Emerging treatments for systemic lupus erythematosus

Yurie Satoh-Kanda , Shingo Nakayamada , Yoshiya Tanaka

Rare Disease and Orphan Drugs Journal ›› 2026, Vol. 5 ›› Issue (1) -5.

PDF
Rare Disease and Orphan Drugs Journal ›› 2026, Vol. 5 ›› Issue (1) -5. DOI: 10.20517/rdodj.2025.45
Review
Emerging treatments for systemic lupus erythematosus
Author information +
History +
PDF

Abstract

It is well known that the failure of multiple past clinical trials in systemic lupus erythematosus (SLE) is partly due to the clinical and immunological heterogeneity of the disease. Appropriate trial designs, endpoints, and patient populations are required to assess the efficacy of SLE treatments. At the same time, interdisciplinary research is gradually revealing multiple targets that contribute to the pathophysiology of SLE. Currently, molecular-targeted therapies tailored to the disease are being developed as treatment strategies that do not rely on glucocorticoids. With the introduction of new treatments and technologies, clinical trials for SLE have significantly accelerated over the past decade. More than 300 interventional studies on SLE and lupus nephritis, both ongoing and planned, are underway. Various trials targeting different pathways are currently being conducted and SLE treatment strategies may be on the verge of a turning point in the near future. However, some challenges remain. In this review, we focus on promising agents in phase 2 clinical trials and beyond to highlight the latest perspectives and unresolved issues related to targeted therapies for SLE, as well as to explore future research directions and therapeutic strategies required for the implementation of personalized medicine for this rare disease.

Keywords

Systemic lupus erythematosus / Targeted therapy / clinical trials

Cite this article

Download citation ▾
Yurie Satoh-Kanda, Shingo Nakayamada, Yoshiya Tanaka. Emerging treatments for systemic lupus erythematosus. Rare Disease and Orphan Drugs Journal, 2026, 5(1): -5 DOI:10.20517/rdodj.2025.45

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Kaul A,Crow MK.Systemic lupus erythematosus.Nat Rev Dis Primers2016;2:16039

[2]

Tanaka Y.Systemic lupus erythematosus.Best Pract Res Clin Rheumatol2022;36:101814

[3]

Barber MRW,Falasinnu T.Global epidemiology of systemic lupus erythematosus.Nat Rev Rheumatol2021;17:515-32 PMCID:PMC8982275

[4]

Arnaud L,Devilliers H.Clinical trial outcomes for SLE: what we have and what we need.Lupus Sci Med2024;11:e001114 PMCID:PMC10875561

[5]

Franklyn K,Navarra SV.Definition and initial validation of a Lupus Low Disease Activity State (LLDAS).Ann Rheum Dis2016;75:1615-21

[6]

van Vollenhoven RF,Doria A.2021 DORIS definition of remission in SLE: final recommendations from an international task force.Lupus Sci Med2021;8:e000538

[7]

Fanouriakis A,Andersen J.EULAR recommendations for the management of systemic lupus erythematosus: 2023 update.Ann Rheum Dis2024;83:15-29

[8]

Nakayamada S,Tanaka Y.Relevance of lymphocyte subsets to B cell-targeted therapy in systemic lupus erythematosus.Int J Rheum Dis2015;18:208-18

[9]

Dörner T.The essential roles of memory B cells in the pathogenesis of systemic lupus erythematosus.Nat Rev Rheumatol2024;20:770-82

[10]

Fra GP,Bartoli E.Remission of refractory lupus nephritis with a protocol including rituximab.Lupus2003;12:783-7

[11]

Leandro MJ,Cambridge G,Isenberg DA.An open study of B lymphocyte depletion in systemic lupus erythematosus.Arthritis Rheum2002;46:2673-7

[12]

Tokunaga M,Kawabata D.Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system.Ann Rheum Dis2007;66:470-5 PMCID:PMC1856059

[13]

Merrill JT,Wallace DJ.Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial.Arthritis Rheum2010;62:222-33 PMCID:PMC4548300

[14]

Rovin BH,Latinis K.Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study.Arthritis Rheum2012;64:1215-26

[15]

Fanouriakis A,Boumpas DT.2019 update of the joint european league against rheumatism and european renal association-european dialysis and transplant association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis.Ann Rheum Dis2020;79:713-23

[16]

Sammaritano LR,Mustafa RA.2024 American College of Rheumatology (ACR) guideline for the screening, treatment, and management of Lupus Nephritis.Arthritis Rheumatol2025;77:1115-35

