NUDT15 p.R139C variant is common and strongly associated with azathioprine-induced early leukopenia and severe alopecia in Korean patients with various neurological diseases

Kim, Sun‐Young; Shin, Jin‐Hong; Park, Jin-Sung; Kang, Sa-Yoon; Nam, Tai‐Seung; Kim, Jong Kuk; Park, Ki-Jong; Huh, So-Young; Oh, Ji Seon; Kang, Boram; Kim, Dae‐Seong

doi:10.1016/j.jns.2017.04.041

Cited by 29 publications

(42 citation statements)

References 17 publications

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“…Among four NUDT15 variants, NUDT15 R139C is the most common and strongly associated with leukopenia in East Asian populations . NUDT15 R139C allele (hetero‐ and homozygosity) carries a 7.86‐fold higher risk of thiopurine‐induced leukocytopenia .…”

Section: Discussionmentioning

confidence: 99%

“…It was spontaneously resolved within 6 months after suspending AZA. The characteristic finding of NUDT15 R139C‐associated thiopurine‐induced hair loss is rapid development of total scalp hair loss, namely anagen effluvium . Anagen effluvium is commonly induced by many chemotherapeutic agents, usually 1–3 weeks after drug administration .…”

Section: Discussionmentioning

confidence: 99%

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Severe thiopurine‐induced leukocytopenia and hair loss in Japanese patients with defective NUDT15 variant: Retrospective case–control study

Kishibe

Nozaki

Fujii

et al. 2018

The Journal of Dermatology

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Azathioprine (AZA)-metabolizing enzyme gene polymorphism is strongly related to thiopurine-induced leukocytopenia, which has not been well recognized in dermatological practice. We tried to see whether NUDT15 gene polymorphism can be the most susceptible genetic factor for AZA toxicity and the gene screening is beneficial to avoid the adverse events of AZA for the treatment of skin diseases. A retrospective study was carried out on 15 adult Japanese patients who were treated with AZA. Gene polymorphism of thiopurine-metabolizing enzymes NUDT15 R139C, ITPA 94C>A, TPMT*2, TPMT*3B and TPMT*3C was analyzed. The single nucleotide polymorphisms were prospectively investigated in eight patients who were considered to have received AZA treatments. Two NUDT15 R139C homozygous patients developed agranulocytosis, severe thrombocytopenia and massive hair loss. The gene screening prior to AZA treatment identified one heterozygote of NUDT15 R139C and ITPA 94C>A, and three heterozygotes of ITPA 94C>A or TMPT*3C. Although this study was a retrospective single-center case-control observational study that enrolled a small number of patients, NUDT15 R139C homozygosity is a genetic risk of thiopurine-induced potentially fetal hematological abnormalities. To avoid serious adverse events, gene screening of thiopurine-metabolizing enzymes, at least NUDT15 R139C, should be considered prior to administration in genetically predisposed populations, such as Japanese. We highlight that massive hair loss in the early period of the initiation of AZA would be a sign of impending severe myelotoxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Severe thiopurine‐induced leukocytopenia and hair loss in Japanese patients with defective NUDT15 variant: Retrospective case–control study

Kishibe

Nozaki

Fujii

et al. 2018

The Journal of Dermatology

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“…A study by Kim et al . showed that alopecia induced by azathioprine in Korean patients is associated with leucopenia and may be associated with nucleoside diphosphate‐linked moiety X motif 15 ( NUDT15 ) gene mutation, resulting in a substitution of arginine to cysteine (p.R139C) . To our knowledge, there is no report of azathioprine‐induced anagen effluvium in patients with pemphigus.…”

