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Maternal Microchimerism Promotes Tolerance Induction Toward Factor VIII in Severe Haemophilia a Children with Inhibitors
27 Pages Posted: 11 Apr 2024
More...Abstract
Background: The deficiency of factor VIII (FVIII) predisposes haemophilia A (HA) patients for the risk of neutralizing alloantibody, i.e inhibitors. Patients free of inhibitors could be attributed to presence of maternal microchimerism (MMc). 60-90% of inhibitor could be eradicated by immune tolerance induction (ITI). In current study, we explored the contribution of MMc for the outcome of ITI therapy.
Methods: In this single center prospective study, pediatric patients with severe or moderate HA (FVIII:C ＜5%) and inhibitors. Three SNPs on X chromosome were adopted for individual identification, and presence of MMc was determined by droplet digital PCR with a detection sensitivity of 1/10,000. Patients were subjected to low-dose ITI regimen (FVIII ~50IU/kg. QoD) (ITI-alone) and rituximab was added in those refractory to ITI alone (ITI-Ritux).
Findings: Between January 2017 and July 2021, 121 patients were enrolled, 101 were MMc detectable, 22/101 (21.8%) were MMc positive (MMc+), others were MMc negative (MMc-). Eighty-eight patients complete the ITI study (18 were MMc+, 70 were MMc-) with a median 20.5 months follow-up. ITI was successful in 68/88 (77.3%) patients, 16/18 (88.9%) with MMc+, 52/70 (74.3%) with MMc-. It took shorter time for MMc+ patients to achieve success than MMc- (median 3.0 months [95% CI 0.1-5.9] vs 9.5 [8.5-10.5]; p<0.001). The median peak inhibitor titer during ITI was significant lower for MMc+ patients than MMc- (5.3BU/ml [95% CI 0-1024.0] vs 37.8 [0-512.0]; p= 0.029). Patients with MMc+ achieved higher rate of rapid success compared with MMc- (50.0% vs 17.1%; p=0.009). The receiver operating characteristic curve analysis showed MMc and peak inhibitor during ITI predicted rapid success (areas under combined curve was 0.837; p<0.001). Both were also the significant predictors of ITI success in multivariate analysis (MMc, HR 3.10 [95%CI 1.694-5.710]) p<0.001; peak inhibitor during ITI, 2.65 [1.583-4.630] p<0.001).
Interpretation: These data suggest that MMc constitutes a beneficial prognosis factor for success of ITI therapy in haemophilia A patients with inhibitor.
Funding: This work was supported by grants from: National Natural Science Foundation of China (82300155), National Natural Science Foundation of China (82270133), Capital Health Development Research Project (Capital Development No. 2022-2-2093), Capital Health Development Research Project (Capital Development No. 2018-2-2094), Beijing Municipal Science & Technology Commission (No. Z221100007422067), The National Key Research and Development Program of China (2022YFC2703100), Natural Science Foundation of Shanghai (22ZR1439500).
Declaration of Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Ethical Approval: The research was approved by the ethics committee of Beijing Children’s hospital, Capital Medical University. Written informed consent was obtained from all guardian of subjects.
Keywords: haemophilia A, FVIII, inhibitor, maternal microchimerism, immune tolerance induction
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