Blau syndrome-the skin as a warning sign.

Blau syndrome is an autosomal dominant chronic inflammatory disease, which may begin with skin manifestations in the first months of life, alerting physicians to the diagnosis. This case reports a patient diagnosed jointly by pediatric dermatology and rheumatology consultants at two years of age.

Causal association of juvenile idiopathic arthritis or JIA-associated uveitis and gut microbiota: a bidirectional two-sample Mendelian randomisation study.

Background: The gut microbiota significantly influences the onset and progression of juvenile idiopathic arthritis (JIA) and associated uveitis (JIAU); however, the causality remains unclear. This study aims to establish a causal link between gut microbiota and JIA or JIAU. Methods: Using publicly available genome-wide association studies (GAWS) summary data, we conducted a two-sample Mendelian randomisation (MR) analysis employing various methods, namely inverse variance weighted (IVW), simple mode, weighted mode, weighted median and MR-Egger regression methods, to assess the causal association between JIA or JIAU and gut microbiota. Sensitivity analyses, including Cochrane's Q test, MR-Egger intercept test, leave-one-out analysis and MR-PRESSO, were performed to evaluate the robustness of the MR results. Subsequently, reverse MR analysis was conducted to determine causality between gene-predicted gut microbiota abundance and JIA or JIAU. Results: The MR analysis revealed a causal association between gut microbiota abundance variations and JIA or JIAU risk. Specifically, the increased abundance of genus Ruminococcaceae UCG013 (OR: 0.055, 95%CI: 0.006-0.103, p = 0.026) and genus Ruminococcaceae UCG003 (ß: 0.06, 95%CI: 0.003-0.117, p = 0.041) correlated with an increased risk of JIA, while genus Lachnospiraceae UCG001 (OR: 0.833, 95%CI: 0.699~0.993, p = 0.042) was associated with a reduced risk of JIA, among others. Sensitivity analysis confirmed MR analysis robustness. Conclusions: This study provides substantial evidence supporting a causal association between genetically predicted gut microbiota and JIA or JIAU. It highlights the significant role of intestinal flora in JIA or JIAU development, suggesting their potential as novel biomarkers for diagnosis and prevention. These findings offer valuable insights to mitigate the impact of JIA or JIAU.

Proteomic Profiling of Tears in Blau Syndrome Patients in Identification of Potential Disease Biomarkers.

Blau syndrome (BS) is a rare autoinflammatory granulomatosis characterized by granulomatous arthritis, uveitis, and dermatitis. Ocular complications are particularly severe in BS, significantly contributing to morbidity. This study aims to identify potential biomarkers for BS ocular degeneration through proteomic profiling of tear samples from affected patients. Seven subjects from the same family, including four carriers of the BS-associated NOD2 mutation (p.E383K), were recruited alongside healthy controls. Tear samples were collected using Schirmer strips and analyzed via mass spectrometry. A total of 387 proteins were identified, with significant differences in protein expression between BS patients, healthy familial subjects, and healthy controls. Key findings include the overexpression of alpha-2-macroglobulin (A2M) and immunoglobulin heavy constant gamma 4 (IGHG4) in BS patients. Bioinformatic analysis revealed that differentially expressed proteins are involved in acute-phase response, extracellular exosome formation, and protein binding. Notably, neutrophils' azurophilic granule components, as azurocidin (AZU1), myeloperoxidases (MPO), and defensins (DEFA3), were highly expressed in the most severely affected subject, suggesting a potential role of neutrophils in BS ocular severity. These proteins might be promising biomarkers for ocular involvement in BS, facilitating early detection and tailored treatment strategies.

Causal role of immune cells in uveitis: Mendelian randomization study.

