Ocular Inflammatory Disorders Research Articles

Suppressive Effects of Azithromycin on Zymosan-Induced Production of Proinflammatory Mediators by Human Corneal Epithelial Cells

In addition to its antibiotic effects, azithromycin has been noted to have anti-inflammatory activity, particularly in the context of microbial infections. This study was conducted to explore the suppressive effects of azithromycin on the production of proinflammatory mediators by human corneal epithelial cells (HCECs) stimulated by a fungal component, zymosan. Primary HCECs were cultured from donor corneal limbal explants and grown to subconfluence. The cells were treated with toll-like receptor (TLR) 2 agonist zymosan (1-50 μg/mL) for 4 to 48 hours, with or without preincubation with azithromycin (1-50 μg/mL), TLR2 antibody, or NF-κB activation inhibitor quinazoline (NF-κB-I). The cells were subjected to total RNA extraction, reverse transcription (RT), and real-time PCR using gene expression assays. Cells treated for 48 hours were used for immunofluorescence staining and Western blot analysis, and their medium supernatants were collected for protein quantitation by immunobead assays. The mRNA expression and protein production of proinflammatory cytokines (TNF-α and IL-1β), chemokines (IL-8 and RANTES), and matrix metalloproteinases (MMP-1, -3, and -9) by HCECs were stimulated by zymosan in a concentration-dependent manner, with peak levels noted at 4 hours. These stimulated levels of proinflammatory mediators by zymosan were significantly inhibited by TLR2 antibody, NF-κB-I, or azithromycin, which blocked zymosan-induced NF-κB activation as determined by p65 protein nuclear translocation. These findings demonstrated that the fungal component zymosan induces proinflammatory responses through TLR2 and NF-κB signaling pathways, whereas azithromycin suppresses its stimulation by blocking NF-κB activation in HCECs, suggesting the potential efficacy of this antibiotic for treating ocular surface inflammatory disorders.

Adalimumab (HumiraTM) in ophthalmology: A review of the literature

Tumor Necrosis Factor alpha (TNF-α) is a pleiotropic cytokine which plays a primary role in the induction of inflammation in autoimmune diseases. The newest anti-TNF-α agent is adalimumab (Humira, Abbott Pharmaceutical Inc.), a human-derived antibody. This review summarizes the characteristics of adalimumab, highlighting its clinical use in systemic and ocular inflammatory disorders, and the possible therapeutic strategies. Adalimumab has been successfully used for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriasis arthritis. More recently, adalimumab has shown promising qualities in controlling intraocular inflammations, even though this has been used prevalently as a rescue therapy for unresponsive cases. This biologic agent was also used in pediatric cases, showing a good safety and efficacy profile. Albeit no direct comparison with other biologics has been done, and adalimumab seems to be equivalent to the other anti-TNF-α, the switching to adalimumab can offer a better uveitic control. Adalimumab is a promising drug for the treatment of uveitis, even though further studies are needed on its application as a primary therapy in uveitis.

General Principles for the Treatment of Non-Infectious Uveitis

Ocular inflammatory disorders constitute a sight-threatening group of diseases that might be managed according to their severity. Their treatment guidelines experience constant changes with new agents that improve the results obtained with former drugs. Nowadays we can make use of a five step protocol in which topical, periocular and systemic corticosteroids remain as the main therapy for non infectious uveitis. In addition, immunosuppresive drugs can be added in order to enhance the anti-inflammatory effects and to develop the role of corticosteroid-saving agents. These can be organized in four other steps: Cyclosporine and Methotrexate in a second one; Azathioprine, Mycophenolate Mofetil and Tacrolimus in a third step; biological anti-TNF drugs in fourth position; and a theoretical last one with Cyclophosphamide and Chlorambucil. In the present review we go through the main characteristics and complications of all these treatments and make a rational of this five-step treatment protocol for non infectious posterior uveitis.

