A2Ar-dependent PD-1+ and TIGIT+ Treg cells have distinct homing requirements to suppress autoimmune uveitis in mice.

The proper function of regulatory T cells (Tregs) to suppress inflammation requires homing to the correct tissue site. Resolution of autoimmune uveitis generates distinct programmed death receptor 1 (PD-1+) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT+) Tregs in an adenosine 2A receptor (A2Ar)-dependent manner found in the spleen. Where and how these Tregs migrate from the spleen to prevent uveitis is not known. In this work, we show that A2Ar-dependent Tregs migrated to the eye and secondary lymphoid tissue and expressed chemokine receptor (CCR)6 and CCR7. Suppression of autoimmune uveitis required CCR6 and CCR7 expression for TIGIT+ Tregs but not PD-1+ Tregs. Moreover, stimulation of A2Ar on T cells from patients showed a decreased capacity to induce TIGIT+ Tregs that expressed CCR6 or CCR7, and PD-1+ Treg that expressed CCR6. This work provides a mechanistic understanding of the homing requirements of each of these Treg populations. Importantly, this work is clinically relevant because patients with chronic autoimmune uveitis are unable to induce the Treg populations identified in mice that home to the target tissue.

Early Real-World Physician Experience with an Intracanalicular Dexamethasone Insert.

Purpose: To describe the early real-world experience of physicians with an intracanalicular dexamethasone insert (DEX) in patients undergoing cataract surgery and to capture the clinical impact of adopting this therapy. Patients and Methods: 23 United States sites including Ambulatory Surgical Center Setting (ASC) and Outpatient Clinical settings. Respondents were physicians who had early experience with DEX in cataract surgery patients. This was a Phase 4 experiential cross-sectional survey study comprised of 3 sequential online physician surveys. Descriptive statistics summarized the surveys' responses to determine the early impressions of the respondents. Results: Forty-two physicians completed surveys. On average, physicians reported feeling comfortable administering DEX after placing 3 inserts (mean 2.7; standard deviation 1.9). Most physicians (92%) were satisfied with DEX, and all physicians (100%) reported that DEX improved patient compliance. Most physicians (62.5%) indicated they would highly prefer DEX over traditional steroid eyedrops for the management of post-surgical inflammation and pain. Conclusion: The surveys exploring the early use of DEX suggest that DEX is a clinically effective treatment with a rapid initial learning curve and integrates well into clinical use. Physicians had a very positive early experience with DEX, including comfort with insertion and satisfaction. DEX shows promise as a primary treatment choice of physicians for ocular inflammation and pain following cataract surgery by offering patients a hands-free innovative therapy that delivers a preservative-free steroid to the ocular surface over approximately 30 days.

Treatment of Noninfectious Retinal Vasculitis Using Subcutaneous Repository Corticotropin Injection.

PURPOSE: To show whether subcutaneous repository corticotropin injection (RCI, Acthar® Gel, a repository corticotropin injection, can be an effective potential therapeutic agent for noninfectious retinal vasculitis. METHODS: Patients with active retinal vasculitis were followed with serial ultra-wide-field fluorescein angiograms and treated with 80 units of subcutaneous repository corticotropin injection twice weekly. RESULTS: Primary outcome of ≥ 50% improvement in response level (RL) for retinal vasculitis and percent improvement in retinal vasculitis severity scoring (RVSS) by more than one quartile ( ≥ 25%) at week 12 was met in 15 and 16 of the 30 total eyes, respectively, including 1 eye with severe retinal vasculitis in each group. Complete resolution of retinal vasculitis was seen in seven eyes with a mean time of 17.1 weeks. Intraocular pressure elevation requiring therapy and cataract progression were noted in two and three eyes, respectively. One patient stopped medication due to side effects (injection site reaction). CONCLUSION: Repository corticotropin injection was well-tolerated overall. Repository corticotropin injection may be an effective therapeutic agent in the treatment of noninfectious retinal vasculitis.

CRYOPYRIN-ASSOCIATED PERIODIC SYNDROME-ASSOCIATED UVEITIS AND PAPILLITIS.

