The genetic associations of acute anterior uveitis and their overlap with the genetics of ankylosing spondylitis

Acute anterior uveitis (AAU) involves inflammation of the iris and ciliary body of the eye. It occurs both in isolation and as a complication of ankylosing spondylitis (AS). It is strongly associated with HLA-B*27, but previous studies have suggested that further genetic factors may confer additional risk. We sought to investigate this using the Illumina Exomechip microarray, to compare 1504 cases with AS and AAU, 1805 with AS but no AAU and 21 133 healthy controls. We also used a heterogeneity test to test the differences in effect size between AS with AAU and AS without AAU. In the analysis comparing AS+AAU+ cases versus controls, HLA-B*27 and HLA-A*02:01 were significantly associated with the presence of AAU (P<10−300 and P=6 × 10−8, respectively). Secondary independent association with PSORS1C3 (P=4.7 × 10−5) and TAP2 (P=1.1 × 10−5) were observed in the major histocompatibility complex. There was a new suggestive association with a low-frequency variant at zinc-finger protein 154 in the AS without AAU versus control analysis (zinc-finger protein 154 (ZNF154), P=2.2 × 10−6). Heterogeneity testing showed that rs30187 in ERAP1 has a larger effect on AAU compared with that in AS alone. These findings also suggest that variants in ERAP1 have a differential impact on the risk of AAU when compared with AS, and hence the genetic risk for AAU differs from AS.

Retinal thickening in HLA-B27 associated acute anterior uveitis: evolution with time and association with severity of inflammatory activity.

Purpose: To describe the evolution of retinal thickness in eyes affected with acute anterior uveitis (AAU) in the course of follow-up and to assess its correlation with severity of inflammatory activity in the anterior chamber. Methods: Design: Prospective, cohort study Setting: Institutional study Patient population: 72 eyes (affected and fellow eyes) of 36 patients Observation procedure: Patients were followed daily until beginning of resolution of inflammatory activity and weekly thereafter. Optical coherence tomography and laser flare photometry were performed at each visit. Treatment consisted of topical corticosteroids Main outcome measures: Retinal thickness of affected eyes, difference in retinal thickness between affected and fellow eyes and their evolution in time, association between maximal retinal thickness and initial laser flare photometry. Results: Difference in retinal thickness between affected and fellow eyes became significant on average seven days from baseline and remained so through-out follow-up (p<0.001). There was a steep increase in retinal thickness of affected eyes followed by a progressive decrease after reaching a peak value. Maximal difference in retinal thickness between affected and fellow eyes was observed between 17 and 25 days from baseline and exhibited a strong, positive correlation with initial laser flare photometry values (p=0.015). Conclusions: Retinal thickness in eyes affected with AAU presents a steep increase over 3 to 4 weeks and then gradually decreases. Severity of inflammation at baseline predicts the amount of retinal thickening in affected eyes. A characteristic pattern of temporal response of retinal anatomy to inflammatory stimuli seems to arise.

Association of bilateral acute anterior uveitis with a capsaicin patch

PURPOSE To report a case of bilateral acute anterior uveitis in association with the application of an analgesic transdermal capsaicin patch. METHODS Case report and review of literature. RESULTS A 38-year-old woman suffered from bilateral acute anterior uveitis, manifesting 12-24 h after application of an analgesic capsaicin patch (Isola Capsicum N Plus) that served to alleviate muscular neck pain. Systemic immune-mediated and infectious diseases were excluded by medical history and laboratory testing. Control of inflammation was achieved with topical corticosteroid treatment within 1 week. Over the course of a 1-year follow-up, no further recurrence of uveitis was observed. CONCLUSIONS The case suggests a possible association of capsaicin-containing transdermal patches and acute anterior uveitis.

Acute Conjunctivitis with Episcleritis and Anterior Uveitis Linked to Adiaspiromycosis and Freshwater Sponges, Amazon Region, Brazil, 2005

Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://www.medscape.com/cme/eidExternal Web Site Icon; (4) view/print certificate. Learning Objectives Upon completion of this activity, participants will be able to: Describe the mechanism of infection for adiaspiromycosis. Identify the age group most susceptible to ocular adiaspiromycosis. Describe presenting symptoms associated with ocular adiaspiromycosis. Describe the frequency of ocular lesions associated with adiaspiromycosis. Identify risk factors for ocular adiaspiromycosis.

