Joachim Van Calster

Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial

BACKGROUND Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids. METHODS We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10-35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov number NCT01124838. FINDINGS Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77-357) in the placebo group and 245 days (119-564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39-0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group). INTERPRETATION Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis. FUNDING AbbVie.

Oximetry in glaucoma: correlation of metabolic change with structural and functional damage

Purpose:  To determine whether retinal vessel oxygen saturation in patients with glaucoma is associated with structural optic disc and retinal nerve fibre layer (RNFL) changes and visual field (VF) defects.

Retinal oxygen metabolism in healthy subjects and glaucoma patients

Background To test whether retinal oxygen metabolism is different in glaucoma patients compared with healthy subjects. Methods This was a two-centre study where retinal vessel oxygen saturation was measured in glaucoma patients and healthy individuals with a non-invasive spectrophotometric retinal oximeter. Visual fields were obtained in the glaucoma patients. Results No statistical difference was found in retinal oxygen saturation in arterioles (p=0.16), venules (p=0.16) and arteriovenous difference (p=0.24) when all glaucoma patients (n=74) were compared with healthy individuals (n=89). When patients with advanced glaucoma (visual field mean defect (MD ≥ 10 dB, n=21)) were compared with healthy individuals, the oxygen saturation in venules was higher in glaucoma patients (58.2%±5.4% vs 53.8%±6.4%; p=0.0054, mean±SD) and the arteriovenous difference was lower in glaucoma patients (36.4%±4.7% vs 39.5%±5.7%; p=0.021). In glaucoma patients with mild glaucoma (visual field MD ≤ 5 dB, n=33), no statistical differences were found in retinal oxygen saturation compared with healthy individuals. Conclusions Glaucoma patients with advanced glaucoma have higher oxygen saturation in venules and lower arteriovenous difference in oxygen saturation compared with healthy individuals. The decreased arteriovenous difference in severe glaucoma may be related to lower oxygen consumption secondary to neuropathy.

Sub-inner limiting membrane haemorrhage: causes and treatment with vitrectomy

Background: Preretinal haemorrhages usually occur at the interface between the posterior hyaloid and inner limiting membrane (ILM). Less frequently, they are located between the ILM and the retinal nerve fibre layer. Sub-ILM haemorrhages have been described in a variety of clinical settings and often lead to severe visual impairment because of their predilection for the macular region. Methods: A consecutive series of five cases in which sub-ILM haemorrhages were clinically suspected and confirmed during early vitrectomy with ILM peeling were reviewed. Results: Sub-ILM haemorrhages were clinically suspected in five patients (median age 32 years) based on the fundoscopic appearance and clinical setting of Terson’s syndrome (n = 1), Valsalva retinopathy (n = 2), blood dyscrasia (n = 1) and blunt facial trauma (n = 1). Vision was severely impaired in all patients (to hand movements in four of five) because of a premacular location of the haemorrhage. All patients were treated with early pars plana vitrectomy because of insufficient spontaneous visual recovery after a median of 6 weeks. The sub-ILM location of the haemorrhage could be confirmed intraoperatively in all patients by biostaining of the membrane overlying the haemorrhage. ILM peeling and aspiration of the haemorrhage resulted in excellent visual recovery in all patients. No procedure-related complications were observed. Conclusions: Sub-ILM haemorrhages often occur in a specific clinical context and can lead to severe visual impairment in young patients. Given the excellent results and low complication rates, timely surgical intervention is justified when spontaneous resorption is insufficient.

Macular Hole Surgery With Inner Limiting Membrane Peeling, Endodrainage, and Heavy Silicone Oil Tamponade

PURPOSE To evaluate the anatomical and functional outcomes in macular hole (MH) patients who underwent vitrectomy with inner limiting membrane (ILM) peeling, endodrainage, and heavy silicone oil (HSO) endotamponade. DESIGN A retrospective case series with 54 consecutive eyes from 53 patients with idiopathic stage 3 or 4 MHs. METHODS Surgery with infracyanine green-assisted ILM peeling and endodrainage was performed. Patients who were phakic underwent a simultaneous phacoemulsification. At the end of the operation, a HSO tamponade was used in all cases. The patient maintained a face-up position for 24 hours postoperatively. The HSO was removed two to three months after initial surgery. Optical coherence tomography was performed preoperatively and postoperatively to determine the MH stage and the anatomical closure rate. RESULTS The mean follow-up time was 6.6 months (range, 3.6 to 18.2 months). The overall median duration between the first symptoms and the surgery was four months (range, two to 37 months). The overall anatomical closure success rate after one surgery was 100%. The median preoperative visual acuity (VA) was 20/200 (range, 20/40 to 20/600) and increased to 20/50 (range, 20/20 to 20/300) postoperatively. The median increase in VA was five lines (mean, 4.8 lines; range, -3 to 12 lines). Of all 54 eyes, 30 (55 %) eyes had a final VA of 20/50 or better. CONCLUSIONS These findings indicate that surgery for MH with ILM peeling, endodrainage, and HSO endotamponade appears to induce a high incidence of anatomical closure with good visual outcome.

