Optical Coherence Tomography Angiographic Follow-Up in a Case of Subacute Sclerosing Panencephalitis and Unilateral Necrotising Retinitis.

We present a 20-year-old woman who was diagnosed with subacute sclerosing panencephalitis (SSPE) 20 months after presenting with unilateral retinitis. At presentation, the patient had two inferotemporal macular lesions in her left eye. Corresponding to these areas, optical coherence tomography (OCT) showed hyporeflective spaces with loss of nearly all of the retinal layers. OCT-angiography (OCTA) demonstrated some flow deficit areas with a reduction in the vessel density. Her serum measles antibody titre was high (IgG >5000.0 mIU/ml). Twenty months later the macular lesions had diminished in size, and there was some focal retinal thinning with interruption of the ellipsoid zone. OCTA showed that the flow deficit areas were diminished in size together with the relatively improved perfusion density. Neurological examination disclosed myoclonic jerks. Neuropsychological assessment demonstrated impaired executive function, attention, and narrowed lexical fluency. Measles IgG antibody was high in the cerebrospinal fluid (>230.0 U/ml). Brain magnetic resonance imaging demonstrated bilateral, non-specific, small foci of T2 hyperintensity in the frontoparietal subcortical white matter and centrum semiovale. The present case is the first where OCTA findings of SSPE-related retinal lesions have been described.

Treat to target in Behcet's disease: Should we follow the paradigm of other systemic rheumatic diseases?

During the last decades the efficacy of biologic agents, mainly of anti-TNFs, in controlling the activity of serious manifestations of Behcet's Disease (BD) has been established. On the other hand, the clinical heterogeneity of BD has precluded the validation of a widely-accepted composite index for disease assessment and for target disease-state definitions, such as low disease activity and remission, and the testing of their implementation in clinical practice. Therefore, in contrast to other systemic rheumatic diseases, a treat-to-target strategy has not yet been developed in BD. There are several challenges towards this approach, including standardization of outcome measures for assessing the disease activity in each-affected organ and construction of a composite disease activity index. The challenges for the development of a treat-to-target strategy and possible solutions are discussed in this position paper, which stemmed from a round table discussion that took place in the 19th International Conference on BD.

Uveitis in Behçet disease - an update.

PURPOSE OF REVIEW: Uveitis is a major manifestation of Behçet disease (BD) and potentially has a high morbidity. This article reviews recently published data on BD uveitis. RECENT FINDINGS: A set of classification criteria and a diagnostic algorithm have been developed for BD uveitis. Recent reports have confirmed male predominance and posterior segment inflammation in the majority of BD uveitis patients. A high uveitis attack severity score, fluorescein angiographic leakage at the posterior pole, and disruption of outer retinal layers on optical coherence tomography (OCT) predict poor visual outcome. OCT-angiography studies have suggested subclinical changes of retinal capillaries in patients with or without ocular involvement. In a randomized controlled trial, interferon-α was superior to cyclosporine. Favorable outcomes were reported with earlier initiation, optimization, and withdrawal of infliximab after remission. Adalimumab as first-line was superior to conventional therapy. SUMMARY: Classification criteria will be used to select a homogeneous group of patients for research and the diagnostic algorithm may help ophthalmologists predict the probability of BD uveitis based on ocular findings. Fluorescein angiography and OCT are the routine imaging modalities. Clinical relevance of OCT-angiography is unclear. Interferon-α, infliximab, and adalimumab have proven superior efficacy compared to conventional therapy.

EULAR study group on 'MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders.

The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

Patterns of cytomegalovirus retinitis at a tertiary referral center in Turkey.

PURPOSE: To analyze predisposing conditions in Turkish patients with CMV retinitis and to compare HIV-positive and HIV-negative patients. METHODS: We reviewed medical charts and ocular images of 41 patients with CMV retinitis diagnosed between 1996 and 2019. RESULTS: Eleven patients (27%) had HIV infection and 30 were immunocompromised from diverse causes. Initial visual acuity, type, zone, and extent of CMV retinitis, and response to anti-CMV treatment were not significantly different between the two groups. Vitreous haze and panretinal occlusive vasculopathy were the presenting features only in non-HIV patients, seen in 34% and 16% of eyes, respectively. Although not statistically significant, recurrent CMV retinitis was more common in non-HIV patients (17.4% vs. 4.3%/eye-year) and immune recovery uveitis was more common in HIV patients (43% vs. 26%/eye-year). Visual outcomes were similar. Final visual acuity of 1 logMAR or worse was significantly associated with the recurrence of CMV retinitis (odds ratio 9.67; p = 0.01) and also with the occurrence of immune recovery uveitis (odds ratio 4.31; p = 0.058). CONCLUSIONS: Diverse immunocompromising conditions are more commonly associated with CMV retinitis than HIV infection in Turkish patients. Intraocular inflammation was more commonly associated with active retinitis in non-HIV patients and immune recovery uveitis was more common in HIV patients.

