients with IBD are at increased risk for infections, in part because of immunosuppressive treatment. In addition, they are more susceptible to certain microorganisms, including enteropathogens such as Clostridioides difficile, and mycobacteria in patients receiving tumor necrosis factor alpha-inhibiting drugs. Second, neoplastic processes, both solid and hematological, can progress with fever, with the disease itself and the use of thiopurines being the main associated risk factors. Other causes of fever that should be considered are inflammatory or autoimmune disorders and drug fever. This protocol proposes an algorithm for the differential diagnosis of febrile illness in patients with IBD.

LOWER MORTALITY RISK WITH COMBINATION THERAPY WITH ANTI-TNF THERAPY AND THRIOPURINE COMPARED TO THIOPURINE ALONE IN ELDERLY PATIENTS WITH UC

Abstract INTRODUCTION Despite increasing incidence rates of ulcerative colitis (UC) in the elderly, efficacy and safety data for medical management in this cohort is lacking due to underrepresentation in clinical trials and registries. Selection of medical therapy is often complex, taking into consideration a multitude of factors, including real and perceived risks of infection and malignancy. In the past, immunomodulators, such as thiopurines, were commonly used as monotherapy for maintenance, offering the added advantages of affordability and oral administration. Indeed, there are elderly patients who have been maintained for decades on thiopurine monotherapy. Further, thiopurines can be used in combination with anti-TNF therapy for improved efficacy and reduced immunogenicity compared to monotherapy with either agent in ulcerative colitis (UC). Whether the use of combination therapy imposes an additive risk compared to thiopurine monotherapy is still unclear. This study aimed to investigate outcomes of thiopurine monotherapy versus combination therapy with anti-TNF agents in elderly patients (age ≥65 years) with UC. METHODS The TriNetX Research Network was accessed on October 15th, 2023, to compare outcomes in elderly patients 65 years or older with UC who are receiving thiopurine monotherapy and patients who are receiving combination therapy with an anti-TNF (adalimumab, certolizumab pegol, golimumab, or infliximab). The outcomes examined were 1-year rate of corticosteroid and colectomy as well as 10-year rate of mortality, colon cancer, skin cancer, and respiratory and urinary tract infections. Statistical risk analysis was performed using the TriNetX analytical platform. RESULTS A total of 2,597 patients (2,245 thiopurines monotherapy and 352 AZA plus anti-TNF combination therapy) were included in the study (Table 1). Among the monotherapy and combination therapy cohorts, mean age was 71 years old and approximately 56% male. Ten-year mortality was higher in the thiopurine monotherapy group (OR 1.67, p=0.002). The combination therapy cohort had higher rates of steroid use (32.4% vs. 24.3%, p=0.001) and colectomy at 1 year compared to the monotherapy cohort (4.5% vs. 1.2%, p<0.001). There was no significant difference in 10-year risk of colon cancer (OR 1.05, p=0.88), skin cancer (OR 1.51, p=0.06), incidence of respiratory (OR 1.48, p=0.07) and urinary tract infections (OR 1.18, p=0.23). CONCLUSION The study findings highlight the risks of thiopurine use in patients over the age of 65 given the significantly higher 10-year mortality risk in thiopurine monotherapy-treated patients. The results also suggest that combination therapy with thiopurine and anti-TNF therapies - despite utilization in patients with more active disease indicators - is not associated with an additive risk in terms of infection and mortality in elderly patients. Table 1 Characteristics and Outcomes of Elderly Patients with UC either on Thiopurine Monotherapy or Combination Therapy with anti-TNF agents

P567 Impact of recent thiopurine use on ozanimod safety in patients with ulcerative colitis: a post hoc analysis of the phase 3 True North study

