Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions

Abstract

In recent years, the pathophysiologic framework of autoimmune hemolytic anemias (AIHAs) has evolved considerably, extending beyond the simplistic paradigm of antibody-mediated red blood cell (RBC) destruction, which is now recognized as a downstream consequence of a broader immune dysregulation. AIHA is fundamentally orchestrated by a complex interplay between innate and adaptive immune components, including autoreactive B and T lymphocytes, macrophages, and the reticuloendothelial system. Central to disease pathogenesis are two interrelated mechanisms: clonal B-cell expansion with autoantibody production and complement activation. These immunologic processes support the heterogeneity of AIHA, delineating distinct clinical entities such as warm AIHA, cold agglutinin disease/syndrome (CAD/CAS), and atypical variants, each characterized by specific therapeutic susceptibilities. Glucocorticoids remain the standard first-line therapy for warm AIHA; in contrast, CAD/CAS is increasingly managed with agents targeting B-cell function or complement activation, including rituximab and sutimlimab. However, therapeutic algorithms are rapidly shifting, particularly in the context of treatment-refractory disease. Emerging therapeutics targeting the classical complement pathway include novel anti-C1s monoclonal antibodies such as riliprubart, which exhibits an extended half-life due to enhanced affinity for the neonatal Fc receptor. Parallel strategies aim to disrupt B-cell receptor (BCR) signaling cascades, employing Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib, spleen tyrosine kinase (SYK) inhibitors such as fostamatinib and sovleplenib, and phosphoinositide 3-kinase (PI3K) inhibitors such as parsaclisib. Collectively, these advances are reshaping the therapeutic landscape of AIHA toward a precision medicine model guided by mechanistic insights into disease biology. In this review, we delineate the evolving immunopathogenesis of AIHAs and examine emerging therapeutic strategies, integrating their underlying rationale, clinical data, and implications for future treatment paradigms.

Keywords: autoimmune hemolytic anemias; cold agglutinin disease; complement system; immunotherapy; pathogenesis; strategy; target therapy; warm autoimmune hemolytic anemia.

Figure 1

Overview of the pathogenesis of autoimmune hemolytic anemias (AIHAs). AIHAs result from a failure of immune tolerance, wherein defects in negative thymic selection permit the survival of autoreactive T lymphocytes. Dysregulation of T_H1/T_H2 homeostasis, coupled with genetic predisposition, contribute to aberrant B-cell activation. Molecular mimicry, often initiated by viral or bacterial infections, may further drive the clonal expansion of autoreactive B cells. In warm AIHA, autoantibodies primarily mediate EVH through splenic clearance via ADCP and ADCC, with a minor contribution from CDC in the liver. In contrast, in CAD, IgM autoantibodies bind erythrocytes at low temperatures, activating the classical complement pathway and leading to both IVH and EVH, primarily in the liver. ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; CAD, cold agglutinin disease; CDC, complement-dependent cytotoxicity. C3bR, C3b receptor; EVs, extracellular vesicles; EVH, extravascular hemolysis; IVH, intravascular hemolysis; MAC, membrane attack complex; TCR, T-cell receptor. Created in BioRender. Costa, A. (2025) https://BioRender.com/l08cmw5.

Figure 2

Major B-cell targeted therapy approaches investigated in autoimmune hemolytic anemias (AIHAs). AAb, autoantibody; ADCC, antibody-dependent cellular cytotoxicity; APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor; BAFF-R, BAFF receptor; BCMA, B cell maturation antigen; BCR, B-cell receptor; BTK; Bruton tyrosine kinase; CAR T, chimeric antigen receptor T; CSA, ciclosporin A; FcγR; Fc γ receptor; FcRn, neonatal Fc receptor; LLPCs, long-lived plasma cells; PI3K, phosphoinositol 3-kinase; PtdIns(3,4,5)P3, phosphatidylinositol-3,4,5-trisphosphate; SYK, splenic tyrosine kinase; TACI, transmembrane activator and CAML Interactor. Created in BioRender. Costa, A. (2025) https://BioRender.com/kl39pwf.

Figure 3

Major therapeutic targets within the complement system in AIHAs. AIHAs, autoimmune hemolytic anemias; AAb, autoantibodies; FcRn, neonatal Fc Receptor; MAC, membrane attack complex; MBL, mannan-binding lectin. Created in BioRender. Costa, A. (2025) https://BioRender.com/lj5h9fv.