Steroid-resistant CD4+ cells in uveitis patients are a potential therapeutic target

The authors of this paper attempted to find out whether patients with immune-mediated uveitis who are steroid resistant had steroid-refractory CD4⁺ T-cells. They investigated the effects on interleukin-2 (IL-2) and CD4⁺ T-cells of immunosuppressive agents used to treat immune-mediated uveitis. Characterization of steroid-refractory CD4⁺ cells helps identify steroid-resistant patients and may assist in the development of early clinical therapies with new therapeutic modalities that target CD4⁺ cells.

Immune-mediated inflammation of the uvea afflicts 1.15 in 1000 people in the Western hemisphere. Although corticosteroids remain first-line systemic therapy for such disorders, a subset of immune-mediated uveitis patients show resistance to corticosteroid therapy. Sustained high-dose corticosteroid treatment may be associated with serious side effects. CD4⁺ T-cells may perpetuate the inflammation in uveitis. The presence of a subpopulation of steroid-refractory CD4⁺ T-cells in steroid-resistant patients has been postulated.

Twenty-seven patients with vision-threatening uveitis and four normal subjects were included in this study. Uveitis patients were classified as steroid-refractory or steroid-sensitive. The authors obtained peripheral blood mononuclear cells from all subjects. In vitro steroid responsiveness was determined by the presence or absence of a subpopulation of steroid-refractory CD4⁺ cells. These CD4⁺ cells were able to proliferate in vitro in the presence of dexamethasone.

There was a highly significant 78 percent agreement between the presence of in vitro steroid-refractory CD4⁺ cells and clinically diagnosed steroid-resistant immune-mediated uveitis (p=0.002). This corresponded to a positive predictive value of 90 percent and a negative predictive value of 71 percent. Suppression of CD4⁺ cells by inhibition of IL-2 in vitro with agents, such as basiliximab and daclizumab, was equivalent to dexamethasone's efficacy in normal subjects.

This study had certain limitations: subjects were not case-matched, the causes of uveitis were variable and some patients were diagnosed with intermediate uveitis, Behcet's disease or HLA-B27-associated disease. It remains unclear whether the response to steroids is the same over time or influenced by disease activity. The study has shown that steroid-refractory CD4⁺ cells may continue to proliferate in the presence of dexamethasone but may remain susceptible to specific IL-2 blockade by daclizumab or basiliximab. Each of the IL-2 inhibitors used in the study showed a similar pattern of T-cell inhibition, suggesting that they have similar mechanisms of action.

This study is important because there is need from the outset to identify patients who may be resistant to steroid therapy rather than subjecting them to a trial period with steroid therapy that could result in irreversible damage due to immune-mediated uveitis. An in vitro test to find out whether patients with immune-mediated uveitis possess steroid-refractory CD4⁺ cells is necessary. This may be used as a biomarker for steroid-resistant uveitis cases. Agents that inhibit IL-2 may interfere with T-cell proliferation and provide early prevention of irreversible damage to sight-sensitive structures and clinically steroid-sparing treatment options.

Financial Disclosures
Dr. Tabbara has no financial interests to disclose.