Small Extracellular Vesicles and Oxidative Pathophysiological Mechanisms in Retinal Degenerative Diseases.

This review focuses on the role of small extracellular vesicles in the pathophysiological mechanisms of retinal degenerative diseases. Many of these mechanisms are related to or modulated by the oxidative burden of retinal cells. It has been recently demonstrated that cellular communication in the retina involves extracellular vesicles and that their rate of release and cargo features might be affected by the cellular environment, and in some instances, they might also be mediated by autophagy. The fate of these vesicles is diverse: they could end up in circulation being used as markers, or target neighbor cells modulating gene and protein expression, or eventually, in angiogenesis. Neovascularization in the retina promotes vision loss in diseases such as diabetic retinopathy and age-related macular degeneration. The importance of micro RNAs, either as small extracellular vesicles' cargo or free circulating, in the regulation of retinal angiogenesis is also discussed.

Intravenous methylprednisolone induces rapid improvement in non-infectious uveitis: a multicentre study of 112 patients.

OBJECTIVES: Rapid control of intraocular inflammation in non-infectious uveitis (NIU) is mandatory to avoid irreversible structural and functional damage. In this study, we assessed the efficacy and safety of intravenous methylprednisolone (IVMP) pulses in the treatment of NIU. METHODS: A retrospective case series of 112 patients who received IVMP for the treatment of NIU, either isolated or associated with different underlying diseases, was studied. Intraocular inflammation (anterior chamber cells and vitritis) was the primary outcome measure. Secondary outcome measures were macular thickness and best corrected visual acuity (BCVA). Patients were assessed at baseline visit, and at days 2-5, 7, 15 and 30 after initiation of IVMP pulse therapy. RESULTS: A total of 112 patients (mean age 42±14.5 yrs) were assessed. An underlying immune-mediated disease was diagnosed in 73 patients. Inflammatory ocular patterns were panuveitis (n=68), posterior uveitis (n=30), anterior uveitis (AU) (n=12), and intermediate uveitis (n=2). Additionally, patients presented cystoid macular oedema (CME) (n=50), retinal vasculitis (n=37), and exudative retinal detachment (n=31). Therapies used before IVMP included intraocular glucocorticoids (n=4), high-dose oral systemic glucocorticoids (n=77), and conventional (n=107) or biologic (n=40) immunosuppressive drugs. IVMP dose ranged from 80 to 1,000 mg/day for 3-5 consecutive days. Improvement was observed in AU, vitritis, BCVA, CME, and retinal vasculitis. At first month evaluation, total remission was achieved in 19 patients. Side effects of IVMP were respiratory infections (n=3), uncontrolled hyperglycaemia (n=1), herpes zoster (n=1), and oral candidiasis (n=1). CONCLUSIONS: IVMP pulse therapy was effective and safe, and achieved rapid control of NIU.

Non-contact wide-angled visualization with chandelier-assisted scleral buckling for primary uncomplicated rhegmatogenous retinal detachment.

PURPOSE: To report our experience in non-contact wide-angled visualization with chandelier-assisted scleral buckling (SB) in uncomplicated primary rhegmatogenous retinal detachments (RRD). METHODS: Retrospective case series of 282 eyes that underwent non-contact wide-angled visualization with chandelier-assisted SB and were followed for a mean of 13.5 months. RESULTS: There were 160 male patients. The average age was 42.6 years old. There were 262 eyes that were phakic, 18 pseudophakic, and 2 aphakic. Two-thirds of eyes presented with the macula detached. Eyes had an average of 1.6 breaks. The single operation anatomic success rate was 85.1% (240/282). The pre-op visual acuity improved from 1.21 to 0.76 logMAR at 6 months (p < 0.0001). Complications included a case of scleral laceration, choroidal hemorrhage, 3 epiretinal membranes, 1 macular fold, and 4 eyes with buckle exposure. CONCLUSION: Non-contact wide-angled visualization with chandelier-assisted SB compares favorably with conventional SB for primary uncomplicated primary RRD.

Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet's Disease.

PURPOSE: To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in a large series of patients with uveitis due to Behçet disease (BD) who achieved remission after the use of this biologic agent. DESIGN: Open-label multicenter study of ADA-treated patients with BD uveitis refractory to conventional immunosuppressants. SUBJECTS: Sixty-five of 74 patients with uveitis due to BD, who achieved remission after a median ADA duration of 6 (range, 3-12) months. ADA was optimized in 23 (35.4%) of them. This biologic agent was maintained at a dose of 40 mg/subcutaneously/2 weeks in the remaining 42 patients. METHODS: After remission, based on a shared decision between the patient and the treating physician, ADA was optimized. When agreement between patient and physician was reached, optimization was performed by prolonging the ADA dosing interval progressively. Comparison between optimized and nonoptimized patients was performed. MAIN OUTCOME MEASURES: Efficacy, safety, and cost-effectiveness in optimized and nonoptimized groups. To determine efficacy, intraocular inflammation (anterior chamber cells, vitritis, and retinal vasculitis), macular thickness, visual acuity, and the sparing effect of glucocorticoids were assessed. RESULTS: No demographic or ocular differences were found at the time of ADA onset between the optimized and the nonoptimized groups. Most ocular outcomes were similar after a mean ± standard deviation follow-up of 34.7±13.3 and 26±21.3 months in the optimized and nonoptimized groups, respectively. However, relevant adverse effects were only seen in the nonoptimized group (lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli, 1 each). Moreover, the mean ADA treatment costs were lower in the optimized group than in the nonoptimized group (6101.25 euros/patient/year vs. 12 339.48; P < 0.01). CONCLUSION: ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective.

New insights into the genetic component of non-infectious uveitis through an Immunochip strategy.

BACKGROUND: Large-scale genetic studies have reported several loci associated with specific disorders involving uveitis. Our aim was to identify genetic risk factors that might predispose to uveitis per se, independent of the clinical diagnosis, by performing a dense genotyping of immune-related loci. METHODS: 613 cases and 3693 unaffected controls from three European case/control sets were genotyped using the Immunochip array. Only patients with non-infectious non-anterior uveitis and without systemic features were selected. To perform a more comprehensive analysis of the human leucocyte antigen (HLA) region, SNPs, classical alleles and polymorphic amino acid variants were obtained via imputation. A meta-analysis combining the three case/control sets was conducted by the inverse variance method. RESULTS: The highest peak belonged to the HLA region. A more detailed analysis of this signal evidenced a strong association between the classical allele HLA-A*2902 and birdshot chorioretinopathy (p=3.21E-35, OR=50.95). An omnibus test yielded HLA-A 62 and 63 as relevant amino acid positions for this disease. In patients with intermediate and posterior uveitis, the strongest associations belonged to the rs7197 polymorphism, within HLA-DRA (p=2.07E-11, OR=1.99), and the HLA-DR15 haplotype (DRB1*1501: p=1.16E-10, OR=2.08; DQA1*0102: p=4.37E-09, OR=1.77; DQB1*0602: p=7.26E-10, OR=2.02). Outside the HLA region, the MAP4K4/IL1R2 locus reached statistical significance (rs7608679: p=8.38E-07, OR=1.42). Suggestive associations were found at five other loci. CONCLUSIONS: We have further interrogated the association between the HLA region and non-infectious non-anterior uveitis. In addition, we have identified a new non-HLA susceptibility factor and proposed additional risk loci with putative roles in this complex condition.

INTRAVITREAL BEVACIZUMAB FOR PROLIFERATIVE DIABETIC RETINOPATHY: Results From the Pan-American Collaborative Retina Study Group (PACORES) at 24 Months of Follow-up.

PURPOSE: To evaluate the effects of intravitreal bevacizumab (IVB) on retinal neovascularization in patients with proliferative diabetic retinopathy (PDR). METHODS: Retrospective multicenter interventional case series. A chart review was performed of 81 consecutive patients (97 eyes) with retinal neovascularization due to PDR, who received at least 1 IVB injection. RESULTS: The mean age of the patients was 55.6 ± 11.6 years. The mean number of IVB injections was 4 ± 2.5 injections (range, 1-8 injections) per eye. The mean interval between IVB applications was 3 ± 7 months. The mean duration of follow-up was 29.6 ± 2 months (range, 24-30 months). Best-corrected visual acuity and optical coherence tomography improved statistically significantly (P < 0.0001, both comparisons). Three eyes without previous panretinal photocoagulation ("naive" eyes) and with vitreous hemorrhage did not require vitreoretinal surgery. Five (5.2%) eyes with PDR progressed to tractional retinal detachment requiring vitrectomy. No systemic adverse events were noted. CONCLUSION: Intravitreal bevacizumab resulted in marked regression of retinal neovascularization in patients with PDR and previous panretinal photocoagulation. Intravitreal bevacizumab in naive eyes resulted in control or regression of 42.1% of eyes without adjunctive laser or vitrectomy during 24 months of follow-up. There were no safety concerns during the 2 years of follow-up of IVB for PDR.

Oxidative stress in retinal pigment epithelium cells increases exosome secretion and promotes angiogenesis in endothelial cells.

The retinal pigment epithelium (RPE), a monolayer located between the photoreceptors and the choroid, is constantly damaged by oxidative stress, particularly because of reactive oxygen species (ROS). As the RPE, because of its physiological functions, is essential for the survival of the retina, any sustained damage may consequently lead to loss of vision. Exosomes are small membranous vesicles released into the extracellular medium by numerous cell types, including RPE cells. Their cargo includes genetic material and proteins, making these vesicles essential for cell-to-cell communication. Exosomes may fuse with neighbouring cells influencing their fate. It has been observed that RPE cells release higher amounts of exosomes when they are under oxidative stress. Exosomes derived from cultured RPE cells were isolated by ultracentrifugation and quantified by flow cytometry. VEGF receptors (VEGFR) were analysed by both flow cytometry and Western blot. RT-PCR and qPCR were conducted to assess mRNA content of VEGFRs in exosomes. Neovascularization assays were performed after applying RPE exosomes into endothelial cell cultures. Our results showed that stressed RPE cells released a higher amount of exosomes than controls, with a higher expression of VEGFR in the membrane, and enclosed an extra cargo of VEGFR mRNA. Angiogenesis assays confirmed that endothelial cells increased their tube formation capacity when exposed to stressed RPE exosomes.

INTRAVITREAL DEXAMETHASONE IMPLANT FOR THE TREATMENT OF REFRACTORY MACULAR EDEMA IN RETINAL VASCULAR DISEASES: Results of the KKESH International Collaborative Retina Study Group.

PURPOSE: To evaluate the safety and efficacy of intravitreal dexamethasone implant (Ozurdex) for treating refractory macular edema in retinal vascular diseases. METHODS: This is a retrospective consecutive series of 53 eyes with refractory macular edema secondary to central retinal vein occlusion (13 eyes), branch retinal vein occlusion (14 eyes), and diabetic macular edema (26 eyes) treated with a single 0.7 mg dexamethasone implant. Data were collected on best-corrected visual acuity, intraocular pressure, and central macular thickness preoperatively and at 1, 3, and 6 months postoperatively. RESULTS: Baseline best-corrected visual acuity was 20/160 and improved statistically significantly to 20/80 and 20/60 at 1 months and 3 months, respectively (P < 0.05, both postoperative visits), and 20/100 at 6 months (P > 0.05). The central macular thickness at baseline was 569.96 ± 178.11 µm, and it decreased statistically significantly to 305.81 ± 155.94 µm, 386 ± 210.79 µm, and 446.41 ± 221.21 µm at 1, 3 and 6 months, respectively (P < 0.05, all visits compared with baseline). Fourteen (26%) eyes developed high intraocular pressure after implantation and was successfully controlled with topical medications, and cataract progressed in 1 (1.8%) eye. CONCLUSION: The dexamethasone implant improved macular edema in refractory cases resulting in statistically significant improvements in best-corrected visual acuity and central macular thickness that remained stable to 3 months and 6 months, respectively.

INTRAVITREAL BEVACIZUMAB FOR CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION: 5-Year Results of The Pan-American Collaborative Retina Study Group.

PURPOSE: To report the long-term anatomical and functional outcomes of patients with choroidal neovascularization secondary to age-related macular degeneration treated with intravitreal bevacizumab (IVB). METHODS: Retrospective case series. Patients diagnosed with subfoveal choroidal neovascularization secondary to age-related macular degeneration that were treated with at least 1 intravitreal injection of 1.25 mg of IVB and had a minimum follow-up of 60 months. Patients underwent best-corrected Snellen visual acuity testing, optical coherence tomography, and ophthalmoscopic examination at baseline and follow-up visits. RESULTS: Two hundred and forty-seven consecutive patients (292 eyes) were included. The mean number of IVB injections per eye was 10.9 ± 6.4. At 5 years, the BCVA decreased from 20/150 (logMAR 0.9 ± 0.6) at baseline to 20/250 (logMAR 1.1 ± 0.7) (P = <0.0001). The mean CMT decreased from 343.1+ 122.3 µm at baseline to 314.7 ± 128.8 µm at 60 months of follow-up (P = 0.009). Geographic atrophy (GA) was observed at baseline in 47 (16%) of 292 eyes. By 5 years, GA developed or progressed in 124 (42.5%) of 292 eyes (P < 0.0001). CONCLUSION: The early visual gains obtained from IVB were not maintained at 5 years of follow-up. In addition, IVB may play a role in the development or progression of GA.

Anti-TNF-α therapy in patients with refractory uveitis due to Behçet's disease: a 1-year follow-up study of 124 patients.

OBJECTIVE: The aim of this study was to assess the efficacy of anti-TNF-α therapy in refractory uveitis due to Behçet's disease (BD). METHODS: We performed a multicentre study of 124 patients with BD uveitis refractory to conventional treatment including high-dose corticosteroids and at least one standard immunosuppressive agent. Patients were treated for at least 12 months with infliximab (IFX) (3-5 mg/kg at 0, 2 and 6 weeks and then every 4-8 weeks) or adalimumab (ADA) (usually 40 mg every 2 weeks). The main outcome measures were degree of anterior and posterior chamber inflammation, visual acuity, macular thickness and immunosuppression load. RESULTS: Sixty-eight men and 56 women (221 affected eyes) were studied. The mean age was 38.6 years (s.d. 10.4). HLA-B51 was positive in 66.1% of patients and uveitis was bilateral in 78.2%. IFX was the first biologic agent in 77 cases (62%) and ADA was first in 47 (38%). In most cases anti-TNF-α drugs were used in combination with conventional immunosuppressive drugs. At the onset of anti-TNF-α therapy, anterior chamber and vitreous inflammation was observed in 57% and 64.4% of patients, respectively. In both conditions the damage decreased significantly after 1 year. At baseline, 50 patients (80 eyes) had macular thickening [optical coherence tomography (OCT) >250 µm] and 35 (49 eyes) had cystoid macular oedema (OCT>300 µm) that improved from 420 µm (s.d. 119.5) at baseline to 271 µm (s.d. 45.6) at month 12 (P < 0.01). The best-corrected visual acuity and the suppression load also showed significant improvement. After 1 year of follow-up, 67.7% of patients were inactive. Biologic therapy was well tolerated in most cases. CONCLUSION: Anti-TNF-α therapy is effective and relatively safe in refractory BD uveitis.

Retinal neurodegenerative changes in the adult insulin receptor substrate-2 deficient mouse.

Insulin receptor substrate-2 (Irs2) mediates peripheral insulin action and is essential for retinal health. Previous investigations have reported severe photoreceptor degeneration and abnormal visual function in Irs2-deficient mice. However, molecular changes in the Irs2(-)(/)(-) mouse retina have not been described. In this study, we examined retinal degenerative changes in neuronal and glial cells of adult (9- and 12-week old) Irs2(-)(/)(-) mice by immunohistochemistry. 9-week old Irs2(-)(/)(-) mice showed significant thinning of outer retinal layers, concomitant to Müller and microglial cell activation. Photoreceptor cells displayed different signs of degeneration, such as outer/inner segment atrophy, redistribution of rod- and cone-opsins and spatial disorganization of cone cells. This was accompanied by synaptic changes at the outer plexiform layer, including the retraction of rod-spherules, reduction of photoreceptor synaptic ribbons and synaptic remodeling in second order neurons (i.e. loss and sprouting of dendritic processes in rod bipolar and horizontal cells). By 12 weeks of age, the thickness of inner retinal layers was severely affected. Although inner plexiform layer stratification remained unchanged at this stage, rod bipolar cell axon terminals were significantly depleted. Significant loss of Brn3a(+) retinal ganglion cells occurred in 12-week old Irs2(-)(/)(-) mice, in contrast to younger ages. Adult Irs2(-)(/)(-) mice showed clear hallmarks of neurodegeneration and disruption of the inner retina with increasing age. Pharmacological stimulation of Irs2 signaling pathway may provide additional neuroprotection in certain degenerative retinopathies.

Outcomes of treatment of pediatric choroidal neovascularization with intravitreal antiangiogenic agents: the results of the KKESH International Collaborative Retina Study Group.

PURPOSE: To evaluate safety and clinical results of intravitreal antiangiogenic agents for choroidal neovascularization in pediatric patients. METHODS: Retrospective, multicenter, interventional case series. A total of 45 eyes of 39 pediatric patients with choroidal neovascularization of various etiologies were treated with intravitreal injection of antiangiogenic agents (1.25 mg per 0.05 mL of bevacizumab or 0.5 mg per 0.05 mL of ranibizumab). RESULTS: There were 24 girls and 15 boys with group median age of 13 years (range, 3-17 years). Mean follow-up period was 12.8 months (range, 3-60 months). Median visual acuity in terms of logarithm of the minimum angle of resolution at presentation and last follow-up was 0.87 and 0.7, respectively (P = 0.0003). Mean and median number of injections received over the follow-up period was 2.2 and 1, respectively. At the last follow-up, 22 eyes (48%) gained more than 3 lines of vision and 27 eyes (60%) had final visual acuity 20/50 or better. Nine eyes (20%) did not improve and had severe vision loss (20/200 or worse). CONCLUSION: Intravitreal antiangiogenic therapy for choroidal neovascularization in pediatric patients seems temporarily safe and effective in majority of affected eyes. Because of the rarity and character of this condition, it is unlikely that any clinical trials will soon take place to study this or other treatment option.

Evaluation of the IL2/IL21, IL2RA and IL2RB genetic variants influence on the endogenous non-anterior uveitis genetic predisposition.

BACKGROUND: Recently, different genetic variants located within the IL2/IL21 genetic region as well as within both IL2RA and IL2RB loci have been associated to multiple autoimmune disorders. We aimed to investigate for the first time the potential influence of the IL2/IL21, IL2RA and IL2RB most associated polymorphisms with autoimmunity on the endogenous non-anterior uveitis genetic predisposition. METHODS: A total of 196 patients with endogenous non-anterior uveitis and 760 healthy controls, all of them from Caucasian population, were included in the current study. The IL2/IL21 (rs2069762, rs6822844 and rs907715), IL2RA (2104286, rs11594656 and rs12722495) and IL2RB (rs743777) genetic variants were genotyped using TaqMan® allelic discrimination assays. RESULTS: A statistically significant difference was found for the rs6822844 (IL2/IL21 region) minor allele frequency in the group of uveitis patients compared with controls (P(-value)=0.02, OR=0.64 CI 95%=0.43-0.94) although the significance was lost after multiple testing correction. Furthermore, no evidence of association with uveitis was detected for the analyzed genetic variants of the IL2RA or IL2RB loci. CONCLUSION: Our results indicate that analyzed IL2/IL21, IL2RA and IL2RB polymorphisms do not seem to play a significant role on the non-anterior uveitis genetic predisposition although further studies are needed in order to clear up the influence of these loci on the non-anterior uveitis susceptibility.

Ranibizumab for serous macular detachment in branch retinal vein occlusions.

BACKGROUND: The purpose of this study was to compare the efficacy of intravitreal ranibizumab in the treatment of macular edema due to branch retinal vein occlusions (BRVO) with and without serous macular neuroretinal detachment (SMD). METHODS: Forty-nine eyes of 49 patients with macular edema due to branch retinal vein occlusion (22 with SMD and 27 without SMD) were included in this prospective, parallel-group, comparative study. Intravitreal injection of ranibizumab was administered at baseline. Thereafter patients were followed monthly and further injections were performed in the presence of persistence or recurrence of macular thickening. Flattening of the macula was considered success. At the last visit, best-corrected visual acuity (BCVA), and spectral-domain optical coherence tomography (SD-OCT) quantitative parameters (central subfield thickness, cube volume, average cube thickness) were compared between groups. RESULTS: In patients with SMD, BCVA and all the SD-OCT quantitative parameters improved significantly after a mean number of 5.0 ranibizumab intravitreal injections through a median follow-up of 12.5 months (range, 7-34). In patients without SMD, all the variables analyzed improved significantly except for the cube volume, after a mean number of 4.3 ranibizumab intravitreal injections through a median follow-up of 10.4 months (range, 6.5-40.2). The numbers of injections were similar in both groups. The final BCVA was better in patients without SMD at baseline but without significant differences in the SD-OCT parameters between groups. CONCLUSIONS: The presence of SMD may be a baseline predictive factor for ranibizumab treatment outcomes in BRVO patients, with no influence in the number of treatments needed between patients with or without SMD at baseline. Further studies are needed in order to confirm the role of SMD as an independent predicitive factor in cases of BRVO.

Intravitreal bevacizumab plus grid laser photocoagulation or intravitreal bevacizumab or grid laser photocoagulation for diffuse diabetic macular edema: results of the Pan-american Collaborative Retina Study Group at 24 months.

PURPOSE: To evaluate the anatomical and functional outcomes at 24 months in patients with diffuse diabetic macular edema treated with primary intravitreal bevacizumab (IVB) plus grid laser photocoagulation (GLP) or primary IVB alone or GLP alone. METHODS: Retrospective, interventional, comparative, multicenter study. We included in this analysis 141 eyes of 120 patients with diffuse diabetic macular edema treated with primary IVB alone (Group A), 120 eyes of 94 patients with GLP therapy (Group B), and 157 eyes of 104 patients treated with IVB plus GLP (Group C). RESULTS: In all 3 groups, the authors observed improvement of Early Treatment Diabetic Retinopathy Study best-corrected visual acuity from baseline to 24-month follow-up (P < 0.0001). The improvement rate in Group A was statistically significantly better than in Group B (analysis of variance, P = 0.013). The authors also found a decrease in central macular thickness in all groups from baseline to the 24-month follow-up (P < 0.0001). The comparison among 3 groups showed higher central macular thickness decrease in Group A than in Groups B and C (analysis of variance, P < 0.001). CONCLUSION: The study provides evidence to support the use of primary IVB with or without GLP as treatment of diffuse diabetic macular edema. Primary IVB without GLP seems to be superior to GLP alone to provide stability or improvement in best-corrected visual acuity in patients with diffuse diabetic macular edema at 24 months.

Residual internal limiting membrane after epiretinal membrane peeling: results of the Pan-American Collaborative Retina Study Group.

PURPOSE: To determine the degree of residual internal limiting membrane (ILM) after idiopathic epiretinal membrane (ERM) peeling and the usefulness of staining with brilliant blue G. METHODS: A prospective, multicenter, observational study of 98 eyes undergoing pars plana vitrectomy and membrane peeling for idiopathic ERM. All eyes underwent core vitrectomy (20, 23, or 25 gauge) followed by intravitreal triamcinolone to verify that the posterior hyaloid had been removed. Brilliant blue G (0.2 mL of 0.25 mg/mL) was injected into the vitreous cavity and washed out immediately. The ERM was peeled and then the surgeon observed and recorded the characteristics of the underlying ILM. The posterior pole was restained with brilliant blue G (0.2 mL of 0.25 mg/mL), and the same observations on the characteristics of the ILM were recorded. Peeling of the remaining ILM was performed. The main outcome measured was the status of the ILM after ERM peel. Secondary outcomes included best-corrected visual acuity and central macular thickness at 6 months postoperatively. RESULTS: After ERM peel, all of the eyes had residual ILM. In 74 eyes, the ILM was present and damaged, whereas in 24 eyes, the ILM was present and undamaged. In 37 eyes, the operating surgeon was unable to determine the status of the ILM before brilliant blue G staining. At 6 months, the logarithm of the minimum angle of resolution best-corrected visual acuity improved from 0.75 ± 0.39 at baseline to 0.31 ± 0.26 (P < 0.0001). The central macular thickness also improved from 460 ± 91 µm at baseline to 297 ± 102 µm (P < 0.003). CONCLUSION: Internal limiting membrane is frequently still present after ERM peeling. Staining with brilliant blue G facilitates its identification.

Usefulness of adalimumab in the treatment of refractory uveitis associated with juvenile idiopathic arthritis.

PURPOSE: To assess the efficacy and safety of adalimumab in patients with juvenile idiopathic arthritis (JIA) and associated refractory uveitis. DESIGN: Multicenter, prospective case series. METHODS: Thirty-nine patients (mean [SD] age of 11.5 [7.9] years) with JIA-associated uveitis who were either not responsive to standard immunosuppressive therapy or intolerant to it were enrolled. Patients aged 13-17 years were treated with 40 mg of adalimumab every other week for 6 months and those aged 4-12 years received 24 mg/m(2) body surface. RESULTS: Inflammation of the anterior chamber (2.02 [1.16] versus 0.42 [0.62]) and of the posterior segment (2.38 [2.97] versus 0.35 [0.71] decreased significantly between baseline and the final visit (P < 0.001). The mean (SD) macular thickness at baseline was 304.54 (125.03) µ and at the end of follow-up was 230.87 (31.12) µ (P < 0.014). Baseline immunosuppression load was 8.10 (3.99) as compared with 5.08 (3.76) at the final visit (P < 0.001). The mean dose of corticosteroids also decreased from 0.25 (0.43) to 0 (0.02) mg (P < 0.001). No significant side effects requiring discontinuation of therapy were observed. CONCLUSION: Adalimumab seems to be an effective and safe treatment for JIA-associated refractory uveitis and may reduce steroid requirement.

Anti-TNF vs tocilizumab in refractory uveitic cystoid macular edema due to Behcet's disease. Multicenter study of 49 patients.

OBJECTIVE: To compare the efficacy of TNF inhibitors (adalimumab (ADA) and infliximab (IFX)) vs tocilizumab (TCZ) in patients with refractory cystoid macular edema (CME) due to Behçet's disease (BD). METHODS: Multicenter study of patients with BD-associated CME refractory to conventional and/or biological immunosuppressive drugs. From a cohort of 177 patients treated with anti-TNF and 14 patients treated with TCZ, we selected those with CME at baseline. We analyzed the evolution of macular thickness (main outcome), best-corrected visual acuity (BCVA) and intraocular inflammation (Tyndall and vitritis) from baseline up to 4 years in the 3 groups mentioned. RESULTS: 49 patients and 72 eyes with CME were included. ADA was used in 25 patients (40 eyes), IFX in 15 (21 eyes) and TCZ in 9 (11 eyes). No statistically significant baseline differences were observed between the 3 groups except for a lower basal BCVA in TCZ group and a higher basal degree of intraocular inflammation in ADA group. Most patients from all groups had received several conventional immunosuppressive drugs. In addition, most patients in the group of TCZ had also received anti-TNF agents. Biological therapy was used in monotherapy (n=8) or combined with conventional immunosuppressive drugs (n=41). Macular thickness progressively decreased in the 3 groups, with no signs of CME after 1 year of treatment. Similarly, BCVA improvement and inflammatory intraocular remission was achieved in all groups. CONCLUSION: Refractory CME associated with BD uveitis can be effectively treated either with ADA, IFX or TCZ. Furthermore, TCZ is effective in patients resistant to anti-TNF therapy.

Treatment of refractory uveitis with adalimumab: a prospective multicenter study of 131 patients.

OBJECTIVE: To evaluate adalimumab therapy in refractory uveitis. DESIGN: Prospective case series. PARTICIPANTS: A total of 131 patients with refractory uveitis and intolerance or failure to respond to prednisone and at least 1 other systemic immunosuppressive drug participated. INTERVENTION: Patients received a 40 mg adalimumab subcutaneous injection every other week for 6 months. The associated immunosuppressants were tapered after administering 3 adalimumab injections (week 6). MAIN OUTCOME MEASURES: Degree of anterior and posterior chamber inflammation (Standardization of Uveitis Nomenclature Working Group criteria), immunosuppression load (as defined by Nussenblatt et al), visual acuity (logarithm of the minimal angle of resolution [logMAR]), and macular thickness (optical coherence tomography). RESULTS: There were 61 men and 70 women (mean age, 27.3 years). The most common causes were juvenile idiopathic arthritis in 39 patients, pars planitis in 16 patients, and Behçet's disease in 13 patients. Twenty-seven patients had uveitis of idiopathic origin. Inflammation in the anterior chamber was present in 82% of patients and in the vitreous cavity in 59% of patients. Anterior chamber inflammation and vitreous inflammation decreased significantly (P < 0.001) from a mean of 1.51 and 1.03 at baseline to 0.25 and 0.14, respectively, at 6 months. Macular thickness was 296 (102) µ at baseline versus 240 (36) µ at the 6-month visit (P < 0.001). Visual acuity improved by -0.3 logMAR in 32 of 150 eyes (21.3%) and worsened by +0.3 logMAR (-15 letters) in 5 eyes (3.3%). The dose of corticosteroids also decreased from 0.74 (3.50) to 0.20 (0.57) mg/kg/day (P < 0.001). Cystoid macular edema, which was present in 40 eyes at baseline, showed complete resolution in 28 eyes at 6 months. The mean suppression load decreased significantly (8.81 [5.05] vs 5.40 [4.43]; P < 0.001). Six months after the initiation of the study, 111 patients (85%) were able to reduce at least 50% of their baseline immunosuppression load. Only 9 patients (6.9%) had severe relapses during the 6 months of follow-up. CONCLUSIONS: Adalimumab seems to be well tolerated and helpful in decreasing inflammatory activity in refractory uveitis and may reduce steroid requirement. Further controlled studies of adalimumab for uveitis are warranted.

Pourfour du Petit syndrome associated with a cervical vertebral anomaly.

Pourfour du Petit syndrome is a rare dysautonomic disorder characterized by mydriasis, eyelid retraction, and hyperhidrosis and is caused by irritative stimulation of the sympathetic cervical chain. The authors describe a 45-year-old woman with iris heterochromia, who presented with episodes of ipsilateral mydriasis and hyperhidrosis and was found to have a cervical vertebral anomaly, probably present since birth, as the cause of Pourfour du Petit syndrome.