Background: Uveitis, characterized by inflammation of the iris, ciliary body, and choroid, presents a significant global clinical challenge, contributing substantially to visual impairment. Risk factors include autoimmune diseases and immune cell dysfunctions, yet many remain unidentified. Immune cells, notably T cells, B cells, and monocytes, play pivotal roles in uveitis pathogenesis. While biologic agents show promise, comprehensive studies on immune cell types in ocular diseases are lacking. Genome-wide association studies (GWAS) and Mendelian randomization (MR) present promising avenues to elucidate genetic susceptibilities and causal relationships between immune cell traits and uveitis risk. Methods: Two-sample MR analysis was used to evaluate the causal relationship between 731 immune cells and uveitis, and genome-wide significance analysis was performed for genetic variation in 731 immune cells traits (P < 5 × 10-8). Immune characteristics include median fluorescence intensity (MFI), relative cell counts (RC), absolute cell counts (AC), and morphological parameters (MP), which were determined by published GWAS, and public data from the IEU Open GWAS database. The main analysis method of MR is inverse variance weighting (IVW). Heterogeneity and horizontal pleiotropy were also assessed. Results: 5 immunophenotypes, including CD62L-DC %DC, IgD+ CD38dim %B cell, CD3 on CM CD4+T cell, CD3 on CD45RA-CD4 +T cell, and CD3 on CD39+ CD4+ Treg may increase the risk of uveitis. 5 immunophenotypes, including CD11b on CD33dim HLA DR-Myeloid cell, HLA DR on CD33dim HLA DR+ CD11b-myeloid cell, CD14-CD16 + %monocyte, HLA DR on CD14-CD16 + monocyte and PDL-1 on CD14-CD16 + monocyte was negatively associated with the risk of uveitis. Among them, HLA DR on CD14-CD16 + monocyte (OR=0.921, 95%CI =0.875-0.970, P=0.001) and HLA DR on CD33dim HLA DR+ CD11b- (OR=0.879, 95%CI = 0.833-0.927, P=0.00) were negatively associated with the risk of uveitis in bi-direction. Conclusion: These results indicate that 10 immune cells traits are significantly associated with the risk of developing uveitis and 2 of them were strongly associated with uveitis bi-directionally, after excluding the effects of confounding factors such as some immune diseases, which provided new ideas and therapeutic targets for the study of immune mechanism of uveitis.

Unmasking an unusual presentation of Hodgkin's lymphoma masquerading as ocular inflammation: a case report.

BACKGROUND: Hodgkin's lymphoma (HL) is an extremely rare cause of ocular inflammation that is usually not considered in the typical workup of uveitis and other eye diseases. A few cases of ocular inflammation were reported previously showcasing HL with absence of typical symptoms of HL at presentation. Acknowledging the potential ocular inflammation associated with HL can prompt ophthalmologists to broaden their diagnostic approach and collaborate with internal medicine departments to investigate this rare yet significant etiology. CASE PRESENTATION: A 17-year-old Caucasian woman presenting unilateral panuveitis was later diagnosed with HL. The ocular findings were non-necrotizing scleritis, anterior uveitis, vitritis, white/yellowish chorioretinal lesions, papillitis and vasculitis. A left supra-clavicular lymph node biopsy confirmed the diagnosis of nodular sclerosing Hodgkin's lymphoma stage IIB. Other causes of uveitis were excluded. Chemotherapy led to remission of the disease and the ocular lesions became quiescent with persistent pigmented chorioretinal scars. CONCLUSIONS: Hodgkin's lymphoma should be considered in the differential diagnosis of diseases that can occasionally be revealed by unilateral ocular inflammation. A comprehensive, multidisciplinary approach is key to properly assessing such cases.

Brolucizumab-associated intraocular inflammation in Indian patients by VRSI study group.

