Shipa, Muhammad RA;
(2023)
Investigating the clinical and immune impact of belimumab after rituximab therapy in Systemic Lupus Erythematosus (SLE).
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The rise in serum B cell activating factor (BAFF) following rituximab treatment in patient with systemic lupus erythematosus (SLE) has been associated with disease flares, and potentially impeding its therapeutic efficacy. The BEAT-LUPUS trial was designed to target this rise in BAFF after rituximab. It was a phase II, 52-week randomised (1:1), double-blind, placebo-controlled, parallel-group superiority trial, with the objective of evaluating the efficacy and safety of adding belimumab following rituximab administration in SLE patients whose disease was refractory to conventional therapy. In total, 52 patients who met the inclusion criteria were recruited. The belimumab group demonstrated a significant reduction in the primary endpoint—serum IgG anti-dsDNA antibody levels at 52 weeks—when compared to the placebo group. Furthermore, this combination not only reduced the risk of severe flares, but also delayed B cell repopulation. There was no observed increase in the incidence of serious adverse events associated with belimumab. While post-hoc analysis did not indicate a significant improvement in major clinical response with belimumab, it did suggest a potential beneficial effect in renal lupus. Further exploratory analyses revealed that baseline serum IgA2 anti-dsDNA antibody levels were a predictive factor for response to belimumab. Patients with elevated serum IgA2 anti-dsDNA antibody levels exhibited better clinical responses and reduced flare risks, and their concentration was reduced by 52-weeks only in belimumab responders. Additionally, CD11c+T-Bet+ DNM-2 (double negative memory B cells type 2) B cells were identified as a biomarker for belimumab response, and a decrease in their proportion was associated with a clinical response to belimumab treatment. While various pathogenic B cell subsets decreased in patients receiving combination therapy, there was an increase in the proportion of hypoactive B cells. Additionally, patients with active renal disease exhibited high serum IgA2 anti-dsDNA antibody levels and frequencies of CD11c+T-Bet+ DNM-2 B cells and plasmablasts. In contrast, active mucocutaneous disease was associated with elevated serum IgA1 anti-dsDNA antibody levels, IFN (Interferon)-α concentrations, and the type I IFN score. These findings imply that the combination of belimumab and rituximab holds promise as a potential therapeutic approach for a subset of SLE patients who do not respond to conventional treatment. Furthermore, these data offer valuable insight into the immune pathogenesis of a specific lupus endotype that responds well to treatment. However, it is crucial to interpret these findings with caution due to the limited sample size in this study, and additional testing of these theragnostic biomarkers is required.
Type: | Thesis (Doctoral) |
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Qualification: | Ph.D |
Title: | Investigating the clinical and immune impact of belimumab after rituximab therapy in Systemic Lupus Erythematosus (SLE) |
Open access status: | An open access version is available from UCL Discovery |
Language: | English |
Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
URI: | https://discovery.ucl.ac.uk/id/eprint/10184035 |
1. | France | 3 |
2. | United Kingdom | 1 |
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