ABSTRACT
Purpose: Nonanterior uveitis frequently involves the retinal vasculature; however, no molecular markers associated with the retinal vascular disease are currently known. In this study, we aimed to identify serum biomarker signatures associated with retinal vascular involvement in noninfectious pediatric uveitis. Methods: We performed a 384-plex targeted proteomic analysis of serum samples of 154 noninfectious pediatric uveitis patients diagnosed with nonanterior uveitis (n = 74), idiopathic chronic anterior uveitis (iCAU, n = 36), or juvenile idiopathic arthritis-associated uveitis (JIA-U, n = 44), as well as 22 noninflammatory pediatric controls. Data on retinal vascular involvement (i.e., papillitis, cystoid macular edema, retinal vasculitis, or retinal capillary leakage on optical coherence tomography and/or fluorescein angiography) were used to stratify cases in the nonanterior uveitis group. Results: In the analysis of nonanterior uveitis, we identified nine proteins significantly associated with retinal vascular involvement, including F13B, MYOM3, and PTPN9. These proteins were enriched through pathway enrichment analysis for the coagulation cascade. Comparing cases and controls, we identified 63 differentially expressed proteins, notably proteins involved in platelet biology and complement cascades, which could be primarily attributed to differences in serum proteomes between anterior uveitis and nonanterior uveitis groups. Conclusions: Serum proteins related to the coagulation and complement cascade are associated with retinal vascular involvement in pediatric uveitis patients. Our results indicate involvement of mediators that could interact with the microcirculation in pediatric uveitis and might serve as potential biomarkers in personalized medicine in the future. Translational Relevance: Our targeted proteomics analysis in serum of pediatric uveitis patients indicates involvement of mediators that could interact with the microcirculation in pediatric uveitis and might serve as potential biomarkers in personalized medicine in the future.
Subject(s)
Retinal Diseases , Uveitis, Anterior , Uveitis , Humans , Child , Proteomics , Uveitis/diagnosis , Uveitis, Anterior/diagnosis , BiomarkersABSTRACT
BACKGROUND: Juvenile idiopathic arthritis (JIA)-associated uveitis typically presents as a silent chronic anterior uveitis and can lead to blindness. Adherence to current screening guidelines is hampered by complex protocols which rely on the knowledge of specific JIA characteristics. The Multinational Interdisciplinary Working Group for Uveitis in Childhood identified the need to simplify screening to enable local eye care professionals (ECPs), who carry the main burden, to screen children with JIA appropriately and with confidence. METHODS: A consensus meeting took place in January 2023 in Barcelona, Spain, with an expert panel of 10 paediatric rheumatologists and 5 ophthalmologists with expertise in paediatric uveitis. A summary of the current evidence for JIA screening was presented. A nominal group technique was used to reach consensus. RESULTS: The need for a practical but safe approach that allows early uveitis detection was identified by the panel. Three screening recommendations were proposed and approved by the voting members. They represent a standardised approach to JIA screening taking into account the patient's age at the onset of JIA to determine the screening interval until adulthood. CONCLUSION: By removing the need for the knowledge of JIA categories, antinuclear antibody positivity or treatment status, the recommendations can be more easily implemented by local ECP, where limited information is available. It would improve the standard of care on the local level significantly. The proposed protocol is less tailored to the individual than the 'gold standard' ones it references and does not aim to substitute those where they are being used with confidence.
ABSTRACT
Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended.
