Hatice Nida Sen

Humanized anti-interleukin-2 (IL-2) receptor alpha therapy: long-term results in uveitis patients and preliminary safety and activity data for establishing parameters for subcutaneous administration

Therapy for severe uveitis is frequently long-term immunosuppression using systemic corticosteroids and cytotoxic agents, but side effects make long-term therapy difficult. A long-term (>4 year) Phase I/II single armed interventional study using intravenous anti-IL-2 receptor alpha treatments (daclizumab) and a short-term Phase II study evaluating the use of a subcutaneous daclizumab formulation were conducted. Patients were tapered off their systemic immunosuppressive therapy and received daclizumab infusions or subcutaneous injections at intervals varying from 2 to 6 weeks. In the long-term study, seven of ten enrolled patients were tapered from their original immunosuppressive medications and maintained exclusively on repeated daclizumab infusions for control of their uveitis for over 4 years. No patient was permanently removed from therapy for an adverse event ascribed to the medication. The use of 6-week infusion intervals led to recurrence of uveitis, while 2- to 4-week intervals did not. Only one patient developed measurable anti-daclizumab antibodies but this disappeared when subcutaneous therapy was begun. In the short-term study, four of the five patients receiving the subcutaneous formulation met the study endpoints for success within the first 12 weeks. All five were successful by 26 weeks. These studies provide preliminary evidence that regularly administered long-term daclizumab therapy can be given in lieu of standard immunosuppression for years to treat severe uveitis and that subcutaneously administered daclizumab appeared to be a clinically viable treatment strategy. These studies suggest that anti-IL-2 receptor blockade could be useful in the treatment of Th1-mediated autoimmune conditions.

A Double-masked, Randomized Study to Investigate the Safety and Efficacy of Daclizumab to Treat the Ocular Complications Related to Behcet's Disease

Purpose: To investigate the safety and efficacy of daclizumab (Zenapax, humanized anti-Tac, HAT) in controlling the ocular manifestations of Behçets disease. Design: Randomized, placebo-controlled, double-masked clinical trial. Participants: Seventeen participants with Behçets disease experiencing at least two prior ocular attacks and requiring treatment with immunosuppressive agents for the ocular complications of Behçets disease. Methods: Participants received either intravenous placebo or daclizumab (1 mg/kg) infusions every two weeks for six weeks, then every four weeks while continuing their standard immunosuppressive regimens. If clinically indicated, tapering of the standard immunosuppressive medications was allowed after six months of study enrollment. Complete ocular and physical examinations and an adverse event assessment were performed at baseline and prior to each study infusion. Main Outcome Measures: Primary safety endpoints were the development of a life-threatening complication or a severe opportunistic infection. Primary efficacy outcomes were the number of ocular attacks and an assessment of systemic immunosuppressive medications required during the study, including the ability to taper concomitant immunosuppressive therapy. Results: Nine participants randomized to daclizumab and eight to placebo were followed monthly. Follow-up ranged from one to 34 months, with a median follow-up of 15 months. Two participants randomized to daclizumab discontinued study therapy prior to the end of the study for personal reasons. No participant experienced a safety endpoint, and visual acuity remained stable in all participants during the course of the study. Ten participants (six daclizumab, four placebo) experienced ocular attacks requiring therapy. The median ocular attack rate during the study was greater in the daclizumab arm than the placebo arm (median 1.27 vs. 0.17 attacks/year, respectively). Participants in the placebo arm also experienced a greater reduction in the immunosuppressive medication score compared to participants receiving daclizumab (median –4.0 vs. –1.0, respectively). Conclusions: The observed results in the placebo group demonstrate that careful follow-up and treatment with standard combination immunosuppressive therapy can be effective for the management of the ocular complications of Behçets disease. In our small study, there was no suggestion that daclizumab was beneficial in comparison with placebo. However, the low observed attack rate limited our ability to make a definitive treatment group comparison.