Evaluation of corneal endothelium and keratic precipitates by specular microscopy in anterior uveitis

Background - The study of corneal endothelium, by specular microscopy, in patients with anterior uveitis has largely been restricted to observations on the endothelial cells. In this prospective study 'keratic precipitates' (KP) in different types of uveitis were examined in different stages of the disease process and the endothelial changes occurring in the vicinity of the KP were evaluated in comparison with the endothelium of the uninvolved eye. Methods - 13 patients with active unilateral uveitis were recruited. The mean age was 42.9 years (range 20-76 years). A Tomey-1100 contact wide field specular (x10) microscope was used to capture endothelial images and KP until the resolution of uveitis. Data regarding type of uveitis, number, size, and nature of KP were recorded. Automated morphometric analysis was done for cell size, cell density and coefficient of variation, and statistical comparisons of cell size and cell density were made (Student's t test) between the endothelium in the vicinity of fresh and resolving KP, fresh KP and normal endothelium, and resolving KP and normal endothelium. Results - On specular microscopy, fresh KP were seen as dense, white glistening deposits occupying 5-10 endothelial cells in diameter and fine KP were widely distributed and were one or two endothelial cells in diameter. The KP in Posner-Schlossman syndrome had a distinct and different morphology. With clinical remission of uveitis, the KP were observed to undergo characteristic morphological changes and old KP demonstrated a large, dark halo surrounding a central white deposit and occasionally a dark shadow or a 'lacuna' replaced the site of the original KP. Endothelial blebs were noted as dark shadows or defects in the endothelial mosaic in patients with recurrent uveitis. There was significant statistical difference in the mean cell size and cell density of endothelial cells in the vicinity of fresh KP compared with normal endothelium of the opposite eye. Conclusion - This study elucidated the different specular microscopic features of KP in anterior uveitis. Distinct morphological features of large and fine KP were noted. These features underwent dramatic changes on resolution of uveitis. The endothelium was abnormal in the vicinity of KP, which returned to near normal values on resolution of uveitis.

Elevated laser flare values correlate with complicated course of anterior uveitis in patients with juvenile idiopathic arthritis

To evaluate the prognostic value of anterior chamber (AC) laser flare (LF) in uveitis associated with juvenile idiopathic arthritis (JIA).

Rituximab as a treatment option for refractory endogenous anterior uveitis

BACKGROUND To report on anti-CD20 antibody therapy in a patient with uveitis refractive to immunosuppression therapy. METHODS Case report with ophthalmoscopic, optical coherence tomography and fluorescein-angiographic findings. RESULTS A 49-year-old woman was suffering from bilateral, noninfectious chronic anterior uveitis refractive to corticosteroids and immunosuppressive drugs. Bilateral visual acuity was 20/100 due to cataract and cystoid macular edema (CME). After treatment with rituximab, vision and CME improved, and uveitis was stable until the final visit (follow-up at 12 months). CONCLUSION The case report suggests that rituximab may be helpful for selected patients with chronic anterior uveitis refractive to corticosteroids and immunosuppressive medication.

Outcome of standard and high-risk patients with acute anterior circulation stroke after stent retriever thrombectomy.

