Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis

Purpose. A majority of experimental data on dry eye disease (DED) immunopathogenesis have been derived from a murine model of DED that combines desiccating environmental stress with systemic muscarinic acetylcholine receptor (mAChR) inhibition. However, to our knowledge the effects of pharmacologic mAChR blockade on the pathogenesis of experimental DED have not been evaluated systemically. The purpose of our study was to investigate the differential effects of desiccating environmental stress and mAChR inhibition on the pathogenesis of DED. Methods. DED was induced in female C57BL/6 mice by exposure to a desiccating environment in the controlled-environment chamber or to systemic scopolamine, or by performing extraorbital lacrimal gland excision. Clinical disease was assessed using corneal fluorescein staining (CFS) and the cotton thread test (CTT). Corneal CD11b+ and conjunctival CD3+ T-cell infiltration were evaluated by flow cytometry. T-cells from draining cervical lymph nodes (CLN) and distant inguinal lymph nodes (ILN) were analyzed for Th1, Th2, Th17, and Treg responses by flow cytometry and ELISA. Results. Desiccating environmental stress and systemic mAChR blockade induced similar clinical signs of DED. However, desiccating environmental stress imparted higher conjunctival CD3+ T-cell infiltration, and greater Th17-cell activity and Treg dysfunction than mAChR blockade, while mAChR blockade decreased tear secretion to a greater extent than desiccating environmental stress. Systemic mAChR blockade attenuated Th17 activity and enhanced Th2 and Treg responses without affecting Th1 activity. Conclusions. In vivo inhibition of mAChRs variably affects CD4+ T-cell subsets, and desiccating environmental stress and systemic mAChR blockade induce DED through different primary pathogenic mechanisms

Single-cell profiling identifies a CD8bright CD244bright Natural Killer cell subset that reflects disease activity in HLA-A29-positive birdshot chorioretinopathy

Birdshot chorioretinopathy is an inflammatory eye condition strongly associated with MHC-I allele HLA-A29. The striking association with MHC-I suggests involvement of T cells, whereas natural killer (NK) cell involvement remains largely unstudied. Here we show that HLA-A29-positive birdshot chorioretinopathy patients have a skewed NK cell pool containing expanded CD16 positive NK cells which produce more proinflammatory cytokines. These NK cells contain populations that express CD8A which is involved in MHC-I recognition on target cells, display gene signatures indicative of high cytotoxic activity (GZMB, PRF1 and ISG15), and signaling through NK cell receptor CD244 (SH2D1B). Long-term monitoring of a cohort of birdshot chorioretinopathy patients with active disease identifies a population of CD8bright CD244bright NK cells, which rapidly declines to normal levels upon clinical remission following successful treatment. Collectively, these studies implicate CD8bright CD244bright NK cells in birdshot chorioretinopathy

Indocyanine Green Angiography in Uveitis

The visualization of the choroidal vasculature with the use of indocyanine green angiography (ICGA) has led to an improved understanding of choroid involving uveitic entities and their pathogenesis. ICGA has also emerged as having an important role in the diagnosis and follow-up of uveitic diseases, as well as in evaluating the full extent of choriocapillaris and choroidal stromal involvement in these diseases. This chapter reviews ICGA findings in the different chorioretinal uveitic diseases

Bilateral Acute Macular Neuroretinopathy after COVID-19 Vaccination and Infection

PURPOSE: To describe a case of acute macular neuroretinopathy (AMN) in a patient with recent COVID-19 vaccination and infection who demonstrated atypical features on presentation. OBSERVATIONS: A 64-year-old woman presented with central vision loss in both eyes (OU). She had recently received the Moderna COVID-19 vaccine and rapidly developed systemic symptoms. Testing revealed COVID-19 infection. Visual acuities were 20/200 OU and near-infrared reflectance revealed hypo-reflective lesions in the maculae OU, optical coherence tomography (OCT) showed outer nuclear layer thinning and ellipsoid zone disruption OU, and OCT-angiography showed flow voids in the deep capillary plexus and choriocapillaris OU, all consistent with AMN. She was treated with oral prednisone with subsequent mild vision improvement and persistent scotomas. DISCUSSION: COVID-19 associated AMN can present with a more severe clinical presentation than classically seen in AMN. Ischemic and inflammatory changes due to COVID-19 infection may contribute to this more advanced presentation

