AUTHOR=Piantoni Silvia , Regola Francesca , Masneri Stefania , Merletti Michele , Lowin Torsten , Airò Paolo , Tincani Angela , Franceschini Franco , Andreoli Laura , Pongratz Georg 

TITLE=Characterization of B- and T-Cell Compartment and B-Cell Related Factors Belonging to the TNF/TNFR Superfamily in Patients With Clinically Active Systemic Lupus Erythematosus: Baseline BAFF Serum Levels Are the Strongest Predictor of Response to Belimumab after Twelve Months of Therapy

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.666971

DOI=10.3389/fphar.2021.666971

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Patients with systemic lupus erythematosus (SLE) show increased serum levels of tumor necrosis factor (TNF)/TNF receptor (R) superfamily member, e.g. BAFF (B lymphocyte stimulator). Belimumab, a monoclonal antibody against soluble BAFF, is used for treatment of SLE. Although B cells are the main target, a BAFF-dependent T-cell activation pathway also plays a role. High levels of anti-DNA antibodies and low complement at baseline are known predictors of response to Belimumab.</p><p><bold>Objectives:</bold> To explore the association of circulating lymphocytes and serum levels of B- cell related TNF/TNFR superfamily members with response to Belimumab in SLE patients.</p><p><bold>Methods:</bold> Twenty-one SLE patients received Belimumab. Clinical evaluation and laboratory tests were performed at baseline, at 6 and 12 months. TNF super-family members (BAFF, APRIL, sBCMA, sCD40L, sTACI, TWEAK) were tested by high-sensitivity ELISA in all patients, and lymphocyte immunophenotyping was performed by flow cytometry in ten subjects. SLE-disease activity was assessed by SLEDAI-2K score. Linear regression modeling was used to investigate parameters influencing SLEDAI-2K and anti-dsDNA antibody titers over time and for predictive models.</p><p><bold>Results:</bold> Clinical improvement was observed in all patients. A global reduction of circulating B cells, especially naïve, was detected, without variation in the T-cell compartment. All TNF family members decreased, whereas APRIL remained constant. The increase in serum levels of C3 (<italic>p</italic> = 0.0004) and sTACI (<italic>p</italic> = 0.0285) was associated with a decrease of SLEDAI-2K. The increase of C4 (<italic>p</italic> = 0.027) and sBCMA (<italic>p</italic> = 0.0015) and the increase of CD8<sup>+</sup> T cells (<italic>p</italic> = 0.0160) were associated with a decrease, whereas an increase of sCD40L in serum (<italic>p</italic> = 0.0018) and increased number of CD4<sup>+</sup> T cells (<italic>p</italic> = 0.0029) were associated with an increase, in anti-dsDNA antibody titers, respectively. Using stepwise forward inclusion, the minimal model to predict SLEDAI-2K response at 12 months included BAFF (<italic>p</italic> = 3.0<italic>e</italic> − 07) and SLEDAI-2K (<italic>p</italic> = 7.0<italic>e</italic> − 04) at baseline. Baseline APRIL levels also showed an association, although the overall model fit was weaker.</p><p><bold>Conclusion:</bold> In our real-life cohort, baseline serum levels of BAFF were the best predictor of response to Belimumab, confirming post-hoc results of the BLISS study and suggesting the utility of this particular biomarker for the identification of patients who are more likely to respond.</p>