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Journal of Crohn's & Colitis Aug 2023Despite its efficacy, rational guidance for starting/stopping first-line biologic treatment in individual paediatric Crohn's disease [CD] patients is needed. We assessed... (Randomized Controlled Trial)
Randomized Controlled Trial
Serum Immune Profiling in Paediatric Crohn's Disease Demonstrates Stronger Immune Modulation With First-Line Infliximab Than Conventional Therapy and Pre-Treatment Profiles Predict Clinical Response to Both Treatments.
BACKGROUND
Despite its efficacy, rational guidance for starting/stopping first-line biologic treatment in individual paediatric Crohn's disease [CD] patients is needed. We assessed how serum immune profiles before and after first-line infliximab [FL-IFX] or conventional [CONV] induction therapy associate with disease remission at week 52.
METHODS
Pre- [n = 86], and 10-14-week post-treatment [n = 84] sera were collected from patients with moderate-to-severe paediatric CD in the TISKids trial, randomized to FL-IFX [n = 48; five 5-mg/kg infusions over 22 weeks] or CONV [n = 43; exclusive enteral nutrition or oral prednisolone]; both groups received azathioprine maintenance. The relative concentrations of 92 inflammatory proteins were determined with Olink Proteomics; fold changes [FC] with |log2FC| > 0.5 after false discovery rate adjustment were considered significant.
RESULTS
FL-IFX modulated a larger number of inflammatory proteins and induced stronger suppression than CONV; 18/30 proteins modulated by FL-IFX were not regulated by CONV. Hierarchical clustering based on IFX-modulated proteins at baseline revealed two clusters of patients: CD-hi patients had significantly higher concentrations of 23/30 IFX-modulated proteins [including oncostatin-M, TNFSF14, HGF and TGF-α], and higher clinical disease activity, C-reactive protein and blood neutrophils at baseline than CD-lo patients. Only 24% of CD-hi FL-IFX-treated patients maintained remission without escalation at week 52 vs 58% of CD-lo FL-IFX-treated patients. Similarly, 6% of CD-hi CONV-treated patients achieved remission vs 20% of CONV-treated CD-lo patients. Clustering based on immune profiles post-induction therapy did not relate to remission at week 52.
CONCLUSION
FL-IFX leads to stronger reductions and modulates more immune proteins than CONV. Stratification on pre-treatment profiles of IFX-modulated proteins directly relates to maintenance of remission without treatment escalation.
TRIAL REGISTRATION NUMBER
NCT02517684.
Topics: Child; Humans; Infliximab; Crohn Disease; Azathioprine; C-Reactive Protein; Remission Induction; Treatment Outcome; Gastrointestinal Agents
PubMed: 36934327
DOI: 10.1093/ecco-jcc/jjad049 -
World Journal of Gastroenterology Jul 2023There is no consensus on the recommended duration of and optimal time to stop azathioprine (AZA) therapy in inflammatory bowel disease (IBD). Determining the optimal...
BACKGROUND
There is no consensus on the recommended duration of and optimal time to stop azathioprine (AZA) therapy in inflammatory bowel disease (IBD). Determining the optimal duration and cessation time can help to balance the risks of long-term intake with the possibility of relapse after cessation.
AIM
To describe the events following AZA cessation.
METHODS
Retrospective analysis was performed to examine data from adult patients affected by IBD who were followed at the University of Padua and had started but then discontinued AZA between 1995 and 2022. Data on therapy duration, reasons for cessation, and type of relapse after cessation were collected. Cox regression models were used to estimate the risk of relapse in different subgroups.
RESULTS
A total of 133 ulcerative colitis patients and 141 Crohn's disease patients were included. Therapy with AZA was stopped in the 1 year in approximately 34% of patients but was continued for more than 10 years in approximately 10% of cases. AZA discontinuation was due to primary failure or disease relapse in 30% of patients and due to disease remission in 25.2% of patients. Most of the remaining cases stopped AZA therapy due to side effects (primarily clinical intolerance, cytopenia, and pancreatic disease). Patients who stopped AZA for clinical remission had an 83% lower risk of relapse during the observation time than other groups, with a relapse-free rate of 89% after 1 year and 79% after 2 years.
CONCLUSION
AZA administration is effective and safe, but it requires careful monitoring for potential minor and major side effects. Only 10% of patients who achieved remission with AZA needed a new treatment within 1 year of drug interruption.
