Zhiyin Zheng

Background: Cyclosporine A (CsA) is the standard first-line treatment for acquired pure red cell aplasia (PRCA), but outcomes vary. Effective salvage strategies for CsA-refractory patients, particularly those with complex secondary subtypes, remain inadequately defined. Additionally, the clinical utility of STAT3/5b mutations in guiding treatment selection remains unclear. Objectives: To evaluate the efficacy of second-line sirolimus for the treatment of PRCA and explore the possible genetic predictors for the response. Design: This study was a retrospective, single center, comparative study. Methods: Patients with acquired PRCA treated between 2021 and 2025, including 36 patients who received first-line CsA and 22 patients who switched to sirolimus due to lack of response or intolerance. Clinical outcomes, including overall response rate (ORR) and time to response (TTR), were compared between primary and secondary PRCA. STAT3/5b mutation status was also analyzed to assess its predictive value for treatment response. Results: The ORR for first-line CsA was 25.0% (9/36), with significantly higher efficacy observed in primary cases (42.1%, 8/19) than in secondary cases (5.9%, 1/17; p = 0.015). In the salvage sirolimus group, the ORR was 54.5%, demonstrating efficacy in both primary (37.5%, 3/8) and secondary cases (64.3%, 9/14). The median TTR did not differ significantly between sirolimus and CsA (3.0 vs. 1.5 months, p = 0.150), and both agents achieved sustained remission in responders. Regarding genetic predictors, no responses to CsA were observed in patients harboring STAT3/5b mutations (0/6). In contrast, sirolimus elicited responses in both mutated (3/6) and wild-type (4/5) patients, indicating efficacy irrespective of STAT3/5b status. Conclusions: CsA is effective in primary PRCA, whereas sirolimus demonstrates efficacy in both primary and secondary cases regardless of STAT3/5b status. Early genetic profiling may facilitate the identification of patients who may not fully response to CsA and potentially earlier transition to sirolimus salvage therapy.

Background: Thyroid dysfunction has been linked to hematologic abnormalities, but whether thyroid function has a causal role in myeloproliferative diseases (MDs), including chronic myeloproliferative disease (CMD), remains unclear. We used Mendelian randomization (MR) to assess the potential causal effects of thyroid‐related traits on MD risk. Methods: A two‐sample MR analysis was performed using genome‐wide association study (GWAS) summary statistics. Outcome data for CMD and MD, excluding chronic myelogenous leukemia (CML), were obtained from the Finnish R12 cohort (European ancestry). Genetic instruments for thyroid traits—including thyrotropin (TSH), free thyroxine (FT4), free/total triiodothyronine (FT3/TT3), FT3/FT4 and TT3/FT4 ratios, high/low TSH, and genetic liability to hyperthyroidism and hypothyroidism—were selected at genome‐wide significance ( p < 5 × 10 ⁻⁸ ), clumped for linkage disequilibrium ( R ² < 0.001, 10,000 kb), and required F‐statistics > 10. Primary causal estimates were obtained using inverse‐variance weighted (IVW) MR, with sensitivity analyses using MR‐Egger, weighted median, weighted mode, MR‐PRESSO, heterogeneity tests, and leave‐one‐out analyses. Steiger tests were applied to assess directionality, and false discovery rate (FDR) correction was used for multiple comparisons. Results: Most thyroid function measures (TSH, FT4, FT3, TT3, hormone ratios, and hypothyroidism) showed no evidence of a causal association with CMD or MD excluding CML (IVW p > 0.05 p > 0.05 p > 0.05). A nominal association was observed between self‐reported hyperthyroidism/thyrotoxicosis and CMD, but the effect estimate was implausibly extreme (IVW OR = 5.53 × 10 ⁻¹⁴ , 95% CI: 7.78 × 10 ⁻²⁷ –0.3935, p = 0.0432) and did not remain significant after FDR correction. After outlier removal, genetically predicted hyperthyroidism was nominally associated with MD excluding CML (OR = 0.8806, 95% CI: 0.7954–0.9750; p = 0.0144), but this also did not survive FDR correction (FDR = 0.2015). Sensitivity analyses and pleiotropy tests did not indicate strong directional pleiotropy for the nominal signals, and Steiger tests supported the hypothesized exposure‐to‐outcome direction. Conclusions: In this MR study, we found no robust evidence for a causal association between most genetically predicted thyroid function traits and MD after multiple‐testing correction. The nominal signals observed for hyperthyroidism were phenotype‐dependent and statistically unstable, particularly for self‐reported CMD. These results emphasize that previously observed associations may be driven by nongenetic factors or clinical confounding. Jingjing Xiang and Jun Yan were co‐first authors.