Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis
Authors: Shunsuke Furuta, Daiki Nakagomi, Yoshihisa Kobayashi, Masaki Hiraguri, Takao Sugiyama, Koichi Amano, Takeshi Umibe, Hajime Kono, Kazuhiro Kurasawa, Yasuhiko Kita, Ryutaro Matsumura, Yuko Kaneko, Keita Ninagawa, Keiju Hiromura, Shin-ichiro Kagami, Yosuke Inaba, Hideki Hanaoka, Kei Ikeda, Hiroshi Nakajima, Kengo Nagashima, Yohei Kawasaki, Yoshito Ozawa, Kokoro Someya, Asako Kono, Daisuke Kashiwakuma, Hiroshi Watanabe, Tamao Nakashita, Norihiro Mimura, Yoshihiro Oya, Michio Fujiwara, Ichiei Narita, Yoko Wada, Takeshi Nakatsue, Noriyoshi Ogawa, Daisuke Suzuki, Kurumi Asako, Hirotoshi Kikuchi, Shunya Uchida, Yoshihide Fujigaki, Toru Sakairi, Reika Maezawa, Hirotoshi Kawashima, Ayako Matsuki, Mieko Yamagata, Yuichiro Ohta, Ryota Sakai, Tomonori Ishii, Atsushi Kawakami, Takayuki Sumida, Norihiko Watanabe, Tatsuya Atsumi, Shun Tanimura, Atsushi Kumanogoh, Takahiko Sugihara, Hideyuki Iwai, Yoshiya Tanaka, Atsushi Komatsuda, Kaori Ito, Yoshihiro Shimojima, Iwao Sekigawa, Yukiko Takakuwa, Yuichi Makino, Ryusuke Yoshimi, Taichi Hayashi, Hiroshi Otani
Journal: JAMA (2021)

<h3>Importance</h3> The current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)–associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids. <h3>Objective</h3> To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis. <h3>Design, Setting, and Participants</h3> This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019. <h3>Interventions</h3> Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m<sup>2</sup>/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70). <h3>Main Outcomes and Measures</h3> The primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was −20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections. <h3>Results</h3> Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, −13.7 to ∞) between the groups met the noninferiority criterion (<i>P</i> = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, −18.1% [95% CI, −33.0% to −3.2%];<i>P</i> = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, −12.8% [95% CI, −24.2% to −1.3%];<i>P</i> = .04). <h3>Conclusions and Relevance</h3> Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02198248