Case Report: Immune dysregulation in proteasome-associated autoinflammatory syndromes: insights from a clinical case study

Background Proteasome-associated autoinflammatory syndrome (PRAAS) is a genetically defined rare immune-dysregulatory disorder associated with impaired proteasome degradation. It is characterized by the type I interferon (IFN) signaling activation and variable systemic inflammation. Case presentation We report a patient with a clinical phenotype consistent with PRAAS who showed short-term clinical and immunological improvement following tofacitinib treatment. The patient presented with recurrent fever, rash, splenomegaly, leukopenia, elevated inflammatory cytokines, and dysregulated lymphocyte subsets, characterized by increased pro-inflammatory T helper (Th)1 and Th17 cells together with reduced frequency and impaired suppressive function of regulatory T cells (Tregs). Trio whole-exome sequencing identified compound heterozygous PSMB8 variants, c.-4118C>T and c.350T>C (p.Met117Thr), inherited from the father and mother, respectively; both variants were classified as variants of uncertain significance. Following treatment with the Janus kinase (JAK) inhibitor tofacitinib, the patient showed improvement in clinical manifestations, inflammatory parameters, and T-cell abnormalities. The integrated clinical, immunological, and genetic findings were considered consistent with a PRAAS phenotype. Conclusions This case highlights the value of comprehensive genetic and immunological evaluation in patients with suspected autoinflammatory disorders and illustrates marked T-cell immune dysregulation in a PRAAS-consistent phenotype. Tofacitinib treatment was associated with short-term clinical and immunological improvement in this patient; however, its long-term therapeutic efficacy requires confirmation in additional patients with longer follow-up.