Mark A Matza1, Cory A Perugino1,2, Liam Harvey1, Ana D Fernandes1, Zachary S Wallace1, Hang Liu1, Hugues Allard-Chamard3, Shiv Pillai2, John H Stone1. 1. Division of Rheumatology, Allergy and Immunology. Massachusetts General Hospital. Harvard Medical School. 55 Fruit Street; Boston, MA 02114. 2. Ragon Institute of MGH, MIT and Harvard. 400 Technology Square; Cambridge, MA 02139. 3. Division of Rheumatology, Faculté de médecine et des sciences de la santé de l' Université de Sherbrooke et Centre de Recherche Clinique Étienne-Le Bel, Sherbrooke, Québec, Canada.
Abstract
Background: There is strong rationale for interference with T cell co-stimulation in IgG4-related disease (IgG4-RD), but the literature to evaluate this is limited to a single case report. Methods: We conducted a ten-subject proof-of-concept trial of abatacept in active IgG4-RD. All subjects met the ACR/EULAR Classification Criteria for IgG4-RD. Subjects received subcutaneous abatacept 125 mg weekly for 24 weeks. Concurrent glucocorticoid treatment was permitted but if used had to be discontinued by week four. The primary endpoint, complete remission at 24 weeks, was defined as an IgG4-RD Responder Index score of 0. Peripheral blood mononuclear cells were collected at baseline, four weeks, and 12 weeks. B and T cell subsets were quantified using a 25-parameter flow cytometry panel. Findings: The subjects' median age was 68 years; seven subjects were male and nine were Caucasian. Baseline organ involvement was diverse with a median of 5 organs affected at the time of enrollment. The median serum IgG4 concentration was 597 mg/dL (IQR 304-913 mg/dL). Three subjects received concomitant prednisone at baseline. Six subjects (60%) had a disease response by week 12, five of whom maintained this response at week 24. Abatacept was stopped in the remaining five subjects (50%) due to flare (N = 1) or lack of response by week 12 (N = 4). Three subjects (30%) achieved the primary endpoint.Baseline proportions of unswitched memory B cells predicted responsiveness to abatacept. Reductions in serum IgE, circulating plasmablasts, and activated type 2 T follicular helper (TFH2) cells correlated with response to treatment. One adverse event (grade two thrombocytopenia) was attributed to abatacept. Interpretation: Abatacept was associated with variable treatment responses in IgG4-RD. Half of the subjects achieved sustained treatment responses to abatacept alone, without glucocorticoids. Correlates of clinical response included reductions in serum IgE, circulating plasmablasts, and activated TFH2 cells. Response to abatacept was predicted by higher proportions of unswitched memory B cells at baseline.
Background: There is strong rationale for interference with T cell co-stimulation in IgG4-related disease (IgG4-RD), but the literature to evaluate this is limited to a single case report. Methods: We conducted a ten-subject proof-of-concept trial of abatacept in active IgG4-RD. All subjects met the ACR/EULAR Classification Criteria for IgG4-RD. Subjects received subcutaneous abatacept 125 mg weekly for 24 weeks. Concurrent glucocorticoid treatment was permitted but if used had to be discontinued by week four. The primary endpoint, complete remission at 24 weeks, was defined as an IgG4-RD Responder Index score of 0. Peripheral blood mononuclear cells were collected at baseline, four weeks, and 12 weeks. B and T cell subsets were quantified using a 25-parameter flow cytometry panel. Findings: The subjects' median age was 68 years; seven subjects were male and nine were Caucasian. Baseline organ involvement was diverse with a median of 5 organs affected at the time of enrollment. The median serum IgG4 concentration was 597 mg/dL (IQR 304-913 mg/dL). Three subjects received concomitant prednisone at baseline. Six subjects (60%) had a disease response by week 12, five of whom maintained this response at week 24. Abatacept was stopped in the remaining five subjects (50%) due to flare (N = 1) or lack of response by week 12 (N = 4). Three subjects (30%) achieved the primary endpoint.Baseline proportions of unswitched memory B cells predicted responsiveness to abatacept. Reductions in serum IgE, circulating plasmablasts, and activated type 2 T follicular helper (TFH2) cells correlated with response to treatment. One adverse event (grade two thrombocytopenia) was attributed to abatacept. Interpretation: Abatacept was associated with variable treatment responses in IgG4-RD. Half of the subjects achieved sustained treatment responses to abatacept alone, without glucocorticoids. Correlates of clinical response included reductions in serum IgE, circulating plasmablasts, and activated TFH2 cells. Response to abatacept was predicted by higher proportions of unswitched memory B cells at baseline.
Authors: Mollie N Carruthers; Mark D Topazian; Arezou Khosroshahi; Thomas E Witzig; Zachary S Wallace; Philip A Hart; Vikram Deshpande; Thomas C Smyrk; Suresh Chari; John H Stone Journal: Ann Rheum Dis Date: 2015-02-09 Impact factor: 19.103
Authors: A Khosroshahi; Z S Wallace; J L Crowe; T Akamizu; A Azumi; M N Carruthers; S T Chari; E Della-Torre; L Frulloni; H Goto; P A Hart; T Kamisawa; S Kawa; M Kawano; M H Kim; Y Kodama; K Kubota; M M Lerch; M Löhr; Y Masaki; S Matsui; T Mimori; S Nakamura; T Nakazawa; H Ohara; K Okazaki; J H Ryu; T Saeki; N Schleinitz; A Shimatsu; T Shimosegawa; H Takahashi; M Takahira; A Tanaka; M Topazian; H Umehara; G J Webster; T E Witzig; M Yamamoto; W Zhang; T Chiba; J H Stone Journal: Arthritis Rheumatol Date: 2015-07 Impact factor: 10.995
Authors: Jorn J Heeringa; A Faiz Karim; Jan A M van Laar; Robert M Verdijk; Dion Paridaens; P Martin van Hagen; Menno C van Zelm Journal: J Allergy Clin Immunol Date: 2017-08-19 Impact factor: 10.793
Authors: Hamid Mattoo; Vinay S Mahajan; Takashi Maehara; Vikram Deshpande; Emanuel Della-Torre; Zachary S Wallace; Maria Kulikova; Jefte M Drijvers; Joe Daccache; Mollie N Carruthers; Flavia V Castelino; James R Stone; John H Stone; Shiv Pillai Journal: J Allergy Clin Immunol Date: 2016-03-11 Impact factor: 10.793
Authors: Natalie M Edner; Frank Heuts; Niclas Thomas; Chun Jing Wang; Lina Petersone; Rupert Kenefeck; Alexandros Kogimtzis; Vitalijs Ovcinnikovs; Ellen M Ross; Elisavet Ntavli; Yassin Elfaki; Martin Eichmann; Roman Baptista; Philip Ambery; Lutz Jermutus; Mark Peakman; Miranda Rosenthal; Lucy S K Walker Journal: Nat Immunol Date: 2020-08-03 Impact factor: 25.606
Authors: Jeffrey A Sparks; Zachary S Wallace; Andrea M Seet; Milena A Gianfrancesco; Zara Izadi; Kimme L Hyrich; Anja Strangfeld; Laure Gossec; Loreto Carmona; Elsa F Mateus; Saskia Lawson-Tovey; Laura Trupin; Stephanie Rush; Patricia Katz; Gabriela Schmajuk; Lindsay Jacobsohn; Leanna Wise; Emily L Gilbert; Ali Duarte-García; Maria O Valenzuela-Almada; Guillermo J Pons-Estel; Carolina A Isnardi; Guillermo A Berbotto; Tiffany Y-T Hsu; Kristin M D'Silva; Naomi J Patel; Lianne Kearsley-Fleet; Martin Schäfer; Sandra Lúcia Euzébio Ribeiro; Samar Al Emadi; Liselotte Tidblad; Carlo Alberto Scirè; Bernd Raffeiner; Thierry Thomas; René-Marc Flipo; Jérôme Avouac; Raphaèle Seror; Miguel Bernardes; Maria Margarida Cunha; Rebecca Hasseli; Hendrik Schulze-Koops; Ulf Müller-Ladner; Christof Specker; Viviane Angelina de Souza; Licia Maria Henrique da Mota; Ana Paula Monteiro Gomides; Philippe Dieudé; Elena Nikiphorou; Vanessa L Kronzer; Namrata Singh; Manuel F Ugarte-Gil; Beth Wallace; Akpabio Akpabio; Ranjeny Thomas; Suleman Bhana; Wendy Costello; Rebecca Grainger; Jonathan S Hausmann; Jean W Liew; Emily Sirotich; Paul Sufka; Philip C Robinson; Pedro M Machado; Jinoos Yazdany Journal: Ann Rheum Dis Date: 2021-05-28 Impact factor: 19.103