Targeting Interleukin-23 in the Treatment of Noninfectious Uveitis.
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ABSTRACT:
SUBMITTER: Pepple KL
PROVIDER: S-EPMC6538052 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
Publications
Targeting Interleukin-23 in the Treatment of Noninfectious Uveitis.
Pepple Kathryn L KL Lin Phoebe P
Ophthalmology 20180704 12
The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of immune-mediated diseases such as psoriasis, psoriatic arthritis, Crohn's disease, and uveitis. Therefore, targeting the IL-23/IL-17 axis has become the focus of multiple clinical trials for drug development in patients with autoimmune diseases. We briefly describe the biology of the IL-23/IL-17 axis and its relevance to the pathogenesis of experimental and clinical uveitis, and review the monoclonal antibody therapies ...[more]
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Project description:ObjectiveWe sought to describe the risk and risk factors for hypotony in a noninfectious uveitis cohort.DesignRetrospective cohort study.ParticipantsPatients with noninfectious uveitis seen between 1979 and 2007 at 4 academic ocular inflammation specialty clinics.MethodsData were collected from medical records by trained, certified, expert reviewers.Main outcome measuresHypotony (<5 mmHg) and low intraocular pressure (<8 mmHg), each sustained for ? 2 visits spanning ? 30 days.ResultsDuring follow-up, 126 of 6785 patients (1.86%) developed hypotony at the rate of 0.61% (95% confidence interval [CI], 0.50-0.75%) per eye-year. Cataract surgery was associated with a 7.5-fold risk (adjusted hazard ratio [aHR], 7.51; 95% CI, 3.97-14.23) of incident hypotony. Phacoemulsification, the type of cataract surgery associated with the least hypotony risk still was associated with nearly 5-fold higher hypotony incidence (aHR, 4.87; 95% CI, 2.25-10.55). Increased risk was observed in children (aHR, 2.92; 95% CI, 1.20-7.10) with respect to young adults, and duration of uveitis of >5 years (aHR, 3.08; 95% CI, 1.30-7.31) with respect to uveitis of <6 month duration. Band keratopathy, ? 3+ vitreous cells, exudative retinal detachment, posterior synechia, and a history of pars plana vitrectomy also were associated with greater hypotony incidence. With respect to anterior uveitis, intermediate uveitis (aHR, 0.17; 95% CI, 0.05-0.56) and posterior uveitis (aHR, 0.11; 95% CI, 0.03-0.45) were associated with lower hypotony risk, whereas panuveitis (aHR, 1.25; 95% CI, 0.67-2.35) was similar. Approximately five-sixths (84.1%) of eyes presenting with hypotony had a visual acuity of ? 20/200 (aOR for visual acuity ? 20/200, 13.85; 95% CI, 7.23-26.53). Risk factors for prevalent hypotony were similar.ConclusionsThe risk of hypotony is low among eyes with noninfectious uveitis, but is more frequently observed in cases with anterior segment inflammation. Signs of present or past inflammation were associated with greater risk, suggesting excellent inflammatory control may reduce the risk of hypotony. Prior ocular surgery also was associated with higher risk; cataract surgery in particular was associated with much higher risk of hypotony. Lower risk of hypotony with phacoemulsification than with alternative cataract surgery approaches suggests the phacoemulsification approach is preferable.
