Uveitis Research Articles

Equine uveitis: Outcome and adverse effects after one or two intravitreal low-dose gentamicin injections.

Uveitis is common in horses, potentially turning chronic (persistent or recurrent) resulting in impaired vision or blindness. All mainstay therapeutics aims at controlling inflammation, but long-term or lifelong treatment is often needed with possibly severe side effects. Therefore, intravitreal injections with low-dose gentamicin (IVGI) have been used in attempt to give a long-lasting result with potentially less side effects. To retrospectively assess outcome and long-term complications following one or two low-dose IVGI in Swedish horses with chronic uveitis. Retrospective case series. Medical records of horses diagnosed with uveitis examined at the Equine Clinic of the University Animal Hospital of Sweden between 2016 and 2021 were reviewed. Inclusion criteria were horses with a diagnosis of chronic uveitis that were treated with 4 mg IVGI. After injection, tapering doses of anti-inflammatory medications were administered. Due to persistence or recurrence of uveitis despite IVGI, some horses received a second injection. A positive outcome was defined as controlled uveitis, despite no or minimal anti-inflammatory medication. 32 eyes (29 horses) were included. Based on clinical evaluation, uveitis was classified as anterior (91%) or panuveitis (9%). 10 eyes were treated with IVGI twice. A positive outcome was observed in 13/32 eyes (41%). Inflammation in 9/32 eyes was controlled after the first, and in 4/10 eyes after the second IVGI treatment. Long-term complications included retinal degeneration in seven eyes, and mature cataracts in five eyes. Enucleations were performed in 14/32 eyes, due to lack of favourable response of IVGI, or due to complications, that is, glaucoma, corneal ulceration, and/or corneal mineralisation. One horse was euthanised due to painful bouts of inflammation in both eyes despite treatment. Small sample size, retrospective design with no control group, no histopathology performed, infrequent sampling for Leptospira and no standardised treatment protocol after the IVGI. In this group of Swedish horses, predominantly diagnosed clinically with anterior uveitis, a positive outcome was observed in 41% of eyes following one or two low-dose IVGI. Retinal degeneration in the visual streak was observed in 22% of eyes, which is a higher proportion of this complication than previously described.

Comparison of Incidence or Recurrence of Anterior Uveitis in Patients with Ankylosing Spondylitis Treated with Tumor Necrosis Factor Inhibitors

Background: Anterior uveitis (AU) is a significant concern in patients with ankylosing spondylitis (AS), and the choice of tumor necrosis factor inhibitors (TNFi) as a treatment modality raises questions regarding its effects on AU. We compared the effects of TNFi on AU in patients with AS. Methods: Patients diagnosed with AS and treated with at least one TNFi, including anti-TNFα antibodies (adalimumab and infliximab) or a soluble TNF receptor molecule (etanercept), between January 2010 and December 2022, were retrospectively reviewed. We compared the recurrence rate of AU in patients with a history of uveitis and the incidence of new-onset AU in those without a history of uveitis among the three TNFi groups. We also compared the effects of two different TNFi agents in patients who underwent TNFi switching. Results: Within two years of treatment initiation, there was no significant difference in AU recurrence among the three TNFi groups. However, the incidence of new-onset AU was significantly higher in the etanercept group than in the adalimumab group (26.4% vs. 6.3%; p = 0.024). After two years, the AU recurrence rate was significantly lower in the adalimumab group than in the other groups (p < 0.001). Among patients who underwent anti-TNFi switching, adalimumab treatment was associated with a significantly lower incidence of uveitis than etanercept (p = 0.023). Conclusion: In the short-term period following TNFi therapy, etanercept induced new-onset AU more frequently than adalimumab in patients with AS. Adalimumab recipients experienced fewer AU recurrences during the subsequent long-term period compared to other TNFi recipients.

Evolving Fuchs' uveitis - A diagnostic challenge.

