Autoimmune haemolytic anaemias (AIHA) area heterogenous group of rare autoimmune diseases divided by serological types, in which red blood ceils are eliminated by antibodies. Notwithstanding the
heterogenous nature of the disease, corticosteroids and B-cell-targeted therapy with rituximab are currently the main pillar of treatment, often however leading to incomplete or short-term remission.
This has led to a large body of clinical research, employing mostly treatments from B cell lymphoproliferative diseases. BTK inhibition has been identified as a key target for therapeutic
intervention beyond B celI depletion in autoimmune diseases. Numerous trials are investigating different BTK inhibitors, often without extensive pre-clinical support, with different outcomes based on
disease types. Contrasting the well understood B celI signalling in CLL (where BTK inhibition emerged), with constitutively active BCR signalling driving the disease, this clonal mechanism is very
different from the complex aberrations in auto immune disease, with additional pathways for activation, and an important role for B-T cel interactions.
Part of the explanation for the often lacking pre-clinical data in autoimmune disease is that blood is the most accessible source for studying autoreactive B cells, however in many auto-immune diseases
circulating blood does not accurately reflect the immunological anomalies present within tissues, and characteristics and roles of autoreactive B cells could differ between these 2 settings. Auto immune
haemolytic anaemia provides a unique opportunity in this respect: antibody binding takes place in the bloodstream, providing optimal circumstances for studying aberrant B cell signalling.
I hypothesize that individual AIHA patients have different aberrations in B celI signalling: some will have constitutive BCR activation while others have B celI activation through other pathways,
explaining differences in clinical phenotype and treatment response. At the Amsterdam UMC, we have the unique DRAIHA cohort, a prospective study combining clinical data with intensive sampling
(including PBMCs) at 2 different timepoints in (currently over 200) well characterised AIHA patients.