Abstract Background Ozanimod, a sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P1 and S1P5, is approved for the treatment of moderately to severely active ulcerative colitis (UC) in adults based on results from the phase 3 True North study (NCT02435992). Reductions in absolute lymphocyte count (ALC) are expected with ozanimod but not associated with treatment-emergent adverse events (TEAEs). This post hoc analysis explored the effect of recent use of thiopurines on ALC and safety outcomes in patients treated with ozanimod. Methods True North was a phase 3 trial of ozanimod induction and maintenance therapy in moderately to severely active UC. Patients in Cohort 1 were randomised to once-daily double-blind treatment with ozanimod 0.92 mg or placebo; patients in Cohort 2 received open-label ozanimod for a 10-week induction period. Patients on concomitant thiopurines were required to stop therapy at study start without a washout period. In this post hoc analysis, patients were stratified by recent prior thiopurine use (within 90 days of ozanimod initiation). ALC was assessed at baseline; ALC, TEAEs, and infectious outcomes were assessed during the induction period at Weeks 5 and 10. Results Of the 1012 patients in True North, 796 were treated with ozanimod and analysed (n=57 with recent thiopurine exposure; n=739 without recent thiopurine exposure). At baseline, mean ALC (×109/L [SD]) was slightly lower in patients with than without recent thiopurine use (Table). Both groups had similar baseline incidence of ALC <200 cells/µL (0%) and <500 cells/µL (range 0.0–0.3%). While ALC <200 cells/µL and <500 cells/µL were more prevalent among patients with than without recent thiopurine use (Figure), the reductions from baseline to Week 10 in ALC were similar in both groups (Table). Rates of infection were also similar in patients with recent thiopurine use (14.7% in Cohort 1 and 13.0% in Cohort 2) and without recent thiopurine use (10.4% and 12.5%, respectively). The most frequent infection was nasopharyngitis in both groups: 8.8% in Cohort 1 and 0% in Cohort 2 in patients with recent thiopurine use; 3.0% and 2.9%, respectively, in patients without recent thiopurine use. There were no serious adverse events (AEs) related to ozanimod treatment, and treatment discontinuations were similar in patients with and without recent thiopurine exposure. Conclusion Lower ALC was observed in patients starting ozanimod within 90 days of thiopurine use but was not associated with an increased incidence of infection or serious AEs. The findings suggest switching from thiopurines to ozanimod without a washout period may be safe and tolerable.

P631 Effectiveness of Early Thiopurine Use in Korean Patients with Moderate-to-Severe Ulcerative Colitis: A Prospective Multicenter Cohort (MOSAIK) study

Abstract Background Thiopurines play an important role in the management of steroid-refractory steroid-dependent ulcerative colitis (UC). However, the effectiveness of the early use of thiopurines in UC remains controversial. Methods In this multicenter prospective cohort study, we divided patients with UC into those who underwent early (within 6 months of diagnosis) and late (6 months after diagnosis) thiopurine therapy to determine the effectiveness of early thiopurine treatment. The primary outcome was the cumulative rate of clinical relapse (Mayo score >2 points). Multivariate Cox proportional hazards regression was used to identify independent clinical factors associated with the outcomes. Results Overall, 333 patients with moderate-to-severe UC were included in the MOSAIK study. Of the 118 patients treated with thiopurines, 65 (55.1%) and 53 (44.9%) received thiopurine therapy within and after 6 months of diagnosis. The cumulative use rate of thiopurines was 38.96% at 3 years after diagnosis. The median initial dose of thiopurines was 0.7 mg/kg (0.3–2.0), and the median maintenance dose was 1.1 mg/kg (0.3–2.4). The cumulative rate of clinical relapse was not significantly different between patients who started thiopurine therapy within 6 months of diagnosis and those who started therapy 6 months after diagnosis during a 3–year period (p = 0.712). Multivariate analysis showed that the presence of extraintestinal manifestations (hazard ratio [HR]: 4.674, 95% CI: 1.210–18.061, p = 0.025) independently predicted an increased risk of clinical relapse. Conclusion Patients with UC who received early thiopurine therapy did not differ significantly in terms of clinical relapse compared with those who received late therapy.