Recurrent Multiple Evanescent White Dot Syndrome (MEWDS) Following First Dose and Booster of the mRNA-1273 COVID-19 Vaccine: Case Report and Review of Literature

To report a rare case of a patient with two recurrent episodes of Multiple Evanescent White Dot Syndrome (MEWDS) associated with the second dose and second booster of the mRNA-1273 COVID-19 vaccine (Moderna), and to perform a literature review on COVID-19-vaccine-associated MEWDS. Case Report: A 31-year-old female was evaluated for a temporal scotoma and photopsias that started two weeks after the second dose of the Moderna COVID-19 vaccine. Dilated fundus findings were remarkable for unilateral, small whitish-yellow dots scattered around posterior pole of the left eye, consistent with a diagnosis of MEWDS. The symptoms resolved three months later without treatment. Approximately one year after the first vaccine, the patient received the second Moderna COVID-19 vaccine booster and experienced a recurrence of symptoms with an enlarged scotoma and similar examination findings. The patient was treated with a course of systemic corticosteroids with subsequent clinical improvement. Conclusion: Although uveitis following COVID-19 vaccines is rare, our case highlights a need for increased awareness amongst practitioners regarding COVID-19-vaccine-associated onset or recurrence of ocular inflammatory diseases

Impact of the COVID-19 pandemic on uveitis patient care

BackgroundThe COVID-19 pandemic has significantly changed practice of medicine and patient care worldwide. The impact of the pandemic on patients with uveitis is unknown. We developed the COVID-19 Practice Patterns Study Group to evaluate the effect of the pandemic on uveitis patient care.MethodsThis is a multicentre, cross-sectional survey of uveitis specialists practising worldwide. A web-based survey was distributed through the mailing lists of international uveitis societies to assess modifications in patient care, and use of immunomodulatory therapies (IMTs),aswell as considerations regarding COVID-19 vaccination.ResultsA diverse group consisting of 187 uveitis specialists from six continents participated in this survey. Most of these experts noted a disruption in clinical management of patients, including clinic closures or decrease in volume, patients missing in-person visits due to the fear of infection and difficulties obtaining laboratory testing. Most participants initiated (66.8%) and continued (93.3%) IMTs based on clinical presentation and did not modify their use of immunosuppressives. In cases of reported exposure to COVID-19 infection, most participants (65.3%) recommended no change in IMTs. However, 73.0% of the respondents did recommend holding all or select IMTs in case of COVID-19 infection. COVID-19 vaccine was recommended universally by almost all the specialists and 52% stated that they would counsel patients regarding the decreased immunogenicity and effectiveness of the vaccine in immunocompromised patients.ConclusionsUveitis patient care has changed significantly since the beginning of the pandemic. The recommendations will continue to evolve as new data on IMTs and vaccination become available

Efficacy of Topical Blockade of Interleukin-1 in Experimental Dry Eye Disease

PURPOSE To evaluate the therapeutic efficacy of topical IL-1Ra in the treatment of Dry Eye Disease (DED). DESIGN Laboratory Investigation. METHODS DED was induced in C57BL/6 female mice through exposure to a desiccating environment within a controlled environment chamber. Topical formulations containing 5% IL-1Ra, 1% methylprednisolone, 0.05% cyclosporin A (CsA), and a vehicle control containing carboxymethylcellulose sodium (CMC) were applied following the induction of dry eye. Corneal fluorescein staining (CFS) was performed by a masked observer in the different treatment groups. Immunohistochemical studies were undertaken to enumerate corneal CD11b+ cells, as well as to evaluate corneal lymphangiogenesis. Real-time polymerase reaction was used to quantify the expression of IL-1β in the cornea. RESULTS A significant decrease in CFS was observed following topical treatment with 5% IL-1Ra (P<0.01), 1% methylprednisolone (P<0.01), and 0.05% CsA (P<0.03). Additionally, a significant decrease in the numbers of central corneal CD11b+ cells (P<0.05), corneal lymphatic growth (P<0.05), and corneal IL-1β expression (P<0.003), compared to vehicle treated, were only demonstrated following treatment with 5% IL-1Ra and 1% methylprednisolone, and were absent following CsA treatment. CONCLUSIONS Topical treatment with IL-1Ra is efficacious in ameliorating the clinical signs of the DED, as well as in reducing underlying inflammation.These effects are comparab le to treatment with topical methylprednisolone. Topical IL-1Ra may hold promise as a novel therapeutic strategy in the treatment of dry eye

