Beneficial mechanisms of dimethyl fumarate in autoimmune uveitis: insights from single-cell RNA sequencing.

BACKGROUND: Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU) is incompletely understood, and studies comprehensively exploring the impact of DMF on immune cells are still lacking. METHODS: To explore the function of DMF in uveitis and its underlying mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) on the cervical draining lymph node (CDLN) cells of normal, experimental autoimmune uveitis (EAU), and DMF-treated EAU mice. Additionally, we integrated scRNA-seq data of the retina and CDLNs to identify the potential impact of DMF on ocular immune cell infiltration. Flow cytometry was conducted to verify the potential target molecules of DMF. RESULTS: Our study showed that DMF treatment effectively ameliorated EAU symptoms. The proportional and transcriptional alterations in each immune cell type during EAU were reversed by DMF treatment. Bioinformatics analysis in our study indicated that the enhanced expression of Pim1 and Cxcr4 in EAU was reversed by DMF treatment. Further experiments demonstrated that DMF restored the balance between effector T (Teff) /regulatory T (Treg) cells through inhibiting the pathway of PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1). By incorporating the scRNA-seq data of the retina from EAU mice into analysis, our study identified that T cells highly expressing Pim1 and Cxcr4 were enriched in the retina. DMF repressed the ocular infiltration of Teff cells, and this effect might depend on its inhibition of PIM1 and CXCR4 expression. Additionally, our study indicated that DMF might reduce the proportion of plasma cells by inhibiting PIM1 expression in B cells. CONCLUSIONS: DMF effectively attenuated EAU symptoms. During EAU, DMF reversed the Teff/Treg cell imbalance and suppressed the ocular infiltration of Teff cells by inhibiting PIM1 and CXCR4 expression. Thus, DMF may act as a new drug option for the treatment of AU.

Successful Remission with Upadacitinib in Two Patients with Anti-TNF-Refractory Macular Edema Associated with Behçet's Uveitis.

PURPOSE: Behçet's syndrome (BS) is a chronic inflammatory disease affecting the small and large vessels of the venous and arterial systems and is characterized by recurrent oral and genital ulcers. Uveitis represents the most typical ocular manifestation and completes the triple symptom complex originally described. Recognized treatments for Behçet's uveitis (BU) include systemic glucocorticoids and immunosuppressive agents. No study has reported on the use of upadacitinib for BS with panuveitis. Herein, we report the use of upadacitinib in two patients with BU suffering from macular edema and persistent inflammation, which was refractory to systemic glucocorticoids and immunosuppressive agents. METHODS: We retrospectively followed-up two cases, including an adolescent girl and a man in his thirties, with a 2- and 10-year history of BS, respectively. RESULTS: Upadacitinib successfully treated BU, leading to improved visual acuity, controlled intraocular inflammation, and the disappearance of macular edema in both patients. The patients in this study were either recalcitrant to or intolerant to conventional therapy and adalimumab. Only the female patient revealed a mildly abnormal blood picture and slight transaminitis after 6 months of upadacitinib administration. However, no serious adverse events were reported in either of the two patients during follow-up. CONCLUSION: Upadacitinib can be considered an important future option for managing recurrent and recalcitrant cases of BU, especially in those with chronic ocular inflammation and macular edema, which are refractory to conventional therapies.