Ocular Inflammatory Disorders Research Articles

Controlled release of corticosteroid with biodegradable nanoparticles for treating experimental autoimmune uveitis

Noninfectious uveitis is a potentially blinding ocular condition that often requires treatment with corticosteroids to prevent inflammation-related ocular complications. Severe forms of uveitis such as panuveitis that affects the whole eye often require a combination of topical and either regional or systemic corticosteroid. Regional corticosteroids are currently delivered inside the eye by intravitreal injection (e.g. Ozurdex®, an intravitreal dexamethasone implant). Intravitreal injection is associated with rare but potentially serious side effects, including endophthalmitis, retinal and vitreous hemorrhage, and retinal detachment. Subconjunctival (SCT) injection is a less invasive option that is a common route used for post-surgical drug administration and treatment of infection and severe inflammation. However, it is the water soluble form of dexamethasone, dexamethasone sodium phosphate (DSP), that has been demonstrated to achieve high intraocular penetration with subconjunctival injection. It is difficult to load highly water soluble drugs, such as DSP, and achieve sustained drug release using conventional encapsulation methods. We found that use of carboxyl-terminated poly(lactic-co-glycolic acid) (PLGA) allowed encapsulation of DSP into biodegradable nanoparticles (NP) with relatively high drug content (6% w/w) if divalent zinc ions were used as an ionic “bridge” between the PLGA and DSP. DSP-Zn-NP had an average diameter of 210 nm, narrow particle size distribution (polydispersity index ~0.1), and near neutral surface charge (−9 mV). DSP-Zn-NP administered by SCT injection provided detectable DSP levels in both the anterior chamber and vitreous chamber of the eye for at least 3 weeks. In a rat model of experimental autoimmune uveitis (EAU), inflammation was significantly reduced in both the front and back of the eye in animals that received a single SCT injection of DSP-Zn-NP as compared to animals that received either aqueous DSP solution or phosphate buffered saline (PBS). DSP-Zn-NP efficacy was evidenced by a reduced clinical disease score, decreased expression of various inflammatory cytokines, and preserved retinal structure and function. Furthermore, SCT DSP-Zn-NP significantly reduced microglia cell density in the retina, a hallmark of EAU in rats. DSP-Zn-NP hold promise as a new strategy to treat noninfectious uveitis and potentially other ocular inflammatory disorders.

Topical Application of TGF-β-Activating Peptide, KRFK, Prevents Inflammatory Manifestations in the TSP-1-Deficient Mouse Model of Chronic Ocular Inflammation.

Chronic inflammation of the ocular surface poses a risk of vision impairment. The understanding of the molecular mechanisms that are involved in the inflammatory response is critical to identify novel molecular targets. Recently, thrombospondin-1 (TSP-1) has emerged as a key player in ocular surface homeostasis that efficiently activates the TGF-β2 isoform that is predominantly expressed in the ocular mucosa. Here, the potential of the peptide derived from TSP-1 (KRFK), that can activate TGF-β, is proposed as a potentially applicable therapeutic for chronic ocular surface inflammatory disorders. Our in vitro results confirm that the chosen peptide activates TGF-β, reducing the expression of co-stimulatory molecules on dendritic cells, driving them towards a tolerogenic phenotype. For the in vivo studies, the TSP-1−/− mouse is used as a pre-clinical model of chronic ocular inflammation. We observe that the topical application of KRFK alters the peripheral balance of effectors by reducing the proportion of pathogenic Th1 and Th17 cells while increasing Treg cell proportion in cervical lymph nodes. In line with these findings, the development of chronic ocular surface inflammation is significantly prevented in KRFK-treated TSP-1−/− mice, as assessed by clinical parameters and inflammatory cytokine expression in conjunctival and lacrimal gland tissues. Together, our results identify the KRFK peptide as a novel therapeutic option to prevent the development of chronic inflammatory manifestations of the ocular surface.

