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.

Effects of Subcutaneous Repository Corticotropin Gel Injection on Regulatory T Cell Population in Noninfectious Retinal Vasculitis.

AIM: To evaluate the effect of repository corticotropin injection (RCI) on regulatory T cell population in patients with noninfectious retinal vasculitis. PATIENTS AND METHODS: Patients with active noninfectious retinal vasculitis were included in a prospective nonrandomized open-label study. RESULTS: Eighteen patients (33 eyes) were included in the study. Eleven (61.1%) patients [20 (60.6%) eyes] and 7 (38.9%) patients [13 (33.3%) eyes] were in the responsive and non-responsive groups, respectively. We did not find any statistically significant difference within the PPP-R group, within the PPP-NR group, or between these two groups in regard to regulatory T cell population. No significant systemic or ocular complications were found. CONCLUSION: RCI may be a complementary treatment in patients with non-infectious retinal vasculitis with or without uveitis. This study did not demonstrate an increase in regulatory T cell population in patients with noninfectious retinal vasculitis.

Diagnostic and Prognostic Roles of Serum Interleukin-6 Levels in Patients with Uveitis.

PURPOSE: To examine the diagnostic and prognostic roles of serum interleukin-6 levels in patients with uveitis. METHODS: This was a retrospective observational case series. Demographic and clinical characteristics were compared between Group One (sixty patients) with normal serum IL-6 levels and Group Two (twenty patients) with high serum interleukin-6 levels. RESULTS: Mean IL-6 level was 1.77 ± 0.97 pg/ml and 10.2 ± 9.7 pg/ml in Group One and Group Two respectively. Age, presence of systemic disease, and mean number of flare-ups were statistically significant (p = .015, p = .000, p = .03, respectively). Multivariate analysis was performed on variables that were statistically significant in univariate analysis and showed that three variables had significant correlation with IL-6 levels in both groups: systemic disease (OR = 10.83, p < .001), Age (OR = 0.95, p = .03) and number of flare-ups (OR = 2.9, p = .02). CONCLUSION: Serum IL-6 levels can provide diagnostic and prognostic information in regard to the course of disease and its treatment.

Clinical features, visual outcome, and poor prognostic factors in occlusive retinal vasculitis.

OBJECTIVE: To investigate the clinical features, treatment, and visual outcome of occlusive retinal vasculitis (ORV), with a focal analysis on prognostic factors associated with poor visual outcome. METHODS: We conducted a retrospective cohort study in patients diagnosed with ORV with at least 6 months of follow-up. Demographic data, ocular features, best corrected visual acuity (BCVA), fluorescein angiography, therapy regimens, and outcomes were collected from the Massachusetts Eye Research and Surgery Institution database from 2006 to 2017. Multivariate logistic regression was performed to analyze the factors independently predicting poor visual outcome. RESULTS: Fifty-two patients (69 eyes) were enrolled, 42 with noninfectious cause, 9 with infectious cause, and 1 with masquerade uveitis. Systemic inflammatory diseases, including necrotizing vasculitis, sarcoidosis, multiple sclerosis, systemic lupus erythematosus, and Behçet's disease comprised the causes of ORV. Forty of the 42 patients with noninfectious ORV received immunomodulatory therapy (IMT), and 35 patients (87.5%) were able to achieve steroid-free remission. Compared with the BCVA at the initial visit (0.66 [±0.11] logMAR), there was significant improvement at the most recent visit (0.37 [±0.07] logMAR, p = 0.001). A multivariate analysis demonstrated that optic nerve atrophy, macular ischemia, and poor BCVA at initial presentation were independently correlated with poor visual outcome. CONCLUSIONS: ORV could be caused by a wide spectrum of systemic inflammatory diseases. Aggressive IMT is preferred to achieve a steroid-free durable remission for noninfectious ORV. Optic nerve atrophy, macular ischemia, and poor BCVA at the initial visit predict a poor visual outcome.

Fixed-Luminance and Multi-Luminance Flicker Electroretinography Parameters in Patients with Early Active Birdshot Chorioretinopathy.

PURPOSE: To evaluate the parameters of the Fixed-Luminance and Multi-Luminance flicker electroretinography protocol among patients with early active birdshot chorioretinopathy. METHODS: Fixed-Luminance magnitude, Fixed-Luminance phase, Multi-Luminance magnitude area under the curve, and Multi-Luminance phase area under the curve parameters were compared between early active birdshot chorioretinopathy patients and an age-matched control group. RESULTS: There was no statistically significant difference between the Fixed-Luminance flicker magnitude (P = .6), the Fixed-Luminance flicker phase (P = .9), and the Multi-Luminance flicker phase area under the curve (P = .55) when each was compared to the normal population; however, the difference between the mean Multi-Luminance flicker magnitude area under the curve in our patients and the healthy control group was statistically significant. (P = .003). CONCLUSIONS: Multi-Luminance flicker magnitude area under the curve has been shown to be significantly different from the normal population in the early active course of the disease. ABBREVIATIONS: BSCR: birdshot chorioretinopathy; cd: Cadmium; ERG: Electroretinography; FA: Fluorescein angiography; FL-: Fixed-luminance; HVF: Humphrey visual field; Hz: Hertz; ICG: Indocyanine green; m2: Square meter; ML-: Multi-luminance; ms: millisecond; SITA: Swedish interactive thresholding algorithm; SWAP: Short wave-length automated perimetry.

