AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in Patients With Malignancy: Commentary.

DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update (CPU) Commentary is to discuss the risks of various malignancies in patients with inflammatory bowel diseases (IBD) and the impact of the available medical therapies on these risks. The CPU will also guide the approach to the patient with IBD who develops a malignancy or the patient with a history of cancer in terms of IBD medication management. METHODS: This CPU was commissioned and approved by the AGA Institute CPU committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPU committee and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. This communication incorporates important and recently published studies in the field, and it reflects the experiences of the authors who are experts in the diagnosis and management of IBD.

Early therapeutic drug monitoring helps to identify inflammatory bowel disease patients with a high risk to fail thiopurine treatment.

AIMS: Conventional thiopurines (azathioprine and mercaptopurine) remain standard therapy to maintain steroid sparing remission in inflammatory bowel disease (IBD), but are regularly discontinued due to adverse drug reactions (ADRs). Measurement of the metabolites 6-thioguanine nucleotides (6-TGN), 6-methylmercaptopurine ribonucleotides (6-MMPR) and the 6-MMPR/6-TGN ratio, may predict the development of these ADRs. Our aim was to evaluate whether early thiopurine metabolite measurements were associated with clinical outcomes. METHODS: A post-hoc analysis was conducted of a multicentre, prospective, observational study on thiopurine-induced hepatotoxicity. IBD patients who initiated thiopurine therapy were included and thiopurine metabolite concentrations were assessed after 7 days (±1) (T1). Patients were monitored for 12 weeks to document the occurrence of ADRs, early treatment discontinuation and effectiveness. RESULTS: In total, 181 patients were evaluated. At T1, 6-MMPR concentrations and 6-TGN/6-MMPR ratios were independently related to treatment discontinuation within 12 weeks after correction for sex, age and body mass index (BMI) (P = .034 and .002, respectively). The largest effects were observed for 6-MMPR ≥3000 pmol/8 × 108 RBC and 6-TGN/6-MMPR ratio ≥17. Furthermore, 6-MMPR concentrations and 6-TGN/6-MMPR ratios at T1 were independently related to skewed metabolism at steady state (Week 8, 6-MMPR/-6TGN ratio ≥11 and ≥20) (both P < .001). The occurrence of ADRs and effectiveness were not independently related to T1 thiopurine metabolite concentrations. CONCLUSIONS: Thiopurine metabolite concentrations at T1 were related to early treatment discontinuation and skewed metabolism at steady state, but not to effectiveness, helping to identify patients with a high risk of thiopurine treatment failure.

Key factors associated with 6-thioguanine and 6-methylmercaptopurine nucleotide concentrations in children treated by thiopurine for acute leukaemia and inflammatory bowel disease.

AIMS: Azathioprine (AZA) and 6-mercaptopurine are prescribed in acute lymphoblastic leukaemia (ALL) and inflammatory bowel diseases (IBD). Metabolism to active 6-thioguanine (6TGN) and 6-methylmercaptopurine nucleotides (6MMPN) is variable but therapeutic drug monitoring (TDM) remains debatable. This study reports on factors impacting on red blood cell (RBC) metabolites concentrations in children to facilitate TDM interpretation. METHODS: The first paediatric TDM samples received during year 2021 were analysed, whatever indication and thiopurine drug. Target concentration ranges were 200-500, <6000 pmol/8 × 108 RBC for 6TGN and 6MMPN. RESULTS: Children (n = 492) had IBD (64.8%), ALL (22.6%) or another autoimmune disease (12.6%): mean ages at TDM were 7.5 in ALL and 13.7 years in IBD (P < .0001). ALL received 6-mercaptopurine (mean dose 1.7 mg/kg/d with methotrexate), IBD received AZA (1.9 mg/kg/d with anti-inflammatory drugs and/or monoclonal antibodies). Median 6TGN and 6MMPN concentrations were 213.7 [interquartile range: 142.5; 309.6] and 1144.6 [419.4; 3574.3] pmol/8 × 108 RBC, 38.8% of patients were in the recommended therapeutic range for both compounds. Aminotransferases and blood tests were abnormal in 57/260 patients: 8.1% patients had high alanine aminotransaminase, 3.4% of patients had abnormal blood count. Factors associated with increased 6TGN were age at TDM and thiopurine methyltransferase genotype in ALL and AZA dose in IBD. The impact of associated treatment in IBD patients was also significant. CONCLUSION: TDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow-up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome.