To study cases of Fuchs' uveitis (FU) diagnosed as uveitis other than FU at initial visits. A retrospective, observational chart review. Details of clinical presentation, initial diagnosis, treatment details, and follow-up before and after the diagnosis of FU was studied. Twenty eyes of 19 patients finally diagnosed with FU. Mean total follow-up was 39 months (range: 3-120 months, median: 30 months) and follow-up after diagnosis of FU was 18 months (range: 0-84 months, median: 11 months). Most of the cases were diagnosed with anterior plus intermediate uveitis at the presentation (n = 8, 42.1%) and received steroid treatment. Keratic precipitates (KPs) typical of FU developed after mean 5.4 months of presentation (range: 1-18 months, median: 2 months). Altered iris pattern was noted after 17 months of presentation (range: 2-70 months, median: 8.5). Vitritis of grades 1-2 was present in all eyes. Overlap of uveitis of other etiology (retinal vasculitis, presumed tubercular intermediate uveitis) was found in three patients. Systemic immune disease (systemic lupus erythematosus, pulmonary sarcoidosis) was present in two patients. No treatment for the ocular inflammation was given after the diagnosis of FU in any patient and no change in the pattern of FU was observed during further follow-up. Evolving FU may lead to misdiagnosis and mismanagement. We suggest a conservative approach, withholding steroid treatment, allowing FU to evolve, in otherwise asymptomatic patients with white eye, mild to moderate anterior chamber (AC) and vitreous inflammation, absent posterior synechiae and normal fundus examination or fundus examination suggestive of resolved uveitis.

Targeted therapies for uveitis in spondyloarthritis: A narrative review

Spondyloarthritis (SpA) encompasses a group of chronic inflammatory disorders of the joints frequently associated with uveitis in almost a quarter of cases. SpA-related uveitis typically affects the eye anterior chamber with sudden onset, causing pain, redness, photophobia, and blurred vision. Ophthalmologists will describe an acute anterior unilateral uveitis. Most patients present with episodic acute anterior non-granulomatous uveitis and retain excellent visual acuity. However, systemic treatments are recommended in the event of frequent relapses (2–3/year) or in rare cases of sight-threatening with ocular complications. The improved understanding of the pathogenesis of SpA has led to the management of this disease by biologics. Here, we review the main data regarding the opportunity to target specific components in inflammatory pathways for the treatment of SpA-related uveitis. These therapies are recommended for long-term control when uveitis relapses occur too frequently despite conventional systemic treatments. Significant benefits have been obtained with the tumor necrosis factor-α inhibitors (TNFis), particularly infliximab and adalimumab. Paradoxically, a high number of uveitis occurrences have been shown on etanercept. Mixed results have been demonstrated with interleukin-17 antagonists (secukinumab) and interleukin-12/interleukin-23 antagonists (ustekinumab) in cases of failure of TNFis. JAK inhibitors seem to be a valuable class of medications for these patients in the future. Although SpA-related uveitis is typically managed with conventional local and/or systemic treatments, these biological/targeted therapies may provide avenues to control both the underlying SpA and uveitis manifestations. Thus, a close collaboration between patients, rheumatologists, internists, and ophthalmologists is needed to optimally manage ocular inflammation in SpA.

Long-term follow-up of a healthy man with endogenous Streptococcus anginosus endophthalmitis

We report the long-term follow-up of an immunocompetent patient who presented with slowly progressive endogenous endophthalmitis secondary to Streptococcus anginosus. A 46-year-old healthy man presented with a two-month history of right eye iritis. On examination, visual acuity was 20/60 with intraocular pressure of 6 mm Hg. There was a small layer of hypopyon with non-granulomatous anterior uveitis and vitritis. On funduscopy, fluffy white peripheral retinal and pre-retinal lesions were noted in superonasal periphery. The patient denied any present or past illness. Diagnostic pars plana vitrectomy was performed. Culture and polymerase chain reaction of the vitreous sample were positive for Streptococcus anginosus. Intravitreal vancomycin and ceftazidime and systemic ceftriaxone were administered. Work-up which included blood and urine cultures, chest x-ray, echocardiography and abdominal ultrasound was unyielding. Subsequently and because of persistent post-infectious inflammatory reaction, intravitreal and oral steroids were administered in addition to oral azathioprine later on. After one year of follow-up, visual acuity was 20/20 with near vision of Jaeger 3 + and no signs of active uveitis were seen. Therefore, Streptococcus anginosus should be considered in the differential diagnosis of a slowly progressive endophthalmitis also in immunocompetent individuals.