Baicalin modulates the Treg/Teff balance to alleviate uveitis by activating the aryl hydrocarbon receptor

Autoimmune uveitis is a sight-threatening ocular inflammatory disorder. Immunological inflammation is regarded as the key to pathogenesis in autoimmune uveitis. Baicalin, the major bioactive component of Scutellaria baicalensis, possesses immunomodulatory properties. However, the role of baicalin in uveitis and its underlying mechanisms remain unclear. In the current study, we found that baicalin treatment obviously inhibited the intraocular inflammatory process in mice with experimental autoimmune uveitis, along with clear declines in infiltrated inflammatory cells and inflammatory cytokine transcription in the retina and draining lymph nodes. Furthermore, baicalin treatment increased the frequency and number of regulatory T cells and decreased the frequency and number of effector T cells (Th1 and Th17 cells) in the draining lymph nodes of mice with experimental autoimmune uveitis. In vitro, baicalin treatment suppressed interphotoreceptor retinoid binding protein-specific CD4+ T cell proliferation and converted CD4+ T cell differentiation. Furthermore, the expression of aryl hydrocarbon receptor was activated by baicalin treatment. Baicalin-mediated modulation of CD4+ T cell differentiation was partially abrogated by the suppression of aryl hydrocarbon receptor. These findings suggest that baicalin modulates the Treg/Teff balance and CD4+ T cell proliferation to ameliorate experimental autoimmune uveitis by activating the aryl hydrocarbon receptor.

Narrow Spectrum Kinase Inhibitors Demonstrate Promise for the Treatment of Dry Eye Disease and Other Ocular Inflammatory Disorders.

The purpose of this study is to determine the potential of narrow spectrum kinase inhibitors (NSKIs) to treat inflammatory eye disorders. Human conjunctival epithelial (HCE) cells were retrieved from subjects via impression cytology. Real-time quantitative PCR (qPCR) was performed on HCE cells to determine gene expression of NSKI kinase targets and proinflammatory cytokines in dry eye disease (DED) patients versus healthy controls. qPCR also assessed p38α expression in hyperosmolar-treated Chang conjunctival epithelial cells. Interaction of NSKI TOP1362 with the kinases was evaluated in ATP-dependent Z-LYTE and competition binding assays. Anti-inflammatory activity was assessed in human peripheral blood mononuclear cells and primary macrophages. In an endotoxin-induced uveitis (EIU) study, lipopolysaccharide (LPS) was administered intravitreally to Lewis rats. TOP1362, dexamethasone, or vehicle was administered topically, and inflammatory cytokine levels were measured 6 hours after LPS injection. HCE cells from DED patients showed significantly increased expression of p38α, spleen tyrosine kinase (Syk), Src, lymphocyte-specific protein tyrosine kinase (Lck), interleukin one beta (IL-1β), interleukin eight (IL-8), monocyte chemotactic protein-1 (MCP-1), and matrix metalloproteinase-9 (MMP-9). TOP1362 strongly inhibited the kinase targets p38α, Syk, Src, and Lck, blocked the rise in p38α expression in hyperosmolar Chang cells, and potently reduced inflammatory cytokine release in cellular models of innate and adaptive immunities. In the EIU model, TOP1362 dose-dependently attenuated the LPS-induced rise in inflammatory cell infiltration and ocular cytokine levels with efficacy comparable to that of dexamethasone. TOP1362 is a potent inhibitor of kinases upregulated in DED and markedly attenuates proinflammatory cytokine release in vitro and in vivo, highlighting the therapeutic potential of NSKIs for treating ocular inflammation, such as that observed in DED.

Mesenchymal Stromal Cells Inhibit Neutrophil Effector Functions in a Murine Model of Ocular Inflammation.

PurposeNeutrophil-secreted effector molecules are one of the primary causes of tissue damage during corneal inflammation. In the present study, we have investigated the effect of stromal cells in regulating neutrophil expression of tissue-damaging enzymes, myeloperoxidase (MPO), and N-elastase (ELANE).MethodsBone marrow–purified nonhematopoietic mesenchymal stromal cells and formyl-methionyl-leucyl-phenylalanine–activated neutrophils were cocultured in the presence or absence of Transwell inserts for 1 hour. Neutrophil effector molecules, MPO and ELANE, were quantified using ELISA. In mice, corneal injury was created by mechanical removal of the corneal epithelium and anterior stroma approximating one third of total corneal thickness, and mesenchymal stromal cells were then intravenously injected 1 hour post injury. Corneas were harvested to evaluate MPO expression and infiltration of CD11b+Ly6G+ neutrophils.ResultsActivated neutrophils cocultured with mesenchymal stromal cells showed a significant 2-fold decrease in secretion of MPO and ELANE compared to neutrophils activated alone (P < 0.05). This suppressive effect was cell–cell contact dependent, as stromal cells cocultured with neutrophils in the presence of Transwell failed to suppress the secretion of neutrophil effector molecules. Following corneal injury, stromal cell–treated mice showed a significant 40% decrease in MPO expression by neutrophils and lower neutrophil frequencies compared to untreated injured controls (P < 0.05). Reduced MPO expression by neutrophils was also accompanied by normalization of corneal tissue structure following stromal cell treatment.ConclusionsMesenchymal stromal cells inhibit neutrophil effector functions via direct cell–cell contact interaction during inflammation. The current findings could have implications for the treatment of inflammatory ocular disorders caused by excessive neutrophil activation.