Anti-drug antibodies against anti-TNF in patients with inflammatory bowel disease: an evaluation of possible strategies.

OBJECTIVE: Immunogenicity against anti-TNF antibodies usually leads to loss of response. We aimed to evaluate the efficacy of clinical strategies to improve clinical remission and pharmacokinetics upon detection of anti-drug antibodies (ADA). METHODS: Inflammatory bowel disease (IBD) patients with ADA against infliximab or adalimumab were identified through a single centre database search covering 2004-2022. Criteria for successful intervention upon ADA detection (baseline) were clinical remission after 1 year without further change in strategy. RESULTS: Two-hundred-and-fifty-five IBD patients (206 Crohn's disease) were identified. At baseline, median ADA level was 77 AU/ml; 50.2% of patients were in clinical remission. Implemented strategies were: (1) 81/255 (32%) conservative management, (2) 102/255 (40%) anti-TNF optimisation, (3) 72/255 (28%) switch within or out of class. Switching was the most successful strategy for clinical remission (from 19% at baseline to 69% at 1 year, p < 0.001). Patients that continued the same dose anti-TNF or discontinued biological therapy were often in clinical remission, but deteriorated significantly (-22.7%, p = 0.004). Anti-TNF dose intensification with immunomodulator optimisation was the fastest (median 3.0 months, p = 0.009) and most effective (65% ADA suppression, p < 0.001) strategy to suppress ADA compared to solely anti-TNF or immunomodulator optimisation. CONCLUSIONS: Switching therapy, within or out of class, is the most successful strategy to regain and maintain clinical remission upon immunogenicity. When switching to another anti-TNF, concomitant immunomodulatory therapy should be started or continued to prevent repeated immunogenic loss of response. Anti-TNF dose escalation with concomitant immunomodulator optimisation is the fastest and most effective strategy to suppress ADA.

Immunogenicity against anti-TNF antibodies is associated with loss of response in patients with inflammatory bowel diseases and remains a clinical challenge. We investigated potential therapeutic strategies in a retrospective patient cohort focusing on clinical efficacy and pharmacokinetics.

Evaluation of Genetic Variants Associated with the Risk of Thiopurine-Related Pancreatitis: A Case Control Study from ENEIDA Registry.

INTRODUCTION: Risk factors for developing pancreatitis due to thiopurines in patients with inflammatory bowel disease (IBD) are not clearly identified. Our aim was to evaluate the predictive pharmacogenetic risk of pancreatitis in IBD patients treated with thiopurines. METHODS: We conducted an observational pharmacogenetic study of acute pancreatitis events in a cohort study of IBD patients treated with thiopurines from the prospectively maintained ENEIDA registry biobank of GETECCU. Samples were obtained and the CASR, CEL, CFTR, CDLN2, CTRC, SPINK1, CPA1, and PRSS1 genes, selected based on their known association with pancreatitis, were fully sequenced. RESULTS: Ninety-five cases and 105 controls were enrolled; a total of 57% were women. Median age at pancreatitis diagnosis was 39 years. We identified 81 benign variants (50 in cases and 67 in controls) and a total of 35 distinct rare pathogenic and unknown significance variants (10 in CEL, 21 in CFTR, 1 in CDLN2, and 3 in CPA1). None of the cases or controls carried pancreatitis-predisposing variants within the CASR, CPA1, PRSS1, and SPINK1 genes, nor a pathogenic CFTR mutation. Four different variants of unknown significance were detected in the CDLN and CPA1 genes; one of them was in the CDLN gene in a single patient with pancreatitis and 3 in the CPA1 gene in 5 controls. After the analysis of the variants detected, no significant differences were observed between cases and controls. CONCLUSION: In patients with IBD, genes known to cause pancreatitis seem not to be involved in thiopurine-related pancreatitis onset.