Treatment challenges in an atypical presentation of tubulointerstitial nephritis and uveitis (TINU)

Purpose: To describe an atypical presentation of Tubulointerstitial Nephritis and Uveitis (TINU), with challenges in treatment course. Observations: A 12-year-old Hispanic female presented to the National Eye Institute's Uveitis clinic with bilateral blurred vision, red eyes and photophobia, not responsive to topical steroids. On exam, she had bilateral severe panuveitis with areas of subretinal fluid. During her evaluation, she was noted to have elevated serum creatinine. A kidney biopsy confirmed the presence of severe tubulointerstitial nephritis and interstitial fibrosis. She was treated with oral steroids with excellent resolution of symptoms and subretinal fluid. She continued to have anterior segment flares with attempts to taper oral prednisone which lead to treatment with multiple immunomodulatory agents. Associated hypertension and kidney damage complicated the choice of a secondary immunosuppressive agent. Conclusions and Importance: Although rare, TINU can present as panuveitis with choroidal involvement which may or may not be preceded by tubulointerstitial nephritis. A renal biopsy is required for definitive diagnosis, but abnormal urinalysis or renal function should raise suspicion for TINU. Keywords: Immunosuppression, Inflammation, Tubulointerstitial nephritis, Uveiti

Antidrug Antibodies to Tumor Necrosis Factor α Inhibitors in Patients With Noninfectious Uveitis

IMPORTANCE: Tumor necrosis factor inhibitors (TNFis) can induce antidrug antibody (ADA) formation and loss of therapeutic response. However, the utility of ADA testing and the association between ADAs and treatment response in patients with noninfectious uveitis (NIU) is not well understood. OBJECTIVE: To assess the frequency of ADAs and their association with drug levels and clinical response in patients with NIU treated with adalimumab or infliximab. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study included patients diagnosed with NIU who received adalimumab or infliximab and underwent testing for serum drug level and ADAs at the National Eye Institute from September 2017 to July 2021. EXPOSURES: Serum drug level testing with reflex testing for ADA levels was performed. MAIN OUTCOMES AND MEASURES: The main outcome was the association between drug levels and ADAs, clinical response, and concurrent antimetabolite use in patients treated with TNFis for NIU. RESULTS: Of 54 patients included in the study, 42 received adalimumab (mean [SD] age, 43.6 [19.6] years; 25 [59.5%] female) and 12 received infliximab (mean [SD] age, 42.7 [20.4] years; 7 [58.3%] male). In the adalimumab group, mean (SD) drug level was 9.72 (6.82) μg/mL, mean (SD) ADA level was 84.2 (172.9) arbitrary units/mL, and ADA frequency was 35.7% (15 of 42 patients). Mean drug level was lower in those with ADAs compared with those without ADAs (mean [SD], 2.8 [2.6] μg/mL vs 13.6 [5.2] μg/mL; difference: 10.8 μg/mL; 95% CI, 8.3-13.2 μg/mL; P \u3c .001). There was a higher mean drug level with concurrent antimetabolite use compared with monotherapy (mean [SD], 11.0 [7.3] μg/mL vs 6.8 [4.5] μg/mL; difference: -4.2 μg/mL; 95% CI, -8.7 to 0.2 μg/mL; P = .06). Multivariable modeling showed that a 1-arbitrary unit increase in ADAs was associated with a -0.02 μg/mL (95% CI, -0.01 to -0.34 μg/mL) difference in mean drug level (P \u3c .001). Favorable clinical response was associated with a threshold drug level above 2.7 μg/mL or an antibody level below 15.2 μg/mL. The mean (SD) drug level in the infliximab group was 27.02 (18.15) μg/mL, and no ADAs were detected. CONCLUSIONS AND RELEVANCE: In this study, 35.7% of adalimumab-treated patients with NIU had ADAs. The presence of ADAs was associated with lower drug levels, and higher ADA levels were associated with increased risk of TNFi treatment failure. Although limited by the retrospective design, our results suggest that therapeutic drug monitoring may be considered among patients experiencing therapy failure to help exclude ADAs as a potential cause of treatment failure