B cell pathway dual inhibition for systemic lupus erythematosus: a prospective single-arm cohort study of telitacicept

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with B-cell hyperactivity. Telitacicept is a transmembrane activator, calcium modulator, and cyclophilin ligand interactor-Fc fusion protein, which can neutralize both B-cell lymphocyte stimulator and a proliferation-inducing ligand. Patients with active SLE who received telitacicept were prospectively followed at month 1, 3, 6, 9, and 12 after telitacicept initiation. Thirty-seven participants were involved and followed for 6.00 [3.00, 6.00] months. SRI-4 rate at month 6 was 44.7%. The median dosage of prednisone was decreased by 43.8% (from 10 to 5.62 mg/d) at month 6. The anti-dsDNA level was significantly decreased, while complement levels were significantly increased at month 6 from baseline. Continuously significant reductions in serum immunoglobin (Ig)G IgA, and IgM levels were also observed. Patients experienced significant decreases in the numbers of total and naive B cells, whereas memory B cells and T cell populations did not change. The number of NK cells was significantly increased during the follow-up. At month 6, 58.3% (14 out of 24) patients experienced improved fatigue accessed by FACIT–Fatigue score exceeding the minimum clinically important difference of 4. Most adverse events were mild, but one each case of severe hypogammaglobulinemia, psychosis with suicidal behavior, and B-cell lymphoma were occurred. In our first prospective real-world study, telitacicept treatment led to a significant clinical and laboratory improvement of disease activity, as well as fatigue amelioration in patients with SLE. Safety profile was favorable overall, but more studies are greatly needed.

Keywords

B cell inhibitor / transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) / lupus / telitacicept / B lymphocyte stimulator (BLyS) / a proliferation-inducing ligand (APRIL)