6-Thioguanine nucleotide levels are associated with infliximab but not adalimumab levels in inflammatory bowel disease patients on combination therapy.

BACKGROUND: Thiopurine co-therapy with anti-tumour necrosis factor-alpha (anti-TNFα) agents is associated with higher anti-TNFα drug levels and reduced immunogenicity in inflammatory bowel disease (IBD). AIMS: We aimed to evaluate the association between 6-thioguanine nucleotide (6-TGN) and anti-TNFα levels and the optimal 6-TGN threshold level associated with higher anti-TNFα levels in combination therapy. METHODS: We performed a retrospective cross-sectional multicentre study of patients with IBD on combination anti-TNFα and thiopurine maintenance therapy between January 2015 and August 2021. Primary outcomes were infliximab and adalimumab levels. Secondary outcomes were antibodies to infliximab (ATI) or adalimumab (ATA). Univariable and multivariable linear regression were performed to identify variables associated with anti-TNFα levels. Receiver operator characteristic curves were used to define the optimal 6-TGN cut-off levels associated with therapeutic anti-TNFα levels. RESULTS: The study included 743 paired 6-TGN and anti-TNFα levels (640 infliximab and 103 adalimumab). 6-TGN levels were associated with infliximab levels, but not adalimumab levels, on univariable and multivariable regression. The optimal 6-TGN cut-off associated with therapeutic infliximab levels (≥5 mcg/mL) was 261 pmol/8 × 108 red blood cell (RBC) (area under the curve (AUC) = 0.57) for standard infliximab dosing and 227.5 pmol/8 × 108 RBC (AUC = 0.58) for escalated dosing. For therapeutic adalimumab levels (≥7.5 mcg/mL), the 6-TGN cut-off was 218.5 pmol/8 × 108 RBC (AUC = 0.59) for standard adalimumab dosing and 237.5 pmol/8 × 108 RBC (AUC = 0.63) for escalated dosing. CONCLUSION: 6-TGN levels were weakly associated with infliximab but not adalimumab levels in combination therapy. 6-TGN levels in the lower end of the therapeutic range (230-260 pmol/8 × 108 RBC) may be adequate to maintain higher infliximab levels, particularly with escalated infliximab dosing.

Risk of Recurrent Acute Arterial Events Associated With Thiopurines and Anti-Tumor Necrosis Factor in Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) are at increased risk of acute arterial events. Treatment with anti-tumor necrosis factor (anti-TNF) agents has been associated with a protective effect against the first occurrence of acute arterial events, but the impact of treatment with anti-TNF in patients with a previous history of acute arterial events remains unclear. We assessed the effect of anti-TNF and thiopurines on the risk of recurrent acute arterial events in patients with IBD in a nationwide cohort. METHODS: Based on the French nationwide health insurance database, patients with IBD and a previous history of an acute arterial event were followed up from January 1, 2009, until December 31, 2018. The risk of acute arterial event recurrence associated with anti-TNF and thiopurine exposure was assessed using marginal structural Cox proportional hazard models adjusted for baseline and time-varying covariates. RESULTS: A total of 27,185 patients were included. During 121,822 person-years (median follow-up period, 4.0 y), 6865 recurrent acute arterial events occurred (incidence rate per 1000 person-years, 56.4; 95% CI, 55.0-57.7). Exposure to both anti-TNF and thiopurines were associated with a decreased risk of recurrent acute arterial events compared with the absence of exposure to either treatment (hazard ratio, 0.75; 95% CI, 0.63-0.90 and hazard ratio, 0.76; 95% CI, 0.66-0.88, respectively). CONCLUSIONS: In a nationwide cohort study of patients with IBD and a previous history of an acute arterial event, exposure to both anti-TNF and thiopurines were associated with a decreased risk of recurrent acute arterial events.

Incidence of cancer in patients with ulcerative colitis 30 years after diagnosis (the IBSEN study).