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Project description:PURPOSE:To evaluate the safety, tolerability, and preliminary efficacy of suprachoroidal injection of triamcinolone acetonide (TA) in patients with noninfectious uveitis. METHODS:In this Phase 1/2 open-label clinical study, a single suprachoroidal injection of 4-mg TA in 100 ?L was performed in the study eye of patients with noninfectious intermediate, posterior, or pan-uveitis, and follow-up obtained for 26 weeks. RESULTS:Nine individuals with chronic uveitis were enrolled. There were 38 reported adverse events (AEs); most were mild or moderate in severity. Approximately half the AEs were ocular. The most common AE was reported by four subjects who experienced ocular pain at or near the time of the injection. All systemic AEs were unrelated to study drug. No steroid-related increases in intraocular pressure (IOP) were observed and no subject required IOP-lowering medication. All eight efficacy-evaluable subjects had improvements in visual acuity. Four subjects, who did not need additional therapy, had on average a greater than 2-line improvement in visual acuity through week 26. Three of four had macular edema at baseline, and two of three had at least a 20% reduction in macular edema at week 26. CONCLUSIONS:The safety and preliminary efficacy data support further investigations of suprachoroidally administered TA as a therapeutic option for the treatment of noninfectious uveitis. TRANSLATIONAL RELEVANCE:Targeted suprachoroidal administration of corticosteroid is a potential local route for the treatment of ocular inflammatory disease, which merits further investigation. (www.ClinicalTrials.gov, NCT01789320).
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Project description:IntroductionNoninfectious inflammation of the posterior eye segment represents an important cause of visual impairment. It often affects relatively young people and causes a significant personal and social impact. Although steroids and nonbiologic- Disease-Modifying Antirheumatic Drugs (nbDMARDs) are effective both in acute and long- lasting diseases, however they are increasingly being replaced by biologic (DMARDs). bDMARD. This article therefore aims to identify recent advances in the therapy of noninfectious posterior segment uveitis.MethodsA Medline-search was conducted using the terms: nbDMARD, bDMARD, posterior uveitis, intermediate uveitis, treatment, corticosteroid. In addition, clinical studies were included as registered at ClinicalTrials.gov.ResultsCurrently two major lines of treatments can be identified: (1) the intraocular application of anti-inflammatory agents and (2) the introduction of new agents, e.g., (bDMARDs) and small-molecule-inhibitors. Whereas intravitreal treatments have the advantage to avoid systemic side effects, new systemic agents are progressively earning credit on the basis of their therapeutic effects.ConclusionEven when current treatment strategies are still hampered by the limited number of randomized controlled trials, promising progress and continuous efforts are seen.
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Project description:ImportanceUveitis involves dysregulation of the ocular immune system. Stress has been shown to affect immune function, but it is unclear whether there is an association between stress and uveitis.ObjectiveTo determine whether having uveitis is associated with psychological stress.Design, setting, and participantsA cross-sectional, case-control study including a self-administered survey, medical records review, and diurnal salivary cortisol test was conducted at a university-based uveitis clinic and comprehensive eye clinic. Participants included 146 consecutive adults with noninfectious uveitis and age-matched controls with no eye disease. The study was conducted from December 1, 2017, to March 14, 2018.Main outcomes and measuresParticipants completed the self-administered, Cohen 10-item Perceived Stress Scale (PSS-10), a demographics questionnaire. Responses to each question were categorized on a 5-point Likert scale, with total scores ranging from 0 (no stress) to 40 (high stress). In addition, participants submitted 3 salivary cortisol samples. Those with uveitis were classified as having recently active or controlled disease through medical records review. The prespecified primary analysis was a linear regression of PSS-10 score and uveitis correcting for age, sex, educational level, employment, and median income. Secondary analyses included comparing PSS-10 scores in patients with recently active and controlled uveitis, determining predictors of stress, and comparing diurnal salivary cortisol between uveitis and control groups.ResultsOf 146 eligible patients, 17 declined participation and 9 consented but were excluded because they did not complete both questionnaires, resulting in 120 patients (80 uveitis; 40 controls) in the final analysis. Eighty participants (66.7%) were women, and 70 (58.3%) were white. Median age was 40 years (interquartile range, 29-59 years). Having uveitis was associated with a 4.3-point increase in PSS-10 score (95% CI, 1.8 to 6.9; P = .002). There was no significant difference in PSS-10 scores between patients with recently active and controlled uveitis (1.0 point greater for patients with active uveitis; 95% CI, -2.0 to 3.9; P = .52). Factors associated with increased PSS-10 score in patients with uveitis included female sex (coefficient, 4.0; 95% CI, 1.6 to 6.5; P = .002), current immunomodulatory therapy (coefficient, 2.5; 95% CI, -0.3 to 5.2; P = .08), history of depression (coefficient, 3.8; 95% CI, 0.8 to 6.8; P = .02), and having posterior or panuveitis (coefficient, 2.6; 95% CI, 0.8 to 4.4; P = .006). Of the 70 participants (58.3%) who had testable samples for cortisol analysis, diurnal salivary cortisol levels did not significantly differ between uveitis and nonuveitis groups.Conclusions and relevanceThese findings suggest that patients with uveitis have higher levels of psychological stress compared with controls, yet no significant difference was identified in the stress of patients with active vs controlled uveitis. Consequently, comprehensive treatment for noninfectious uveitis may be able to address the psychological results of this disease.
