PD-1+ melanocortin receptor dependent-Treg cells prevent autoimmune disease.

Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis marked by ocular autoantigen-specific regulatory immunity in the spleen. The melanocortin 5 receptor (MC5r) and adenosine 2 A receptor (A2Ar) are required for induction of post-EAU regulatory T cells (Tregs) which provide resistance to EAU. We show that blocking the PD-1/PD-L1 pathway prevented suppression of EAU by post-EAU Tregs. A2Ar induction of PD-1+FoxP3+ Tregs in uveitis patients was similar compared to healthy controls, but was significantly reduced with melanocortin stimulation. Further, lower body mass index correlated with responsiveness to stimulation of this pathway. These observations indicate an importance of the PD-1/PD-L1 pathway to provide resistance to relapsing uveitis and shows a reduced capacity of uveitis patients to induce Tregs when stimulated through melanocortin receptors, but that it is possible to bypass this part of the pathway through direct stimulation of A2Ar.

The variable efficacy of intravitreal bevacizumab and triamcinolone acetonide for cystoid macular edema due to radiation retinopathy.

BACKGROUND: Both intravitreal bevacizumab and triamcinolone have been shown to be effective in treating macular edema secondary to VEGF-mediated disease. The purpose of this study is to describe the variable effects of intravitreal bevacizumab (IVB) and triamcinolone acetonide (IVTA) in the treatment of macular edema secondary to radiation retinopathy. METHODS: Retrospective, nonrandomized, interventional case series. Charts of five patients with macular edema due to radiation retinopathy who received IVB with subsequent IVTA were reviewed. Clinical examination, Snellen visual acuity (VA), and central macular thickness (CMT) on optical coherence tomography (OCT) were examined. Main outcome measures included VA and CMT. RESULTS: Of the five patients reviewed, patient 1 demonstrated complete resolution of macular edema both clinically and by OCT with IVB after the first two injections with a decrease in CMT to 243 and 284 µm from a baseline CMT of 340 µm. However, response diminished following successive injections and the patient was switched to IVTA with a complete response. Mean CMT was 249 µm following four injections of IVTA and vision improved 3 lines. Patients 2 and 3 demonstrated a partial response to IVB with a mean CMT of 362 and 451 µm from 436 and 596 µm, respectively. They similarly had a partial response to IVTA with a mean CMT of 363 and 433 µm from 460 and 429 µm. There was no improvement in vision. Patient 2 was then switched to a combination of IVB and IVTA with complete resolution of macular edema with a CMT of 299 and 289 µm following two treatments. Patients 4 and 5 failed to respond to IVB with a mean increase in CMT of 64.5 and 6 µm. Both responded well to IVTA with complete resolution of macular edema. Mean decrease in CMT was 146 and 183 µm with a mean CMT of 254 and 281 µm. Final vision was stable in patient 4 and improved 3 lines from 20/100 to 20/50 in patient 5. CONCLUSION: IVB and IVTA have variable effects on the reduction of macular edema due to radiation retinopathy. IVB appears to have an initial effect in reducing macular edema in some patients but after multiple injections there can be resistance to its effects. IVTA was effective in three of five patients with complete resolution of macular edema. The combination of IVB and IVTA completely resolved macular edema in one patient resistant to IVB or IVTA alone. The reason for this may be due to their different therapeutic mechanisms of action and consideration should therefore be given to their use in combination.

Corticosteroid-associated osteonecrosis: a rare, but serious, complication in uveitis.

PURPOSE: To examine the incidence and prevalence of osteonecrosis in uveitis patients. METHODS: An electronic medical record database search was conducted to identify uveitis patients with osteonecrosis and the number at risk for corticosteroid-related osteonecrosis from 2003 to 2012. The clinical and ophthalmologic features of the uveitis patients with osteonecrosis were assessed with retrospective chart reviews. RESULTS: Six uveitis patients with osteonecrosis were identified, comprising a prevalence of 1.5%. The incidence density was 0.19 per 100 person-years of follow-up. The uveitides included sarcoidosis, sympathetic ophthalmia, idiopathic retinal vasculitis, idiopathic chronic anterior and intermediate uveitis, Vogt-Koyanagi Harada disease, and Cogan syndrome. The duration of systemic corticosteroid treatment ranged from 6 weeks to 6 years. The potential systemic risk factors were Raynaud phenomenon, antiphospholipid and autoantibodies, sickle cell trait, and thalassemia. CONCLUSIONS: Although osteonecrosis appears to be a rare complication among uveitis patients, physicians should strive to minimize systemic corticosteroid use when appropriate. A higher level of suspicion for osteonecrosis may be warranted in patients with additional systemic risk factors.