[17]

Iwata S,Tokunaga M.B cell or T cell-dominant recurrence after rituximab therapy in patients with SLE.Ann Rheum Dis2012;71:1749-50

[18]

Furie RA,Cascino MD.B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial.Ann Rheum Dis2022;81:100-7 PMCID:PMC8762029

[19]

Chu SY,Karki S.Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcgammaRIIb with Fc-engineered antibodies.Mol Immunol2008;45:3926-33

[20]

Singh JA,Mudano AS.Belimumab for systemic lupus erythematosus.Cochrane Database Syst Rev2021;2:CD010668 PMCID:PMC8095005

[21]

Furie R,Houssiau F.Two-year, randomized, controlled trial of belimumab in lupus nephritis.N Engl J Med2020;383:1117-28

[22]

Furie R,Houssiau F.Safety and efficacy of belimumab in patients with lupus nephritis: open-label extension of BLISS-LN study.Clin J Am Soc Nephrol2022;17:1620-30

[23]

Rovin BH,Teng YKO.A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis.Kidney Int2022;101:403-13

[24]

Carter LM,Ehrenstein MR.Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus.Arthritis Rheum2013;65:2672-9

[25]

Shipa M,Nguyen DX.Identification of biomarkers to stratify response to B-cell-targeted therapies in systemic lupus erythematosus: an exploratory analysis of a randomised controlled trial.Lancet Rheumatol2023;5:e24-35

[26]

Atisha-Fregoso Y,Harris KM.Phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis.Arthritis Rheumatol2021;73:121-31 PMCID:PMC7839443

[27]

Agmon-Levin N,Gordienko A.OP0089|phase 2 safety and efficacy of subcutaneous (S.C.) dose ianalumab (VAY736; anti-BAFFR mAb) administered every 4 weeks up to 48 weeks in patients with systemic lupus erythematosus (SLE).Ann Rheum Dis2024;83:140-2

[28]

Dörner T,Oliver S.POS0540 reduction of B cell subsets, autoantibodies and disease-relevant pathways in ianalumab treated patients with systemic lupus erythematosus: findings from a phase 2 clinical trial.Ann Rheum Dis2024;83:956-7

[29]

Isenberg D,Licu D,Rossi CP.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 Dis2015;74:2006-15 PMCID:PMC4680140

[30]

Wu D,Xu D.Telitacicept in patients with active systemic lupus erythematosus: results of a phase 2b, randomised, double-blind, placebo-controlled trial.Ann Rheum Dis2024;83:475-87 PMCID:PMC10958275

[31]

Evans LS,DeMonte D.Povetacicept, an enhanced dual APRIL/BAFF antagonist that modulates B lymphocytes and pathogenic autoantibodies for the treatment of lupus and other B cell-related autoimmune diseases.Arthritis Rheumatol2023;75:1187-202

[32]

Nakayamada S,Kanno Y.Helper T cell diversity and plasticity.Curr Opin Immunol2012;24:297-302 PMCID:PMC3383341

[33]

Ramanujam M,Visvanathan S,Fine JS.Phoenix from the flames: rediscovering the role of the CD40-CD40L pathway in systemic lupus erythematosus and lupus nephritis.Autoimmun Rev2020;19:102668

[34]

Furie RA,Dörner T.Phase 2, randomized, placebo-controlled trial of dapirolizumab pegol in patients with moderate-to-severe active systemic lupus erythematosus.Rheumatology2021;60:5397-407 PMCID:PMC9194804

[35]

Cutcutache I,Skelton A.POS0334 dapirolizumab pegol impacts important immunologic pathways in systemic lupus erythematosus: pharmacodynamic analysis of B cell and type I interferon pathways from a phase 2B trial.Ann Rheum Dis2024;83:265

[36]

Clowse M,Merrill J. Dapirolizumab pegol demonstrated significant improvement in systemic lupus erythematosus disease activity: efficacy and safety results of a phase 3 trial [abstract]; 2024. Available from: https://acrabstracts.org/abstract/dapirolizumab-pegol-demonstrated-significant-improvement-in-systemic-lupus-erythematosus-disease-activity-efficacy-and-safety-results-of-a-phase-3-trial/ [Last accessed on 26 Feb 2026].