Stromal Keratitis Associated With Cytomegalovirus Anterior Uveitis.

Human cytomegalovirus (CMV) has commonly been reported as a cause of anterior uveitis and corneal endotheliitis. Unlike its other herpetic family members, herpes simplex virus and varicella zoster virus, involvement of the corneal stroma in CMV is uncommon. In this case series, we describe patients with CMV stromal keratitis. This was a retrospective chart review of patients seen at a tertiary referral center from 1999 to 2023 with stromal keratitis who tested positive for CMV by directed polymerase chain reaction of aqueous fluid or corneal tissue. This series describes 5 patients, 4 of whom presented with anterior uveitis and stromal keratitis and were confirmed to be positive for CMV through the polymerase chain reaction of aqueous fluid. The fifth patient experienced recurrent corneal graft failures, with the most recent failed graft being positive for CMV based on immunohistochemical stains of the corneal stroma. The average age of patients was 62 years (range 36-80 years). Only 1 patient (20%) exhibited elevated intraocular pressure with stellate keratic precipitates at the initial presentation, whereas 3 other patients (60%) had a known history of glaucoma. Uveitis specialists are well aware of CMV as a cause of recurrent, hypertensive anterior uveitis but should also consider CMV in cases featuring stromal keratitis. The corneal endothelium may serve as a reservoir for both anterior uveitis and development of corneal stromal inflammation as demonstrated by the immunohistopathology exhibited in 1 case.

A pediatric case of tubulointerstitial nephritis and uveitis syndrome

Tubulointerstitial Nephritis and Uveitis Syndrome (TINU Syndrome) is a rare entity of unknown origin. Most cases described affect adolescents and women. It often implies a renal biopsy and is established upon the presence of uveitis and tubulointerstitial nephritis in the same patient, after all possible causes are excluded. The authors report the case of a 12-year-old teenage boy with nausea, vomiting, and weight loss lasting two weeks, taken to his local hospital with acute kidney injury, oliguria, and high blood pressure. After transfer to a specialized centre and exclusion of infectious, toxic, and autoimmune causes, intravenous and oral corticosteroid therapy was started. Renal biopsy confirmed interstitial nephritis of undetermined aetiology and the patient was discharged after favourable restauration of renal function, with a course of 4 weeks of steroids and progressive decrements over 10 weeks. Four months after the onset of the condition, the teenager was taken to the hospital with eye redness and tenderness. Bilateral anterior uveitis was described, which established the diagnosis of TINU Syndrome. After two years of joint follow-up by Paediatric Nephrology and Ophthalmology, the patient remains stable, without relapses, or ocular or renal sequelae.

A modern approach to diagnostic methods of the cornea and aqueous humor of anterior chamber of the eye in patients with anterior uveitis, associated with spondyloarthritis

Anterior uveitis is the dominant clinical extra-articular manifestation of spondyloarthritis associated with the carriage of the human leukocyte antigen allele (HLA-B27), which may precede joint and spinal involvement. In 20–30% of cases, uveitis occurs with frequent relapses – up to 5–6 exacerbations per year, often has a protracted character and is poorly amenable to local anti-inflammatory therapy, which leads to a decrease in vision and a deterioration in the quality of life. Timely and accurate assessment of the severity of intraocular inflammation plays an important role in making a diagnosis and in choosing the right treatment tactics for treating anterior uveitis in patients with HLA-B27-associated spondyloarthritis. The current standard clinical approach to assessing inflammation is the presence and number of inflammatory cells in the anterior chamber aqua humor according to the SUN classification using slit lamp imaging. However, the assessment of SUN is very subjective. Moreover, the individual variability in anterior chamber cell count, which is the main diagnostic criterion for uveitis, can be exacerbated by certain testing conditions, such as the brightness of the slit lamp light bar, light beam size calibration, light source intensity. Advances in optical imaging technology, the application of the latest technologies and the improvement of already known methods offer new opportunities for an objective, accurate and quantitative assessment of inflammation. The article describes the possibilities of studying the cornea and the anterior chamber of the eye using anterior segment optical coherence tomography, confocal microscopy of the cornea and keratotopometry.