Fundus Autofluorescence Imaging of the White Dot Syndromes

OBJECTIVE To characterize the fundus autofluorescence (FAF) findings in patients with white dot syndromes (WDSs). METHODS Patients with WDSs underwent ophthalmic examination, fundus photography, fluorescein angiography, and FAF imaging. Patients were categorized as having no, minimal, or predominant foveal hypoautofluorescence. The severity of visual impairment was then correlated with the degree of foveal hypoautofluorescence. RESULTS Fifty-five eyes of 28 patients with WDSs were evaluated. Visual acuities ranged from 20/12.5 to hand motions. Diagnoses included serpiginous choroidopathy (5 patients), birdshot retinochoroidopathy (10), multifocal choroiditis (8), relentless placoid chorioretinitis (1), presumed tuberculosis-associated serpiginouslike choroidopathy (1), acute posterior multifocal placoid pigment epitheliopathy (1), and acute zonal occult outer retinopathy (2). In active serpiginous choroidopathy, notable hyperautofluorescence in active disease distinguished it from the variegated FAF features of tuberculosis-associated serpiginouslike choroidopathy. The percentage of patients with visual acuity impairment of less than 20/40 differed among eyes with no, minimal, and predominant foveal hypoautofluorescence (P < .001). Patients with predominant foveal hypoautofluorescence demonstrated worse visual acuity than those with minimal or no foveal hypoautofluorescence (both P < .001). CONCLUSIONS Fundus autofluorescence imaging is useful in the evaluation of the WDS. Visual acuity impairment is correlated with foveal hypoautofluorescence. Further studies are needed to evaluate the precise role of FAF imaging in the WDSs.

High-dose humanized anti-IL-2 receptor alpha antibody (daclizumab) for the treatment of active, non-infectious uveitis.

PURPOSE This study was designed to provide preliminary data regarding the safety and efficacy of high-dose humanized anti-IL-2 receptor (daclizumab) therapy for the treatment of active intermediate, posterior or panuveitis. METHODS Five patients were recruited into this non-randomized, prospective pilot study of high-dose intravenous induction daclizumab therapy given at doses of 8mg/kg at day 0 and 4mg/kg at day 14. Patients who did not meet a safety endpoint at the 3-week follow-up evaluation were given the option of continuing therapy with subcutaneous daclizumab at 2mg/kg every 4 weeks for 52 weeks. The primary outcome assessed was a two-step decrease in vitreous haze at day 21. Secondary outcomes evaluated included best-corrected visual acuity, retinal thickness as measured by optical coherence tomography, retinal vascular leakage assessed by fluorescein angiography, anterior chamber and vitreous cellular inflammation. RESULTS Four male patients and one female patient were enrolled. Diagnoses included birdshot retinochoroidopathy (two patients), Vogt-Koyanagi-Haradas disease, bilateral idiopathic panuveitis and bilateral idiopathic intermediate uveitis. By the 4th week, four of five patients demonstrated a two-step decrease in vitreous haze. The other participant did not meet this criterion until week 20, but all five patients maintained stability in vitreous haze grade throughout their follow-up periods. At enrollment, mean visual acuity (10 eyes in 5 patients) was 69.2 ETDRS letters and following treatment was 78.2 letters (p<0.12). Anterior chamber cell, vitreous cell, and vitreous haze also improved in the majority of eyes. Adverse events were generally mild except for one episode of left-lower lobe pneumonia requiring hospitalization and treatment. CONCLUSION This is the first demonstration that high-dose daclizumab can reduce inflammation in active uveitis. Daclizumab was well tolerated but there may be a potential increased risk of infection associated with immunosuppression. All five patients demonstrated a decrease in vitreous haze and measures of intraocular inflammation at final follow-up. The results of this small, non-randomized pilot study support the consideration of high-dose daclizumab therapy in cases of active posterior uveitis.

Update on ocular tuberculosis.

Purpose of review Despite recent downtrends, tuberculosis remains a worldwide public health concern. This review provides an update on recent demographic data, clinical and experimental data, and diagnostic modalities. Recent findings Quantitative PCR showing mycobacterial load in intraocular fluids may have an emerging role in the diagnosis of ocular tuberculosis when used in combination with ophthalmic features of tuberculosis. Recent investigations in porcine models of ocular tuberculosis have provided valuable insight into the microbiologic, histologic, and clinical features of Mycobacterium tuberculosis infection of the choroid. Differentiating features between sarcoidosis and tuberculosis include tuberculin skin test status, the presence of ocular surface disease, and the anatomic relationship between vasculitis and choroiditis. Summary The diagnosis of presumed ocular tuberculosis remains a clinical challenge with currently available diagnostic modalities. Although newer interferon-&ggr; release assays can distinguish exposure to M. tuberculosis from the Bacille–Calmette–Guérin vaccine strain, they currently lack the specificity to distinguish between latent tuberculosis infection and active tuberculosis. Continued improvement in the currently available molecular diagnostic techniques including quantitative PCR may be valuable in our ability to establish an earlier etiologic diagnosis and institute appropriate antimycobacterial therapy.

Subconjunctival corticosteroid injection for the treatment of non-necrotising anterior scleritis.

