Filgotinib in Active Noninfectious Uveitis: The HUMBOLDT Randomized Clinical Trial.

Importance: Noninfectious uveitis is a leading cause of visual impairment with an unmet need for additional treatment options. Objective: To assess the efficacy and safety of filgotinib, a Janus kinase 1 (JAK1) preferential inhibitor, for the treatment of noninfectious uveitis. Design, Setting, and Participants: The HUMBOLDT trial was a double-masked, placebo-controlled, phase 2, randomized clinical trial conducted from July 2017 to April 2021 at 26 centers in 7 countries. Eligible participants (aged ≥18 years) had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite at least 2 weeks of treatment with oral prednisone (10-60 mg per day). Interventions: Participants were randomly assigned 1:1 to receive filgotinib, 200 mg, or placebo orally once daily for up to 52 weeks. Main Outcomes and Measures: The primary end point was the proportion of participants experiencing treatment failure by week 24. Treatment failure was a composite end point represented by assessment of the presence of chorioretinal and/or retinal vascular lesions, best-corrected visual acuity, and anterior chamber cell and vitreous haze grades. Safety was assessed in participants who received at least 1 dose of study drug or placebo. Results: Between July 26, 2017, and April 22, 2021, 116 participants were screened, and 74 (mean [SD] age, 46 [16] years; 43 female [59.7%] of 72 participants, as 2 participants did not receive treatment doses) were randomly assigned to receive filgotinib (n = 38) or placebo (n = 36). Despite early termination of the trial for business reasons ahead of meeting enrollment targets, a significantly reduced proportion of participants who received filgotinib experienced treatment failure by week 24 vs placebo (12 of 32 participants [37.5%] vs 23 of 34 participants [67.6%]; difference vs placebo -30.1%; 95% CI, -56.2% to -4.1%; P = .006). Business reasons were unrelated to efficacy or safety. Adverse events were reported in 30 of 37 participants (81.1%) who received filgotinib and in 24 of 35 participants (68.6%) who received placebo. Serious adverse events were reported in 5 of 37 participants (13.5%) in the filgotinib group and in 2 of 35 participants (5.7%) in the placebo group. No deaths were reported during the trial. Conclusions and Relevance: Results of this randomized clinical trial show that filgotinib lowered the risk of treatment failure in participants with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis vs placebo. Although the HUMBOLDT trial provided evidence supporting the efficacy of filgotinib in patients with active noninfectious uveitis, the premature termination of the trial prevented collection of additional safety or efficacy information of this JAK1 preferential inhibitor. Trial Registration: ClinicalTrials.gov Identifier: NCT03207815.

Panuveitis following Vaccination for COVID-19.

Background: COVID-19 vaccination has been accompanied by reports of inflammatory events. This report details a case of panuveitis following vaccination for COVID-19 Case.Description: A 43 year old female developed panuveitis with decreased vision three days after her second dose of Pfizer-Biontech mRNA vaccine. The choroid was significantly thickened and there was anterior chamber and vitreous inflammation. Shortly after onset of ocular symptoms she was also found have an asymptomatic COVID-19 infection. Treatment with oral and topical corticosteroids resulted in improvement in the panuveitis, with a mild recurrence after the initial attempt to taper these drugs.Conclusion: This report demonstrates a likely occurrence of vaccine-related panuveitis secondary to the Pfizer-Biotech mRNA vaccine for COVID-19.

Dexamethasone Intravitreal Implant in the Treatment of Uveitic Macular Edema in the Perioperative Cataract Setting: A Case Series.

PURPOSE: To examine the efficacy of the dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc, Irvine, California, USA) in the control of uveitic macular edema in the perioperative setting of cataract surgery. DESIGN: Retrospective observational case series. METHODS: setting: Clinical practice. PARTICIPANTS: A total of 17 eyes of 14 patients that received a DEX implant for cystoids macular edema (CME) associated with noninfectious uveitis who underwent subsequent phacoemulsification within 4 months. INTERVENTION: Each patient was treated with a DEX 0.7 mg intravitreal implant and underwent phacoemulsification with intraocular lens placement. MAIN OUTCOME MEASURES: Primary outcome measure was the change in central macular thickness (CMT) measured by optical coherence tomography (OCT), measured preoperatively and postoperatively. RESULTS: Seventeen eyes (14 patients) were included for analysis. There was no statistically significant change from preoperative CMT (mean 302 µm) to postoperative CMT (307 µm) on OCT. In the subset of eyes that underwent phacoemulsification within 4 weeks of the DEX implant (8 eyes), the mean change in CMT was -47.0 µm, compared to +51.1 µm in those that received the DEX implant greater than 4 weeks prior to phacoemulsification (P = .005). CONCLUSIONS: Intravitreal dexamethasone implant was shown to prevent the recurrence or worsening of macular edema in uveitic patients with a history of CME who underwent phacoemulsification. The mean CMT decreased in the subset of eyes that received the DEX implant within 4 weeks prior to cataract surgery.

