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Background: Ocular inflammatory diseases, including scleritis and uveitis, have been widely treated with immunomodulatory therapies (IMTs) as a steroid-sparing approach. Such strategy includes conventional therapies (antimetabolites, alkylating agents, and calcineurin inhibitors) as well as biologic agents like adalimumab, infliximab, rituximab, and tocilizumab. Cyclophosphamide (CP) is an alkylating agent and mainly inhibits the functioning of both T and B cells. Though known to have potential adverse events, including bone marrow suppression, hemorrhagic cystitis, and sterility, CP has been shown to be efficacious, especially in recalcitrant cases and when used intravenous (IV) for a limited period. Main findings: We conducted a retrospective case-series to assess the safety and efficacy of CP therapy for patients with severe ocular inflammatory diseases who failed other IMTs. Medical records of 1295 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were reviewed. Seven patients (10 eyes) who received CP therapy for ocular inflammatory diseases with at least one year of follow-up were included. The mean age of the patients (4 males, 3 females) was 61.6 ± 14.9 (43.0–89.0) years. Clinical diagnoses included necrotizing scleritis (5 eyes), peripheral ulcerative keratitis (2 eyes), orbital pseudotumor (1 eye), HLA-B27 associated panuveitis and retinal vasculitis (2 eyes). Ocular disease was idiopathic in 3 patients, and was associated with rheumatoid arthritis, IgG-4 sclerosing disease, dermatomyositis, and ankylosing spondylitis in 1 patient each. All the patients had history of previous IMT use including methotrexate (5), mycophenolate mofetil (3), azathioprine (1), tacrolimus (1), adalimumab (2), infliximab (4), and rituximab (1). The mean follow-up time was 34.4 ± 11.0 (13–45) months, and mean duration of CP therapy was 11.9 ± 8.8 (5–28) months. Remission was achieved in 5 patients (71.4%). Four patients (57.1%) experienced transient leukopenia (white blood cell count < 4000/mL). Short conclusion: CP therapy can be considered a potentially effective and relatively safe therapeutic option for patients with severe ocular inflammatory diseases who failed other IMTs including biologics (TNFa and CD20 inhibitors). [ABSTRACT FROM AUTHOR]

Background: Unresolved retinal fluid and high injection burden are major challenges for patients with neovascular age-related macular degeneration. Brolucizumab addresses these challenges by providing robust vision gains and superior fluid resolution, with the potential for longer treatment intervals. Brolucizumab has been associated with adverse events of retinal vasculitis and retinal vascular occlusion typically in the presence of intraocular inflammation (IOI). To define the incidence of the adverse events, Novartis convened an external safety review committee, which found a rate of 4.6% for definite or probable IOI, 3.3% for retinal vasculitis, and 2.1% for retinal vascular occlusion in the HAWK and HARRIER trials. Novartis also established a coalition to explore 4 areas regarding the adverse events: root cause, patient characterization, event mitigation and vigilance, and treatment protocols for the adverse events. Based on the coalition findings, a risk mitigation framework was developed. Prior to initiating treatment with brolucizumab, it is important to weigh the potential benefit against risk of adverse events and to consider patient risk factors such as prior history of IOI and/or retinal vascular occlusion. To mitigate the potential for IOI-related adverse events, it is important to conduct a thorough dilated eye examination before each injection and closely monitor patients throughout treatment. Patients should be educated on symptoms of IOI to monitor for. Brolucizumab should not be injected in the presence of active IOI. If an adverse event is identified, prompt and intensive treatment should be considered. Conclusion: Progress has been made in understanding how to mitigate IOI-related adverse events following treatment with brolucizumab. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) is an autoimmune disorder associated with obstetrical complications, thrombotic complications involving both arteries and veins, and non-thrombotic manifestations affecting multiple other systems presenting in various clinical forms. Diagnosis requires the presence of antiphospholipid antibodies. The exact pathogenesis of APS is not fully known. However, it has recently been shown that activation of different types of cells by antiphospholipid antibodies plays an important role in thrombosis formation. Ocular involvement is one of the important clinical manifestations of APS and can vary in presentations. Therefore, as an ophthalmologist, it is crucial to be familiar with the ocular findings of APS to prevent further complications that can develop. Furthermore, the ongoing identification of new and specific factors contributing to the pathogenesis of APS may provide new therapeutic options in the management of the disease in the future. [ABSTRACT FROM AUTHOR]

