Dynamics of Serum Cytokines and Chemokines in Patients With Idiopathic Multicentric Castleman Disease: From a Phase Ib Investigator-Initiated Trial of Filgotinib

Overview

Journal Cureus

Specialty Biomedical Engineering

Date 2025 Feb 17

PMID 39958406

Authors

Shoichi Fukui

Remi Sumiyoshi

Tomohiro Koga

Naoki Hosogaya

Sawana Narita

Shimpei Morimoto

Hiroshi Yano

Atsushi Katsube

Shingo Yano

Yasufumi Masaki

Shinichiro Tsunoda

Shuzo Sato

Kiyoshi Migita

Atsushi Kawakami

Affiliations

Soon will be listed here.

Abstract

Background Idiopathic multicentric Castleman disease (iMCD) is a chronic inflammatory condition for which Janus kinase (JAK) inhibition has been hypothesized to be a potential treatment. However, filgotinib, a JAK1 preferential inhibitor, did not show apparent efficacy for iMCD in a clinical trial at eight weeks. This study aimed to compare the serum cytokine and chemokine profiles of patients treated with filgotinib with those of patients treated with tocilizumab to speculate why filgotinib was not effective at eight weeks. Methods This study included five patients treated with filgotinib who participated in a phase Ib single-arm clinical trial of filgotinib for iMCD and five tocilizumab-treated patients whose data were collected retrospectively. Serum levels of 41 cytokines/chemokines before and after treatment were measured. Results The tocilizumab group showed improvement in C-reactive protein, hemoglobin, and albumin levels after treatment while the filgotinib group showed no changes in these markers. The tocilizumab group showed significant changes in 12 cytokines/chemokines from baseline to after treatment, whereas the filgotinib group showed only a decrease in IL-18 and IL-27 levels. After treatment, significant differences were observed between the two groups for 10 cytokines/chemokines. Five cytokines (FGF-2, IL-4, IL-6, TNF-β, and VEGF-A) showed significant changes after tocilizumab treatment and differences between the tocilizumab and filgotinib groups after treatment. Conclusion This study identified FGF-2, IL-4, IL-6, TNF-β, and VEGF-A as potential factors that could explain the lack of apparent efficacy of filgotinib in iMCD treatment at eight weeks. These findings may contribute to future drug development for iMCD.

References

Gao Y, Duan M, Li J, Zhang L . Ruxolitinib for the Treatment of Refractory Idiopathic Multicentric Castleman Disease: A Case Report. Turk J Haematol. 2024; 41(1):61-63. PMC: 10918405. DOI: 10.4274/tjh.galenos.2024.2023.0477. View

Fukui S, Sumiyoshi R, Koga T, Hosogaya N, Narita S, Morimoto S . A Phase Ib Investigator-Initiated Trial of Filgotinib in Patients With Idiopathic Multicentric Castleman Disease. Cureus. 2025; 17(2):e78865. PMC: 11813720. DOI: 10.7759/cureus.78865. View

Nishimura Y, Fajgenbaum D, Pierson S, Iwaki N, Nishikori A, Kawano M . Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease. Am J Hematol. 2021; 96(10):1241-1252. PMC: 9642098. DOI: 10.1002/ajh.26292. View

Feagan B, Danese S, Loftus Jr E, Vermeire S, Schreiber S, Ritter T . Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet. 2021; 397(10292):2372-2384. DOI: 10.1016/S0140-6736(21)00666-8. View

Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S . Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005; 106(8):2627-32. DOI: 10.1182/blood-2004-12-4602. View

Nishi J, Maruyama I . Increased expression of vascular endothelial growth factor (VEGF) in Castleman's disease: proposed pathomechanism of vascular proliferation in the affected lymph node. Leuk Lymphoma. 2000; 38(3-4):387-94. DOI: 10.3109/10428190009087030. View

