Correlation between Thiopurine S-Methyltransferase Genotype and Adverse Events in Inflammatory Bowel Disease Patients

Background and Objectives: In patients with inflammatory bowel diseases (IBD), the use of azathioprine results in adverse events at a rate of 5% to 20%. The aim of the study was to assess a possible correlation between genetic variability of the enzyme thiopurine S-methyltransferase (TPMT) and the development of toxicity to azathioprine. Materials and Methods: A retrospective, single center, blind, case-control study was conducted on 200 IBD patients, of whom 60 cases suspended azathioprine due to toxicity (leukopenia, pancreatitis, hepatitis, and nausea or vomiting), and 140 controls continued treatment with the drug without adverse events. Results: In the entire cohort, only 8 cases of heterozygous mutations of TPMT were observed, corresponding to 4% mutated haplotype rate, much lower than that reported in literature (close to 10%). No homozygous mutation was found. Regarding the TPMT allelic variants, we did not find any statistically significant difference between patients who tolerated azathioprine and those who suffered from adverse events. (OR = 0.77, 95% CI = 0.08–7.72; p = 0.82). Conclusions: According to our study, in IBD patients, the search for TPMT gene mutations before starting treatment with azathioprine is not helpful in predicting the occurrence of adverse events. Importantly, patients with allelic variants should not be denied the therapeutic option of azathioprine, as they may tolerate this drug.

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Thiopurine S-methyltransferase genetic polymorphisms in adult patients with inflammatory bowel diseases in the Latvian population

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284820937426 ◽

2020 ◽

Vol 13 ◽

pp. 175628482093742

Author(s):

Polina Zalizko ◽

Juris Stefanovics ◽

Jelizaveta Sokolovska ◽

Natalia Paramonova ◽

Evija Klavina ◽

...

Keyword(s):

Gene Polymorphisms ◽

Fragment Length Polymorphism ◽

Nucleotide Polymorphisms ◽

Wild Type ◽

Single Nucleotide ◽

Allelic Variants ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Tpmt Gene ◽

European Populations

Background: Thiopurine methyltransferase (TPMT) plays a significant role in the metabolism of thiopurines, and, for patients with inflammatory bowel disease (IBD), it is useful to perform TPMT genotyping prior to azathioprine (AZA) treatment. In this study, we determined TPMT gene polymorphisms in a cohort of IBD patients in Latvia. Methods: DNA samples were obtained from 244 IBD patients, and qPCR was performed for detection of rs1800462, rs1800460, and rs1142345 single-nucleotide polymorphisms (SNPs). Three common, non-functional TPMT alleles ( TPMT*2, *3B, and *3C) were identified (women, 51%; men, 49%). TPMT*2, *3A, *3B, and *3C allelic variants detected using qPCR were consistent with restriction fragment length polymorphism (RFLP) data. Results: Among patients, 78% had ulcerative colitis and 22% had Crohn’s disease, with 93.9% of the former carrying a wild-type homozygous TPMT*1/*1 genotype and 6.1% carrying heterozygous genotypes. The most frequent polymorphisms were TPMT*1/*3A (5.3%: two variants: TPMT*3B and TPMT*3C), TPMT*1/*3C (0.4%), and TPMT*1/*2 (0.4%). None of the patients carried a TPMT*3B polymorphism and no patients were homozygous for any mutation. Conclusion: This is the first study to identify TPMT gene polymorphisms in adult IBD patients in Latvia. The results indicate that the frequency of common TPMT alleles is similar to that of other European populations.

