Non-anti TNFα biologic agents for noninfectious uveitis associated with systemic inflammatory diseases: a systematic review.

INTRODUCTION: Noninfectious uveitis related to systemic inflammatory diseases represents a leading cause of blindness. Anti-TNFα agents are the first-line biologic therapy after traditional immunosuppressants, for ocular and systemic involvement. However, some patients fails anti-TNFα agents, due to primary inefficacy, loss of efficacy or adverse events. AREAS COVERED: This systematic review summarizes evidence on the efficacy and safety of non-anti-TNFα biologics in adult patients with noninfectious uveitis associated with systemic inflammatory diseases. The systematic review of PubMed and Embase yielded 3663 records, from which 16 studies were included (13 non-controlled, 3 controlled trials). Most studies focused on Behçet's syndrome (BS) and juvenile idiopathic arthritis (JIA) and assessed the efficacy of tocilizumab (n = 11), rituximab (n = 3), secukinumab (n = 1), or anakinra/canakinumab (n = 1). A body of evidence supports the use of tocilizumab BS and JIA-associated uveitis, for improving visual acuity, reducing central macular thickness, inducing ocular remission, and sparing corticosteroids. Preliminary data suggest that rituximab may represent a valid alternative, particularly in JIA, while anakinra/canakinumab might play a role in BS-associated uveitis. The role of secukinumab appears limited. EXPERT OPINION: Current evidence encourages investigations on the efficacy and safety of non-anti-TNFα agents in noninfectious non-idiopathic uveitis.

Evaluation of intraoperative slow-release dexamethasone implant combined with idiopathic epiretinal membrane removal.

PURPOSE: To evaluate the efficacy of intraoperative slow-release dexamethasone implant (DEX) combined with removal of idiopathic epiretinal membrane (ERM). METHODS: In this observational retrospective study, data of 40 patients with phakic eyes affected by idiopathic ERM were analysed. All patients underwent cataract phacoemulsification, 25-gauge (G) pars plana vitrectomy (PPV), ERM removal with DEX implant ("DEX YES" group, #20) or without DEX implant ("DEX NO" group, #20). We collected data on best-corrected visual acuity (BCVA) < 20/40 Snellen charts, central macular thickness (CMT) ≤ 400 µm (measured by SD-OCT) and integrity of sub-foveal ellipsoid/myoid zone. BCVA, CMT and intraocular pressure (IOP) were evaluated at baseline as well as 15, 30 and 90 days after surgery. RESULTS: In the "DEX YES" group, statistically significant BCVA improvement was observed at 15, 30 and 90 days (p < 0.001), while in the "DEX NO" group, improvements were observed only at 30 and 90 days (p < 0.001). In both groups, CMT significantly decreased at each follow-up visit (p < 0.001), and no statistically significant increase of IOP was detected at each follow-up visit. CONCLUSIONS: In this study, DEX accelerated the improvement of BCVA at 15 days after surgery. However, no evidence of further anatomical (CMT) and functional (BCVA) DEX effectiveness combined with removal of idiopathic ERM by 25-G PPV at 30 and 90 days follow-up was observed.

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.

Morpho-Functional Evaluation of Full-Thickness Macular Holes by the Integration of Optical Coherence Tomography Angiography and Microperimetry.

(1) Objective: To use optical coherence tomography angiography (OCTA) and microperimetry (MP) to evaluate the correlation between retinal structure and function in patients with idiopathic, full-thickness macular holes (FTMHs) (2) Methods: This prospective, observational study included 11 eyes of 10 patients with FTMHs evaluated before surgery using OCTA and MP. MP sensitivity maps were superimposed and registered on slabs corresponding to superficial capillary plexus (SCP) and deep capillary plexus (DCP) on OCTA, and on the outer plexiform layer (OPL) and the Henle fiber layer (HFL) complex in en face OCT. On these maps, mean retinal sensitivity was calculated at 2° and 4°, all centered on the FTMH. Cystic cavity extension was assessed on the slab corresponding to the OPL + HFL complex in en face OCT and DCP in OCTA using the Image J software (Version 1.49v; National Institutes of Health, Bethesda, MD, USA); (3) Results: Absolute scotomas were observed corresponding to the FTMH. Additionally, rings of relative scotoma in the perilesional area were detected and correlated to the cystic spaces on en face OCT and OCTA. There was a significant correlation between reduced retinal sensitivity at 2° and 4° diameters around the FTMH and the extension of cystic areas (p < 0.01). There was a significant correlation between the extension of cystic cavities and BCVA (p < 0.01). (4) Conclusions: Morpho-functional analysis of FTMH using OCTA and MP, and the correlation between vascular abnormalities and impaired retinal sensitivity, may provide new, useful information. This integrated evaluation of FTMH may be useful to determine the function-structure correlation before and after vitreoretinal surgery, in order to gain a better understanding of the functional consequences induced by the morphological alterations, assessing outcomes in a more objective way, and potentially adding new surgical prognostic factors.