Mumau M, Gonzalez M, Ma C, Irvine A, Sarmiento Bustamante M, Shyamsundar S . Identifying and Targeting TNF Signaling in Idiopathic Multicentric Castleman's Disease. N Engl J Med. 2025; 392(6):616-618. PMC: 11801236. DOI: 10.1056/NEJMc2412494. View

van Rhee F, Fayad L, Voorhees P, Furman R, Lonial S, Borghaei H . Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease. J Clin Oncol. 2010; 28(23):3701-8. DOI: 10.1200/JCO.2009.27.2377. View

Genovese M, Kalunian K, Gottenberg J, Mozaffarian N, Bartok B, Matzkies F . Effect of Filgotinib vs Placebo on Clinical Response in Patients With Moderate to Severe Rheumatoid Arthritis Refractory to Disease-Modifying Antirheumatic Drug Therapy: The FINCH 2 Randomized Clinical Trial. JAMA. 2019; 322(4):315-325. PMC: 6652745. DOI: 10.1001/jama.2019.9055. View

10.

Kojima M, Nakamura N, Tsukamoto N, Otuski Y, Shimizu K, Itoh H . Clinical implications of idiopathic multicentric castleman disease among Japanese: a report of 28 cases. Int J Surg Pathol. 2008; 16(4):391-8. DOI: 10.1177/1066896908315812. View

11.

Nishikori A, Nishimura M, Tomida S, Chijimatsu R, Ueta H, Lai Y . Transcriptome analysis of the cytokine storm-related genes among the subtypes of idiopathic multicentric Castleman disease. J Clin Exp Hematop. 2024; 64(4):297-306. PMC: 11786152. DOI: 10.3960/jslrt.24061. View

12.

Winter S, Howard T, Ritchey A, Keller F, Ware R . Elevated levels of tumor necrosis factor-beta, gamma-interferon, and IL-6 mRNA in Castleman's disease. Med Pediatr Oncol. 1996; 26(1):48-53. DOI: 10.1002/(SICI)1096-911X(199601)26:1<48::AID-MPO6>3.0.CO;2-V. View

13.

Lang E, van Rhee F . Idiopathic multicentric Castleman disease: An update in diagnosis and treatment advances. Blood Rev. 2023; 64:101161. DOI: 10.1016/j.blre.2023.101161. View

14.

Nishi J, Arimura K, Utsunomiya A, Yonezawa S, Kawakami K, Maeno N . Expression of vascular endothelial growth factor in sera and lymph nodes of the plasma cell type of Castleman's disease. Br J Haematol. 1999; 104(3):482-5. DOI: 10.1046/j.1365-2141.1999.01208.x. View

15.

Foss H, Araujo I, Demel G, Klotzbach H, Hummel M, STEIN H . Expression of vascular endothelial growth factor in lymphomas and Castleman's disease. J Pathol. 1997; 183(1):44-50. DOI: 10.1002/(SICI)1096-9896(199709)183:1<44::AID-PATH1103>3.0.CO;2-I. View

16.

Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T . Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008; 112(10):3959-64. DOI: 10.1182/blood-2008-05-155846. View

17.

Pierson S, Shenoy S, Oromendia A, Gorzewski A, Langan Pai R, Nabel C . Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease. Blood Adv. 2021; 5(17):3445-3456. PMC: 8525223. DOI: 10.1182/bloodadvances.2020004016. View

18.

OShea J, Schwartz D, Villarino A, Gadina M, McInnes I, Laurence A . The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015; 66:311-28. PMC: 5634336. DOI: 10.1146/annurev-med-051113-024537. View

19.

van Rhee F, Voorhees P, Dispenzieri A, Fossa A, Srkalovic G, Ide M . International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 2018; 132(20):2115-2124. PMC: 6238190. DOI: 10.1182/blood-2018-07-862334. View

20.

Fujimoto S, Koga T, Kawakami A, Kawabata H, Okamoto S, Mizuki M . Tentative diagnostic criteria and disease severity classification for Castleman disease: A report of the research group on Castleman disease in Japan. Mod Rheumatol. 2017; 28(1):161-167. DOI: 10.1080/14397595.2017.1366093. View