The uveitides are a collection of more than 30 diseases characterized by intraocular inflammation. Many cases of juvenile idiopathic arthritis-associated uveitis, many cases of intermediate uveitis, ...and most cases of posterior and panuveitides requiring treatment are treated with corticosteroids and immunosuppression. Disease-specific, time-updated modeling of clinical data for several uveitides suggests superior prevention of ocular complications and visual outcomes with immunosuppression. These studies also suggest that oral corticosteroids at doses low enough for safe long-term therapy (i.e., <7.5 mg/day) are ineffective, implying that immunosuppression should be part of the initial regimen. The Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study was a randomized comparative effectiveness trial comparing systemic therapy with oral corticosteroids and immunosuppression with regional corticosteroid treatment. It demonstrated that, when used properly, oral corticosteroids and immunosuppression can be given safely for up to 7 years with no evident increased risk of systemic side effects compared with regional corticosteroid therapy, except for greater antibiotic use for infections. The Systemic Treatment for Eye Diseases (SITE) Cohort Study suggested long-term safety for this approach, when the immunosuppressive agents were antimetabolites or calcineurin inhibitors. Thus, oral corticosteroids and immunosuppression may be a preferred initial therapy for many noninfectious, intermediate, posterior, and panuveitides. Nonalkylating-agent immunosuppression has a low rate of sustained, drug-free remissions, <10%/year. Nonalkylating-agent immunosuppression for >3 years with control of the inflammation for >2 years is associated with a decreased risk of relapse after discontinuing immunosuppression. Alkylating agents can induce sustained drug-free remissions but likely increase the lifetime risk of cancer. Biologics, which target specific cytokines and pathways, hold promise for the future. Monoclonal antibodies directed against tumor necrosis factor (TNF)-α have been studied most often, and one, adalimumab, is U.S. Food and Drug Administration approved for the treatment of noninfectious, intermediate, posterior, and panuveitides.
Purpose To update information on cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) and to integrate information on its pathogenesis and clinical outcomes. ...Design Literature review. Methods Selected articles from the medical literature, particularly large epidemiologic studies, including the Johns Hopkins Cytomegalovirus Retinitis Cohort Study, the Longitudinal Study of the Ocular Complications of AIDS, and the Cytomegalovirus Retinitis and Viral Resistance Study, were reviewed. Clinical information is discussed in light of knowledge on CMV, its pathogenesis, and its interactions with human immunodeficiency virus (HIV). Results Cytomegalovirus uses several mechanisms to evade the immune system and establish latent infection in immunologically normal hosts. With immune deficiency, such as late-stage AIDS, CMV reactivates, is disseminated to the eye, and establishes a productive infection, resulting in retinal necrosis. HIV and CMV potentiate each other: CMV accelerates HIV disease, and CMV retinitis is associated with increased mortality. Randomized clinical trials have demonstrated the efficacy of treatments for CMV retinitis. Systemically administered treatment for CMV retinitis decreases AIDS mortality. Highly active antiretroviral therapy (HAART) effectively suppresses HIV replication, resulting in immune recovery, which, if sufficient, controls retinitis without anti-CMV therapy. Resistant CMV, detected in the blood, correlates with resistant virus in the eye and is associated with worse clinical outcomes, including mortality. Host factors, including host genetics and access to care, play a role in the development of CMV retinitis. Conclusions Clinical outcomes of CMV retinitis in patients with AIDS are dependent on characteristics of the virus and host and on HIV-CMV interactions.
Purpose To describe an approach to diagnosing the uveitides, a collection of about 30 separate diseases characterized by intraocular inflammation. Design Perspective. Methods Integration of clinical ...approach with a more formal, informatics-derived approach to characterization and a Bayesian approach to laboratory testing. Results The patient's uveitis is characterized along several dimensions: course, laterality, anatomic location of the inflammation, morphology, presence of active infection, and the host (age, presence of a systemic disease). Posterior uveitis can be characterized further by whether it is primarily a retinitis, choroiditis, or retinal vasculitis; by whether it is paucifocal or multifocal; and by the morphology of the lesions. This characterization narrows the differential diagnosis to 1 or, at most, a few diseases. Laboratory screening (ie, testing all patients) should be reserved for those diseases that can present as any type of uveitis, whereas targeted testing (ie, testing a subset with specific features) is used selectively. Laboratory testing should be used to identify an infection (which will alter therapy) or a systemic disease that will affect the patient's health. A uveitis that is not one of the established diagnoses is designated as “undifferentiated” with the course, laterality, and anatomic location (eg, undifferentiated bilateral chronic anterior uveitis). We avoid the term “idiopathic” uveitis as most identified noninfectious uveitic diseases are idiopathic, and most systemic diseases associated with uveitis also are idiopathic (eg, juvenile idiopathic arthritis). Conclusion This approach should lead to the correct diagnosis of the specific uveitic disease in the large majority of cases without overuse of laboratory testing.