Comparative risk of incident and recurrent acute anterior uveitis across different biological agents in patients with ankylosing spondylitis.

To evaluate the comparative risk of incident and recurrent acute anterior uveitis (AAU) across different biological disease-modifying anti-rheumatic drugs (bDMARDs) in patients with ankylosing spondylitis (AS). A retrospective nationwide cohort study was conducted on 34 621 patients with AS without a previous history of AAU using a national claims database. Patients were followed-up from 2010 to 2021. The comparative risk of incident and recurrent AAU across different bDMARDs was examined using multivariable time-dependent Cox models and counting process (AG) models, respectively. The adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for incident AAU (bDMARDs non-exposure as reference) were: adalimumab 0.674 (0.581-0.891), etanercept 1.760 (1.540-2.012), golimumab 0.771 (0.620-0.959), infliximab 0.891 (0.741-1.071), and secukinumab 1.324 (0.794-2.209). Compared with adalimumab exposure, etanercept (aHR = 2.553 [2.114-3.083]), infliximab (aHR = 1.303 [1.039-1.634]), and secukinumab exposures (aHR = 2.173 [1.273-3.710]) showed a higher risk of incident AAU. The aHRs and 95% CIs for recurrent AAU (bDMARDs non-exposure as reference) were: adalimumab 0.798 (0.659-0.968), etanercept 1.416 (1.185-1.693), golimumab 0.874 (0.645-1.185), infliximab 0.926 (0.729-1.177), and secukinumab 1.257 (0.670-2.359). Compared with adalimumab exposure, etanercept exposure (aHR = 1.793 [1.403-2.292]) was associated with a higher risk of recurrent AAU. Our data suggest preference for bDMARDs in the following order: adalimumab/golimumab > infliximab > secukinumab > etanercept (for incident AAU prevention) and adalimumab > golimumab/infliximab/secukinumab > etanercept (for recurrent AAU prevention).

Outcome of cataract surgery in children with presumed trematode-induced granulomatous anterior uveitis

PurposeTo examine the 6-month visual outcomes and complications following cataract surgery in patients with persumed trematode induced granulomatous anterior uveitis.SettingAssiut university hospital, Assiut, Egypt.DesignThis is a retrospective non comparative case series study.MethodsPatients presenting with significant cataract secondary to uveitis caused by trematode induced anterior chamber granuloma were included in this study.Cases with active anterior uveitis, within the last 3 months preceding surgery, and those with a history of trauma, were excluded from this study.Data collected included demographic characteristics, history of the condition including when uveitis started, treatment received and history of other health conditions that may be relevant to uveitis.Complete opthalmologic examination including assessment of best corrected visual acuity (BCVA) and OCT macula, if possible, were done. These was repeated 1 week, 1 month, 3 months and 6 months after surgery. Specular microscopy was performed preoperatively and 3 months after surgery. Patients underwent cataract surgery with posterior chamber intra ocular lens and statistical analysis was performed to compare preoperative and postoperative BCVA and corneal endothelial cell counts. Postoperative complications were recorded.ResultsFive eyes of 5 patients were included in the study. All study eyes showed improvement in the post-operative visual acuity.A statistically significant improvement was observed in VA in the sixth postoperative month compared to the baseline measurements (p = 0.004). No statistically significant difference was observed between the preoperative and postoperative endothelial cell counts (p = 0.696). Cystoid macular edema did not occur as a postoperative complication.ConclusionVisual outcomes of cataract surgery in eyes with persumed trematode induced granulametous anterior uveitis are favorable. No sight threatening complication was observed in our series.