BACKGROUND AND PURPOSE Stent retrievers have become an important tool for the treatment of acute ischemic stroke. The aim of this study was to analyze outcome and complications in a large cohort of patients with stroke treated with the Solitaire stent retriever. The study also included patients who did not meet standard inclusion criteria for endovascular treatment: low or high baseline National Institutes of Health Stroke Scale score, ≥80 years of age, extensive ischemic signs in middle cerebral artery territory, and time from symptom onset to endovascular intervention>8 hours. METHODS Consecutive patients with acute anterior circulation stroke treated with the Solitaire FR were analyzed. Data on characteristics of endovascular interventions, complications, and clinical outcome were collected prospectively. Patients who met standard inclusion criteria were compared with those who did not. RESULTS A total of 227 patients were included. Mean age was 68.2±14.7 years, and median National Institutes of Health Stroke Scale score on admission was 16 (range, 2-36). Reperfusion was successful (thrombolysis in cerebral infarction, 2b-3) in 70.9%. Outcome was favorable (modified Rankin Scale, 0-2) in 57.7% of patients who met standard inclusion criteria and 30.3% of those who did not. The rates for symptomatic intracranial hemorrhage were 3.7% and 13.1%, for death 11.4% and 33.8%, and for symptomatic intraprocedural complications 2.5% and 4.8%, respectively. CONCLUSIONS Patients<80 years of age, without extensive pretreatment ischemic signs, and baseline National Institutes of Health Stroke Scale score≤30 had high rates of favorable outcome and low periprocedural complication rates after Solitaire thrombectomy. Successful reperfusion was also common in patients not fulfilling standard inclusion criteria, but worse clinical outcomes warrant further research with a special focus on optimal patient selection.

Dynamic Intraligamentary Stabilization (DIS) for treatment of acute anterior cruciate ligament ruptures: case series experience of the first three years.

BACKGROUND In recent years, the scientific discussion has focused on new strategies to enable a torn anterior cruciate ligament (ACL) to heal into mechanically stable scar tissue. Dynamic intraligamentary stabilization (DIS) was first performed in a pilot study of 10 patients. The purpose of the current study was to evaluate whether DIS would lead to similarly sufficient stability and good clinical function in a larger case series. METHODS Acute ACL ruptures were treated by using an internal stabilizer, combined with anatomical repositioning of torn bundles and microfracturing to promote self-healing. Clinical assessment (Tegner, Lysholm, IKDC, and visual analogue scale [VAS] for patient satisfaction scores) and assessment of knee laxity was performed at 3, 6, 12, and 24 months. A one-sample design with a non-inferiority margin was chosen to compare the preoperative and postoperative IKDS and Lysholm scores. RESULTS 278 patients with a 6:4 male to female ratio were included. Average patient age was 31 years. Preoperative mean IKDC, Lysholm, and Tegner scores were 98.8, 99.3, and 5.1 points, respectively. The mean anteroposterior (AP) translation difference from the healthy contralateral knee was 4.7 mm preoperatively. After DIS treatment, the mean 12-month IKDC, Lysholm, and Tegner scores were 93.6, 96.2, and 4.9 points, respectively, and the mean AP translation difference was 2.3 mm. All these outcomes were significantly non-inferior to the preoperative or healthy contralateral values (p < 0.0001). Mean patient satisfaction was 8.8 (VAS 0-10). Eight ACL reruptures occurred and 3 patients reported insufficient subjective stability of the knee at the end of the study period. CONCLUSIONS Anatomical repositioning, along with DIS and microfracturing, leads to clinically stable healing of the torn ACL in the large majority of patients. Most patients exhibited almost normal knee function, reported excellent satisfaction, and were able to return to their previous levels of sporting activity. Moreover, this strategy resulted in stable healing of all sutured menisci, which could lower the rate of osteoarthritic changes in future. The present findings support the discussion of a new paradigm in ACL treatment based on preservation and self-healing of the torn ligament.

Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis

Objective: To determine the influence of HLA-B27 homozygosity and HLA-DRB1 alleles in the susceptibility to, and severity of, ankylosing spondylitis in a Finnish population. Methods: 673 individuals from 261 families with ankylosing spondylitis were genotyped for HLA-DRB1 alleles and HLA-B27 heterozygosity/ homozygosity. The frequencies of HLA-B27 homozygotes in probands from these families were compared with the expected number of HLA-B27 homozygotes in controls under Hardy-Weinberg equilibrium (HWE). The effect of HLA-DRB1 alleles was assessed using a logistic regression procedure conditioned on HLA-B27 and case-control analysis. Results: HLA-B27 was detected in 93% of cases of ankylosing spondylitis. An overrepresentation of HLA-B27 homozygotes was noted in ankylosing spondylitis (11%) compared with the expected number of HLA-B27 homozygotes under HWE (4%) (odds ratio (OR) = 3.3 (95% confidence interval, 1.6 to 6.8), p = 0.002). HLA-B27 homozygosity was marginally associated with reduced BASDAI (HLA-B27 homozygotes, 4.5 (1.6); HLA-B27 heterozygotes, 5.4 (1.8) (mean (SD)), p = 0.05). Acute anterior uveitis (AAU) was present in significantly more HLA-B27 positive cases (50%) than HLA-B27 negative cases (16%) (OR = 5.4 (1.7 to 17), p<0.004). HLA-B27 positive cases had a lower average age of symptom onset (26.7 (8.0) years) compared with HLA-B27 negative cases (35.7 (11.2) years) (p<0.0001). Conclusions: HLA-627 homozygosity is associated with a moderately increased risk of ankylosing spondylitis compared with HLA-β27 heterozygosity. HLA-B27 positive cases had an earlier age of onset of ankylosing spondylitis than HLA-B27 negative cases and were more likely to develop AAU. HLA-DRB1 alleles may influence the age of symptom onset of ankylosing spondylitis.

Ankylosing spondylitis: genomic and functional characterization of candidate genes and their repercussion in clinical practice

