VVN461 Solution in Patients with Acute Noninfectious Anterior Uveitis.

Macular Thickening in Acute Anterior Uveitis

Spondyloarthritis (SpA) is a heterogeneous group of diseases that includes ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), inflammatory bowel disease-associated spondyloarthritis (IBD-SpA), and undifferentiated spondyloarthritis (unSpA). This group of diseases shares several clinical, imaging, and genetic features; the integration of these diseases in the group of SpA is needed for an early diagnosis and a prompt treatment. Uveitis is the most common extra-articular manifestation of SpA. HLA-B27-associated acute anterior uveitis (AAU) is the most frequent form of uveitis encountered in the SpA group. The general prevalence of HLA-B27-associated AAU in the group of SpA is about 30% and the general prevalence of SpA in patients with HLA-B27-associated AAU is over 50%. There are several differences in the clinical picture and evolution of HLA-B27-associated AAU in patients with SpA and knowing this is very important for the best therapeutic decision. Tumor necrosis factor α (TNFα) is a very important mediator not only in the pathogenic mechanisms of SpA, but also in the immune reactions that characterize HLA-B27-associated AAU in SpA. There is much evidence of the role of TNFα in SpA and HLA-B27-associated AAU, multiple studies showing efficacy of anti-TNFα drugs not only on rheumatic manifestations but also on ocular involvement. Conventional therapy of HLA-B27-associated AAU with local or systemic glucocorticoids and immunosuppressive drugs (sulfasalazine, methotrexate, azathioprine, etc.) in order to diminish the ocular inflammation is associated with many side effects, some of them being very severe and even life threatening. Therefore, new treatments, especially biologic therapy with anti-TNFα drugs, open a new opportunity for the treatment of these patients. It is very important to emphasize that antibody anti-TNFα agents (infliximab, adalimumab, golimumab) may be more efficient than soluble receptors of TNFα (etanercept) in decreasing the risk of HLA-B27-associated AAU in patients with SpA. The aim of this review made by a group of ophthalmologists and rheumatologists with recent and fruitful experience regarding the anti-TNF treatment of uveitis in patients with SpA is to make the community of ophthalmologists aware of this biologic therapy and that it is the right time to use it. Abbreviations: AU = anterior uveitis; AAU = acute anterior uveitis; AS = ankylosing spondylitis; ASAS = Assessment of SpondyloArthritis Society; DBP = vitamin D binding protein; ESSG = European Spondyloarthropathy Study Group; HLA-B27 = human leukocyte antigen B27; IBD = inflammatory bowel disease; PsA = psoriatic arthritis; ReA = reactive arthritis; SpA = spondyloarthritis; TLRs = Toll-like receptors; TNFα = tumor necrosis factor α; unSpA = undifferentiated spondyloarthritis.

Noninfectious uveitis (NIU), which pathogenesis is often autoimmune nature, occurs as a symptom of systemic syndromes or only in the eye. The standard treatment of NIU is local, topical, and oral administration of corticosteroids (CS) in combination with immunomodulatory therapy (IMT). However, additional therapeutic strategies involving topical and systemic administration of CS or others to treat relapse or exacerbation of ocular inflammation in NIU which present as various ocular manifestations have not been established. The aim of this study was to investigate therapeutic strategies used for various ocular inflammations in relapse or exacerbation of NIU and to evaluate factors associated with the treatment pattern in Japan. The subjects were 198 eyes of 156 NIU patients with relapse or exacerbation of ocular inflammation at 6 university hospitals in Japan. The most frequent disease was sarcoidosis in 23.7% of the cases, followed by Behçet disease (BD) in 21.2%, Vogt-Koyanagi-Harada (VKH) disease in 13.6%, acute anterior uveitis (AAU) in 5.6%, tubulointerstitial nephritis and uveitis syndrome (TINU) in 4.0%, and juvenile idiopathic arthritis (JIA)-associated uveitis in 3.0%. Common ocular findings were worsened anterior inflammation (AI) in 67.2% of the cases, vitreous opacity (VO) in 46.5%, macular edema (ME) in 26.8%, retinal vasculitis (RV) in 23.7%, serous retinal detachment (SRD) in 9.1%, and optic perineuritis (OPN) in 4.0%. Reinforcement of betamethasone eye drop (ED) monotherapy for only AI in both unilateral and bilateral AI, sub-tenon injection of triamcinolone acetonide (STTA) for unilateral posterior inflammation including VO and ME, and systemic therapy using CS and/or IMT for bilateral anterior and posterior inflammation were significantly more frequent. Frequencies of exacerbated individual ocular findings in sarcoidosis and BD were similar, and severe ocular inflammation associated with panuveitis required both topical and systemic therapies. These results demonstrate that reinforcement of betamethasone EDs, topical administration of triamcinolone acetonide, and long-term administration of systemic corticosteroids are the major therapeutic strategies, and reinforcement of betamethasone EDs was used for exacerbated AI independently from its use for posterior inflammation. In addition, STTA was preferentially used for VO and ME associated with posterior inflammation.

