Antoine P. Brézin

Adalimumab in Patients with Active Noninfectious Uveitis.

BACKGROUND Patients with noninfectious uveitis are at risk for long-term complications of uncontrolled inflammation, as well as for the adverse effects of long-term glucocorticoid therapy. We conducted a trial to assess the efficacy and safety of adalimumab as a glucocorticoid-sparing agent for the treatment of noninfectious uveitis. METHODS This multinational phase 3 trial involved adults who had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite having received prednisone treatment for 2 or more weeks. Investigators and patients were unaware of the study-group assignments. Patients were randomly assigned in a 1:1 ratio to receive adalimumab (a loading dose of 80 mg followed by a dose of 40 mg every 2 weeks) or matched placebo. All patients received a mandatory prednisone burst followed by tapering of prednisone over the course of 15 weeks. The primary efficacy end point was the time to treatment failure occurring at or after week 6. Treatment failure was a multicomponent outcome that was based on assessment of new inflammatory lesions, best corrected visual acuity, anterior chamber cell grade, and vitreous haze grade. Nine ranked secondary efficacy end points were assessed, and adverse events were reported. RESULTS The median time to treatment failure was 24 weeks in the adalimumab group and 13 weeks in the placebo group. Among the 217 patients in the intention-to-treat population, those receiving adalimumab were less likely than those in the placebo group to have treatment failure (hazard ratio, 0.50; 95% confidence interval, 0.36 to 0.70; P<0.001). Outcomes with regard to three secondary end points (change in anterior chamber cell grade, change in vitreous haze grade, and change in best corrected visual acuity) were significantly better in the adalimumab group than in the placebo group. Adverse events and serious adverse events were reported more frequently among patients who received adalimumab (1052.4 vs. 971.7 adverse events and 28.8 vs. 13.6 serious adverse events per 100 person-years). CONCLUSIONS In our trial, adalimumab was found to be associated with a lower risk of uveitic flare or visual impairment and with more adverse events and serious adverse events than was placebo. (Funded by AbbVie; VISUAL I ClinicalTrials.gov number, NCT01138657 .).

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.

Comparison of Nd : YAG capsulotomy rates following phacoemulsification with implantation of PMMA, silicone, or acrylic intra-ocular lenses in four European countries.

PURPOSE The aim of this study was to compare the incidence of Nd : YAG laser capsulotomy after cataract surgery according to the type of intra-ocular lens material (PMMA, silicone, hydrophilic acrylic, hydrophobic acrylic) implanted in four European countries (France, Italy, Germany, Spain). DESIGN A retrospective record review. PARTICIPANTS A review of 1525 patients (first operated eye), aged 50 to 80 years, operated on for cataract in 1996 or 1997 in 16 surgical centers (4 per country). METHODS The study employed a retrospective cohort design. Charts were reviewed to collect information during at least a three-year period following cataract surgery to identify patients who underwent Nd : YAG laser capsulotomy postoperatively. MAIN OUTCOME MEASURES Data on the type of intra-ocular lens implanted was extracted from the patient notes, as was the date and outcome of the Nd : YAG laser intervention. Kaplan-Meier survival curve analysis with the time to Nd : YAG laser was performed on the data. RESULTS A total of 1525 patients (first operated eye) were available for the study (n = 294 for hydrophilic acrylic, n = 384 for PMMA, n = 421 for hydrophobic acrylic, n = 426 for silicone). There was a highly statistically significant difference between the IOL groups for the incidence of posterior capsule opacification (p < 0.001) and for Nd : YAG laser treatment (p < 0.001). The mean delay of Nd : YAG laser treatment from the date of cataract operation was 2.48 years (±1.70, ranging from 0 to 5.88 years).The rate of Nd : YAG laser capsulotomy over the follow-up period was lowest in the hydrophobic acrylic group (7.1%), followed by silicone (16.2%), PMMA (19.3%) and hydrophilic acrylic (31.1%), respectively. CONCLUSIONS A low incidence of posterior capsular opacification (PCO) and Nd : YAG laser treatment was detected in hydrophobic acrylic IOLs in comparison to three other types of IOLs implanted in a large cohort of persons with age-related cataract. Choice of IOL type may reduce the need for Nd : YAG laser treatment, although further research on the reasons for this is needed.