Subject(s)
Dermatitis, Atopic , Eczema , Humans , Antibodies, Monoclonal/therapeutic use , Prospective Studies , Treatment Outcome , Biological Therapy , Severity of Illness IndexABSTRACT
Scleritis is a severe and painful ophthalmic disorder, in which a pathogenic role for collagen-directed autoimmunity was repeatedly suggested. We evaluated the presence of sclera-specific antibodies in a large cohort of patients with non-infectious scleritis. Therefore, we prospectively collected serum samples from 121 patients with non-infectious scleritis in a multicenter cohort study in the Netherlands. In addition, healthy (n = 39) and uveitis controls (n = 48) were included. Serum samples were tested for anti-native human type II collagen antibodies using a validated enzyme-linked immunosorbent assay (ELISA). Further, sclera-specific antibodies were determined using indirect immunofluorescence (IIF) on primate retinal/scleral cryosections. Lastly, human leukocyte antigen (HLA) typing was performed in 111 patients with scleritis. Anti-type II collagen antibodies were found in 13% of scleritis patients, in 10% of healthy controls and in 11% of uveitis controls (p = 0.91). A specific reaction to scleral nerve tissue on IIF was observed in 33% of patients with scleritis, which was higher than in healthy controls (11%; p = 0.01), but similar to uveitis controls (25%; p = 0.36). Reactivity to the scleral nerve tissue was significantly associated with earlier onset of scleritis (48 versus 56 years; p < 0.001), bilateral involvement (65% versus 42%; p = 0.01), and less frequent development of scleral necrosis (5% versus 22%; p = 0.02). HLA-B27 was found to be twice as prevalent in patients with scleritis (15.3%) compared to a healthy population (7.2%). In conclusion, scleral nerve autoantibody reactivity was more common in scleritis and uveitis patients in contrast to healthy controls. Further research is needed to characterize these scleral-nerve directed antibodies and assess their clinical value.
Subject(s)
Scleritis , Uveitis , Animals , Humans , Autoimmunity , Cohort Studies , Sclera/pathology , Scleritis/pathology , Uveitis/pathologyABSTRACT
Infectious pediatric uveitis is a rare disease that can cause severe ocular damage if not detected rapidly and treated properly. Additionally, early identification of an infection can protect the child from life-threatening systemic infection. Infectious uveitis can be congenital or acquired and may manifest as a primary ocular infection or as a reactivation. Nevertheless, publications on infectious paediatric uveitis are usually limited to a small number of patients or a case report. So far, most studies on uveitis in children have focused primarily on noninfectious uveitis, and a systematic study on infectious uveitis is lacking. In this review, we summarize the literature on infectious uveitis in pediatric populations and report on the epidemiology, pathophysiology, clinical signs, diagnostic tests, and treatment. We will describe the different possible pathogens causing uveitis in childhood by microbiological group (i.e. parasites, viruses, bacteria, and fungi). We aim to contribute to early diagnosis and management of infectious pediatric uveitis, which in turn might improve not only visual outcome, but also the general health outcome.
Subject(s)
Uveitis , Humans , Uveitis/diagnosis , Uveitis/microbiology , Uveitis/epidemiology , Child , Eye Infections/diagnosis , Eye Infections/microbiology , Eye Infections, Bacterial/diagnosis , Eye Infections, Bacterial/microbiology , Eye Infections, Bacterial/epidemiologyABSTRACT
Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.
Subject(s)
Autoimmune Diseases , Polymorphism, Single Nucleotide , Humans , Polymorphism, Single Nucleotide/genetics , Genetic Predisposition to Disease/genetics , Autoimmune Diseases/genetics , Promoter Regions, Genetic/genetics , Aminopeptidases/geneticsABSTRACT
AIMS: To present current expert practice patterns and to formulate a consensus for the management of HSV and VZV AU by uveitis specialists worldwide. METHODS: A two-round online modified Delphi survey with masking of the study team was conducted. Responses were collected from 76 international uveitis experts from 21 countries. Current practices in the diagnosis and treatment of HSV and VZV AU were identified. A working group (The Infectious Uveitis Treatment Algorithm Network [TITAN]) developed data into consensus guidelines. Consensus is defined as a particular response towards a specific question meeting ≥75% of agreement or IQR ≤ 1 when a Likert scale is used. RESULTS: Unilaterality, increased intraocular pressure (IOP), decreased corneal sensation and diffuse or sectoral iris atrophy are quite specific for HSV or VZV AU from consensus opinion. Sectoral iris atrophy is characteristic of HSV AU. Treatment initiation is highly variable, but most experts preferred valacyclovir owing to simpler dosing. Topical corticosteroids and beta-blockers should be used if necessary. Resolution of inflammation and normalisation of IOP are clinical endpoints. CONCLUSIONS: Consensus was reached on several aspects of diagnosis, choice of initial treatment, and treatment endpoints for HSV and VZV AU. Treatment duration and management of recurrences varied between experts.
