Treatment Of Posterior Uveitis Research Articles

Commentary: Behçet's uveitis - Expanding treatment horizons.

Behçet’s disease is a complex multisystem disease. A standalone positive typing for HLA-B51 is not considered diagnostic, and the diagnosis of this uveitic entity is based on a myriad of multisystem clinical signs that make up the diagnostic criteria.[1] The genetic predisposition to this disease afforded by HLA-B51 positivity (along with other non-HLA genes) has been postulated to get along with an altered microbiome in the gut of Behçet patients, with an additional possible contribution from infectious agents such as Streptococcus sanguinis, to trigger and then sustain an immune response, which disrupts a previously intact T-cell homeostatic environment. This recent understanding has expanded treatment horizons beyond standard treatment protocols, to include biologic therapy, especially tumor necrosis factor-alpha (TNF-α) antagonists, to achieve control of repeated disrupted immune response.[1] Progressive sight-threatening Behçet’s disease involving the entire uveal tract blinds up to 25% of patients within a course of 10 years, after which the disease progression tends to stabilize.[1,2] This mandates an excellent control of inflammation within this all-important “window period” to save the eye either from the direct inflammatory manifestations of Behçet’s uveitis or its potentially blinding complications.[1] The consensus in uveitis management in Behçet’s disease (according to the European Alliance of Associations of Rheumatology [EULAR] and the American Academy of Ophthalmologists’ guidelines) recommends limitation of steroid administration for control of acute inflammation and substituting steroids with conventional disease-modifying antirheumatic drugs (DMARDs) or biologic therapy. Furthermore, the American Academy of Ophthalmology goes a step further to recommend bypassing the “classic DMARDs” in favor of anti-TNF-α agents in severe, sight-threatening uveitis.[3] Thus, EULAR updated its guidelines in 2018 to recommend administering steroids in posterior segment ocular Behçet’s disease patients, but only in combination with steroid-sparing therapies such as azathioprine (AZA), cyclosporine A (CsA), interferon alpha, or monoclonal anti-TNF antibodies.[3] In the current study[4] of Behçet’s disease with ocular lesions from India, all patients have received steroids and 80% patients have been treated with immunosuppression along with steroids. Randomized controlled trials have shown that the antimetabolite AZA and T-cell inhibitor CsA are effective in the treatment of posterior uveitis in Behçet’s disease. Hence, the updated 2018 EULAR guidelines recommended the use of these two drugs (as against others) in the initial therapy of posterior uveitis.[3] Further, the combined use of AZA and CsA, whether as first- or second-line therapy, has shown efficacy in controlling ocular Behçet’s disease (with more periodic side effect monitoring).[1] In the current study from India, AZA and CsA have been combined in 24% of the patients.[4] In Behçet’s disease, TNF-α production by macrophages, CD4+ and CD8+ T cells, and natural killer cells is increased. The reduction of circulating TNF-α has been shown to result in dramatic improvement in the inflammatory activity of patients with severe pan or posterior uveitis.[1] These anti-TNF-α drugs used are recombinant monoclonal antibodies directed against TNF-α. Due to their potent and fast effects, these agents are now used alone or in combination therapy in refractory ocular Behçet’s cases, or sometimes even as first-line treatment in severe sight-threatening attacks.[3] Adalimumab (ADA) is a fully human monoclonal antibody directed against TNF-α and has been tested against a placebo in both active and quiescent, noninfectious uveitis (VISUAL I and VISUAL II studies, respectively). Ocular Behçet’s disease represented 7% of the uveitic cases enrolled in them.[1] Further, other uncontrolled studies have shown significant results regarding the efficacy of ADA in Behçet’s uveitis.[5] Early initiation of ADA in two children with Behçet’s uveitis succeeded in control of the disease activity, allowing tapering of topical and systemic steroids.[6] Comparative studies have been conducted between ADA and the other agent infliximab (IFX), notably a multicenter study on 177 patients with refractory Behçet’s disease uveitis, which found that both agents gave significantly better control in terms of disease activity as the first-line treatment, but the ADA group had higher percentage of patients with better best corrected visual acuity and fewer drug-related reactions.[7] One must remember that exclusion of tuberculosis and other infectious diseases as well as occult malignancies is mandatory before starting therapy with these agents. Also, an additional immunosuppressant (like methotrexate) may be advisable to prevent anti-chimeric, or antihuman, antibody production, which decreases the efficacy of these agents leading to secondary failure.[1] In the current study from India, biologic agents have been used in 40% of the patients; of which ADA was used in 28% and IFX in 12% of patients.[4] Finally, studies have recently reported success with Janus kinase (JAK) inhibitors in the treatment of noninfectious autoimmune uveitis refractory to conventional DMARDs and anti-TNF-α agents. Successful results have been reported with the JAK inhibitor tofacitinib in refractory Behçet’s disease uveitis,[8] and moving forward, these agents shall most likely further expand our treatment horizons for Behçet’s disease.