Dexamethasone intravitreal implant in the treatment of persistent uveitic macular edema in the absence of active inflammation.

PURPOSE: To examine the observational effectiveness of the dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc., Irvine, CA) in the treatment of noninfectious uveitic macular edema in patients with otherwise quiescent uveitis. DESIGN: Retrospective chart review. PARTICIPANTS: A total of 27 consecutive patients with persistent macular edema resistant to standard short-term therapy despite quiescent noninfectious intermediate or posterior uveitis. METHODS: Each patient was treated with a DEX 0.7 mg implant. MAIN OUTCOME MEASURES: Primary outcome measure was resolution of macular edema 1 month after injection as measured by decrease in central macular thickness (CMT). Secondary outcome was change in visual acuity 1, 2, and 3 months after injection. RESULTS: A total of 27 eyes of 27 patients were included for analysis. One eye was randomly selected for 6 of these patients who received bilateral DEX implants. There was a statistically significant reduction in mean CMT 1 month after DEX implantation (mean, 278.9 µm; range, 206-352 µm) compared with baseline (mean, 478.7 µm; range, 330-667 µm) (P < 0.0001). There was a statistically significant improvement in visual acuity at 3 months (logarithm of the minimum angle of resolution [logMAR] 0.41; 20/51) compared with baseline (logMAR 0.60; 20/80) (P = 0.0005). There were no major complications after DEX implantation. CONCLUSIONS: The DEX implant resulted in a statistically significant improvement in mean CMT and visual acuity without any serious adverse events.

Bilateral uveitis associated with fluoroquinolone therapy.

CONTEXT: Retrospective case series, database study and literature review. Forty case reports are described. OBJECTIVE: To report a possible association between fluoroquinolones and uveitis. MATERIALS AND METHODS: Spontaneous reports from the National Registry of Drug-Induced Ocular Side effects, World Health Organization, and Food and Drug Administration were collected on uveitis associated with systemic fluoroquinolone therapy. A literature review was performed using keywords "uveitis", "fluoroquinolones", and each individual fluoroquinolone name. Additional case reports were collected from the practices of six uveitis subspecialists and one neuro-ophthalmologist. MAIN OUTCOME MEASURES: Data garnered from the reports include the type of fluoroquinolone, age, gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of uveitis, concomitant drugs, systemic disease, dechallenge and rechallenge data. RESULTS: A total of 40 case reports of uveitis associated with fluoroquinolones were identified including 12 men, 27 women, and 1 case in which the gender was not specified. The median age was 54 years. Dosage varied between the different fluoroquinolone drugs, with the median dosage within the range recommended in the package insert for each different fluoroquinolone. Median time from beginning of therapy to appearance of the ADR was 13 days (range 0-20 days). Thirteen patients were 60 years or older, and one patient was taking systemic anti-inflammatory steroids. There were five positive dechallenge case reports. DISCUSSION: According to World Health Organization criteria, the relationship between fluoroquinolone therapy and uveitis is "possible". Causality assessments are based on the time relationship of drug administration, uveitis development, and dechallenge data. CONCLUSIONS: Clinicians should be aware of a possible bilateral fluoroquinolone-associated uveitis, particularly the finding of iris transillumination and pigment dispersion.

Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2.

PURPOSE: To report a novel mouse model of achromatopsia with a cpfl3 mutation found in the ALS/LtJ strain. METHODS: The effects of a cpfl3 mutation were documented using fundus photography, electroretinography (ERG), and histopathology. Genetic analysis was performed using linkage studies and PCR gene identification. RESULTS: Homozygous cpfl3 mice had poor cone-mediated responses on ERG at 3 weeks that became undetectable by 9 months. Rod-mediated waveforms were initially normal, but declined with age. Microscopy of the retinas revealed progressive vacuolization of the photoreceptor outer segments. Immunocytochemistry with cone-specific markers showed progressive loss of labeling for alpha-transducin, but the cone outer segments in the oldest mice examined remained intact and positive with peanut agglutinin (PNA). The cpfl3 mapped to mouse chromosome 3 at the same location as human GNAT2, known to cause achromatopsia. Sequence analysis revealed a missense mutation due to a single base pair substitution in exon 6 in cpfl3. CONCLUSIONS: The Gnat2(cpfl3) mutation leads to cone dysfunction and the progressive loss of cone alpha-transducin immunolabeling. Despite a poor cone ERG signal and loss of cone alpha-transducin label, the cones survive at 14 weeks as demonstrated by PNA staining. This mouse model of achromatopsia will be useful in the study of the development, pathophysiology, and treatment of achromatopsia and other cone degenerations. The gene symbol for the cpfl3 mutation has been changed to Gnat2(cpfl3).