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 baricitinib^{4 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.

References

1. 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.

2. 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.

3. 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.

4. 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

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

Learning Objectives

• 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