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.

Reliability of Conjunctival Biopsy for Diagnosis of Ocular Mucous Membrane Pemphigoid: Redetermination of the Standard for Diagnosis and Outcomes of Previously Biopsy-Negative Patients.

Purpose: To demonstrate the reliability of conjunctival biopsy analyzed by direct immunofluorescence (DIF) and supplemented with avidin-biotin complex immunoperoxidase (ABC) in diagnosing oMMP, and report therapy response in biopsy-positive patients, particularly when previously biopsy-negative elsewhere.Methods: Retrospective outcomes review of 136 consecutive patients after conjunctival biopsy for suspected oMMP.Results: Among 136 patients, 66% were diagnosed with oMMP by DIF and 13% via supplemental ABC immunoperoxidase. Sensitivity increased from 79.6% with DIF to 95.6% with supplemental ABC. Among 57 biopsy-positive patients, 77% were in remission at 1-year follow-up and 88% after 2 years. Of 34 previous biopsy-negative but now biopsy-positive patients with a 2-year follow-up, 91% achieved remission, including all 16 diagnosed via DIF and ABC.Conclusion: Conjunctival biopsy analyzed by histopathology and DIF supplemented by ABC has high reliability for diagnosing oMMP and is a useful tool to use before starting long-term immunomodulatory therapy in a patient with suspected oMMP.

Combination of Intravenous Methotrexate and Methylprednisolone Therapy in the Treatment of Severe Ocular Inflammatory Diseases.

Purpose: To evaluate the efficacy of intravenous methotrexate and methylprednisolone in severe, sight-threatening ocular inflammatory conditions.Methods: This was a retrospective observational case series. Patients who had received intravenous methotrexate for ocular inflammation with at least 24 months of follow-up were included in the study.Results: Ten patients (20 eyes) were included in this study. Mean age of the patients was 47.2 ± 17.7 (range:19-74). At 1-month follow-up visit, nine patients showed improvement and one patient failed treatment. At 12-month follow-up visit, all patients were in remission. Two patients were only on intravenous methotrexate infusions. At twenty-four-month follow-up visit, only one patient, in remission, was on intravenous methotrexate therapy. Leukopenia was the only adverse effect observed.Conclusion: Intravenous methotrexate and methylprednisolone infusions can be an effective method of treatment in patients with severe, sight-threatening ocular inflammatory conditions.

Efficacy and Safety of Infliximab in HLA-B27-associated Ocular Inflammation Refractory or Intolerant to Conventional Immunomodulatory Therapy.

PURPOSE: To determine the efficacy and safety of infliximab therapy in patients with HLA B-27-associated ocular inflammation resistant or intolerant to conventional immunomodulatory therapy. METHODS: This was a retrospective observational case series. All cases were uveitic patients with positive HLA-B27, confirmed through HLA testing, resistant or intolerant to conventional immunomodulatory therapy. The primary outcome of the study was to identify the efficacy of infliximab determined by the control of inflammation, duration of remission, and the ability to reduce conventional immunomodulatory therapy. The secondary outcome was an improvement of two or more lines of best-corrected visual acuity (BCVA) on the Snellen visual acuity chart. RESULTS: Twenty-four patients (38 eyes) were included in the study. All patients were followed for 24 months. Twenty-one (87.5%) patients completed 24 months of follow-up. Sixteen (66.7%) patients had active uveitis at the beginning of therapy. One patient out of these active patients had active inflammation at the end of follow-up period. Thirteen (87.5%) out of sixteen active patients were in steroid-free remission. The mean duration of treatment to induce remission was 16.5 months (range 6-24 months). Corticosteroid was stopped in 19 (90.5%) patients by the end of the study. At the end of the study, in patients who achieved remission, 14 (58.3%) patients were in remission on infliximab therapy and 6 (25%) patients were in remission off infliximab therapy. Of the 38 eyes, 8 (21.05%) showed improvement in BCVA (three eyes had successful cataract extraction with intraocular lens implantation during infliximab therapy with no subsequent inflammation), while 26 eyes (68.4%) had stable BCVA over the 24-month study period. The side effects included allergic reaction, fatigue, cellulitis, headache, restlessness, elevation of liver enzymes, and anemia. Two patients (n = 24, 8.3%) experienced severe adverse effects and the treatment was stopped prematurely in these two patients. CONCLUSION: Infliximab might induce and maintain the steroid-free remission in HLA-B27-associated ocular inflammation in patients resistant or intolerant to conventional immunomodulatory therapy.

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.