Subject(s)
Herpes Simplex , Herpes Zoster Ophthalmicus , Herpes Zoster , Uveitis, Anterior , Uveitis , Humans , Herpesvirus 3, Human , Simplexvirus , Herpes Zoster Ophthalmicus/diagnosis , Herpes Zoster Ophthalmicus/drug therapy , Uveitis, Anterior/diagnosis , Uveitis, Anterior/drug therapy , Atrophy , Herpes Simplex/diagnosis , Herpes Simplex/drug therapyABSTRACT
AIMS: To present current practice patterns in the diagnosis and management of Cytomegalovirus anterior uveitis (CMV AU) by uveitis experts worldwide. METHODS: A two-round modified Delphi survey with masking of the study team was performed. Based on experience and expertise, 100 international uveitis specialists from 21 countries were invited to participate in the survey. Variation in the diagnostic approaches and preferred management of CMV AU was captured using an online survey platform. RESULTS: Seventy-five experts completed both surveys. Fifty-five of the 75 experts (73.3%) would always perform diagnostic aqueous tap in suspected CMV AU cases. Consensus was achieved for starting topical antiviral treatment (85% of experts). About half of the experts (48%) would only commence systemic antiviral treatment for severe, prolonged, or atypical presentation. The preferred specific route was ganciclovir gel 0.15% for topical treatment (selected by 70% of experts) and oral valganciclovir for systemic treatment (78% of experts). The majority of experts (77%) would commence treatment with topical corticosteroid four times daily for one to two weeks along with antiviral coverage, with subsequent adjustment depending on the clinical response. Prednisolone acetate 1% was the drug of choice (opted by 70% of experts). Long-term maintenance treatment (up to 12 months) can be considered for chronic course of inflammation (88% of experts) and those with at least 2 episodes of CMV AU within a year (75-88% of experts). CONCLUSIONS: Preferred management practices for CMV AU vary widely. Further research is necessary to refine diagnosis and management and provide higher-level evidence.
Subject(s)
Cytomegalovirus Infections , Uveitis, Anterior , Humans , Cytomegalovirus , Cytomegalovirus Infections/diagnosis , Cytomegalovirus Infections/drug therapy , Aqueous Humor , Ganciclovir/therapeutic use , Antiviral Agents/therapeutic use , Uveitis, Anterior/diagnosis , Uveitis, Anterior/drug therapyABSTRACT
Juvenile idiopathic arthritis (JIA) is the most common cause of uveitis in children. While symptoms are usually mild, persistent eye inflammation could lead to severe complications and impaired vision. It is essential that JIA patients at risk are diagnosed with uveitis early, receive adequate treatment, and avoid developing complications, such as cataract, glaucoma, and amblyopia. The purpose of this mini-review is to summarize the screening strategies and clinical management for JIA-associated uveitis (JIA-U) as well as the current state of molecular markers linked to this condition. Because glaucoma is one of the most common causes of visual loss in JIA-U, special focus will be put on this serious complication. We conclude by describing the current evidence regarding the long-standing question of whether chronic anterior uveitis without arthritis may be the same disease entity as JIA-U.