Behçet's disease uveitis: is there a need for new emerging drugs?

Introduction: Behçet's disease uveitis (BDU) is a potentially blinding disorder. Systemic treatment with disease-modifying anti-rheumatic drugs (DMARDs) is mandatory in patients with intraocular inflammation involving the posterior segment of the eye. Areas covered: This article discusses existing systemic treatment with corticosteroids and conventional and biologic DMARDs as well as adjunctive local therapy in BDU. An overview is provided for a wide range of biologic DMARDs that have shown promise or investigated in clinical trials. Most recently introduced biologic DMARDs and targeted synthetic DMARDs are also reviewed for their potential in the treatment of BDU. Expert opinion: The prognosis of patients with BDU has remarkably improved after the introduction of biologic DMARDs. An expanding therapeutic armamentarium will allow treatment of most refractory cases. The ultimate goal is to provide drug-free remission with preservation of 20/20 vision.

Vogt-Koyanagi-Harada disease: recurrence rates after initial-onset disease differ according to treatment modality and geographic area.

Background/Purpose Vogt-Koyanagi-Harada (VKH) disease is a primary autoimmune stromal choroiditis producing a spill-over panuveitis. For initial-onset VKH disease, it is increasingly thought that corticosteroid therapy is not sufficient and additional non-steroidal immunosuppressive therapy is needed. At the 11th workshop on VKH, the disease was said to be well controlled with corticosteroids alone in Japanese patients. The aim of this study was to review the literature to determine whether different levels of severity exist in different geographical areas. METHODS: Literature was reviewed for studies on the evolution of initial-onset VKH disease, looking at treatment modalities and proportion of cases with chronic evolution and/or sunset-glow fundus (SGF). RESULTS: PubMed search yielded 1249 references containing the term of Vogt-Koyanagi-Harada. Twenty references (15 from outside of Japan and 5 from Japan) contained information on the evolution of treated initial-onset disease. For the "international" group, percentage of chronic evolution after systemic corticosteroid monotherapy was 61%, and after combined steroidal and non-steroidal therapy it fell to 2% (0% in 3/4 studies). In the Japanese studies where all patients received systemic corticosteroids alone, chronic evolution was reported in 25%; however, SGF amounted to 61%. CONCLUSION: In the world at large, chronic evolution of initial-onset VKH disease treated with corticosteroids alone concerned two-thirds of patients. Japanese studies showed that chronic evolution was substantially less frequent, indicating possibly less severe disease in Japan. This proportion fell to almost zero when dual steroidal and non-steroidal immunosuppression was given at onset.

2018 update of the EULAR recommendations for the management of Behçet's syndrome.

Several new treatment modalities with different mechanisms of action have been studied in patients with Behçet's syndrome (BS). The aim of the current effort was to update the recommendations in the light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities.

Management of major organ involvement of Behçet's syndrome: a systematic review for update of the EULAR recommendations.

Objective: To assess the efficacy and safety of treatment modalities for major organ involvement of Behçet's syndrome (BS), in order to inform the update of the EULAR recommendations for the management of BS. Methods: A systematic literature review of all randomized controlled trials, controlled clinical trials, or open label trials assessing eye, vascular, nervous system or gastrointestinal system involvement of BS was performed. If controlled trials were not available for answering a specific research question, uncontrolled studies or case series were also included. Results: We reviewed the titles and abstracts of 3927 references and 161 studies met our inclusion criteria. There were only nine randomized controlled trials. Observational studies with IFN-α and monoclonal anti-TNF antibodies showed beneficial results for refractory uveitis. Meta-analysis of case-control studies showed that immunosuppressives decreased the recurrence rate of deep vein thrombosis significantly whereas anticoagulants did not. CYC and high dose glucocorticoids decreased mortality in pulmonary arterial aneurysms and postoperative complications in peripheral artery aneurysms. Beneficial results for gastrointestinal involvement were obtained with 5-ASA derivatives and AZA as first line treatment and with thalidomide and/or monoclonal anti-TNF antibodies in refractory cases. Observational studies for nervous system involvement showed improved outcome with immunosuppressives and glucocorticoids. Meta-analysis of case-control studies showed an increased risk of developing nervous system involvement with ciclosporin-A. Conclusion: The majority of studies related to major organ involvement that informed the updated EULAR recommendations for the management of BS were observational studies.