Objective Acute anterior uveitis (AAU) is the most common extra-articular manifestation in patients with axial spondyloarthritis (axSpA). However, the relationship between AAU and radiographic progression in axSpA remains unclear. Hence, we investigated whether the presence of AAU is associated with radiographic structural damage in patients with axSpA. Methods Clinical and radiographic data were obtained from 253 patients with axSpA. Radiographic progression over 2 years was assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Progression was defined as mSASSS worsening by ≥ two units. Using propensity score (PS) matching, differences between patients with and without AAU were analyzed. Results The proportion of progressors among patients with AAU was lower than that of patients without AAU (13.6% vs. 29.5%, p=0.058). The rate of increase in mSASSS and number of syndesmophytes were lower in patients with AAU than patients without AAU (0.57±1.37 vs. 1.02±1.79, p=0.085 and 0.46±1.45 vs. 0.83±1.62, p=0.158). In multivariate regression analysis, presence of AAU was independently associated with slowed radiographic progression (odds ratio [95% confidence interval] 0.21 [0.07, 0.67], p=0.004). Conclusion PS-matched axSpA patients with AAU showed significantly less radiographic progression than those without AAU.

PurposeAcute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B27, implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS.MethodsWe undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available after SNP microarray genotyping, imputation, and quality-control filtering.ResultsWe identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 × 10−8, odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 × 10−7, OR = 1.22) and NOS2 (rs2274894, P = 8.22 × 10−7, OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rs10171979, P = 2.56 × 10−6, OR = 1.20), KIFAP3 (rs508063, P = 5.64 × 10−7, OR = 1.20), CLCN7 (rs67412457, P = 1.33 × 10−6, OR = 1.25), ACAA2 (rs9947182, P = 9.70 × 10−7, OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone.ConclusionsWe report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.

Acute Anterior Uveitis and HLA-B27

Acute anterior uveitis is an intraocular inflammation and the responsible factors of its pathogenesis are mostly unknown. Some viruses such as HSV, CMV and VZV may be implicated in the etiology. Noninfectious uveitis is thought to be autoimmune. Chronic hepatitis B virus (HBV) infection may cause multiple complications, which are thought to be immune system mediated. Recently, some studies suggested that HBV could be one of the triggers for uveitis. In this paper we present an anterior uveitis case developed in a woman who has had a chronic HBV infection. The reason for uveitis was unknown and we considered HBV as possible etiologic agent.

Introductionand importance: Multiple immunologic phenomena were reported following the administration of COVID-19 vaccines. However, the important point is that their possible association with medium-vessel vasculitis involving the celiac trunk and its branches with acute anterior uveitis in the same patient has not been reported before. Case presentationIn this manuscript, we are reporting a case of a middle-aged gentleman who developed vasculitis involving the celiac trunk and its branches, and acute anterior uveitis one week and three weeks after the second dose of Pfizer BioNTech COVID-19 vaccine, respectively. The patient showed significant clinical and radiographic improvement after receiving corticosteroids and azathioprine. Clinical discussionPreviously reported cases of vasculitis following COVID-19 vaccines included both renal-limited and more generalized vasculitis with some being positive and others negative for ANCA (anti-neutrophil cytoplasmic antibodies). Nevertheless, it is worth mentioning that most cases responded to immunosuppressive treatment. Post-COVID-19 vaccine uveitis was reported in patients with different age spans including both anterior and posterior uveitis, with remission being achieved after the use of corticosteroids. ConclusionsMultiple cases of vasculitis and acute anterior uveitis were reported following COVID-19 vaccines; however, it is important to mention that more research is needed to establish an association between the COVID-19 vaccine and both vasculitis and acute anterior uveitis. In our opinion, the benefits of the COIVID-19 vaccine largely outweigh the expected risks.