P748 Place of thiopurine monotherapy in the treatment of Crohn's Disease in the era of biologic therapies: results of a long-term tertiary single-center experience

Abstract Background Crohn's disease (CD) is a chronic and disabling immune-mediated disease of the digestive tract, and immunosuppressive drugs are a cornerstone in the therapeutic approach, particularly purine analogues which are widely used in the treatment of CD as an agent to maintain remission. Despite their widespread use, adverse effects are frequent and lead to discontinuation of treatment in a significant proportion of patients so the increasing use of anti-TNFα biologics may have had an impact on the use of thiopurines. We present a long-term retrospective experience from a tertiary hospital center aimed at studying the evolution of thiopurine monotherapy use in the era of biologics, based on current therapeutic goals and safety standards. Methods We performed a retrospective analysis of all Crohn's disease patients followed up in our hepato-gastroenterology department who received AZA monotherapy at the standard dose (2-2.5 mg/kg/d) or 6-MP (1-1.5 mg/kg/d) at any time during their follow-up between January 2016 and June 2023 and who were still being followed up at that time. Patients who had received prior or concomitant biological treatment were excluded from the analysis. Various socio-demographic and phenotypic data were collected. Failure was defined as discontinuation of treatment due to lack of efficacy or AE. Statistical analysis was performed using SPSS2.0 software. Statistical significance was set at p < 0.05. Results A total of 383 patients were included: 46.5% were men and the mean age was 31 years (range 17-65). Median follow-up was 66 months. Indications for thiopurine monotherapy were cortico-dependence (306 patients, 80%) or prevention of postoperative recurrence (77 patients, 20%). Overall, 147 patients (38%) failed. The observational study of our patients showed that 74 patients (18.4%) discontinued AZA due to an adverse event (most of which occurred during the first month of treatment), 73 (19%) due to lack of efficacy. Among the main indications for AZA we note: prevention of postoperative recurrence, male gender gave better results than steroid dependence (p =0.001); perianal fistulization of CD and grecal localization gave worse results (p = 0.002). Conclusion In our experience, a significant proportion of CD patients on thiopurine monotherapy failed. Although IS monotherapy remains useful for CD in the era of biologics, current clinical practice is moving towards anti-TNFα biologics in an increasing proportion of patients.

P607 Increased rates of fractures and malignancy in elderly onset IBD in Singapore

Abstract Background Elderly onset inflammatory bowel disease (EOIBD) has variable characteristics in the published literature. We performed this study to report the disease characteristics, treatment exposure, and clinical outcomes of EOIBD compared to adult onset IBD (AOIBD) in Singapore. Methods This is a retrospective study involving IBD patients seen at two tertiary hospitals in Singapore from January 2020 to September 2023. Patients were identified from the Singapore National IBD registry. Those with missing data on age of IBD diagnosis were excluded. Data on baseline demographics, disease characteristics, treatment and disease-related complications were collected. EOIBD is defined as age of diagnosis ≥ 60 years old and AOIBD as those diagnosed from age 18 to 59 years old. The characteristics was compared between these two groups. Data was analysed using SPSS version 27.0. Results 1116 patients were included in the final analysis, 10.6% (n =118) were EOIBD as shown in Figure 1. 50% were male with a mean age of diagnosis at 68 years old. The comparison between EOIBD and AOIBD are shown in Figure 1 and Table 1. There is a higher proportion of Crohn’s disease (CD) (45.7% vs 37.4%) in EOIBD. In terms of treatment, there is significantly lower use of thiopurines amongst EOIBD (34.5% vs 46.8%, p = 0.012). There was a trend of higher use of methotrexate among EIOBD (19.6% vs 10.6%, p = 0.067) although this was not statistically significant and this is similarly observed in the use of biologics (32.8% in EOIBD vs 27.1% in AOIBD, p = 0.205). There were no significant differences in corticosteroids (CS) exposure, CS dependence and mean number of CS courses used. There was a lower proportion of IBD-related surgery in EOIBD (12.1 vs 18.5%, p = 0.094) with EOID having a significantly lower mean number of IBD-related surgery (1.1 vs 1.6, p <0.001). Among EOIBD, there were significantly higher rates of malignancy (17% vs 6%, p <0.001) and fractures (18.1% vs 9.2%, p = 0.02); the latter despite a statistically higher mean level of vitamin D (20.9 ng/ml vs 18.3 ng/ml, p = 0.026). There were no differences in IBD-related hospitalization. Conclusion EOIBD is associated with increased rates of fractures and malignancy compared to AOIBD. Therefore, bone health and malignancy screening should be regularly performed in this group of patients to clinical outcomes.

