Ocular Behcet Research Articles

Epidemiology and Clinical Course of Pediatric Uveitis in a Tertiary Referral Center in Northeastern Iran

ABSTRACT Purpose To describe the distribution, clinical findings, treatment, complications, and visual outcomes of pediatric uveitis at a tertiary referral ophthalmic center. Methods The medical records of all patients ≤18 years diagnosed with and managed as uveitis from August 2016 to August 2021 were reviewed retrospectively. Results Of the 97 patients, 52.6% were female, and the mean age at the onset was 10.5 ± 4.6 years (6 months to 18 years). Uveitis cases were predominantly anterior (33 [34%]), chronic (59 [60.8%]), bilateral (63 [64.9%]), and non-infectious (80 [82.5%]). A total of 36.1% (35 patients) of cases were idiopathic, and the most frequent systemic associations were juvenile idiopathic arthritis (JIA), 16 [16.5%]) and Behcet’s disease (15 [15.5%]). Most patients (74 [76.3%]) experienced ocular complications, including vasculitis (29 [29.9%]), posterior synechiae (23 [23.7%]), and cataracts (22 [22.7%]). Patients with uveitis of all anatomic locations experienced an improvement in best-corrected visual acuity during the follow-up period (p < 0.01). Conclusion The most prevalent systemic associations were JIA and Behcet’s disease. Ocular Behcet is a common etiology of pediatric uveitis in northeastern Iran. A timely and appropriate treatment could result in satisfactory visual outcomes.

Optical coherence tomography findings due to structural changes of the choroid and retina in Behçet's uveitis

Aims: To evaluate the change in central macular and retinal nerve fiber layer (RNFL) thickness by using optical coherence tomography (OCT) and choroidal thickness by using enhanced depth imaging optical coherence tomography (EDI-OCT) in posterior uveitis of Behcet’s disease, to compare these results with the healthy population and to investigate the relationship between these parameters and Behcet’s disease duration, the number of ocular attacks and visual acuity. Methods: Sixteen patients with the active phase and 33 patients with the inactive phase of Behcet’s disease, were followed up at Uvea Clinic in Ulucanlar Eye Training and Research Hospital, and 35 healthy cases were enrolled in this prospective study. All the individuals underwent visual acuity testing, intraocular pressure measurement, biomicroscopy, and fundus examinations. By using OCT and EDI-OCT central macular, RNFL thicknesses and subfoveal, at nasal 500 µm, nasal 1000 µm, temporal 500 µm, and temporal 1000 µm choroidal thicknesses were measured in all cases. The results of Behcet’s patients and healthy subjects were compared and the relationship between these parameters and Behcet’s disease duration, the number of ocular attacks, and visual acuity were assessed. Results: Five patients (31,3%) were female, 11 (68,8%) were male in the active group and 8 patients (24,2%) were female and 25 (75,8%) were male in the inactive group. In active patients central macular and RNFL thicknesses were significantly thicker than inactive patients and the control group (p=0,000). In inactive patients with Behcet’s disease duration and the number of ocular attacks RNFL thickness was getting thinner than in active patients (p=0,023, p=0,007). In active, inactive patients and healthy subjects subfoveal choroidal thicknesses were 449,31±111,36, 318,21±94,81 and 364,34±82,88 µm respectively; at nasal 500 µm choroidal thicknesses were 437,44±105,51, 308,33±95,36 and 355,97±83,81 µm respectively; at nasal 1000 µm choroidal thickness were 418,25±112,71, 286,33±96,06 and 337,26±87,11 µm respectively; at temporal 500 µm choroidal thickness were 429,44±102,98, 305,67±88,56 and 360,51±83,78 µm respectively; at temporal 1000 µm, choroidal thickness were 407,44±102,64, 299,73±76,30 and 360,71±86,67 µm respectively. In active patients subfoveal, at nasal 500 and 1000 µm choroidal thickness was significantly thicker than inactive patients and control group (p&lt;0,01), in inactive patients at temporal 500 and 1000 µm choroidal thickness were significantly thinner than control subjects (p&lt;0,05). Conclusion: By using OCT and EDI-OCT, in patients with active phase of Behcet’s disease central macular, RNFL, and choroidal thicknesses were found significantly thicker than inactive and control subjects. In inactive patients, choroidal thicknesses were significantly thinner than in healthy cases. In this study, the results showed that OCT and EDI-OCT findings were found to be beneficial in ocular Behcet’s disease diagnosis and follow-up period.