CONTEXT: Concerns about brolucizumab's (Pagenax®) association with intraocular inflammation (IOI) limit its use despite its cost-effectiveness and efficacy. This multicentric study analyzes IOI incidence across 21 tertiary eyecare centers in India since its introduction in October 2020. PURPOSE: To determine the real-world incidence rate of IOI in Indian patients secondary to intravitreal brolucizumab across 21 tertiary eye care centers in India. SETTINGS AND DESIGN: Retrospective multicentric, survey-based study. METHODS: Data including number of patients treated, clinical indications, side effects encountered, and IOI case details was collected via Google Forms in 21 Indian tertiary eye care centers since October 2020. Mean, median, frequency, and standard deviation were calculated for statistical analysis. RESULTS: All centers used pro re nata protocol for brolucizumab injections with a minimum injection interval of 8 weeks. The incidence of IOI was 0.79% (21 events out of 2655 eyes). Treatment indications included idiopathic polypoidal choroidal vasculopathy, neovascular age-related macular degeneration, diabetic macular edema, and off-label uses. IOI was experienced after the first injection (57%) in majority of cases with a median onset of 14 days (range: 1-65 days). IOI was mild in 28.5%, moderate in 33%, and severe in 38% of cases. Eighteen out of 21 IOI eyes recovered preinjection best corrected visual acuity or better. CONCLUSIONS: Our study found a lower IOI incidence (0.79%) with brolucizumab (Pagenax) in Indian patients compared to previously reported literature. IOI events were mostly mild to moderate, and post-treatment, most patients improved or maintained BCVA. Larger prospective multicentric studies with PRN dosing protocol are needed to confirm these findings.

Cytokines in PD-1 immune checkpoint inhibitor adverse events and implications for the treatment of uveitis.

Immune checkpoint inhibitors (ICI) such as Programmed cell Death 1 (PD-1) inhibitors have improved cancer treatment by enhancing the immune system's ability to target malignant cells. Their use is associated with immune-related adverse events (irAEs), including uveitis. The profile of pro-inflammatory cytokines underlying Anti-PD-1-induced uveitis shares significant overlap with that of non-infectious uveitis. Current corticosteroid treatments for uveitis while effective are fraught with vision threatening side effects. The cytokine profile in ICI-related uveitis has a large overlap with that of noninfectious uveitis, this overlap strongly supports the potential for therapy that activates the PD-1 axis in the eye to treat uveitis. Indeed, ICI related uveitis often resolves with cessation of the ICI, restoring the endogenous PD-1 axis. The potential benefit of targeting many pro-inflammatory cytokines via local PD-1 axis activation is mitigating ocular inflammation while minimizing adverse effects.

Influence of gender on clinical presentation, management practices and outcomes of ocular syphilis.

Ocular syphilis is a re-emerging inflammatory eye disease with a clear gender imbalance, disproportionately affecting men. We investigated the impact of gender on the presentation, management practices and clinical outcomes of this condition. Data generated from a study of patients consecutively diagnosed with ocular syphilis who attended a subspecialist uveitis service at one of four hospitals in Brazil over a 30-month period were disaggregated for analysis by gender. Two-hundred and fourteen eyes (161 men and 53 women) of 127 patients (96 men and 31 women) were included. Posterior uveitis was the most common presentation in both men and women (80.1% vs. 66.7%, p > 0.05), but men were significantly more likely to have vitritis as a feature of their disease (49.4% versus 28.8%, p = 0.019). Three eyes of women had nodular anterior scleritis (p = 0.015). Men were more likely to undergo a lumbar puncture to assess for neurosyphilis (71.9% vs. 51.6%, p = 0.048), but men and women undergoing a lumbar puncture were equally likely to have a cerebrospinal fluid abnormality (36.2% vs. 25.0%, p = 0.393). All patients were treated with aqueous penicillin G or ceftriaxone, and there was a trend towards more men receiving adjunctive systemic corticosteroid treatment as part of their management (65.2% vs. 46.7%, p = 0.071). There were no significant differences in the age of presentation, bilaterality of disease, anatomical classification of uveitis, initial or final visual acuity, and rates of ocular complications between men and women. Our findings indicate that ocular syphilis has comparable outcomes in men and women, but that there are differences in the type of ocular inflammation and management practices between the genders.

[Uveitis and multiple sclerosis : Clinical aspects, diagnostics, management and treatment]. / Uveitis und multiple Sklerose : Klinik, Diagnostik, Management und Therapie.

