Laser Flare Photometry: A Useful Tool for Monitoring Patients with Juvenile Idiopathic Arthritis-associated Uveitis.

PURPOSE: We evaluated laser flare photometry (LFP) values in patients with juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: Retrospective study. A decrease of the LFP value between baseline visit and 1 month after anti-inflammatory treatment intensification allowed us to define two groups of patients: group 1 (decreased LFP value ≥50%) and group 2 (<50%). We evaluated the prevalence of vision-threatening complications in both groups. RESULTS: Fifty-four patients (87 eyes) were followed for 9.9 ± 5 years. Group 1 eyes (n = 54) had significantly fewer ocular complications than group 2 eyes (n = 33) at both 5 years visit (p = .03) and final visit (p = .047). At the final visit, group 2 eyes had significantly more band keratopathy, trabeculectomy, cataract surgery, glaucoma and papille edema. Group 1 eyes kept a better visual acuity (p < .0001). CONCLUSION: The decrease of LFP values ≥50% of the initial value 1 month after treatment intensification is a good early prognostic factor.

Efficacy and Safety of Intravitreal Sirolimus for Noninfectious Uveitis of the Posterior Segment: Results from the Sirolimus Study Assessing Double-Masked Uveitis Treatment (SAKURA) Program.

PURPOSE: To evaluate the efficacy and safety of intravitreal sirolimus in the management of noninfectious uveitis of the posterior segment (NIU-PS). DESIGN: Combined analysis of 2 phase 3, randomized, double-masked, multinational, 6-month studies. PARTICIPANTS: Adults with active NIU-PS (intermediate uveitis, posterior uveitis, or panuveitis; defined as vitreous haze [VH] ≥1.5+ on modified Standardization of Uveitis Nomenclature scale). METHODS: Patients were randomized 1:1:1 to receive intravitreal sirolimus 44 µg (n = 208), 440 µg (n = 208), or 880 µg (n = 177) on days 1, 60, and 120. Patients discontinued medications for NIU-PS except for systemic corticosteroids, which were tapered according to protocol. Enrollment in the 880-µg group was terminated after interim results found no significant difference in efficacy compared with the 440-µg dose. MAIN OUTCOME MEASURES: The primary efficacy end point was the percentage of patients with VH of 0 at month 5 in the study eye without the use of rescue therapy. Secondary efficacy end points included VH of 0 or 0.5+, corticosteroid-tapering success, and changes in best-corrected visual acuity (BCVA). Safety measures included ocular and nonocular adverse events. RESULTS: A total of 592 patients were randomized. Significantly higher proportions of patients treated with 440 µg compared with 44 µg intravitreal sirolimus achieved VH of 0 (21.2% vs. 13.5%; P = 0.038) and VH of 0 or 0.5+ (50.0% vs. 40.4%; P = 0.049) at month 5. Best-corrected visual acuity was stable (absolute change <5 ETDRS letters) or improved >5 letters in 80.1% and 80.2% of patients in the 440-µg and 44-µg groups, respectively. At month 5, corticosteroids were tapered successfully in 69.6% and 68.8% of patients in the 440-µg and 44-µg groups, and among these patients, VH of 0 or 0.5+ was achieved by 43.5% and 28.1% in the 440-µg and 44-µg groups. Both doses were generally well tolerated. Mean changes from baseline intraocular pressure (IOP) in the study eye at each analysis visit were minimal in all treatment groups. CONCLUSIONS: Intravitreal sirolimus 440 µg improved ocular inflammation, as measured by VH, compared with the 44-µg dose, with minimal impact on IOP, while preserving BCVA.

Primary vitreoretinal lymphomas display a remarkably restricted immunoglobulin gene repertoire.