Subject(s)
Arthritis, Juvenile , Endophthalmitis , Glaucoma , Uveitis, Anterior , Uveitis , Child , Humans , Arthritis, Juvenile/complications , Arthritis, Juvenile/diagnosis , Arthritis, Juvenile/drug therapy , Uveitis/diagnosis , Uveitis/etiology , Uveitis/drug therapy , Endophthalmitis/complications , Uveitis, Anterior/etiology , Uveitis, Anterior/complicationsABSTRACT
Purpose: Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are neurotropic human alphaherpesviruses endemic worldwide. Upon primary infection, both viruses establish lifelong latency in neurons and reactivate intermittently to cause a variety of mild to severe diseases. Acute retinal necrosis (ARN) is a rare, sight-threatening eye disease induced by ocular VZV or HSV infection. The virus and host factors involved in ARN pathogenesis remain incompletely described. We hypothesize an underlying genetic defect in at least part of ARN cases. Methods: We collected blood from 17 patients with HSV-or VZV-induced ARN, isolated DNA and performed Whole Exome Sequencing by Illumina followed by analysis in Varseq with criteria of CADD score > 15 and frequency in GnomAD < 0.1% combined with biological filters. Gene modifications relative to healthy control genomes were filtered according to high quality and read-depth, low frequency, high deleteriousness predictions and biological relevance. Results: We identified a total of 50 potentially disease-causing genetic variants, including missense, frameshift and splice site variants and on in-frame deletion in 16 of the 17 patients. The vast majority of these genes are involved in innate immunity, followed by adaptive immunity, autophagy, and apoptosis; in several instances variants within a given gene or pathway was identified in several patients. Discussion: We propose that the identified variants may contribute to insufficient viral control and increased necrosis ocular disease presentation in the patients and serve as a knowledge base and starting point for the development of improved diagnostic, prophylactic, and therapeutic applications.
ABSTRACT
BACKGROUND: Pediatric uveitis is a severe inflammatory ocular condition that can lead to sight-threatening complications and can negatively impact quality of life. The retinal microcirculation is often affected in intermediate uveitis and panuveitis. Here, we examined the extraocular (i.e., systemic) microcirculation in pediatric uveitis cases and healthy controls using nailfold capillaroscopy (NFC). METHODS: We performed NFC in 119 children with noninfectious uveitis and 25 healthy pediatric controls, and assessed the following parameters: capillary density (number of capillaries/mm), dilated capillaries (apex > 20 µm), avascular area, the presence of microhemorrhages, and capillary morphology. Differences in NFC parameters between cases and controls were calculated using regression analysis after adjusting for age and sex. RESULTS: The mean (± SD) age of the patient group was 13.7 (± 3) years, with 56% females; 46%, 18%, and 36% of cases presented as anterior uveitis, intermediate uveitis, and panuveitis, respectively, with an overall mean disease duration of 4.7 (± 4.0) years. Compared to the control group, the pediatric uveitis cases had a significantly higher number of dilated capillaries/mm and a higher prevalence of ramified capillaries. Moreover, compared to the control group the intermediate uveitis cases had a significantly higher number of dilated capillaries, whereas the anterior uveitis cases had a lower capillary density and a higher prevalence of ramified capillaries. CONCLUSIONS: Children with uveitis without systemic disease can present with changes in systemic microcirculation. These changes vary amongst the subtypes of uveitis.
Subject(s)
Panuveitis , Uveitis, Anterior , Uveitis, Intermediate , Uveitis , Female , Humans , Child , Adolescent , Male , Microcirculation , Quality of Life , Nails/blood supply , Uveitis/etiology , Microscopic AngioscopyABSTRACT
Purpose: Eye inflammation may occur in patients with inherited retinal dystrophies (IRDs) and is seen frequently in IRDs associated with mutations in the CRB1 gene. The purpose of this study was to determine the types of inflammatory cells involved in IRDs, by deep profiling the composition of peripheral blood mononuclear cells of patients with a CRB1-associated IRD. Methods: This study included 33 patients with an IRD with confirmed CRB1 mutations and 32 healthy controls. A 43-parameter flow cytometry analysis was performed on peripheral blood mononuclear cells isolated from venous blood. FlowSOM and manual Boolean combination gating were used to identify and quantify immune cell subsets. Results: Comparing patients with controls revealed a significant increase in patients in the abundance of circulating CD4+ T cells and CD8+ T cells that express sialyl Lewis X antigen. Furthermore, we detected a decrease in plasmacytoid dendritic cells and an IgA+CD24+CD38+ transitional B-cell subset in patients with an IRD. Conclusions: Patients with a CRB1-associated IRD show marked changes in blood leukocyte composition, affecting lymphocyte and dendritic cell populations. These results implicate inflammatory pathways in the disease manifestations of IRDs.