Interleukin-2 receptor targeted therapy of ocular disease of HTLV-1-associated adult T-cell leukemia.

PURPOSE: To report two cases of patients with ocular manifestations of human T-cell lymphotropic virus type-1 (HTLV-1) associated adult T-cell leukemia/lymphoma (ATL) who were successfully treated with interleukin-2 receptor targeted therapies. METHOD: Case series. RESULTS: Two patients with HTLV-1-associated ATL developed symptomatic scleritis. In the first case, conjunctival biopsy showed leukemic infiltration that was confirmed by T-cell receptor polymerase chain reaction (PCR) demonstrating a clonal rearrangement. As treatment for ATL, both cases received interleukin-2 receptor targeted therapy. In one patient, daclizumab, a monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor, was used. The second patient was treated with denileukin diftitox, an immunotoxin fusion protein that targets the IL-2 receptor. Improvement in scleritis was noted in both patients. CONCLUSION: Scleritis in patients with underlying HTLV-1-associated ATL is responsive to IL-2 receptor targeted therapies.

Subconjunctival sirolimus for the treatment of chronic active anterior uveitis: results of a pilot trial.

PURPOSE: To evaluate the safety and possible efficacy of subconjunctival sirolimus for the treatment of chronic active anterior uveitis. DESIGN: Prospective, nonrandomized, open-label clinical trial. METHODS: This single-center pilot trial enrolled 5 patients with chronic active anterior uveitis. The study drug was administered as a single subconjunctival injection of 30 µL (1320 µg) sirolimus in the study eye at the baseline visit. Study visits were performed at baseline, at 2 weeks, at 4 weeks, and monthly until 4 months, and included a complete ophthalmic examination, review of systems, adverse event assessment at each visit, physical examination, and ancillary ophthalmic testing at some visits. The primary outcome measure was a 2-step reduction in the anterior chamber inflammation within 4 weeks of injection of the study drug. RESULTS: There were 3 female and 2 male patients; 4 patients had idiopathic anterior uveitis and 1 had psoriatic arthritis-associated anterior uveitis. Three of the 5 patients met the primary outcome criteria by showing at least a 2-step decrease in inflammation within 4 weeks; 2 patients showed a 1-step decrease in inflammation within the same time frame. No recurrence was encountered during a 4-month follow-up. There were no serious adverse events. CONCLUSIONS: Subconjunctival sirolimus appears to be well tolerated in this pilot trial and shows promise as a treatment for active inflammation in patients with chronic anterior uveitis. Larger studies are needed to assess its usefulness in uveitis.

Hypotony in patients with uveitis: The Multicenter Uveitis Steroid Treatment (MUST) Trial.

PURPOSE: To assess the prevalence of hypotony in patients with severe forms of uveitis. METHODS: The Multicenter Uveitis Steroid Treatment (MUST) Trial, a randomized study, enrolled 255 patients. Patients with hypotony at the baseline visit were identified. RESULTS: Twenty (8.3%) of 240 patients with sufficient data had hypotony. Hypotony was more common in patients with uveitis ≥5 years duration (odds ratio [OR] = 5.0; p < .01), and in eyes with a history of ocular surgery (vitrectomy vs. none, OR = 3.1; p = .03). Hypotony was less in patients with older age of uveitis onset (>51 years vs. <51 years, OR = 0.1; p = .02), in Caucasian patients (OR = 0.1; p < .01) compared to African American patients. Hypotonous eyes were more likely to have visual impairment (OR = 22.9; p < .01). CONCLUSIONS: Hypotony is an important complication of uveitis and more commonly affects African-American patients, those with uveitis onset at a younger age, and those with longer disease duration. It is associated with visual impairment.

The incidence of central retinal artery occlusion in Olmsted County, Minnesota.