OBJECTIVES: Patients with ulcerative colitis (UC) have shown an increased risk for colorectal cancer, hepatobiliary, hematologic, and skin cancers, but updated long-term data is needed. This study aimed to estimate the risk of cancer in patients with UC compared to the general Norwegian population, in a population-based cohort (the IBSEN study), 30 years after diagnosis; and to identify possible risk factors associated with cancer. METHODS: The IBSEN cohort prospectively included all incident patients between 1990 and 1993. Cancer incidence data were obtained from the Cancer Registry of Norway. The overall and cancer-specific hazard ratios (HR) were modelled using Cox regression. Standardized incidence ratios were estimated compared to the general population. RESULTS: In total, the cohort included 519 patients, and 83 cases were diagnosed with cancer. There was no statistically significant difference in the overall cancer risk (HR = 1.01, 95% CI: [0.79-1.29]) and colorectal cancer risk (HR = 1.37, 95% CI: [0.75-2.47]) between patients and controls. The incidence of biliary tract cancer was higher than expected (SIR = 9.84, 95%CI: [3.19-20.15]), especially when UC patients suffered from primary sclerosing cholangitis. Male UC patients were also more at risk of being diagnosed with hematologic malignancies (HR = 3.48, 95% CI: [1.55-7.82]). Being prescribed thiopurines was associated with a higher risk of cancer (HR = 2.03, 95% CI: [1.02-4.01]). CONCLUSIONS: At 30 years after diagnosis, the risk of all cancer in patients with UC was not significantly increased compared with the general population. However, the risks of biliary tract cancer and hematologic cancers were increased, particularly in male patients.

Feasibility of Reduced Clinical Monitoring in Patients with Inflammatory Bowel Disease Treated with Thiopurine Therapy.

BACKGROUND: Outpatient visits and laboratory assessments are routinely scheduled every 3 to 4 months in thiopurine-treated patients with inflammatory bowel disease (IBD) to timely detect thiopurine-related adverse events (AEs). AEs that require therapy adjustment beyond 12 months of treatment are rare. AIM AND METHODS: This single-center prospective cohort study evaluated the safety of a reduced 6-monthly monitoring strategy in steroid-free patients with quiescent IBD on stable dose of azathioprine, mercaptopurine, or thioguanine monotherapy. The primary outcome was thiopurine-related AEs requiring therapy adjustments during a follow-up period of 24 months. Secondary outcomes included all AEs including laboratory toxicity, disease flares until 12 months, and the net monetary benefit from this strategy concerning IBD-related health care use. RESULTS: We enrolled 85 patients with IBD (median age 42 years, 61% Crohn's disease, 62% female), with a median disease duration of 12.5 years and median thiopurine treatment duration of 6.7 years. During follow-up, 3 patients (4%) ceased thiopurines due to AEs: recurrent infections, non-melanoma skin cancer, and gastrointestinal complaints (nausea, vomiting). At 12 months, 25 laboratory toxicities were observed (including 13% myelotoxicity, 17% hepatotoxicity); none required therapy adjustments and all were transient. A reduced monitoring strategy had a net benefit of €136 per patient. CONCLUSION: Three patients (4%) ceased thiopurine therapy due to thiopurine-related AEs, while no laboratory toxicity required therapy adjustments. Monitoring frequency of every 6 months seems feasible in patients with stable IBD on long-term (median duration > 6 years) maintenance thiopurine therapy and may contribute to reduced patient-burden and health care costs.

Proactive Metabolite Testing in Patients on Thiopurine May Yield Long-Term Clinical Benefits in Inflammatory Bowel Disease.