Approximately 0.5-1% of patients with multiple sclerosis (MS) have co-existing uveitis. Both intraocular inflammation and MS mainly affect women in younger adulthood. The MS in patients is most frequently associated with an often bilateral intermediate uveitis with typical concomitant retinal vasculitis. Both diseases share similar characteristics with chronic inflammatory diseases with a relapsing course and an immune-mediated pathogenesis; however, it is still unclear whether the co-occurrence of uveitis and MS in the same patient represents a coincidence of two separate disease entities or whether uveitis is a rare clinical manifestation of MS. In the differential diagnostics of intermediate uveitis, clinical symptoms and signs of MS should be considered. As both diseases are considered to be immune-mediated, immunotherapy is the main treatment option. In recent years the range of medications has expanded and includes several disease modifying drugs (biologics). When selecting the active substance it must be taken into account that tumor necrosis factor (TNF) alpha blockers are contraindicated in patients with MS.

Quantitative urinary proteome analysis reveals potential biomarkers for disease activity of Behcet's disease uveitis.

PURPOSE: Behçet's disease-associated uveitis (BDU) is a severe, recurrent inflammatory condition affecting the eye and is part of a systemic vasculitis with unknown etiology, making biomarker discovery essential for disease management. In this study, we intend to investigate potential urinary biomarkers to monitor the disease activity of BDU. METHODS: Firstly, label-free data-dependent acquisition (DDA) and tandem mass tag (TMT)-labeled quantitative proteomics methods were used to profile the proteomes of urine from active and quiescent BDU patients, respectively. For further exploration, the remaining fifty urine samples were analyzed by a data-independent acquisition (DIA) quantitative proteomics method. RESULTS: Twenty-nine and 21 differential proteins were identified in the same urine from BDU patients by label-free DDA and TMT-labeled analyses, respectively. Seventy-nine differentially expressed proteins (DEPs) were significantly changed in other active BDU urine samples compared to those in quiescent BDU urine samples by IDA analysis. Gene Ontology (GO) and protein-protein interaction (PPI) analyses revealed that the DEPs were associated with multiple functions, including the immune and neutrophil activation responses. Finally, seven proteins were identified as candidate biomarkers for BDU monitoring and recurrence prediction, namely, CD38, KCRB, DPP4, FUCA2, MTPN, S100A8 and S100A9. CONCLUSIONS: Our results showed that urine can be a good source of biomarkers for BDU. These dysregulated proteins provide potential urinary biomarkers for BDU activity monitoring and provide valuable clues for the analysis of the pathogenic mechanisms of BDU.

Pulmonary manifestation of VEXAS syndrome.

This case report presents the diagnostic journey of a man in his mid-70s who experienced shortness of breath, cough, recurrent episodes of fever, weight loss, pruritic erythroderma, uveitis and macrocytic anaemia. The initial diagnosis of cryptogenic organising pneumonia was made based on antibiotic refractory infiltrates seen in the lung CT scan. The patient initially responded favourably to immunosuppression but experienced a recurrence of symptoms when the corticosteroid dose was tapered. Despite ongoing systemic inflammation and refractory symptoms, it took nearly a year to establish the diagnosis of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic) syndrome. This case highlights the challenges in diagnosing and managing VEXAS syndrome due to its recent discovery and limited awareness in the medical community, as well as the need to consider this syndrome as a rare differential diagnosis of therapy-refractory pulmonary infiltrates.

Cataract Development Among Pediatric Patients With Uveitis.