Reggio Emilia (Northern Italy) Interdisciplinary Uveitis Clinic: What We Have Learned in the Last 20 Years

ABSTRACT Purpose To analyze the referral patterns and the clinical and therapeutic features of patients diagnosed with uveitis in an Italian tertiary referral center to provide a comparison with previously published series from the same center. Methods Retrospective retrieval of data on all new referrals to the Ocular Immunology Unit in Reggio Emilia (Italy) between November 2015 and April 2022 and comparison with previously published series from the same center. Results Among the 1557 patients, the male-to-female ratio was 1:1.27. Anterior uveitis was the most common diagnosis (53.7%), followed by posterior (21.6%), pan- (18.5%), and intermediate (6.2%) uveitis. The most identifiable specific diagnoses were anterior herpetic uveitis (18.4%), Fuchs uveitis (12.8%), and tuberculosis (6.1%). Infectious etiologies were the most frequent (34.1%) and were more diffuse among non-Caucasian patients (p < 0.001), followed by systemic disease-associated uveitis (26.5%), and ocular-specific conditions (20%). Idiopathic uveitis accounted for 19.4% of cases. Fuchs uveitis presented the longest median diagnostic delay (21 months). Immunosuppressants were administered to 25.2% of patients. Antimetabolites, calcineurin inhibitors, and biologicals were prescribed to 18.4%, 3%, and 11.4% of cases, respectively. Compared to our previous reports, we observed a significant increase in foreign-born patients and in infectious uveitis, a decrease in idiopathic conditions, and an increasing use of non-biological and biological steroid-sparing drugs. Conclusions The patterns of uveitis in Italy have been changing over the last 20 years, very likely due to migration flows. Diagnostic improvements and a more widespread interdisciplinary approach could reduce the incidence of idiopathic uveitis as well as diagnostic delay.

The Leading Causes of Optic Disc Edema Seen in Tertiary Care, Academic Neuro-Ophthalmology Clinics.

Optic disc edema (ODE) is one of the most common reasons for referral to a neuro-ophthalmologist. There are various causes that require vastly different workup. Thus, differentiating among each cause is important. Our goal was to determine the causes of ODE and various clinical characteristics of consecutive patients with ODE presenting to neuro-ophthalmology clinics. A retrospective review of consecutive patients with ODE over a period of 5 years were included. Fundus photographs were routinely obtained as part of clinical care. Clinical data including retinal nerve fiber layer thickness, best-corrected visual acuity, and visual field mean deviation were retrieved, and patients were grouped by etiology. A total of 654 patients (n = 462 or 70.6% women and 192 or 29.4% men) with ODE were included with a mean age of 41.2 ± 17.9 years. Female patients were significantly younger than male patients (mean age female participants: 38.7 years, male participants: 47.6; P < 0.001). The top 5 most common causes of ODE in our clinics were idiopathic intracranial hypertension (IIH; 351/654 or 53.7%), nonarteritic anterior ischemic optic neuropathy (NAION; 116/654 or 17.4%), non-IIH papilledema (71/654 or 10.9%), optic neuritis (ON; 46/654 or 7.0%), and uveitis (17/654 or 2.6%). When considering female-only patients, the top 3 causes of ODE were IIH, non-IIH papilledema, and NAION. Among male-only patients, the top 3 causes were NAION, IIH, and non-IIH. Among the top 5 causes of ODE, visual acuity was the worst at presentation in the ON group and the best in the patients with IIH. The Humphrey mean deviation was the worst in ON/NAION groups and best in IIH group. The ODE was most severe in patients with non-IIH papilledema and least severe in ON group. Non-IIH patients with papilledema were not significantly different in visual acuity and visual field parameters at presentation compared with patients with IIH papilledema. Patients with papilledema (both IIH and non-IIH etiologies) had significantly better visual function at presentation compared with other top causes of disc edema (P < 0.001). The most common cause of ODE seen in neuro-ophthalmology clinics was IIH, and these patients were more likely to present with preserved visual function. The higher prevalence of IIH was likely why most patients with ODE were women. Visual function at presentation was not able to differentiate the specific cause of papilledema; however, it was an important differentiating factor for all papilledema cases compared with all other causes of ODE including ON and NAION.