Primary vitreoretinal lymphoma (PVRL) is a high-grade lymphoma affecting the vitreous and/or the retina. The vast majority of cases are histopathologically classified as diffuse large B-cell lymphoma (DLBCL) and considered a subtype of primary central nervous system lymphoma (PCNSL). To obtain more insight into the ontogenetic relationship between PVRL and PCNSL, we adopted an immunogenetic perspective and explored the respective immunoglobulin gene repertoire profiles from 55 PVRL cases and 48 PCNSL cases. In addition, considering that both entities are predominantly related to activated B-cell (ABC) DLBCL, we compared their repertoire with that of publicly available 262 immunoglobulin heavy variable domain gene rearrangement sequences from systemic ABC-type DLBCLs. PVRL displayed a strikingly biased repertoire, with the IGHV4-34 gene being used in 63.6% of cases, which was significantly higher than in PCNSL (34.7%) or in DLBCL (30.2%). Further repertoire bias was evident by (1) restricted associations of IGHV4-34 expressing heavy chains, with κ light chains utilizing the IGKV3-20/IGKJ1 gene pair, including 5 cases with quasi-identical sequences, and (2) the presence of a subset of stereotyped IGHV3-7 rearrangements. All PVRL IGHV sequences were highly mutated, with evidence of antigen selection and ongoing mutations. Finally, half of PVRL and PCNSL cases carried the MYD88 L265P mutation, which was present in all 4 PVRL cases with stereotyped IGHV3-7 rearrangements. In conclusion, the massive bias in the immunoglobulin gene repertoire of PVRL delineates it from PCNSL and points to antigen selection as a major driving force in their development.

Predictive Factors of Intraocular Pressure Level Evolution Over Time and Glaucoma Severity in Fuchs' Heterochromic Iridocyclitis.

Purpose: To investigate the clinical and virologic-associated and predictive factors of intraocular pressure (IOP) evolution over time and its severity in Fuchs' heterochromic iridocyclitis (FHC). Methods: Consecutive patients with both clinical FHC and intraocular synthesis of rubella virus (RV)-specific antibodies were included in this study. Specific ocular production of RV antibodies was confirmed using the quotient of serum/aqueous humor ratio of RV IgGs (Crv) and control antiviral IgGs (Cctl), using quantitative serology methods. Epidemiologic, clinical, biological, and virologic data at referral were collected and correlated with IOP values over time, occurrence, and severity of glaucoma. Results: Sixty-eight eyes of 68 patients were included. Mean age at diagnosis was 40.7 ± 11.1 years. Mean follow-up was 4.3 ± 4.3 years. Mean baseline Crv and Cctl values were 12.34 ± 14.67 and 216.70 ± 98.4, respectively. Mean baseline IOP was 17.2 ± 7.2 mm Hg (range, 9-40) and 15.6 ± 5.6 (range, 3-30) 5 years after referral. The predictive factors for pejorative IOP evolution over time and glaucoma severity were male sex (P = 0.03) and decreased Crv (P = 0.04) and presence of iris nodules (P < 0.001) and decreased Cctl (P = 0.02), respectively. Diagnostic delay was associated with increased likelihood of undergoing glaucoma surgery (P = 0.02). Conclusions: Time to diagnosis, male sex, presence of iris nodules at baseline, and decreased Crv and Cctl ratios were associated with increased likelihood of pejorative IOP evolution over time. Given the aggressiveness of glaucoma in FHC, these results provide interesting insight into what category of patients should need the closest screening.

Neoplasia and intraocular inflammation: From masquerade syndromes to immunotherapy-induced uveitis.

Masquerade syndromes represent a large set of ophthalmological entities that mimic inflammatory conditions. Any delay in their diagnosis may be correlated with systemic dissemination or worsening of the causal disease and, therefore, with poor prognosis. One of the disadvantages of the new potent treatments of uveitis is the delay that they can induce in the diagnosis of neoplastic intraocular infiltrations. Thorough and careful clinical examination of all patients referred for uveitis, especially when they are Caucasian, over 50 years of age, and with posterior segment involvement, is of paramount importance in this context. Ancillary investigations and often-invasive histo-pathologic evaluation of tissue specimens or ocular fluids are regularly required in these situations. The most common masquerade syndrome is primary vitreoretinal lymphoma (PVRL). New molecular diagnostic tools may be helpful in challenging cases lacking cytological confirmation. Therapeutic strategies targeting tumoral cells in the eye and also in the central nervous system can improve the life expectancy of affected patients. In this review, we discuss diagnostic strategies and current therapies in PVRL and provide an overview of other conditions that can mimic primary ocular inflammation, especially in the field of oncology and its new therapeutic armamentarium.

