Ruxolitinib mitigates interferon-induced autoimmune toxicity: Clinical insights from a 465-patient MPN Cohort Retrospective study

Abstract Background: Myeloproliferative neoplasms (MPNs) are characterized by intrinsic immune dysregulation, with a high incidence of autoimmune diseases (AIDs). Although interferon-α (IFN-α) is a first-line therapy, its immune-activating properties may exacerbate AID risk, which is a critical safety concern that has been poorly studied. Methods: A retrospective analysis of 473 MPN patients (234 males [49.5%], 239 females [50.5%]; median age 62 [31-89] years) was performed. New-onset AID and non-AID cohorts were compared using 1:3 propensity score matching (PSM). Multivariate competing risk models (Fine-Gray) and sensitivity analyses were applied to evaluate the impact of clinical indicators, while IFN use, ruxolitinib (RUX) use, baseline inflammatory cytokines, and immune cells on AID development. The RUX-IFN interaction effect was also examined. Results: With a median follow-up of 5 (1-29) years, the incidence rate of AID was 16.9 (12.9-22.3) per 1000 person-years. ① There were no significant differences in the rates of complete hematologic response (CHR), partial hematologic response (PHR), complete molecular response (CMR), or partial molecular response (PMR) between the IFN monotherapy group and the IFN+RUX group (all p>0.05). However, the IFN monotherapy group had a lower proportion of patients achieving ≥35% splenic volume reduction (SVR35) (p<0.05) and a significantly higher incidence of AID (19% vs 7.8%, P=0.005). ② Before PSM, after adjusting for confounding factors such as gender, age, and diagnosis, the multivariate model showed that IFN-α treatment (HR=1.981, 95%CI: 1.040-3.773, P=0.038), history of prior AID (HR=4.226, 95%CI: 2.233-7.996, P<0.001), serum globulin ≥35g/L (HR=2.045, 95%CI: 1.062-3.940, P=0.032), and peripheral blood CD19+B cells >18% (HR=2.464, 95%CI: 1.212-5.009, P=0.013) were independent risk factors for AID, while RUX exhibited a significant protective effect (HR=0.17, 95%CI: 0.040-0.717, P=0.016). ③ After PSM and sensitivity analyses, IFN treatment, prior AID history, and CD19+B cells >18% remained independent risk factors (all P<0.05). ④ The RUX-IFN interaction significantly reduced IFN-associated AID risk (sHR=0.34, 95%CI: 0.17-0.68; P=0.018). ⑤ Mechanistic exploration revealed that the IFN+RUX group had significantly lower levels of IL-1β, IL-6, IL-17A, and TNF-α compared to the IFN monotherapy group (all P<0.05). Conclusions: This study is the first to confirm in an MPN cohort that IFN-α treatment is an independent risk factor for new-onset AID. RUX therapy is an independent protective factor against AID. Baseline peripheral blood CD19+B lymphocyte count >18% is a novel biomarker for predicting AID risk. For MPN patients with peripheral blood CD19+B lymphocytes >18% receiving IFN therapy, proactive combination with RUX represents a new therapeutic strategy to reduce AID risk. These findings provide important insights for optimizing MPN treatment strategies and managing drug side effects.