Scleritis commonly is a recurrent disease that requires long term immunosuppressive treatment that can be associated with significant adverse effects.1 Although topical and periorbital steroids are accepted therapeutic options for treatment of scleritis, subconjunctival administration of depot corticosteroids has been considered unsafe owing to the risk of scleral thinning and perforation.2–4 Recently, this has been challenged by reports describing the safe and effective use of subconjunctival depot steroid injections in patients with non-necrotising scleritis.5–7 Based on these reports we reviewed our experience using subconjunctival corticosteroid injections (SCI) in the management of non-infectious, non-necrotising anterior scleritis. A retrospective, non-comparative review of the clinical records of patients with scleritis evaluated at the National Eye Institute was performed and four patients treated with SCI were identified. Subconjunctival triamcinolone acetonide (Kenalog 40 mg/ml, Westwood Squibb Pharmaceuticals, Buffalo, NY, USA) (2–12 mg per injection) was given …

Fundus autofluorescence changes in cytomegalovirus retinitis

Purpose: The purpose of this study was to describe fundus autofluorescence imaging features of cytomegalovirus (CMV) retinitis and to correlate fundus autofluorescence features with clinical activity. Methods: A retrospective case series was undertaken to evaluate nine eyes of six patients with active CMV retinitis. Patients were evaluated with a comprehensive ophthalmic examination, fundus autofluorescence imaging, and fundus photography. Oral valganciclovir, intravitreal ganciclovir, intravitreal foscarnet, or an ganciclovir implant was administered as clinically indicated. Results: In all nine eyes with active CMV retinitis, a hyperautofluorescent signal on fundus autofluorescence imaging was correlated spatially with the border of advancing CMV retinitis. Stippled areas of alternating hyperautofluorescence and hypoautofluorescence were observed in regions of retinal pigment epithelium atrophy from prior CMV retinitis. In three eyes with subtle CMV reactivation, a hyperautofluorescent border was helpful in the detection and localization of active CMV retinitis. In another patient, diffuse, punctate hyperautofluorescence after intravitreal ganciclovir and foscarnet was a concern for medication-related toxicity. Conclusion: Fundus autofluorescence imaging was valuable in highlighting areas of active CMV retinitis in all patients in this series, including two patients with subtle clinical features. Fundus autofluorescence may be useful as an adjunctive imaging modality for the detection of CMV activity and aid in our understanding of the structural changes during episodes of CMV retinitis.

Gender Disparities in Ocular Inflammatory Disorders

Abstract Ocular inflammatory disorders disproportionately affect women, and the majority of affected women are of childbearing age. The role of sex or reproductive hormones has been proposed in many other inflammatory or autoimmune disorders, and findings from non-ocular autoimmune diseases suggest a complex interaction between sex hormones, genetic factors and the immune system. However, despite the age and sex bias, factors that influence this disparity are complicated and unclear. This review aims to evaluate the gender disparities in prevalence, incidence and severity of the most common infectious and non-infectious ocular inflammatory disorders.

Syphilitic Outer Retinopathy

Abstract Purpose: To present ocular syphilis masquerading as an outer retinopathy. Methods: Retrospective case series, including 2 patients with features of acute zonal occult outer retinopathy (AZOOR) complex diseases. Results: Laboratory results confirmed the diagnosis of syphilis in the 2 cases. Therapy with intravenous penicillin led to an improvement in symptoms, visual acuity, and ancillary testing. Conclusions: The protean ophthalmic presentations of syphilis are well known. However, AZOOR-like presentation has not been described previously. This atypical outer retinopathy should alert physicians to keep syphilis in the differential diagnosis of any inflammatory disorder.

A rare case of endogenous Aspergillus conicus endophthalmitis in an immunocompromised patient

BackgroundThe purpose of this study was to report the case of a patient with bilateral panuveitis who was found to have a rarely reported intraocular fungus, Aspergillus conicus. A 40-year-old man presented with gradual vision loss in both eyes. He had bilateral anterior uveitis, granulomatous vitritis with a preretinal granuloma in the right eye, and nongranulomatous vitritis with two quadrants of chorioretinal scarring in the left.FindingsSerological testing revealed a new diagnosis of human immunodeficiency virus as well as positive rapid plasma reagin and fluorescent treponemal antibody. Polymerase chain reaction (PCR) testing of the aqueous humor from the right eye identified A. conicus. Due to the indolent course of the endogenous fungal infection, the patient was treated with prednisolone acetate 1% eye drops, oral voriconazole, and highly active antiretroviral therapy. More than 1 year later, his vision remained 20/20 in both eyes without any episodes of recurrent inflammation.ConclusionsPCR testing helped identify a rare intraocular infection in an immunocompromised patient. In this case, A. conicus behaved less aggressively than other species of Aspergillus implicated in intraocular infection.