QUANTITATIVE ANALYSIS OF STRUCTURAL ALTERATIONS IN THE CHOROID OF PATIENTS WITH ACTIVE BEHÇET UVEITIS.

PURPOSE: To quantitatively analyze in vivo morphology of subfoveal choroid during an acute attack of Behçet uveitis. METHODS: In this prospective study, 28 patients with Behçet uveitis of ≤4-year duration, and 28 control subjects underwent enhanced depth imaging optical coherence tomography. A novel custom software was used to calculate choroidal stroma-to-choroidal vessel lumen ratio. Subfoveal choroidal thickness was measured at fovea and 750 µm nasal, temporal, superior, and inferior to fovea. Patients underwent fluorescein angiography and indocyanine green angiography. Receiver operating characteristic curve and area under the curve were computed for central foveal thickness. The eye with a higher Behçet disease ocular attack score 24 was studied. The main outcome measures were choroidal stroma-to-choroidal vessel lumen ratio and choroidal thickness. RESULTS: The mean total Behçet disease ocular attack score 24, fluorescein angiography, and indocyanine green angiography scores were 7.42 ± 4.10, 17.42 ± 6.03, and 0.66 ± 0.73, respectively. Choroidal stroma-to-choroidal vessel lumen ratio was significantly higher in patients (0.413 ± 0.056 vs. 0.351 ± 0.063, P = 0.003). There were no significant differences in subfoveal choroidal thickness between patients and control subjects. Choroidal stroma-to-choroidal vessel lumen ratio correlated with retinal vascular staining and leakage score of fluorescein angiography (r = 0.300, P = 0.036). Central foveal thickness was significantly increased in patients (352.750 ± 107.134 µm vs. 263.500 ± 20.819 µm, P < 0.001). Central foveal thickness showed significant correlations with logarithm of minimum angle of resolution vision, Behçet disease ocular attack score 24, total fluorescein angiography score, retinal vascular staining and/or leakage and capillary leakage scores of fluorescein angiography, and total indocyanine green angiography score. At 275 µm cutoff, diagnostic sensitivity and specificity of central foveal thickness for acute Behçet uveitis were 89% and 72%, respectively (area under the curve = 0.902; 95% CI = 0.826-0.978, P < 0.001). CONCLUSION: There was choroidal stromal expansion which was not associated with thickening of the choroid. Central foveal thickness may be used as a noninvasive measure to assess inflammatory activity in early Behçet uveitis.

Systemic vasculitis and the eye.

PURPOSE OF REVIEW: The primary systemic vasculitides represent a spectrum of rare but life-threatening conditions that may also affect the eye in various forms. This article reviews recently published data on ocular manifestations of systemic vasculitis. RECENT FINDINGS: Early diagnosis and timely treatment has led to better visual outcomes in giant cell arteritis (GCA). Gene expression from orbital tissues could distinguish granulomatosis with polyangiitis (GPA) from sarcoidosis and Graves disease, but not from idiopathic orbital inflammation. Rituximab was an effective therapeutic option in ocular GPA. An ocular attack severity scoring system, flare levels, fluorescein angiography and optical coherence tomography parameters have been suggested as predictors of visual prognosis in Behçet disease. Efficacy of tumor necrosis factor-alpha inhibitors, interferon α and anti-interleukin-1 agents was shown in noncontrolled studies of ocular Behçet disease. SUMMARY: Widely used fast-track pathway care as well as ocular imaging to detect subclinical involvement may enable earlier diagnosis of GCA and prevention of permanent visual loss. Orbital inflammation may not remain idiopathic with advances in gene expression profiling of orbital tissues. With an increased availability and the use of biologic agents, visual prognosis will improve in patients with severe ocular complications of systemic vasculitides.

Ophthalmic manifestations of bartonella infection.