Genes and genetics in eye diseases: a genomic medicine approach for investigating hereditary and inflammatory ocular disorders.

Past 25y have witnessed an exponential increase in knowledge and understanding of ocular diseases and their respective genetic underpinnings. As a result, scientists have mapped many genes and their variants that can influence vision and health of our eyes. Based on these findings, it is becoming clear that an early diagnosis employing genetic testing can help evaluate patients' conditions for instituting treatment plan(s) and follow-up care to avoid vision complications later. For example, knowing family history becomes crucial for inherited eye diseases as it can benefit members in family who may have similar eye diseases or predispositions. Therefore, gathering information from an elaborate examination along with complete assessment of past medical illness by ophthalmologists followed by consultation with geneticists can help create a roadmap for making diagnosis and treatment precise and beneficial. In this review, we present an update on ocular genomic medicine that we believe has tremendous potential towards unraveling genetic implications in ocular diseases and patients' susceptibilities. We also discuss translational aspects of genetic ophthalmology and genome engineering that may help advance molecular diagnostics and therapeutics.

Optimization, Biopharmaceutical Profile and Therapeutic Efficacy of Pioglitazone-loaded PLGA-PEG Nanospheres as a Novel Strategy for Ocular Inflammatory Disorders.

The main goal of this study was to encapsulate Pioglitazone (PGZ), in biodegradable polymeric nanoparticles as a new strategy for the treatment of ocular inflammatory processes. To improve their biopharmaceutical profile for the treatment of ocular inflammatory disorders, nanospheres (NSs) of PGZ were formulated by factorial design with poly (lactic-co-glycolic acid) polyethylene glycol (PLGA-PEG). Interactions drug-polymer have been carried out by spectroscopic (X-ray spectroscopy, FTIR) and thermal methods (DSC). The PGZ-NSs were tested for their in vitro release profile, cytotoxicity, and ocular tolerance (HET-CAM® test); ex vivo corneal permeation, and in vivo inflammatory prevention and bioavailability. The optimized system showed a negative surface charge of -13.9mV, an average particle size (Zav) of around 160nm, a polydispersity index (PI) below 0.1, and a high encapsulation efficiency (EE) of around 92%. According to the DSC results, the drug was incorporated into the NSs polymeric matrix. The drug release was sustained for up to 14h. PGZ-NSs up to 10μg/ml exhibited no retinoblastoma cell toxicity. The ex vivo corneal and scleral permeation profiles of PGZ-NSs showed that retention and permeation through the sclera were higher than through the cornea. Ocular tolerance in vitro and in vivo demonstrated the non-irritant character of the formulation. The in vivo anti-inflammatory efficacy of developed PGZ-NSs indicates this colloidal system could constitute a new approach to prevent ocular inflammation.

Downregulation of interferon-γ-induced protein 10 in the tears of patients with Stevens-Johnson syndrome with severe ocular complications in the chronic stage

ObjectivesStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute inflammatory vesiculobullous reactions of the skin and mucosa such as the ocular surface, oral cavity and genitals. Severe ocular complications...

