H. Nida Sen

Epidemiology and Course of Disease in Childhood Uveitis

PURPOSE To describe the disease characteristics and visual outcome of pediatric uveitis. DESIGN Retrospective, longitudinal observation. PARTICIPANTS Five hundred twenty-seven pediatric uveitis patients from the National Eye Institute, University of Illinois, Chicago, and Oregon Health Sciences University. METHODS Retrospective chart review. MAIN OUTCOME MEASURES Demographics, uveitis disease characteristics, complications, treatments, and visual outcomes were determined at baseline and at 1-, 3-, 5-, and 10-year time points. RESULTS The patient population was 54% female; 62.4% white, 12.5% black, 2.7% Asian, 2.1% multiracial, and 14.61% Hispanic. Median age at diagnosis was 9.4 years. The leading diagnoses were idiopathic uveitis (28.8%), juvenile idiopathic arthritis-associated uveitis (20.9%), and pars planitis (17.1%). Insidious onset (58%) and persistent duration (75.3%) were most common. Anterior uveitis was predominant (44.6%). Complications were frequent, and cystoid macular edema (odds ratio [OR] 2.94; P = 0.006) and hypotony (OR, 4.54; P = 0.026) had the most significant visual impact. Ocular surgery was performed in 18.9% of patients. The prevalence of legal blindness was 9.23% at baseline, 6.52% at 1 year, 3.17% at 3 years, 15.15% at 5 years, and 7.69% at 10 years. Posterior uveitis and panuveitis had more severe vision loss. Hispanic ethnicity was associated with a higher prevalence of infectious uveitis and vision loss at baseline. CONCLUSIONS The rate and spectrum of vision threatening complications of pediatric uveitis are significant. Prospective studies using standard outcome measures and including diverse populations are needed to identify children most at risk.

Cytotoxic T Lymphocyte-Associated Antigen 4 Blockade in Patients with Metastatic Melanoma A New Cause of Uveitis

Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4) is an important costimultory receptor expressed on activated T cells. CTLA-4 blockade using a monoclonal antibody (mAb) in conjunction with tumor vaccines has improved tumor responses in animal models and enhanced numerous models of T cell-associated autoimmune diseases. Two patients with stage IV metastatic melanoma vaccinated with the gp 100 melanocyte/melanoma differentiation antigen either before or during anti-CTLA-4 mAb therapy developed uveitis. This is the first report of autoimmune disease involving the eye in patients treated with anti-CTLA-4 mAb. This suggests that CTLA-4 is an important regulatory molecule for maintenance of tolerance to melanosomal antigens and prevention of uveitis.

Complement component C5a Promotes Expression of IL-22 and IL-17 from Human T cells and its Implication in Age-related Macular Degeneration

BackgroundAge related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly populations worldwide. Inflammation, among many factors, has been suggested to play an important role in AMD pathogenesis. Recent studies have demonstrated a strong genetic association between AMD and complement factor H (CFH), the down-regulatory factor of complement activation. Elevated levels of complement activating molecules including complement component 5a (C5a) have been found in the serum of AMD patients. Our aim is to study whether C5a can impact human T cells and its implication in AMD.MethodsHuman peripheral blood mononuclear cells (PBMCs) were isolated from the blood of exudative form of AMD patients using a Ficoll gradient centrifugation protocol. Intracellular staining and enzyme-linked immunosorbent assays were used to measure protein expression. Apoptotic cells were detected by staining of cells with the annexin-V and TUNEL technology and analyzed by a FACS Caliber flow cytometer. SNP genotyping was analyzed by TaqMan genotyping assay using the Real-time PCR system 7500.ResultsWe show that C5a promotes interleukin (IL)-22 and IL-17 expression by human CD4+ T cells. This effect is dependent on B7, IL-1β and IL-6 expression from monocytes. We have also found that C5a could protect human CD4+ cells from undergoing apoptosis. Importantly, consistent with a role of C5a in promoting IL-22 and IL-17 expression, significant elevation in IL-22 and IL-17 levels was found in AMD patients as compared to non-AMD controls.ConclusionsOur results support the notion that C5a may be one of the factors contributing to the elevated serum IL-22 and IL-17 levels in AMD patients. The possible involvement of IL-22 and IL-17 in the inflammation that contributes to AMD may herald a new approach to treat AMD.

Hypomethylation of the IL17RC promoter associates with age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. Although recent studies have demonstrated strong genetic associations between AMD and SNPs in a number of genes, other modes of regulation are also likely to play a role in the etiology of this disease. We identified a significantly decreased level of methylation on the IL17RC promoter in AMD patients. Furthermore, we showed that hypomethylation of the IL17RC promoter in AMD patients led to an elevated expression of its protein and messenger RNA in peripheral blood as well as in the affected retina and choroid, suggesting that the DNA methylation pattern and expression of IL17RC may potentially serve as a biomarker for the diagnosis of AMD and likely plays a role in disease pathogenesis.

