Discussion

The relapse phenotype was clinically similar to cold agglutinin disease, with winter worsening, markedly elevated cold agglutinin titers, erythrocyte agglutination, C3d‐dominant DAT findings, low C4 before treatment, and hematologic improvement after C1s inhibition. However, the same patient initially presented with anti‐IgG‐positive hemolysis and was later reassessed as having mixed AIHA after cold‐triggered relapse [5]. We therefore interpreted the later episode as a cold‐ and complement‐dominant relapse within the longitudinal course of mixed AIHA rather than as newly developed isolated cold agglutinin disease.

The rapid transfusion‐free increase in hemoglobin, reduction in LDH, recovery of C4, and suppression of CH50 after sutimlimab were consistent with classical complement pathway inhibition [3, 4]. Persistent cold agglutinin titers, direct agglutination, and DAT reactivity during the early response suggested that the treatment controlled the complement‐dependent effector phase without eliminating upstream antibody activity.

The cellular source of the antibody activity remained unresolved. The pretreatment κ‐restricted CD20‐positive population was no longer detectable by flow cytometry at relapse, although marrow histology showed approximately 1% CD20‐positive B cells. IgG‐κ and IgM‐κ monoclonal proteins were identified later, but their antigen specificity, pathogenicity, cellular source, and clonal relationship were not established. Detection of the IgG‐κ protein did not establish that the warm‐reactive erythrocyte antibody was monoclonal. Neither marrow examination showed lymphoplasmacytic infiltration or lymphoid aggregates, and pre‐rituximab CT showed no lymphadenopathy or splenomegaly. However, relapse–phase imaging, MYD88 L265P testing, next‐generation sequencing, IGH clonality analysis, and clonal tracking were not performed; an underlying small B‐cell lymphoproliferative disorder therefore could not be definitively excluded [6]. The mechanism underlying renewed anti‐IgG DAT reactivity during early sutimlimab treatment remained unresolved.

Several limitations affect interpretation of the longitudinal changes. Cold agglutinin testing was not performed at initial presentation, preventing complete characterization of the baseline phenotype. Immunofixation was not repeated between Day 50 and relapse, so the timing of the IgG‐κ and IgM‐κ proteins remains unknown. Formal thermal‐amplitude testing, I/i antigen specificity testing, MYD88 L265P testing, next‐generation sequencing, IGH clonality analysis, clonal tracking, and relapse–phase imaging were not performed. The temporal response in a single patient cannot establish the efficacy of sutimlimab across mixed AIHA.