Formulations and toxicologic in vivo studies of aqueous cyclosporin A eye drops with cyclodextrin nanoparticles

Cyclosporin A (CyA) is an immunosuppressive drug used topically to treat ocular inflammatory disorder such as dry eye disease (DES). It is a lipophilic cyclic peptide with molecular weight of 1202.6Da. The aim of this study was to develop surfactant free aqueous 0.2% (w/v) CyA eye drops where the drug is present in an aqueous vehicle containing CyA/cyclodextrin (CyA/CD) nanoparticles and then do three-month toxicological testing in rabbits. Five formulations of different CD concentrations were studied, all of them contained 12.5% (w/v) of α-cyclodextrin (αCD) and various amounts of γ-cyclodextrin (γCD) (ranging from 0 to 12.5% w/v). αCD was used to solubilize the drug and γCD to promote formation of complex aggregates. CyA/CD complex aggregates were formed in all the formulations tested. However, the formulation containing 12.5% (w/v) αCD and 12.5% (w/v) γCD created more CyA/CD nanoparticles of suitable size and was therefore tested in vivo. The eye drops did not cause ocular irritation or toxic side effects upon topical administration to rabbits once or twice a day for three months.

Proglycosomes: A novel nano-vesicle for ocular delivery of tacrolimus

Tacrolimus is an emerging candidate for the treatment of immune-mediated inflammatory ocular disorders (IIODs) however its ocular delivery remained a challenge due to its hydrophobic nature, high molecular weight and physiological and anatomical constraints of the eye. The present work describes vesicles composed of propylene glycol, phospholipid and water, proglycosomes (PNVs), as novel carriers for ocular delivery of tacrolimus. Addition of propylene glycol decreases vesicle aggregation, increases encapsulation of tacrolimus and prevented drug leakage. Developed PNVs were of nanosize (111.5±3.2nm) and 5-fold more elastic than conventional liposomes. PNVs showed prolonged drug release over period of 12h and higher corneal permeation, 5-fold and 13-fold, compared to conventional liposomes and tacrolimus solution, respectively. Studies in rabbits demonstrated prolonged precorneal retention (upto 8h) and manifestly improved intraocular drug levels, well above therapeutic levels, at all tested time-points following topical application of PNV formulation compared to drug solution. Further, PNVs were found to be safe for ocular use. In conclusion, the developed PNVs are prospective carriers for enhanced ocular delivery of tacrolimus.

The application of optical coherence tomography angiography in uveitis and inflammatory eye diseases

Since its introduction in the early 1990s, optical coherence tomography (OCT) has evolved in resolution and technological advances, and in recent years its initial application of assessing the morphology of a tissue has been implemented by the study of its functional blood flow, through optical coherence tomography angiography (OCTA). This novel technique details capillary networks by comparing the amount of light returned from static and moving targets without the need for intravenous dye administration. While this imaging modality has been used for various ocular conditions, the application OCTA to uveitis conditions remains sparse. This review aims to establish the basis of OCTA and its current application to ocular inflammatory disorders, with an emphasis on monitoring progression and response to treatment, as well as predicting visual complications. In particular, this review explores the use of OCTA in iris vessel dilation seen in various forms of iritis, as a predictive factor for further episodes of inflammation. OCTA can also depict ischemia in the deep plexus layers of the retina and identify true choroicapillaris ischemia in cases of placoid diseases or masking of the indocyanine green dye, as in multiple evanescent white dot syndrome. In addition, OCTA can depict neovascularization in granulomatous disease of the retina or choroid not previously depicted with previous imaging methods. While OCTA provides several advancements in the imaging, management and prognosis of uveitis diseases, we emphasize that further studies are required to fully understand its application to these conditions.

Systemic Treatment for Noninfectious Intraocular Inflammation

Although uncommon, uveitis and other ocular inflammatory disorders may pose a serious threat to a patient’s vision and quality of life. The purpose of this review is to evaluate the indications for immunosuppressive therapy in the treatment of uveitis and to appraise the data regarding their usage, including efficacy and potential side effects. While some agents such as antimetabolites have been used to treat uveitis for decades, there are now newer medications such as biologics that have recently met with great success. Adalimumab is the first biologic therapy FDA approved for the treatment of uveitis. There are multiple immunosuppressive therapies available for the treatment of uveitis that allow for sustained control of ocular inflammation and limitation of systemic corticosteroid exposure. Additional research will be necessary to characterize the efficacy of newer agents to determine if they may be superior and tolerated as older therapies.

Emerging therapeutics for ocular surface disease.