To provide recommendations for the use of anti-tumor necrosis factor α (TNF-α) biologic agents in patients with ocular inflammatory disorders.
Ocular inflammatory diseases remain a leading cause of ...vision loss worldwide. Anti-TNF-α agents are used widely in treatment of rheumatologic diseases. A committee of the American Uveitis Society performed a systematic review of literature to generate guidelines for use of these agents in ocular inflammatory conditions.
A systematic review of published studies was performed. Recommendations were generated using the Grading of Recommendations Assessment, Development, and Evaluation group criteria.
Numerous studies including controlled clinical trials have demonstrated that anti-TNF-α biologic agents (in particular infliximab and adalimumab) are effective in the treatment of severe ocular inflammatory disease. Based on these studies, the expert panel makes the following recommendations.
Infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçet's disease. Infliximab and adalimumab can be considered as second-line immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis. Infliximab and adalimumab can be considered as potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy, and scleritis in patients requiring immunomodulation in patients who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. Infliximab and adalimumab can be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success.
The uveitides are a heterogeneous group of diseases characterized by inflammation inside the eye. The uveitides are classified as infectious or non-infectious. The non-infectious uveitides, which are ...presumed to be immune mediated, can be further divided into those that are associated with a known systemic disease and those that are eye limited,-ie, not associated with a systemic disease. The ophthalmologist identifies the specific uveitic entity by medical history, clinical examination, and ocular imaging, as well as supplemental laboratory testing, if indicated. Treatment of the infectious uveitides is tailored to the particular infectious organism and may include regional and/or systemic medication. First line treatment for non-infectious uveitides is corticosteroids that can be administered topically, as regional injections or surgical implants, or systemically. Systemic immunosuppressive therapy is used in patients with severe disease who cannot tolerate corticosteroids, require chronic corticosteroids at >7.5 mg/day prednisone, or in whom the disease is known to respond better to immunosuppression. Management of many of these diseases is optimized by coordination between the ophthalmologist and rheumatologist or internist.
To compare the relative effectiveness of systemic corticosteroids plus immunosuppression when indicated (systemic therapy) versus fluocinolone acetonide implant (implant therapy) for noninfectious ...intermediate, posterior, or panuveitis (uveitis).
Randomized controlled parallel superiority trial.
Patients with active or recently active uveitis.
Participants were randomized (allocation ratio 1:1) to systemic or implant therapy at 23 centers (3 countries). Implant-assigned participants with bilateral uveitis were assigned to have each eye that warranted study treatment implanted. Treatment-outcome associations were analyzed by assigned treatment for all eyes with uveitis.
Masked examiners measured the primary outcome: change in best-corrected visual acuity from baseline. Secondary outcomes included patient-reported quality of life, ophthalmologist-graded uveitis activity, and local and systemic complications of uveitis or therapy. Reading Center graders and glaucoma specialists assessing ocular complications were masked. Participants, ophthalmologists, and coordinators were unmasked.
On evaluation of changes from baseline to 24 months among 255 patients randomized to implant and systemic therapy (479 eyes with uveitis), the implant and systemic therapy groups had an improvement in visual acuity of +6.0 and +3.2 letters (P = 0.16, 95% confidence interval on difference in improvement between groups, -1.2 to +6.7 letters, positive values favoring implant), an improvement in vision-related quality of life of +11.4 and +6.8 units (P = 0.043), a change in EuroQol-EQ5D health utility of +0.02 and -0.02 (P = 0.060), and residual active uveitis in 12% and 29% (P=0.001), respectively. Over the 24 month period, implant-assigned eyes had a higher risk of cataract surgery (80%, hazard ratio HR = 3.3, P < 0.0001), treatment for elevated intraocular pressure (61%, HR=4.2, P < 0.0001), and glaucoma (17%, HR=4.2, P = 0.0008). Patients assigned to systemic therapy had more prescription-requiring infections than patients assigned to implant therapy (0.60 vs 0.36/person-year, P=0.034), without notable long-term consequences; systemic adverse outcomes otherwise were unusual in both groups, with minimal differences between groups.