P843 Effectiveness and tolerability of methotrexate combined with biologics in patients with Crohn’s disease: A multicenter observational study

Abstract Background Methotrexate (MTX) combination therapy with biological agents has gained increasing interest. Here, we assessed the efficacy and tolerability of the MTX combination therapy in patients with Crohn’s disease (CD). Methods We performed a multicenter observational study with 185 patients with CD with MTX and biologics combination therapy; the patients were recruited from three IBD Clinics in Korea. We evaluated the outcomes of the MTX combination therapy and examined the predictive factors of clinical and endoscopic remission. Results MTX was administered orally to 62.7% of patients; the mean dose was 15.5 mg per week, and the mean treatment duration was 36 months. Of the 169 patients treated with MTX combination therapy for over 6 months, the steroid-free clinical remission rates were 34.3%, 26.0%, 29.8%, and 32.7% at 4, 12, 18, and 24 months, respectively. Previous thiopurine use was a significant negatively associated independent factor (p < 0.001), and a higher dose of MTX (≥15 mg/week) was a positively associated independent factor of steroid-free clinical remission (p = 0.035). Ninety-six patients underwent follow-up endoscopy after 28 months, and 36 (37.5%) achieved endoscopic remission. Longer disease duration (p = 0.006), ileocolonic type of Montreal location (p = 0.036), and baseline C-reactive protein (CRP) level of more than 5 mg/L (p = 0.035) were significant negatively associated independent factors and a higher dose of MTX (≥15 mg/week) was a positively associated independent factor of endoscopic remission (p = 0.037). Conclusion MTX combination therapy with biologics was effective and tolerable in patients with CD.

P622 Network meta-analysis comparing efficacy between biologics and conventional therapies to prevent endoscopic postoperative recurrence in patients with Crohn's disease

Abstract Background As no direct comparison between IBD drugs to prevent endoscopic postoperative recurrence (POR) In Crohn’s disease (CD) are available, hierarchizing these therapeutic options remains challenging. The objective of this network meta-analysis was to compare the effectiveness of treatments to prevent endoscopic POR of CD. Methods We performed a systematic review and network meta-analysis of comparative studies conducted in adults, evaluating a treatment to prevent endoscopic POR after ileocecal resection. The selection of studies was made according to PRISMA guidelines. The primary endpoint was endoscopic POR at 6 months defined as Rutgeerts score ≥ i2. The network meta-analysis was carried out according to a random effects model. The results are presented as odds ratio (OR) with 95% confidence interval, adjusted for risk factors of POR. The risk of bias of the studies was assessed according to the Cochrane risk-of-bias tool for randomized trials and overall statistical heterogeneity between studies was assessed using τ². The SUCRA ranking method (surface under the cumulative ranking) was used to rank the treatments. Results Twenty studies were included in this network meta-analysis, including a total of 2414 patients. Overall heterogeneity was moderate (τ²=0.34). After adjustment for POR risk factors, ustekinumab (OR = 0.23 [0.07-0.70]), vedolizumab (OR = 0.17 [0.05 -0.59]), infliximab (OR = (0.18 [0.36-0.88]) and adalimumab (OR = 0.17 [0.07-0.42]) were superior to placebo to prevent endoscopic POR, contrary to 5-ASA (OR = 0.79 [0.42 -1.48]) and thiopurines (RR = 0.52 [0.22-1.24]) (Table 1). Ustekinumab (OR = 0.29 [0.08-0.99]), vedolizumab (OR = 0.22 [0.06-0.85]), infliximab (OR = (0.23 [0.09-0.54]) and adalimumab (OR = 0.22 [0.08-0.59]) were more effective than 5-ASA in preventing endoscopic POR. Adalimumab (OR = 0.33 [0.15-0.74]) and infliximab (OR = 0.34 [0.13-0.87]) were also more effective than thiopurines. We observed no difference in efficacy between the 4 biologics (infliximab, adalimumab, ustekinumab and vedolizumab) (Table 1). The SUCRA ranking identified adalimumab (SUCRA=0.81), infliximab (SUCRA=0.80), vedolizumab (SUCRA=0.79) and ustekinumab (SUCRA=0.72) as the most effective treatments. The likelihood that thiopurines (SUCRA=0.41), 5-ASA (SUCRA=0.24), placebo (SUCRA = 0.16) and antibiotics (SUCRA=0.08) was the best option is very low. Conclusion This network meta-analysis confirms the efficacy of anti-TNF agents, vedolizumab and ustekinumab in preventing endoscopic CD POR without any difference between them. When prophylactic therapy is necessary, biologics appear as the best therapeutic option to prevent of endoscopic POR. Due to lower efficacy, the use of 5-ASA and thiopurines should be limited in this situation.