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.

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.

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.

Long-term retention rates of adalimumab and infliximab in non-infectious intermediate, posterior, and panuveitis.

The aim of the present study was to compare long-term adalimumab (ADA) and infliximab (IFX) retention rates in patients with intermediate, posterior, or panuveitis. Additional aims are as follows: (i) to identify any difference in the causes of treatment discontinuation between patients treated with ADA and IFX; (ii) to assess any impact of demographic features, concomitant treatments, and different lines of biologic therapy on ADA and IFX retention rates; and (iii) to identify any correlation between ADA and IFX treatment duration and the age at uveitis onset, the age at onset of the associated systemic diseases, and the age at the start of treatment. Clinical, therapeutic, and demographic data from patients with non-infectious intermediate, posterior, or panuveitis treated with ADA or IFX were retrospectively collected. Kaplan-Meier plot and log-rank (Mantel-Cox) test were used to assess survival curves. One hundred eight patients (188 eyes) were enrolled; in 87 (80.6%) patients, uveitis was associated with a systemic disease. ADA and IFX were administered in 62 and 46 patients, respectively. No statistically significant differences were identified between ADA and IFX retention rates (p value = 0.22). Similarly, no differences were identified between ADA and IFX retention rates in relation to gender (p value = 0.61 for males, p value = 0.09 for females), monotherapy (p value = 0.08), combination therapy with conventional disease-modifying antirheumatic drugs (log-rank p value = 0.63), and different lines of biologic therapy (p value = 0.79 for biologic-naïve patients; p value = 0.81 for subjects previously treated with other biologics). In conclusion, ADA and IFX have similar long-term retention rates in patients with non-infectious intermediate, posterior, and panuveitis. Demographic, clinical, and therapeutic features do not affect their long-term effectiveness.

Comparative efficacy between adalimumab and infliximab in the treatment of non-infectious intermediate uveitis, posterior uveitis, and panuveitis: a retrospective observational study of 107 patients.

To compare the efficacy of adalimumab (ADA) and infliximab (IFX) in patients with non-infectious intermediate uveitis, posterior uveitis, and panuveitis. Demographic, clinical, instrumental, and therapeutic data from patients enrolled were collected at the start of treatment, at 12-month follow-up, and at the last follow-up assessment. One hundred seven patients (46 females, 187 eyes) were enrolled, 66 (61.7%) treated with ADA and 41 (38.3%) with IFX. Bilateral involvement was observed in 80 cases. The mean follow-up was 26.45 ± 21.71 months for ADA patients and 56.60 ± 56.04 months for IFX patients. The overall decrease of uveitis frequency during the first 12 months of treatment was 66.7% in the IFX group and 84.2% in the ADA group, compared to the previous 12 months (p = 0.09). A significantly higher corticosteroid dosage was found among patients treated with ADA at the last follow-up visit (p = 0.008). The percentage of patients co-administered with corticosteroids was significantly higher among ADA patients both at the 12-month visit (p = 0.03) and at the last visit (p = 0.0004). The frequency of uveitic macular edema (UME) was significantly higher among patients treated with ADA compared to those treated with IFX at the 12-month assessment (p = 0.015) and at the last follow-up visit (p = 0.011); central macular thickness was significantly higher in ADA group compared to the IFX group at the last follow-up assessment (p = 0.04). ADA and IFX have shown a similar efficacy in controlling uveitis relapses, but IFX showed a more pronounced corticosteroid sparing effect and a significantly higher capacity in resolving UME compared to ADA.

Efficacy of adalimumab and infliximab in recalcitrant retinal vasculitis inadequately responsive to other immunomodulatory therapies.

