Challenges for further successful development of tumor necrosis factor targeting therapies for uveitis.

INTRODUCTION: Uveitis is a heterogeneous group of ocular conditions characterized by inflammation of the uveal tract and is one of the leading causes of vision impairment. In developed countries, noninfectious uveitis (NIU) represents most cases and is challenging to treat due to its severity, chronicity, and high recurrence rates. The advent of anti-tumor necrosis factor-α (anti-TNF-α) agents have dramatically improved outcomes and changed treatment paradigms in NIU. AREAS COVERED: The index article summarizes the present experience of anti-TNF-α agents in NIU pharmacotherapy and highlights the barriers to further research and development of anti-TNF-α agents for uveitis. Common challenges faced in NIU clinical drugs trials, specific difficulties in anti-TNF-α drug development, and promising competitor drug candidates are discussed and evaluated. EXPERT OPINION: Anti-TNF-α agents have revolutionized NIU pharmacotherapy and greatly improved outcomes with good safety profiles. The great success of systemic infliximab and adalimumab in NIU treatment has resulted in little impetus for further development of this class of medication. Attempts have been made to deliver anti-TNF-α agents intravitreally but that has not been successful thus far. With expiring patents, competition from biosimilars and newer, novel molecules, it may not be viable to continue pursuing anti-TNF-α drug development.

Recent advances in uveitis therapy: focus on selected phase 2 and 3 clinical trials.

INTRODUCTION: Uveitis is a heterogeneous group of ocular conditions characterized by inflammation of the uveal tract. It is a leading cause of blindness in developed countries and exerts significant psychological, social, and economic impact on both patients and the larger society. While there are numerous pharmacotherapy options, posterior segment noninfectious uveitis remains a significant challenge to treat due to its severity, chronicity, and high recurrence rates. AREAS COVERED: The index review highlights the unmet needs of uveitis pharmacotherapy and its research and the shortcomings of existing ocular and systemic therapeutic options for noninfectious uveitis. The more promising novel ocular drug delivery methods and therapeutic targets/drugs are discussed, and evidence from the clinical trials is evaluated. EXPERT OPINION: There has been incredible growth in the number of treatment options available to uveitis patients today, especially with the new generation of biologic drugs. Available evidence suggests that these newer options may be superior to conventional immunosuppressive therapies in terms of efficacy and side effect profiles. Further high-quality research and additional clinical trials will be needed to clarify their roles in the stepladder treatment approach of noninfectious uveitis.

Longitudinal Comparative Analysis of Semi-Automated Aqueous Flare Measurements with Clinical Grading and Visual Outcomes in Uveitic Eyes.

PURPOSE: To evaluate the correlation between longitudinal changes in aqueous flare measured by laser flare photometer (LFP), best-corrected visual acuity (BCVA), and clinical grade using both Standardization of Uveitis Nomenclature (SUN) and modified SUN (MSUN) scales uveitis patients. METHODS: Patients were classified according to both SUN and MSUN grading scales. LFP measurements were acquired (Kowa FM-700) at each visit. Mean change in LFP was assessed longitudinally, comparing with those in visual acuity, SUN, and MSUN grading scales. RESULTS: Mean change in LFP was correlated to those in BCVA (p = .018), SUN scale (p < .001), and MSUN scale (p = .008). Cases within same initial SUN (0 and 1+) and MSUN (0.5+ and 1+) grades and different longitudinal flare prognosis (decreased/unchanged/increased) had significantly different initial LFP values (all p < .05). CONCLUSIONS: LFP measurement is beneficial in monitoring inflammatory activity. Cases of identical clinical flare scores with different clinical prognosis may be predicted by LFP.

Correlation of Clinical Aqueous Flare Grading to Semi-Automated Flare Measurements Using Laser Flare Photometry.

PURPOSE: To compare laser flare photometry (LFP) measurements of aqueous flare with Standardization of Uveitis Nomenclature (SUN) and modified SUN grading. METHODS: In this prospective study with multicenter design, uveitis patients were classified according to SUN and modified SUN grading scales. LFP was performed with Kowa FM-700 flaremeter. Mean LFP values were compared with SUN and MSUN scores. RESULTS: The study included 475 LFP measurements, of which 216, 48, 150, 31, 28 and 2 had 0, 0.5+, 1+, 1.5+, 2+ and 3+ flare, respectively. LFP values were significantly different between each two consecutive steps for both clinical gradings (all P < .05). Cut-off values for modified SUN grading steps were defined as 5.7, 9.7, 15.7 and 43.2 for 0/0.5+, 0.5+/ 1+, 1+/1.5+ and 1.5/2+ borders of clinical flare, respectively. CONCLUSIONS: LFP proves to be an objective measurement in analyzing aqueous flare comparable to both SUN and MSUN clinical grading systems.

Current concepts in the diagnosis and management of antiphospholipid syndrome and ocular manifestations.

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.

Correction of perceived visual distortions using a software application and correlation to age-related macular degeneration.

PURPOSE: To investigate the use of software-generated corrections in neutralizing perceived distortions in age-related macular degeneration. METHODS: A tablet-based application was utilized to elicit distortions. Five subjects (seven eyes: neovascular age-related macular degeneration and three eyes: non-neovascular age-related macular degeneration) traced the reference lines, and their distortion traces were recorded. To counter distortion, a software-generated trace was re-traced by subjects to produce a corrected trace. Final traces were superimposed on optical coherence tomography images and following distances calculated: (a) dDT: distance between distortion trace and reference line; (b) dGT: distance between software-generated trace and corrected trace; (c) dCT: distance between corrected trace and reference line. Mean percent improvement in distortion was reported. Mean effectiveness of correction was also reported by utilizing t test to compare dDT and dCT. The number of distortion traces with underlying lesions on optical coherence tomography was also analyzed. RESULTS: Mean age of the subjects was 76.6 (±9.5) years. Each patient traced six reference lines and each was considered a separate case. Out of 30 cases, 17 (56.6%) elicited distortion. Mean percent improvement in distortion was 71.3 ± 23% (p < 0.05). Twelve cases (70.6%) had an underlying lesion (eight cases: disrupted photoreceptor layer and four cases: normal photoreceptor layer). Mean percent improvement in cases with normal photoreceptor layer (90.8 ± 5.45%) was higher than with abnormal photoreceptor layer (58.5 ± 7.17%) (p < 0.05). Five cases with distortion had no associated underlying lesion. Mean percent improvement in these subjects was significantly higher than those with photoreceptor layer disruption. CONCLUSION: Software-generated corrections can potentially correct for perceived distortions in patients with age-related macular degeneration, especially in cases with preserved photoreceptor layer.

Blue light versus green light fundus autofluorescence in normal subjects and in patients with retinochoroidopathy secondary to retinal and uveitic diseases.

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.