Ophthalmic outcomes after prenatal and postnatal treatment of congenital toxoplasmosis

PURPOSE To describe the ophthalmologic outcomes of cases of congenital toxoplasmosis treated prenatally and postnatally. DESIGN Observational case series. METHOD Follow-up ophthalmologic examinations of 18 children born to mothers who were infected before 25 weeks gestation were performed concurrently by two ophthalmologists. The infection in these children was first suspected when their mothers seroconverted during gestation. Toxoplasmic infection of the fetus was diagnosed by fetal blood or amniotic fluid analysis. Mothers were treated by a regimen of alternating pyrimethamine-sulfonamides and spiramycin during gestation. Pyrimethamine-sulfonamides treatment was continued from birth to 1 year of age. RESULTS The median age of the children was 4.5 years (range 1-11), when the follow-up ophthalmologic examinations were performed. Visual acuity was decreased in only one child, who had extensive bilateral macular and peripheral lesions. A posterior pole scar was noted in four eyes (four children) for whom visual acuity remained normal. Peripheral lesions were observed in nine eyes (five children). Both eyes were normal in 11 of 18 (61%) of the children. CONCLUSIONS In these children at a high risk for congenital toxoplasmic retinochoroiditis, a favorable visual outcome was observed in all but one case.

Evaluation of Non-Medical Costs Associated with Visual Impairment in Four European Countries

IntroductionVisual impairment is a severe disability that puts a heavy burden on individuals, families and society. In developed countries, the two major diseases leading to irreversible visual impairment are glaucoma and age-related macular degeneration. Their prevalence will increase dramatically with population aging. The economic consequences of visual impairment are considerable, but have rarely been documented, apart from some ‘top-down’ estimates based on national statistics. We estimated the non-medical costs related to visual impairment in four European countries: France, Italy, Germany and the UK.MethodsPrevalence rates of visual impairment, defined according to local regulations, were taken from national registers and, for France, from two recent nationwide surveys conducted by the French Institute for National Statistics and Economic Studies (Institut National de la Statistique et des Etudes Economiques [INSEE]). Estimates of the number of non-registered persons were obtained from the literature and expert opinion. Estimates of non-medical costs included institutional care, non-medical devices, residential adaptations, burden on carer, paid home help, loss of income and social allowances related to visual impairment. Unit costs (year 2004) were extracted from national databases and manufacturers. Healthcare professionals were interviewed to estimate the duration of assistance required by visually impaired persons. These durations were used to evaluate the cost of paid assistance at home in the four countries.ResultsThe numbers of visually impaired persons were 1.27 million in France, 0.73 million in Germany, 1.03 million in Italy and 1.11 million in the UK, including, respectively, 56%, 11%, 80% and 72% non-registered persons. The frequency of institutionalisation for visually impaired persons were, respectively, 7.8%, 9.6%, 10.9% and 10%. Total annual costs for visually impaired persons were estimated at €10 749 million in France, €9214 million in Germany, €12 069 million in Italy and €15 180 million in the UK. This translated into average annual costs per affected individual of €8434, €12 662, €11 701 and €13 674, respectively. The main cost components of visual impairment in the community were ‘loss of income’ (23–43% of community costs), ‘burden on carer’ (24–39%) and ‘paid assistance’ (13–29%).ConclusionTotal non-medical costs associated with visual impairment are considerable. The present analysis demonstrates that the preponderant economic consequences of visual impairment lie beyond healthcare systems, and that visual impairment has a considerable negative impact on productivity. Considering the non-medical social dimensions of visual impairment related to the consequent incapacity and dependency should encourage payers to finance health innovations that aim to preserve vision.

Clinical Manifestations of Ocular Toxoplasmosis

Clinical manifestations of ocular toxoplasmosis are reviewed. Findings of congenital and acute acquired ocular toxoplasmosis include retinal scars, white-appearing lesions in the active phase often associated with vitritis. Complications can include fibrous bands, secondary serous or rhegmatogenous retinal detachments, optic neuritis and neuropathy, cataracts, increased intraocular pressure during active infection, and choroidal neovascular membranes. Recurrences in untreated congenital toxoplasmosis occur in teenage years. Manifestations at birth are less severe, and recurrences are fewer in those who were treated promptly early in the course of their disease in utero and in the first year of life. Severe retinal involvement is common at diagnosis of symptomatic congenital toxoplasmosis in the United States and Brazil. Acute acquired infections also may be complicated by toxoplasmic retinochoroiditis, with recurrences most common close to the time of acquisition. Suppressive treatment can reduce recurrent disease.