Association of Long Non-coding RNA C1RL-AS1 and PTPN6 Gene Polymorphisms with Ocular Behcet’s Disease in Han Chinese

ABSTRACT Purpose To explore the association of the polymorphisms in PTPN6 and LncRNA C1RL-AS1 genes with ocular BD in Han Chinese patients. Methods Correlation study was performed using the iPLEX system on a cohort of ocular BD patients andcontrols. The genotyping of 7 SNPs for LncRNA C1RL-AS1 and PTPN6 genes in ocular BD patients was performed using the iPLEX Gold genotype. Results The frequencies of rs4013722 AG genotype/A allele in LncRNA C1RL-AS1 were significantly decreased in BD patients, and the frequency of GG genotype was significantly increased in BD patients. The rs4013722 was associated with ocular BD in male patients, but not in female patients. The AG and GG genotype of rs4013722 were associated with skin lesions in male patients. The gene polymorphisms of PTPN6 were not associated with BD patients. Conclusions The LncRNA C1RL-AS1/rs4013722 polymorphism conferred susceptibility to ocular BD in Han Chinese patients, which was influenced by sex. Abbreviations: LncRNA: Long Non-coding RNA; BD: Behcet’s disease; SNP: single nucleotide polymorphism; PBMCs: peripheral blood mononuclear cells; PTPs: Protein tyrosine phosphatases; PTPN6: protein tyrosine phosphatase non-receptor 6; GWAS: genome-wide association study; HWE: Hardy-Weinberg equilibrium; LD: linkage disequilibrium; OR: odds ratio; CI: confidence interval; eQTL: expression quantitative trait loci; IBD: inflammatory bowel disease; RA: rheumatoid arthritis; Padj : Bonferroni corrected P value; NS: non-significant.

Kyrieleis like plaques - atypical presentation of ocular Behcet’s disease

Purpose: To report an unusual presentation with kyrieleis like plaques in a patient with ocular Behcet’s disease.Case presentation: A 28-year-old young male presented with blurring of vision in the left eye, fundus examination revealing focal segmental intra-arterial plaques involving all branches of retinal artery characteristics of kyrieleis-like plaques with no features of retinitis in retinal periphery and mild vitritis. All routine investigations were normal, the patient testing positive for HLA-B51 marker, diagnosed as a case of ocular Bechet’s disease and managed with oral steroids and immunosuppressive agents. Results: The patient had good recovery of vision with substantial resolution of intra-arterial plaques.Conclusion: Ocular Bechet’s disease can present with uncommon features of kyrieleis like plaques. Ophthalmologists need to be vigilant for the presence of such potential ocular manifestations as the likely initial presentation in order to obtain early diagnosis and initiate timely management.

Fluorescein angiographic findings and Behcet's disease ocular attack score 24 (BOS24) as prognostic factors for visual outcome in patients with ocular Behcet's disease

PurposeTo determine the application of fluorescein angiographic (FA) findings and Behcet’s disease ocular attack score 24 (BOS24) scoring system in predicting poor visual outcome in patients with ocular Behcet’s disease.Study designRetrospective cohort study.MethodsWe included 73 eyes of 38 patients with ocular Behcet’s disease who underwent FA and reviewed FA images, anterior chamber cells, vitreous opacity, retinal and optic disc lesions, which are parameters in BOS24. The correlation between FA findings, BOS24, and visual acuity was assessed.ResultsOptic disc hyperfluoresence (74%), diffuse posterior pole leakage (52%) and diffuse peripheral leakage (52%) were the three most common findings. Common complications were peripheral capillary nonperfusion (29%), arterial narrowing (22%), and macular ischemia (19%). BOS24 scores of ≥ 6 (p < 0.0001), arterial narrowing (p < 0.0001), and severe posterior pole leakage (p = 0.004) were significantly associated with poor visual outcome. Combining significant FA findings: arterial narrowing and severe posterior pole leakage, to BOS24 ≥ 6 results in an increased relative risk of developing poor visual acuity from 7.30 to 10.43 and 1.89 to 2.02 respectively.ConclusionFluorescein angiography is an important investigation for predicting poor visual outcome. BOS24 may be a useful alternative when fluorescein angiographic is unavailable.

