Prevalence of polymorphisms in thiopurine metabolism and association with adverse outcomes: a South Asian region-specific systematic review and meta-analysis

Jena, Anuraag; Jha, Daya Krishna; Kumar‐M, Praveen; Kasudhan, Kripa Shanker; Kumar, Ankit; Sarwal, Dhruv; Mishra, Shubhra; Singh, Anupam; Bhatia, Prateek; Patil, Amol; Sharma, Vishal

doi:10.1080/17512433.2021.1900729

Cited by 22 publications

(13 citation statements)

References 49 publications

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“…These differences could be related to certain key differences in our study including prospective follow-up, inclusion of more patients with active disease and protocol-based increments in thiopurine dosages resulting in higher mean dose used. Our findings are consistent with a recent systematic review on prevalence of polymorphisms in thiopurine in South Asian region which suggested similar higher prevalence of NUDT15 polymorphism in healthy controls and non-IBD diseased populations also [ 21 ]. In consonance with recent reports of severe and fatal toxicity of thiopurine in those homozygous for NUDT15 polymorphisms, our study makes a strong case for pre-emptive testing for these in South Asian populations [ 22 , 23 ].…”

Section: Discussionsupporting

confidence: 93%

“…In consonance with recent reports of severe and fatal toxicity of thiopurine in those homozygous for NUDT15 polymorphisms, our study makes a strong case for pre-emptive testing for these in South Asian populations [ 22 , 23 ]. Further, in centers and populations where the biologic use is not common including those where steroids and cyclosporine (as second line therapy in acute severe colitis) continues to be used for IBD, azathioprine is an important drug for maintenance of remission and therefore preemptive testing of NUDT15 polymorphisms may help improve tolerance to thiopurine therapy [ 21 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

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TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India

et al. 2021

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Background Polymorphisms in thiopurine methyltransferase (TPMT) and Nudix hydrolase-15 (NUDT15) have been implicated as the predominant cause of thiopurine induced leukopenia in the Western countries and East Asia respectively. Exact role of these polymorphisms in South Asian population with inflammatory bowel disease (IBD) is uncertain. Methods We included consecutive patients with IBD who were initiated on thiopurines at a center in North India. The dosage of thiopurines was titrated using regular monitoring of hemogram and liver function tests. Three TPMT polymorphisms (c.238 G > C, c.460 G > A, and c.719A > G) and one NUDT15 polymorphism (c.415 C > T) were assessed. Comparison regarding incidence of leukopenia and maximum tolerated thiopurine dosage was performed between those with wild polymorphism and those with TPMT and NUDT15 polymorphisms, respectively. Results Of the 119 patients (61 males, mean age 36.8 ± 13.5 years), 105 (88.2%) had ulcerative colitis and 14 (11.8%) had Crohn’s disease. Leukopenia was noted in 33 (27.7%), gastrointestinal intolerance in 5 (4.2%) and pancreatitis in 2 (1.6%). TPMT polymorphisms were detected amongst five patients of whom 1 developed leukopenia. NUDT15 polymorphism was noted in 13 patients of whom 7 had leukopenia. The odds of developing leukopenia in TPMT polymorphism were non-significant (0.77, 95% CI:0.0822 to 7.2134, P = 0.819) but were significantly higher in those with NUDT15 polymorphism (3.5933, 1.1041 to 11.6951, P value: = 0.0336). Conclusion NUDT15 polymorphism was more frequent than TPMT polymorphisms and was associated with thiopurine induced leukopenia. However, the tested polymorphisms account for only 24.2% of the risk of thiopurine induced leukopenia.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India

et al. 2021

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“…15 Conversely, although one of the adverse events of Azathioprine therapy is bone marrow suppression including neutropenia, our patient's blood parameters were maintained to normal levels while on treatment for six years. Usually, these established adverse events have a genetic predisposition since the recognized association stems from inadequate level of the degrading enzymes thiopurine methyltransferase (TPMT) and Nudix hydrolase (NUDT15) that metabolize azathioprine 16 Nevertheless, our patient has stable blood counts for a long time before his current presentation, which indicates that his pan-cytopenia is probably induced by infection. Taking that into consideration, our patient presented with grade 4 severe neutropenia (ANC 0.3 × 10 3 µl) which most likely related to the severe acute COVID-19 disease rather than prior immunosuppressants therapy with rituximab and azathioprine.…”

Section: Discussionmentioning

confidence: 85%

“…Conversely, although one of the adverse events of Azathioprine therapy is bone marrow suppression including neutropenia, our patient's blood parameters were maintained to normal levels while on treatment for six years. Usually, these established adverse events have a genetic predisposition since the recognized association stems from inadequate level of the degrading enzymes thiopurine methyltransferase (TPMT) and Nudix hydrolase (NUDT15) that metabolize azathioprine 16 …”