Identification of Toxoplasma gondii in Paraffin-Embedded Sections by the Polymerase Chain Reaction

We used the polymerase chain reaction to amplify DNA fragments specific to Toxoplasma gondii. The sensitivity of the technique allowed for the detection of as few as ten cultured T. gondii tachyzoites. We applied the same amplification technique to deparaffinized ocular sections from two cases of ocular toxoplasmosis. Although toxoplasmic cysts could only be seen in one eye by optical microscopy, polymerase chain reaction allowed the identification of the parasite in both cases. Our study indicates the feasibility of a sensitive DNA-based assay to complement pathologic studies of an ocular parasitic disease.

Ophthalmologic Manifestations of Systemic Necrotizing Vasculitides at Diagnosis: A Retrospective Study of 1286 Patients and Review of the Literature

OBJECTIVE To determine the frequencies and types of ophthalmologic manifestations in patients with systemic necrotizing vasculitides (SNV), including polyarteritis nodosa (PAN) and ANCA-associated vasculitides (granulomatosis with polyangiitis (Wegeners, GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA); Churg-Strauss syndrome (CSS)) and review the literature on eye involvement in these diseases. METHODS This retrospective analysis was conducted on the ophthalmologic manifestations of SNV patients entered into the French Vasculitis Study Group database between July 1955 and August 2008. RESULTS Among the 1286 identified patients, 214 (16.6%) had ophthalmologic manifestations at diagnosis, significantly more often in GPA (117/343, 34.1%) than in EGPA (30/270, 11.1%; P = 0.0001), PAN (42/393, 10.7%; P = 0.0001) or MPA (25/280, 8.9%; P = 0.0001). The 3 most common recorded ophthalmologic manifestations were conjunctivitis (89, (7%)), episcleritis (56, (4%)), and/or blurred vision (44, (3%)), mainly caused by retinal vasculitis in 5, oculomotor nerve palsy in 4, uveitis in 4 and/or optic neuropathy in 3. Orbital inflammatory tumor, another common feature was rather specific to GPA (23/349, 6.6% (P = 0.0001)) compared to other SNV. The literature on ophthalmologic manifestations of SNV is limited to case reports except for GPA, in which the eye involvement frequency ranged from 29% to 57%. CONCLUSIONS Eye manifestations were more common in GPA than MPA, PAN and EGPA, but can be sight-threatening in any SNV. Given the heterogeneity of ophthalmologic involvement in SNV, close collaboration between the ophthalmologists and internists is critical.

Ocular inflammatory diseases associated with rheumatoid arthritis.

The extra-articular complications of rheumatoid arthritis (RA) include ophthalmological manifestations, which can, in some cases, be the first signs of the disease. These inflammatory ophthalmological conditions include episcleritis, scleritis and peripheral ulcerative keratitis (PUK). RA is the leading cause of necrotizing scleritis and of PUK, which are the two most severe ocular conditions associated with the disease. These conditions can rapidly threaten ocular prognosis and are associated with excess mortality in patients with RA owing to their association with systemic vasculitis. Close collaboration between the ophthalmologist and the rheumatologist or internal medicine expert is required for the diagnosis and therapeutic management of these patients. In this Review, we provide an overview of ocular inflammatory diseases in patients with RA with particular focus on the diagnosis and current available therapies (including biologic agents) for these conditions. Furthermore, we propose a decision tree to assist clinicians in their choice of treatment for patients with RA who also have ocular inflammatory disease.

HLA-A29 and Birdshot Chorioretinopathy

Birdshot chorioretinopathy primarily affects patients of European descent. At least 96%, if not all patients, are HLA-A29 carriers. HLA-A*29:01 and HLA-A*29:02, the two main subtypes of HLA-A29, differ only by a single mutation. In the general population HLA-A*29:02 is most frequent in whites, while HLA-A*29:01 is more frequent in Asians. The differential distribution of HLA-A*29:01 and HLA-A*29:02 has been actively debated as an explanation for the selective development of the disease in patients of European descent, but is no longer a valid argument. Another factor, probably not HLA linked, is either protective in Asians and in Africans or, conversely, triggers an autoimmune reactivity that is possibly present in whites and absent in Asians and in Africans. HLA-A*29:02 transgenic mice in which a spontaneous posterior uveitis is observed after 6 months of age provide further evidence that the HLA-A29 molecule plays a role in the pathogenesis of the disease.