Specific sweat metabolite profile in ocular Behcet’s disease

BackgroundBehcet’s disease (BD) is an autoimmune disorder with the serious possibility of blindness, calling for further research on its pathogenesis. Our aim was to study the metabolite composition of sweat in BD and to identify possible biomarkers. MethodsMetabolomics analysis was performed on sweat samples from 20 BD patients and 18 normal controls by liquid chromatography tandem mass spectrometry. ResultsA significantly different metabolic profile of sweat was observed when BD patients were compared with healthy controls. The result of the orthogonal partial least squared-discrimination analysis (OPLS-DA) showed that these two comparison groups could be separated with a relatively satisfactory fitting degree (R2Y = 0.995 and Q2 = 0.817 in positive ion mode; R2Y = 0.991 and Q2 = 0.721 in negative ion mode). Based on OPLS-DA, a panel of metabolites was selected as candidate biomarkers, including l-citrulline, l-pyroglutamic acid, urocanic acid, 2-oxoadipic acid, cholesterol 3-sulfate, and pentadecanoic acid. ConclusionThis is the first report on the metabolite profile of sweat in BD. Our results demonstrated a significantly different metabolite composition of sweat in BD compared to that of healthy controls.

A Case of Bilateral Peripheral Ulcerative Keratitis

Peripheral ulcerative keratitis (PUK) is an aggressive, potentially sight-threatening cause for peripheral corneal thinning. It may precede the diagnosis of the systemic condition and therefore these cases require urgent investigation. A 43-year-old woman presented with bilateral tearing and ocular pain persisting for 7 months. Visual acuity was 6/6 in both eyes. On biomicroscopic examination, presence of crescent shaped corneal ulcer with perilesional haziness. A tear film study demonstrated decreased Schirmer test results (5mm in both eyes) and tear film break-up time (5 sec in both eyes). The interrogation and the patient revealed he had recurrent skin lesions in both legs with chronic itching, and recurrent oral and genital ulcers healing spontaneously. The diagnosis of Behcet disease was proposed. Pathergy test was negative, HLA B51 was positif. Systemic therapy was started with colchicine at a dose of 2mg/day. Eye drops and systemic prednisolone at 1mg/kg/day was continued with progressive decrease. The follow up at 3 months and 6 months showed no signs of recurrence of ulceration in both eyes. Corneal manifestation has rarely been reported in Behcet’s disease. Combined intraocular anterior and posterior segment inflammation are most common features of ocular Behcet disease. Collaborative management of ophthalmic patients having systemic illness along with internists improves overall outcomes and prevents morbidity in such patients.

Serum IL-4, IL-12, IL-13, IL-27, and IL-33 levels in active and inactive ocular Behcet's disease.

To investigate serum levels of interleukin (IL)-12 (Th1 cytokine), IL-27 (an immunomodulatory cytokine), IL-4 (suppressor of Th1-cell growth), IL-13 (a stimulatory signal for Th2 cytokines), and IL-33 (an epithelial cell-derived cytokine) and their relations with the disease activity in Behcet's Disease (BD). Four groups, each composed of 20 participants were enrolled in the study; active ocular BD (Group-A), ocular BD in remission (Group-B), nonocular BD in remission (Group-C) and healthy controls (Group-D). IL levels were compared between the study groups and their correlation with the disease activity parameters were analyzed. IL-13 and IL-33 were higher in Group-A. IL-27 was lower in all BD groups. Additionally, IL-13 and IL-33 levels were positively correlated with disease activity parameters. These findings show Th2 dominance in the active phase of BD. Besides, decreased levels of IL-27, and presumably, its protective anti-inflammatory effect in all study groups may exert a new pathologic finding in BD.

