The Standardization of Uveitis Nomenclature (SUN) Project. Development of a clinical evidence base utilizing informatics tools and techniques.

BACKGROUND: Given the recent increased focus on evidence-based medicine, it is critical that diseases and syndromes have accurate and complete descriptions, including standardized and widely accepted terminologies. Standardizing these descriptions and terminologies is necessary to develop tools such as computerized data entry forms and classification criteria. This need is especially true for diseases that are relatively uncommon, such as uveitis. OBJECTIVES: To develop a standardized and internationally accepted terminology for the field of uveitis. METHODS: The Standardization of Uveitis Nomenclature (SUN) Working Group (WG) is an international group of 79 uveitis experts from 18 countries and 62 clinical centers. Initial terminology was developed utilizing a "modified" green field approach, which was enhanced through web-based surveys and teleconferences via a "modified" Delphi technique. Terms were mapped provisionally into ontologic dimensions for each syndrome. The Working Group then met and utilized nominal group techniques as a formalized method of finalizing the mappings. RESULTS: Mapping of terms into dimensions to describe 28 major uveitic diseases was confirmed using nominal group techniques (achieving super-majority consensus) for each of the diseases at a meeting of the entire WG. CONCLUSIONS: The SUN WG utilized an informatics-based approach to develop a standardized and internationally accepted terminology for the uveitides.

Scleritis and multiple systemic autoimmune manifestations in chronic natural killer cell lymphocytosis associated with elevated TCRalpha/beta+CD3+CD4-CD8- double-negative T cells.

BACKGROUND/AIMS: Chronic natural killer lymphocytosis (CNKL) has been associated with systemic autoimmunity; however, its association with scleritis or ocular autoimmunity has not been characterised. The natural killer (NK) cell function and immunophenotype of a patient with CNKL who developed bilateral scleritis and multiple systemic autoimmune findings were evaluated. METHODS: The ophthalmic records of a patient with CNKL and scleritis were reviewed over a 6-year period. Flow cytometry was performed to evaluate T cell, NK and B cell populations. NK cellular functions (ie, NK cytotoxicity and cytokine/chemokine production following interleukin 2 (IL2) stimulation) were evaluated. RESULTS: A 56-year-old woman with vitiligo, psoriatic arthritis, thyroiditis, erythema nodosum, bilateral anterior scleritis and Sjogren syndrome was managed with multiple immunosuppressive medications, including prednisone, mycophenolate mofetil and methotrexate. Flow cytometry showed a persistent elevation of CD56(+)CD3(-) NK cells greater than 40%, which was consistent with CNKL. NK cell cytotoxicity assay identified a deficiency of K562 cell lysis in the patient (1.46 mean-fold greater in control vs patient). NK cytokine/chemokine production following IL2 stimulation was also deficient (2.5-32.5-fold greater in control). Cytokines/chemokines assessed included pro-inflammatory (interferon gamma, tumor necrosis factor alpha, IL1, monocyte chemotactic protein 1) and immunoregulatory cytokines (IL4, IL5 and IL10). An abnormal elevation of TCRalpha/beta(+) CD3(+)CD4(-)CD8(-) T cells suggestive of autoimmune lymphoproliferative syndrome was observed; however, apoptosis dysfunction was not found. CONCLUSION: The association of increased but dysfunctional NK cells in the context of multiple systemic and ocular manifestations suggests a role of NK cells in the pathogenesis of our patient's disease. Further studies regarding NK cell dysfunction and ocular autoimmunity are needed.

Interferon-beta and adhesion molecules (E-selectin and s-intracellular adhesion molecule-1) are detected in sera from patients with retinal vasculitis and are induced in retinal vascular endothelial cells by Toll-like receptor 3 signalling.