Section: Discussionmentioning

confidence: 96%

Increased risk of severe course of pemphigus in patients with pemphigus‐associated alopecia: a prospective observational study

et al. 2018

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Summary Background Pemphigus‐associated alopecia is considered rare, and has not been studied in detail. Aim To evaluate the clinical and immunological characteristics of patients with pemphigus‐associated alopecia. Methods This prospective observational study included 80 consecutive patients with histopathologically and immunopathologically confirmed pemphigus, of whom 11 (13.8%) were found to have pemphigus‐associated alopecia. Alopecia was observed in 11/52 patients with pemphigus and scalp involvement: [0/28 (35.7%) with pemphigus vulgaris and 1/24 (4.2%) with pemphigus foliaceus. The clinical and immunological characteristics of these patients were analysed. Results Patients with pemphigus‐associated alopecia had a significantly higher Pemphigus Disease Area Index total activity score compared with patients who had no pemphigus‐associated alopecia (21.8 ± 18.6 and 11.0 ± 20.5, respectively; P = 0.02). Mean serum anti‐desmoglein (Dsg)1 antibody concentration was 141.8 ± 66.9 U/mL and 60.0 ± 52.6 U/mL, respectively (P = 0.03), and mean serum anti‐Dsg3 concentration was 126.6 ± 36.7 U/mL and 67.4 ± 52.5 U/mL, respectively (P = 0.03). The values for achieving serological remission were 10% and 70%, respectively (P = 0.02). Conclusions Pemphigus‐associated alopecia is a marker of severe disease and a treatment‐resistant disease course.

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“…Azathioprine (AZA), one of the most widely applied immunosuppressants, has been used to treat CD as an adjunctive therapy or a steroid‐sparing agent . Unfortunately, AZA cannot be tolerated by many Asian patients, in whom leukopenia and severe hair loss are the most commonly observed adverse events . Studies on the patients with inflammatory bowel disease (IBD) in China, South Korea and Japan have shown that NUDT15 R139C mutation is closely related to these two adverse events .…”

Section: Introductionmentioning

confidence: 99%

“…1 Unfortunately, AZA cannot be tolerated by many Asian patients, in whom leukopenia and severe hair loss are the most commonly observed adverse events. [2][3][4][5] Studies on the patients with inflammatory bowel disease (IBD) in China, South Korea and Japan have shown that NUDT15 R139C mutation is closely related to these two adverse events. 3,5,6 Moreover, several side effects associated with the use of AZA can be prevented by using NUDT15 polymorphism testing before the drug is given to the patients; however, alternatives are still needed for those who cannot tolerate AZA.…”

Section: Introductionmentioning

confidence: 99%

A single‐center experience with methotrexate in the treatment of Chinese Crohn’s disease patients

Wang

Qiao

Zou

et al. 2018

J of Digest Diseases

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Objective Methotrexate (MTX) can be used as an alternative for patients with Crohn’s disease (CD) who are intolerant of thiopurine. This retrospective study aimed to provide some clues about MTX treatment in Chinese patients with CD. Methods Medical records of 27 adult patients with CD who were treated with MTX between 2012 and 2017 at Renji Hospital were reviewed. MTX was administered at 15 mg or 20 mg intramuscularly once per week. The remission and response rates and adverse reactions of MTX were recorded and analyzed. Results Thirteen (48.1%) of the patients achieved remission for more than 12 months, whereas four (14.8%) responded clinically. Eight (29.6%) patients discontinued MTX due to adverse events. The mean age of those who maintained remission was significantly younger than that of those who did not ([35.62 ± 10.99] years vs. [45.43 ± 11.93] years, P < 0.05). The pretreatment C‐reactive protein (CRP) level was higher in the group who maintained remission than that in those who did not ([17.20 ± 17.26] mg/L vs. [6.98 ± 5.66] mg/L, P < 0.05). Conclusions MTX is effective and relatively safe for patients at doses of 15 mg/week or 20 mg/week and may be an alternative therapy for patients who are intolerant of thiopurine. Elderly patients with CD and patients with normal pretreatment CRP level may have a reduced response to MTX.

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NUDT15 p.R139C variant is common and strongly associated with azathioprine-induced early leukopenia and severe alopecia in Korean patients with various neurological diseases

Cited by 29 publications

References 17 publications

Severe thiopurine‐induced leukocytopenia and hair loss in Japanese patients with defective NUDT15 variant: Retrospective case–control study

Severe thiopurine‐induced leukocytopenia and hair loss in Japanese patients with defective NUDT15 variant: Retrospective case–control study

Increased risk of severe course of pemphigus in patients with pemphigus‐associated alopecia: a prospective observational study

A single‐center experience with methotrexate in the treatment of Chinese Crohn’s disease patients

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