Pharmacokinetics of Ocriplasmin in Vitreous

PURPOSE Ocriplasmin contains the active moiety of plasmin enzyme. At a physiologic pH, ocriplasmin is highly proteolytic and autolytic, limiting its duration of activity. Specific inhibitors of plasmin are present in the vitreous under normal and disease conditions and could affect its activity. Each may contribute to its mode of action. METHODS Degradation characteristics were determined in porcine, human vitreous, and PBS under reducing conditions with different incubation periods between 0 and 24 hours on SDS-PAGE Tris-glycine gels. Residual activity was determined by spectrophotometry of p-nitroaniline release through hydrolysis of L-pyroglutamyl-L-phenylalanyl-L-lysine-p-nitroaniline hydrochloride. The presence of endogenous inactivators of ocriplasmin in human vitreous was determined in a series of vitreous samples using an ELISA specific for alpha(2)-antiplasmin, antithrombin, and antitrypsin. RESULTS Degradation productions from autolysis are similar between vitreous and PBS with a significant prolongation of the effect in vitreous. Both follow a nonlinear pattern over time. The degradation corresponds best to a second-order kinetic process. The resulting rate constants were 207 ± 60 M(-1) s(-1) in PBS, 81 ± 15 M(-1) s(-1) in porcine vitreous, and 195 M(-1) s(-1) in human vitreous natural inhibitors were identified in samples of donor vitreous. Amounts differed significantly between samples, which may help explain the observed variability in human subjects. CONCLUSIONS Ocriplasmin is autolytic in vitreous. Biologic activity extends to several days following injection. The exact duration will vary based on the presence and concentration of serine protease inhibitors.

Educational paper: Retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease affecting the premature infant with an incompletely vascularized retina. The spectrum of ophthalmological findings in ROP exists from minimal sequelae, which do not affect vision, to bilateral retinal detachment and total blindness. With the increased survival of very small infants, retinopathy of prematurity has become one of the leading causes of childhood blindness. Over the past two decades, major advances have been made in understanding the pathogenesis of ROP, to a large extent as a result of changes in clinical risk factors (oxygen and non-oxygen related) and characteristics observed in ROP cases. This article provides a literature review on the evolution in clinical characteristics, classification and treatment modalities and indications of ROP. Special attention is hereby paid to the neonatal factors influencing the development of ROP and to the necessity for everyone caring for premature babies to have a well-defined screening and treatment protocol for ROP. Such screening protocol needs to be based on a unit-specific ROP risk profile and, consequently, may vary between different European regions. Conclusion: Retinopathy of prematurity is an important cause of ocular morbidity and blindness in children. With better understanding of the pathogenesis, screening and treatment guidelines have changed over time and are unit specific.

Predictive Value of a Topical Dexamethasone Provocative Test before Intravitreal Triamcinolone Acetonide Injection

PURPOSE To investigate the diagnostic value of a topical dexamethasone (DXM) provocative test before intravitreal triamcinolone acetonide (IVTA) injection for a steroid response. METHODS Eligible patients scheduled for first-time IVTA who did not have glaucoma or a history of a steroid response received DXM 0.1% drops 4 times daily over 4 weeks. After that, IVTA was given except in DXM responders with an IOP increase greater than 15 mm Hg. IOP was measured at baseline, 4 weeks after DXM treatment, at weeks 1, 2, and 4, and at months 3 and 6 after IVTA. A steroid response after the DXM test or after IVTA was defined as an IOP increase of 6 mm Hg or greater. RESULTS Thirty-six patients (36 eyes) were analyzed. The DXM test had a sensitivity of 25% (95% confidence interval [CI], 0.07-0.52), a specificity of 100% (95% CI, 0.83-1.00), a positive predictive value of 100% (95% CI, 0.40-1.00), and a negative predictive value of 62% (95% CI, 0.44-0.79) for a steroid response after IVTA. In DXM responders, the IOP increase after IVTA was 17.0+/-7.8 mm Hg versus 5.0+/-4.4 mm Hg in DXM nonresponders (P=0.005). The IOP increase after the DXM test correlated with the IOP increase after IVTA (P=0.001). CONCLUSIONS The topical DXM test had a low sensitivity, a high specificity, a high positive predictive value, and a moderate negative predictive value and may be useful to predict a steroid response after IVTA. DXM responders demonstrated high IOP increases after IVTA, and the IOP increase after the DXM test correlated with the IOP increase after IVTA. If the DXM test result is positive, risks and benefits of IVTA should be more carefully weighted.

A new and standardized method to sample and analyse vitreous samples by the Cellient automated cell block system.

In this prospective study, a universal protocol for sampling and analysing vitreous material was investigated. Vitreous biopsies are difficult to handle because of the paucity of cells and the gelatinous structure of the vitreous. Histopathological analysis of the vitreous is useful in difficult uveitis cases to differentiate uveitis from lymphoma or infection and to define the type of cellular reaction.

Early diagnosis and successful treatment of paraneoplastic melanocytic proliferation

Background Paraneoplastic melanocytic proliferation (bilateral diffuse uveal melanocytic proliferation, BDUMP) is a rare but devastating disease that causes progressive visual loss in patients who usually have an occult malignancy. Visual loss occurs as a result of paraneoplastic changes in the uveal tissue. Methods In a masked fashion, the serum of two patients with BDUMP was evaluated for the presence of cultured melanocyte elongation and proliferation (CMEP) factor using cultured human melanocytes. We evaluated the efficacy of plasmapheresis as a treatment modality early in the disease in conjunction with radiation and chemotherapy. Results The serum of the first case patient was investigated after plasmapheresis and did not demonstrate proliferation of cultured human melanocytes. The serum of the second case was evaluated prior to treatment with plasmapheresis and did induce this proliferation. These findings are in accordance with the diminution of CMEP factor after plasmapheresis. Treatment with plasmapheresis managed to stabilise the ocular disease progression in both patients. Conclusions In the past, visual loss due to paraneoplastic melanocytic proliferation was considered progressive and irreversible. We treated two patients successfully with plasmapheresis and demonstrated a relation between CMEP factor in the serum of these patients and proliferation of cultured melanocytes.