Topics: Adult; Humans; Azathioprine; Immunosuppressive Agents; Retrospective Studies; Inflammatory Bowel Diseases; Colitis, Ulcerative; Remission Induction
PubMed: 37545640
DOI: 10.3748/wjg.v29.i27.4334 -
Cancer Reports (Hoboken, N.J.) Feb 2024Mercaptopurine is an important component of acute lymphoblastic leukemia (ALL) and lymphoma (LLy) maintenance therapy. The 6-thioguanine nucleosides (6-TGN) are believed...
Assessment on the use of allopurinol to improve safety and efficacy of mercaptopurine in pediatric patients with Acute Lymphoblastic Leukemia and Lymphoma during maintenance therapy.
BACKGROUND
Mercaptopurine is an important component of acute lymphoblastic leukemia (ALL) and lymphoma (LLy) maintenance therapy. The 6-thioguanine nucleosides (6-TGN) are believed to be the primary contributor to myelosuppression and immunosuppressive effects, while 6-methylmercaptopurine (6-MMPN) is believed to be responsible for several toxicities including hepatotoxicity, pancreatitis, and hypoglycemia. Previous reports suggest the addition of allopurinol may reduce these toxicities.
AIMS
To assess the use of allopurinol to improve both safety and efficacy of mercaptopurine in pediatric patients with ALL and LLy during maintenance therapy. Secondary objectives included evaluating patient tolerability and skewed metabolism. In addition, we also analyzed mercaptopurine daily dose reduction upon allopurinol initiation.
METHODS AND RESULTS
The primary endpoint was time within goal ANC prior to and after initiation of allopurinol. Secondary endpoints included; improvement in selective toxicities (hepatotoxicity, pancreatitis, and hypoglycemia) and 6-MMPN to 6-TGN ratio prior to and after allopurinol initiation. In addition, an exploratory endpoint assessing mercaptopurine daily dose reduction prior to and after allopurinol initiation was included. Sixteen patients met inclusion criteria and 15 (94%) of which were included in this study. Median percent of maintenance days within goal ANC prior to and after initiation of allopurinol was 27.8 (IQR 22.6-44.9) and 41.6 (IQR 20.2-58.2) respectively. All patients experienced selective toxicities; 15 (100%) hepatotoxicity, 1 (7%) pancreatitis, and 3 (20%) hypoglycemia. Improvement of toxicities was seen in 13/15 (87%), 1/1 (100%), and 2/3 (67%) respectively. Average 6-MMPN:6-TGN ratio prior to allopurinol initiation was 304:1 and after, allopurinol initiation improved to 15:1, resulting in a 95% reduction. Average mercaptopurine dose prior to and after allopurinol initiation decreased by about 56% (63 to 28 mg/m /day).
CONCLUSION
Results suggest that the use of allopurinol in pediatric patients with ALL and LLy receiving mercaptopurine during maintenance therapy is both safe and effective.
Topics: Humans; Child; Mercaptopurine; Allopurinol; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hypoglycemia; Drug-Related Side Effects and Adverse Reactions; Chemical and Drug Induced Liver Injury; Lymphoma; Pancreatitis
PubMed: 38351548
DOI: 10.1002/cnr2.1987 -
Indian Journal of Gastroenterology :... Feb 2024Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that encompasses two major conditions: Crohn's disease (CD) and... (Review)
Review
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that encompasses two major conditions: Crohn's disease (CD) and ulcerative colitis (UC). Historically, IBD has been primarily reported in western countries, but over the past decades, its prevalence is rapidly increasing, especially in lower and middle-income countries (LMICs) such as India and China and also in Sub-Saharan Africa. The prevalence of IBD in LMICs has been the subject of growing concern due to the impact of access to public healthcare and the burden it places on healthcare resources. The classical thiopurines face significant challenges due to cessation of therapy in approximately half of patients within one year due to side effects or ineffectiveness. In this article, we highlight innovating thiopurine treatment for IBD patients in downregulating side effects and improving efficacy.
Topics: Humans; Inflammatory Bowel Diseases; Crohn Disease; Colitis, Ulcerative; Mercaptopurine; Azathioprine; Immunosuppressive Agents; Purines; Sulfhydryl Compounds
PubMed: 38383877
DOI: 10.1007/s12664-024-01529-x -
Metabolites Oct 2023Tioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However,...
Tioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients. In this retrospective cohort study, all determined genotypes (2016-2021) were evaluated for aberrant metabolism (i.e., intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant genotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness. genotypes were determined in 485 patients, of whom, 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy. Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late-occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT.