Metagenomic analysis of the ocular toxoplasmosis in children uveitis from Fayoum governorate, Egypt

Granulomatous anterior uveitis with single or numerous gelatinous nodules was found in children living in rural Egypt. All ocular diseases were originally thought to be water-born and related to digenic flukes. The current study sought to learn more about the causes of anterior granulomatous uveitis in Egyptian youngsters who used to swim in rural water canals. 50 children with eye lesions that had not responded to medical treatment were recruited. Four samples were surgically extracted and examined using real-time PCR, transmission electron microscopy (TEM), and shotgun metagenomic sequencing (SMS). Toxoplasma gondii was detected free within the syncytium's distal section, while the proximal part exhibited active synthesis of a presumably extra-polymeric material, possibly released by the microbial population. Toxoplasma gondii was found in 30 samples. Serologically, distinct anti-Toxoplasma antibodies were not found in 91.6% of patients. SMS showed that the T. gondii ME 49 strain had the greatest percentage (29–25%) in all samples within an Acinetobacter-containing microbial community. These findings suggested that these bacteria entered the body via the exterior route rather than the circulatory route. The lack of genetic evidence for subsequent parasite stages invalidates the prior findings about the assumed trematode stage.

Effectiveness and Safety of Biosimilars in Pediatric Non-infectious Uveitis: Real-Life Data from the International AIDA Network Uveitis Registry.

Since many biological drug patents have expired, biosimilar agents (BIOs) have been developed; however, there are still some reservations in their use, especially in childhood. The aim of the current study is to evaluate the efficacy and safety of tumor necrosis factor (TNF) inhibitors BIOs as treatment for pediatric non-infectious uveitis (NIU). Data from pediatric patients with NIU treated with TNF inhibitors BIOs were drawn from the international AutoInflammatory Disease Alliance (AIDA) registries dedicated to uveitis and Behçet's disease. The effectiveness and safety of BIOs were assessed in terms of frequency of relapses, risk for developing ocular flares, best-corrected visual acuity (BCVA), glucocorticoids (GCs)-sparing effect, drug survival, frequency of ocular complications, and adverse drug event (AE). Forty-seven patients (77 affected eyes) were enrolled. The BIOs employed were adalimumab (ADA) (89.4%), etanercept (ETA) (5.3%), and infliximab (IFX) (5.3%). The number of relapses 12months prior to BIOs and at last follow-up was 282.14 and 52.43 per 100 patients/year. The relative risk of developing ocular flares before BIOs introduction compared to the period following the start of BIOs was 4.49 (95% confidence interval [CI] 3.38-5.98, p = 0.004). The number needed to treat (NNT) for ocular flares was 3.53. Median BCVA was maintained during the whole BIOs treatment (p = 0.92). A significant GCs-sparing effect was observed throughout the treatment period (p = 0.002). The estimated drug retention rate (DRR) at 12-, 24-, and 36-month follow-up were 92.7, 83.3, and 70.8%, respectively. The risk rate for developing structural ocular complications was 89.9/100 patients/year before starting BIOs and 12.7/100 patients/year during BIOs treatment, with a risk ratio of new ocular complications without BIOs of 7.1 (CI 3.4-14.9, p = 0.0003). Three minor AEs were reported. TNF inhibitors BIOs are effective in reducing the number of ocular uveitis relapses, preserving visual acuity, allowing a significant GCs-sparing effect, and preventing structural ocular complications. ClinicalTrials.gov ID NCT05200715.

Lesions and viral antigen distribution in bald eagles, red-tailed hawks, and great horned owls naturally infected with H5N1 clade 2.3.4.4b highly pathogenic avian influenza virus.

An epidemic of highly pathogenic avian influenza (HPAI) began in North America in the winter of 2021. The introduced Eurasian H5N1 clade 2.3.4.4b virus subsequently reassorted with North American avian influenza strains. This postmortem study describes the lesions and influenza A virus antigen distribution in 3 species of raptors, including bald eagles (Haliaeetus leucocephalus, n = 6), red-tailed hawks (Buteo jamaicensis, n = 9), and great horned owls (Bubo virginianus, n = 8), naturally infected with this virus strain based on positive reverse transcriptase polymerase chain reaction and sequencing results from oropharyngeal swabs. The birds presented with severe neurologic signs and either died or were euthanized because of the severity of their clinical signs and suspected influenza virus infection. Gross lesions were uncommon and included forebrain hemorrhages in 2 eagles, myocarditis in 1 hawk, and multifocal pancreatic necrosis in 3 owls. Histological lesions were common and included encephalitis, myocarditis, multifocal pancreas necrosis, multifocal adrenal necrosis, histiocytic splenitis, and anterior uveitis in decreasing frequency. Influenza A viral antigen was detected in brain, heart, pancreas, adrenal gland, kidney, spleen, liver, and eye. In conclusion, bald eagles, red-tailed hawks, and great horned owls infected with the HPAI clade 2.3.4.4b virus strain and showing neurological signs of illness may develop severe or fatal disease with histologically detectable lesions in the brain that are frequently positive for viral antigen.