The frequency of associated rheumatic diseases was studied in 271 patients with acute anterior uveitis (AAU). In a retrospective examination of 154 patients with AUU (mean follow-up period of 6 years) associated rheumatic symptoms were observed in 64 (41.6%). Forty-one patients (26.6%) had ankylosing spondylitis and 39 (25.3%) manifestations of Reiter's disease. Radiographic sacro-iliitis was seen in 35 (34%) of 103 consecutive x-ray examined patients with AAU. Furthermore, in another series of 38 patients, who all, in addition to having AAU, also complained of low back pain or had manifestations of Reiter's disease, 23 (60.5%) had radiographic sacro-iliitis. Classical ankylosing spondylitis was more frequent in men with AAU whereas milder forms of the disease occurred more equally in both sexes. HLA-B27 occurred in 35 (87.5%) of 40 HLA-typed patients with AAU. Associated rheumatic diseases occurred in 18 (51.4%) of the 35 HLA-B27 positive patients but in none of the HLA-B27 negative patients. The results support the hypothesis that a pleiotropic HLA-B27 associated gene may determine the susceptibility to AAU, sacro-iliitis, ankylosing spondylitis, and Reiter's disease.

Background: Acute anterior uveitis (AAU) is a potentially serious ocular condition, which frequently presents to the General Practitioner (GP). In some cases, it can be misdiagnosed with consequent delay in the initiation of appropriate treatment.Objectives: To analyse the diagnostic features of AAU presenting to the emergency service at Manchester Royal Eye Hospital; to investigate the prior management of AAU in the community and identify management problems amenable to constructive feedback. Methods: A list of reasonable standards expected from primary carers was compiled and information collected prospectively by nurse practitioners over two months using a specifically designed pro-forma. Data was analysed against these standards and compared to the relevant literature.Results: Of the AAU patients 18/69 had previously seen the GP. 14 had first episodes, 4 were recurrent. Mean interval between symptom onset and eye emergency attendance was 9.2 days compared to 4.3 days for those not seen by GP. Symptoms elicited, in those previously seen by a GP, were: ocular pain (18/18); photophobia (17/18); unilateral red eye (17/18); and blurred vision (15/18). GP performed ocular examination in 12 patients. Seven patients were not treated by GP but referred on the same day. The other 11 patients were prescribed topical antibiotics by GP and 2/11 also received topical steroid. 9 of these 11 patients eventually self-checked into eye emergency, whereas two were subsequently referred after re-visiting the GP.Conclusion: A significant number of AAU patients present to the GP and may be misdiagnosed with an alternative condition such as conjunctivitis. Awareness of AAU presentation and the need for prompt referral, to avoid potential visual loss, needs to be improved by providing feedback to GPs following patient attendance to eye emergency services.

Recent studies have shown that a decrease of regulatory T (Treg) cells may contribute to the activity of acute anterior uveitis (AAU) and ankylosing spondylitis (AS). A number of immunogenetic factors including IL2RA, miR-27a, miR-182, and FoxO1 are associated with Treg cell function. In this study, we investigated the association between polymorphisms of these genes and AAU with or without AS in a Chinese Han population. Using PCR-restricted fragment length polymorphism (RFLP) assay, a two-stage association study was performed in 680 AAU patients with or without AS and 1280 controls. Gene expression was quantified by real-time PCR. In the first stage study, an association analysis of 10 single nucleotide polymorphisms (SNPs) was performed in 230 AAU patients with AS, 240 AAU patients without AS, and 650 controls. The results showed significantly increased frequencies of the FoxO1/rs2297626 AA genotype and A allele in AAU patients with AS (AA genotype: P = 6.23 × 10(-5), odds ratio [OR] = 1.86; A allele: P = 2.17 × 10(-4), OR = 1.53). No significant association of the other 9 SNPs with AAU with or without AS was observed. In the second stage study, an association analysis of FoxO1/rs2297626 was performed in 210 AAU patients with AS and 630 controls. The second stage and combined studies confirmed the association of FoxO1/rs2297626 with AAU with AS (AA genotype: P = 3.45 × 10(-8), OR = 1.85; A allele: P = 1.55 × 10(-7), OR = 1.55). This study suggests that FoxO1, but not miR-27a, miR-182, and IL2RA, contributes to the genetic susceptibility of AAU with AS, but none of the tested polymorphisms confer risk to AAU without AS.

SAT0237 Dublin Uveitis Evaluation Tool (DUET): A Proposed Algorithm and Its Performance Evaluation for the Best Referral By Ophthalmologists of Acute Anterior Uveitis Patients with Possible Underlying Spondyloarthropathy