Innate Immunity of the Ocular Surface and Ocular Surface Inflammatory Disorders

Ocular surface epithelial cells selectively respond to microbial components and induce limited inflammation, whereas immune competent cells such as macrophages can recognize various microbial components through Toll-like receptors (TLRs), induce inflammation, and, thereby, exclude microbes. The difference between macrophages and ocular surface epithelial cells could be due to their dissimilarity in coexistence with commensal bacteria. The unique innate immune response of the ocular surface epithelium might contribute to its coexistence with commensal bacteria. Moreover, we suspect that some ocular surface inflammatory disorders might be caused by abnormality of the mucosal innate immunity. We considered the possibility that there is an association between Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)--a severe variant of SJS--and a disordered innate immune response. In gene expression analysis of CD14 cells, we found that interleukin-4 receptor (IL-4R) gene expression was different between patients with SJS/TEN and normal control subjects upon lipopolysaccharide (LPS) stimulation: it was downregulated in the former and slightly upregulated in the latter. Furthermore, expression of mRNA specific for IkappaBzeta and interleukin (IL)-1alpha was lower in patients with SJS/TEN than in normal controls after 1-hour culture. We next performed single nucleotide polymorphism (SNP) association analysis of IL-4R, IkappaBzeta, and IL1alpha genes and TLR2 and TLR3--genes associated with innate immunity--in 80 Japanese patients with SJS/TEN and 160 Japanese healthy volunteers. IL4R SNP Gln551Arg (rs.1801275) (P = 0.0004), TLR3 rs.3775296T/G SNP (P = 0.0001) and TLR3 rs.3775290A/G SNP (P = 0.009) showed a significant association with SJS/TEN. IkappaBzeta SNP rs.595788G/A showed a weak inverse association (P = 0.04). Genetic and environmental factors may play a role in an integrated etiology of SJS/TEN, and there is possibly an association between SJS/TEN and a disordered innate immunity.

Malignancies after Tacrolimus therapy in the management of ocular inflammatory disease

Abstract Purpose The appearance of “de novo” tumors in adults receiving immunosuppressive treatment with tacrolimus in ocular inflammatory disorders has not been elucidated. Methods All 180 patients who received Tacrolimus as a steroid sparing agent for the management of high risk PKP, uveitis, scleritis or corneal stem cell allograft were studied. Tacrolimus treatment schedule, monitoring and duration of treatment was noted. Results During the last 8 years a total of 11 patients who had received Tacrolimus for their immunosuppresion developed a malignancy. Three patients developed cancer of prostate, bladder (1), bronchogenic carcinoma – squammous cell carcinoma (SCC) (1), cancer skin ‐ (SCC) (1), breast cancer(2), recurrence of NHL (1) and recurrence of breast cancer (1) and large intestinal tumour (1). The primary diagnosis for the commencement of Tacrolimus included high‐risk PKP (8), Scleritis (1), Panuveitis (1) and Wegeners Granulomatosis (1). The rate of increase of bladder cancer was 149.26 followed by NHL 82.33 and recurrent breast carcinoma 30.7. The rest of tumours had a rate of increase in the range of 10 ‐ 20 fold. The average dose of Tacrolimus was 1954.37 mg SD +/‐ 2197 mg. Female/male ratio was 2:1. The mean age of patients was 73 years SD +/‐ 10.4 years. The mean follow‐up time of tumour patients on treatment was 45 months with SD +/‐ 26 months and the mean duration of follow‐up after diagnosis was 23 SD +/‐ 19 months. None of the eleven patients had any additional predisposing factors or were on any other carcinogenic agents which could affect their mortality by the cancer identified. Conclusion Long term immunosuppressive management of patients requires regular oncologic screening.