DOP06 Development of simplified scoring system to predict two-year clinical remission of patients with Ulcerative Colitis after treatment with vedolizumab

Abstract Background No prospective study had been conducted to demonstrate the efficacy of vedolizumab in patients with ulcerative colitis (UC). While several studies have identified predictive factors for achieving mucosal healing, a well-validated algorithm is lacking. We aimed to identify the predictive factors and develop a practical scoring system to assess the efficacy of vedolizumab in patients with UC. Methods We performed a logistic regression analysis from the data of withdrawal versus continuation of thiopurine in vedolizumab-treated patients with ulcerative colitis (VIEWS) study which is a prospective multi-center longitudinal cohort in UC patients in Australia who had clinical and endoscopic remission (Mayo score ≤ 1) at baseline and continued vedolizumab as maintenance treatment. Predictive factors of two-year steroid-free clinical remission were developed into a model that predicted the outcome of treatment. We then validated our scoring system in a separate retrospective cohort of patients with UC who received vedolizumab in routine practice during 2016-2021. Results The derivation cohort comprised 62 patients, with 48 patients (77.4%) maintaining clinical remission at 2 years. Patient characteristics are presented in table1. Independent predictive factors used in developing the model included combination of thiopurine continuation (OR 3.6, P-value 0.11), absence of exposure to anti-tumor necrosis factor (TNF) (OR 3.75, P-value 0.047), histologic remission at baseline (OR 10.79, P-value 0.002), and duration of UC < 5 years (OR 9.29, P-value 0.04). The final simplified score is as follows: 3x (thiopurine continuation) + 2x (absence of exposure to anti-TNF) + 3x (histologic remission at baseline) + 2x (duration of UC < 5 years) yielding the area under the receiver operating characteristic curve (AUROC) of 0.86 in the derivation cohort (figure 1). In the validation cohort, there were 43 UC patients who had been initiated and continued vedolizumab as maintenance treatment, with 30 patients (69.8%) remained in clinical remission at two years. The AUROC of validation cohort was 0.75 after applying simplified score. At a cut-off level of 4 points, the model can identify two-year clinical remission with 83% sensitivity and 54% specificity, respectively. Conclusion We developed the practical predictive scoring system to determine UC patients who are likely to remain in clinical remission after two years of treatment with vedolizumab. In high-risk UC patients, combination use of vedolizumab and thiopurine is strongly recommended.

OP07 Consistent IBD treatment approaches across South Asian and White ethnicities despite phenotypic variations: a study of 33,157 patients using the IBD BioResource