Foxo1 Drives the TGFβ1-Dependent Dichotomy of Th17 Cell Fates.

T-helper 17 (Th17) cells play a dual role in immunological responses, serving as essential components in tissue homeostasis and host defense against microbial pathogens while also contributing to pro-inflammatory conditions and autoimmunity. While Transforming Growth Factor-beta 1 (TGFβ1) is pivotal for the differentiation of non-pathogenic Th17 cells, the role of TGFβ3 and Activin in steering Th17 cells toward a pathogenic phenotype has been acknowledged. However, the molecular mechanisms governing this dichotomy remain elusive. In this study, we demonstrate that the transcription factor Foxo1 is upregulated in a TGFβ1 dose-dependent manner, serving as a critical regulator that specifically modulates the fate of pathogenic Th17 cells. Analyses in both uveitis patients and an Experimental Autoimmune Uveitis (EAU) mouse model reveal a strong correlation between disease severity and diminished Foxo1 expression levels. Ectopic expression of Foxo1 selectively attenuates IL-17A production under pathogenic Th17-inducing conditions. Moreover, enhanced Foxo1 expression, triggered by TGFβ1 signaling, is implicated in fatty acid metabolism pathways that favor non-pathogenic Th17 differentiation. Our drug screening identifies several FDA-approved compounds can upregulate Foxo1. Collectively, our findings offer evidence that Foxo1 serves as a molecular switch to specifically control pathogenic versus non-pathogenic Th17 differentiation in a TGFβ1-dependent manner. Suggest that targeting Foxo1 could be a promising therapeutic strategy for autoimmune diseases.

Long-Term Visual Outcome of Patients with Blau Syndrome

ABSTRACT Purpose To document the long-term visual outcomes in patients with Blau syndrome. Methods A retrospective institutional cohort study was conducted, and 13 patients with genetically confirmed Blau syndrome were included. Demographic and clinical data were collected from standardised medical charts. Baseline was defined as the first detected uveitis and data were recorded onwards at intervals of 1, 3, 5, 10, 15 and 20 years. Results Anterior uveitis was the most common classification at baseline (57.1%). Among patients with documented uveitis lasting 10 years or more, all of them developed panuveitis. Median logMAR visual acuity at baseline was 0 (range −0.5; 0.7), 0.19 (range 0; 1.5) at year 5, and 0.7 (range 0.1 – no perception of light) at year 20, as recorded in 13, 16, and 10 eyes, respectively. All patients received treatment with topical and oral steroids, and multiple systemic immunosuppressants including biologics. Disease control, defined as having cells <1+ in both eyes and using topical steroid eye drops less than twice daily, was achieved in 14.3% to 37.5% of patients at the different time points. Cataract surgery was performed in 12 eyes of 8 patients, 3 eyes of 3 patients necessitated glaucoma surgery, and 4 eyes of 4 patients required surgery for retinal detachment. Conclusion Uveitis associated with Blau syndrome commonly leads to severe, chronic panuveitis, requiring long-term systemic immunosuppression. Early diagnosis and timely initiation of biologics may prevent significant visual impairment.

4-Octyl Itaconate Inhibits Proinflammatory Cytokine Production in Behcet's Uveitis and Experimental Autoimmune Uveitis.