Cytokines and chemokines in immune-based ocular surface inflammation

Altered levels of several cytokines and chemokines have been found in different types of inflammatory ocular surface diseases, such as allergy or dry-eye syndrome. It has also been demonstrated that epithelial cells play a key role in the persistence and even initiation of chronic mucosal inflammation. The recent development of ‘multiplex detection’ technologies has facilitated the identification of specific patterns of expression of these molecules in some ocular immune-based inflammatory disorders. Analysis of these molecules in tissues, cells (in vivo and in vitro) and tears has revealed that not only inflammatory cells but also epithelial and fibroblast resident cells are sources of these molecules. The purpose of this review is to summarize recent studies in this field.

The Short-Term Effect of Topical Cyclosporine A 0.05% in Various Ocular Surface Disorder

Purpose: To evaluate the efficacy of topical cyclosporine A 0.05% (Restasis) in the treatment of dry eye symptoms caused by various ocular surface inflammatory disorders. Methods: Thirty?three patients with ocular surface diseases, including 17 with Sj?gren syndrome, 8 with meibomian gland dysfunction (MGD), 4 with Thygeson’s keratitis, and 4 with atopic keratoconjunctivitis (AKC) were treated with Restasis twice a day for 3 months. During follow?up, the symptom severity assessment (burning, itching, foreign body sensation, blurring, photophobia, and pain), TBUT (tear break?up time), Schirmer score, frequencies of artificial tear use, onset of symptomatic relief, subjective satisfaction score, and side effects were evaluated. Results: In patients with Sj?gren syndrome, foreign body sensation, blurring, photophobia, and pain were reduced after treatment, and the mean Schirmer score, TBUT increased and frequencies of artificial tear use decreased significantly. In patients with MGD, photophobia was reduced after treatment, TBUT and artificial tear use improved after 2 months, and the Schirmer score increased at 3 months. In patient’s with Thygeson’s keratitis, foreign body sensation and photophobia reduced, and the Schirmer score was increased at 3 months. No significant changes in symptoms, Schirmer score, or TBUT were observed in patients with Of all subjects, 55% reported symptomatic relief between 3 and 5 weeks after treatment. The mean satisfaction score after treatment was the highest for patients with Sj?gren syndrome. Two subjects reported a temporary burning sensation, and one subject quit using Restasis because of bitter taste and a burning sensation. Conclusions: Treatment with Restasis appeared to be effective in treating dry eye symptoms in patients with Sj?gren syndrome. It was shown to be partially helpful in patients with MGD and Thygeson’s keratitis, while it showed no beneficial effect in patients with AKC.

Treatment of Ocular Inflammatory Disorders with Adalimumab: A Retrospective Case Series

Treatment of Ocular Inflammatory Disorders with Adalimumab: A Retrospective Case Series

Practical approach to diagnosis and treatment of ocular allergy: a 1-year systematic review

A 1-year systematic review in the field of ocular allergy was carried out to select new information which may be useful for a practical approach to allergic conjunctivitis. Out of the 56 articles listed by PubMed, 27 papers were included in the review following a consensus achieved among the authors who had independently reviewed all abstracts. Selected articles were classified according to their main focus: antihistamines, omalizumab, new treatments for vernal keratoconjunctivitis and inflammatory ocular disorders, and sublingual immunotherapy. The data reviewed are discussed with the aim of underlining unmet needs and making recommendations for future studies on diagnosis and treatment of ocular allergy which may better guide clinical practice in this important area of allergy and clinical immunology.

Pharmacology, clinical efficacy and safety of bromfenac ophthalmic solution

NSAIDs are widely used not only for systemic control of acute or chronic pain and inflammation, but also for ocular surface and anterior segment inflammation as a topical instillation. Bromfenac sodium is a NSAID approved for the treatment of postoperative inflammation and ocular inflammatory disorder (blepharitis, conjunctivitis and scleritis/episcleritis). Bromfenac ophthalmic solution has been demonstrated to be very effective for ocular inflammation with twice-daily instillation, resulting from preclinical and pharmacokinetic features. Bromfenac ophthalmic solution is well tolerated, and the incidence of serious adverse events is very low. These results demonstrate that bromfenac ophthalmic solution is clinically useful and a convenient ophthalmic NSAID.

Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis

Although bisphosphonates do inhibit bone resorption in postmenopausal women and lessen the risk of vertebral and hip fractures, as many as half of patients no longer adhere to prescribed oral treatment after 12 months. A single intravenous infusion of zoledronic acid reportedly decreases bone turnover and improves bone mineral density (BMD) for at least a year. In the HORIZON (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly) Pivotal Fracture Trial, an international, randomized, double-blind, placebo-controlled study, postmenopausal women ranging in age from 65 to 89 years were assigned to receive either a 15-minute IV infusion of 5 mg of zoledronic acid or placebo at yearly intervals up to 24 months. All women received a daily supplement of 1000-1500 mg of calcium and 400-1200 IU of vitamin D. Participants had a bone mineral density (BMD) T score of -2.5 or less at the femoral neck or a score of -1.5 or less with 1 or more vertebral fractures. The efficacy analysis included 7736 patients, and the safety analysis, 7714 patients. The 3-year incidence of vertebral fracture was 10.9% in the placebo group and 3.3% in women given zoledronic acid, a 70% reduction (relative risk, 0.30; 95% confidence interval [CI], 0.24-0.38). Similar effects were noted after 1 and 2 years. Hip fractures were reduced 41% in actively treated women (hazard ratio, 0.59; 95% CI, 0.42-0.83). Nonvertebral fractures, all clinical fractures, and clinical vertebral fractures all were significantly less frequent in women given zoledronic acid-by 25%, 33%, and 77%, respectively. Actively treated women lost significantly less height than placebo recipients (-4.2 mm vs. -7.0 mm). BMD rose significantly at all measurement sites in the active treatment group compared to placebo recipients. Biochemical markers of bone turnover-including serum C-telopeptide of type I collagen, bone-specific alkaline phosphatase, and N-terminal propeptide of type I collagen-all decreased significantly with active treatment. Postdose symptoms were more frequent in actively treated women, but there were no significant group differences in numbers of deaths. Renal function was not compromised by zoledronic acid therapy. Serious atrial fibrillation was more frequent in actively treated women than in placebo patients (1.3% vs. 0.5%), as was the prevalence of inflammatory ocular disorders, mainly conjunctivitis. One patient in each group had potential osteonecrosis of the jaw. In this large-scale trial, once-a-year infusion of zoledronic acid was associated with a sustained decrease in vertebral, hip, and other fractures in postmenopausal women with osteoporosis over a 3-year period. Treatment was generally well tolerated and had a favorable safety profile.

Vogt-Koyanagi-Harada syndrome and mesenteric ischemia: A case report

Vogt-Koyanagi-Harada (VKH) disease is a rare inflammatory ocular disorder that is characterized by bilateral granulomatous panuveitis, neuropathy, and aseptic meningitis, along with various extraocular manifestations. VKH disease has been reported to be associated with various immune disorders. In this report, a case of VKH disease is presented that is associated with mesenteric vascular disease and intestinal necrosis, with an emphasis on the fact that this is the first case documented in the literature of both diseases occurring simultaneously.

Immunosuppressive Agents and Nonsteroidal Anti-inflammatory Drugs for Ocular Immune and Inflammatory Disorders

We now have at our disposal several nonsteroidal immunosuppressive and anti-inflammatory agents that may be used in addition to or instead of corticosteroids to treat ocular diseases. This article discusses some of the nonsteroidal immunosuppressive and anti-inflammatory agents available to the ophthalmologist.