PubMed: 37887379
DOI: 10.3390/metabo13101054 -
Biomedicine & Pharmacotherapy =... Nov 2023Luteolin, naringenin, myricetin, and ampelopsin are abundant flavonoids in nature, and several dietary supplements also contain them at very high doses. After the...
Luteolin, naringenin, myricetin, and ampelopsin are abundant flavonoids in nature, and several dietary supplements also contain them at very high doses. After the peroral intake, flavonoids go through extensive presystemic biotransformation; therefore, typically their sulfate/glucuronic acid conjugates reach high concentrations in the circulation. Xanthine oxidase (XO) enzyme is involved in uric acid production, and it also takes part in the elimination of certain drugs (e.g., 6-mercaptopurine). The inhibitory effects of flavonoid aglycones on XO have been widely studied; however, only limited data are available regarding their sulfate and glucuronic acid conjugates. In this study, we examined the impacts of luteolin, naringenin, myricetin, ampelopsin, and their sulfate/glucuronide derivatives on XO-catalyzed xanthine and 6-mercaptopurine oxidations employing in vitro enzyme incubation assays and molecular modeling studies. Our major results/conclusions are the following: (1) Sulfate metabolites were stronger while glucuronic acid derivatives were weaker inhibitors of XO compared to the parent flavonoids. (2) Naringenin, ampelopsin, and their metabolites were weak inhibitors of the enzyme. (3) Luteolin, myricetin, and their sulfates were highly potent inhibitors of XO, and the glucuronides of luteolin showed moderate inhibitory impacts. (4) Conjugated metabolites of luteolin and myricetin can be involved in the inhibitory effects of these flavonoids on XO enzyme.
PubMed: 37734263
DOI: 10.1016/j.biopha.2023.115548 -
Lupus Science & Medicine Oct 2023To investigate the association of medication copayment and treatment adherence to hydroxychloroquine and immunosuppressants for SLE.
OBJECTIVE
To investigate the association of medication copayment and treatment adherence to hydroxychloroquine and immunosuppressants for SLE.
METHODS
We conducted a retrospective analysis of health claims data using Optum's de-identified Clinformatics Data Mart Database. Individuals with SLE continuously enrolled for 180 days from 1 July 2010 to 31 December 2019 were included. Adherence was defined as the proportion of days covered ≥80%. Copayment for a 30-day supply of medication was dichotomised as high (≥$10) or low (<$10). We examined the association between copayment and odds of adherence in multivariable-adjusted logistic regression models, including age, sex, race or ethnicity, comorbidities, educational attainment and household income.
RESULTS
We identified 12 510 individuals (age 54.2±15.5 years; 88.2% female sex), of whom 9510 (76%) were prescribed hydroxychloroquine and 1880 (15%) prescribed hydroxychloroquine and an additional immunosuppressant (azathioprine, methotrexate or mycophenolate mofetil). Median (IQR) 30-day copayments were $8 (4-10) for hydroxychloroquine, $7 (2-10) for azathioprine, $8 (3-11) for methotrexate and $10 (5-20) for mycophenolate mofetil. High copayments were associated with OR of adherence of 0.61 (95% CI 0.55 to 0.68) for hydroxychloroquine, OR 0.44 (95% CI 0.30 to 0.66) for azathioprine and OR 0.69 (95% CI 0.49 to 0.96) for mycophenolate mofetil. For methotrexate, the association was not significant.
CONCLUSION
In a large, administrative health claims database, we identified that high copayments were associated with reduced adherence to commonly prescribed medications for SLE. Incorporating awareness of the burden of copayments and its consequences into healthcare is essential to promote optimal medication adherence.
Topics: Humans; Female; Adult; Middle Aged; Aged; Male; Lupus Erythematosus, Systemic; Hydroxychloroquine; Azathioprine; Methotrexate; Mycophenolic Acid; Retrospective Studies; Immunosuppressive Agents; Medication Adherence
PubMed: 37852670
DOI: 10.1136/lupus-2023-000966 -
The Journal of Clinical Endocrinology... Sep 2023Graves orbitopathy is both disabling and disfiguring. Medical therapies to reduce inflammation are widely used, but there is limited trial data beyond 18 months of... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
Graves orbitopathy is both disabling and disfiguring. Medical therapies to reduce inflammation are widely used, but there is limited trial data beyond 18 months of follow-up.