In each treatment group, mean visual acuity improved over 24 months, with neither approach superior to a degree detectable with the study's power. Therefore, the specific advantages and disadvantages identified should dictate selection between the alternative treatments in consideration of individual patients' particular circumstances. Systemic therapy with aggressive use of corticosteroid-sparing immunosuppression was well tolerated, suggesting that this approach is reasonably safe for local and systemic inflammatory disorders.
Proprietary or commercial disclosure may be found after the references.
To develop classification criteria for 25 of the most common uveitides.
Machine learning using 5,766 cases of 25 uveitides.
Cases were collected in an informatics-designed preliminary database. Using ...formal consensus techniques, a final database was constructed of 4,046 cases achieving supermajority agreement on the diagnosis. Cases were analyzed within uveitic class and were split into a training set and a validation set. Machine learning used multinomial logistic regression with lasso regularization on the training set to determine a parsimonious set of criteria for each disease and to minimize misclassification rates. The resulting criteria were evaluated in the validation set. Accuracy of the rules developed to express the machine learning criteria was evaluated by a masked observer in a 10% random sample of cases.
Overall accuracy estimates by uveitic class in the validation set were as follows: anterior uveitides 96.7% (95% confidence interval CI 92.4, 98.6); intermediate uveitides 99.3% (95% CI 96.1, 99.9); posterior uveitides 98.0% (95% CI 94.3, 99.3); panuveitides 94.0% (95% CI 89.0, 96.8); and infectious posterior uveitides / panuveitides 93.3% (95% CI 89.1, 96.3). Accuracies of the masked evaluation of the “rules” were anterior uveitides 96.5% (95% CI 91.4, 98.6) intermediate uveitides 98.4% (91.5, 99.7), posterior uveitides 99.2% (95% CI 95.4, 99.9), panuveitides 98.9% (95% CI 94.3, 99.8), and infectious posterior uveitides / panuveitides 98.8% (95% CI 93.4, 99.9).
The classification criteria for these 25 uveitides had high overall accuracy (ie, low misclassification rates) and seemed to perform well enough for use in clinical and translational research.
Background. While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains ...unclear. Methods. We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy-mediated viral suppression, nadir CD4⁺ T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency. Results. Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4⁺ T-cell count (all P ≤001). A higher percentage of CD38⁺HLA-DR⁺ cells in the CD8⁺ T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4⁺ T-cell count. Frequencies of senescent (defined as CD28⁻CD57⁺ cells), exhausted (defined as PD1⁺ cells), naive, and CMV-specific T cells did not predict mortality. Conclusions. Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation—but not T-cell activation, senescence, and exhaustion—independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.
The accuracies of the SUN criteria for panuveitides overall and for early-stage Vogt−Koyanagi−Harada (VKH) disease were excellent, 93.3% and 92.3%, respectively.1,2 Precision, the machine learning ...equivalent to specificity, was 94.4% for early-stage VKH.1 The SUN VKH criteria included both full-fledged early-stage VKH with panuveitis and neurologic involvement and the more limited “Harada disease” presentation with only exudative detachments; but the criteria for the latter required an exudative detachment with the classic features on fluorescein angiography and/or optical coherence tomography for classification as early-stage VKH. Many previous authors have added the phrase “exclude all other diseases” to their criteria sets to address this concern.3 However, this approach results in a tautology and is problematic to implement, as the necessary testing is unspecified.3 The SUN Working Group decided on a more measured approach, namely the exclusion of diseases most likely to be in the differential diagnosis.1 Carreno et al,4 in their comment on the SUN article “Classification Criteria for Vogt−Koyanagi−Harada Disease,” correctly note that the SUN Working Group did not perform machine learning against several non-uveitic diseases, including posterior scleritis, lupus choroidopathy, IgA nephropathy, central serous choroidopathy, and preeclampsia; and they cited a case report of acute posterior multifocal placoid epitheliopathy (APMPPE) having optical coherence tomography (OCT) features similar to those of early-stage VKH. ...in practice, these diseases are unlikely to substantially affect the accuracy (and the precision) of the SUN VKH criteria.
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