Co-Expression of Podoplanin and CD44 in Proliferative Vitreoretinopathy Epiretinal Membranes.

Epiretinal membranes (ERMs) are sheets of tissue that pathologically develop in the vitreoretinal interface leading to progressive vision loss. They are formed by different cell types and by an exuberant deposition of extracellular matrix proteins. Recently, we reviewed ERMs' extracellular matrix components to better understand molecular dysfunctions that trigger and fuel the onset and development of this disease. The bioinformatics approach we applied delineated a comprehensive overview on this fibrocellular tissue and on critical proteins that could really impact ERM physiopathology. Our interactomic analysis proposed the hyaluronic-acid-receptor cluster of differentiation 44 (CD44) as a central regulator of ERM aberrant dynamics and progression. Interestingly, the interaction between CD44 and podoplanin (PDPN) was shown to promote directional migration in epithelial cells. PDPN is a glycoprotein overexpressed in various cancers and a growing body of evidence indicates its relevant function in several fibrotic and inflammatory pathologies. The binding of PDPN to partner proteins and/or its ligand results in the modulation of signaling pathways regulating proliferation, contractility, migration, epithelial-mesenchymal transition, and extracellular matrix remodeling, all processes that are vital in ERM formation. In this context, the understanding of the PDPN role can help to modulate signaling during fibrosis, hence opening a new line of therapy.

The extracellular matrix complexity of idiopathic epiretinal membranes and the bilaminar arrangement of the associated internal limiting membrane in the posterior retina.

PURPOSE: To study the composition of the internal limiting membrane (ILM) of the retina, the extracellular matrix (ECM) of idiopathic epiretinal membranes (iERMs), and the relationships occurring between the two membranes. METHODS: Forty-six iERMs, 24 of them associated with the ILM, were collected and included in this study. The investigation has been carried out by immunofluorescence and confocal microscopy on glutaraldehyde- and osmium-fixed epon-embedded samples and on frozen samples. Sections were double or triple labelled with antibodies against vimentin; collagens I, III, IV, α5(IV), and VI; laminin 1 + 2; laminin α2-, α4-, α5-, ß1-, ß2-, ß3-, γ1-, and γ2-chains; entactin; and fibronectin. RESULTS: iERM thickness was not uniform. Almost 14% of iERMs showed thickenings due to folding of their ECM component under the cell layer. The vitreal side of iERMs was often shorter than the attached ILM. In this case, the ILM resulted folded under the iERM. ILMs contained laminin 111; laminin α2-, α5-, ß1-, ß2-, and γ1-chains; entactin; collagens I; α5(IV); [α1(IV)]2α2(IV); and VI. Laminins, entactin, and α5(IV) were gathered on the retinal half of the ILM, whereas collagens [α1(IV)]2α2(IV) and I were restricted to the vitreal side. Collagen VI was detected on both sides of the ILM. iERMs expressed laminin 111, collagens III, [α1(IV)]2α2(IV) and VI, entactin, and fibronectin. Entactin co-localized with laminins and collagen IV. CONCLUSIONS: Analysis of laminins and collagen chain expression indicates that ILM contains laminin 111 (former laminin 1), laminin 521 (former laminin 11), laminin 211 (former laminin 2), collagen [α1(IV)]2α2(IV), and collagen α3(IV)α4(IV)α5. In contrast, iERMs express only collagen [α1(IV)]2α2(IV) and laminin 111. In addition, both iERMs and ILMs contain entactin. The presence of three major constituents of the basement membranes co-localized together in iERMs is suggestive for a deranged process of basement membrane formation which fails to assemble properly. In view of the many interactions occurring among its proteins, the ECM of either the iERMs or the ILMs can account for their reciprocal adhesiveness. In addition, the peculiar deposition of the ECM observed in some samples of iERM is suggestive for its involvement in the formation of macular puckers.

CD93 Signaling via Rho Proteins Drives Cytoskeletal Remodeling in Spreading Endothelial Cells.

During angiogenesis, cell adhesion molecules expressed on the endothelial cell surface promote the growth and survival of newly forming vessels. Hence, elucidation of the signaling pathways activated by cell-to-matrix adhesion may assist in the discovery of new targets to be used in antiangiogenic therapy. In proliferating endothelial cells, the single-pass transmembrane glycoprotein CD93 has recently emerged as an important endothelial cell adhesion molecule regulating vascular maturation. In this study, we unveil a signaling pathway triggered by CD93 that regulates actin cytoskeletal dynamics responsible of endothelial cell adhesion. We show that the Src-dependent phosphorylation of CD93 and the adaptor protein Cbl leads to the recruitment of Crk, which works as a downstream integrator in the CD93-mediated signaling. Moreover, confocal microscopy analysis of FRET-based biosensors shows that CD93 drives the coordinated activation of Rac1 and RhoA at the cell edge of spreading cells, thus promoting the establishment of cell polarity and adhesion required for cell motility.

Superior Properties of N-Acetylcysteine Ethyl Ester over N-Acetyl Cysteine to Prevent Retinal Pigment Epithelial Cells Oxidative Damage.

Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats' eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results.

LRG1 Expression Is Elevated in the Eyes of Patients with Neovascular Age-Related Macular Degeneration.

Leucine-rich a-2-glycoprotein 1 (LRG1) is a candidate therapeutic target for treating the neovascular form of age-related macular degeneration (nvAMD). In this study we examined the expression of LRG1 in eyes of nvAMD patients. Choroidal neovascular membranes (CNVMs) from patients who underwent submacular surgery for retinal pigment epithelium-choroid graft transplantation were collected from 5 nvAMD patients without any prior intravitreal anti-VEGF injection, and from six patients who received intravitreal anti-VEGF injections before surgery. As controls free of nvAMD, retina sections were obtained from the eyes resected from a patient with lacrimal sac tumor and from a patient with neuroblastoma. CNVMs were immunostained for CD34, LRG1, and α-smooth muscle actin (α-SMA). Aqueous humor samples were collected from 58 untreated-naïve nvAMD patients prior to the intravitreal injection of anti-VEGF and 51 age-matched cataract control patients, and LRG1 concentration was measured by ELISA. The level of LRG1 immunostaining is frequently high in both the endothelial cells of the blood vessels, and myofibroblasts in the surrounding tissue of CNVMs of treatment-naïve nvAMD patients. Furthermore, the average concentration of LRG1 was significantly higher in the aqueous humor of nvAMD patients than in controls. These observations provide a strong experimental basis and scientific rationale for the progression of a therapeutic anti-LRG1 monoclonal antibody into clinical trials with patients with nvAMD.

Effectiveness of TNF-α blockade in the treatment of refractory non-infectious scleritis: a multicentre study.

OBJECTIVES: To evaluate the efficacy of tumour necrosis factor (TNF)-α inhibitors in refractory non-infectious scleritis. METHODS: We carried out a retrospective study assessing the efficacy of TNF-α inhibitors in the treatment of scleritis, scleritis relapses, glucocorticoid (GC)-sparing effect, impact on best-corrected visual acuity (BCVA) and safety profile. RESULTS: Nineteen patients (28 eyes) were eligible for analysis. Scleritis inflammatory grading significantly improved from baseline to the last follow-up (median ± IQR 2±4 and 0±0 respectively, p=0.0006). Scleritis relapses significantly decreased between the 12 months preceding and following biologic therapy (p=0.001). Mean GC dosage decreased from baseline (19.00±13.56 mg) to the last follow-up (7.59±5.56 mg) (p=0.003). No significant differences regarding BCVA were observed. Two AEs were recorded (1 severe urticaria and 1 case of pneumonia and paradoxical psoriasis). CONCLUSIONS: TNF-α inhibitors are effective in the treatment of scleritis while allowing a GC-sparing effect and preserving BCVA.

Efficacy of monoclonal anti-tumour necrosis factor-α antibodies in uveitic macular oedema.

OBJECTIVES: To assess the efficacy of anti-tumour necrosis factor (TNF)-α agents in the treatment of refractory uveitic macular oedema (UME). METHODS: Patients with refractory UME treated with TNF-α blockers were retrospectively enrolled. Central macular thickness (CMT) was assessed at optical coherence tomography (OCT) at the start of TNF-α inhibition, after 3 and 12 months, and at the last follow-up visit. RESULTS: Thirty-six patients (56 eyes with UME) were enrolled. The mean follow-up period was 29.9±40.8 (4-184) months. A statistically significant decrease was observed in the frequency of UME (p<0.0001) and in the mean CMT values (p<0.0001) during the study period. Best corrected visual acuity improved in 35 eyes (62.5%), remained stable in 12 eyes (21.4%), reduced in 9 eyes (16.1%). The mean corticosteroid dosage significantly decreased during the study period (p=0.016). CONCLUSIONS: TNF-α inhibitors represent a useful treatment in patients with severe or resistant UME.

The Role of Multimodality Imaging in Monitoring Disease Activity and Therapeutic Response to Tocilizumab in Giant Cell Arteritis.

INTRODUCTION: Giant cell arteritis (GCA) is a large vessel (LV) vasculitis, mainly affecting elder patients. Monitoring GCA activity during tocilizumab (TCZ) treatment is an unmet need, since low serum levels of C-reactive protein (CRP) during treatment may underestimate disease activity. To date, few data are available on the role of different imaging techniques in monitoring GCA activity and response to treatment. We report herein a cohort of GCA patients treated with TCZ and followed up with multimodal imaging. Patients and Methods. We collected clinical, laboratory, and imaging data of 11 GCA patients treated with TCZ 162 mg subcutaneously every week. Disease activity was assessed at baseline and within 12 months from the start of treatment using different imaging techniques such as color Doppler ultrasonography (CDUS), magnetic resonance imaging/angiography (MRI/MRA), computed tomography angiography (CTA), and/or positron emission tomography (PET). RESULTS: Four patients were affected by cranial and 7 by LV-GCA. All patients were treated with oral glucocorticoids (GCs) (mean dose 55.68 mg ± 8.19 of prednisone or equivalent) in combination with TCZ. Treatment was preceded in 5 cases by 3 intravenous boluses of 1000 mg methylprednisolone. A significant decrease of the mean dose of oral GCs was observed between baseline and the last follow-up visit (4.65 ± 3.69 mg) (p = 0.003). TCZ treatment significantly decreased erythrocyte sedimentation rate (p < 0.01) and CRP levels (p < 0.01). At follow-up (mean 8.18 ± 3.63 months), all patients were in clinical and serological remission. Moreover, PET, CDUS, MRI/MRA, and CTA did not show any LVV finding. CONCLUSIONS: Our study highlights TCZ efficacy in inducing GCA remission and its steroid-sparing effect. We highlighted a reliability of imaging procedures in the evaluation of disease activity and treatment response. A close disease monitoring with imaging techniques should be taken into account in GCA patients during TCZ treatment.

Long-Term Outcomes of Behçet's Syndrome-Related Uveitis: A Monocentric Italian Experience.

OBJECTIVES: To examine demographic and clinical characteristics and long-term visual outcome in a cohort of Italian patients affected by Behçet's uveitis (BU). MATERIALS AND METHODS: Retrospective chart review of 47 patients with BU attending our unit between January 2018 and December 2019. Ophthalmologic manifestations, best-corrected visual acuity (BCVA), fluoroangiography and optical coherence tomography findings, and ocular complications were recorded. Predictive factors of a poor visual outcome and long-term complications were also investigated. RESULTS: Forty-seven patients (23 males and 24 females) for a total of 84 eyes were enrolled. Uveitis was bilateral in 37 (78.7%) patients with panuveitis being the most frequent anatomical pattern (40 out of 84 eyes), whereas 27 eyes presented a posterior uveitis. Isolated anterior uveitis was detected in 16 eyes. A significant improvement of median BCVA between baseline and last follow-up values was detected (p = 0.042). A higher risk of poor visual prognosis was observed in patients with uveitis duration greater than 15 years (p = 0.019). A significant resolution of retinal vasculitis was detected between baseline and last follow-up evaluation (p < 0.0001) whereas the mean ± SD macular thickness did not decrease significantly between baseline (376.00 ± 97.45 µm) and last follow-up evaluation (338.08 ± 55.81 µm). Forty-two eyes developed 57 complications during the disease course. Cataract was the most frequent (n = 12), followed by epiretinal membranes (n = 11) and cystoid macular edema (n = 6). The following variables were identified as predictors of long-term complications: human leukocyte antigen- (HLA-) B51 (p = 0.006), panuveitis (p = 0.037), and a uveitis duration of more than 15 years (p = 0.049). CONCLUSIONS: In Italian patients, BU typically arises in the third decade and predominantly manifests as a bilateral posterior uveitis or panuveitis. Its duration is associated with a poor visual prognosis. Uveitis duration, the presence of HLA-B51, and panuveitis are predictors of long-term structural complications, thus representing main drivers in the treatment decision-making.

New Potential Weapons for Refractory Scleritis in the Era of Targeted Therapy.

OBJECTIVE: To assess the efficacy of biologic drugs, beyond tumor necrosis factor- (TNF-) α inhibitors, in the management of noninfectious refractory scleritis, either idiopathic or associated with systemic immune-mediated disorders. Patients and Methods. This is a retrospective study assessing the efficacy of several biologic agents (rituximab, anakinra, tocilizumab, and abatacept) and the small molecule tofacitinib in the treatment of scleritis through assessment of scleral inflammation and relapses, as well as treatment impact on best-corrected visual acuity (BCVA) and safety profile. RESULTS: Fourteen patients (19 eyes) were enrolled in the study. Scleritis inflammatory grading significantly improved from baseline to 3 months (p = 0.002) and from baseline to the last follow-up visit (p = 0.002). Scleritis relapses significantly decreased between the 12 months preceding and following biologic therapy (p = 0.007). No differences regarding BCVA were observed (p = 0.67). Regarding adverse events, only one patient developed pneumonia and septic shock under rituximab treatment. CONCLUSIONS: Our results, though limited to a low number of patients, highlight the effectiveness of different biologic therapies in the treatment of noninfectious refractory scleritis, showing to control scleral inflammation and allowing a significant reduction in the number of relapses.

MicroRNA Expression in the Aqueous Humor of Patients with Diabetic Macular Edema.

We identified and compared secreted microRNA (miRNA) expression in aqueous humor (AH) and plasma samples among patients with: type 2 diabetes mellitus (T2D) complicated by non-proliferative diabetic retinopathy (DR) associated with diabetic macular edema (DME) (DME group: 12 patients); T2D patients without DR (D group: 8 patients); and non-diabetic patients (CTR group: 10 patients). Individual patient AH samples from five subjects in each group were profiled on TaqMan Low Density MicroRNA Array Cards. Differentially expressed miRNAs identified from profiling were then validated in single assay for all subjects. The miRNAs validated in AH were then evaluated in single assay in plasma. Gene Ontology (GO) analysis was conducted. From AH profiling, 119 mature miRNAs were detected: 86 in the DME group, 113 in the D group and 107 in the CTR group. miRNA underexpression in the DME group was confirmed in single assay for let-7c-5p, miR-200b-3p, miR-199a-3p and miR-365-3p. Of these four, miR-199a-3p and miR-365-3p were downregulated also in the plasma of the DME group. GO highlighted 54 validated target genes of miR-199a-3p, miR-200b-3p and miR-365-3p potentially implied in DME pathogenesis. Although more studies are needed, miR-200b-3p, let-7c-5p, miR-365-3p and miR-199a-3p represent interesting molecules in the study of DME pathogenesis.

Adalimumab effectively controls both anterior and posterior noninfectious uveitis associated with systemic inflammatory diseases: focus on Behçet's syndrome.

BACKGROUND: To compare the efficacy of Adalimumab (ADA) in noninfectious anterior uveitis (AU) and posterior segment (PS) involvement, associated with different conditions, with a focus on Behçet's syndrome (BS). METHODS: In this retrospective, multicenter post-hoc study, we evaluated the efficacy of ADA in terms of ocular control and relapses in 96 patients with AU and PS uveitis, either idiopathic (IU) or associated with BS or with other systemic disorders (OSD) (Juvenile Idiopathic Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Vogt-Koyanagi-Harada, Inflammatory Bowel Disease), followed in three tertiary referral centers. RESULTS: Ninety-six patients (45 AU; 51 PS uveitis) were included. Eleven had IU, 58 BS, and 27 OSD. All patients with AU achieved complete long-term ocular control. In PS uveitis, 89%, 67% and 100% of patients with BS, IU and OSD achieved ocular control at the last follow-up (> 12 months), respectively. The lowest ocular relapse rate occurred in patients with AU with BS (1/13) or IU (0/2). ADA accounted for long-term disease control, and no predictors of ocular control and relapse were identified; particularly, ocular relapses seemed not related to systemic ones. Macular edema resolved in 75% and 67% of PS uveitis with BS and IU, respectively. CONCLUSIONS: ADA controls both anterior and posterior uveitis, with an efficacy similar in IU, BS and OSD patients. In BS, the efficacy of ADA seems to be independent of demographic and clinical characteristics, and ocular relapses mostly occurred independently from systemic ones. Based on our results, ADA may represent a valid alternative in anterior refractory uveitis.

A study of quiet eye's phenomenon in the shooting section of "laser run" of modern pentathlon.

The aim of the study was to evaluate the effects of the Quiet eye (QE) phenomenon on performances during the shooting section of "Laser Run" of Modern Pentathlon, in two samples of athletes (novices and experts). The "Laser Run" consists of running and shooting activities. The study involved 18 experienced athletes of the Italian National Team of Modern Pentathlon (i.e., "elite" group) and 18 young and nonexpert athletes of a local Pentathlon club (i.e., "novice" group). Participants performed, in ecological conditions, five trials of four series of shootings (as it occurs in the real competitions), for a total of 20 series. During the shooting trials, athletes wore a mobile Eye Tracking System to record eye movements (saccades, blinks, and fixations). Key measures of the study were QE parameters (QE Duration [QED], Relative QED [RQED], and QE Onset), as well as the performance (accuracy and time to perform the event). The results revealed that both groups of athletes had a longer QED, RQED, and an earlier onset during their best shots than during the worse ones. Furthermore, differences between the groups showed that elite athletes had an earlier onset and a shorter QED than the novice group of athletes. These results provide insightful information about different cognitive and perceptual processes involved in Modern Pentathlon's athletes' performances at both the elite and non-elite level.

Long-term evaluation of corneal sub-basal nerve recovery after photorefractive keratectomy and influence of pars plana vitrectomy.

The corneal sub-basal nerve (SBN) plexus is destroyed during photorefractive keratectomy (PRK) and its recovery is still a matter of debate. In vivo confocal microscopy (IVCM) was used to evaluate SBN plexus in 23 patients at a distance of 10-25 years (mean 15.6 years) from myopic PRK. Because 8 out of the 23 PRK patients underwent pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment, IVCM was also performed on those patients 6 months after PPV. Thirteen patients matched for age and myopia served as controls (non-PRK). SBN plexus was markedly reduced after PRK compared with non-PRK eyes and showed a slow, continuous but incomplete recovery up to the end of our follow-up (range 10-25 years). PRK and non-PRK eyes showed a marked reduction in SBN density 6 months after PPV, thus demonstrating a detrimental effect exerted by PPV on SBN plexus.

The small GTPase Rab5c is a key regulator of trafficking of the CD93/Multimerin-2/ß1 integrin complex in endothelial cell adhesion and migration.

BACKGROUND: In the endothelium, the single-pass membrane protein CD93, through its interaction with the extracellular matrix protein Multimerin-2, activates signaling pathways that are critical for vascular development and angiogenesis. Trafficking of adhesion molecules through endosomal compartments modulates their signaling output. However, the mechanistic basis coordinating CD93 recycling and its implications for endothelial cell (EC) function remain elusive. METHODS: Human umbilical vein ECs (HUVECs) and human dermal blood ECs (HDBEC) were used in this study. Fluorescence confocal microscopy was employed to follow CD93 retrieval, recycling, and protein colocalization in spreading cells. To better define CD93 trafficking, drug treatments and transfected chimeric wild type and mutant CD93 proteins were used. The scratch assay was used to evaluate cell migration. Gene silencing strategies, flow citometry, and quantification of migratory capability were used to determine the role of Rab5c during CD93 recycling to the cell surface. RESULTS: Here, we identify the recycling pathway of CD93 following EC adhesion and migration. We show that the cytoplasmic domain of CD93, by its interaction with Moesin and F-actin, is instrumental for CD93 retrieval in adhering and migrating cells and that aberrant endosomal trafficking of CD93 prevents its localization at the leading edge of migration. Moreover, the small GTPase Rab5c turns out to be a key component of the molecular machinery that is able to drive CD93 recycling to the EC surface. Finally, in the Rab5c endosomal compartment CD93 forms a complex with Multimerin-2 and active ß1 integrin, which is recycled back to the basolaterally-polarized cell surface by clathrin-independent endocytosis. CONCLUSIONS: Our findings, focusing on the pro-angiogenic receptor CD93, unveil the mechanisms of its polarized trafficking during EC adhesion and migration, opening novel therapeutic opportunities for angiogenic diseases.

Efficacy and safety of certolizumab pegol and golimumab in the treatment of non-infectious uveitis.

OBJECTIVES: The aim of the study was to evaluate the efficacy of golimumab (GOL) and certolizumab pegol (CZP) as additional treatment options for the treatment of uveitis. METHODS: Patients with longstanding uveitis receiving either GOL or CZP were retrospectively evaluated in terms of frequency of ocular flares, drug survival, changes in best corrected visual acuity (BCVA) and steroid-sparing effect. RESULTS: Twenty-one patients (30 eyes), 17 of whom being female, were enrolled in the study; 16 out of 21 patients had been previously treated with other tumour necrosis factor (TNF)-α blockers. A significant reduction in ocular flares (from 128.6 bouts for 100 patients-year to 42.9 events for 100 patients-year) was observed between the 12 months prior to the start of GOL or CZP and the 12 months thereafter (p=0.01). The 36-month drug survival was 54.5% for CZP and 50.0% for GOL with no statistically significant differences between the two biologic agents. No differences were detected concerning BCVA values and the mean corticosteroid intake between baseline and the last follow-up. The safety profile was excellent. CONCLUSIONS: GOL and CZP represent effective and safe treatment choices for patients with uveitis also when unsuccessfully treated with other anti-TNF-α drugs, permitting a significant reduction in the frequency of ocular flares and preserving visual function with a good long-term retention rate.

Efficacy of anti-tumour necrosis factor-α monoclonal antibodies in patients with non-infectious anterior uveitis.

OBJECTIVES: To assess the efficacy of monoclonal anti-tumour necrosis factor (TNF)-α agents in patients with anterior uveitis (AU) in terms of decrease of recurrences, variation of visual acuity and steroid sparing effect and to identify any demographic, clinical or therapeutic variables associated with a sustained response to monoclonal TNF-α inhibitors. METHODS: Data from patients suffering from AU treated with adalimumab, infliximab, golimumab or certolizumab pegol were retrospectively collected and statistically analysed. RESULTS: Sixty-nine patients (22 males, 47 females), corresponding to 101 eyes, were enrolled. The mean follow-up period was 29.25±23.51 months. The rate of ocular flares decreased from 42.03 events/100 patients/year recorded during the 12 months preceding the start of TNF-α inhibitors to 2.9 flares/100 patients/year after the start of treatment (p<0.0001). The overall decrease in ocular flares was 93.1%. No statistically significant changes were identified in the best corrected visual acuity during the follow-up period (p>0.99). The number of patients treated with corticosteroids at baseline was significantly higher compared with that referred to the 12-month evaluation (p<0.001) and to the last follow-up visit (p=0.006). Concomitant treatment with conventional disease-modifying anti-rheumatic drugs (cDMARDs) represented the sole clinical, demographic or therapeutic variable associated with long-term treatment duration (p=0.045, R2=0.87). CONCLUSIONS: Monoclonal TNF-α inhibitors induce a remarkable decrease in the recurrence of AU during a long-term follow-up period and lead to a significant steroid sparing effect along with stabilisation of visual acuity. Concomitant treatment with cDMARDs represented the sole variable associated with treatment duration in the long-term.

Adalimumab Accounts for Long-Term Control of Noninfectious Uveitis Also in the Absence of Concomitant DMARD Treatment: A Multicenter Retrospective Study.

OBJECTIVE: This study was aimed at assessing the long-term ocular control of adalimumab (ADA) in a large real-world population with noninfectious primary or secondary uveitis, focusing on the steroid-sparing effect and on disease-modifying antirheumatic drug (DMARD) cotreatment. METHODS: In this retrospective, multicenter study, the efficacy of ADA was evaluated in terms of ocular control, changes in best-corrected visual acuity (BCVA), corticosteroid-sparing effect, and drug retention rate, overall and stratified according to DMARD cotreatment. RESULTS: 106 patients were included. 88.7% had an associated systemic disease. After 6 and 12 months, proportions of patients with effective ocular control were 83.7% and 83.3%, respectively. At last the follow-up, 94.6% of patients had satisfactory ocular control. No difference in terms of ocular control at all time points emerged among patients starting ADA for ocular vs. systemic involvements. Patients with poor baseline BCVA remained stable or improved, while those with good BCVA hardly worsened. At 6 and 12 months, the median dose of prednisone significantly reduced to 5 mg/day (0-5) and 2.5 mg/day (0-5) (p < 0.001). Over a median follow-up of 36 months, 38 subjects discontinued ADA treatment. Mild to moderate side effects were reported in 7 patients (6.6%). ADA ocular control, corticosteroid-sparing effect, and drug retention rate were not influenced by the concomitant use of DMARDs. CONCLUSION: The long-term ocular control of ADA in noninfectious primary or secondary uveitis is confirmed, also for BCVA preservation. Concomitant use of DMARDs does not provide additional benefits to ADA alone in terms of ocular control, steroid spare, and drug retention rate.

The eye involvement in monogenic autoinflammatory diseases: literature review and update.

Monogenic autoinflammatory diseases (AIDs) are rare entities characterised by improper activation of the innate immune system. This in turn determines recurrent episodes of systemic inflammation characterised by fever, which is variously combined with a wide range of inflammatory manifestations involving the skin, joints, serous membranes, gastrointestinal tract, and central nervous system. As shown by research efforts conducted during the last decade, the eye is not exempt from the systemic inflammatory process and may be involved in almost all of the most frequent AIDs, with several distinct peculiarities. Ocular affections may severely impact patients' quality of life due to orbital pain, impairment of visual acuity, and/ or long-term, sight-threatening complications. Consequently, in the context of a multidisciplinary team, ophthalmologists should be aware of ocular manifestations related to these disorders as they may have a dominant diagnostic weight in patients with a challenging presentation as well as a salient role in therapeutic choice in sight-threatening situations. This review describes a variety of aspects of ophthalmologic involvement in AIDs, looking at both well-recognised eye manifestations as well as rarely reported ocular presentations, with a particular focus on the recent literature.

Serum immunoglobulin D levels in patients with Behçet's disease according to different clinical manifestations.

OBJECTIVES: Behçet's disease (BD) is an autoinflammatory disorders mainly characterised by recurrent oral aphthosis, genital ulcers, and uveitis. The involvement of immunoglobulin D (IgD) in BD physiopathology is still unclear. The aim of our study was to assess the role of IgD in BD by comparing circulating levels of IgD in a cohort of BD patients and healthy controls (HC), as well as by correlating IgD levels with BD activity and different clinical presentations. METHODS: Serum IgD and SAA levels were analysed by ELISA assay in ninety-nine serum samples collected from 72 BD patients and in 29 HC subjects. RESULTS: Serum concentration of IgD were higher in BD patients compared with HC (p=0.029), in patients with high serum amyloid A (SAA) levels compared with patients with normal SAA levels (p=0.035), and among subjects with active mucocutaneous involvement compared with other patients (p=0.036). No correlations were identified between IgD serum levels and disease activity assessed by the BD current activity form (BDCAF) (p=0.640). No differences were observed in the IgD serum levels between patients with and without specific disease manifestations. Increased SAA levels (Odds Ratio = 3.978, CI: 1.356 -11.676) and active mucocutaneous BD manifestations (Odds Ratio = 4.286, CI: 1.192 - 15.407) were associated with a high risk for increased IgD serum levels. CONCLUSIONS: Serum IgD levels are significantly increased in BD patients, especially among patients with active mucocutaneous manifestations, suggesting a possible role of IgD in BD pathogenesis and in the onset of mucosal and skin lesions.