The primary aim of the study was to evaluate the efficacy of tumor necrosis factor (TNF)-α blockers adalimumab (ADA) and infliximab (IFX) in refractory sight-threatening retinal vasculitis (RV) during a 12-month follow-up period. Secondary aims were to evaluate (i) any impact of concomitant conventional disease-modifying anti-rheumatic drugs (cDMARDs) and different lines of biologic therapy; (ii) any difference in terms of efficacy between ADA and IFX; (iii) consequences of biotherapies on the best-corrected visual acuity (BCVA); (iv) corticosteroid-sparing effect; and (vi) ocular complications during anti-TNF-α treatment. Demographic, clinical, and therapeutic data were retrospectively collected from the medical records and statistically analyzed. Forty-eight patients (82 eyes) were recruited, 22 (45.8%) of which received IFX and 26 (54.2%) ADA. The percentages of patients achieving RV remission within 3 and 12 months were 54 and 86%, respectively. A significant decrease in RV detection was identified from baseline to 3-month (p < 0.0001) and 12-month (p < 0.0001) assessments and between 3-month and 12-month visits (p = 0.004). No differences were identified in terms of RV resolution between (i) patients undergoing monotherapy and those co-administered with cDMARDs at 3-month (p = 0.560) and 12-month (p = 0.611) follow-up; (ii) biologic-naïve patients and those already exposed to other biologics at 3-month (p = 0.497) and 12-month (p > 0.99) visits; and (iii) patients treated with ADA and those treated with IFX (p = 0.357). During the study period, a statistically significant corticosteroid-sparing effect was observed (p = 0.0002), while BCVA values did not significantly change (p = 0.950). Anti-TNF-α monoclonal antibodies have proved excellent results in patients with recalcitrant sight-threatening RV.

Safety testing of blue vital dyes using cell culture models.

PURPOSE: To investigate the safety of trypan blue, brilliant blue G (BBG), Evans blue (EB), patent blue, Chicago blue (CB), and bromophenol blue (BB), with and without halogen and xenon light exposure. METHODS: All dyes were diluted in a balanced saline solution at a concentration of 0.5%. Cells of the human RPE line ARPE-19 and rat RGC5 were exposed to vital dyes for 5 min. Experiments with and without xenon or halogen illumination were performed. The viability of ARPE-19 and RGC5 cells was determined at 12, 24, or 120 h by a cell proliferation assay using WST-1 reagent. The apoptotic events as well as cell numbers were registered for 72 h and counted by time-lapse videomicroscopy. RESULTS: There was no evidence of ARPE-19 or RGC5 toxicity, immediate (0 and 24 h) or delayed (120 h), following exclusive exposure to each single dye. After halogen light exposure, ARPE-19 cell lines did not show any significant toxicity, except for when they were exposed to EB. After xenon illumination, ARPE-19 cells showed a marked decrease in cell viability when exposed to EB or CB and a moderate decrease when exposed to BBG and BB. After xenon illumination, RGC5 cells showed the highest decrease in cell viability when exposed to EB and CB; BB caused the same decrease in cell viability as in ARPE-19 cells. CONCLUSION: Interaction of light from endo-illumination source and blue vital dyes may increase the risk of retinal toxicity.

Acquired retinoschisis with giant outer layer break and retinal detachment.

PURPOSE: To evaluate the natural history of a case of retinoschisis with giant outer layer break and retinal detachment. METHODS: A 42-year-old patient with a sudden paracentral scotoma in the visual field of the right eye underwent the following examinations: best-corrected visual acuity, slit-lamp biomicroscopy, optical coherence tomography, ocular echography, and fundus photography. RESULTS: The eye examination revealed inferotemporal retinoschisis-detachment with a giant outer retinal layer break and absence of foveal involvement. No breaks in the internal retinal layer were noted. No treatment was advised in the right eye. During the 3-year follow-up, a progressive reabsorption of subretinal fluid was detected and visual acuity remained unchanged. CONCLUSIONS: Deliberate nontreatment of a case of nonprogressive retinoschisis-detachment carries less risk of serious complications or loss of vision than does either surgical or prophylactic treatment.

Evaluation of macular thickness after uncomplicated cataract surgery using optical coherence tomography.

PURPOSE: To evaluate central macular thickness (CMT) after cataract surgery in selected groups of patients. 
 METHODS: The study comprised 4 groups-patients with epiretinal membrane, patients with high myopia, patients with diabetes without retinopathy, and healthy subjects-who underwent phacoemulsification and intraocular lens implantation. Central macular thickness was measured with spectral domain optical coherence tomography (OCT) using the 3D macular cube scan. The OCT evaluation was performed preoperatively and 1, 6, 15, 30, 60, 90, and 360 days after surgery. Visual acuity was measured preoperatively and after 6 and 360 days after surgery.
 RESULTS: The study included 258 patients, 164 women and 94 men, with a mean age of 74 (SD 7.6) years. A statistically significant increase in CMT was observed from day 30 in patients with epiretinal membrane (p = 0.010) and diabetic patients (p = 0.026), reaching its maximum thickness at day 60 (p = 0.001 and p = 0.001), while it was observed only on day 360 in healthy subjects (p = 0.018) and those with high myopia (p = 0.003). The correlation between CMT and visual acuity was statistically significant only in the diabetic group (r = 0.61, p<0.01).
 CONCLUSIONS: Following cataract surgery, CMT changes according to characteristic patterns in the different groups studied. These changes did not prevent an optimal recovery of visual function.