Introduction:Acute anterior uveitis (AAU), affecting up to 40% of patients with axial spondyloarthritis (axSpA), risks permanent visual deficits if not adequately treated. We report 2-year results from C-VIEW, the first study to prospectively investigate certolizumab pegol (CZP) on AAU in patients with active axSpA at high risk of recurrent AAU.Patients and methods:C-VIEW (NCT03020992) was a 104-week (96 weeks plus 8-week safety follow-up), open-label, multicenter study. Eligible patients had active axSpA, human leukocyte antigen-B27 (HLA-B27) positivity and a history of recurrent AAU (⩾2 AAU flares in total; ⩾1 in the year prior to baseline). Patients received CZP 400 mg at weeks 0, 2 and 4, then 200 mg every 2 weeks to week 96. The primary efficacy endpoint was the AAU flare event rate during 96 weeks’ CZP versus 2 years pre-baseline.Results:Of 115 enrolled patients, 89 initiated CZP (male: 63%; radiographic/non-radiographic axSpA: 85%/15%; mean disease duration: 9.1 years); 83 completed week 96. There was a significant 82% reduction in AAU flare event rate during CZP versus pre-baseline [rate ratio (95% confidence interval): 0.18 (0.12–0.28), p < 0.001]. One hundred percent and 59.6% of patients experienced ⩾1 and ⩾2 AAU flares pre-baseline, respectively, compared to 20.2% and 11.2% during treatment. Age, sex and axSpA population subgroup analyses were consistent with the primary analysis. There were substantial improvements in axSpA disease activity with no new safety signal identified.Conclusion:CZP treatment significantly reduced AAU flare event rate in patients with axSpA and a history of AAU, indicating CZP is a suitable treatment option for patients at risk of recurrent AAU.Trial Registration ClinicalTrials.gov:NCT03020992, URL: https://clinicaltrials.gov/ct2/show/NCT03020992

Uveitis is a multifactorial disease, originating from the interplay between our genes, the environment and stochastic factors.1 In contrast, only a handful of exceptional uveitic entities are monogenic.To understand the immunogenetics of uveitis, one must understand the concept of multifactorial disease. These diseases are characterized by multigenic involvement, with any one variant allele being neither necessary nor sufficient for disease initiation. Rather, it is the combination of multiple variants in multiple genes, which all increase the susceptibility of an individual to develop a particular disease. The second concept is that of the environmental trigger, such as an infection or exposure to a drug, which triggers the disease in genetically susceptible individuals. Stochastic factors may also play a role in disease genesis.2In the context of uveitis, genetic polymorphisms in genes of the class I major histocompatibility complex (MHC), such as HLA‐A, or HLA‐B, are associated with common non‐infectious uveitides (NIU) like HLA‐B27‐associated acute anterior uveitis (AAU), Behçet's disease, and Birdshot retinochoroiditis (BRC).3Specifically, HLA‐B27 carrier frequency in the Caucasian US population is around 7%, while it is present in approximately 50% of patients who develop AAU, and 90% of patients who develop ankylosing spondylitis (AS). This represents a relative risk (RR) for carriers of HLA‐B27 of around 8 for developing AAU,4 and around 50 to 100 for developing AS.5HLA‐B51 carrier frequency in populations along the Silk Road is around 10‐30%,6 compared to 50‐80% in Behçet's disease patients, conferring a RR of 5‐10 to develop the disease.7The third major HLA polymorphism associated with uveitis is HLA‐A29, whose carrier frequency in the Western European population is reported to be 5‐10%,8 compared to the 97.5% in BRC patients,3,9 conferring an astronomically high RR of 50‐224 for developing BRC in carriers of HLA‐A29 versus non‐carriers.4,9 BRC is actually the immunological disease with the strongest HLA association ever described.4Some weaker HLA associations have been reported with other NIU entities, such as HLA‐DR4/HLA‐DRB1*04 with Vogt‐Koyanagi‐Harada disease,10,11 HLA‐DRB1*04:05, HLA‐DQB1*04:01, and the DRB1*04:05‐DQB1*04:01 haplotype with sympathetic ophthalmia,12 or HLA‐DRB1*15:01 and the IL2‐RA gene polymorphism rs2104286 A&gt;G with multiple sclerosis‐associated uveitis.13In addition to HLA typing and polymorphisms, there has been much interest in evaluating single‐nucleotide polymorphisms of various mediators of the immune response. For example, polymorphisms in the ERAP1, ERAP2 or IL‐23R genes, have been described in association with uveitis.14,15 Many other associations have been described.That being said, the reason why these genetic associations predispose individuals to immunological disease remains a mystery. Some of the hypotheses put forward over the years include interaction of the HLA molecules with the gut microbiome resulting in increased gut permeability and leakage of bacterial products in the circulation, while others think molecular mimicry acting as a trigger for activation of autoreactive lymphocytes specific for the neuroretina might play a role.16–18In summary, genetic polymorphisms play a major role in the immunogenetics of some prevalent NIU entities. These may help shape our understanding of pathophysiological mechanisms in the future.

AB0699 Contribution of Extra-Articular Manifestations to the Burden of Disease in Ankylosing Spondylitis. A Longitudinal Study