Laurent Sailler

Age-associated B cells (ABCs) have emerged as critical components of adaptive immune responses linked to autoimmune disorders, aging-associated diseases, and chronic infections. Accumulation of ABCs is subjected to sex-specific regulation. A group of X-linked genes, including TLR7 and CXorf21/TASL, an adaptor that regulates IRF5 activity, are key regulators of ABCs. Because these genes can escape X chromosome inactivation (XCI) in immune cells, we investigated the contribution of biallelic expression of TLR7 and CXorf21/TASL, using RNA fluorescence in situ hybridization, in the TLR-driven development of ABCs and plasmablasts (PBs) in human B cells. Here we show that ABCs are more frequent in PBMCs from female of reproductive age as compared to age-matched males. Using a BCR/TLR/IFN-γ–driven ABC-differentiation model from naïve B cells, we show that ABCs, with dysregulated XCI at the TLR7 locus, are positively selected during TLR7-driven differentiation, but not in response to TLR9 stimulation. A similar trend was observed for CXorf21/TASL biallelic cells. We establish that IgD−CD27− (double-negative [DN]) B cells, that contain ABCs, were the immediate precursors of CD27hiIRF4+ PBs, in response to TLR stimulation. Interestingly, female B cells were more prone to generate PBs than male cells only in response to TLR7 stimulation compared to TLR9. This sex bias was associated with enhanced expression from both X chromosomes of TLR7 and, to a lesser extent, CXorf21 in TLR7-stimulated PBs. In conclusion, TLR7-induced ABCs and DN B-cell–derived PBs are associated with enhanced XCI escape of TLR7, suggesting positive selection of biallelic B cells upon cognate TLR engagement.

Objectives: This study aims to assess urinary soluble CD163 normalized to creatinuria (usCD163/Cre) alongside conventional biomarkers as indicators of renal activity and therapeutic response in LN. Methods: A monocentric and retrospective cohort analysis involving 214 patients with SLE was conducted, among whom 129 were referred as LN and assessed longitudinally. Of these, 39 underwent kidney biopsy at sample collection. Data were extracted from medical records, including metrics on renal activity (SLEDAI-R), histological characteristics and therapeutic response according to KDIGO 2024 outcome criteria. The characteristics of usCD163/Cre (ELLA-G2) were compared against routinely used biomarkers and confounding factors including renal function and concomitant medication use. Results: The cross-sectional analysis indicated that usCD163/Cre [area under the curve (AUC) = 0.999], spot urine protein/creatinine ratio or PCR (AUC = 0.994) and serum albumin levels (AUC = 0.940) distinguished between active LN and inactive states, and correlated with SLEDAI-R scores. At the time of kidney biopsy, usCD163/Cre was the only reliable predictor of histological activity (AUC = 0.962; threshold 1200 ng/mmol). During follow-up assessments, usCD163/Cre outperformed PCR to discriminate disease flares (>520 ng/mmol), and categorization into low (1200 ng/mmol) usCD163/Cre levels at 3 and 6 months, following therapy introduction, allows to predict complete, partial and non-responders as an independent factor. Conclusion: Our findings support the involvement of CD163 positive macrophages (M2c) in the pathophysiology of LN and advocate for the inclusion of usCD163/Cre measurement in the standard of LN management to assess LN flare episodes and as an early predictor of therapy response.

Objectives: To investigate the ex vivo IFN-γ release assay (IGRA) as a biomarker of systemic lupus erythematosus (SLE) activity and disease outcome. Methods: This retrospective study, conducted between 2008 and 2024 at a single tertiary care centre, included 145 SLE patients at various disease stages. Data were collected on spontaneous IFN-γ levels (IGRA-nil) and on phytohemagglutinin-induced IFN-γ levels (IGRA-PHA, after subtracting the IGRA-nil result). Results: The ex vivo spontaneous IFN-γ release was increased (IGRA-nil; P = 0.0004) and the PHA-induced IFN-γ release was decreased in active SLE patients (IGRA-PHA; P < 10−4), regardless of treatment, including glucocorticoids. Nephritis, serositis, constitutional symptoms, mucocutaneous and musculoskeletal manifestations were associated with impaired IGRA-PHA release (P < 0.05 for each association). An IGRA-PHA ≥ 8.0 IU/ml, corresponding to the optimal Youden index, predicted clinically inactive SLE better than IGRA-nil (area under the curve = 0.853 vs 0.722) and IGRA-PHA <1.6 IU/ml indicated 100% specificity for active disease. Moreover, IGRA-PHA ≥ 8.0 IU/ml was an independent predictor of clinically inactive SLE in multivariate regression analysis (OR: 10.6 [95% CI: 3.72–30.17]; P = 9.7 × 10−6), and IGRA-PHA ≤1.6 IU/ml was associated with a longer time to achieve remission in a log-rank test (P = 2.4 × 10−6). Conclusion: The IGRA-PHA assay appears to be a powerful and independent biomarker for clinically active SLE, when performed at the initiation or intensification of therapy, and as a predictor of treatment-induced remission at therapy evaluation.