RESUMO: Introdução: A espondilite anquilosante (EA) é uma doença inflamatória crónica caracterizada pela inflamação das articulações sacroilíacas e da coluna. A anquilose progressiva motiva uma deterioração gradual da função física e da qualidade de vida. O diagnóstico e o tratamento precoces podem contribuir para um melhor prognóstico. Neste contexto, a identificação de biomarcadores, assume-se como sendo muito útil para a prática clínica e representa hoje um grande desafio para a comunidade científica. Objetivos: Este estudo teve como objetivos: 1 - caracterizar a EA em Portugal; 2 - investigar possíveis associações entre genes, MHC e não-MHC, com a suscetibilidade e as características fenotípicas da EA; 3 - identificar genes candidatos associados a EA através da tecnologia de microarray. Material e Métodos: Foram recrutados doentes com EA, de acordo com os critérios modificados de Nova Iorque, nas consultas de Reumatologia dos diferentes hospitais participantes. Colecionaram-se dados demográficos, clínicos e radiológicos e colhidas amostras de sangue periférico. Selecionaram-se de forma aleatória, doentes HLA-B27 positivos, os quais foram tipados em termos de HLA classe I e II por PCR-rSSOP. Os haplótipos HLA estendidos foram estimados pelo algoritmo Expectation Maximization com recurso ao software Arlequin v3.11. As variantes alélicas dos genes IL23R, ERAP1 e ANKH foram estudadas através de ensaios de discriminação alélica TaqMan. A análise de associação foi realizada utilizando testes da Cochrane-Armitage e de regressão linear, tal como implementado pelo PLINK, para variáveis qualitativas e quantitativas, respetivamente. O estudo de expressão génica foi realizado por Illumina HT-12 Whole-Genome Expression BeadChips. Os genes candidatos foram validados usando qPCR-based TaqMan Low Density Arrays (TLDAs). Resultados: Foram incluídos 369 doentes (62,3% do sexo masculino, com idade média de 45,4 ± 13,2 anos, duração média da doença de 11,4 ± 10,5 anos). No momento da avaliação, 49,9% tinham doença axial, 2,4% periférica, 40,9% mista e 7,1% entesopática. A uveíte anterior aguda (33,6%) foi a manifestação extra-articular mais comum. Foram positivos para o HLA-B27, 80,3% dos doentes. Os haplótipo A*02/B*27/Cw*02/DRB1*01/DQB1*05 parece conferir suscetibilidade para a EA, e o A*02/B*27/Cw*01/DRB1*08/DQB1*04 parece conferir proteção em termos de atividade, repercussão funcional e radiológica da doença. Três variantes (2 para IL23R e 1 para ERAP1) mostraram significativa associação com a doença, confirmando a associação destes genes com a EA na população Portuguesa. O mesmo não se verificou com as variantes estudadas do ANKH. Não se verificou associação entre as variantes génicas não-MHC e as manifestações clínicas da EA. Foi identificado um perfil de expressão génica para a EA, tendo sido validados catorze genes - alguns têm um papel bem documentado em termos de inflamação, outros no metabolismo da cartilagem e do osso. Conclusões: Foi estabelecido um perfil demográfico e clínico dos doentes com EA em Portugal. A identificação de variantes génicas e de um perfil de expressão contribuem para uma melhor compreensão da sua fisiopatologia e podem ser úteis para estabelecer modelos com relevância em termos de diagnóstico, prognóstico e orientação terapêutica dos doentes. -----------ABSTRACT: Background: Ankylosing Spondylitis (AS) is a chronic inflammatory disorder characterized by inflammation in the spine and sacroiliac joints leading to progressive joint ankylosis and in progressive deterioration of physical function and quality of life. An early diagnosis and early therapy may contribute to a better prognosis. The identification of biomarkers would be helpful and represents a great challenge for the scientific community. Objectives: The present study had the following aims: 1- to characterize the pattern of AS in Portuguese patients; 2- to investigate MHC and non-MHC gene associations with susceptibility and phenotypic features of AS and; 3- to identify candidate genes associated with AS by means of whole-genome microarray. Material and Methods: AS was defined in accordance to the modified New York criteria and AS cases were recruited from hospital outcares patient clinics. Demographic and clinical data were recorded and blood samples collected. A random group of HLA-B27 positive patients and controls were selected and typed for HLA class I and II by PCR-rSSOP. The extended HLA haplotypes were estimated by Expectation Maximization Algorithm using Arlequin v3.11 software. Genotyping of IL23R, ERAP1 and ANKH allelic variants was carried out with TaqMan allelic discrimination assays. Association analysis was performed using the Cochrane-Armitage and linear regression tests as implemented in PLINK, for dichotomous and quantitative variables, respectively. Gene expression profile was carried out using Illumina HT-12 Whole-Genome Expression BeadChips and candidate genes were validated using qPCR-based TaqMan Low Density Arrays (TLDAs). Results: A total of 369 patients (62.3% male; mean age 45.4±13.2 years; mean disease duration 11.4±10.5 years), were included. Regarding clinical disease pattern, at the time of assessment, 49.9% had axial disease, 2.4% peripheral disease, 40.9% mixed disease and 7.1% isolated enthesopathic disease. Acute anterior uveitis (33.6%) was the most common extra-articular manifestation. 80.3% of AS patients were HLA-B27 positive. The haplotype A*02/B*27/Cw*02/DRB1*01/DQB1*05 seems to confer susceptibility to AS, whereas A*02/B*27/Cw*01/DRB1*08/DQB1*04 seems to provide protection in terms of disease activity, functional and radiological repercussion. Three markers (two for IL23R and one for ERAP1) showed significant single-locus disease associations. Association of these genes with AS in the Portuguese population was confirmed, whereas ANKH markers studied did not show an association with AS. No association was seen between non-MHC genes and clinical manifestations of AS. A gene expression signature for AS was established; among the fourteen validated genes, a number of them have a well-documented inflammatory role or in modulation of cartilage and bone metabolism. Conclusions: A demographic and clinical profile of patients with AS in Portugal was established. Identification of genetic variants of target genes as well as gene expression signatures could provide a better understanding of AS pathophysiology and could be useful to establish models with relevance in terms of susceptibility, prognosis, and potential therapeutic guidance.