Retinal vasculitis is a major component of ocular inflammation that plays a role in retinal tissue damage in patients with idiopathic uveitis and Behçet's disease. Here we show that type 1 interferons (IFN alpha/beta) were not detected in sera from normal individuals but were identified in up to 46% of the sera from retinal vasculitis patients. The predominant form of IFN observed was IFN-beta, which was detected in 39% of Behçet's disease patients and 47% of idiopathic uveitis patients. Seven patients whose sera contained IFN-beta were monitored prospectively. IFN-beta was shown to be present for 6-12 months in all seven of the sera samples tested. Furthermore, the adhesion molecule profile identified in this study was strikingly different when Behçet's and uveitis patient sera were compared to sera from normal controls. Sera from Behçet's disease patients contained significantly elevated levels of the soluble adhesion molecules, sE-selectin and s-intracellular adhesion molecule-1 (sICAM-1), whereas sera from patients with idiopathic uveitis contained significantly increased sE-selectin. In vitro studies evaluating the cell source of these cytokines revealed that polyriboinosinic polyribocytidylic acid (poly I:C) activated retinal vascular endothelial cells produce sE-selectin, sICAM-1 and IFN-beta. Production of these molecules was inhibited by pretreatment with anti-Toll-like receptor 3 (TLR-3) antibody. In conclusion, IFN-beta, sE-selectin and sICAM-1 are elevated in patients with retinal vasculitis and are induced in retinal vascular endothelial cells in vitro by activating the innate immune system through TLR-3. Further analysis of innate immune signalling may prove to be a novel target for future studies on pathogenic mechanisms and therapeutic approaches in retinal vasculitis.

Alpha tropomyosin as a self-antigen in patients with Behçet's disease.

We report for the first time a significant increased lymphoproliferative response to alpha tropomyosin as well as observing autoantibodies to tropomyosin observed in Behcet's disease (BD) patients with posterior uveitis. Peripheral blood mononuclear cells (PBMCs) from 18 BD patients with posterior uveitis, 18 patients with other forms of noninfectious uveitis, 9 patients with retinal damage due to photocoagulation as well as 18 healthy donors were evaluated for antigen-specific lymphoproliferative responses to alpha tropomyosin and its derivative peptides. The proliferative responses of PBMCs to these antigens were studied using (3)H thymidine incorporation assay. Serum samples were also screened by ELISA for autoantibodies against tropomyosin. Six of the 18 (33%) BD patients with posterior uveitis showed increased proliferative response to alpha tropomyosin or its derivative peptides, while none of the healthy, disease controls were positive. The mean lymphoproliferative responses to tropomyosin were significantly higher (P < 0.02) in the BD patients compared to healthy or disease controls. Higher titres of anti-tropomyosin antibodies were also seen in four of the 18 BD patients but none in the healthy or disease control groups (P < 0.002). The occurrence of these abnormalities supports a possible role for alpha tropomyosin as a self-antigen in a subset of patients with Behcet's disease.

Human S-antigen determinant recognition in uveitis.

PURPOSE: Soluble antigen (S-Ag) is a member of the arrestin family of protein with which it shares a high level of homology. It is an immunologically privileged retinal antigen that can elicit experimental autoimmune uveitis (EAU) and is thought to be a target for ocular inflammatory diseases. This study was conducted to identify in humans, the immunogenic determinants of human S-Ag and to establish whether a specific response profile occurs in particular ocular inflammatory conditions. METHODS: Peripheral blood lymphocyte responses were measured against a panel of 40 overlapping synthetic peptides of human S-Ag in patients with chronic uveitis and compared with control subjects. Patients with Behçet disease, sarcoidosis, Vogt-Koyanagi-Harada, and sympathetic ophthalmia were tested. RESULTS: A limited number of immunodominant determinants were identified for Behçet disease and sarcoidosis. These were all located at sites of limited homology with other known arrestins. In addition, several individual patients had prominent proliferative responses to multiple determinants well above that of control subjects. This determinant spread was observed in all disease entities except sympathetic ophthalmia, which did not show any immunoreactivity to S-Ag. Significant response shifts were also noted over time in two patients. CONCLUSIONS: The results indicate that there are specific immunodominant determinants to human S-Ag in patients with certain forms of uveitis. However, in individual patients, response is not limited to these determinants. In the chronic stage of disease, response is spread over many determinants.