Abstract Background The current evidence suggests ethnic distinctions in IBD phenotype, and differences in the provision of treatment have been reported. This multi-centre cohort study utilised the UK IBD BioResource dataset to evaluate phenotypic differences between South Asian (SA) and White (WH) IBD, and to explore if these were associated with differences in treatment. Methods Phenotypic and outcome data were extracted from the IBD BioResource. Chi2 (categorical data) and Mann-Whitney U (continuous data) tests were used. Propensity score matching (PSM) accounted for age at diagnosis, sex, smoking status, disease location and behaviour and perianal disease (CD). Differences in medication use (multivariable logistic regression) and surgical outcomes (Kaplan-Meier and Cox regression analysis) were assessed in propensity-matched (PM) cohorts. Results 33,157 (31,932 WH; 1225 SA) individuals were included (48.1% CD, 45.4% UC, 6.5% IBD-U). UC was the predominant disease subtype in SA (UC, SA 57.3% vs WH 44.9%, p<0.001). SA were younger at diagnosis [CD, SA 24 (IQR 17-36) vs WH 26 (IQR 19-39) years, p<0.001; UC, SA 29 (IQR 22-38) vs WH 35 (25-48) years, p<0.001]. SA CD had less ileal disease (SA 30.3% vs WH 38.4%, padj=0.008), and more perianal involvement (SA 38.5% vs WH 32.3%, p=0.009) than WH. SA CD had less stricturing disease (SA 16.9% vs WH 25.6%, padj<0.001). SA UC were more likely to have extensive disease (SA 41.7% vs WH 34.1%, padj<0.001). Initial analyses in non-PSM cohorts showed that fewer SA CD underwent surgery [SA (n=157,37.4%) vs WH (n=7532,50.4%), p<0.001], and that similar proportions of SA (n=33,5.1%) and WH (n=747,5.5%; p=0.15) UC underwent a colectomy. PSM was used to match 355 SA to 355 WH in CD, and 525 SA to 525 WH in UC. Variables were well-balanced. There were no differences in 5-ASA, corticosteroid, thiopurine, anti-TNF or Vedolizumab use (Table 1). In CD, 126 (36.5%) SA and 152 (44.7%) had surgery. Survival analysis in CD showed no difference in the time to surgery (Fig 1A, log-rank 0.28). SA ethnicity was not associated with increased risk of surgery in CD (HR 0.82, 95% CI 0.63-1.07, p=0.14). In UC, 25 (4.8%) and 37 (7.1%) WH had a colectomy. There was no significant difference in the time to colectomy (Fig 1B, log-rank 0.12) nor was SA ethnicity associated with an increased risk of having a colectomy (HR 0.65, 95% CI 0.39-1.11, p=0.12). Conclusion In the largest analysis of SA IBD to date, we have demonstrated phenotypic differences associated with ethnicity. Accounting for these variations, we have shown comparable provision of medical and surgical treatment in SA and WH. These findings indicate consistent care of IBD patients from different ethnic backgrounds in the UK.

Risk of Primary Gastrointestinal Lymphoma in Patients With Inflammatory Conditions Exposed to Tumor Necrosis Factor Alpha Inhibitors and Immunomodulators: A Case-Control Study.

The aim of this case-control study was to determine if exposure to tumor necrosis factor alpha inhibitors (TNFIs) or immunomodulators (thiopurines or methotrexate) was associated with development of primary gastrointestinal lymphoma (PGIL) in patients with chronic inflammatory conditions. Patients with PGIL and controls evaluated at a tertiary care center over 20 years were matched 1:3 using a medical record informatics search engine based on their chronic inflammatory condition (Crohn's disease [CD], ulcerative colitis [UC], rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis) and duration of follow-up. Patients who started on TNFI within 3 months of PGIL diagnosis were excluded. We extracted demographics, medical history, and medications used. Univariate models using conditional logistic regression were used due to the small number of matched pairs. Twenty PGIL cases matched with 60 controls were followed for a mean 9.9 ± 6.9 and 9.7 ± 8.6 years, respectively. Mean age at time of PGIL diagnosis was 47.5 ± 22.0 (standard deviation) years and the majority (75%) were males. The most common inflammatory diagnosis was inflammatory bowel disease (80% of cases; 45% with UC and 35% with CD). Development of PGIL was not associated with TNFI (odds ratio [OR] = 2.6; 95% confidence interval [CI] 0.69-11.01; P = .18), but with use of TNFI in combination with thiopurines (OR = 8.93; 95% CI 1.43-80.25; P = .014). Risk of PGIL increased with every additional TNFI (2.277 (1.002-5.713); P = .0494). All cases exposed to multiple TNFI were also exposed to thiopurines. Use of thiopurines (alone or in combination) was the greatest risk factor (OR = 6.32; 95% CI 1.55-37.05; P = 0.006) to develop PGIL. TNFI therapy was not associated with increased risk for PGIL unless used in combination with thiopurines and with every switch to a different TNFI.

White Blood Cell Counts and Future Relapse in Ulcerative Colitis under Low-Dose Thiopurine Treatment in Real-World Practice: A 3-Year Japanese Multi-Center Retrospective Cohort Study

Introduction: Whether white blood cell (WBC) counts are predictors for the effectiveness of thiopurine treatment in ulcerative colitis (UC) has been inconclusive in previous studies with small sample sizes. We investigated the association between WBC counts and future relapses in UC patients in a large-scale multi-center study. Methods: This retrospective cohort study enrolled a total of 723 UC patients in remission from 33 hospitals and followed up for 3 years. Relapse was defined as a need for treatment intensification. The risk of relapse was compared among patients with the baseline WBC counts <3,000/µL (N = 31), 3,000–4,000/µL (N = 167), 4,000–5,000/µL (N = 241), and ≥5,000/µL (N = 284) using a Cox regression model analysis. Moreover, exploratory analyses were conducted to identify other factors predicting relapse. Results: During a median follow-up period of 1,095 (interquartile range, 1,032–1,119) days, relapse occurred in 17.2% (125/723). In a crude analysis, WBC counts were not associated with relapse; hazard ratios (HRs) (95% confidence interval [CI]) were 1.50 (0.74–3.06), 1.02 (0.66–1.59), and 0.67 (0.43–1.05) in WBC <3,000/µL, 3,000–4,000/µL, and 4,000–5,000/µL groups, respectively (WBC ≥5,000/µL group, as reference). Multivariable-adjusted analyses showed similar results; HRs (95% CI) were 1.21 (0.59–2.49), 1.08 (0.69–1.69), and 0.69 (0.44–1.07), in <3,000/µL, 3,000–4,000/µL, and 4,000–5,000/µL groups, respectively. In the exploratory analyses, thiopurine use <1 year and a mean corpuscular volume <90 fL were predictors for relapse. Discussion/Conclusion: WBC counts were not predictors for future relapses in patients with UC treated with thiopurine as a maintenance therapy.

Thiopurines exert harmful effects on spermatogenesis in Nudt15R138C knock-in mice.

The association between thiopurine use and testicular reproductive functions remains unclear. In this study, we investigated whether thiopurines affect testicular functions based on the NUDT15 genotypes using Nudt15R138C knock-in mice. The male Nudt15R138C knock-in mice (9-12weeks) were treated with mercaptopurine (MP: 0.5mg/kg/day) for 4 or 12weeks. To examine reversibility, some mice were maintained for a further 12weeks under MP-free condition. After MP treatment for 4weeks, Nudt15R138C/R138C mice exhibited a significant reduction of testis weight compared to Nudt15+/+ mice and Nudt15+/R138C mice. The epithelial height and diameter of seminiferous tubules were significantly reduced in Nudt15R138C/R138C mice compared to Nudt15+/+ and Nudt15+/R138C mice. Apoptotic cells were significantly increased in Nudt15R138C/R138C mice, and most of apoptotic cells were spermatogonia. There were no significant changes in sperm counts and sperm morphology in MP-treated Nudt15R138C/R138C mice after 4-week MP treatment. On the other hand, after MP treatment for 12weeks, the Nudt15+/R138C mice, but not Nudt15+/+ mice, exhibited a significant reduction in the testis weight and atrophic changes of seminiferous tubules, but these changes disappeared after 12-week rearing under MP-free condition. Despite a significant increase in abnormal sperm rate, there were no changes in the ability to conceive. No differences in serum levels of follicle-stimulating hormone or testosterone were observed between MP-treated Nudt15+/R138C and Nudt15+/+ mice after 12-week MP treatment. Thiopurines exert harmful effects on testicular reproductive function according to host NUDT15 genotypes.