Ethnic Influence in Clinical and Functional Measures of Brazilian Patients with Spondyloarthritis

Objective. Spondyloarthritides (SpA) can present different disease spectra according to ethnic background. The Brazilian Registry of Spondyloarthritis (RBE) is a nationwide registry that comprises a large databank on clinical, functional, and treatment data on Brazilian patients with SpA. The aim of our study was to analyze the influence of ethnic background in SpA disease patterns in a large series of Brazilian patients. Methods. A common protocol of investigation was prospectively applied to 1318 SpA patients in 29 centers distributed through the main geographical regions in Brazil. The group comprised whites (65%), African Brazilians (31.3%), and people of mixed origins (3.7%). Clinical and demographic variables and various disease index scores were compiled. Ankylosing spondylitis (AS) was the most frequent disease in the group (65.1%); others were psoriatic arthritis (18.3%), undifferentiated SpA (6.8%), enteropathic arthritis (3.7%), and reactive arthritis (3.4%). Results. White patients were significantly associated with psoriasis (p = 0.002), positive HLA-B27 (p = 0.014), and use of corticosteroids (p < 0.0001). Hip involvement (p = 0.02), axial inflammatory pain (p = 0.04), and radiographic sacroiliitis (p = 0.025) were associated with African Brazilian descent. Sex distribution, family history, and presence of peripheral arthritis, uveitis, dactylitis, urethritis, and inflammatory bowel disease were similar in the 3 groups, as well as age at disease onset, time from first symptom until diagnosis, and use of anti-tumor necrosis factor-a agents (p > 0.05). Schober test and thoracic expansion were similar in the 3 groups, whereas African Brazilians had higher Maastricht Ankylasing Spondylitis Enthesitis Scores (p = 0.005) and decreased lateral lumbar flexion (p = 0.003), while whites had a higher occiput-to-wall distance (p = 0.02). African Brazilians reported a worse patient global assessment of disease (p = 0.011). Other index scores and prevalence of work incapacity were similar in the 3 groups, although African Brazilians had worse performance in the Ankylosing Spondylitis Quality of Life questionnaire (p < 0.001). Conclusion. Ethnic background is associated with distinct clinical aspects of SpA in Brazilian patients. African Brazilian patients with SpA have a poorer quality of life and report worse disease compared to whites, (First Release Nov 1 2011; J Rheumatol 2012;39:141-7; doi:10.3899/jrheum.110372)

Uveitis and Acute Interstitial Nephritis: What to Expect

A 46-year-old female patient presenting with acute interstitial nephritis and anterior uveitis was admitted. The renal biopsy disclosed the presence of interstitial nephritis, confirming the clinical diagnosis of tubulointerstitial nephritis and uveitis (TINU) syndrome. Treatment with oral steroids was started, with prompt improvement of symptoms and laboratory abnormalities.

Late reactivation of herpes zoster keratitis results in band keratopathy

Purpose To report an unusual case of a late-stage reactivation of immune stromal keratitis associated with herpes zoster ophthalmicus (HZO), occurring without any apparent predisposing factors, more than 4 years after an acute zoster dermatomal rash. Significant corneal hypoesthesia and a central band keratopathy developed within 6 months of the late-stage reactivation. The clinical case management, issues associated with management, and management options are discussed, including the use of standardized, regulatory approved, antibacterial medical honey. Case Report An 83-year-old woman presented for routine review with a reactivation of right anterior stromal keratitis and mild anterior uveitis, occurring more than 4 years after an acute HZO dermatomal rash and an associated initial episode of anterior stromal keratitis. Corneal sensation became markedly impaired, and over the subsequent 6 months, a right central band keratopathy developed despite oral antiviral and topical steroid therapy. Visual acuity with pinhole was reduced to 20/100 in the affected eye and moderate irritation and epiphora were experienced. The patient declined the surgical intervention options of chelation, lamellar keratectomy, and phototherapeutic keratectomy to treat the band keratopathy. Longer-term management has involved preservative-free artificial tears, eyelid hygiene, standardized antibacterial medical honey, topical nonpreserved steroid, and UV-protective wraparound sunglasses. The clinical condition has improved over 14 months with this ocular surface management regimen, and visual acuity of 20/30 is currently achieved in a comfortable eye. Conclusions The chronic and recurrent nature of HZO can be associated with significant corneal morbidity, even many years after the initial zoster episode. Long-term review and management of patients with a history of herpes zoster stromal keratitis are indicated following the initial corneal involvement. Standardized antibacterial medical honey can be considered in the management of the chronic ocular surface disease associated with HZO and warrants further evaluation in clinical trials.