Aqueous humor and plasma vascular endothelial growth factor in uveitis-associated cystoid macular edema.

PURPOSE: To determine the association between cystoid macular edema and vascular endothelial growth factor concentration in the aqueous humor and plasma of uveitis patients. METHODS: Cross-sectional study. Vascular endothelial growth factor concentrations were measured by enzyme-linked immunosorbent assay in the aqueous humor of 20 uveitis patients (9 with and 11 without cystoid macular edema), and in the plasma of 40 uveitis patients (20 with and 20 without cystoid macular edema) and 20 healthy volunteers. RESULTS: Mean aqueous humor vascular endothelial growth factor concentrations for uveitis patients with and without cystoid macular edema were 152.3 and 109.5 pg/ml, respectively, P =.044. Mean plasma vascular endothelial growth factor concentrations in uveitis patients with and without cystoid macular edema and in healthy volunteers were 32.2, 29.6, and 55.0 pg/ml, respectively. Uveitis patients had lower plasma vascular endothelial growth factor levels than did healthy volunteers, P =.0002. CONCLUSION: In uveitis patients, vascular endothelial growth factor concentration is increased in the aqueous humor of eyes with cystoid macular edema. It may be useful to investigate vascular endothelial growth factor antagonists as a treatment for uveitis-associated cystoid macular edema.

Pharmacokinetics and toxicity of intravitreal chemotherapy for primary intraocular lymphoma.

OBJECTIVE: To investigate the pharmacokinetics and toxicity of intravitreal chemotherapeutic agents in the rabbit eye for the potential treatment of primary intraocular lymphoma and other intraocular malignancies. METHODS: The ocular pharmacokinetics of intravitreal methotrexate sodium (400 microg) was studied in 10 New Zealand white rabbits, and a single-compartment, first-order elimination model was used to calculate the drug half-life. With the use of these data, a treatment schedule using serial injections of intravitreal methotrexate and single injections of fluorouracil and dexamethasone sodium phosphate was developed. This schedule was studied in 4 New Zealand white rabbits to explore the combined toxicity of these agents. RESULTS: Methotrexate vitreous levels, following a 400-microg intravitreal injection, remained therapeutic (>0.5 microM) in the rabbit eye for 48 to 72 hours. Intravitreal methotrexate, combined with fluorouracil and dexamethasone, showed no evidence of drug toxicity as determined by electroretinography and histopathologic examination. CONCLUSIONS: A treatment schedule for primary intraocular lymphoma consisting of methotrexate intravitreal injections every 48 to 72 hours provides therapeutic drug concentrations in the vitreous and, in combination with fluorouracil and dexamethasone, appears to be safe in the rabbit eye. CLINICAL RELEVANCE: Although responsive to conventional chemotherapy or radiotherapy, recurrence of ocular involvement with primary central nervous system lymphoma occurs in more than 50% of treated cases. Anecdotal reports of the use of intravitreal chemotherapy for primary intraocular lymphoma have been encouraging. However, animal data on the pharmacokinetics and toxicity of combined intravitreal agents for the treatment of this disease are lacking.

Immune response to retinal antigens in patients with gyrate atrophy and other hereditary retinal dystrophies.