4-octyl itaconate (4-OI) is an anti-inflammatory metabolite that activates the nuclear-factor-E2-related factor 2 (NRF2) signaling. In the current work, we investigated whether 4-OI could affect the production of proinflammatory cytokines in Behcet's uveitis (BU) and experimental autoimmune uveitis (EAU). Peripheral blood mononuclear cells (PBMCs) of active BU patients and healthy individuals with in vitro 4-OI treatment were performed to assess the influence of 4-OI on the proinflammatory cytokine production. EAU was induced and used for investigating the influence of 4-OI on the proinflammatory cytokine production in vivo. The flow cytometry, qPCR, and ELISA were performed to detect proinflammatory cytokine expression. NRF2 signaling activation was evaluated by qPCR and western blotting (WB). Splenic lymphocyte transcriptome was performed by RNA sequencing. The NRF2 expression by BU patients-derived PBMCs was lower than that by healthy individuals. After treatment with 4-OI, the proportion of Th17 cells, along with the expression of proinflammatory cytokines (IL-17, TNF-α, MCP-1, and IL-6) by PBMCs, were downregulated, and anti-inflammatory cytokine (IL-10) expression was upregulated, although IFN-γ expression was unaffected. The EAU severity was ameliorated by 4-OI in association with a lower splenic Th1/Th17 cell proportion and increased nuclear NRF2 expression. Additionally, 4-OI downregulated a set of 248 genes, which were enriched in pathways of positive regulation of immune responses. The present study shows an inhibitory effect of 4-OI on the proinflammatory cytokine production in active BU patients and EAU mice, possibly mediated through activating NRF2 signaling. These findings suggest that 4-OI could act as a potential therapeutic drug for the treatment and prevention of BU in the future study.

A Rare Syndrome with Tubulointerstitial Nephritis: TINU Syndrome

Tubulointerstitial nephritis (TIN) is a condition that can occur for different reasons and can lead to acute kidney injury or chronic kidney failure. Acute tubulointerstitial nephritis (ATIN) is a disease that involves both tubules and interstitium of the kidney parenchyma, mostly reversible and characterized by inflammatory cell infiltration (lymphocyte, monocytes and macrophages) in the tubulointerstitial area. There are 4 main causes of acute tubulointerstitial nephritis: drugs (75%), systemic diseases (10-15%), infections (5-10%), uveitis with tubulointerstitial nephritis (TINU) (5-10%) (1,2). Although the pathogenesis of acute tubulointerstitial nephritis is not clear, it is thought to be an autoimmune disease that develops as a result of the effects of both cellular and humoral immune mechanisms (4.5). ATN may therefore accompany other autoimmune diseases. Antigens that cross-react with kidney tubule cells and eye ciliary body epithelium are thought to be responsible for the initial pathogenesis of uveitis associated with tubulointerstitial nephritis (3). In this article, anterior uveitis syndrome with tubulointerstitial nephritis, which is rarely seen, is presented.

Ocular extraintestinal manifestations and treatments in patients with inflammatory bowel disease.

Between 3-47% of patients with inflammatory bowel disease (IBD) have extraintestinal manifestations (EIMs), and between 1.3-86.9% of patients with IBD suffer from ocular EIMs (O-EIMs) making the eye the third most common organ affected. These O-EIMs exist among a spectrum, with a variety of types and amounts of inflammation which can lead to decreased vision, and in some cases, vision loss, without treatment. We performed a literature review concerning O-EIMs in patients who had or were later found to have a diagnosis of IBD in order to identify ocular EIMs that commonly occur with IBD and to assess which patients with IBD may be at higher risk of developing O-EIMs. We were also interested in ascertaining whether O-EIMs were more common in specific populations of people or in specific subtypes of IBD. Lastly, we explored the common treatments of O-EIMs in patients with IBD. Upon review of the literature, we found that the most common O-EIMs are episcleritis and uveitis. Anterior uveitis is more commonly seen, although, inflammation may occur in the posterior segment of the eye as well and may also manifest as retinal vasculitis. While these diagnoses are sometimes known retrospectively, most patients present with nonspecific eye complaints of which decreased vision with or without pain is the most common. Visual symptoms associated with ocular EIMs may be non-specific so physicians should have a low threshold to refer to ophthalmology for visual complaints. It is important to keep in mind that ocular EIMs can cluster with skin and joint EIMs. Screening should be prioritized for female patients with Crohn's disease and concurrent arthritis. Treatments for O-EIMs are outlined and compared in this paper as well.