Importance: The long-term estimated risk of development of cataracts among pediatric patients with uveitis is not clear. Objective: To describe factors associated with the development of cataracts among pediatric patients with uveitis. Design, Setting, and Participants: This cohort study used the international TriNetX database to enroll pediatric patients with and without uveitis from January 1, 2002, to December 31, 2022. The nonuveitis cohort consisted of randomly selected control patients matched by age, sex, race and ethnicity, and specific comorbidities. Exposure: Diagnosis of uveitis, identified using diagnostic codes. Main Outcomes and Measures: The primary outcome was the risk of developing cataracts among the uveitis group compared with the nonuveitis comparison group, with hazard ratios (HRs) and 95% CIs reported. Results: A total of 22 687 pediatric patients with uveitis (mean [SD] age, 10.3 [5.6] years; 54.2% male) and 22 687 comparators without uveitis (mean [SD] age, 10.3 [5.6] years; 54.5% male) were enrolled in the study. The risk of cataracts was increased among pediatric patients with uveitis up to a follow-up duration of 20 years (HR, 17.17; 95%CI, 12.90-22.80) from the index date. Subgroup analyses revealed an elevated cataract risk across age groups: 0 to 6 years (HR, 19.09; 95% CI, 10.10-36.00), 7 to 12 years (HR, 27.16; 95% CI, 15.59-47.20), and 13 to 18 years (HR, 13.39; 95% CI, 8.84-20.30); both female sex (HR, 13.76; 95% CI, 9.60-19.71) and male sex (HR, 11.97; 95% CI, 8.47-16.91); and Asian (HR, 13.80; 95% CI, 3.28-58.07), Black or African American (HR, 10.41; 95% CI, 5.60-19.36), and White (HR, 15.82; 95% CI, 11.05-22.60) race. Furthermore, increased cataract risks were also observed among those with and without a history of immunosuppressive agents (with: HR, 26.52 [95% CI, 16.75-41.90]; without: HR, 17.69 [95% CI: 11.39-27.40]), a history of steroid eye drop use (with: HR, 29.51 [95% CI, 14.56-59.70]; without: HR, 16.49 [95% CI, 11.92-22.70]), and a history of intraocular procedures (with: HR, 11.07 [95%CI, 4.42-27.71]; without: HR, 14.49 [95% CI, 10.11-20.70]). Conclusions and Relevance: In this cohort study of pediatric patients with uveitis, an elevated risk of cataracts following a uveitis diagnosis was found compared with pediatric patients without uveitis. The findings suggest that pediatric patients with uveitis should be monitored for cataract development.

Epithelial inclusion cyst secondary to glaucoma surgery: A case series.

Epithelial inclusion cysts (EIC) are a rare ocular disease and its physiopathology is not well-known. They consist on growths of ocular surface epithelial cells inside the anterior segment of the eye in the form of a cyst. To date several cases have been published in the literature, none of them related to glaucoma surgery. We describe two cases of EIC after glaucoma devices implantation. An 86 year-old male patient with primary open angle glaucoma develop an EIC in right eye three years after removal of PRESERFLO™ MicroShunt (Santen, Osaka, Japan) and a 9 year-old female patient with glaucoma secondary to uveitis for juvenile idiopathic arthritis develops an EIC under the tube of an Ahmed valve implant during postoperative period. EIC develop after ocular penetrating wounds and an inflammatory stimulus. They are benign proliferations, follow-up is necessary to detect space complications early, so less mutilating surgery is needed for removal.

Topical ophthalmic instillation of engineered hMSCs-derived exosomes: A novel non-invasive therapeutic strategy for ocular posterior-segment disorder.

Due to the presence of protective mechanisms and blood-ocular barriers in the eye, drugs aimed at treating posterior segment ophthalmic disorder have to be administrated mostly through periocular or intravitreal injection. In the current study, we sought to investigate whether topical ophthalmic instillation of human mesenchymal stem cells (hMSCs)-derived exosomes can prevent and treat experimental autoimmune uveitis (EAU), a posterior segment ophthalmic disease induced in animals and considered a model of human autoimmune diseases of the eye. Our studies reveal that topical ophthalmic instillation of hMSCs-derived exosomes can effectively ameliorate EAU. More importantly, we demonstrate that exosomes modified by trans-activator of transcription peptide (TAT) were more effective than naive exosomes in penetrating ocular barrier and preventing/treating EAU. Taken together, these results indicate that topical ophthalmic instillation of TAT-peptide modified exosomes represents a novel non-invasive therapeutic strategy for posterior-segment ophthalmic disorders.

Course of Uveitis in Patients with Ankylosing Spondylitis during the Interleukin17 Inhibitors Therapy.