METHODS
Three-year follow-up of a subset of the CIRTED trial (N = 68), which randomized patients to receive high-dose oral steroid with azathioprine/placebo and radiotherapy/sham radiotherapy.
RESULTS
Data were available at 3 years from 68 of 126 randomized subjects (54%). No additional benefit was seen at 3 years for patients randomized to azathioprine or radiotherapy with regard to a binary clinical composite outcome measure (BCCOM), modified European Group on Graves' Orbitopathy score, or Ophthalmopathy Index.Clinical Activity Score (CAS), Ophthalmopathy Index, and Total Eye Score improved over 3 years (P < .001). However, quality of life at 3 years remained poor. Of 64 individuals with available surgical outcome data, 24 of 64 (37.5%) required surgical intervention. Disease duration of greater than 6 months before treatment was associated with increased need for surgery [odds ratio (OR) 16.8; 95% CI 2.95, 95.0; P = .001]. Higher baseline levels of CAS, Ophthalmopathy Index, and Total Eye Score but not early improvement in CAS were associated with increased requirement for surgery.
CONCLUSION
In this long-term follow-up from a clinical trial, 3-year outcomes remained suboptimal with ongoing poor quality of life and high numbers requiring surgery. Importantly, reduction in CAS in the first year, a commonly used surrogate outcome measure, was not associated with improved long-term outcomes.
Topics: Humans; Graves Ophthalmopathy; Azathioprine; Follow-Up Studies; Quality of Life; Inflammation; Treatment Outcome
PubMed: 36971324
DOI: 10.1210/clinem/dgad084 -
Journal of Gastroenterology Jun 2024This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world...
BACKGROUND
This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies.
METHODS
A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status.
RESULTS
Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users.
CONCLUSIONS
NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.
Topics: Humans; Pyrophosphatases; Female; Male; Retrospective Studies; Adult; Middle Aged; Mercaptopurine; Genotype; Inflammatory Bowel Diseases; Japan; Azathioprine; Young Adult; Aged; Immunosuppressive Agents; Adolescent; Risk Factors; Codon; Nudix Hydrolases
PubMed: 38589597
DOI: 10.1007/s00535-024-02099-7 -
Arquivos Brasileiros de Cardiologia Oct 2023Chagas' disease (CD) is an important cause of heart transplantation (HT). The main obstacle is Chagas' disease reactivation (CDR), usually associated to high doses of...
Chagas' disease (CD) is an important cause of heart transplantation (HT). The main obstacle is Chagas' disease reactivation (CDR), usually associated to high doses of immunosuppressants. Previous studies have suggested an association of mycophenolate mofetil with increased CDR. However, mortality predictors are unknown. To identify mortality risk factors in heart transplant patients with CD and the impact of antiproliferative regimen on survival. Retrospective study with CD patients who underwent HT between January 2004 and September 2020, under immunosuppression protocol that prioritized azathioprine and change to mycophenolate mofetil in case of rejection. We performed univariate regression to identify mortality predictors; and compared survival, rejection and evidence of CDR between who received azathioprine, mycophenolate mofetil and those who changed from azathioprine to mycophenolate mofetil after discharge ("Change" group). A p-value < 0.05 was considered statistically significant. Eighty-five patients were included, 54.1% men, median age 49 (39-57) years, and 91.8% were given priority in waiting list. Nineteen (22.4%) used azathioprine, 37 (43.5%) mycophenolate mofetil and 29 (34.1%) switched therapy; survival was not different between groups, 2.9 (1.6-5.0) x 2.9 (1.8-4.8) x 4.2 (2.0-5.0) years, respectively; p=0.4. There was no difference in rejection (42%, 73% and 59% respectively; p=0.08) or in CDR (T. cruzi positive by endomyocardial biopsy 5% x 11% x 7%; p=0.7; benznidazole use 58% x 65% x 69%; p=0.8; positive PCR for T. cruzi 20% x 68% x 42% respectively; p=0.1) rates. This retrospective study did not show difference in survival in heart transplant patients with CD receiving different antiproliferative regimens. Mycophenolate mofetil was not associated with statistically higher rates of CDR or graft rejection in this cohort. New randomized clinical trials are necessary to address this issue.
Topics: Male; Humans; Middle Aged; Female; Azathioprine; Mycophenolic Acid; Retrospective Studies; Immunosuppressive Agents; Heart Transplantation; Chagas Disease; Graft Rejection
PubMed: 37909604
DOI: 10.36660/abc.20230133