Assessment of choroid thickness by swept‑source optical coherence tomography (SS-OCT) in patients with posterior uveitis

Background: This study aimed to measure the changes in choroid thickness using Swept-Source Optical Coherence Tomography (SS-OCT) after treatment of posterior uveitis along with changes in fundus auto-fluorescence pattern. Material and methods: This prospective observational cohort study was conducted from December 2018 to May 2020, in which 32 eyes of 20 patients presenting in the out-patient department with a clinical diagnosis of posterior uveitis were enrolled. Best-corrected visual acuity (BCVA) by Snellen chart, intraocular pressure (IOP) Measurement using a non-contact tonometer, choroidal thickness by SS-OCT, and fundus imaging by Fundus Autofluorescence was done. All tests were done at baseline, first follow-up of 2 ± 1 weeks and the second follow-up of 6 ± 2 weeks. Data was compiled and analyzed. Results: The mean age of patients was 31 ± 6.9 years with M:F of 3:1. During the second follow-up, with the healing of the lesions, there was a significant reduction in the choroidal thickness at all levels by SS-OCT (p < 0.05), with significant improvement in BCVA (0.05 vs. 0.14 vs. 0.31, p < 0.05). IOP increased significantly at the first follow-up to 17.31 from baseline (16.25) (p = 0.032). However, the rise at the second follow-up was not significant (17.03 vs. 16.25 at baseline, p = 0.15). On fundus autofluorescence, normal autofluorescence and hypofluorescence increased at the second follow-up of 6 weeks (p < 0.0001) Conclusion: SS-OCT showed a significant decrease in the choroidal thickness at all levels during the follow-ups. The healing of the posterior uveitis lesions and fundus autofluorescence became normal simultaneously.

A grafted copolymer-based nanomicelles for topical ocular delivery of everolimus: Formulation, characterization, ex-vivo permeation, in-vitro ocular toxicity, and stability study

Treatment of posterior uveitis via topical route is desirable but cannot be achieved by conventional drug delivery strategies. Therefore, the aim of this study is to develop a topical nanomicellar formulation of an immunosuppressant drug, everolimus using Soluplus®, a grafted copolymer of polyvinyl caprolactam-polyvinylalcohol-polyethyleneglycol (PVCL-PVA-PEG) for improved permeation through ocular epithelia with minimal or no irritation resulting in enhanced ocular bioavailability at the posterior segments of the eye for the treatment of uveitis. Soluplus-everolimus nano micelles were found to have a low CMC (7.2 µg/ml) and 65.55 nm in size. The prepared nanomicelles were characterized for surface morphology by TEM, SEM, and AFM and found to have spherical particles with a smooth surface. The nanomicelles were found to have high encapsulation efficiency and result in sustained release of everolimus when compared with everolimus suspension. The everolimus nanomicelles showed significantly higher permeation across goat cornea than everolimus suspension (p<0.001). CLSM of prepared nanomicelles confirmed the deeper permeation through the goat cornea. These results indicated the significantly higher accessibility and improved drug bioavailability thus, everolimus nanomicelles could be considered a promising topical drug delivery nanocarrier for treating uveitis.

The Effectiveness of Intraocular Methotrexate in the Treatment of Posterior Uveitis in Behçet's Disease Patients Compared to Retrobulbar Steroids Injection.