Variability of peripheral blood lymphocyte subsets in ocular Behcet’s disease

Variability of peripheral blood lymphocyte subsets in ocular Behcet’s disease

Association of LACC1, CEBPB-PTPN1, RIPK2 and ADO-EGR2 with ocular Behcet’s disease in a Chinese Han population

BackgroundAn Immunochip study recently identified the association of a number of new genetic loci with Behcet’s disease (BD).ObjectiveTo confirm the association between new genetic loci reported in an Immunochip study...

Decreased expression of A20 is associated with ocular Behcet’s disease (BD) but not with Vogt-Koyanagi-Harada (VKH) disease

PurposeA20 is a ubiquitously expressed and inducible cytosolic protein, which plays an important role in the negative regulation of inflammation and immunity. In this study, we investigated the role of...

Association of genetic variations in PTPN2 and CD122 with ocular Behcet’s disease

BackgroundProtein tyrosine phosphatases (PTPs) play critical roles in human autoimmunity. Previous studies found that PTPN2 may be the key regulatory factor in the T-cell-mediated immune response. PTPN2 regulates the Janus...

Vision-Threatening Behcet’s Disease: Severity of Ocular Involvement Predictors

Purpose To examine and spot systemic findings commonly associated with a serious form of ocular Behcet's disease. This could potentially help ophthalmologists categorize their patients based on future risk and plan treatment accordingly. Subjects and Methods The data of 249 patients with Behcet's disease were examined thoroughly. Correlations between systemic and ocular findings were recorded. Patients were further subgrouped by the authors as having a vision-threatening form of the disease or not. Regression analysis was done to spot predictors for a vision-threatening form of the disease. Results The presence of systemic vasculitis and oral and genital ulcers in a patient with Behcet's disease was found to be associated with a milder form of ocular affection or none at all and vice versa. Certain correlations between findings were also found. Conclusion Certain findings in Behcet's disease may act as predictors for the severity of ocular affection. Directing our attention to these factors by the internist and ophthalmologist can help plan the frequency of follow-up as well as the aggressiveness of treatment in patients with Behcet's disease.

Hypermethylation of Interferon Regulatory Factor 8 (IRF8) Confers Risk to Vogt-Koyanagi-Harada Disease

Aberrant methylation change of IRF8 confers risk to various tumors, and abnormal expression of IRF8 is involved in many autoimmune diseases, including ocular Behcet’s disease. However, whether the methylation change of IRF8 is associated with Vogt-Koyanagi-Harada (VKH) disease remains unknown. In the present study, we found a decreased IRF8 mRNA expression in association with a higher methylation level in monocyte-derived dendritic cells (DCs) from active VKH patients compared with the normal and inactive subjects. DCs incubated with cyclosporin a (CsA) or dexamethasone (DEX) showed a lower methylation and higher mRNA expression of IRF8 in active VKH patients. A demethylation reagent, 5-Aza-2′-deoxycytidine (DAC) showed a notable demethylation effect as evidenced by increasing the mRNA expression and reducing the methylation level of IRF8. It also suppressed the Th1 and Th17 responses through down-regulating the expression of co-stimulatory molecules (CD86, CD80, CD40), and reducing the production of pro-inflammatory cytokines (IL-6, IL-1β, IL-23, IL-12) produced by DCs. These findings shows that hypermethylation of IRF8 in DCs confers risk to VKH disease. Demethylation of IRF8 may offer a novel therapeutic strategy protect against VKH disease.

Ocular Behcet's disease is associated with aberrant methylation of interferon regulatory factor 8 (IRF8) in monocyte-derived dendritic cells.