Biological disease-modifying antirheumatic drugs (bDMARDs) can have different effects on various clinical manifestations of ankylosing spondylitis (AS). Data on the effects of interleukin 17 inhibitors (IL17-i) on uveitis in AS continue to accumulate. Objective: to evaluate the effect of IL17-i therapy on the course of uveitis in AS. The study involved 73 patients with AS (New York criteria, 1984), who received IL17-i (57-secukinumab (SEC), 22-netakimab (NTK)) for at least 1 year. The average age of patients at the time of inclusion in the study was 41.93 ± 8.95 years, the average duration of AS was 10.75 ± 6.22 years. There were 40 men (56.7%) and 33 women (43.3%) among the patients. HLA-B27 was detected in 62/73 (85%), coxitis in 58 (79%), enthesitis in 63 (86.3%), peripheral arthritis in 57 (78%), psoriasis in 7 (9.5%), and inflammatory bowel disease (IBD) in 3 (4.1%) patients; in 6 (8.2%) patients, the disease started before the age of 16; 19 (26%) patients had at least one episode of uveitis during the course of the disease. The rates of uveitis was estimated by comparing the number of incidences per 100 patient-years before the start of bDMARDs therapy and during IL17-i using. The incidence rate of uveitis before the start of bDMARDs therapy for all patients was 8.3 per 100 pt-years (95% CI 0.065-0.107), during IL17-i therapy- 9.2 per 100 pt-years (95% CI 0.06-0.15), p = 0.72. The incidence rate of uveitis among patients who used SEC was 10.1 per 100 pt-years (95% CI 0.079-0.13) before the start of bDMARDs therapy and 9.4 per 100 pt-years (95% CI 0.05-0.15), p = 0.74 during SEC therapy. The incidence rate of uveitis among patients who used NTK was 4.8 per 100 pt-years (95% CI 0.028-0.08) before the start of bDMARDs therapy and 7.1 per 100 pt-years (95% CI 0.019-022), p = 0.3 during the NTK therapy. For patients with a history of uveitis, the incidence rate of uveitis was 22.5 per 100 pt-years (95% CI 0.18-0.28) before the start of therapy with bDMARDs and 29.1 per 100 pt-years (95% CI 0.18-0.43), p = 0.29 during IL17-i therapy. Occurrences of uveitis were observed in 4 of 57 patients (7%) during SEC therapy and in 1 of 25 (4%) patients during the NTK therapy. One case of new-onset uveitis was recorded during the using of SEC. There were no significant differences in the incidence rates of uveitis during IL17-i therapy compared with non-biological therapy. IL17-i therapy have not demonstrated a significant effect on the course of uveitis in AS in the study group.

Polyvinylpyrrolidone-curcumin nanoparticles with immune regulatory and metabolism regulatory effects for the treatment of experimental autoimmune uveitis.

Uveitis comprises a cluster of intraocular inflammatory disorders characterized by uncontrolled autoimmune responses and excessive oxidative stress leading to vision loss worldwide. In the present study, curcumin (CUR) was conjugated with polyvinylpyrrolidone (PVP) to form PVP-CUR nanoparticles with significantly elevated solubility and outstanding multiple radical scavenging abilities. In vitro studies revealed that PVP-CUR nanoparticles markedly mitigated oxidative stress and reduced apoptosis in a H2O2-induced human retinal pigment epithelial cell line (ARPE-19) and promoted phenotypic polarization from M1 to M2 in an LPS-induced human microglial cell line (HMC3). Further in vivo studies demonstrated the prominent therapeutic effects of PVP-CUR nanoparticles on experimental autoimmune uveitis (EAU), which relieved clinical and pathological progression, improved perfusion and tomographic manifestations of retinal vessels, and reduced blood-retinal barrier (BRB) leakage; these effects may be mediated by mitigating oxidative stress and attenuating macrophage/microglia-elicited inflammation. Notably, treatment with PVP-CUR nanoparticles was shown to regulate metabolite alterations in EAU rats, providing novel insights into the underlying mechanisms involved. Additionally, the PVP-CUR nanoparticles showed great biocompatibility in vivo. In summary, our study revealed that PVP-CUR nanoparticles may serve as effective and safe nanodrugs for treating uveitis and other oxidative stress- and inflammation-related diseases.