[37]

Karnell JL,Drabic S.A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity.Sci Transl Med2019;11:eaar6584

[38]

Furie R,Merola JF.Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus.J Clin Invest2019;129:1359-71

[39]

Furie RA,Kalunian K.Trial of anti-BDCA2 antibody litifilimab for systemic lupus erythematosus.N Engl J Med2022;387:894-904

[40]

Werth VP,Romero-Diaz J.Trial of anti-BDCA2 antibody litifilimab for cutaneous lupus erythematosus.N Engl J Med2022;387:321-31

[41]

Ostendorf L,Durek P.Targeting CD38 with daratumumab in refractory systemic lupus erythematosus.N Engl J Med2020;383:1149-55

[42]

Roccatello D,Caniggia I.Daratumumab monotherapy for refractory lupus nephritis.Nat Med2023;29:2041-7 PMCID:PMC10427415

[43]

Manzi S,Morand EF.Efficacy and safety of subcutaneous anifrolumab in systemic lupus erythematosus: a randomized, phase 3 study.Arthritis Rheumatol2025;

[44]

Alduraibi F,Hamilton JA,Hsu HC.Lupus nephritis correlates with B cell interferon-β, anti-Smith, and anti-DNA: a retrospective study.Arthritis Res Ther2022;24:87 PMCID:PMC9014622

[45]

Tanaka Y,O'Shea JJ.Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach.Nat Rev Rheumatol2022;18:133-45 PMCID:PMC8730299

[46]

Kubo S,Kondo M.The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells.Ann Rheum Dis2014;73:2192-8

[47]

Merrill JT,D'Cruz D.Efficacy and safety of upadacitinib or elsubrutinib alone or in combination for patients with systemic lupus erythematosus: a phase 2 randomized controlled trial.Arthritis Rheumatol2024;76:1518-29

[48]

Merrill J,Aringer M. Efficacy and safety of ABBV-599 (elsubrutinib and upadacitinib combination) and upadacitinib monotherapy for the treatment of systemic lupus erythematosus: results through 104 weeks in a long-term extension study; 2024. Available from: https://acrabstracts.org/abstract/efficacy-and-safety-of-abbv-599-elsubrutinib-and-upadacitinib-combination-and-upadacitinib-monotherapy-for-the-treatment-of-systemic-lupus-erythematosus-results-through-104-weeks-in-a-long-term-ext/ [Last accessed on 26 Feb 2026]

[49]

Hasni SA,Davis M.Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus.Nat Commun2021;12:3391 PMCID:PMC8185103

[50]

Dörner T,Dow ER.Mechanism of action of baricitinib and identification of biomarkers and key immune pathways in patients with active systemic lupus erythematosus.Ann Rheum Dis2022;81:1267-72 PMCID:PMC9380497

[51]

Werth VP,Robern M.Filgotinib or lanraplenib in moderate to severe cutaneous lupus erythematosus: a phase 2, randomized, double-blind, placebo-controlled study.Rheumatology2022;61:2413-23 PMCID:PMC9157055

[52]

Morand E,Tanaka Y,Fleischmann R.TYK2: an emerging therapeutic target in rheumatic disease.Nat Rev Rheumatol2024;20:232-40

[53]

Satoh-Kanda Y,Kubo S.Modifying T cell phenotypes using TYK2 inhibitor and its implications for the treatment of systemic lupus erythematosus.RMD Open2024;10:e003991 PMCID:PMC11177773

[54]

Morand E,Merrill JT.Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: a phase II, randomized, double-blind, placebo-controlled trial.Arthritis Rheumatol2023;75:242-52 PMCID:PMC10100399

[55]

Su LC,Huang AF.IRAK family in inflammatory autoimmune diseases.Autoimmun Rev2020;19:102461

[56]

Isenberg D,Jones NS.Efficacy, safety, and pharmacodynamic effects of the bruton's tyrosine kinase inhibitor fenebrutinib (GDC-0853) in systemic lupus erythematosus: results of a phase II, randomized, double-blind, placebo-controlled trial.Arthritis Rheumatol2021;73:1835-46

[57]

Li R,Liu S.LB0005 orelabrutinib, an irreversible inhibitor of bruton's tyrosine kinase (BTK), for the treatment of systemic lupus erythematosus (SLE): RESULTS of a randomized, double-blind, placebo-controlled, phase IB/IIA dose-finding study.Ann Rheum Dis2022;81:210

[58]

Fillatreau S,Dörner T.Toll-like receptor signalling in B cells during systemic lupus erythematosus.Nat Rev Rheumatol2021;17:98-108 PMCID:PMC7747191

