Peripheral blood UBA1 variant burden predicts poor outcomes in VEXAS syndrome: a nationwide prospective study.
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Kirino Yohei, Maeda Ayaka, Higashitani Kana, Horita Nobuyuki, Asano Tomoyuki, Migita Kiyoshi, Motomura Yoshikazu, Rokutanda Ryo, Kobayashi Daisuke, Tamura Masao, Kanazawa Nobuo, Furuhashi Kazunori, Kondo Yasushi, Nagahata Ken, Takahashi Hiroki, Kobayashi Hiroshi, Yao Shuhei, Yamagami Keiko, Uchino Kaori, Hidaka Yukiko, Ida Hiroaki, Kishida Dai, Sato Tomohito, Ichinose Kunihiro, Miyamae Takako, Tsujimoto Kohei, Inoue Yuta, Fujieda Yuichiro, Mishima Koji, Tsuji Tomohiro, Tanaka Kazuki, Noda Haruka, Isogai Shuntaro, Miyoshi Yuji, Yokogawa Naoto, Ota Shinji, Sakuraba Hirotake, Nishi Jumpei, Inoue Takuya, Muraoka Sei, Nanki Toshihiro, Shimizu Toshimasa, Koga Tomohiro, Inaba Yutaka, Matsubara Masaki, Yoshimoto Kiyomi, Hasegawa Anna, Ikeda Kei, Motohashi Rena, Takeuchi Yoichi, Shiratsuchi Motoaki, Moriyama Masayori, Noda Kentaro, Saito Shinichiro, Hagiyama Hiroyuki, Honda Tetsuya, Kageyama Reiko, Nakatani Norie, Goto Tatsunori, Kishimoto Mitsumasa, Watanabe Tomoya, Yamaguchi Yukie, Nishikomori Ryuta, Ohara Osamu, Ban Tatsuma, Tamura Tomohiko, Nakajima Hideaki
Аннотация
METHODS: We conducted a nationwide prospective registry in Japan, in which all suspected cases underwent next-generation sequencing to detect pathogenic UBA1 variants and estimate the variant allele frequency (VAF) at baseline. Disease activity (VEXAS Current Activity Form [VEXASCAF]), serum C-reactive protein (CRP) level, prednisolone (PSL) dose, adverse events (AEs), mortality, and transfusion dependency were evaluated every 3 months for 1 year.
RESULTS: Among the screened patients, we included 60 patients with pathogenic UBA1 variants (all males; median age, 74 years) and 45 male patients with VS-like syndrome of similar age but without UBA1 variants served as controls. During a median follow-up of 343 days, the VEXASCAF and CRP levels decreased, whereas the PSL dose did not significantly change. Grade ≥3 AEs occurred in 50% of patients within 1 year. In the multivariable Cox regression analysis, a higher baseline VAF and higher PSL dose independently predicted poor prognosis, defined as death or transfusion dependence. The association between a higher VAF and poor outcomes was confirmed in 34 independent patients with VS. After adjusting for disease onset, patients carrying the UBA1 p.Met41Leu variant showed better survival. A similarly poor prognosis was observed in VEXAS-like patients.
CONCLUSIONS: Baseline pathogenic UBA1 VAF serves as a potent prognostic biomarker for poor outcomes in VS and highlights its potential role in risk stratification.