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Anti-PD-1-Induced Hidradenitis Suppurativa

Dermatopathology ◽

10.3390/dermatopathology8010007 ◽

2021 ◽

Vol 8 (1) ◽

pp. 37-39

Author(s):

Alexia Maillard ◽

Damien Pastor ◽

Rastine Merat

Keyword(s):

Adverse Events ◽

Hidradenitis Suppurativa ◽

Checkpoint Inhibitors ◽

Latency Period ◽

The Body ◽

Skin Reactions ◽

Zinc Gluconate ◽

Severe Acne ◽

Bowel Diseases ◽

Inflammatory Bowel

Mucocutaneous adverse events are commonly observed under immune checkpoint inhibitors (ICIs) therapy. Here, we report the case of a 43-year-old male patient with a stage IIIC melanoma disease who developed hidradenitis suppurativa (HS) three months after the beginning of an anti-PD-1 (nivolumab) adjuvant therapy. The patient had no comorbidities other than obesity and severe acne during adolescence. After an unsuccessful course of lymecycline while he was still treated with nivolumab, he gradually improved under zinc gluconate therapy and, more importantly, after nivolumab cessation. HS is a recurrent follicular inflammatory disease in the apocrine gland-bearing areas of the body often associated with obesity, metabolic syndrome, tobacco smoking, inflammatory bowel diseases, psoriasis, and arthritis. In our patient, the latency period between drug initiation and onset of HS symptoms and the improvement after immunotherapy discontinuation, argued strongly in favor of an anti-PD-1-induced HS. Anti-PD-1 therapies often trigger T cells-mediated adverse events that mimic Th17-mediated inflammatory and neutrophilic diseases. We suggest that HS, as other pustular skin reactions and ICIs-induced neutrophilic colitis, can be part of the anti-PD-1 mucocutaneous adverse event spectrum.

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Sa1716 - High Anti-TNF Drugs Trough Levels are not Associated with the Occurrence of Adverse Events in Patients with Inflammatory Bowel Diseases

Gastroenterology ◽

10.1016/s0016-5085(18)31540-3 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-367

Author(s):

Giorgia Bodini ◽

Maria Giulia Demarzo ◽

Margherita Saracco ◽

Claudia Coppo ◽

Isabella Baldissarro ◽

...

Keyword(s):

Adverse Events ◽

Inflammatory Bowel Diseases ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Trough Levels

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Thioguanine Therapy in Inflammatory Bowel Diseases. A Practical Guide

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld-2765 ◽

2020 ◽

Vol 29 (4) ◽

pp. 637-645

Author(s):

Femke Crouwel ◽

Melek Simsek ◽

Chris J.J. Mulder ◽

Hans J.C. Buiter ◽

Nanne K De Boer

Keyword(s):

Adverse Events ◽

Inflammatory Bowel Diseases ◽

Nodular Regenerative Hyperplasia ◽

Therapy Failure ◽

Safety Issues ◽

Thiopurine Therapy ◽

Routine Monitoring ◽

Bowel Diseases ◽

Discontinue Therapy ◽

Inflammatory Bowel

Thiopurine-derivates azathioprine and mercaptopurine are frequently used to maintain remission in inflammatory bowel diseases (IBD). Despite their efficacy, more than 50% of patients discontinue therapy, mainly due to the development of adverse events. Thioguanine is an alternative thiopurine and has been conditionally licensed in The Netherlands as IBD treatment for patients after conventional thiopurine therapy failure. In this review we will provide practical information on initiating and maintaining thioguanine therapy in IBD and provide information concerning safety issues and future perspectives. The thioguanine toxicity profile is relatively mild and the reported incidence of nodular regenerative hyperplasia related to thioguanine use seems comparable to conventional thiopurines and the background incidence in IBD patients. Routine monitoring of laboratory parameters and adverse events is recommended, comparable to the monitoring of patients on conventional thiopurine therapy.

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Effectiveness of Mediterranean Diet’s Adherence in Children with Inflammatory Bowel Diseases

Nutrients ◽

10.3390/nu12103206 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3206 ◽

Cited By ~ 2

Author(s):

Caterina Strisciuglio ◽

Sabrina Cenni ◽

Maria Rosaria Serra ◽

Pasquale Dolce ◽

Massimo Martinelli ◽

...