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Project description:Noninfectious uveitis is a predominantly T cell-mediated autoimmune, intraocular inflammatory disease. To characterize the gene expression profile from patients with noninfectious uveitis, PBMCs were isolated from 50 patients with clinically characterized noninfectious uveitis syndrome. A pathway-specific cDNA microarray was used for gene expression profiling and real-time PCR array for further confirmation. Sixty-seven inflammation- and autoimmune-associated genes were found differentially expressed in uveitis patients, with 28 of those genes being validated by real-time PCR. Several genes previously unknown for autoimmune uveitis, including IL-22, IL-19, IL-20, and IL-25/IL-17E, were found to be highly expressed among uveitis patients compared with the normal subjects with IL-22 expression highly variable among the patients. Furthermore, we show that IL-22 can affect primary human retinal pigment epithelial cells by decreasing total tissue resistance and inducing apoptosis possibly by decreasing phospho-Bad level. In addition, the microarray data identified a possible uveitis-associated gene expression pattern, showed distinct gene expression profiles in patients during periods of clinical activity and quiescence, and demonstrated similar expression patterns in related patients with similar clinical phenotypes. Our data provide the first evidence that a subset of IL-10 family genes are implicated in noninfectious uveitis and that IL-22 can affect human retinal pigment epithelial cells. The results may facilitate further understanding of the molecular mechanisms of autoimmune uveitis and other autoimmune originated inflammatory diseases.
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Project description:PURPOSE:To investigate time trade-off (TTO) utility values in patients with noninfectious uveitis and determine whether patient demographics and clinical characteristics are associated with utility scores. DESIGN:Time trade-off utility analysis. METHODS:Setting: A tertiary care uveitis center in San Francisco, California, USA. PATIENT POPULATION:One hundred and four consecutive adults with noninfectious uveitis, enrolled between November 2016 and February 2017. MAIN OUTCOME MEASURES:TTO utility values, as collected by an interviewer-guided survey. Information regarding general health, ocular symptoms, and religion was also collected and medical record review was conducted to record anatomic location of uveitis, disease activity, visual acuity, and treatments. Multivariable regression analysis with backward selection was used to identify variables associated with TTO values. RESULTS:Median TTO score was 0.975 (interquartile range [IQR]: 0.8-1.0), corresponding to trading a median 1.28 years of remaining life for healthy eyes (IQR: 0-6.29). Regression analysis revealed that worse eye visual acuity, >6 months of oral corticosteroid use, and current antidepressant use were associated with lower TTO scores (P = .008, P = .006, P = .008, respectively), controlling for age and sex. In particular, patients who had been taking oral corticosteroids for more than 6 months, regardless of dose, were 10.5 times more likely to trade 20% or more years of remaining life (TTO ?0.8) than patients not taking oral corticosteroids (95% confidence interval: 2.3, 48.1; P = .002). CONCLUSIONS:Patients with noninfectious uveitis had measurable, though modest, reductions in quality of life, as assessed by TTO, and these decreases were significantly associated with visual acuity in the worse eye and long-term oral corticosteroid use.
