Abstract
Purpose :
Individual non-steroidal therapies for uveitis are efficacious in 50-80% of patients. This heterogeneity makes predicting therapeutic responses challenging. Single-cell RNA sequencing (scRNA-Seq) allows unbiased phenotypic analysis that may lead to a precision-medicine approach to uveitis. JAKs are signaling molecules for many inflammatory cytokine pathways and JAK inhibitors are approved for rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. We hypothesized that targeting JAKs, which we found enriched in ocular inflammatory cells by scRNA-Seq, would also be efficacious for uveitis.
Methods :
scRNA-Seq was performed on ocular and peripheral blood cells from patients with uveitis (n=4). A prospective, open-label trial was conducted to assess the efficacy of tofacitinib, a small molecule inhibitor of JAK1 and 3, in birdshot chorioretinitis (N=5). Patients were treated with a 1 mg/kg prednisone taper and started on tofacitinib 11 mg daily. The primary endpoint was treatment failure at 24 weeks, defined as new inflammatory lesions, a 2-step increase in anterior chamber cell or vitreous haze or worsening visual acuity by 2 or more EDTRS rows.
Results :
JAK transcripts (JAK1, JAK2, JAK3 and TYK2) were increased in ocular cells compared to peripheral blood with most striking enrichment of JAK3 (6.4-fold in dendritic cells, 2.3- in monocytes, 1.8- in B cells and 1.7- in T cells). Patient-specific differences were also seen. JAK3 expression was more than 2-fold higher in ocular T cells from one patient compared to the other 3, and highest in a population of clonally-expanded CD4+ T cells.
No patient failed tofactinib therapy, but 3 had mild increase in inflammation at 24 weeks, therefore mycophenolate was added for two, and one patient withdrew. Notably, 2 patients experienced complete quiescence on tofacitinib monotherapy for up to 34 weeks, including one who had previously failed methotrexate, mycophenolate and adalimumab.
Conclusions :
Our results demonstrate that JAK transcripts are increased in ocular inflammatory cells from patients with uveitis, particularly dendritic cells and clonally-expanded T cells. Furthermore, our pilot clinical trial suggests that inhibition of JAKs by tofacitinib may be effective in uveitis. While this study is limited by size and lack of placebo, it provides rationale for future evaluation of mechanisms by which JAK inhibition may be efficacious in uveitis.
This is a 2020 ARVO Annual Meeting abstract.