IgA2+ B cells and IgA2 anti-dsDNA antibodies are selectively targeted by belimumab after rituximab therapy in systemic lupus erythematosus

Daniel McCluskey; Muhammad R A Shipa; Kashfia Chowdhury; Judith A James; Laura A Cooney; Michael R Ehrenstein

doi:10.1016/j.xcrm.2025.102247

IgA2⁺ B cells and IgA2 anti-dsDNA antibodies are selectively targeted by belimumab after rituximab therapy in systemic lupus erythematosus

Cell Rep Med. 2025 Aug 19;6(8):102247. doi: 10.1016/j.xcrm.2025.102247. Epub 2025 Jul 23.

Authors

Daniel McCluskey¹, Muhammad R A Shipa¹, Kashfia Chowdhury², Judith A James³, Laura A Cooney⁴, Michael R Ehrenstein⁵

Affiliations

¹ Department of Ageing, Rheumatology and Regenerative Medicine, University College London, London, UK.
² Comprehensive Clinical Trials Unit, University College London, London, UK.
³ Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
⁴ Immune Tolerance Network, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Ageing, Rheumatology and Regenerative Medicine, University College London, London, UK. Electronic address: m.ehrenstein@ucl.ac.uk.

Abstract

No theragnostic biomarkers exist for systemic lupus erythematosus (SLE) to enable a precision medicine approach. Baseline serum IgA2 anti-double-stranded DNA (dsDNA) antibody levels are associated with response to combination belimumab after rituximab therapy in SLE (BEAT-lupus trial, ISRCTN 47873003). Analysis of the CALIBRATE trial (NCT02260934) confirms that baseline IgA2 anti-dsDNA antibody levels are specifically associated with response to belimumab after rituximab (odds ratio [OR] = 16.9, confidence interval [CI]: 2.8-101, compared to rituximab alone-CALIBRATE and BEAT-lupus combined data). IgA2 anti-dsDNA antibody levels decrease alongside IgA2 expression in plasmablasts only after this combination treatment. Increased serum B cell-activating factor (BAFF) levels are associated with rising IgA2 anti-dsDNA antibody levels after rituximab. IgA2 plasmablasts have increased BAFF receptor and interleukin (IL)-10 expression compared to IgA1 plasmablasts and have a distinct integrin profile implicating a gut mucosal origin. These findings validate IgA2 anti-dsDNA antibodies as a theragnostic biomarker of response and provide mechanistic insight into the selective targeting of IgA2⁺ B cells by combination belimumab after rituximab in SLE.

Keywords: BAFF; CD11c(+)Tbet(+) age-related B cells; IgA2 anti-dsDNA antibodies; SLE; belimumab; rituximab; theragnostic biomarker.

Publication types

Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial

MeSH terms

Adult
Antibodies, Antinuclear* / blood
Antibodies, Antinuclear* / immunology
Antibodies, Monoclonal, Humanized* / pharmacology
Antibodies, Monoclonal, Humanized* / therapeutic use
B-Cell Activating Factor / blood
B-Cell Activation Factor Receptor / metabolism
B-Lymphocytes* / drug effects
B-Lymphocytes* / immunology
DNA / immunology
Female
Humans
Immunoglobulin A* / blood
Immunoglobulin A* / immunology
Interleukin-10 / metabolism
Lupus Erythematosus, Systemic* / blood
Lupus Erythematosus, Systemic* / drug therapy
Lupus Erythematosus, Systemic* / immunology
Male
Middle Aged
Rituximab* / pharmacology
Rituximab* / therapeutic use

Substances

Antibodies, Antinuclear
Antibodies, Monoclonal, Humanized
B-Cell Activating Factor
B-Cell Activation Factor Receptor
belimumab
DNA
Immunoglobulin A
Interleukin-10
Rituximab
TNFSF13B protein, human