Aim of Work. To evaluate the efficacy of intravitreal methotrexate (MTX) compared to retrobulbar triamcinolone acetonide (TAA), in controlling posterior segment involvement and inducing remissions among Behçet's disease (BD) patients. Study Design. This is a cross-sectional nonrandomized comparative study. Patients and Methods. 31 adult BD male patients with a mean disease duration of 5.45 years who presented with bilateral posterior segment involvement were included. Each patient received intravitreal injection of 400 μg/0.1 mL (MTX) for the right eye (Group A) and 1 mL of retrobulbar 40 mg/mL TAA for the left eye (Group B). Results. 90% of eyes showed complete improvement of anterior chamber reaction, whereas an improvement in vitreous activity in 77% with no significant differences between both groups (p ≤ 0.1). BCVA improved in 77.4% eyes (Group A) compared to 87.1% (Group B) (p ≤ 0.4). Relapses were noted in 11 eyes (35.5%), in group A, with the mean duration of remission being 19.1 weeks ± 2.13 compared to 7.35 ± 2.8 in 20 eyes (64.5%) in group B (p ≤ 0.1). Conclusion. No statistical differences were found between both treatment modalities; however, based on clinical observations, intravitreal MTX may ensure better control of inflammatory reaction and may encourage longer remission as compared to retrobulbar TAA in BD patients.

Mycophenolate mofetil and cyclophosphamide treatment suppress inflammation intensity in experimental model of autoimmune uveitis

AbstractPurpose The research in experimental models of autoimmune uveitis helps to find new therapeutical strategies. The aim of this study is to compare the effect of cyclophosphamide (CPA), mycophenolate mofetil (MMF) and golimumab on inflammation intensity in mice model of experimental autoimmune uveitis (EAU).Methods EAU was induced in C57BL/6 mice by subcutaneous application of IRBP (interphotoreceptor retinoid binding protein) in complete Freund’s adjuvant and pertussis toxin. CPA was injected intraperitoneally in a single dose of 100 mg/kg, MMF intraperitoneally daily in a dose of 30 and 50 mg/kg, golimumab subcutaneously weekly in a dose of 70 mg/kg. Mice with EAU without treatment and group with EAU with sham treatment served as controls. Histological grading of uveitis at day 35 post induction of EAU was used.Results The comparison of intensity of inflammation in group of treated and untreated mice shows that MMF significantly suppressed the inflammation (p˂0,05). The absolute suppression of inflammation by CPA (p˂0,0001) was shown. On the contrary, golimumab enhanced the ocular inflammation.Conclusion In this study, we have confirmed the efficacy of CPA and MMF in treatment of posterior uveitis, which supports its use in human medicine. This project was supported by grant IGA MZ NT/14017‐3/2013 and SVV‐266505/2013.

Development and characterization of an intraocular biodegradable polymer system containing cyclosporine-A for the treatment of posterior uveitis

The aim of this study was to synthesize and characterize the biodegradable intraocular implants based on poly (D,L-lactide-co-glycolide) (PLGA 75:25) with Cyclosporine-A (CyA) and to evaluate their in vitro drug delivery profile. Thermal analysis was conducted by using Thermogravimetry (TG) and Differential Scanning Calorimetry (DSC). Phase analysis and crystallinity of the polymer-CyA samples were assessed through X ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Finally, microstructure and morphology of the systems were investigated by Scanning Electron Microscopy (SEM). The results showed that CyA was successfully incorporated into PLGA network with drug loading of approximately 31.6%. Also, based on FTIR and thermal analyses (TGA/DSC) no significant physical-chemical interaction was detected at the micro-nanoscale level between polymer/drug. SEM micrographs have indicated a uniform drug distribution in PLGA matrix. XRD patterns have showed that the incorporated semi-crystalline structure of CyA has not significantly altered the polymeric mainly amorphous network. In addition, the results have confirmed the chemical and biological drug stability, the drug distribution into the polymeric matrix and the possibility of cyclosporine prolonged delivery system profile.