PURPOSE: To determine the incidence of central retinal artery occlusion in Olmsted County, Minnesota. DESIGN: Retrospective chart review. METHODS: Medical records of all patients living in Olmsted County, Minnesota between 1976 and 2005 diagnosed with central retinal artery occlusion were identified using the Rochester Epidemiology Project medical records linkage system. RESULTS: Forty-three cases were identified for an unadjusted annual incidence in the female population of 1.02 per 100,000 and 1.67 per 100,000 in the male population, with a combined incidence of 1.33. Incidence rates were also age- and/or sex-adjusted to the 2000 census figures for the US white population using direct standardization. Age-adjusted annual incidence per 100,000 for the female population was 1.15 (95% confidence interval [CI], 0.60-1.71), for the male population was 2.78 (95% CI, 1.69-3.86), and combined was 1.87 (95% CI, 1.31-2.43). When adjusted for age and sex, the incidence was 1.90 per 100,000 (95% CI, 1.33-2.47). CONCLUSION: Central retinal artery occlusion is a rare event. The incidence is 1.3 per 100,000 in Olmsted County, Minnesota, or 1.90 per 100,000 when age- and sex-adjusted for the United States white population.

Emerging drugs for uveitis.

INTRODUCTION: Uveitis is a challenging disease covering both infectious and noninfectious conditions. The current treatment strategies are hampered by the paucity of randomized controlled trials and trials comparing the efficacy of different agents. AREAS COVERED: This review describes the current and future treatments of uveitis. A literature search was performed in PUBMED from 1965 to 2010 on drugs treating ocular inflammation with emphasis placed on more recent, larger studies. Readers should gain a basic understanding of current treatment strategies beginning with corticosteroids and transitioning to steroid sparing agents. Steroid sparing agents include antimetabolites such as methotrexate, azathioprine and mycophenolate mofetil; calcineurin inhibitors which include cyclosporine, tacrolimus; alkylating agents which include cyclophosphamide and chlorambucil; and biologics which include the TNF-α inhibitors infliximab, adalimumab and etanercept and daclizumab, IFN-α(2a) and rituximab. EXPERT OPINION: Newer agents are typically formulated from existing drugs or developed based on new advances in immunology. Future treatment will require a better understanding of the mechanisms involved in autoimmune diseases and better delivery systems in order to provide targeted treatment with minimal side effects.

Intraocular inflammation following intravitreal injection of bevacizumab.

BACKGROUND: Injection of drugs into the vitreous can lead to intraocular inflammation through infectious and non-infectious processes. Failure to recognize an eye with anterior chamber and vitreous cell as sterile inflammation can lead to unnecessary treatment for endophthalmitis. METHODS: Four cases of uveitis following intravitreal bevacizumab (Avastin) for exudative age-related macular degeneration are described followed by review of the literature. RESULTS: Four patients presented with uveitis. Two patients presented with pain and red eye associated with iritis and two patients with vitritis, several days following intravitreal injection of bevacizumab. No paracentesis was performed and no corneal epithelial defect was created. Both patients with iritis were presumed to have sterile intraocular inflammation since the anterior chamber cell was much greater than the vitreous cell and resolved with cycloplegic and topical corticosteroid therapy. The third patient presented only with vitreous cell which resolved without therapy. The fourth patient had anterior chamber cell and vitreous cell with clumps, which resolved with topical prednisolone acetate. The inflammation resolved in all cases within 1 to 2 weeks. CONCLUSION: There are few published cases of uveitis following bevacizumab. With its rising use, it is important to be aware of its potential to be associated with intraocular inflammation.

Synergistic and antagonistic roles of the Sonic hedgehog N- and C-terminal lipids.

The Shh protein contains both N-terminal and C-terminal lipids. The functional redundancy of these lipid moieties is presently unclear. Here, we compare the relative roles of the N- and C-terminal lipids in early rat striatal neuronal differentiation, membrane association and multimerization, and ventralizing activity in the zebrafish forebrain. We show that these lipid act synergistically in cell tethering and the formation of a large (L) multimer (669 kDa). However, the C-terminal lipid antagonizes the rat striatal neuronal differentiation-inducing activity of the N-terminal lipid. In addition, multimerization is required but not sufficient for the differentiation-inducing activity. Based on the presence of different N- and C-lipid-containing Shh proteins in the rat embryo, and on their different activities, we propose that both N- and C-terminal lipids are required for the formation of multimers involved in long-range signaling, and that the C-terminal lipid may function in long-range signaling by reducing Shh activity until it reaches its long-range target. Comparative analysis of the ventralizing activities of different N- and C-terminal lipid-containing Shh proteins in the zebrafish forebrain shows that the presence of at least one lipid is required for signaling activity, suggesting that lipid modification of Shh is a conserved requirement for signaling in the forebrain of rodents and zebrafish.