Keyword(s):

Mediterranean Diet ◽

Protein Intake ◽

Intestinal Inflammation ◽

Fecal Calprotectin ◽

Dietary Intakes ◽

Food Diary ◽

Significant Difference ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

The Mediterranean

Background: Nutritional support is very important in the treatment of Paediatric Inflammatory Bowel Disease (IBD). The role of the Mediterranean Diet (MD) has been understudied in children with IBD. The aims of this study were to assess the dietary intakes of IBD children in comparison with healthy controls (HCs), their adherence to MD; and the relationship between inflammation and dietary behaviors. Methods: Paediatric IBD patients in clinical remission and HCs were enrolled. The nutritional status and adherence to the Mediterranean Diet was evaluated through a 3-day food diary and the Mediterranean Diet Quality Index for Children and Adolescents (KIDMED). Results: The analysis of food diaries showed a significantly higher kilocalorie intake in IBD patients compared to HCs (p = 0.012), an increase in carbohydrates (p = 0.015) and in protein intake (p = 0.024). Both IBD and HCs have an intermediate adherence to MD. The comparison between Crohn’s disease (CD) and Ulcerative colitis (UC) patients showed significant difference in protein intake in CD patients (p = 0.047), as well as for vitamin D (p = 0.044) and iron intake (p = 0.023). Interestingly; in IBD patients we found a significant association between adherence to MD and a low level of fecal calprotectin (p = 0.027). Conclusion: Children with IBD in remission have a sub-optimal food intake compared to HCs. MD seems to correlate to decreased intestinal inflammation.

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The Effect of Dream Anxiety on Sleep Quality in Inflammatory Bowel Diseases

Digestive Diseases ◽

10.1159/000504748 ◽

2019 ◽

Vol 38 (5) ◽

pp. 380-389

Author(s):

Haluk Tarik Kani ◽

Ayse Sakalli Kani ◽

Uzay Dural ◽

Emre Basgoze ◽

Cagri Aksu ◽

...

Keyword(s):

Sleep Quality ◽

Trait Anxiety ◽

Daytime Sleepiness ◽

State Anxiety ◽

Depression And Anxiety ◽

Anxiety Trait ◽

Significant Difference ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

First Time

Introduction: Declining sleep quality is a well-known issue in inflammatory bowel disease (IBD), but dream characteristics of patients with IBD and their role in sleep quality are unknown. In this study, we aimed to examine whether and how patients with ulcerative colitis (UC) and Crohn’s disease (CD) differ on sleep quality, sleepiness level, and dream anxiety (DA) level compared to healthy controls (HC), controlling for their depressive and anxious tendencies. Methods: Patients and HCs were enrolled prospectively into the study. The Van DA Scale, Pittsburg Sleep Quality Index, Epworth Sleepiness Scale, Beck Depression Index, and State-Trait Anxiety Inventories were used to assess DA, sleep quality, sleepiness, depression, and anxiety, respectively. Results: Patients with IBD had significantly lower depression (p = 0.004), state anxiety (p = 0.0001), trait anxiety (p = 0.004), and DA (p = 0.0001) than HCs. Although no statistically significant difference in sleep quality was found (p = 0.99), daytime sleepiness was more common in HCs than in IBD patients (p = 0.0001). No statistically significant difference was seen in depression, state anxiety, trait anxiety, DA, sleep quality, and daytime sleepiness between patients with CD and those with UC. No correlation was found between disease activity indices and psychological parameters. Conclusion: In contrast to previous studies, this study found lower anxiety and depression levels in patients with IBD than in HCs. Moreover, DA score was higher in HCs. For the first time, we revealed that DA may be one of the factors leading to sleep disturbance in patients with IBD.

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Importance of genotyping of Thiopurine S-methyltransferase in children with acute lymphoblastic leukaemia during maintenance therapy

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh0812609d ◽

2008 ◽

Vol 136 (11-12) ◽

pp. 609-616 ◽

Cited By ~ 3

Author(s):

Lidija Dokmanovic ◽

Dragana Janic ◽

Nada Krstovski ◽

Branka Zukic ◽

Natasa Tosic ◽

...