Aberrant methylation of interferon regulatory factor 8 (IRF8) has been noted in various tumors. IRF8 has also been reported to be involved in many autoimmune diseases, including Behcet's disease (BD). However, the methylation status of IRF8 in BD has not been reported. To address this issue, we investigated whether the degree of methylation of IRF8 in dendritic cells (DCs) plays a role in the development of BD. We found a lower mRNA expression and a higher methylation level of IRF8 in active ocular BD patients as compared to normal subjects and inactive patients. Treatment with a demethylation agent, 5-Aza-2’-deoxycytidine (DAC) resulted in an increase of mRNA expression and a reduction of the IRF8 methylation level. It also down-regulated the expression of the co-stimulatory molecules CD86, CD80, CD40, and reduced the production of IL-6, IL-1β, IL-23 and IL-12. An inhibition of Th1/Th17 responses was observed as evidenced by a decreased production of IFN-γ, IL-17, and a reduction of IFN-γ/IL-17- producing CD4+ T cells following treatment with DAC. This study shows that active ocular BD patients have an aberrant IRF8 methylation status. These findings suggest that epigenetic control of IRF8 expression may offer a future target in the treatment of ocular BD.

Assessment of Vascular Change Using Swept-Source Optical Coherence Tomography Angiography: A New Theory Explains Central Visual Loss in Behcet's Disease.

Objective To evaluate retinal vascular structural change in ocular Behcet's using optical coherence tomography angiography (OCTA) and fluorescein angiography (FA). Methods An analytic cross-sectional study of 37 eyes of 21 Behcet's uveitic patients was performed. Foveal retinal thickness (FRT), perifoveal hypoperfusion areas in superficial capillary plexus (SCP), and deep capillary plexus (DCP) were measured with swept-source optical coherence tomography and OCTA. FA images were used for assessing the vascular features and correlation. Results Twenty-one patients were enrolled (52.4% males). The average age at onset was 36.7 ± 12.93 years. The median of disease duration was 5 years (1–25). FRT was 118.1 ± 52.35 μm, which correlated with visual acuity (95% CI −60.47, −13.92). Using OCTA, the area of hypoperfusion in SCP (0.47 ± 0.17 mm2) was smaller than that in DCP (1.94 ± 3.87 mm2) (p < 0.001). Superficial to deep capillary plexus nonperfusion (SCP : DCP) ratio was 0.57 ± 0.27 which had the positive coefficient correlation with visual acuity (95% CI −0.644, −0.015). Conclusions OCTA is an alternative noninvasive method to monitor macular ischemia in Behcet. Behcet's uveitis affects DCP more than SCP. Decreasing SCP : DCP ratio and decrease FRT correlates with poor visual acuity. Macular ischemia and DCP loss can be found early and can explain vision loss in Behcet.

Berberine exerts an anti-inflammatory role in ocular Behcet's disease.

Behcet's disease is a multi-system inflammatory disorder, and ocular Behcet's disease (OBD) is one of the most common causes of uveitis in China. A number of studies have indicated that Th17 cells, a subset of interleukin-17 (IL-17)-producing CD4+ T-helper cells, serve important roles in the pathogenesis of OBD. Berberine (BBR) is an isoquinoline derivative alkaloid isolated from Chinese herbs, and has been used traditionally for the treatment of gastrointestinal disorders. The aim of the present study was to investigate the effect of BBR on Th17 cell proliferation and cytokine secretion, and the expression and activation of the signal transducer and activator of transcription 3 (STAT3) transcription factor in OBD in vitro. Blood samples were obtained from healthy controls and patients with active ocular Behcet's disease. Peripheral blood mononuclear cells (PBMCs) or CD4+ T cells were cultured for three days with or without BBR and in the presence of anti-CD3 and anti-CD28 antibodies. IL-17 expression in cell sample supernatants was determined by enzyme-linked immunosorbent assay, and cell viability was measured using the Cell Counting kit-8 assay. The number of CD4+IL-17+ cells and the expression level of phosphorylated (p)-STAT3 in CD4+ T cells was determined using flow cytometry analysis. The expression of IL-17 was increased in patients with active OBD following the activation of PBMCs and CD4+ T cells with anti-CD3 and anti-CD28 antibodies when compared with healthy controls. However, no significant difference in cell viability following exposure to BBR was observed in PBMCs derived from healthy controls or patients with OBD. Following incubation with BBR, the expression of IL-17 was reduced and the number of CD4+IL-17+ cells was decreased in patients with active OBD and healthy controls. Furthermore, the expression of p-STAT3 was significantly decreased in the presence of BBR in healthy controls. In conclusion, the results of the present study demonstrate that BBR may suppress the Th17 response in patients with OBD by reducing STAT3 phosphorylation. BBR may be a potential therapeutic agent for the treatment of OBD.