Background: The current article is a short review of an Alimera Sciences-sponsored symposium held during The 15th International Ocular Inflammation Society Congress in Taiwan on the 14th November 2019 entitled, 'Preventing relapse of non-infectious uveitis effecting the posterior segment of the eye – evaluating the 0.2 μg/day fluocinolone acetonide intravitreal implant.' Main text: The fluocinolone acetonide intravitreal implant was approved in Europe for the prevention of relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye and offers a systemic therapy-sparing treatment option by providing low daily dose of corticosteroid into the vitreous for up to 3 years. In the symposium, the presenters reported clinical outcomes from patients with non-infectious uveitis effecting the posterior segment of the eye to support the effectiveness and safety of the implant for up to 3 years in both randomised controlled trials and real-world practices. Conclusions: Data showed that over a 36 month period, treatment with the fluocinolone acetonide intravitreal implant was associated with significantly fewer episodes of uveitic recurrence, a significantly longer time to uveitic recurrence, greater improvement in visual acuity, a lower need for adjunctive therapy, and an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Purpose: To correlate the findings of retinal function with multifocal electroretinogram (mfERG), microperimetry (MP), and structural assessments with spectral-domain optical coherence tomography (SD-OCT) in topographically corresponding areas of the macula of patients with birdshot chorioretinopathy (BSCR). Methods: Patients diagnosed with BSCR by clinical and imaging findings were included in the study. The mfERG was performed using 61 hexagon stimulus patterns grouped into 5 rings (Diagnosys Inc., USA). Individual responses [N1-P1 amplitudes in nanovolt (NV)/degree2 and P1 implicit time in milliseconds (msec)] for each hexagon in the central 3 rings (R1, 0°–2.3°; R2,2.3°–7.7°; and R3, 7.7°–12°) were obtained (19 hexagons). MP examination consisted of Polar 3–12° test with 28 points in 3 concentric rings with diameters of approximately 2.3°, 6.6°, and 11.1° from the foveal center. SD-OCT was performed using macular scans of 20° × 20°. The retinal sensitivity values on MP and thickness values of retinal layers were correlated with the responses on the mfERG for each topographically correlated hexagon. Results: Sixteen eyes of eight patients were included in the study (mean age, 59.87 ± 10.01 years; range, 41–73 years). The amplitudes and the implicit times on mfERG and retinal sensitivities on MP were decreased for each of the 19 hexagons. Considering retinotopically matched points, there was correlation between the retinal sensitivities and mfERG implicit times and response amplitudes in all three rings. The thickness of the retinal pigment epithelium showed modest correlation with the mfERG parameters (ρ = 0.29; p = 0.04). The structural changes on SD-OCT, such as IS-OS disruption, were associated with changes in the mfERG trace arrays. Conclusions: The structural and functional assessments in retinae of eyes with BSCR suggest that each imaging tool may be capturing unique aspects of retinal dysfunction. Multimodal imaging may allow detailed analyses of retinal damage at various corresponding loci. These findings are important when considering the use of these techniques in BSCR. [ABSTRACT FROM AUTHOR]

Background: Conventional fundus imaging has been used to assess vitreous haze (VH) in patients with uveitis. Ultra-wide field (UWF) retinal imaging that uses scanning laser technology has not been evaluated for the detection of VH. This pilot study evaluates the ability of UWF imaging in detecting VH. Patients with intermediate, posterior, or panuveitis were examined to assess the level of VH using slit-lamp biomicroscopy. Colored fundus images were acquired using a Carl Zeiss FF450 camera. The same photographer obtained fundus images of the same eyes during the same visit by Optos UWF P200Tx retinal camera. Two graders independently analyzed UWF fundus images for presence or absence of VH, without quantifying the degree of VH using any scale. The images were analyzed using the composite red plus red-free wavelengths utilized by the Optos UWF camera and by using each wavelength exclusively. These findings were compared to clinical detection of VH and detection of VH using conventional fundus