Keyword(s):

Acute Lymphoblastic Leukaemia ◽

Lymphoblastic Leukaemia ◽

Tandem Repeats ◽

Gene Mutations ◽

Maintenance Phase ◽

Variable Number ◽

Childhood All ◽

Dose Therapy ◽

Significant Difference ◽

Tpmt Gene

INTRODUCTION Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyses the inactivation of mercaptopurine (MP) which is widely used in the treatment of acute lymphoblastic leukaemia (ALL) of childhood. Potentially fatal myelotoxicity may develop after standard doses of MP in TPMT deficient patients. OBJECTIVES To establish if individually tailored doses of MP can reduce myelotoxicity in ALL patients carrying mutations in the TPMT gene. To establish if variable number of tandem repeats (VNTR) genotype influences the treatment effects of MP. METHOD Fifty randomly selected patients treated according to ALL IC-BFM 2002 protocol were tested for most frequent TPMT gene mutations using PCR based methods. VNTR genotype was determined in 20 children by PCR methods. During the maintenance phase, we recorded the number of weeks when therapy was applied in either full doses, reduced doses or when patients were without any therapy. RESULTS Fifty children were examined, 29 boys (58%) and 21 girls (42%); age ranged from 1.8-17.3 years (median 6.2 years). Four patients (8%) were heterozygous for TPMT mutations, all of them carrying the TPMT*3A variant. After 12, 14, 16 and 19 weeks of therapy with reduced doses of MP, the patients switched to full doses due to good tolerance. There was no therapy omission. Cumulative dose of MP was reduced for 7.8%, 7.4%, 11.2% and 16.6%, respectively, in patients with TPMT mutations. No significant difference was found between children with no mutations and TPMT heterozygotes regarding full dose therapy (53.6 vs. 55.7 weeks, respectively) and reduced dose therapy (19.9 vs. 15.2 weeks respectively). The number of detected VNTRs ranged from four to seven. The majority of patients had different number of VNTRs on homologous chromosomes. Most frequently detected polymorphism was VNTR*5. No correlation was found between TPMT and VNTR genotype inheritance. CONCLUSION Obeying pharmacogenetic principles in the treatment of childhood ALL may improve the tolerance of therapy with MP.

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P305 Effectiveness and Safety of Vedolizumab in Biologic-Naïve Patients: Real-World Data from the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD)

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.429 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S333-S333

Author(s):

F Macaluso ◽

W Fries ◽

S Renna ◽

A Viola ◽

M Muscianisi ◽

...

Keyword(s):

Clinical Response ◽

Real World ◽

Primary Outcome ◽

Real World Data ◽

Mayo Score ◽

Significant Difference ◽

Bowel Diseases ◽

Observational Cohort ◽

Inflammatory Bowel

Abstract Background Biologic-naïve patients treated with Vedolizumab (VDZ) are largely underrepresented in real-world cohorts. We performed a multicentre, observational, cohort study on the effectiveness and safety of VDZ as treatment for Crohn’s disease (CD) and ulcerative colitis (UC) among biologic-naïve subjects. Methods Data of consecutive biologic-naïve patients with CD and UC treated with VDZ from July 2016 to December 2019 were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD). The primary outcome was the clinical response at 14 and 52 weeks evaluated with Harvey Bradshaw Index in CD and partial Mayo score in UC. Results 172 consecutive patients (CD: n=88; UC: n=84; median age 66.0 years) were included, with a median follow-up of 58.8 weeks. After 14 weeks, a clinical response was reported in 68.2% of patients with CD and 67.9% of patients with UC treated with VDZ, including 45.5% patients in the CD group and 46.4% patients in the UC group who achieved steroid-free remission. After 52 weeks, a clinical response was reported in 77.4% of CD and in 73.8% of UC patients treated with VDZ, including 59.7% patients in the CD group and 60.7% patients in the UC group who achieved steroid-free remission. All differences between CD and UC were not statistically significant. Cox survival analysis showed no significant difference in the probability of treatment discontinuation between CD and UC patients (log-rank p=0.73). Conclusion This large, real-world, multicenter study demonstrated the effectiveness and safety of VDZ as a first-line biologic, showing high rates of clinical response and steroid-free remission at both induction and maintenance.

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Children With Inflammatory Bowel Disease in the COVID-19 Main Endemic Focus: The Lombardy Experience

Frontiers in Pediatrics ◽

10.3389/fped.2021.607285 ◽

2021 ◽

Vol 9 ◽

Author(s):

Naire Sansotta ◽

Lorenzo Norsa ◽

Giovanna Zuin ◽

Roberto Panceri ◽

Dario Dilillo ◽

...