Clinical and Biological Factors Associated With Recurrences of Severe Toxoplasmic Retinochoroiditis Confirmed by Aqueous Humor Analysis.

PURPOSE: To investigate clinical and biological factors influencing recurrences of severe toxoplasmic retinochoroiditis (TRC) confirmed by aqueous humor analysis. DESIGN: Retrospective case series. METHODS: Retrospective analysis of 87 subjects with severe TRC, proven by positive Goldmann-Witmer coefficient (GWC), Toxoplasma gondii (T. gondii) immunoblot, or T. gondii-specific polymerase chain reaction (PCR) in aqueous humor. Cases with immunosuppression or retinal scars without previous recorded episode were excluded. Time-dependent, clinical, treatment-related, and biological factors were explored by univariate and multivariate shared frailty survival analyses. RESULTS: Among 44 included subjects (age, 40.4 ± 17.6 years; follow-up, 8.3 ± 2.7 years), 22 presented recurrences. There was 0.11 recurrence/patient/year and mean disease-free interval was 5.0 ± 2.9 years. The risk of recurrence was higher immediately after an episode (P < .0001). Among recurrent cases, the risk of multiple recurrences was higher when the first recurrence occurred after longer disease-free intervals (P = .046). In univariate analysis, the recurrence risk declined with higher number of intense bands on aqueous T. gondii immunoblot (P = .006), and increased when venous vasculitis was present initially (P = .019). Multivariate analysis confirmed that eyes with more intense bands on immunoblot had fewer recurrences (P = .041). There was a near-significant risk elevation after pyrimethamine/azithromycin treatment (P = .078 and P = .054, univariate and multivariate). Intravenous corticosteroid administration, oral corticosteroid administration, aqueous GWC, and T. gondii PCR did not influence recurrences (P = .12, P = .10, P = .39, and P = .96, respectively). CONCLUSIONS: Recurrences of severe TRC are not random and may be influenced by clinical and biological factors possibly related to blood-retinal barrier alterations. These results may contribute to identifying biomarkers for TRC reactivation.

Cytomegalovirus Anterior Uveitis: Clinical Characteristics and Long-term Outcomes in a French Series.

PURPOSE: To report the characteristics of cytomegalovirus anterior uveitis (CMV AU) and the comparative response to 2 types of antiviral induction treatments. DESIGN: Retrospective, consecutive case series. METHODS: Consecutive immunocompetent patients with polymerase chain reaction-positive CMV AU were included. For each patient, best-corrected visual acuity (BCVA), intraocular pressure (IOP), clinical characteristics at baseline and latest visit, and number of relapses were recorded. All patients received an induction dose of intravenous (IV) ganciclovir or oral valganciclovir and a maintenance dose of oral valganciclovir. RESULTS: Thirty-six eyes of 35 patients were included. Mean age at diagnosis was 55.5 years. Mean follow-up was 4.13 years. Posner-Schlossman and chronic nonspecific AU were observed in 69.4% and 30.6% of cases, respectively. We did not observe any case of Fuchs uveitis or endotheliitis. At baseline, mean BCVA was 20/25 and mean IOP was 29.19 mm Hg. Keratic precipitates and iris atrophy were seen in 91.4% and 25.7% of cases. Induction therapy consisted of oral valganciclovir and IV ganciclovir in 40% and 60% of cases. A total of 94.2% of patients responded to the first line of therapy. Recurrence was reported in 73.5% of cases. Glaucoma surgery was necessary in 25.7% of cases. Early initiation of antiviral therapy (≤700 days) seemed to decrease the recourse to glaucoma surgery. Both IV and oral induction treatments seemed similar in terms of BCVA changes and occurrence of relapses. CONCLUSIONS: Characteristics of CMV AU seem to show specificities in this French cohort. Early initiation of antiviral therapy seems to reduce the severity of glaucoma.

Superficial and deep retinal foveal avascular zone OCTA findings of non-infectious anterior and posterior uveitis.