The present review provides an overview on the potential of different systemic and topical treatments in chronic forms of ocular allergy and dry eye disorder (DED). The impact on anterior surface of ocular inflammatory disorder encompasses an array of conditions, which are frequently underreported. This can contribute to underdiagnoses and ineffective management from healthcare providers such as an allergist and/or ophthalmologist who routinely provide care for these common disorders. Owing to the current limited therapeutic options, healthcare providers are routinely seeking alternative treatments that could facilitate effective management of the conditions. Recent advances in immunopathophysiology of ocular surface disorders has provided new potential targets and therapeutic strategies for the treatment of DED and ocular allergy that may include various immunobiological modulators. These modulators have focused on regulating the Th1 and Th2 immune-mediated inflammatory pathways that inhibit various cytokines (e.g. IL-1, IL-4, IL-5, IL-9, IL-13) antibodies (e.g. IgE), and other surface markers of various cell lines (e.g. activated T-lymphocytes, lymphocyte function-associated antigen-1). Recent findings about the pathophysiology of DED and ocular allergy have led to the greater understanding of the molecular and cellular mechanisms of ocular surface diseases leading to the potential novel targets for immunomodulation of anterior surface ocular disorders. New topical glucocorticoids, leukotriene receptor antagonists, IL-1 antagonists, IL-5, IL-4/IL-13 antagonists, integrin antagonists, and quinolone derivatives appear to be encouraging.

Ocular Inflammatory Disorders in Autoimmune Lymphoproliferative Syndrome (ALPS)

ABSTRACTPurpose: To describe inflammatory ocular findings in patients with autoimmune lymphoproliferative syndrome (ALPS).Methods: A retrospective review of medical records for ALPS patients seen at the National Eye Institute between 2003 and 2013.Results: A total of 29 ALPS patients previously referred for ocular or visual symptoms or with a history of prolonged corticosteroid use, were identified. Mean age was 20 years (range: 4–66 years). The majority were male (n = 21, 72.4%) and Caucasian (n = 24, 82.8%). Ten (34.5%) had abnormal ocular findings, the most common of which was an ocular inflammatory disorder (n = 4, 13.8%). Uveitis was seen in two patients with ALPS-FAS and one with ALPS-U, all of whom required long-term systemic immunosuppression. One patient with ALPS-FAS had a history of optic neuritis.Conclusions: ALPS can have intraocular inflammatory manifestations that require routine follow-up to ensure appropriate and timely treatment of intraocular disease. Long-term immunosuppression may be needed for patients with ALPS-associated uveitis.

Immunological impression cytology of the conjunctival epithelium in patients with thyroid orbitopathy-related dry eye

Thyroid orbitopathy (TO) is an autoimmune disease that is complicated by ocular surface disorders, leading to discomfort. Dry eye is very prevalent in patients with TO. Recent studies on the pathogenesis of dry eye have focused on the inflammatory process, and some supporting evidence has been discovered. Because TO is a disorder of autoimmune origin, we assumed that the association between TO and dry eye is related to inflammation. Inflammation of the ocular surface in TO-related dry eye has not been well studied. In this study, we assessed cellular inflammation of the ocular surface and the cytokine profiles in patients with TO-related dry eye. Conjunctival impression cytology (CIC) was assessed with an immunofluorescent assay. TO-related dry eye was diagnosed by using the Schirmer test, tear break-up time, thyroid function, and clinical signs. CIC was combined with immunological staining of interleukin-1a (IL-1a), IL-1b, and IL- 6. The immunological impression cytology (IC) grade was compared to the clinical activity score of TO. All TO patients with dry eye were positive for IL-1a, IL-1b, and IL-6. However, the normal controls were also positive for IL-1a. A trend was observed between the clinical inflammatory score and immunological IC grade. This study was the first to delineate the immunological IC of TO-related dry eye. Our study aimed to investigate the pathogenesis of dry eye in TO. Our findings suggest that the conjunctival cytokines IL-1a, IL-1b, and IL-6 may play a role. The results of this study will be useful for future studies of additional inflammatory cytokines, and the levels of these cytokines could be used as an outcome to assess the efficacy of treatment, such as anti-cytokine or immunosuppression therapy, in patients with TO-related dry eye or other ocular surface inflammatory disorders.

Superoxide Dismutase 1 Nanozyme for Treatment of Eye Inflammation.