[59]

Morand EF,Deshpande A.AB0444 enpatoran: preclinical evidence supporting glucocorticoid dose reduction and phase II study design in patients with SLE and/or CLE (willow).Ann Rheum Dis2022;81:1350-1

[60]

Pearson D,Wenzel J.Randomized, placebo-controlled phase II study of enpatoran, a small molecule toll-like receptor 7/8 inhibitor, in cutaneous lupus erythematosus: results from cohort A.J Rheumatol2025;52 Suppl 1:1-269

[61]

Morand E,Furie RA.LB0004 randomised, placebo-controlled phase II study of oral enpatoran, a first-in-class toll-like receptor 7/8 inhibitor, in systemic lupus erythematosus.Ann Rheum Dis2025;84:316-7

[62]

Tanaka Y,Atsumi T.Safety, pharmacokinetics, biomarker response and efficacy of E6742: a dual antagonist of Toll-like receptors 7 and 8, in a first in patient, randomised, double-blind, phase I/II study in systemic lupus erythematosus.RMD Open2024;10:e004701 PMCID:PMC11409405

[63]

Rovin BH,Ginzler EM.Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.Lancet2021;397:2070-80

[64]

Abdalhadi HM,Alduraibi FK.CAR-T-cell therapy for systemic lupus erythematosus: a comprehensive overview.Int J Mol Sci2024;25:10511 PMCID:PMC11476835

[65]

Mougiakakos D,Völkl S.CD19-targeted CAR T cells in refractory systemic lupus erythematosus.N Engl J Med2021;385:567-9

[66]

Müller F,Bucci L.CD19 CAR T-cell therapy in autoimmune disease - a case series with follow-up.N Engl J Med2024;390:687-700

[67]

Kollert F,Schuler F. Characterization of RO7507062, a CD19-targeting T-cell bispecific antibody (CD19TCB), and design of its ongoing phase 1 trial in systemic lupus erythematosus; 2024. Available from: https://acrabstracts.org/abstract/characterization-of-ro7507062-a-cd19-targeting-t-cell-bispecific-antibody-cd19tcb-and-design-of-its-ongoing-phase-1-trial-in-systemic-lupus-erythematosus/ [Last accessed on 26 Feb 2026]

[68]

Domingo-Gonzalez R,Oyasu M.POS1062 therapeutic potential of imvotamab, a CD20-targeted bispecific IGM T cell engager, for the treatment of refractory autoimmune disease patients.Ann Rheum Dis2024;83:935

[69]

Quigley M,Jones J. CLN-978, a CD19-directed T cell engager (TCE), leads to rapid and deep B cell depletion and has broad potential for development in autoimmune diseases; 2024. Available from: https://acrabstracts.org/abstract/cln-978-a-cd19-directed-t-cell-engager-tce-leads-to-rapid-and-deep-b-cell-depletion-and-has-broad-potential-for-development-in-autoimmune-diseases/ [Last accessed on 26 Feb 2026]

[70]

Alexander T,Cheng Q,Krönke G.Teclistamab-induced remission in refractory systemic lupus erythematosus.N Engl J Med2024;391:864-6

[71]

Askanase A,Navarra S. Efficacy and safety of cenerimod in patients with moderate to severe systemic lupus erythematosus (SLE): a multicenter, randomized, parallel-group, double-blind, placebo-controlled, dose-finding phase 2b trial; 2022. Available from: https://acrabstracts.org/abstract/efficacy-and-safety-of-cenerimod-in-patients-with-moderate-to-severe-systemic-lupus-erythematosus-sle-a-multicenter-randomized-parallel-group-double-blind-placebo-controlled-dose-finding-phase/ [Last accessed on 26 Feb 2026]

[72]

Zhang SJ,Kang LL.Biomarkers for systemic lupus erythematosus: a scoping review.Immun Inflamm Dis2024;12:e70022 PMCID:PMC11450456

[73]

Connelly K,Koelmeyer R.Towards a novel clinical outcome assessment for systemic lupus erythematosus: first outcomes of an international taskforce.Nat Rev Rheumatol2023;19:592-602

[74]

Garces S,Merrill JT.Improving resource utilisation in SLE drug development through innovative trial design.Lupus Sci Med2023;10:e000890 PMCID:PMC10373732

PDF

0

Accesses

0

Citation

Detail

Sections
Recommended

/