References

1	L Mu, Y Hao, Y Fan, et al. Mortality and prognostic factors in Chinese patients with systemic lupus erythematosus. Lupus. 2018;27(10):1742-1752. doi:
2	M Kiriakidou, CL Ching. Systemic lupus erythematosus. Ann Intern Med. 2020;172(11):ITC81-ITC96. doi:
3	GC Tsokos. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110-2121. doi:
4	GS Cooper, MA Dooley, EL Treadwell, EW St Clair, CG Parks, GS Gilkeson. Hormonal, environmental, and infectious risk factors for developing systemic lupus erythematosus. Arthritis Rheum. 1998;41(10):1714-1724. doi:
5	RG Lahita. The role of sex hormones in systemic lupus erythematosus. Curr Opin Rheumatol. 1999;11(5):352-356. doi:
6	F Shi, R Xue, X Zhou, P Shen, S Wang, Y Yang. Telitacicept as a BLyS/APRIL dual inhibitor for autoimmune disease. Immunopharmacol Immunotoxicol. 2021;43(6):666-673. doi:
7	FB Vincent, EF Morand, P Schneider, F Mackay. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol. 2014;10(6):365-373. doi:
8	S Nakayamada, Y Tanaka. BAFF- and APRIL-targeted therapy in systemic autoimmune diseases. Inflamm Regen. 2016;36:6. doi:
9	C Bossen, P Schneider. BAFF, APRIL and their receptors: structure, function and signaling. Semin Immunol. 2006;18(5):263-275. doi:
10	Y Fan, D Gao, Z Zhang. Telitacicept, a novel humanized, recombinant TACI-Fc fusion protein, for the treatment of systemic lupus erythematosus. Drugs Today Barc Spain 1998. 2022;58(1):23-32. doi:
11	Y Liu, L Zhang, Y Wu, et al. Therapeutic effects of TACI-Ig on collagen-induced arthritis by regulating T and B lymphocytes function in DBA/1 mice. Eur J Pharmacol. 2011;654(3):304-314. doi:
12	S Dhillon. Telitacicept: first approval. Drugs. 2021;81(14):1671-1675. doi:
13	D Wu, J Li, D Xu, et al. Telitacicept in patients with active systemic lupus erythematosus: results of a phase 2b, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. Published online December 21, 2023. doi:
14	SV Navarra, RM Guzmán, AE Gallacher, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet Lond Engl. 2011;377(9767):721-731. doi:
15	R Furie, M Petri, O Zamani, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918-3930. doi:
16	Telitacicept, a Human Recombinant Fusion Protein Targeting B Lymphocyte Stimulator (BlyS) and a Proliferation-Inducing Ligand (APRIL), in Systemic Lupus Erythematosus (SLE): Results of a Phase 3 Study. ACR Meeting Abstracts. Accessed May 29, 2023.
17	L Sun, Q Shen, Y Gong, et al. Safety and efficacy of telitacicept in refractory childhood-onset systemic lupus erythematosus: a self-controlled before-after trial. Lupus. 2022;31(8):998-1006. doi:
18	R Chen, R Fu, Z Lin, C Huang, W Huang. The efficacy and safety of telitacicept for the treatment of systemic lupus erythematosus: a real life observational study. Lupus. 2023;32(1):94-100. doi:
19	HZ Jin, Y-J Li, X Wang, et al. Efficacy and safety of telitacicept in patients with systemic lupus erythematosus: a multicentre, retrospective, real-world study. Lupus Sci Med. 2023;10(2):e001074. doi:
20	RF van Vollenhoven, MA Petri, R Cervera, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012;71(8):1343-1349. doi:
21	M Gatto, F Saccon, M Zen, et al. Early disease and low baseline damage as predictors of response to belimumab in patients with systemic lupus erythematosus in a real-life setting. Arthritis Rheumatol. 2020;72(8):1314-1324. doi:
22	I Parodis, A Gomez, J Lindblom, JW Chow, A Doria, M Gatto. Early changes in B and plasma cell subsets and traditional serological markers as predictors of sri-4 response to therapy in systemic lupus erythematosus. Front Med. 2022;9:852162. doi:
23	W Stohl, F Hiepe, KM Latinis, et al. Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus. Arthritis Rheum. 2012;64(7):2328-2337. doi:
24	A Henriques, L Teixeira, L Inês, et al. NK cells dysfunction in systemic lupus erythematosus: relation to disease activity. Clin Rheumatol. 2013;32(6):805-813. doi:
25	R Spada, JM Rojas, DF Barber. Recent findings on the role of natural killer cells in the pathogenesis of systemic lupus erythematosus. J Leukoc Biol. 2015;98(4):479-487. doi:
26	J Lv, L Liu, C Hao, et al. Randomized phase 2 trial of telitacicept in patients with IgA nephropathy with persistent proteinuria. Kidney Int Rep. 2023;8(3):499-506. doi:
27	D Isenberg, C Gordon, D Licu, S Copt, CP Rossi, D Wofsy. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). Ann Rheum Dis. 2015;74(11):2006-2015. doi:
28	Belimumab (Benlysta▼): increased risk of serious psychiatric events seen in clinical trials. GOV.UK. Accessed July 8, 2023.
29	W Xie, H Huang, S Zhan, Z Zhang. Risk of psychiatric disorders and all-cause mortality with belimumab therapy in patients with systemic lupus erythematosus: a meta-analysis of randomised controlled trials. Lupus Sci Med. 2021;8(1):e000534. doi:
30	C M?rth, A Valachis, A Abu Sabaa, et al. Autoimmune disease in patients with diffuse large B-cell lymphoma: occurrence and impact on outcome. Acta Oncol Stockh Swed. 2019;58(8):1170-1177. doi:
31	D Gao, Y Hao, L Mu, et al. Frequencies and predictors of the lupus low disease activity state and remission in treatment-na?ve patients with systemic lupus erythematosus. Rheumatol Oxf Engl. 2020;59(11):3400-3407. doi:
32	Y Hao, S Oon, L Ji, et al. Determinants and protective associations of the lupus low disease activity state in a prospective Chinese cohort. Clin Rheumatol. 2022;41(2):357-366. doi:
33	L Ji, D Gao, Y Hao, et al. Low-dose glucocorticoids withdrawn in systemic lupus erythematosus: a desirable and attainable goal. Rheumatol Oxf Engl. 2022;62(1):181-189. doi:
34	DD Gladman, D Iba?ez, MB Urowitz. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29(2):288-291.
35	EM Hay, PA Bacon, C Gordon, et al. The BILAG index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus. Q J Med. 1993;86(7):447-458.
36	C Aranow, A Askanase, S Oon, et al. Laboratory investigation results influence Physician's Global Assessment (PGA) of disease activity in SLE. Ann Rheum Dis. 2020;79(6):787-792. doi:
37	SB Yellen, DF Cella, K Webster, C Blendowski, E Kaplan. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage. 1997;13(2):63-74. doi:
38	K Webster, D Cella, K Yost. The Functional Assessment of Chronic Illness Therapy (FACIT) measurement system: properties, applications, and interpretation. Health Qual Life Outcomes. 2003;1:79. doi:
39	M Kosinski, K Gajria, AW Fernandes, D Cella. Qualitative validation of the FACIT-fatigue scale in systemic lupus erythematosus. Lupus. 2013;22(5):422-430. doi:
40	V Strand, P Berry, X Lin, Y Asukai, R Punwaney, S Ramachandran. Long-Term impact of belimumab on health-related quality of life and fatigue in patients with systemic lupus erythematosus: six years of treatment. Arthritis Care Res. 2019;71(6):829-838. doi:
41	RA Furie, MA Petri, DJ Wallace, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009;61(9):1143-1151. doi:
42	M Petri, J Buyon, M Kim. Classification and definition of major flares in SLE clinical trials. Lupus. 1999;8(8):685-691. doi: