The Evolving Landscape of Targeted Therapies in Systemic Lupus Erythematosus: A Review of Phase 3 Clinical Trials
Source abstract
Abstract
Systemic lupus erythematosus (SLE) is a chronic, heterogeneous autoimmune disease characterized by multisystem involvement and substantial morbidity. Although survival has improved over recent decades, disease burden remains considerable due to cumulative organ damage, comorbidities, and treatment-related toxicity, particularly from long-term glucocorticoid use. Advances in the understanding of SLE immunopathogenesis have led to the development of targeted therapies. Currently approved agents include belimumab and anifrolumab, while obinutuzumab has been approved for lupus nephritis and has also demonstrated significant efficacy in phase III trials in SLE. Several additional agents are in late-stage clinical development, including litifilimab (targeting plasmacytoid dendritic cells), telitacicept and ianalumab (BAFF/APRIL and B-cell modulation), dapirolizumab pegol (CD40L blockade), deucravacitinib and upadacitinib (TYK2/JAK inhibition), and cenerimod (S1P11 modulation). This narrative review summarizes current phase III evidence and emerging therapeutic strategies, highlighting the ongoing transition toward precision medicine and individualized treatment approaches in SLE.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Systemic Lupus Erythematosus Research · Multiple Sclerosis Research Studies · Rheumatoid Arthritis Research and Therapies
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Clinic of Rheumatology, University Hospital “St. Ivan Rilski”, 1612 Sofia, Bulgaria
Clinic of Rheumatology, University Hospital “St. Marina”, Medical University “Prof. Dr. Paraskev Stoyanov”-Varna, 9010 Varna, Bulgaria
Department of Internal Diseases, Medical Faculty, Medical University-Sofia, 1431 Sofia, Bulgaria
References (100+)
Show source-provided references
1. Systemic Lupus Erythematosus10.1038/nrdp.2016.39 ↗
2. New Biologics and Targeted Therapies in Systemic Lupus: From New Molecular Targets to New Indications. A Systematic Review10.1016/j.jbspin.2023.105523 ↗
3. EULAR Recommendations for the Management of Systemic Lupus Erythematosus: 2023 Update10.1136/ard-2023-224762 ↗
4. EULAR Recommendations for the Management of Systemic Lupus Erythematosus with Kidney Involvement: 2025 Update10.1016/j.ard.2025.09.007 ↗
5. Treat-to-Target in Systemic Lupus Erythematosus: Advancing towards Its Implementation10.1038/s41584-021-00739-3 ↗
6. Definition and Initial Validation of a Lupus Low Disease Activity State (LLDAS)10.1136/annrheumdis-2015-207726 ↗
7. 2021 DORIS Definition of Remission in SLE: Final Recommendations from an International Task Force10.1136/lupus-2021-000538 ↗
8. Advances in the Treatment of Systemic Lupus Erythematosus10.1038/s41573-025-01242-0 ↗
9. Drivers of the Immunopathogenesis in Systemic Lupus Erythematosus10.1016/j.berh.2017.09.007 ↗
10. Pathogenesis of Systemic Lupus Erythematosus: Risks, Mechanisms and Therapeutic Targets10.1136/ard-2022-223741 ↗
11. Shiozawa, S. (2025). Pathogenesis of Autoimmunity/Systemic Lupus Erythematosus (SLE). Cells, 14.10.3390/cells14141080 ↗
12. Recent Developments in Systemic Lupus Erythematosus Pathogenesis and Applications for Therapy10.1097/BOR.0000000000000474 ↗
13. Updates in Lupus Genetics10.1007/s11926-017-0695-z ↗
14. From Mechanism to Therapies in Systemic Lupus Erythematosus10.1097/BOR.0000000000000369 ↗
15. Accapezzato, D., Caccavale, R., Paroli, M.P., Gioia, C., Nguyen, B.L., Spadea, L., and Paroli, M. (2023). Advances in the Pathogenesis and Treatment of Systemic Lupus Erythematosus. Int. J. Mol. Sci., 24.10.3390/ijms24076578 ↗
16. The Innate Immune System in Human Systemic Lupus Erythematosus10.1042/CS20160415 ↗
17. The Contribution of Macrophages to Systemic Lupus Erythematosus10.1016/j.clim.2019.06.009 ↗
18. Mustelin, T., Lood, C., and Giltiay, N.V. (2019). Sources of Pathogenic Nucleic Acids in Systemic Lupus Erythematosus. Front. Immunol., 10.10.3389/fimmu.2019.01028 ↗
19. Self-dsDNA in the Pathogenesis of Systemic Lupus Erythematosus10.1111/cei.13041 ↗
20. At the Bedside: Neutrophil Extracellular Traps (NETs) as Targets for Biomarkers and Therapies in Autoimmune Diseases10.1189/jlb.5BT0615-234R ↗
21. Immunometabolic Regulation of Innate Immunity in Systemic Lupus Erythematosus
22. Coordination between Innate Immune Cells, Type I IFNs and IRF5 Drives SLE Pathogenesis10.1016/j.cyto.2019.05.018 ↗
23. Plasmacytoid Dendritic Cells in Autoimmunity10.1016/j.coi.2016.10.006 ↗
24. Emerging Concepts of Type I Interferons in SLE Pathogenesis and Therapy
25. Type I Interferon Pathway in Pediatric Systemic Lupus Erythematosus10.1007/s12519-024-00811-4 ↗
26. Abnormalities of the Type I Interferon Signaling Pathway in Lupus Autoimmunity10.1016/j.cyto.2021.155633 ↗
27. Ishihara, R., Watanabe, R., Shiomi, M., Fujita, Y., Katsushima, M., Fukumoto, K., Yamada, S., and Hashimoto, M. (2025). The Type I Interferon Axis in Systemic Autoimmune Diseases: From Molecular Pathways to Targeted Therapy. Biomolecules, 15.10.3390/biom15111586 ↗
28. Type I Interferon in the Pathogenesis of Systemic Lupus Erythematosus10.1016/j.coi.2020.10.014 ↗
29. Lai, B., Luo, S.-F., and Lai, J.-H. (2024). Therapeutically Targeting Proinflammatory Type I Interferons in Systemic Lupus Erythematosus: Efficacy and Insufficiency with a Specific Focus on Lupus Nephritis. Front. Immunol., 15.10.3389/fimmu.2024.1489205 ↗
30. Type I Interferon-Mediated Autoimmune Diseases: Pathogenesis, Diagnosis and Targeted Therapy
31. Importance of B Cells (Review)
32. Tariq, F., Charavanmuttu, Y., Labiba, K., and Wincup, C. (2025). Aberrant B Cell Responses as Drivers of Autoantibody Generation and Epitope Diversification in SLE Pathogenesis. Front. Immunol., 16.10.3389/fimmu.2025.1731285 ↗
33. Meant to B: B Cells as a Therapeutic Target in Systemic Lupus Erythematosus10.1172/JCI149095 ↗
34. Biological Targeted Therapy for Lupus Nephritis-the Role of BLYS and APRIL10.1080/0886022X.2025.2561791 ↗
35. BAFF in Autoimmune Kidney Diseases: Pathogenic Pathways, Biomarker Potential, and Therapeutic Horizons10.1080/0886022X.2025.2577164 ↗
36. The Pathological Role of B Cells in Systemic Lupus Erythematosus: From Basic Research to Clinical10.1080/08916934.2019.1700232 ↗
37. Poznyak, A.V., Gerasimova, E.V., Orekhov, N.A., Karimova, A.E., Vergun, M.A., Lapshina, K.O., Sukhorukov, V.N., and Orekhov, A.N. (2025). Exploring the Role of APRIL in Autoimmunity: Implications for Therapeutic Targeting in Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Sjögren’s Syndrome. Front. Immunol., 16.10.3389/fimmu.2025.1523392 ↗
38. The Role of Polyreactive Memory B Cells in Systemic Lupus Erythematosus10.1093/intimm/dxae058 ↗
39. Beyond Pan-B-Cell-Directed Therapy—New Avenues and Insights into the Pathogenesis of SLE10.1038/nrrheum.2016.158 ↗
40. Regulatory and Effector B Cells: Friends or Foes?10.1016/j.jdermsci.2018.11.008 ↗
41. B Cells and Atherosclerosis in Systemic Lupus Erythematosus10.1080/1744666X.2019.1571411 ↗
42. Fetter, T., Niebel, D., Braegelmann, C., and Wenzel, J. (2020). Skin-Associated B Cells in the Pathogenesis of Cutaneous Autoimmune Diseases-Implications for Therapeutic Approaches. Cells, 9.10.3390/cells9122627 ↗
43. The Mechanistic Impact of CD22 Engagement with Epratuzumab on B Cell Function: Implications for the Treatment of Systemic Lupus Erythematosus10.1016/j.autrev.2015.07.013 ↗
44. Vinuesa, C.G., Shrotri, M., and Rahman, A. (2026). TLR7 in Systemic Lupus Erythematosus: Genetics and Emerging Therapies. Nat. Rev. Rheumatol.10.1038/s41584-026-01388-0 ↗
45. Immune Cell Aberrations in Systemic Lupus Erythematosus: Navigating the Targeted Therapies toward Precision Management10.1186/s11658-025-00749-z ↗
46. Balogh, L., Kovács, V.G., Nagy, G., and Németh, T. (2025). Signaling Pathways in Systemic Lupus Erythematosus and Therapeutic Implications. Front. Immunol., 16.10.3389/fimmu.2025.1735301 ↗
47. Phoenix from the Flames: Rediscovering the Role of the CD40-CD40L Pathway in Systemic Lupus Erythematosus and Lupus Nephritis10.1016/j.autrev.2020.102668 ↗
48. Allard, C.C., Salti, S., Mourad, W., and Hassan, G.S. (2024). Implications of CD154 and Its Receptors in the Pathogenesis and Treatment of Systemic Lupus Erythematosus. Cells, 13.10.3390/cells13191621 ↗
49. Dapirolizumab Pegol Demonstrated Improvement in Quality of Life of Patients with Systemic Lupus Erythematosus: Lupusqol Results from a Phase 3 Trial10.3899/jrheum.2025-0390.O011 ↗
50. Efficacy, Pharmacokinetics and Safety of Iscalimab (CFZ533) in Patients with Proliferative Lupus Nephritis: A Randomised, Double-Blind, Placebo-Controlled, Phase II Study10.1136/rmdopen-2025-005557 ↗
51. The Role of STAT Signaling Pathways in the Pathogenesis of Systemic Lupus Erythematosus10.1007/s12016-016-8550-y ↗
52. STAT Signaling as a Marker of SLE Disease Severity and Implications for Clinical Therapy10.1016/j.autrev.2018.08.010 ↗
53. Fine-Tuning SLE Treatment: The Potential of Selective TYK2 Inhibition10.1136/rmdopen-2024-005072 ↗
54. Advances in Systemic Lupus Erythematosus Pathogenesis via mTOR Signaling Pathway10.1016/j.semarthrit.2019.09.022 ↗
55. Montano, H., Allen, I.C., and Reilly, C.M. (2025). The Path Less Traveled: The Non-Canonical NF-κB Pathway in Systemic Lupus Erythematosus. Front. Immunol., 16.10.3389/fimmu.2025.1588486 ↗
56. Brune, Z., Rice, M.R., and Barnes, B.J. (2020). Potential T Cell-Intrinsic Regulatory Roles for IRF5 via Cytokine Modulation in T Helper Subset Differentiation and Function. Front. Immunol., 11.10.3389/fimmu.2020.01143 ↗
57. Post-Translational Modifications in T Cells in Systemic Erythematosus Lupus10.1093/rheumatology/keab095 ↗
58. Tiny Warriors, Big Impact: Targeted Immunotherapy in Kidney Diseases10.1016/j.kint.2026.01.032 ↗
59. Type I Interferon Inhibitor Anifrolumab in Active Systemic Lupus Erythematosus (TULIP-1): A Randomised, Controlled, Phase 3 Trial10.1016/S2665-9913(19)30076-1 ↗
60. Trial of Anifrolumab in Active Systemic Lupus Erythematosus10.1056/NEJMoa1912196 ↗
61. Long-Term Effect of Anifrolumab on Patient-Reported Outcomes in Systemic Lupus Erythematosus (TULIP-LTE): A Randomised, Placebo-Controlled, Phase 3 Long-Term Extension Trial10.1016/S2665-9913(25)00022-0 ↗
62. (2026, May 06). SAPHNELO Approved in the US for Subcutaneous Self-Administration as a New Autoinjector for the Treatment of Systemic Lupus Erythematosus. Available online: https://www.astrazeneca-us.com/media/press-releases/2026/SAPHNELO-approved-in-the-US-for-subcutaneous-self-administration-as-a-new-autoinjector-for-the-treatment-of-systemic-lupus-erythematosus.html.
63. (2026, May 05). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT05138133.
64. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT05835310.
65. The Development of Litifilimab (BIIB 059) for Cutaneous and Systemic Lupus Erythematosus10.2217/imt-2023-0086 ↗
66. LP-184 Rationale and Design of Two Phase 3, Randomized, Double-Blind, Placebo-Controlled Studies of the Efficacy and Safety of Litifilimab in Adults with Active Systemic Lupus Erythematosus: TOPAZ-1 and TOPAZ-2
67. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT05531565.
68. Wu, C., Wang, Y., Chen, S., Lin, Y., Du, F., Wang, X., Chen, S., Lu, L., Ye, S., and Ding, H. (2025). Obinutuzumab in Systemic Lupus Erythematosus: A Real-World Experience. Front. Immunol., 16.10.3389/fimmu.2025.1764419 ↗
69. A Tale of Two Antibodies: Obinutuzumab versus Rituximab10.1111/bjh.15232 ↗
70. B-Cell Depletion with Obinutuzumab for the Treatment of Proliferative Lupus Nephritis: A Randomised, Double-Blind, Placebo-Controlled Trial10.1136/annrheumdis-2021-220920 ↗
71. Efficacy and Safety of Obinutuzumab in Active Lupus Nephritis10.1056/NEJMoa2410965 ↗
72. Furie, R.A., Dall’Era, M., Vital, E.M., Garg, J.P., Irazoque Palazuelos, F., Zuta Santillán, A.E., Ravelo-Hernández, J., Santiago, M.B., Zazueta Montiel, B., and Botha, S. (2026). Efficacy and Safety of Obinutuzumab in Active Systemic Lupus Erythematosus. N. Engl. J. Med.10.1056/NEJMoa2516150 ↗
73. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT04702256.
74. Telitacicept: A Novel Horizon in Targeting Autoimmunity and Rheumatic Diseases10.1016/j.jaut.2024.103291 ↗
75. Belimumab versus Telitacicept in Sequential Treatment after Rituximab for Refractory Lupus Nephritis: A Real-World Multicentre Study10.1136/lupus-2024-001296 ↗
76. A Phase 3 Trial of Telitacicept for Systemic Lupus Erythematosus10.1056/NEJMoa2414719 ↗
77. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT06456567.
78. Ianalumab’s Dual Mode of Action: Targeting b Cells through Enhanced b Cell Depletion and Blockade of b Cell-Activating Factor Receptor Signaling10.3899/jrheum.2025-0390.PV262 ↗
79. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT05639114.
80. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT05624749.
81. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT05126277.
82. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT06133972.
83. Population Pharmacokinetics and Exposure-Response for Dapirolizumab Pegol from a Phase 2b Trial in Patients with Systemic Lupus Erythematosus10.1002/jcph.2188 ↗
84. (2026, May 06). Achievement of Low Disease Activity and Remission in Patients with Systemic Lupus Erythematosus Treated with Dapirolizumab Pegol: 48-Week Results from a Phase 3 Trial. Available online: https://acrabstracts.org/abstract/achievement-of-low-disease-activity-and-remission-in-patients-with-systemic-lupus-erythematosus-treated-with-dapirolizumab-pegol-48-week-results-from-a-phase-3-trial/.
85. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT06617325.
86. Deucravacitinib Is an Allosteric TYK2 Protein Kinase Inhibitor FDA-Approved for the Treatment of Psoriasis10.1016/j.phrs.2022.106642 ↗
87. Deucravacitinib, a Tyrosine Kinase 2 Inhibitor, in Systemic Lupus Erythematosus: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial10.1002/art.42391 ↗
88. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT05617677.
89. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT05620407.
90. Upadacitinib: Mechanism of Action, Clinical, and Translational Science10.1111/cts.13688 ↗
91. Efficacy and Safety of Upadacitinib or Elsubrutinib Alone or in Combination for Patients with Systemic Lupus Erythematosus: A Phase 2 Randomized Controlled Trial10.1002/art.42926 ↗
92. Efficacy and Safety of Upadacitinib as Monotherapy or Combined with Elsubrutinib for the Treatment of Systemic Lupus Erythematosus: Results through 104 Weeks in a Long-Term Extension Study10.1136/rmdopen-2025-005742 ↗
93. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT05843643.
94. Role of Sphingosine-1-Phosphate Mediated Signalling in Systemic Lupus Erythematosus10.1016/j.prostaglandins.2021.106584 ↗
95. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis10.1056/NEJMoa0909494 ↗
96. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT05648500.
97. (2026, May 06). Clinicaltrials.gov, Available online: https://clinicaltrials.gov/study/NCT05672576.
98. Qualitative Validation of the FACIT-Fatigue Scale in Systemic Lupus Erythematosus10.1177/0961203313476360 ↗
99. The MOS 36-Item Short-Form Health Survey (SF-36). I. Conceptual Framework and Item Selection10.1097/00005650-199206000-00002 ↗
100. Measures of Health-Related Quality of Life in Pediatric Systemic Lupus Erythematosus: Childhood Health Assessment Questionnaire (C-HAQ), Child Health Questionnaire (CHQ), Pediatric Quality of Life Inventory Generic Core Module (PedsQL-GC), Pediatric Quality of Life Inventory Rheumatology Module (PedsQL-RM), and Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY)10.1002/acr.20559 ↗