PURPOSE: Gyrate atrophy (GA) is a rare hereditary disease that causes retinal destruction. Retinal damage in GA and other heredodegenerative diseases such as retinitis pigmentosa (RP) releases sequestered antigens and may trigger immune response to these molecules. Here, we studied the immune response to retinal antigens in patients with GA and RP and compared it with that of patients with inactive posterior uveitis and normal volunteers. PATIENTS AND METHODS: Peripheral blood was collected from 24 patients with RP, 10 patients with GA, 10 patients with inactive posterior uveitis, and 16 normal volunteers. Cell-mediated immune responses to human S-antigen (HS-Ag), bovine S-antigen (BS-Ag), and interphotoreceptor retinoid-binding protein (IRBP) were investigated by lymphocyte proliferation assay. In addition, serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were studied by ELISA. Immunologic data were correlated with clinical and electrophysiological findings. RESULTS: Patients with GA or RP responded to HS-Ag and BS-Ag more vigorously than patients with uveitis or healthy controls, as shown by higher mean stimulation indices and larger proportions of responders. Unlike S-Ag, IRBP stimulated low lymphocyte responses in only a small proportion of RP patients. The mean sVCAM-1 levels were significantly higher in the sera from patients with GA than in that from normal controls. CONCLUSION: An elevated cellular immune response to S-Ag is common in patients with GA and RP. This elevated cellular immune response to S-Ag may exacerbate retinal destruction in patients with GA and RP.

Assessment of visual function in patients with gyrate atrophy who are considered candidates for gene replacement.

OBJECTIVE: To assess the course of change of visual function outcome variables in 5 patients with gyrate atrophy before a gene replacement therapy clinical trial. METHODS: The outcome variables selected were visual field sensitivity and electroretinogram amplitude. The course of change of these outcome variables was determined by calculation of their half-lives. RESULTS: In the 4 to 6 years during which each patient was followed up for this study, median visual field half-lives were 17.0 years (static perimetry) and 11.4 years (kinetic perimetry). Median electroretinogram half-lives were 16.0 years (maximal response) and 10.7 years (flicker response). CONCLUSIONS: The course of the decline of visual function outcome variables is frequently slow. Thus, a long-term clinical trial would be required to assess the efficacy of the intervention in the preservation of visual function.

Ocular manifestations of central nervous system lymphoma.

Primary intraocular lymphoma (PIOL) is a variant of primary central nervous system lymphoma in which lymphoma cells are initially present only in the eyes without evidence of disease in the brain or cerebrospinal fluid. Patients with PIOL are typically older adults who present with blurred vision and floaters. The ophthalmic examination characteristically shows a cellular infiltrate in the vitreous with or without the presence of subretinal infiltrates. Diagnostic evaluation for PIOL includes neuroimaging, cytologic examination of the cerebrospinal fluid, and a diagnostic vitrectomy with special handling of the vitreous specimen, if the former is nondiagnostic. Molecular and cytokine analyses are useful adjuncts to cytology for the diagnosis of PIOL. Recent molecular studies demonstrating viral DNA in the ocular lymphoma cells suggest a role for infectious agents in the pathogenesis of PIOL. To date, the best mode for treatment of PIOL or recurrent primary central nervous system lymphoma involving only the eyes remains undefined.

A follow-up study of Toxoplasma gondii infection in southern Brazil.

PURPOSE: To understand better the natural history of ocular toxoplasmosis by reexamining a well-characterized population in Southern Brazil. METHODS: Ophthalmological examination and serologic tests for Toxoplasma gondii infection were performed in 1997 on 383 individuals who had undergone the same evaluation in 1990. RESULTS: Of 109 seronegative subjects in 1990, 21 (19.3%) became seropositive by 1997, and 2 (1.5% of previously seronegative patients; 9.5% of those known to have seroconverted) developed ocular toxoplasmosis. Seroconversion occurred more frequently in individuals under 17 years of age (16 of 46 patients, 34.8%) than in those greater than 17 years of age (5 of 63 patients, 7.9%; p = 0.002). Of 131 seropositive individuals who did not have ocular lesions in 1990, 11 (8.3%) had typical toxoplasmic lesions in 1997. Of the 13 individuals with non-specific hyperpigmented small retinal lesions in 1990, 3 (23%) presented with typical lesions in 1997. CONCLUSIONS: Acquired T. gondii infection can result in late development of ocular lesions. Small, non-specific hyperpigmented retinal lesions may represent sites of T. gondii infection in seropositive individuals.

