Janus kinase inhibitor therapy for the treatment of spondyloenchondrodysplasia with immune dysregulation due to novel ACP5 variants: a multicenter study

Background Spondyloenchondrodysplasia with immune dysregulation (SPENCD) is a rare autosomal recessive disorder caused by biallelic ACP5 mutations and is characterized by skeletal dysplasia, neurological involvement, and immune dysregulation. According to the latest International Union of Immunological Societies (IUIS) classification, SPENCD is categorized as an inborn error of immunity within the autoinflammatory disorders spectrum; however, targeted therapeutic strategies for immune manifestations remain limited. Methods We conducted a multicenter study including five patients from India and from Chongqing and Tianjin, China. Whole-exome sequencing identified six ACP5 variants across the five patients, including four novel variants. The diagnosis of SPENCD was established based on the genetic findings in combination with characteristic clinical features and radiological manifestations. Three patients received treatment with Janus kinase (JAK) inhibitors. In one representative treated patient (Patient 1), immunological parameters before and after treatment were evaluated using flow cytometry and quantitative PCR. Results Four novel ACP5 variants were identified in this cohort. All three patients treated with tofacitinib (a JAK inhibitor) showed variable but overall clinical improvement. In one representative patient, immunological changes were observed after treatment, including a reduction in CD21 low B cells and changes in T helper cell subsets. Conclusion This study expands the spectrum of ACP5 mutations and provides clinical and immunological observations suggesting JAK inhibitor therapy may be considered for immune dysregulation in patients with SPENCD.