Use of antioxidants to mitigate oxidative stress during ocular inflammatory diseases has shown therapeutic potential. This work examines a nanoscale therapeutic modality for the eye on the base of antioxidant enzyme, superoxide dismutase 1 (SOD1), termed “nanozyme.” The nanozyme is produced by electrostatic coupling of the SOD1 with a cationic block copolymer, poly(L-lysine)-poly(ethyleneglycol), followed by covalent cross-linking of the complexes with 3,3′-dithiobis(sulfosuccinimidylpropionate) sodium salt. The ability of SOD1 nanozyme as well as the native SOD1 to reduce inflammatory processes in the eye was examined in vivo in rabbits with immunogenic uveitis. Results suggested that topical instillations of both enzyme forms demonstrated anti-inflammatory activity; however, the nanozyme was much more effective compared to the free enzyme in decreasing uveitis manifestations. In particular, we noted statistically significant differences in such inflammatory signs in the eye as the intensities of corneal and iris edema, hyperemia of conjunctiva, lens opacity, fibrin clots, and the protein content in aqueous humor. Clinical findings were confirmed by histological data. Thus, SOD1-containing nanozyme is potentially useful therapeutic agent for the treatment of ocular inflammatory disorders.

Evaluation of the Ocular Tolerance of Three Tacrolimus Topical Pharmaceutical Preparations by Bovine Corneal Opacity and Permeability Test

ABSTRACT Purpose: Tacrolimus ocular preparations are commonly employed in autoimmune or inflammatory ocular disorders. However, currently there are not yet approved ocular formulations. Tacrolimus ocular side effects have been reported in clinical use, so the evaluation of different pharmaceutical preparations is mandatory. In this study, the local corneal tolerance and safety profile of three common tacrolimus 0.03% pharmaceutical preparations were evaluated. Material and methods: Corneal irritation and permeability of tacrolimus preparations were evaluated with the bovine corneal opacity and permeability (BCOP) test. Complementary corneal hematoxylin/eosin and immunohistochemistry staining for tight junctions and adherent junctions E-cadherin, VE-cadherin and zonula occludens-1 were examined and scored to evaluate and to confirm corneal disruption and irritation scores obtained with the BCOP method. Results: Commercial brand ointment (Protopic®), topical compounded eye ointment (pharmacy elaboration) and tacrolimus suspension eye drops (elaborated from parenteral prograf®) were tested as potential ocular preparations to be used in clinics. Tacrolimus preparations hereby studied do not alter the opacity and permeability of the bovine cornea by more than three units, measured by the In Vitro Irritancy Score, neither affected the immunohistochemical parameters, composite score or transepithelial electrical resistance. Conclusions: Tacrolimus preparations studied can be safely applied as a topical ocular treatment.

Development of a dexamethasone intravitreal implant for the treatment of noninfectious posterior segment uveitis.

Uveitis is a group of ocular inflammatory disorders that can lead to severe vision loss. Despite advances in anti-inflammatory therapy, many patients are resistant to or intolerant of existing treatments. A biodegradable, sustained-release implant, dexamethasone intravitreal implant 0.7 mg (Ozurdex), has been developed to deliver dexamethasone to target tissues in the posterior segment of the eye, minimizing systemic drug exposure and limiting side effects. The implant releases dexamethasone over a period of up to 6 months as the poly(D,L-lactide-co-glycolide) polymer matrix of the implant is metabolized to carbon dioxide and water. The implant is placed in the vitreous of the eye with a single-use applicator in a sutureless, office-based procedure. Treatment with a single dexamethasone intravitreal implant in patients with noninfectious intermediate or posterior uveitis has been shown to produce significant improvements in intraocular inflammation and best-corrected visual acuity with treatment benefit sustained for 6 months. Dexamethasone intravitreal implant has also been shown to reduce central retinal thickness and improve best-corrected visual acuity in patients with macular edema of various etiologies. The implant has been approved for treatment of noninfectious uveitis involving the posterior segment, diabetic macular edema, and macular edema associated with branch and central retinal vein occlusion.