photography. Results: Ninety-two eyes were included in the study. For composite UWF images, sensitivity was 0.27, specificity was 0.88, PPV was 0.31, NPV was 0.86, positive LR was 2.25, and negative LR was 0.83. For the conventional Zeiss images, sensitivity was 0.5, specificity was 0.84, PPV was 0.33, NPV was 0.91, positive LR was 3.13, and negative LR was 0.6. Agreement between the composite UWF and Zeiss techniques was substantial with k = 0.64. Inter-observer agreement for composite UWF images was also substantial with k = 0.65. Inter-observer agreement for Zeiss images was moderate with k = 0.471. Intra-observer agreement for both imaging modalities was substantial with a composite UWF k = 0.76 and Zeiss k = 0.7. Conclusions: UWF fundus imaging using scanning laser technique may be used to assess VH and employed in the management of intermediate, posterior, and panuveitis. [ABSTRACT FROM AUTHOR]

Background: The purpose of this paper is to study the spatial agreement between visual field defects and ultra-wide field (UWF) fundus autofluorescence (FAF) in patients with birdshot chorioretinopathy (BSCR). The study is a retrospective, cross-sectional analysis of a university uveitis practice. Eight (8) eyes of five (5) patients with BSCR were included. Inclusion criteria were ability to fixate reliably. Goldmann visual fields (GVF) and UWF FAF were obtained, digitalized, and standardized. Analysis was performed by measuring areas of overlap of hypo-autofluorescent FAF lesions and GVF scotomas within the central 60°. Overlap was calculated as a percentage of the total area of FAF and GVF, respectively. Average areas were also calculated. Results: The mean age of the subjects was 51 ± 12.28 years (range 38-69 years). 14 ± 23 % of the total lesion area identified as hypo-autofluorescent on FAF overlapped with scotoma. 28 ± 41 % of the GVF scotomas overlapped with hypo-autofluorescent FAF lesions. Average area of FAF hypo-autofluorescence was much larger (15.19 disc areas) than GVF (3.45 disc areas). Conclusions: There appear to be larger total areas of hypo-autofluorescence on FAF than scotoma evidenced by GVF and only a small amount of overlap. The finding suggests that GVF is relatively insensitive to anatomic loss, which can be detected using FAF. Further studies are required to assess whether this finding holds true for automated white-on-white perimetry. In addition, more selective psychophysical stimuli may have higher sensitivity in detecting early functional loss that accompanies anatomic damage. [ABSTRACT FROM AUTHOR]

Background: Uveitis consists of a spectrum of inflammatory disorders characterized by ocular inflammation. The underlying pathophysiology consists of a complex interplay of various inflammatory pathways. Interleukin 6 is an important mediator of inflammation in uveitis and constitutes focus of research toward development of newer biological therapies in the management of non-infectious uveitis. Main body: Pan-blockade of the inflammatory pathways with steroids is generally the first step in the management of acute non-infectious uveitis. However, long-term therapy with steroids is associated with systemic and ocular side effects, thereby necessitating the need for development of steroid sparing agents. IL-6 is a cytokine produced by various immune cells, in response to molecular patterns and affects multiple inflammatory cells. In particular, IL-6 is involved in differentiation of CD-4 cells into Th-17 cells that have been shown to play a significant role in various immune-mediated diseases such as uveitis. This broad-spectrum immunomodulatory activity makes IL-6 an excellent target for immunomodulatory therapy. Tocilizumab was the first IL-6 inhibitor to demonstrate efficacy in humans. It inhibits IL-6 from binding to both membrane-bound and soluble receptor and can be administered via intravenous (IV) and subcutaneous (SC) routes. It has been FDA approved for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Following the approval in systemic diseases, its efficacy was demonstrated in various uveitis studies including a phase 2 clinical trial (STOP-Uveitis). Overall, tocilizumab has shown a good safety profile with the risk of malignancy consistent with that expected in patients with rheumatoid arthritis. However, tocilizumab therapy has been shown to increase the risk for gastrointestinal perforation and dose-dependent neutropenia. Following the success of tocilizumab, several other agents targeting the IL-6 pathway are in the pipeline. These include sirukumab, siltuximab, olokizumab, clazakizumab, and EBI-031 which target IL-6; Sarilumab and ALX-0061 act on the IL-6 receptor. Conclusion: Studies have shown that IL-6 inhibitors can be effective in the management of NIU. In addition, the levels of IL-6 are elevated in other ocular vascular diseases such as retinal vein occlusion and diabetic macular edema. The roles of IL-6 inhibition may be broadened in the future to include the management of retinal vascular diseases and non-uveitic macular edema. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the role of vitreomacular adhesion (VMA) in visual and anatomic outcomes in patients with non-infectious uveitis. Design: Phase 2 clinical trial Participants: Data from the Safety, Tolerability, and Efficacy of Tocilizumab in Patients with Non-infectious Uveitis (STOP-Uveitis) study was analyzed. Methods: In the STOP-Uveitis study, patients with non-infectious uveitis (NIU) received monthly intravenous infusions of either 4 or 8 mg/kg tocilizumab until month 6 (M6). Spectral domain optical coherence tomography (SD-OCT) images of patients that completed M6 of the study were analyzed at baseline to stratify the patients by the presence (VMA+) or absence (VMA−) of VMA. Patients with vitreomacular traction (VMT) or epiretinal membrane causing structural abnormalities within center 1 mm were excluded. All images were graded by two independent graders. Main outcome measures: Mean change in best-corrected visual acuity (BCVA), central retinal thickness (CRT), and vitreous haze (VH) at M6. Results: Out of 37 patients randomized in the STOP-Uveitis study, 48 eyes (27 patients) were eligible based on the study criteria. At baseline, 19 eyes were classified as VMA+, and 32 eyes were classified as VMA−. The distribution of two doses of TCZ (4 mg/kg and 8 mg/kg) were similar between the two groups. At M6, the mean improvement in BCVA was 2.00 ± 5.3 and 6.50 ± 7.98 letters in the VMA+ and VMA− groups, respectively (p = 0.02). The mean improvement in CRT was 34.85 ± 72.36 and 80.37 ± 157.21 μm in the VMA+ and VMA− groups, respectively (p = 0.18). Similarly, the mean change in VH was − 0.65 ± 0.47 and − 0.76 ± 0.71 in the VMA+ and VMA− groups, respectively (p = 0.32). Out of 16 eyes with VMA at baseline, 3 eyes developed posterior vitreous detachment (PVD) at M6. The mean change in BCVA was significantly higher (p = 0.02), while CRT and VH score were similar (p > 0.05) in eyes with PVD compared to eyes with persistent VMA. Conclusions: The absence of VMA or development of PVD in eyes with VMA seems to have a beneficial effect on the vision of subjects receiving treatment for uveitis. Therefore, patients with uveitis should be assessed using SD-OCT for the presence of vitreomacular interface abnormalities. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to evaluate the differences in the fundus autofluorescence (FAF) signal between the blue light autofluorescence (BAF) from Spectralis® (Heidelberg, CA) and green light autofluorescence (GAF) 200TxTM (OPTOS, UK, in normal subjects and in patients with retinochoroidopathies (RC).Methods: In this prospective study, FAF was performed using BL (λ = 488 nm) and GL (λ = 532 nm) on normal subjects and patients with RC. The corresponding pairs of BAF and GAF images from both groups were analyzed using Photoshop. The strength of the FAF signal was measured on a gray scale, where optic disc was a standard to indicate absence of AF. In addition, gray values obtained from three identical points (foveal center, and points of hypo and hyper autofluorescence) in the corresponding BAF and GAF images of normal and RC subjects were divided by the optic disc value to calculate autofluorescence signal ratio (R). The R values at fovea (R1), hypoautofluorescent point (R2), and hyperautofluorescent point (R3) were compared between BAF and GAF modalities, in normal and in RC subjects separately.Results: One hundred six pairs (106 eyes) of FAF images analyzed (37 pairs: normal and 69 pairs: RC subjects). In normal subjects, the mean R1, R2, and R3 values for BAF were (1.5 ± 0.88, 1.23 ± 0.58, and 4.73 ± 2.85, respectively) and for GAF were (0.78 ± 0.20, 0.78 ± 0.20, and 1.62 ± 0.39, respectively). Similarly, in subjects with RC, the mean R1, R2, and R3 values for BAF were (1.68 ± 1.02, 1.66 ± 1.15, and 7.75 ± 6.82, respectively) and for GAF were (0.95 ± 0.59, 0.79 ± 0.45, and 2.50 ± 1.65, respectively). The mean difference in the R1, R2, and R3 ratios between BAF and GAF in normal and in RC subjects was statistically significant (p < 0.001). The strength of the correlation (r) between ratios for BAF and GAF was weak or not statistically significant in both normal and RC subjects (p > 0.05).Conclusion: The distribution and intensity of the AF signal differ in BAF and GAF and cannot be used interchangeably. In BAF, optic disc signal is always weaker than in other areas, which was not true for GAF where optic disc signal was stronger than fovea and hypoautofluorescent point in both groups. [ABSTRACT FROM AUTHOR]