PURPOSE: To report a case of uveitis and papillitis in a patient with cryopyrin-associated periodic syndrome. METHODS: Case report. A 44-year-old white woman with a long history of inflammatory arthritis, diffuse erythematous rashes and hives, and hearing loss was referred to the Massachusetts Eye Research and Surgery Institution for an evaluation of chronic ocular inflammation. She was diagnosed with bilateral papillitis and uveitis after a comprehensive eye examination, which included dilated fundoscopy, optic nerve ocular coherence tomography, fluorescein angiography, indocyanine green angiography, and B-scan ultrasonography. She was later diagnosed with cryopyrin-associated periodic syndrome, an interleukin-1-driven autoimmune disease, as confirmed by genetic testing. Soon after starting treatment with anakinra, a human interleukin-1 receptor antagonist, she experienced rapid improvement of her ocular and systemic symptoms, including rash, uveitis, and arthritis. RESULTS: Cryopyrin-associated periodic syndrome-associated ocular inflammation in remission with anakinra 100-mg daily subcutaneous injection. CONCLUSION: Anakinra is a very effective treatment for both cryopyrin-associated periodic syndrome and cryopyrin-associated periodic syndrome-associated ocular inflammation.

TIGIT+ A2Ar-Dependent anti-uveitic Treg cells are a novel subset of Tregs associated with resolution of autoimmune uveitis.

Regulatory T cells (Tregs) are necessary to prevent autoimmune disease. As such, stable FoxP3 expression is required for the proper function of Tregs in the control of autoimmune disease. Different Treg subsets that utilize different mechanisms of suppression have been identified. The T-cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif (TIGIT) is a relatively new Treg cell marker that has a suppressive function. We have previously identified the adenosine 2A receptor (A2Ar) as a requirement for the emergence of Tregs following resolution of autoimmune disease. Using a FoxP3-GFP-Cre reporter mouse, we identify FoxP3 and 'exFoxP3' cells, show FoxP3 and not exFoxP3 cells are suppressive. We further show FoxP3 cells express TIGIT, and are induced through A2Ar in healthy volunteers, but not patients with autoimmune disease. Furthermore, we show Tregs emerge in the target tissue at the onset of autoimmune disease in an A2Ar-dependent manner. In summary, we identify a novel subset of TIGIT+ Tregs that are induced through stimulation of the A2Ar.

Long-term outcomes of systemic corticosteroid-sparing immunomodulatory therapy for Birdshot Retinochoroidopathy.

PURPOSE: To report the visual prognosis, electroretinography (ERG) and perimetry outcomes of systemic corticosteroid-sparing immunomodulatory treatment (IMT) for birdshot retinochoroidopathy (BSRC). METHODS: Retrospective non-comparative case series of 132 patients (264 eyes) with BSRC treated with IMT from Massachusetts Eye Research and Surgery Institution. RESULTS: The average follow-up time was 60.1 months. After one year on IMT, 39.4% showed no clinically active inflammation. After 5 years of IMT, 78.0% had no signs of clinical inflammation. No significant differences were observed on best-corrected visual acuity (BCVA), ERG parameters, and perimetry parameters between baseline and subsequent visits on IMT. CONCLUSION: Long-term systemic corticosteroid-sparing IMT was associated with a low rate of BSRC disease exacerbation. While differences were seen on testing parameters, they were not consistent trends and difference were attributed to variability of testing or fluctuation of inflammation that may be expected in the course of the disease.

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 Challenge of Pediatric Uveitis: Tertiary Referral Center Experience in the United States.

Purpose: To describe the distribution, clinical findings, visual outcomes, treatment, and complications of children with uveitis at a tertiary referral ophthalmic center. Methods: Retrospective cohort study. We reviewed the medical records of all patients ≤16 years with uveitis referred to Massachusetts Eye Research and Surgery Institution from March 2005 to July 2016. Results: Of 286 included children, 62.24% were female. Mean age of onset was 8.4 years. The uveitis was mainly anterior (61.9%), recurrent (68.53%), bilateral (81.82%), and noninfectious (96.5%). Idiopathic cases accounted for 51.4%. The most frequent systemic association was juvenile idiopathic arthritis (34.96%). The majority of patients (78.32%) experienced complications. All patients, except one, needed systemic therapy. Conclusion: Pediatric uveitis is challenging to diagnose and manage, with frequent and potentially severe complications. Most cases were bilateral, recurrent, and idiopathic. Prompt referral to uveitis-specialized centers and an appropriate systemic therapy are mandatory for good visual outcomes.

Outcomes of "Early" Withdrawal of Corticosteroid Sparing Immunomodulatory Therapy for Birdshot Retinochoroidopathy.

