Efficacy and safety of steroid‐sparing strategy in the treatment of AIHA associated with KSHV/HHV‐8 positive multicentric Castleman disease

Multicentric Castleman disease (MCD) related to HHV-8 (human herpesvirus-8 or Kaposi sarcoma-associated herpesvirus, KSHV) is a lymphoproliferative disorder mainly affecting immunocompromised individuals. Flares present with lymphadenopathy, splenomegaly, inflammation, and high HHV-8 viremia.1, 2 Diagnosis requires a lymph node biopsy showing plasma-cell or mixed type MCD features with infected large B cells in the mantle zone. Life-threatening complications include hemophagocytic lympho-histiocytosis (HLH) and HHV-8-related lymphoma, while autoimmune manifestations such as dysglycemia, thrombotic thrombocytopenic purpura (TTP), and cytopenias are also observed.2-5 Standard of care relies on rituximab, often combined with etoposide or liposomal doxorubicin, for the management of acute flares.6, 7 Autoimmune hemolytic anemia (AIHA) is an acquired autoimmune disorder caused by autoantibody-mediated red blood cells (RBCs) destruction. It is classified as warm or cold AIHA, according to the antibodies' thermal range. Corticosteroids (CS) remain the first-line therapy for primary warm AIHA (wAIHA), with rituximab used as a second-line treatment.8 HHV-8 MCD is a rare but recognized cause of wAIHA, as documented in a few case reports, but the characteristics, evolution, and management of this complication have never been fully addressed. CS are often used with rituximab, as in primary wAIHA, but this strategy might increase Kaposi sarcoma (KS) risk and worsen immune deficiency.9, 10 Patients were identified through the French National Reference Center for Castleman Disease (see details in Supplemental Methods). AIHA was defined by hemoglobin (Hb) < 12 g/dL, with ≥2 hemolysis features and a positive direct antiglobulin test (DAT). Patients with any other cause of hemolytic anemia were excluded. Complete response (CR) was defined by Hb >12 g/dL without hemolysis, and partial response (PR) by Hb increase >2 g/dL or normalization of Hb with persistent hemolysis.8 Overall response (OR) was defined as the sum of PR and CR. Between 1995 and 2024, 344 patients with a biopsy-proven HHV-8 MCD were identified. Fifty-nine patients (17%) met AIHA criteria (AIHA+), with a median age at diagnosis of 45 years (Table 1). All patients had MCD flare at AHAI diagnosis, and all had detectable HHV-8 viremia. Thirty-eight patients (64%) were living with HIV (PLWH), including 10 patients who initiated antiretroviral therapy (ART) at the time of AIHA diagnosis. Eight AIHA+ patients (21% of PLWH) had undetectable HIV viremia. Median Hb values were similar between PLWH and HIV-negative patients (5.3 g/dL [interquartile range; IQR 4.3–6.6] vs. 5.1 g/dL [IQR 4.9–5.9], respectively), favoring a minimal direct role of HIV in the genesis of anemia. AIHA occurred during the first flare of MCD in most cases (n = 54/59, 92%), with a median time from AIHA onset to MCD diagnosis of 11 days (range: 8–65 days). No acquired TTP or dysglycemia was diagnosed. When compared to MCD patients without AIHA (AIHA−), AIHA+ patients were more often from Sub-Saharan ancestry (54% vs. 36%, P = 0.03). There were no differences between the two groups regarding HLH frequency, HIV infection, HHV-8 viremia, or KS at the time of AIHA diagnosis. At onset, the median Hb level was 5.2 g/dL (4.4–6.4), and the majority of AIHA+ patients presented with very severe (