Fluocinolone acetonide intravitreal sustained release device ? a new addition to the armamentarium of uveitic management

Uveitis is a potentially sight-threatening inflammatory eye disease caused by multiple infectious and non-infectious etiologies for which the standard of care involves corticosteroids or various immunomodulary therapy (IMT) drugs. These available treatments, although effective, may cause significant morbidity and sometimes mortality in uveitis patients due to their toxic side-effects and the necessity of long-term therapy to prevent recurrences. In order to avoid the systemic toxicity ofcorticosteroids and IMT or the repeated injections of local steroids necessary to control ocular inflammation, and to prevent development of cumulative damage resulting from recurrent episodes of inflammation, researchers have developed a number of local corticosteroid sustained-release devices that can be implanted directly into the vitreous of the eye, at the site of the inflammatory disease. Preliminary studies of such a device, the fluocinolone acetonide (Retisert) implant, have shown significant reductions in the number of inflammatory episodes and decreased reliance on systemic corticosteroids or other IMT. This review explores the current research evaluating the fluocinolone sustained-release intravitreal implant in the treatment of posterior uveitis and the implications for its future use on a wider scale.

Intravitreal Triamcinolone Acetonide Injection for the Treatment of Posterior Uveitis

Purpose: To assess the efficacy and complications of intravitreal triamcinolone acetonide (IVTA) injection in the treatment of posterior uveitis and to compare the outcomes with patients who had received systemic corticosteroids. Methods: This prospective, interventional, clinical case series study included 11 eyes of 9 patients who received 8 mg/0.2 ml of IVTA injection for posterior uveitis that involved vitreous inflammation (group 1). Control group (group 2) consisted of 15 eyes of 12 patients who had received systemic corticosteroids for treatment of posterior uveitis with vitreous inflammation. The main outcome measures included best-corrected visual acuity, vitreous inflammation score and intraocular pressure. Results: In group 1, mean visual acuity improved significantly (P < 0.001) from a mean logarithm of the minimum angle of resolution (LogMAR) value of 2.05 ± 0.82 at baseline to a maximum of 0.33 ± 0.22 during the follow-up period of 5.0 ± 2.8 months. In control group, mean LogMAR visual acuity before systemic corticosteroid therapy was 1.82 ± 0.78, and it has reached a maximum of 0.40 ± 0.22 after treatment (P < 0.001). The mean inflammatory scores decreased significantly in both groups when compared with preinjection values (for each, P < 0.05). There were no statistically significant differences between group 1 and group 2 when pre-and posttreatment visual acuities and inflammatory scores at 1-, 3-, and 5-month follow-up examinations were compared (for each, P > 0.05). In group 1, mean intraocular pressure (IOP) increased significantly from 13.4 ± 2.6 mmHg to a mean maximal value of 19.3 ± 4.3 mmHg (P < 0.001), but there was no statistically significant difference between mean IOP at 5-month after IVTA injection and pretreatment value (P = 0.06). Cataract progression was observed in one eye. Conclusions: IVTA application may be an alternative therapeutic option for the treatment of acute posterior uveitis that involves vitreous inflammation, especially in patients who carry risks for systemic corticosteroid therapy.

Infliximab in the treatment of posterior uveitis in Behçet's disease: Long term follow up in four patients

To evaluate the efficacy of infliximab as adjuvant therapy for refractory uveitis in Behçet's disease.Retrospective evaluation of 4 patients with Behçet's disease and severe uveitis, refractory to conventional corticosteroid and immunosuppressant regimens, to which infliximab (anti-tumor necrosis factor-alpha (TNFalpha) antibodies) was added. The outcome measures were intraocular inflammation, visual acuity, reduction of daily corticosteroid dose, and adverse effects.The mean follow-up period was 11 months (range: 2-29 months). Patients received a mean of 8 (range: 3-16) infliximab infusions. TNFalpha blockade with infliximab was effective for 2 of our 4 patients: the effect for them was rapid but transient. One patient experienced a thoracic herpes zoster, a severe adverse effect not previously reported.Response to infliximab was variable in patients with Behçet's disease for whom conventional immunosuppression had failed. Infliximab allowed the daily corticosteroid dose to be reduced for some patients but required repeated infusions.

Ciclosporin-Monitoring bei Patienten mit chronischer Uveitis

Cyclosporine (CsA) is a widely used drug in the treatment of posterior uveitis. Whereas treatment with CsA has considerably improved the visual prognosis of uveitis patients, the therapeutic benefits of CsA are partially outweighed by its adverse effects, most notably nephrotoxicity and hypertension. Recently, monitoring the CsA 2-h postdose level (C(2)) has been recommended as the most sensitive assay and predictor of clinical outcome in transplantation. This prospective clinical trial included 15 patients with posterior uveitis who received oral CsA (5 mg/kg BW b.i.d.). The relationship of C(2) to C0 blood levels was analyzed and correlated with clinical safety and efficacy. A high intrapatient and interpatient variability was observed regarding the C0 values depending on several factors including comedication and intestinal resorption. C(2) values corresponded to control measurements of intraocular inflammation. C(2) monitoring offers a simple and accurate alternative for clinical monitoring of CsA. It allows the dose of CsA to be individualized effectively for each patient.