Emerging Drugs for Uveitis

Introduction: Uveitis is a challenging disease covering both infectious and noninfectious conditions. The current treatment strategies are hampered by the paucity of randomized controlled trials and trials comparing the efficacy of different agents. Areas covered: This review describes the current and future treatments of uveitis. A literature search was performed in PUBMED from 1965 to 2010 on drugs treating ocular inflammation with emphasis placed on more recent, larger studies. Readers should gain a basic understanding of current treatment strategies beginning with corticosteroids and transitioning to steroid sparing agents. Steroid sparing agents include antimetabolites such as methotrexate, azathioprine and mycophenolate mofetil; calcineurin inhibitors which include cyclosporine, tacrolimus; alkylating agents which include cyclophosphamide and chlorambucil; and biologics which include the TNF-α inhibitors infliximab, adalimumab and etanercept and daclizumab, IFN-α2a and rituximab. Expert opinion: Newer agents are typically formulated from existing drugs or developed based on new advances in immunology. Future treatment will require a better understanding of the mechanisms involved in autoimmune diseases and better delivery systems in order to provide targeted treatment with minimal side effects.

High-dose Daclizumab for the Treatment of Juvenile Idiopathic Arthritis–Associated Active Anterior Uveitis

PURPOSE To provide preliminary data regarding the safety and efficacy of high-dose intravenous daclizumab (Zenapax; Roche Inc, Nutley, New Jersey, USA) therapy for the treatment of juvenile idiopathic arthritis (JIA)-associated active anterior uveitis. DESIGN Interventional case series; open-label prospective, phase II pilot study. METHODS Six patients were recruited into the study and received daclizumab therapy at doses of 8 mg/kg at baseline, 4 mg/kg at week 2, and 2 mg/kg every 4 weeks thereafter, for a total of 52 weeks. The study was done at the National Eye Institute between June 29, 2005 and July 9, 2008. The primary outcome was a two-step decrease in inflammation grade assessed at week 12. Primary safety outcome was assessed at weeks 2 and 4. The ocular inflammation was assessed according to the Standardization of Uveitis Nomenclature criteria. RESULTS Four of the 6 participants achieved two-step reduction in anterior chamber cells according to Standardization of Uveitis Nomenclature Working Group grading scheme for anterior chamber cells 12 weeks into the study and met the primary efficacy endpoint. One additional patient responded to reinduction whereas 1 patient failed reinduction and was considered an ocular treatment failure. Visual acuity improved from a mean of 68 Early Treatment Diabetic Retinopathy Study letters in the worse eye to a mean of 79.6 letters (2 Snellen lines). Three participants were terminated before 52 weeks: First, because of a rash possibly induced by daclizumab; Second, because of ocular treatment failure; and Last, because of uncontrolled systemic manifestations of JIA. CONCLUSION High-dose intravenous daclizumab can help reduce active inflammation in active JIA-associated anterior uveitis; however, patients need to be monitored for potential side effects. Larger randomized trials are needed to better assess treatment effect and safety.

Mycophenolate mofetil for the treatment of scleritis

PURPOSE To evaluate the usefulness of mycophenolate mofetil (MMF) (CellCept, Roche, Nutley, NJ), an antimetabolite immunosuppressant with a selective antiproliferative effect on T and B lymphocytes, for the treatment of scleritis. DESIGN Retrospective, noncomparative case series. PARTICIPANTS Eight patients with scleritis treated with MMF in a tertiary referral center. METHODS Review of the clinical records of patients evaluated at the National Eye Institute and prescribed MMF for the treatment of scleritis. MAIN OUTCOME MEASURES Control of scleral inflammation, the ability to taper prednisone or other immunosuppressive medications, and adverse events were recorded for each patient. Mycophenolate mofetil was determined to be an effective steroid-sparing agent if the daily prednisone dosage could be reduced by 50% or more and was determined to be an effective adjunctive immunosuppressive agent if the scleral inflammation was controlled in patients with active scleritis. RESULTS Four patients with diffuse anterior scleritis, two with necrotizing scleritis with inflammation, one with nodular anterior scleritis, and one with nodular anterior and posterior scleritis, were identified. Mycophenolate mofetil administration was initiated as a steroid-sparing agent in 4 patients with controlled scleritis and as an additional immunosuppressive agent in 4 patients with active scleritis receiving concomitant treatment with prednisone and cyclosporine or methotrexate. In 3 of the 4 patients started on MMF as a steroid-sparing agent, the scleritis remained controlled while the prednisone dosage was tapered by more than 50%. One of the patients started on MMF as a steroid-sparing agent had recurrent scleritis, and each of the patients with active scleritis continued to have persistent scleral inflammation requiring additional immunosuppressive therapy. Adverse effects recorded in 4 of the 8 patients included a rash, gastrointestinal symptoms, paresthesias, and laboratory evidence of hepatotoxicity and renal toxicity. CONCLUSIONS Although MMF maybe be useful as a steroid-sparing agent, it was not effective as an adjunctive immunosuppressive agent in patients with active scleritis in our small, tertiary referral series. The adverse effects encountered with the use of MMF in this study cannot be attributed conclusively to MMF and are more likely complications of the multiagent systemic immunosuppressive therapy required for the treatment of recalcitrant scleritis.

