Systemic lupus erythematosus (SLE) is a heterogeneous disease characterised by abnormalities in cellular and humoral immunity. There is evidence that abnormalities of B lineage cells (B and plasma cells) and imprints of type I interferon are key drivers in this disease. However, these findings are not found uniquely in each SLE patient which has implications for translational research: Delineation of molecular SLE endotypes have been identified that may allow better prediction of treatment response. Recent discoveries of gain-of-function mutations in toll-like TLR7 signalling in certain patients suffering from monogenetic SLE indicate the role of this pathway as potential treatment target.1 Targeting enhanced cytokine signalling, in particular Jak/STAT continuous to be of interest as recent data of upadacitinib2 and deucravacitinib.3 were promising, although development of baricitinib4 5 has not been continued.
Clinical experiences with belimumab provide evidence that indirectly blocking B cell survival can change the clinical course of the disease, including prevention of damage accrual. Advanced B cell targeting following the concepts of deeper tissue depletion overcoming the status of anergic B cells6 and co-targeting plasma cells has been studied recently. These include more profound targeting by second generation anti-CD20 modalities (obinutuzumab),7 CD19-CART8 or employing other immune targets, such as CD38 (daratumumab),9 BAFFR (ianalumab)10 or the use of immune proteasome inhibition (zetomipzomib).11 As more defined immune abnormalities in SLE may be identified as targets for treatment, use of bispecific antibodies12 may hold promise to improve selective immune therapy with at least similar or even better efficacy/safety compared to current strategies.
Brown GJ, et al. TLR7 gain-of-function genetic variation causes human lupus. Nature. 2022 May;605(7909):349–356. doi: 10.1038/s41586-022-04642-z. Epub 2022 Apr 27.
Merrill JT, et al. Efficacy and safety of ABBV-599 high dose (elsubrutinib 60 mg and upadacitinib 30 mg) and upadacitinib monotherapy for the treatment of systemic lupus erythematosus: a phase 2, double-blind, placebo-controlled trial. Ann Rheum Dis. 2023;82:91–92. OP0139.
Morand E, et al. Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: a phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2023 Feb;75(2):242–252. doi: 10.1002/art.42391. Epub 2022 Nov 11.
Petri M, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II). Lancet. 2023 Mar 25;401(10381):1011–1019. doi: 10.1016/S0140-6736(22)02546-6. Epub 2023 Feb 24
Morand EF, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-I). Lancet. 2023 Mar 25;401(10381):1001–1010. doi: 10.1016/S0140-6736(22)02607-1. Epub 2023 Feb 24.
Weißenberg SY, et al. Identification and characterization of post-activated B cells in systemic autoimmune diseases. Front Immunol. 2019 Sep 24;10:2136. doi: 10.3389/fimmu.2019.02136.
Furie RA, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022 Jan;81(1):100–107. doi: 10.1136/annrheumdis-2021-220920. Epub 2021 Oct 6.
Mackensen A, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022 Oct;28(10):2124–2132. doi: 10.1038/s41591-022-02017-5. Epub 2022 Sep 15. Erratum in: Nat Med. 2022 Nov 3.
Ostendorf L, et al. Targeting CD38 with daratumumab in refractory systemic lupus erythematosus. N Engl J Med. 2020 Sep 17;383(12):1149–1155. doi: 10.1056/NEJMoa2023325.
Cortés-Hernández J, et al. Safety and efficacy of subcutaneous (S.C.) dose ianalumab (VAY736; anti-BAFFR mAb) administered monthly over 28 weeks in patients with systemic lupus erythematosus (SLE). Ann Rheum Dis. 2023;82:275–276. POS0120.
Saxena A, et al. Zetomipzomib (KZR-616) treatment results in clinically meaningful renal responses in patients with lupus nephritis. Ann Rheum Dis; 2023;82:891–892. POS1128.
Dang VD, et al. B- and plasma cell subsets in autoimmune diseases: translational perspectives. J Invest Dermatol. 2022 Mar;142(3 Pt B):811–822. doi: 10.1016/j.jid.2021.05.038. Epub 2021 Dec 24.
Discuss the translational concepts of the SLE key signatures: type I IFN (convergence of various activated pathways) and B lineage abnormalities (plasmablasts including CD19-CXCR5- pre-plasmablasts, anergic B cells)
Explain the impact of targeting type IFN abnormalities by blocking Jak/STAT and TL/signaling
Discuss new concepts with deeper depletion of tissue-resident B cells and partial targeting of bone marrow plasma cells
Develop the concept that bispecific antibodies may have value in treating SLE
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