TNF?-Inhibitoren in der Uveitistherapie

Tumor necrosis factor alpha (TNFalpha) is a pleiotropic cytokine that plays a pivotal role in chronic inflammatory diseases. Data from animal experiments indicate that TNFalpha is an important part of the pro-inflammatory processes in non-infectious uveitis. Neutralization of TNFalpha with TNF receptor fusion proteins or monoclonal antibodies, therefore, represents a promising strategy for the treatment of uveitis. In addition, the currently available TNFalpha inhibitors demonstrate a favourable profile of side effects compared to conventional immunosuppressive agents. Previous studies showed the immunological efficacy of TNFalpha inhibitors in the treatment of posterior uveitis. However, the available data on anterior uveitis are inconclusive with respect to the clinical efficacy of these agents.

Clinical trial to compare efficacy and side‐effects of injection of posterior sub‐Tenon triamcinolone versus orbital floor methylprednisolone in the management of posterior uveitis

To compare the efficacy and side-effects of posterior sub-Tenon injection of triamcinolone acetonide (Kenalog) with orbital floor injection of methylpredisolone acetate (Depomedrone) in the management of posterior uveitis. Non-randomized comparative prospective clinical study. Sixty-four eyes from 60 consecutive patients with non-infectious posterior uveitis requiring treatment were allocated on an alternate 1:1 basis to receive either orbital floor methylprednisolone or sub-Tenon triamcinolone using standard procedures and assessed at 6 and 12 weeks. After five eyes of five patients who had received the same treatment bilaterally were excluded from the statistical analysis, 14 out of 29 eyes treated with orbital floor methylprednisolone and 10 out of the 30 eyes given sub-Tenon triamcinolone improved at 6 weeks. There was no statistically significant difference in the improvement rate between the two groups. However, two patients given triamcinolone had prolonged upper lid ptosis, which required surgery, and another two developed markedly raised intraocular pressure, neither of which occurred in the methylprednisolone-treated group. Although the two drugs and routes compared were of similar efficacy, lid ptosis occurred in the triamcinolone-treated but not the methylprednisolone group. This should be borne in mind when choosing the preferred route of delivery of periocular corticosteroid in the treatment of posterior uveitis.

Recent Developments in the Treatment of Posterior Uveitis

Uveitis is an intraocular inflammation that can be caused by infection, autoimmune disease, trauma or malignancy. It is a serious cause of visual handicap and therapy is targeted at: removal of possible infectious agents, the immunological processes that lead to or sustain the inflammation and finally to prevent or treat the destructive effects of the inflammation on the delicate ocular structures. In this review the latest developments concerning the treatment of posterior uveitis are illuminated, e. g., new approaches concerning the treatment of infectious uveitis including the therapy of herpes virus (VZV, HSV and CMV), bacterial and toxoplasma infections of the eye. Several new ways to influence the immune response and inflammation are described including the use of interferons, modulation of cytokines, soft steroids, other new immunosuppressive drugs and treatment of autoimmune uveitis by oral tolerization. An overview is given to illustrate new ways to administer drugs into eyes, such as intravitreal devices. Finally new developments in the field of the treatment of the various complications of uveitis (cystoid macular edema) are described.

Noninfectious Posterior Uveitis

Posterior uveitis encompasses a broad range of clinical entities with multiple manifestations. A complete history and physical examination provide diagnostic clues and guide an appropriate laboratory evaluation. An infectious cause should always be considered before instituting therapy. Periocular and systemic corticosteroids are the mainstay of treatment, but additional immunosuppressive agents may be required to control inflammation and minimize side effects. An atypical response to therapy should provoke further testing to rule out a masquerade process. This article reviews the common clinical findings, differential diagnosis, and treatment of posterior uveitis.

Systemic immunosuppression in the treatment of posterior uveitis.

Systemic immunosuppression in the treatment of posterior uveitis.