A RANDOMIZED PILOT STUDY OF SYSTEMIC IMMUNOSUPPRESSION IN THE TREATMENT OF AGE-RELATED MACULAR DEGENERATION WITH CHOROIDAL NEOVASCULARIZATION

Background: Age-related macular degeneration remains the leading cause of irreversible blindness in the United States and the developed world. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) medications have become standard of care for the treatment of the wet form of the disease. Recent reports have demonstrated an association with various immune factors. We aimed to investigate the effect of immunosuppressive therapy in the clinical course of the wet form of the disease. We compared anti-VEGF therapy plus one of three systemic immunosuppressive therapies versus anti-VEGF therapy alone for recurrent choroidal neovascularization associated with age-related macular degeneration. Methods: This was a pilot, Phase I/II, prospective, randomized, unmasked, single-center trial. Patients with subretinal exudation secondary to recurrent choroidal neovascularization associated with age-related macular degeneration were included in the study. Patients were randomized to 1 of 3 systemic arms immunosuppressive agents (daclizumab, rapamycin, or infliximab) for 6 months plus intraocular anti-VEGF therapy if indicated, compared with a group who received only anti-VEGF therapy if indicated. Results: The number of anti-VEGF injections per group, visual acuity, retinal thickness, and safety measures were assessed in all groups. Thirteen patients were randomized; comparing anti-VEGF injections before and during the study, a decrease in the number of injections from 0.73 injections per month to 0.42 for daclizumab and from 0.67 to 0.34 for sirolimus was seen, while no apparent decrease was seen for either infliximab or observation. Visual acuities were maintained in all groups. Conclusion: These preliminary data suggest that some immunosuppressive agents given systemically can alter the clinical course of the wet form of the disease and support the notion that more definitive clinical trials of immune mediation of age-related macular degeneration are indicated.

Periocular Corticosteroid Injections in Uveitis: Effects and Complications

PURPOSE To evaluate the benefits and complications of periocular depot corticosteroid injections in patients with ocular inflammatory disorders. DESIGN Multicenter, retrospective cohort study. PARTICIPANTS A total of 914 patients (1192 eyes) who had received ≥ 1 periocular corticosteroid injection at 5 tertiary uveitis clinics in the United States. METHODS Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained at every visit via medical record review by trained reviewers. MAIN OUTCOME MEASURES Control of inflammation, improvement of visual acuity (VA) to ≥ 20/40, improvement of VA loss attributed to macular edema (ME), incident cataract affecting VA, cataract surgery, ocular hypertension, and glaucoma surgery. RESULTS Among 914 patients (1192 eyes) who received ≥ 1 periocular injection during follow-up, 286 (31.3%) were classified as having anterior uveitis, 303 (33.3%) as intermediate uveitis, and 324 (35.4%) as posterior or panuveitis. Cumulatively by ≤ 6 months, 72.7% (95% CI, 69.1-76.3) of the eyes achieved complete control of inflammation and 49.7% (95% CI, 45.5-54.1) showed an improvement in VA from <20/40 to ≥ 20/40. Among the subset with VA <20/40 attributed to ME, 33.1% (95% CI, 25.2-42.7) improved to ≥ 20/40. By 12 months, the cumulative incidence of ≥ 1 visits with an intraocular pressure of ≥ 24 mmHg and ≥ 30 mmHg was 34.0% (95% CI, 24.8-45.4) and 15.0% (95% CI, 11.8-19.1) respectively; glaucoma surgery was performed in 2.4% of eyes (95% CI, 1.4-3.9). Within 12 months, among phakic eyes initially ≥ 20/40, the incidence of a reduction in VA to <20/40 attributed to cataract was 20.2% (95% CI, 15.9-25.6); cataract surgery was performed within 12 months in 13.8% of the initially phakic eyes (95% CI, 11.1-17.2). CONCLUSIONS Periocular injections were effective in treating active intraocular inflammation and in improving reduced VA attributed to ME in a majority of patients. The response pattern was similar across anatomic locations of uveitis. Overall, VA improved in one half of the patients at some point within 6 months. However, cataract and ocular hypertension occurred in a substantial minority.

Primary intraocular lymphoma: diagnosis and differential diagnosis.

Diagnosis of PIOL can be challenging. It requires a high degree of clinical suspicion and differential diagnosis includes infectious and non-infectious etiologies particularly the common masquaraders sarcoidosis, tuberculosis, viral retinitis and syphilis. The definitive diagnosis depends on demonstration of malignant lymphoma cells in ocular specimens or CSF. Ocular specimen could include vitreous, aqueous or chorioretinal biopsy. Ocular pathologist should be consulted prior to the diagnostic procedure to help handle and process the specimen appropriately. In addition to cytology, flow cytometry, immunohistochemistry, molecular analysis and cytokines may be used as adjuncts in facilitating the diagnosis.