BACKGROUND: The thiopurine medications are well established in the treatment of inflammatory bowel disease (IBD). There is significant variation in levels of toxic and therapeutic metabolites. Current data from small or short-term studies support therapeutic drug monitoring (TDM) in assessing azathioprine (AZA) and 6-mercaptopurine (6MP). TDM of thiopurines involves measurement and interpretation of metabolites 6-TGN and 6-MMPR. AIMS: This study aimed to assess long-cterm outcomes of patients on thiopurines following therapeutic drug monitoring. METHODS: A multicenter retrospective observational study of outcomes post thiopurine TDM was conducted. Demographics, disease characteristics, physician global assessment, IBD therapy at baseline TDM and again at 12 months were collected. Clinical outcomes were analyzed according to TDM result, and indication for TDM including proactive and other indications. RESULTS: The study included 541 patients. Only 39% of patients had appropriate dosing of thiopurines. AZA/6MP TDM informed a management change in 61.9%, and enabled 88.8% of the cohort to continue AZA/6MP following TDM. At 12 months following TDM the majority (74.1%) of the cohort remained on AZA/6MP. Clinical remission was higher at 12-months following thiopurines TDM (68%) compared to baseline (37%), including proactive TDM. Post TDM, 13.0% of patients were identified as shunters and commenced on thiopurine-allopurinol co-therapy. CONCLUSION: Thiopurine TDM resulted in a change in management for the majority of patients. Post TDM significantly more patients were in remission. TDM allowed the identification of non-adherence and shunters who, without intervention, would not reach therapeutic drug levels. Proactive TDM allowed identification and management of inappropriate dosing, and was associated with increased levels of clinical remission.

Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity.

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

Thiopurines Analogues with Additional Ring: Synthesis, Spectroscopic Properties, and Anticancer Potency.

Purine scaffolds constitute a starting point for the synthesis of numerous chemotherapeutics used in treating cancer, viruses, parasites, as well as bacterial and fungal infections. In this work, we synthesized a group of guanosine analogues containing an additional five-membered ring and a sulfur atom at the C-9 position. The spectral, photophysical, and biological properties of the synthesized compounds were investigated. The spectroscopic studies revealed that a combination of the thiocarbonyl chromophore and the tricyclic structure of guanine analogues shifts the absorption region above 350 nm, allowing for selective excitation when present in biological systems. Unfortunately, due to the low fluorescence quantum yield, this process cannot be used to monitor the presence of these compounds in cells. The synthesized compounds were evaluated for their effect on the viability of human cervical carcinoma (HeLa) and mouse fibroblast (NIH/3T3) cells. It was found that all of them display anticancer activity. In vitro studies were preceded by in silico ADME and PASS analyses, which confirmed that the designed compounds are promising candidates for anticancer agents.

Evaluation of tolerance to mercaptopurine in patients with inflammatory bowel disease and gastrointestinal intolerance to azathioprine.

BACKGROUND: Thiopurines such as azathioprine (AZA) and mercaptopurine (MP) are commonly utilized to treat inflammatory bowel disease (IBD). Their use is frequently restricted due to gastrointestinal intolerance (GI). Previous retrospective studies have reported that AZA-intolerant patients may benefit from a switch to MP; yet the effectiveness of this strategy has not been prospectively evaluated. AIMS: To assess GI tolerance to MP in patients who are intolerant to AZA, and to identify clinical predictors of GI intolerance to AZA or MP. METHODS: A prospective, observational, single-cohort study was performed in 92 thiopurine-naïve IBD patients. They were started on a 50mg dose of AZA and escalated to 2.5mg/kg per day by week 2. Those with GI intolerance were rechallenged with a 50% dose of AZA, after which another dose escalation attempt was made. If symptoms persisted, they were switched to MP. RESULTS: Thirty (32.6%) of the recruited patients suffered from GI intolerance to AZA. Of these, 15 did not present recurrence of symptoms after rechallenge with lower doses. Of 15 intolerant patients, 14 were switched to MP. Within the MP cohort, 8 patients (57%) were also intolerant to MP, 5 (36%) had no symptoms, and 1 (7%) was lost to follow-up. Female gender was the only independent predictor of GI intolerance to AZA. CONCLUSIONS: Up to half of the AZA-intolerant patients tolerated a 50% dose rechallenge that was successfully escalated. A switch to MP was tolerated in over a third of cases whom rechallenge failed. Our strategy (challenge-rechallenge-switch) achieved an overall GI tolerance to thiopurines in most of the patients.

Serious Infections in Children Born to Mothers With Inflammatory Bowel Disease With In Utero Exposure to Thiopurines and Anti-Tumor Necrosis Factor.

BACKGROUND & AIMS: We aimed to compare the risk of serious infections in children with in utero exposure to thiopurines and/or anti-tumor necrosis factor (TNF) born to mothers with inflammatory bowel disease (IBD). METHODS: Using the French national health database, which covers 99% of the French population (around 66,000,000 people), we identified live births among women with IBD in France between 2010 and 2018. The risks of serious infections in children during the first 5 years of life were compared according to treatment exposures during pregnancy using propensity score-weighted marginal Cox models. RESULTS: A total of 26,561 children were included: 3392 were exposed to thiopurine monotherapy, 3399 to anti-TNF monotherapy, 816 to combination therapy, and 18,954 were not exposed to any of these drugs. The risks of serious infections during the first year of life among children exposed to thiopurine monotherapy (adjusted hazard ratio [aHR], 0.94; 95% confidence interval [CI], 0.83-1.07) and anti-TNF monotherapy (aHR, 1.10; 95% CI, 0.95-1.27) were similar to those of unexposed children; a higher risk was observed in children exposed to combination therapy (aHR, 1.36; 95% CI, 1.04-1.79). The highest increased risks were observed for nervous system infections and viral infections. The risk of serious infections during the second to fifth years of life was not associated with IBD treatments. CONCLUSIONS: In children born to mothers with IBD, in utero exposure to thiopurine and anti-TNF monotherapies do not increase the risk of serious infections during the first 5 years of life. Combination therapy is associated with an increased risk of serious infections during the first year of life.

Effectiveness and Durability of COVID-19 Vaccination in 9447 Patients With IBD: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: The serological responses after severe acute respiratory syndrome coronavirus 2 vaccination may be attenuated in immunocompromised individuals. The study aimed to systematically evaluate the seroconversion rates after complete vaccination for coronavirus disease 2019 (COVID-19) in patients with inflammatory bowel disease (IBD). METHODS: Electronic databases were searched to identify studies reporting response to COVID-19 vaccination in IBD. Pooled seroconversion rates after complete vaccination were calculated. Subgroup analysis for vaccine types was also performed. Pooled seroconversion rates for various drugs or classes were also estimated. The pooled rates of breakthrough infections in vaccinated IBD patients were estimated. The pooled neutralization rates after complete vaccination were also estimated. The studies reporting durability of titers were systematically assessed. RESULTS: A total of 46 studies were included. The pooled seroconversion rate for complete vaccination (31 studies, 9447 patients) was 0.96 (95% confidence interval [CI], 0.94-0.97; I2 = 90%). When compared with healthy control subjects, the pooled relative risk of seroconversion was lower (0.98; 95% CI, 0.98-0.99; I2 = 39%). The pooled seroconversion rates were statistically similar among various drug classes. The pooled positivity of neutralization assays (8 studies, 771 participants) was 0.80 (95% CI, 0.70-0.87; I2 = 82%). The pooled relative risk of breakthrough infections in vaccinated IBD patients was similar to vaccinated control subjects (0.60; 95% CI, 0.25-1.42; I2 = 79%). Most studies suggested that titers fall after 4 weeks of COVID-19 vaccination, and the decay was higher in patients on anti-tumor necrosis factor alone or combination with immunomodulators. An additional dose of COVID-19 vaccine elicited serological response in most nonresponders to complete vaccination. CONCLUSIONS: Complete COVID-19 vaccination is associated with seroconversion in most patients with IBD. The decay in titers over time necessitates consideration of additional doses in these patients.

Rac1/pSTAT3 expression: A pharmacodynamic marker panel as a first step toward optimization of thiopurine therapy in inflammatory bowel disease patients.