Purpose: To review early withdrawal of immunomodulatory therapy (IMT) for birdshot retinochoroidopathy (BSRC). Design: Retrospective case-series of sixteen patients with Human-leukocyte-antigen-A29-positive BSRC treated with IMT ≥ 1 year and discontinued prior to achieving durable remission, observed ≥ 6 months off IMT. Results: Mean duration on IMT was 42.4 months. At discontinuation, quiescence was achieved in 75.0% of eyes. Subjects off IMT for 6 months, 1 year, and 3 years showed quiescence in 75.0%, 77.8%, and 80.0% of eyes. No significantly decreased vision was found 6 or 12 months after discontinuation. One eye experienced significantly decreased vision following 3 years without IMT. Significantly decreased amplitude on electroretinography and worse deviation parameters in perimetry were found in patients 3 years after withdrawal that experienced early discontinuation when compared with those achieving durable remission on IMT > 2 years (p < 0.05). Conclusion: The possibility of electroretinography and perimetry results worsening after early IMT discontinuation remained if the patients couldn't achieve remission.

Novel Dexamethasone Sodium Phosphate Treatment (DSP-Visulex) for Noninfectious Anterior Uveitis: A Randomized Phase I/II Clinical Trial.

PURPOSE: Frequent steroid drops represent a challenge in patient compliance. This study evaluated the safety and efficacy of 5 minute topical dexamethasone sodium phosphate-Visulex (DSP-Visulex) treatment regimen (two applications on the first week then weekly after) compared to daily prednisolone acetate 1% (PA) for noninfectious anterior uveitis. MATERIALS AND METHODS: Forty-four patients were randomized to 8% DSP-Visulex with placebo eye drops (8% group, n = 14), 15% DSP-Visulex with placebo eye drops (15% group, n = 15), or Vehicle-Visulex with PA eye drops (PA group, n = 15). Patients received daily eye drops and Visulex treatments on days 1, 3, 8, and 15 with an optional treatment on day 22. Efficacy measures were change in anterior chamber cell (ACC) count from baseline and proportion of patients with zero ACC count at days 8, 15, and 29. Safety measures were adverse events (AEs), visual acuity, ocular symptoms, and intraocular pressure (IOP). RESULTS: ACC resolution over time was similar among the three groups. The percentage of patients with clear ACC was 18%, 22%, and 15% on day 8; 27%, 56%, and 54% on day 15; and 90%, 88%, and 77% on day 29 for the 8%, 15%, and PA groups, respectively. The numbers of reported AEs were 10, 36, and 12 for the 8%, 15%, and PA groups, respectively. Ten patients among all groups experienced treatment-related AEs, which included headache, eye pain, corneal abrasion, conjunctival/corneal staining, conjunctivitis, visual acuity reduction, and keratitis all of which were resolved during the timeframe of patients' participation in the study. IOP elevation was noted in the PA group throughout the study, whereas IOP elevation in the DSP-Visulex groups was observed at day 3 but not thereafter. CONCLUSIONS: The efficacy of the DSP-Visulex applications was comparable to the daily PA drops in the treatment of noninfectious anterior uveitis. Both 8% and 15% DSP-Visulex treatments were safe and well tolerated.

Ahmed glaucoma valve in uveitic patients with fluocinolone acetonide implant-induced glaucoma: 3-year follow-up.

PURPOSE: To evaluate the efficacy and safety of Ahmed glaucoma valve (AGV) in eyes with noninfectious uveitis that had fluocinolone acetonide intravitreal implant (Retisert™)-induced glaucoma. METHODS: This retrospective study reviewed the safety and efficacy of AGV implantation in patients with persistently elevated intraocular pressure (IOP) after implantation of a fluocinolone acetonide intravitreal implant at the Massachusetts Eye Research and Surgery Institution between August 2006 and November 2015. RESULTS: Nine patients with 10 uveitic eyes were included in this study, none of which had preexisting glaucoma in the study eye. Mean patient age was 42 years; 6 patients were female and 3 were male. Baseline mean IOP was 30.6 mmHg prior to AGV placement while mean IOP-lowering medications were 2.9. In the treatment groups, there was a statistically significant reduction in post-AGV IOP. IOP was lowest at 1-week after AGV implantation (9.0 mmHg). Nine out of 10 eyes achieved an IOP below target value of 22 mmHg and/or a 20% reduction in IOP from baseline 1 month and 1 year following AGV placement. All other postoperative time points showed all 10 eyes reaching this goal. A statistically significant decrease in IOP-lowering medication was seen at the 1-week, 1-month, and 3-year time points compared to baseline, while a statistically significant increase was seen at the 3-month, 6-month, and 2-year post-AGV time points. No significant change in retinal nerve thickness or visual field analysis was found. CONCLUSION: AGV is an effective and safe method of treatment in fluocinolone acetonide intravitreal implant-induced glaucoma. High survival rate is expected for at least 3 years.