Section: Discussionmentioning

confidence: 99%

Dilemma of Tocilizumab therapy for a patient with critical COVID‐19 disease and neutropenia: Case report and review of the literature

Bishawi

Abdalla

Askar

et al. 2022

Clinical Case Reports

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Infection following SARS‐Co V‐2 leading to COVID‐19 disease is associated with significant morbidity and mortality. The clinical entity, COVID‐19 cytokine storm syndrome (CSS) is a severe immunological manifestation of the disease associated with ominous consequences. Tocilizumab is interleukin‐6 inhibitors that has been shown to hamper the catastrophic outcomes of CCS including the need for mechanical ventilation as well as reduce mortality, but the usage is limited by warnings of reactivation of potential latent infections or immune dysfunctions including severe neutropenia. We describe a case of 39‐year‐old Nepalese male patient with a background of scleritis maintained on azathioprine and rituximab therapy with normal baseline parameters including complete blood count who presented with acute COVID‐19 infection including associated leukopenia as well as severe neutropenia (absolute neutrophil count of 300 cells/µl), then progressed to critical disease culminating into CSS. Based on risks and benefits evaluation, the patient was treated with tocilizumab reinforced with granulocytes‐colony stimulating factor (G‐CSF, Filgrastim) to full recovery and safe outcome including reversal of neutropenia.

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“…8 This variation can be attributed to the differential metabolism of thiopurines in different population owing to varying prevalence of thiopurine methyltransferase (TPMT) and nucleotide triphosphate diphosphatase 15 (NUDT 15) gene polymorphism, with TPMT being more common in Caucasians, and NUDT 15 gene polymorphism being more common in Asians. 9 Recent studies from India have shown that NUDT 15 gene polymorphism is more prevalent and a better predictor of leukopenia compared with TPMT gene polymorphism. [10][11][12] Thiopurines affect both innate and acquired immune systems thereby increasing the risk of opportunistic as well as non-opportunistic infections, and malignancies such as lymphoma (both Hodgkin and non-Hodgkin) and non-melanoma skin cancer.…”

Section: Introductionmentioning

confidence: 99%

Minimal risk of lymphoma and non‐melanoma skin cancer despite long‐term use of thiopurines in patients with inflammatory bowel disease: A longitudinal cohort analysis from northern India

Ranjan

Kante

Vuyyuru

et al. 2022

J of Gastro and Hepatol

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Background and Aim Thiopurines are widely used to maintain remission in both ulcerative colitis (UC) and Crohn's disease (CD). Reported effectiveness and tolerability rates have been variable across studies. There are only sparse data in Asian population regarding the long‐term efficacy and safety of thiopurines. Methods Records of 5351 patients followed up at inflammatory bowel disease (IBD) clinic, All India Institute of Medical Sciences, New Delhi from 2004 to 2020 were evaluated retrospectively. Safety was evaluated in terms of long‐term adverse events and development of malignancy. Results Of 5351 patients with IBD, 1093 who received thiopurine for > 3 months (UC = 788 [proctitis—1.9%, left‐sided colitis—44.9%, & pancolitis—53.1%] & CD = 305 [inflammatory—42.6%, stricturing—46.9%, & fistulizing—10.5%]) were included (60.8%—male patients). Follow up and treatment duration on thiopurine were 7 (4–12) years and 39.4 ± 40.3 months, respectively, with 254 (23.2%) patients receiving thiopurines for more than 5 and 68 (6.2%) receiving for more than 10 years. Three hundred and fifty‐nine (UC: 249 [31.6%]; CD: 110 [36.1%]; P = 0.1) patients developed adverse events; commonest was myelosuppression (23.4%) followed by gastrointestinal intolerance (3%), flu‐like illness (1.7%), and arthralgia/myalgia (1.4%). Myelosuppression was the commonest cause of thiopurine withdrawal. No patient (including 254 patients on thiopurine for ≥ 5 years) developed lymphoma or non‐melanoma skin cancer. The cumulative probability of staying free from adverse events in overall IBD cohort at 1, 2, and 5 years was 78.6%, 71.9%, and 68.4%, respectively, and this was comparable between UC and CD (P = 0.09). Conclusion Long‐term follow up of patients with IBD from northern India on thiopurine monotherapy demonstrated minimal risk of development of lymphoma as well as non‐melanoma skin cancer.

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Prevalence of polymorphisms in thiopurine metabolism and association with adverse outcomes: a South Asian region-specific systematic review and meta-analysis

Cited by 22 publications

References 49 publications

TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India

TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India

Dilemma of Tocilizumab therapy for a patient with critical COVID‐19 disease and neutropenia: Case report and review of the literature

Minimal risk of lymphoma and non‐melanoma skin cancer despite long‐term use of thiopurines in patients with inflammatory bowel disease: A longitudinal cohort analysis from northern India

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