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Project description:The IL-23/IL-17 pathway has been implicated in the etiopathogenesis of axial spondyloarthritis through studies of genetic polymorphisms associated with disease, an animal model with over-expression of IL-23 that resembles human disease, and observations that cytokines in this pathway can be found at the site of disease in both humans and animal models. However, the most direct evidence has emerged from clinical trials of agents targeting cytokines in this pathway. Monoclonal antibodies targeting IL-17A have been shown to ameliorate signs and symptoms, as well as MRI inflammation in the spine and sacroiliac joints, in patients with radiographic and non-radiographic axial spondyloarthritis. This was evident in patients refractory to non-steroidal anti-inflammatory agents as well as patients failing treatment with tumor necrosis factor inhibitor therapies. Treatment with a bispecific antibody targeting both IL-17A and IL-17F was also effective in a phase II study. Post-hoc analyses have even suggested a potential disease-modifying effect in reducing development of spinal ankylosis. However, benefits for extra-articular manifestations were limited to psoriasis and did not extend to colitis and uveitis. Conversely, trials of therapies targeting IL-23 did not demonstrate any significant impact on signs, symptoms, and MRI inflammation in axial spondyloarthritis. These developments coincide with recent observations that expression of these cytokines is evident in many different cell types with roles in innate as well as adaptive immunity. Moreover, evidence has emerged for the existence of both IL-23-dependent and IL-23-independent pathways regulating expression of IL-17, potentially associated with different roles in intestinal and axial skeletal inflammation.
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Project description:PurposeTo describe the risk and risk factors for ocular hypertension (OHT) in adults with noninfectious uveitis.DesignRetrospective, multicenter, cohort study.ParticipantsPatients aged ≥18 years with noninfectious uveitis seen between 1979 and 2007 at 5 tertiary uveitis clinics.MethodsDemographic, ocular, and treatment data were extracted from medical records of uveitis cases.Main outcome measuresPrevalent and incident OHT with intraocular pressures (IOPs) of ≥21 mmHg, ≥30 mmHg, and increase of ≥10 mmHg from documented IOP recordings (or use of treatment for OHT).ResultsAmong 5270 uveitic eyes of 3308 patients followed for OHT, the mean annual incidence rates for OHT ≥21 mmHg and OHT ≥30 mmHg are 14.4% (95% confidence interval [CI], 13.4-15.5) and 5.1% (95% CI, 4.7-5.6) per year, respectively. Statistically significant risk factors for incident OHT ≥30 mmHg included systemic hypertension (adjusted hazard ratio [aHR], 1.29); worse presenting visual acuity (≤20/200 vs. ≥20/40, aHR, 1.47); pars plana vitrectomy (aHR, 1.87); history of OHT in the other eye: IOP ≥21 mmHg (aHR, 2.68), ≥30 mmHg (aHR, 4.86) and prior/current use of IOP-lowering drops or surgery in the other eye (aHR, 4.17); anterior chamber cells: 1+ (aHR, 1.43) and ≥2+ (aHR, 1.59) vs. none; epiretinal membrane (aHR, 1.25); peripheral anterior synechiae (aHR, 1.81); current use of prednisone >7.5 mg/day (aHR, 1.86); periocular corticosteroids in the last 3 months (aHR, 2.23); current topical corticosteroid use [≥8×/day vs. none] (aHR, 2.58); and prior use of fluocinolone acetonide implants (aHR, 9.75). Bilateral uveitis (aHR, 0.69) and previous hypotony (aHR, 0.43) were associated with statistically significantly lower risk of OHT.ConclusionsOcular hypertension is sufficiently common in eyes treated for uveitis that surveillance for OHT is essential at all visits for all cases. Patients with 1 or more of the several risk factors identified are at particularly high risk and must be carefully managed. Modifiable risk factors, such as use of corticosteroids, suggest opportunities to reduce OHT risk within the constraints of the overriding need to control the primary ocular inflammatory disease.
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