Data about hydroxychloroquine (HCQ) levels during pregnancy are sparse. We assessed HCQ whole blood levels at first trimester of pregnancy as a potential predictor of maternal and obstetric/fetal outcomes in patients with systemic lupus erythematosus (SLE). We included pregnant SLE patients enrolled in the prospective GR2 study receiving HCQ, with at least one available first-trimester whole-blood HCQ assay. We evaluated several cut-offs for HCQ whole blood levels, including ≤200 ng/ml for severe non-adherence. Primary outcomes were maternal flares during the second and third trimesters of pregnancy, and adverse pregnancy outcomes (APOs: fetal/neonatal death, placental insufficiency with preterm delivery, and small-for-gestational-age neonates). We included 174 patients (median age: 32.1 years, IQR 28.8–35.2). Thirty (17.2%) patients had flares, 4 (2.3%) being severe. APOs occurred in 28 patients (16.1%). There were no significant differences in APOs by HCQ level for either those with subtherapeutic HCQ levels (≤500 ng/ml vs >500 ng/ml: 23.5% vs 14.3%, p = 0.19) or those with non-adherent HCQ levels (≤200 ng/ml vs >200 ng/ml: 20.0% vs 15.7%, p = 0.71). Similarly, the overall rate of maternal flares did not differ significantly by HCQ level cut-off, but patients with subtherapeutic (HCQ ≤500 ng/ml: 8.8% vs 0.7%, p = 0.02) and non-adherent HCQ levels (≤200 ng/ml: 13.3% vs 1.3%, p = 0.04) had significantly more severe flares. In this large prospective study of pregnant SLE patients, first-trimester subtherapeutic (≤500 ng/ml) and severe non-adherent (≤200 ng/ml) HCQ levels were associated with severe maternal flares, but not with APOs. ClinicalTrials.gov, NCT02450396

Objective: Tocilizumab (TCZ), an interleukin 6 (IL-6) receptor antagonist, is approved for giant cell arteritis (GCA) as a cortisone-sparing strategy and in refractory patients. This study assessed the real-world efficacy, safety, and long-term outcomes of patients with GCA treated with TCZ.Methods: We conducted a multicenter retrospective observational study at 3 French centers. All patients aged ≥ 50 years who met the American College of Rheumatology (ACR) criteria, and had received at least 1 dose of TCZ were included. Relapse was defined by therapeutic escalation, such as increased doses of corticosteroids (CS), resumption of CS after weaning, or introduction or intensification of adjuvant therapy.Results: Between 2013 and 2019, 43 patients were included. Patients were followed up for a median 511 days between GCA diagnosis and inclusion, with 34/43 (79%) patients experiencing relapses. At inclusion, median age was 77 years, and median dose of CS was 15 mg/day. After inclusion, the mean cumulative dose of CS was 2.1 g/year vs 9.4 g/year before inclusion (P < 2 × 10^–7), with 12/43 (28%) patients experiencing relapses on TCZ. Among 29 patients undergoing TCZ discontinuation, 18 (62%) experienced relapses. Factors associated with relapse after inclusion were introduction of TCZ > 6 months after diagnosis (P = 0.005), absence of ischemic signs at diagnosis (P = 0.006), relapse rate > 0.8/year (P = 0.03), and absence of CS tapering ≤ 5 mg/day (P = 0.03) before inclusion. Serious adverse events occurred in 18/43 patients (42%), including 4 deaths.Conclusion: Our results confirm the effectiveness of TCZ for CS sparing, but after discontinuation of treatment, TCZ allows for a prolonged remission in < 50% of patients. Attention must be paid to the tolerance of this long-term treatment in this elderly, heavily treated refractory population.