Sustained depression of B cell counts in lupus nephritis after treatment with rituximab and/or belimumab is associated with fewer disease flares.

OBJECTIVE: To study the risk of lupus nephritis flare (LNF) or severe lupus flare (SLF) as a function of B cell count kinetics in lupus nephritis (LN) patients after they achieve at least a partial renal response (PRR) with induction treatment that includes rituximab (RTX) and/or belimumab (BLM). METHODS: We performed a retrospective analysis of a cohort of 19 patients with severe LN that received a B cell agent (BCA), RTX and/or BLM, as part of an initial treatment regimen for an LN flare and had subsequent CD19+ B cell measurements in peripheral blood. We then characterized the follow-up periods, after B cell depressions occurred and PRR were achieved, by the corresponding trajectories of B cell counts (BCC). Time periods with sustained low BCC were type 1 (T1) episodes, while those with repletion of BCC>100 cells/µL were called type 2 (T2) episodes. Time periods with rapid BCC repletion, defined as >50 cells/µL in ≤6 months, were called T2b episodes. Corresponding C3, C4, and anti-dsDNA levels were recorded for each episode. The time from PRR until an event, either a LNF or SLF, or to censoring, either at the end of the study period or the end of available patient follow-up, was assessed for each episode type. Kaplan-Meier survival analysis was used to compare time to flare between T1 and T2 episodes. RESULTS: There were 26 episodes of B cell depression. Seventeen (65%) were T1 and 9 (35%) were T2. Compared to T1 episodes, T2 episodes were 9.0 times more likely to result in flare over the follow-up period (hazard ratio (HR) = 9.0, 95% CI for HR = 2.2-36.7); this risk was even larger for T2b vs T1 episodes. Median BCC was 14 cells/µL in T1 and 160 cells/µL in T2 episodes. Both C3 and C4 levels significantly increased over the duration of the episode in T1 episodes only. CONCLUSION: Sustained low BCC was associated with prolonged serologic and clinical response, whereas repletion, and particularly rapid repletion, of B cells after treatment with BCA was associated with subsequent disease flare.

Low Peripheral B-Cell Counts in Patients With Systemic Rheumatic Diseases Due to Treatment With Belimumab and/or Rituximab Are Associated With Low Antibody Responses to Primary COVID-19 Vaccination.

Background: Immunosuppressive agents inhibit COVID-19 vaccine antibody (Ab) responses in patients with systemic rheumatic diseases. Rituximab may fully block Ab responses when B cells become undetected. The effect of detected but low number of B cells due to treatment with a B-cell agent (belimumab and/or rituximab) has not been established. Purpose: We sought to examine whether there is an association between a low number of B cells due to treatment with belimumab and/or rituximab and impaired primary COVID-19 vaccination spike Ab responses in patients with systemic rheumatic diseases. Methods: We retrospectively examined Ab responses to COVID-19 vaccinations, especially in relation to B-cell counts after treatment with belimumab and/or rituximab, in 58 patients with systemic rheumatic diseases: 22 on and 36 not on B-cell agents. We used Kruskal-Wallis and Mann-Whitney U tests for comparison of Ab values between the groups and Fisher exact test for relative risk calculations. Results: Median (interquartile range) postvaccination Ab responses were lower in patients on versus those not on B-cell agents: 3.91 (0.77-20.00) versus 20.00 (14.32-20.00), respectively. Among patients on belimumab and/or rituximab, Ab responses of less than 25% of the assay's upper limit were exclusively observed in those with B-cell counts lower than 40/µL. Patients with B-cell counts lower than 40/µL exhibit a relative risk of 6.092 (95% CI: 2.75-14.24) for Ab responses of less than 25% of the upper limit compared with patients not on B-cell agents. This relative risk remained significant, even after excluding patients with undetected B cells. Conclusion: This retrospective study found an association between low B-cell counts (less than 40/µL) and decreased Ab responses to primary COVID-19 vaccination in patients with systemic rheumatic diseases treated with belimumab and/or rituximab. Despite the small number of patients studied, these findings add to the accumulating evidence on the importance of B-cell count in predicting spike Ab responses to COVID-19 vaccination.

Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses.

Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). We report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-α production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced in pDCs, which inversely correlated with IFN-I-stimulated gene expression. CXCL4, a chemokine highly secreted in SSc patients, downregulated IRE1α-XBP1-controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1-PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.