Subject(s)
Eye Abnormalities , Retinal Dystrophies , Humans , Leukocytes, Mononuclear/metabolism , Eye Proteins/genetics , Eye Proteins/metabolism , Retinal Dystrophies/genetics , Mutation , T-Lymphocytes/metabolism , Membrane Proteins/genetics , Nerve Tissue Proteins/geneticsABSTRACT
BACKGROUND: Immunization with meningococcal ACWY conjugate vaccine induces protective antibodies against invasive meningococcal disease (IMD) caused by serogroups A, C, W and Y. We studied MenACWY-TT vaccine immunogenicity in adolescents with a heterogenous group of primary and secondary immune deficiency including patients with systemic lupus erythematosus, mixed connective tissue disease, vasculitis, uveitis, 22Q11 syndrome, sickle cell disease, and patients who underwent stem cell transplantation for bone marrow failure. FINDINGS: We enrolled 69 individuals aged 14-18 years diagnosed with a primary or secondary immune deficiency in a prospective observational cohort study. All patients received a single dose of MenACWY-TT vaccine during the catch-up campaign 2018-19 because of the IMD-W outbreak in the Netherlands. Capsular polysaccharide-specific (PS) IgG concentrations against MenACWY were measured before and 3-6, 12, and 24 months after vaccination. Overall, geometric mean concentrations (GMCs) of MenACWY-PS-specific IgG were lower in patients compared to data from healthy, aged-matched controls (n = 75) reaching significance at 12 months postvaccination for serogroup A and W (adjusted GMC ratios 0.26 [95% CI: 0.15-0.47] and 0.22 [95% CI: 0.10-0.49], respectively). No serious adverse events were reported by study participants. CONCLUSIONS: The MenACWY conjugate vaccine was less immunogenic in adolescent patients with primary or secondary immunodeficiency compared to healthy controls, urging the need for further surveillance of these patients and supporting considerations for booster MenACWY conjugate vaccinations in these patient groups.
Subject(s)
Meningococcal Infections , Meningococcal Vaccines , Humans , Adolescent , Vaccines, Conjugate/adverse effects , Immunogenicity, Vaccine , Prospective Studies , Antibodies, Bacterial , Meningococcal Infections/prevention & control , Meningococcal Infections/chemically induced , Meningococcal Vaccines/adverse effects , Immunoglobulin GABSTRACT
Importance: Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. Objective: To identify the genes and pathways associated with idiopathic MFC. Design, Setting, and Participants: This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Main outcomes and measures: Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. Results: This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10-8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Conclusions and relevance: Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.
Subject(s)
Choroiditis , Complement Factor H , Humans , Male , Female , Middle Aged , Complement Factor H/genetics , Multifocal Choroiditis , Genome-Wide Association Study , Proteomics , Polymorphism, Single Nucleotide , Choroiditis/diagnosis , Choroiditis/genetics , Proteins/geneticsABSTRACT
BACKGROUND: Immunogenicity to meningococcal serogroup ACWY (MenACWY) conjugate vaccine has not been studied in immunocompromised minors with juvenile idiopathic arthritis (JIA) or inflammatory bowel disease (IBD). We determined immunogenicity of a MenACWY-TT vaccine in JIA and IBD patients at adolescent age and compared results to data from aged-matched healthy controls (HCs). METHODS: We performed a prospective observational cohort study in JIA and IBD patients (14-18 years old), who received a MenACWY vaccination during a nationwide catch-up campaign (2018-2019) in the Netherlands. Primary aim was to compare MenACWY polysaccharide-specific serum IgG geometric mean concentrations (GMCs) in patients with HCs and secondary between patients with or without anti-TNF therapy. GMCs were determined before and 3-6, 12, and 24 months postvaccination and compared with data from HCs at baseline and 12 months postvaccination. Serum bactericidal antibody (SBA) titers were determined in a subset of patients at 12 months postvaccination. RESULTS: We included 226 JIA and IBD patients (66 % and 34 % respectively). GMCs were lower for MenA and MenW (GMC ratio 0·24 [0·17-0·34] and 0·16 [0·10-0·26] respectively, p < 0·01) in patients compared to HCs at 12 months postvaccination. Anti-TNF users had lower MenACWY GMCs postvaccination compared with those without anti-TNF (p < 0·01). The proportion protected (SBA ≥ 8) for MenW was reduced in anti-TNF users (76 % versus 92 % in non-anti-TNF and 100 % in HCs, p < 0.01). CONCLUSION: The MenACWY conjugate vaccine was immunogenic in the vast majority of JIA and IBD patients at adolescent age, but seroprotection was lower in patients using anti-TNF agents. Therefore, an extra booster MenACWY vaccination should be considered.