The Incidence of Uveitis in Ankylosing Spondylitis Patients Undergoing Tumor Necrosis Factor Inhibiting Therapy in Korea

Ankylosing spondylitis (AS), a chronic inflammatory rheumatic disease that primarily affects the sacroiliac joints and causes inflammatory back pain, is often accompanied by inflammatory extra-articular manifestations such as Crohn’s disease, psoriasis, and uveitis [1]. In a systematic literature review of extra-articular manifestations in patients with AS, acute anterior uveitis (26%) was more common than psoriasis (9%) or inflammatory bowel disease (7%) [2]. Other studies have estimated that 25% to 50% of patients experience at least one episode of uveitis during the course of AS. Characteristics of uveitis in patients with AS include predominantly acute, unilateral onset; anterior location; strong association with human leukocyte antigen (HLA)-B27 positivity; and tendency to recur, often in the opposite eye. In addition, the incidence of uveitis increases with longer disease duration, ranging from 17% for patients with disease duration ＜10 years to 39% for patients with disease duration ＞20 years [2]. Uveitis is a painful, often recurrent, and potentially serious inflammation of the eye. It is the most preventable cause of blindness worldwide and also has a negative effect on health-related quality of life. AS patients with extraarticular manifestations utilize more medical resources and incur more health care costs compared with AS patients who do not develop extra-articular manifestations. Complications of inadequately treated uveitis include cataract formation, glaucoma, and maculopathy, all of which can lead to visual acuity loss and ultimately blindness. In patients with spondyloarthropathies, uveitis was associated with reduced visual acuity in 8% of patients; and approximately 50% of patients had at least one recurrent flare [3]. Tumor necrosis factor (TNF) is involved in the pathogenesis of both uveitis and AS. TNF is elevated in the aqueous humor and serum of patients affected by uveitis and the joints of patients with AS. Anti-TNF therapy has been shown to reduce ocular inflammation and preserve vision in patients with sight-threatening uveitis, and there is considerable interest in the use of biologic treatments for uveitis and other ocular inflammatory disorders. The anti-TNF agents adalimumab and infliximab have been shown to reduce uveitis flares in patients with AS [4,5], whereas evidence for the ability of etanercept to prevent uveitis flares is mixed [5,6]. Conversely, uveitis develops in some patients, whose articular symptoms are well controlled with anti-TNF therapy, suggesting that the ocular and articular inflammation develop via different pathways. The degree to which new-onset uveitis occurs in patients receiving anti-TNF therapy has been characterized in a retrospective cohort study, with the majority of cases occurring during therapy with etanercept; of 31 cases of uveitis identified, 19 were in AS, 4 were in psoriatic arthritis, 6 were in rheumatoid arthritis, and 2 were in juvenile idiopathic arthritis. Of the 19 cases associated with AS, that anti-TNF agent at the time of the first onset of uveitis was etanercept in 12 cases, infliximab in 4 cases, and adalimumab in 3 cases; the pattern of results was similar among 121 cases identified in a systematic literature review [6]. In South Korea, Kim et al. [7]. re

Technology allows detection of target molecules and production of biologic agents for treatment of ocular inflammatory disorders.

Although the precise pathogenic mechanisms of uveitis remain unknown, cytokines, chemokines and soluble adhesion molecules appear to play a major role in uveitis. They influence the communications between various cell types and alter vascular endothelial properties. Several recent studies have disclosed the beneficial role of aqueous humor samples for investigating involved molecular targets in various diseases leading to uveitis and potentially for specific treatments. Anterior chamber paracentesis for obtaining aqueous humor allows measurement of therapeutic targets and enables investigators to produce specific antagonists. Three classes of immunosuppressive drugs have been most frequently used for treatment of uveitis; these include antimetabolites, T‑cell inhibitors and alkylating agents all of which are slow acting and cause treatment efficacy in up to 76% of cases. [1,2] There are other drawbacks to these class of agents: In autoimmune disease, immunosuppressive therapies affecting one organ or site may not necessarily be effective on another organ/site, even when the inflammation is the manifestation of the same disease in the same individual. Furthermore, treatment with immunosuppressive agents may be complicated by serious side effects. A new development in uveitis treatment during the recent years is the development of biologic agents. Refractory cases of uveitis with or without retinal vasculitis may benefit from biologic agents of which, interferon‑alpha (INF‑α), interleukin (IL) 1 blocking agents, and tumor necrosis factor (TNF) blockers have been used successfully in some case reports. There is strong evidence that aqueous humor levels of many cytokines such as IL‑6, IL‑10, IL‑15, IL‑17, IL‑23, IL‑27, IL‑35, TNF‑α, transforming growth factor beta (TGF‑β), interferon‑γ and vascular endothelial growth factor (VEGF) in noninfectious autoimmune uveitis are elevated and the earlier mentioned and upcoming new biologic agents will be increasingly used