Frosted branch angiitis in a child with HIV infection.

PURPOSE: In adults with human immunodeficiency virus (HIV) infection, frosted branch angiitis is commonly associated with cytomegalovirus retinitis and responds to anti-cytomegalovirus therapy. We describe the first pediatric case of HIV-associated frosted branch angiitis. METHODS: Case report. RESULTS: A 7-year-old HIV-infected male with frosted branch angiitis was refractory to induction doses of intravenous ganciclovir and foscarnet over a 2-month period. Although cytomegalovirus antigenemia resolved, the angiitis only improved after subsequent treatment with systemic corticosteroids. CONCLUSION: Frosted branch angiitis in this patient was not attributed to cytomegalovirus. The pathogenesis of HIV-associated frosted branch angiitis may differ between children and adults.

Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

PURPOSE: To provide recommendations for the use of immunosuppressive drugs in the treatment of patients with ocular inflammatory disorders. PARTICIPANTS: A 12-person panel of physicians with expertise in ophthalmologic, pediatric, and rheumatologic disease, in research, and in the use of immunosuppressive drugs in patient care. EVIDENCE: Published clinical study results. Recommendations were rated according to the quality and strength of available evidence. PROCESS: The panel was convened in September of 1999 and met regularly through May 2000. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although corticosteroids represent one of the mainstays in the management of patients with ocular inflammation, in many patients, the severity of the disease, the presence of corticosteroid side effects, or the requirement for doses of systemic corticosteroids highly likely to result in corticosteroid complications supports the rationale for immunosuppressive drugs (for example, antimetabolites, T-cell inhibitors, and alkylating agents) being used in the management of these patients. Because of the potential for side effects, treatment must be individualized and regular monitoring performed. With careful use of immunosuppressive drugs for treatment of ocular inflammatory disorders, many patients will benefit from them either with better control of the ocular inflammation or with a decrease in corticosteroid side effects.

Iris involvement in primary intraocular lymphoma: report of two cases and review of the literature.

Non-Hodgkin's lymphoma involves ocular tissues either as a primary tumor or as secondary metastasis from systemic disease. Diagnosis is based on the identification of malignant cells in the eye by biopsy. Although primary intraocular lymphoma cells have been identified in the optic nerve, ciliary body, and iris of a small number of patients by histopathology, these sites of infiltration have rarely been observed on clinical examination. We studied clinical and histopathological findings of two patients with iris infiltration by primary intraocular lymphoma and reviewed the findings of 163 cases reported in the literature.

Discrimination between patients with acquired toxoplasmosis and congenital toxoplasmosis on the basis of the immune response to parasite antigens.

Many persons infected with Toxoplasma gondii develop ocular lesions. Immunologic parameters in the response to T. gondii were evaluated in infected persons with and without ocular lesions and in noninfected controls. Subjects were divided into groups on the basis of presence of serum antibodies to T. gondii, presence of ocular lesions, and clinical history. Production of interleukin-2 and interferon-gamma by peripheral blood mononuclear cells from patients with probable congenital toxoplasmosis was decreased, compared with that in persons with presumed acquired infection. Cell proliferation and delayed-type skin reaction induced by soluble toxoplasma tachyzoite antigen followed the same pattern. Asymptomatic persons showed high levels of interleukin-12 and interferon-gamma, whereas persons with ocular lesions had high interleukin-1 and tumor necrosis factor-alpha responses toward soluble toxoplasma tachyzoite antigen. These data suggest that patients with ocular disease due to congenital infection show tolerance toward the parasite. Furthermore, susceptibility to ocular lesions after acquired toxoplasmosis is associated with high levels of interleukin-1 and tumor necrosis factor-alpha, whereas resistance is associated with high levels of interleukin-12 and interferon-gamma.