Thiopurine derivatives, such as azathioprine and mercaptopurine, are standard conventional treatment options in inflammatory bowel disease (IBD). Unfortunately, approximately half of patients discontinue thiopurine therapy within 2 years. To improve the prediction of clinical effectiveness, thiopurine therapy is currently optimized using therapeutic drug monitoring. Ras-related C3 botulinum toxin substrate 1 (Rac1) has been suggested as a potential pharmacodynamic marker of the thiopurine effect in lymphocytes. The active thiopurine metabolite 6-thioguanine triphosphate (6-Thio-GTP) causes T cell apoptosis via Rac1 and the downstream transcription factor signal transducer and activator of transcription 3 (STAT3). The aim of this study was to develop and validate a functional pharmacodynamic multiparameter flow cytometric assay to determine Rac1/pSTAT3 expression in the various leukocyte subpopulations in peripheral blood in order to predict therapeutic response in IBD patients in the future. Peripheral blood samples of healthy subjects (no fever or clinical complaints of active disease, C-reactive protein < 10 mg/L) were used for immunocytochemical labeling, applying an optimized fixation and permeabilization strategy. A gating procedure was performed to separate all leukocyte subpopulations. Quantitative data were obtained by measuring presence and median fluorescent intensity. In vitro, Rac1 presence and expression were detectable in all leukocyte subpopulations. After IL-6 stimulation, used as proxy for inflammation, a distinct pSTAT3 signal could be detected in T lymphocytes of healthy subjects. In vivo, an upregulated pSTAT3 signal was detected in nearly all IBD patients with active disease and differed substantially from the signal found in IBD patients in remission on thiopurines and healthy subjects. We developed and validated a functional flow cytometric assay to assess Rac1 and pSTAT3 presence and expression. This opens a venue for a pharmacodynamic assay to predict thiopurine effectiveness in IBD patients.

Thiopurine Enhanced ALL Maintenance (TEAM): study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0-45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol.

BACKGROUND: A critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance. METHODS: TEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0-45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5-12.5 mg/m2/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m2/day. A total of 778 patients will be included in TEAM during ~ 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse, TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients. DISCUSSION: TEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms. TRIAL REGISTRATION: EudraCT, 2018-001795-38. Registered 2020-05-15, Clinicaltrials.gov , NCT04307576 . Registered 2020-03-13, https://clinicaltrials.gov/ct2/show/NCT04307576.

Relapse rates after withdrawal of thiopurines in patients with inflammatory bowel disease.

PURPOSE: Withdrawal of thiopurines after remission is associated with an increased risk of relapse in patients with inflammatory bowel disease (IBD). However, long-term data on thiopurine withdrawal is limited, especially from developing countries where the cost of long-term therapy poses a significant burden on patients. METHODS: Patients with IBD on thiopurine monotherapy for ≥ 4 months, who stopped thiopurines while in clinical remission and were not on any other immunomodulator or biologics at the time of withdrawal, were included in this retrospective analysis. RESULTS: Among 1093 patients with IBD on thiopurine monotherapy, 461 patients stopped thiopurine due to various reasons. Among these, 218 (ulcerative colitis (UC) = 179; Crohn's disease (CD) = 39) patients were in clinical remission and were continued on mesalamine. Overall, 36.7% (n = 80) relapsed after a median duration of 20 months (IQR: 9-49). Relapse rate was higher in UC than CD (39.7% vs 23%, p = 0.055). Cumulative probabilities of relapse were 17%, 34%, and 44% at the end of 1, 3, and 5 years, respectively. The relapse rate at 5 years was significantly lower in patients who had stopped azathioprine after 4 years of therapy (31% vs 54%, p = 0.007). On multi-variate cox regression analysis, male sex [HR: 1.6(1.0-2.6), p = 0.02] and short duration of therapy with thiopurines [HR: 1.02 (1.01-1.02), p = 0.004] before withdrawal were associated with increased risk of relapse. CONCLUSION: Approximately 50% patients with IBD in remission would relapse after 5 years of thiopurine withdrawal. Male sex and shorter treatment duration predict relapse. Treatment should be continued in patients who tolerate and maintain remission on long-term thiopurine.

Adverse Events of Thiopurine Therapy in Pediatric Inflammatory Bowel Disease and Correlations with Metabolites: A Cohort Study.

BACKGROUND: In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity. AIMS: We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival. METHODS: We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient. RESULTS: Of 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase. CONCLUSIONS: Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities.

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

BACKGROUND: 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. AIMS: To assess the efficacy of thiopurine monotherapy for maintenance of mild-moderate IBD and clinical variables associated with treatment outcome. METHODS: 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. RESULTS: From 230 CD patients, 64 (72%) were free of treatment failure with mean follow-up of 3.3 years. 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 3.3 years. 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. CONCLUSIONS: 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.