Subject(s)
Arthritis, Juvenile , Meningococcal Infections , Meningococcal Vaccines , Adolescent , Humans , Antibodies, Bacterial , Arthritis, Juvenile/drug therapy , Immunogenicity, Vaccine , Meningococcal Infections/prevention & control , Meningococcal Vaccines/adverse effects , Prospective Studies , Vaccines, Conjugate/adverse effectsABSTRACT
PURPOSE: To investigate the diagnostic value of using retinal nerve fiber layer thickness measured on optical coherence tomography (OCT-RNFL) to diagnose papillitis in pediatric uveitis. DESIGN: Retrospective cohort study. METHODS: Demographic and clinical data were collected retrospectively for 257 children with uveitis (with 455 affected eyes). Receiver operating characteristic (ROC) analysis was performed to compare fluorescein angiography (FA, the diagnostic gold standard for papillitis) to OCT-RNFL in a subgroup of 93 patients. An ideal cut-off value for OCT-RNFL was then determined by calculating the highest Youden index. Finally, a multivariate analysis was applied to the clinical ophthalmological data. RESULTS: Based on a subset of 93 patients who underwent both OCT-RNFL and FA, the ideal cut-off OCT-RNFL for diagnosing papillitis was >130 µm, with 79% sensitivity and 85% specificity. Among the entire cohort, the prevalence of OCT-RNFL >130 µm was 19% (27/141), 72% (26/36), and 45% (36/80) in patients with anterior uveitis, intermediate uveitis, and panuveitis, respectively. Our multivariate analysis of the clinical data revealed that OCT-RNFL >130 µm was associated with a higher prevalence of cystoid macular edema, active uveitis, and optic disc swelling on fundoscopy, with odds ratios of 5.3, 4.3, and 13.7, respectively (all P < .001). CONCLUSIONS: OCT-RNFL can be a useful noninvasive additional imaging tool for diagnosing papillitis in pediatric uveitis with relatively high sensitivity and specificity. OCT-RNFL was >130 µm in approximately one-third of all children with uveitis and was particularly prevalent in cases of intermediate uveitis and panuveitis.
Subject(s)
Panuveitis , Papilledema , Uveitis, Intermediate , Uveitis , Humans , Child , Papilledema/diagnosis , Retrospective Studies , Retinal Ganglion Cells , Tomography, Optical Coherence/methods , Uveitis/diagnosis , Nerve FibersABSTRACT
Background: Type I interferons (IFNs) promote the expansion of subsets of CD1c+ conventional dendritic cells (CD1c+ DCs), but the molecular basis of CD1c+ DCs involvement in conditions not associated without elevated type I IFNs remains unclear. Methods: We analyzed CD1c+ DCs from two cohorts of non-infectious uveitis patients and healthy donors using RNA-sequencing followed by high-dimensional flow cytometry to characterize the CD1c+ DC populations. Results: We report that the CD1c+ DCs pool from patients with non-infectious uveitis is skewed toward a gene module with the chemokine receptor CX3CR1 as the key hub gene. We confirmed these results in an independent case-control cohort and show that the disease-associated gene module is not mediated by type I IFNs. An analysis of peripheral blood using flow cytometry revealed that CX3CR1+ DC3s were diminished, whereas CX3CR1- DC3s were not. Stimulated CX3CR1+ DC3s secrete high levels of inflammatory cytokines, including TNF-alpha, and CX3CR1+ DC3 like cells can be detected in inflamed eyes of patients. Conclusions: These results show that CX3CR1+ DC3s are implicated in non-infectious uveitis and can secrete proinflammatory mediators implicated in its pathophysiology. Funding: The presented work is supported by UitZicht (project number #2014-4, #2019-10, and #2021-4). The funders had no role in the design, execution, interpretation, or writing of the study.