A Case of Vogt-Koyanagi-Harada Disease Associated with Malignant Lymphoma

Vogt-Koyanagi-Harada disease (VKH), an inflammatory ocular disorder characterized by bilateral granulomatous panuveitis and a variety of extraocular manifestations, has been reported to be associated with various immune disorders but has not been linked to malignant lymphoma (ML). We present here a case of VKH associated with a recurrence of ML. A 69-year-old man who initially had ML presented with a history of sudden bilateral visual acuity loss. Funduscopy showed papilloedema and serous retinal detachment in both eyes, and a diagnosis of VKH was reached soon thereafter. Chest X-ray and an abdominal computed tomography scan indicated the metastatic focus of the ML. A recurrence was suspected because the ML-associated soluble interleukin-2 receptor (sIL-2R) in the serum was highly elevated. Treatment successfully resolved both the ML and the VKH. The inflammatory activities of VKH and ML were found to correlate with the serum levels of sIL-2R. This case suggests an association between sIL-2R levels and disease activity in VKH and ML, and provides additional evidence that VKH can be induced by immune disorders caused by high sIL-2R levels in ML.

MMF and eye disease

Immunosuppressive treatment has shown to be effective in various ocular inflammatory disorders. Factors limiting their use are the individual response and the rate of side effects. This report summarizes our knowledge about the use of mycophenolate mofetil (MMF) in the treatment of ocular cicatricial pemphigoid (OCP), uveitis, atopic keratoconjunctivitis (AKC), prevention of graft rejection after penetrating keratoplasty (PK) and scleritis. Controlled studies have been performed for prevention of graft rejection after PK, showing MMF as effective in the prevention of graft rejection as cyclosporine A. In experimental uveitis, MMF has been demonstrated to be highly effective in prevention of retinal destruction. A number of studies have now shown that MMF also seems effective in uveitis. There are also studies with smaller patient groups which point out the effectiveness of MMF in OCP, AKC, and scleritis. In most of the studies, the spectrum of side effects was small, compared to other immunosuppressives.

Identification of tribbles homolog 2 as an autoantigen in autoimmune uveitis by phage display

Autoimmune uveitis is a group of ocular inflammatory disorders with unknown causes. As in other autoimmune diseases, identification of autoantigens from uveitis patients would markedly improve our understanding of the disease mechanism. Here, we report that a candidate autoantigen was identified by phage display in an unbiased fashion. A bacteriophage T7 display cDNA library was generated from human eye and characterized. Patient-specific phages were enriched by four rounds of phage display with purified patient IgG. Enriched phages demonstrated a 20-fold increase in binding specificity to the patient IgG compared with control IgG. Two clonal phages with particularly high relative binding specificities were isolated and characterized. The encoded genes, tribbles homolog 2 (TRB2) and an unknown protein, had 170- and 42-fold increases in their binding specificities to the patient IgG, respectively. The patient-specific immunoreactivities were further confirmed by Western blotting. Anti-TRB2 antibody activities were detected in several uveitis patients but not in control subjects, suggesting that TRB2 is a uveitis-associated candidate autoantigen. These results demonstrate that autoantigens can be identified by phage display using uveitis patient serum.

Complications of intravitreal injection of triamcinolone acetonide

Background: Intravitreal injection of triamcinolone acetonide appears to be a promising treatment for a variety of proliferative, edematous, neovascular and inflammatory ocular disorders. Reported complications include intraocular pressure (IOP) elevation, cataract formation, retinal detachment, vitreous hemorrhage and endophthalmitis.The purpose of this investigation was to report the complications of intravitreal triamcinolone injection that may be attributable to the injection procedure or to the corticosteroid suspension.Methods: A total of 212 eyes of 180 patients who underwent intravitreal triamcin-olone acetonide injection for various indications were enrolled. All patients received 8 mg/0.2 mL of triamcinolone. A total of 270 injections were performed by the same surgeon under topical anesthesia. The patients were followed for a mean of 9.2 months. Complications related to the injection procedure and to the corticosteroid were recorded.Results: The most common complication encountered during follow-up was transient elevation of the IOP above 21 mm Hg (44 eyes [20.8%]).The average IOP rose by 28.5%, 38.2%, 16.7% and 4.2% from baseline at 1,3,6 and 9 months respectively.The mean IOP values at 1,3 and 6 months were statistically significantly higher than the mean preinjection value (p < 0.001). Fourteen eyes (6.6%) had cataract progression and underwent cataract surgery with intraocular lens implantation. Endophthalmitis developed in one eye (0.5%); the patient underwent vitrectomy with silicone oil injection. Pseudoendophthalmitis occurred in one eye (0.5%), and pseudohypopyon was observed in two eyes (0.9%).Interpretation: Intravitreal triamcinolone injection was effective in a variety of ocular disorders. Patients should be monitored closely given the potential for complications of the injection procedure or the corti-costeroid suspension.