PURPOSE: To compare the superficial (FAZ-S) and deep foveal avascular zones (FAZ-D) of non-infectious anterior and posterior uveitis to healthy controls, using optical coherence tomography angiography (OCTA). METHODS: OCTA was performed on 74 eyes: 34 eyes with non-infectious posterior uveitis (with (post+CME) and without macular edema (post-CME)), 11 eyes with non-infectious anterior uveitis (with (ant+CME) and without macular edema (ant-CME)), and the control group which included 29 healthy eyes. RESULTS: Eyes suffering from non-infectious posterior uveitis presented with significantly larger FAZ-D when compared to healthy controls, both in the presence or in the absence of macular edema (p < 0.001). In the presence of macular edema, eyes presenting with anterior uveitis (ant+CME) also showed significantly larger FAZ-S (p = 0.03) and FAZ-D (p < 0.001), when compared to healthy controls. In the absence of macular edema, eyes with anterior uveitis cannot be distinguished from controls (p > 0.6). CONCLUSION: The deep retinal foveal avascular zone seems to be enlarged in eyes presenting with non-infectious posterior uveitis, both in the presence or absence of macular edema.

Cataract Surgery with Primary Lens Implantation in Children with Chronic Uveitis.

PURPOSE: To evaluate the evolution of chronic uveitis in children undergoing cataract surgery with primary intraocular lens (IOL) implantation. METHODS: Twelve children with chronic uveitis underwent cataract surgery with primary posterior chamber intraocular lens (IOL) implantation. RESULTS: Fourteen eyes were implanted with a foldable hydrophobic acrylic IOL. The mean follow-up was 35.39 months (8.72-69.57). The mean BCDVA before surgery and at the end of follow-up was 1.11 (0.40-2.30; SD: 0.57) and 0.48 (0-3; SD: 0.77; p=0.007) respectively. The mean oral corticosteroids dosage after surgery and at the end of follow-up was 0.80 mg/kg/day (SD: 0.37) and 0.17 mg/kg/day (SD: 0.24; p=0.001) respectively. All patients except one were treated with methotrexate. Four patients (5 eyes) were additionally treated with anti-tumor necrosis factor agent. CONCLUSIONS: Cataract surgery with primary posterior chamber hydrophobic IOL implantation is possible and leads to a good visual recovery in cases of pediatric chronic uveitis. This surgery requires aggressive anti-inflammatory management with immunosuppressive drugs to control inflammation and reduce the corticosteroids dosage.

Inflammatory Choroidal Neovascularization: Beyond the Intravitreal Approach.

PURPOSE: To describe the importance of a customized combined systemic and local therapy in the management of inflammatory choroidal neovascularization (iCNV). METHODS: Observational retrospective case series. RESULTS: Four iCNV cases, complicating posterior uveitis or panuveitis affecting young patients, are reported. Combination of both intravitreal (IVT) and systemic drugs represented a successful treatment strategy. CONCLUSIONS: iCNV is a sight-threatening disease which affects mostly young people. Customized and both systemic and IVT therapies might represent the best therapeutic option in order to obtain disease control and good prognosis.

Regulatory T Cell Therapy for Uveitis: A New Promising Challenge.

Uveitis is a sight-threatening primary intraocular inflammation of various origins in mainly young and active patients. Due to the absence of biomarkers in most of the cases, the current treatment of noninfectious entities remains nonspecific, using corticosteroids, conventional immunosuppressors, and more recently biological agents. Identification of regulatory T cells in different models of autoimmune uveitis together with the evaluation of this important subpopulation in different entities paved the way for new therapeutic strategies, in addition to exclusive pharmaceutical approaches. Upregulation of regulatory T cells induced by biological agents has been recently highlighted. Development of cell therapy in autoimmune diseases is at its stammering needing more experimental data and robust clinical trials to demonstrate safety and efficacy before larger developments. Specific or polyclonal Tregs may be used, but it is of utmost importance to determine the method of selection, the level of activation, and the route of administration. Mastering immune cell therapy remains a challenging goal in patients with autoimmune diseases, but it may significantly enlarge our therapeutic possibilities in severe and refractory situations.

Interferon-alpha2a and Systemic Corticosteroid in Monotherapy in Chronic Uveitis: Results of the Randomized Controlled BIRDFERON Study.