Subject(s)
Transcriptome , Uveitis , Humans , Antigens, CD1/analysis , Cytokines , Dendritic Cells/physiology , Uveitis/genetics , Flow Cytometry , CX3C Chemokine Receptor 1/geneticsABSTRACT
OBJECTIVE: To study the effect of methotrexate (MTX) therapy on new-onset uveitis in patients with biological-naïve juvenile idiopathic arthritis (JIA). METHODS: In this matched case-control study, we compared MTX exposure between cases with JIA-associated chronic uveitis (JIA-U) and patients with JIA and without JIA-U at the time of matching (controls). Data were collected from electronic health records of the University Medical Centre Utrecht, the Netherlands. Cases with JIA-U were matched 1:1 to JIA control patients based on JIA diagnosis date, age at JIA diagnosis, JIA subtype, antinuclear antibodies status and disease duration. The effect of MTX on JIA-U onset was analysed using a multivariable time-varying Cox regression analysis. RESULTS: Ninety-two patients with JIA were included and characteristics were similar between cases with JIA-U (n=46) and controls (n=46). Both ever-use of MTX and exposure years were lower in cases with JIA-U than in controls. Cases with JIA-U significantly more often discontinued MTX treatment (p=0.03) and out of those who did, 50% afterwards developed uveitis within 1 year. On adjusted analysis, MTX was associated with a significantly reduced new-onset uveitis rate (HR: 0.35; 95% CI: 0.17 to 0.75). No different effect was observed between a low (<10 mg/m2/week) and standard MTX dose (≥10 mg/m2/week). CONCLUSION: This study demonstrates an independent protective effect of MTX on new-onset uveitis in patients with biological-naïve JIA. Clinicians might consider early initiation of MTX in patients at high uveitis risk. We advocate more frequent ophthalmologic screening in the first 6-12 months after MTX discontinuation.
Subject(s)
Antirheumatic Agents , Arthritis, Juvenile , Uveitis , Humans , Methotrexate/therapeutic use , Arthritis, Juvenile/drug therapy , Antirheumatic Agents/therapeutic use , Case-Control Studies , Uveitis/drug therapyABSTRACT
BACKGROUND: Dupilumab-associated ocular surface disease (DAOSD) is frequently reported as side effect in atopic dermatitis (AD) patients. Therefore, the aim of this study was to investigate the frequency and severity of DAOSD, ophthalmic treatment response and to learn more about the effect of dupilumab on conjunctival goblet cells (GC). METHODS: This prospective study included dupilumab-treated AD patients between February 2020 and June 2022 from the University Medical Centre Utrecht. Patients were examined by an ophthalmologist and a dermatologist before start (baseline), and after 4 and 28 weeks of dupilumab treatment. Ophthalmological examination was assessed by the Utrecht Ophthalmic Inflammatory and Allergic disease (UTOPIA) score. DAOSD was defined as an increase in UTOPIA score of ≥3 points from baseline. To quantify conjunctival GCs and to investigate the percentage of Cytokeratin 19 (CK19)-CD45-Mucin 5 AC (MUC5AC)+ cells, conjunctival impression cytology samples were analysed. RESULTS: Ocular surface disease (OSD) was present in 91.3% (n = 63/69) patients at baseline. DAOSD was observed in 28.9% (n = 20/69) patients, in whom GC numbers remained stable and the percentage of CK19-CD45-MUC5AC+ cells decreased at onset of DAOSD compared with baseline. After 28 weeks of dupilumab treatment, DAOSD was seen in 14.5% (n = 10/69) patients. Of the 85.5% (n = 59/69) patients without DAOSD or with controlled DAOSD at Week 28, 40.7% (n = 24/59) patients received anti-inflammatory ophthalmic drugs. CONCLUSIONS: Ocular surface disease is common in moderate-to-severe AD patients before starting dupilumab. During treatment with dupilumab DAOSD severity improves with early ophthalmic treatment. The decrease in percentage of CK19-CD45-MUC5AC+ cells during dupilumab treatment suggests an impairment of the GC function due to dupilumab treatment.