Keyword(s):

Medical Records ◽

Clinical Form ◽

Cross Sectional Survey ◽

Cross Sectional ◽

Infectious Colitis ◽

Endemic Focus ◽

Significant Difference ◽

Bowel Diseases ◽

Immunosuppressed Patients ◽

Inflammatory Bowel

Objectives: In the era of Coronavirus 2019 (COVID-19), concern has been raised for immunosuppressed patients, including children with inflammatory bowel diseases (IBD). We aimed to collect data from IBD tertiary centers of Lombardy during pandemic.Methods: A cross-sectional survey enrolling IBD children has been completed by seven major IBD centers in Lombardy during lockdown. The clinical form included questions on any symptom consistent with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the IBD adherence treatment. Furthermore, we have reviewed all IBD medical records including new IBD diagnoses and flares in known IBD patients after the lockdown.Results: Questionnaires of 290 IBD children were returned during lockdown. Out of them, 24 children (8%) complained of mild symptoms suspicious of SARS-CoV-2 infection without needing hospitalization or changing IBD treatment. During the lockdown, one patient presented with IBD flare and one had infectious colitis, with no new IBD cases. Conversely, after lockdown, 12/290 (4%) children relapsed and 15 children were newly diagnosed with IBD. Last year, in the same timeframe, 20/300 (7%) children presented with IBD flare, while 17 children had IBD onset with no statistical difference.Conclusions: Our data on children with IBD in a high COVID-19 prevalence region are reassuring. Only a minority of IBD children had mild symptoms, and no hospitalization or treatment modification was needed. Standard IBD treatments including biologics were safely continued. New IBD diagnoses and flares in known IBD children occurred after the lockdown phase, although no significant difference was found compared with the previous year.

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Long-term Outcomes of Stereotactic Radiosurgery for Skull Base Tumors Involving the Cavernous Sinus

10.21203/rs.3.rs-986293/v1 ◽

2021 ◽

Author(s):

Motoyuki Umekawa ◽

YUKI SHINYA ◽

Hirotaka Hasegawa ◽

Masahiro Shin ◽

Mariko Kawashima ◽

...

Keyword(s):

Cavernous Sinus ◽

Therapeutic Option ◽

Rank Test ◽

Tumor Control ◽

Long Term Outcomes ◽

Entire Cohort ◽

Neurological Outcomes ◽

Trigeminal Schwannoma ◽

Significant Difference

Abstract PurposeStereotactic radiosurgery (SRS) is an effective and less invasive therapeutic option for cavernous sinus (CS) tumors. However, its long-term effectiveness and neurological outcomes have yet to be fully elucidated. We aimed to examine the long-term outcomes of SRS for CS tumors.MethodsOverall, 127 patients with benign CS tumors, including 91 with meningioma, 14 with trigeminal schwannoma (TS), 14 with non-functioning pituitary adenoma (PA), and eight with cavernous hemangioma (CH), treated with SRS at our institution from 1990 to 2018, were included. Tumor control and functional preservation/recovery were evaluated in detail.ResultsThe mean post-SRS follow-up period was 102 months. The progression-free survivals (PFSs) were 97% at 5 years, 90% at 10 years, and 88% at 15 years for the entire cohort; 96% at 5 years and 87% at 10 years for meningiomas; and 100% at 10 years for the other tumors. No significant difference was observed among the tumor types (log-rank test; meningioma vs. TS, p = 0.232, meningioma vs. PA, p = 0.297, meningioma vs. CH, p = 0.277). Improvement in cranial nerve (CN) function was observed in 35 (27%) patients. TSs tended to show CN improvements more often than meningiomas did (total improvements, 62% vs. 23%; p = 0.004, eye movement function, 100% vs. 20%; p = 0.002). Deterioration, or development of new CN deficits, was observed in 11 (9%) patients.ConclusionSRS provides durable tumor control and contributes to sufficient preservation of CN function.

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