PURPOSE: Macular edema is the leading cause of vision loss in bilateral chronic noninfectious posterior uveitis, and is currently being treated using corticosteroids, immunosuppressive agents, and biotherapies. The aim of this trial was to assess and compare the efficacy and safety of corticosteroids and interferon-α (IFN-α) in adults with such conditions. DESIGN: Randomized controlled trial. METHODS: Subjects: Adult patients with bilateral posterior autoimmune noninfectious and nontumoral uveitis complicated by macular edema in at least 1 eye. INTERVENTION: Patients received either subcutaneous IFN-α2a, systemic corticosteroids, or no treatment for 4 months. The efficacy and safety were assessed for up to 4 months. MAIN OUTCOME MEASURES: The main endpoint was the change of the central foveal thickness (CFT) obtained by optical coherence tomography. RESULTS: Forty-eight patients were included. In intention-to-treat analysis, the median CFT change showed no significant difference. However, the per-protocol analysis showed a significant difference between groups for both eyes (OD and OS), and for the worse and better eyes. Statistically significant difference was found between the control and corticosteroid groups for the OD (P = .0285), and between the control and IFN-α groups for the OD (P = .0424) and worse eye (P = .0354). Serious adverse events occurred in 2 patients in the IFN group, in 1 patient in the corticosteroid group, and in 2 patients in the control group and were completely resolved after switch. CONCLUSIONS: IFN-α and systemic corticosteroids, compared with no treatment, were associated with significant anatomic and visual improvement shown in the per-protocol study.

Evaluation of outer retinal tubulations in eyes switched from intravitreal ranibizumab to aflibercept for treatment of exudative age-related macular degeneration.

PURPOSE: To evaluate the changes of outer retinal tubulations (ORTs) as seen on spectral-domain optical coherence tomography (SD OCT) in eyes with neovascular age-related macular degeneration (AMD) where treatment was switched from intravitreal ranibizumab to intravitreal aflibercept. METHODS: This was a prospective study of eyes diagnosed with neovascular AMD and previously treated with >6 intravitreal ranibizumab injections and switched to aflibercept, conducted at a single centre (Department of Ophthalmology at Pitié Salpetriere Hospital, Paris VI University) from January to July 2015. Before and after treatment was switched from ranibizumab to aflibercept, SD-OCT was used to evaluate the presence of ORTs. Additional assessments in this patient group included best-corrected visual acuity (BCVA), fluorescein angiography (FA), indocyanine green angiography (ICGA). Changes in pigment epithelium detachments (PED), presence of intraretinal cysts, and presence of subretinal fluid (SRF) were also noted. RESULTS: Twenty-four eyes of 24 consecutive patients (15 female/nine male, mean age 70 years) diagnosed with neovascular AMD and previously treated with >6 intravitreal ranibizumab injections and switched to aflibercept were included in the analysis. After receiving aflibercept, patients were followed for a mean of 6.1 months. Prior to treatment switch, 97 % of eyes showed ORTs, while after treatment switch to aflibercept, at the end of the study period, 75 % had ORTs (p = 0.219). Changes in BCVA (LogMAR) were not statistically significant (1.16 ± 0.44 to 1.18 ± 1.06, p = 0.12), however, a significant reduction in central macular thickness (CMT) (from 406 µm ± 112 to 263 µm ± 68, p = 0.001), PED (from 70.8 % to 41.7 % , p = 0.016), presence of intraretinal cysts (from 83.3 % to 33.3 %, p = 0.002) and SRF (from 91.7 % to 25 %, p = 0.001 ) were noted. CONCLUSION: After switching from ranibizumab treatment to aflibercept, ORTs remained present in 75 % of eyes, and significant reductions in CMT, PED, and SRF, and presence of intraretinal cysts were observed.

Intraocular T-cell Lymphoma: Clinical Presentation, Diagnosis, Treatment, and Outcome.