MMF and Eye Disease

Immunosuppressive treatment has shown to be effective in various ocular inflammatory disorders. Factors limiting their use are the individual response and the rate of side effects. This report summarizes our knowledge about the use of mycophenolate mofetil (MMF) in the treatment of ocular cicatricial pemphigoid (OCP), uveitis, atopic keratoconjunctivitis (AKC), prevention of graft rejection after penetrating keratoplasty (PK) and scleritis. Controlled studies have been performed for prevention of graft rejection after PK, showing MMF as effective in the prevention of graft rejection as cyclosporine A. In experimental uveitis, MMF has been demonstrated to be highly effective in prevention of retinal destruction. A number of studies have now shown that MMF also seems effective in uveitis. There are also studies with smaller patient groups which point out the effectiveness of MMF in OCP, AKC, and scleritis. In most of the studies, the spectrum of side effects was small, compared to other immunosuppressives.

Mycophenolate mofetil as an immunomodulatory agent in the treatment of chronic ocular inflammatory disorders

Purpose To evaluate the outcomes of patients with chronic ocular inflammatory disease treated with mycophenolate mofetil as an immunosuppressive and steroid-sparing agent. Design Retrospective noncomparative interventional case series. Participants All patients with ocular inflammatory disease treated with mycophenolate mofetil at a single institution between 1998 and 2001. Methods Charts of patients seen on the Ocular Immunology and Uveitis Service at the Massachusetts Eye and Ear Infirmary were reviewed. Patients with chronic ocular inflammatory disease were included in the study. Main outcome measures Control of inflammation, steroid-sparing effect, visual acuity, and adverse reactions were measured. Results A total of 54 patients were evaluated. Control of ocular inflammation with mycophenolate mofetil as monotherapy was achieved in 35 patients (65%) and in 67 eyes (62%), and a steroid-sparing effect was achieved in 29 (54%) patients. Visual acuity was maintained or improved in 51 patients (94%) and in 97 eyes (90%). Side effects requiring discontinuation of medication occurred in 10 patients (18%). There was neither long-term morbidity nor mortality due to mycophenolate mofetil. Conclusions Mycophenolate mofetil is effective in the treatment of patients with steroid-dependent or -resistant chronic ocular inflammatory disorders that fail to respond to conventional steroid treatment. It is a safe and effective steroid-sparing immunomodulatory agent and can be considered an important addition to our armamentarium in the care of patients with ocular inflammatory disease.

Treatment of ocular inflammatory disorders with daclizumab

Purpose To evaluate the efficacy and safety of daclizumab therapy for patients with various ophthalmologic inflammatory disorders (all having previously failed standard treatment methods). Design Retrospective, nonrandomized case series. Participants Fourteen patients. Methods Fourteen patients were treated with daclizumab after previously failing standard treatment methods. Main outcome measures Inflammation and visual acuity. Results Twelve of 27 (44%) eyes and 5 of 14 (36%) patients had improvement in visual acuity; 9 of 27 (33%) eyes and 5 of 14 (36%) patients had no change in visual acuity; and 6 of 27 (22%) eyes and 4 of 14 (27%) patients had continued visual loss. Based on degree of inflammation, 16 of 27 eyes (59%) had improvement, 3 of 27 (11%) eyes had no change, and 8 of 27 (30%) eyes worsened. Conclusions Daclizumab is safe and, at least in some patients, appears to be an effective medication in the treatment of ocular inflammatory disorders.