The Role of Pharmacogenetics in the Therapeutic Response to Thiopurines in the Treatment of Inflammatory Bowel Disease: A Systematic Review.

This study focuses on the use of thiopurines for treating inflammatory bowel diseases (IBD). These drugs undergo enzymatic changes within the body, resulting in active and inactive metabolites that influence their therapeutic effects. The research examines the role of genetic polymorphisms in the enzyme thiopurine S-methyltransferase (TPMT) in predicting the therapeutic response and adverse effects of thiopurine treatment. The TPMT genotype variations impact the individual responses to thiopurines. Patients with reduced TPMT activity are more susceptible to adverse reactions (AEs), such leukopenia, hepatotoxicity, pancreatitis, and nausea, which are common adverse effects of thiopurine therapy. The therapeutic monitoring of the metabolites 6-thioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine (6-MMP) is proposed to optimize treatment and minimize AEs. Patients with higher 6-TGN levels tend to have better clinical responses, while elevated 6-MMP levels are linked to hepatotoxicity. Genotyping for TPMT before or during treatment initiation is suggested to tailor dosing strategies and enhance treatment efficacy while reducing the risk of myelosuppression. In conclusion, this study highlights the importance of considering genetic variations and metabolite levels in optimizing thiopurine therapy for IBD patients, focusing on balance therapeutic efficacy with the prevention of adverse effects and contributing to personalized treatment and better patient outcomes.

Factors contributing to flares of ulcerative colitis in North India- a case-control study

BackgroundUlcerative colitis is a relapsing and remitting disease that may be associated with flares. The causes of flares in the Indian setting are not well recognized.MethodsThe present prospective case-control study was conducted at a single center in North India. Cases were defined as patients admitted for flare of ulcerative colitis, while controls were patients in remission enrolled from the outpatient department. The basis of the diagnosis of flare was a simple clinical colitis activity index (SCCAI) of ≥ 5 and endoscopic activity, while remission was based on SCCAI < 4 and a normal fecal calprotectin. A questionnaire evaluating recent infections, stress, drug intake (antibiotics, pain medication), adherence to therapy, and use of complementary and alternative therapy (CAM) was administered.ResultsWe included 84 patients (51 with flare and 33 in remission) with a median age of 38 years, of whom 47 (55.9%) were males. The two groups were similar for baseline parameters, including age (38, 23–50 and 38, 25.5–48.5 years), male gender (52.9% and 60.6%), extent of disease, extraintestinal manifestations (21.6% and 12.1%), use of 5-aminosalicylates (76.5% and 90.9%). The thiopurine use was lower in those having a flare (15.7% and 36.4%). Amongst the predictors of flare, the recent infections (39.2% and 30.3%), recent travel (31.4 and 27.3%), eating outside food (47.1% and 39.4%), consumption of milk products (88.2% and 75.8%), use of pain medication (43.1% and 33.3%) and recent stress (62.7% and 60.6%) were similar between cases and controls. The rates of antibiotic use (29.4% and 6.1%), lack of adherence (50.9% and 15.2%), and intake of CAM (70.6% and 33.3%) were higher in those with flare. Patients attributed a lack of adherence to the cost of therapy, presumed cure (due to lack of symptoms), and fear of adverse effects.ConclusionLack of adherence to inflammatory bowel disease therapies and recent CAM and antibiotic intake was higher in patients with flares of UC. The study makes ground for educational intervention(s) promoting knowledge and adherence to IBD therapies.

Safety Summary of Pediatric Inflammatory Bowel Disease Therapies

Therapeutic options for the treatment of pediatric inflammatory bowel disease include aminosalicylates, enteral nutrition , corticosteroids, immunomodulators , biologics, and emerging small molecule agents. Infectious risk due to systemic immunosuppression should be mitigated by appropriate screening before therapy initiation. Rare but serious malignancies have been associated with thiopurine use alone and in combination with anti-tumor necrosis factor agents, often in the setting of a primary Epstein–Barr virus infection. Potential agent-specific adverse events such as cytopenias , hepatotoxicity , and nephrotoxicity warrant regular clinical and laboratory monitoring.