PURPOSE: To report on the clinical data of seven patients with T-cell intraocular lymphoma (IOL). METHODS: Retrospective case series. RESULTS: Seven immunocompetent patients, 12 eyes, 6 women, with T-cell-IOL were included from five countries. Mean age was 53.5 years (range: 25-82). Four patients had systemic-ocular lymphoma, two had CNS-ocular lymphoma, and one had systemic-CNS- ocular lymphoma. Vitritis was the most frequent clinical sign, followed by anterior uveitis and serous retinal detachment. Cytopathologic examination was performed on all ocular specimens (vitreous in six and iris mass biopsy in one patient). Adjunctive diagnostic procedures included immunohistochemistry, molecular tests, and cytokine profiling of vitreous samples. Treatment modalities included systemic chemotherapy (five patients), intravitreal methotrexate (three patients), globe radiotherapy, and intrathecal chemotherapy. Mean survival from diagnosis was 21.7 months (range: 2-69). Two patients are still alive. CONCLUSIONS: T-cell IOL has variable clinical manifestations and prognosis. Systemic involvement, SRD, and vitreoretinal involvement were frequently observed.

Treatment of Non-infectious Uveitic Macular Edema with the Intravitreal Dexamethasone Implant.

PURPOSE: To describe the clinical outcome of phakic eyes with macular edema (ME) due to non-infectious uveitis treated with a dexamethasone intravitreal implant. METHODS: A retrospective analysis of 41 eyes treated with a total of 58 dexamethasone intravitreal implants was conducted. Best corrected visual acuity (BCVA), central retinal thickness (CRT) and complications data were collected. RESULTS: One month after the first implant, even as CRT improved significantly in most eyes (p<0.001), 31.7% showed no improvement in BCVA. At 6 months post-implantation, CRT and BCVA had deteriorated in up to 70% of patients. Thirteen eyes were re-implanted, with a similar effect to that of the first implant. Ocular hypertension developed in 36.2% of eyes, and three eyes had cataract surgery, all in eyes with repeated implants. CONCLUSIONS: The dexamethasone intravitreal implant can be safely used to treat ME due to non-infectious uveitis, but with a limited and short effect on BCVA.

Long-term Efficacy of Interferon in Severe Uveitis Associated with Behçet Disease.

PURPOSE: To retrospectively assess the frequency of ocular relapse and the possibility of long-term remission in patients treated with interferon (IFN) for severe uveitis associated with Behçet disease. METHODS: All patients were treated with an initial dosage of 3 million IU IFN three times a week. The main outcome measure was the number of relapses per person per year before, during, and after IFN treatment. RESULTS: Of 36 patients (67 eyes), 31 (86.1%) responded to IFN. The mean follow-up was 8.19 years. Twenty-one out of 36 patients discontinued IFN and 76% of these have not relapsed within 5.05 years after discontinuation. The mean relapse per person per year decreased significantly from 1.39 to 0.0496 (p = 1.82×10-10) during the treatment period and remained at 0.057 relapses per person per year after IFN discontinuation. CONCLUSION: IFN efficiently decreases the relapse rate and seems to permit long-term remission even after discontinuation.

Failure to Integrate Quantitative Measurement Methods of Ocular Inflammation Hampers Clinical Practice and Trials on New Therapies for Posterior Uveitis.

Uveitis is one of the fields in ophthalmology where a tremendous evolution took place in the past 25 years. Not only did we gain access to more efficient, more targeted, and better tolerated therapies, but also in parallel precise and quantitative measurement methods developed allowing the clinician to evaluate these therapies and adjust therapeutic intervention with a high degree of precision. Objective and quantitative measurement of the global level of intraocular inflammation became possible for most inflammatory diseases with direct or spill-over anterior chamber inflammation, thanks to laser flare photometry. The amount of retinal inflammation could be quantified by using fluorescein angiography to score retinal angiographic signs. Indocyanine green angiography gave imaging insight into the hitherto inaccessible choroidal compartment, rendering possible the quantification of choroiditis by scoring indocyanine green angiographic signs. Optical coherence tomography has enabled measurement and objective monitoring of retinal and choroidal thickness. This multimodal quantitative appraisal of intraocular inflammation represents an exquisite security in monitoring uveitis. What is enigmatic, however, is the slow pace with which these improvements are integrated in some areas. What is even more difficult to understand is the fact that clinical trials to assess new therapeutic agents still mostly rely on subjective parameters such as clinical evaluation of vitreous haze as a main endpoint; whereas a whole array of precise, quantitative, and objective modalities are available for the design of clinical studies. The scope of this work was to review the quantitative investigations that improved the management of uveitis in the past 2-3 decades.