Case Report: Sirolimus as management strategy for thrombocytopenia related to ARPC1B deficiency

Biallelic mutations in ARPC1B gene are responsible for an inborn error of immunity (IEI) characterized by thrombocytopenia and combined immunodeficiency with heterogeneous immune-dysregulatory features. Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor, which is successfully used in patients affected by primary or secondary autoimmune cytopenias. We report the case of a patient suffering from refractory/relapsing thrombocytopenia secondary to a previously unreported homozygous variant on ARPC1B and successfully managed with sirolimus. Additional mild immune dysregulatory features, such as lymphoproliferation and autoantibodies, also resolved after sirolimus treatment. Protein's functional analysis showed an interaction between ARPC1B's role in actin cytoskeleton function and mTOR signaling pathway. However, the actin polymerization assay evaluation on samples collected before and after sirolimus treatment showed no significant differences. This result might suggest that the efficacy of sirolimus in controlling thrombocytopenia was mainly due to its immunomodulatory effect to reduce autoimmunity. The absence of a direct effect on actin cytoskeleton may also explain the lack of efficacy of sirolimus in previously reported ARPC1B-deficient patients affected by broader immune dysregulation features, including at least three or more systems involved. Although increased evidence is supporting early hematopoietic stem cell transplantation (HSCT) as an option for more severe broad-spectrum phenotypes, sirolimus could represent a therapeutic option in ARPC1B deficiency in case of a less severe immune-dysregulation phenotype or as a bridge therapy before transplant. Prospective observation can help in defining patients' evolution and prognosis with sirolimus monotherapy, and the risks and benefits of combination strategies with steroids or immune-modulating drugs should be compared with HSCT progress and results in transplant-related mortality.