Progress and prospect of treatment for ocular Behçet disease

Ocular Behcet disease, which usually presents as panuveitis, with characteristic of vision impairment and relapse, is one of the most refractory uveitis entities.Usually, one or more conventional immunosuppressive agents, such as glucocorticoid, ciclosporin, chlorambucil, cyclophosphamide, etc, are needed in disease management.However, long-term use of immunosuppressive agents would result in severe adverse effects.New biologics, such as interferon, antitumor necrosis factor agents, interleukin or its receptor antagonists, provide new therapeutic approaches to the treatment for this disease.This paper reviewed the conventional therapies and biologics applied in ocular Behcet disease. Key words: Behcet disease, Uveitis; Treatment; Immunosuppressive agent; Biologics

Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses.

Herpesvirus entry mediator (HVEM), a member of the TNFR superfamily, serves as a unique molecular switch to mediate both stimulatory and inhibitory cosignals, depending on its functions as a receptor or ligand interacting with multiple binding partners. In this study, we explored the cosignaling functions of HVEM in experimental autoimmune uveitis (EAU), a mouse model resembling human autoimmune uveitis conditions such as ocular sarcoidosis and Behcet disease. Our studies revealed that EAU severity significantly decreased in HVEM-knockout mice compared with wild-type mice, suggesting that stimulatory cosignals from the HVEM receptor are predominant in EAU. Further studies elucidated that the HVEM cosignal plays an important role in the induction of both Th1- and Th17-type pathogenic T cells in EAU, including differentiation of IL-17-producing αβ(+)γδ(-) conventional CD4(+) T cells. Mice lacking lymphotoxin-like, inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes : LIGHT), B- and T-lymphocyte attenuator (BTLA) or both LIGHT and BTLA are also less susceptible to EAU, indicating that LIGHT-HVEM and BTLA-HVEM interactions, two major molecular pathways mediating HVEM functions, are both important in determining EAU pathogenesis. Finally, blocking HVEM cosignals by antagonistic anti-HVEM Abs ameliorated EAU. Taken together, our studies revealed a novel function of the HVEM cosignaling molecule and its ligands in EAU pathogenesis through the induction of Th1- and Th17-type T cell responses and suggested that HVEM-related molecular pathways can be therapeutic targets in autoimmune uveitis.

Copy number variations and gene polymorphisms of Complement components in ocular Behcet’s disease and Vogt-Koyanagi-Harada syndrome

Complement is involved in many immune-mediated diseases. However, the association of its copy number variations (CNVs) and polymorphisms with Behcet’s disease (BD) and Vogt-Koyanagi-Harada syndrome (VKH) is unknown. We examined copy number and mRNA expression by real-time PCR. Cytokine production by stimulated peripheral blood mononuclear cells (PBMCs) in genotyped individuals was measured by ELISA. The frequencies of having more than two copies of C3 were significantly increased in BD and VKH, whereas CNV of C5 was only associated with BD. Increased frequencies of the GG genotype of C3 rs408290 and C5 rs2269067 were found in BD. No association was observed between C3 and C5 SNPs and VKH. mRNA expression in the high CNV group and GG cases of C3 and C5 was significantly higher compared to other genotypes. Increased interleukin-17 and IFN-γ was observed in the high CNV group and GG genotype cases of C3. Interleukin-17 but not IFN-γ was increased in the high CNV group and GG genotype cases of C5. No effect of C3 or C5 genetic variants was seen on the production of TNF-α, IL-10, IL-1β, MCP-1, IL-6 and IL-8. Our study thus provides further evidence for a role of complement in the pathogenesis of uveitis.