NecLip-pdFVIII

The most serious complication in treatment of hemophilia A is the development of factor (F)Ⅷ anti-drug antibodies (ADAs), while immunological danger signals seem to play a critical role in ADA development. Accordingly, we have shown in previous studies that plasma-derived (pd) FⅧ in presence of the bacterial danger signal lipopolysaccharide (LPS) synergistically activates dendritic cells (DCs), which in turn induce proliferation of (FⅧ-specific) CD4⁺ T helper cells. However, our in vitro assays using DC and T cells from healthy donors revealed that only cells from some donations can be synergistically activated upon treatment with pdFⅧ plus LPS, while cells from others cannot.

Therefore, we investigated a data pool of 160 donations for DC activation and 265 donations for T-cell proliferation from healthy donors collected by 3 different experimenters between 2012 and 2023 to determine parameters that correlate with pdFⅧ plus LPS-induced immune cell activation.

Human immune cells from healthy donors are synergistically activated by pdFⅧ plus LPS. However, neither DC activation nor T-cell proliferation depended on a specific pdFⅧ product, did not correlate with the donor's biological sex, and was not donor- but rather time point-dependent. Analyses of different activation markers revealed seasonal differences in CD86 expression, and low expression correlated with DC activation and tumor necrosis factor-α expression.

In fact, we could demonstrate that the meteorological season correlates with the basal CD86 expression on DC. This, in turn, determined the capability of synergistic DC activation and cytokine secretion, as well as partially impacted T-cell proliferation.

The last 15 years have seen new extended half‐life (EHL) recombinant FVIII/IX concentrates and nonreplacement therapy for haemophilia A (emicizumab) introduced in Europe. These changes affect FVIII/IX exposure in previously untreated patients (PUPs) and previously treated patients (PTPs) with severe haemophilia A and B (SHA and SHB) and may modify inhibitor development and/or detection.

To report trends in treatment for severe haemophilia and concomitant changes in inhibitor incidence.

Between 2008 and 2022, 97 centres reported inhibitor development against FVIII/IX concentrates to the European Haemophilia Safety Surveillance System (EUHASS). Inhibitors were reported quarterly, and PUPs without inhibitor development annually. Cumulative inhibitor incidences (95% confidence intervals [CI]) were calculated for PUPs and incidence rates/1000 years (CI) for PTPs.

By 2022, SHA‐PUPs ( n  = 1574) received emicizumab (44%), SHL‐rFVIII (21.5%), pdFVIII (17.5%) and EHL‐rFVIII (17%). SHB‐PUPs ( n  = 236) received EHL‐rFIX (79%) and SHL‐rFIX (21%). SHA‐PTPs (68,772 years) received EHL‐rFVIII (31%), SHL‐rFVIII (28%), emicizumab (25%), and pdFVIII (15%). SHB PTPs (11,185 years) received EHL‐rFIX (69%), pdFIX (15%) and SHL‐rFIX (15%). Observed Inhibitor incidence in SHA‐PUPs decreased from 24% before 2016 to 6% in 2022 ( p < 0.001), and potentially in SHB‐PUPs too (from 9% to 3%; p  = 0.066), but remained stable in SHA/SHB PTPs.

In 2022, 44% of SHA‐PUPs and 25% of SHA‐PTPs received emicizumab prophylaxis. Concomitantly, observed inhibitor incidence reduced to 6% in SHA‐PUPs. In SHB, EHL‐rFIX treatment increased to 79% in SHB‐PUPs and 69% in SHB‐PTPs. Assessing inhibitor incidence for new concentrates is likely to be hampered by novel treatments causing delayed exposure to FVIII/FIX.