PURPOSE OF REVIEW: The eye is commonly affected in disseminated cat scratch disease (CSD) caused by Bartonella species. This article reviews recently published data on epidemiology of CSD, clinical features of ocular involvement, diagnosis and treatment. RECENT FINDINGS: The annual incidence of CSD has been estimated as 4.7 per 100 000 in the United States. It occurs predominantly in the southern states, with a peak in January, and disproportionately affects children. Retinal infiltrates, neuroretinitis and branch retinal artery occlusions have been reported as common manifestations of ocular bartonellosis in recent series. The use of different antigens for serodiagnosis and new real-time PCR assays for molecular diagnosis have been described. Despite lack of a standard treatment, good visual outcomes were generally reported in patients with ocular bartonellosis. SUMMARY: Bartonella infections continue to be a burden worldwide and epidemiologic features may guide preventive measures in high-risk regions and populations. An increased awareness of diverse posterior segment manifestations will lead to an early diagnosis of ocular bartonellosis. Laboratory diagnostic methods continue to evolve and may be applied to the investigation of ocular fluids for a definitive diagnosis of ocular bartonellosis. Well designed clinical trials are required to establish the optimum treatment of especially sight-threatening manifestations.

The importance of quantitative measurement methods for uveitis: laser flare photometry endorsed in Europe while neglected in Japan where the technology measuring quantitatively intraocular inflammation was developed.

Laser flare photometry (LFP) is an objective and quantitative method to measure intraocular inflammation. The LFP technology was developed in Japan and has been commercially available since 1990. The aim of this work was to review the application of LFP in uveitis practice in Europe compared to Japan where the technology was born. We reviewed PubMed articles published on LFP and uveitis. Although LFP has been largely integrated in routine uveitis practice in Europe, it has been comparatively neglected in Japan and still has not received FDA approval in the USA. As LFP is the only method that provides a precise measure of intraocular inflammation, it should be used as a gold standard in uveitis centres worldwide.

Reappraisal of the management of Vogt-Koyanagi-Harada disease: sunset glow fundus is no more a fatality.

PURPOSE: Vogt-Koyanagi-Harada (VKH) disease is a primary autoimmune stromal choroiditis. Aim of the study was to gather a body of evidence from the literature and from experts that systemic corticosteroid combined with non-steroidal immunosuppressive therapy should become the standard of care in initial-onset VKH disease. METHODS: Literature was reviewed and leading experts in VKH were consulted in different parts of the world in order to put forward a consensus attitude in the management of initial-onset VKH disease. RESULTS: There was a substantial body of evidence in the literature that early aggressive and sustained corticosteroid and non-steroidal immunosuppressive therapy in initial-onset VKH disease allows to achieve full control of choroidal inflammation, eliminating any subclinical choroidal inflammation, and substantially reduces recurrences with improvement of anatomical and functional outcomes. This was in agreement with experts' opinion and practice. ICGA was the method of choice to monitor disease evolution. CONCLUSION: Since the choroidal space is easily accessible to systemic therapy and because inflammation in VKH disease is exclusively originating from the choroidal stroma, early and sustained treatment right at the onset of the disease process with dual corticosteroid and non-steroidal immunosuppressive therapy can result in full "healing" in many cases preventing sunset glow fundus which results from depigmentation from chronic uncontrolled inflammation.

A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet's disease in HLA-B*51 carriers.

INTRODUCTION: Endoplasmic reticulum aminopeptidase-1 (ERAP1) protein is highly polymorphic with numerous missense amino acid variants. We sought to determine the naturally occurring ERAP1 protein allotypes and their contribution to Behçet's disease. METHODS: Genotypes of all reported missense ERAP1 gene variants with 1000 Genomes Project EUR superpopulation frequency >1% were determined in 1900 Behçet's disease cases and 1779 controls from Turkey. ERAP1 protein allotypes and their contributions to Behçet's disease risk were determined by haplotype identification and disease association analyses. RESULTS: One ERAP1 protein allotype with five non-ancestral amino acids was recessively associated with disease (p=3.13×10-6, OR 2.55, 95% CI 1.70 to 3.82). The ERAP1 association was absent in individuals who lacked HLA-B*51. Individuals who carry HLA-B*51 and who are also homozygous for the haplotype had an increased disease odds compared with those with neither risk factor (p=4.80×10-20, OR 10.96, 95% CI 5.91 to 20.32). DISCUSSION: The Behçet's disease-associated ERAP1 protein allotype was previously shown to have poor peptide trimming activity. Combined with its requirement for HLA-B*51, these data suggest that a hypoactive ERAP1 allotype contributes to Behçet's disease risk by altering the peptides available for binding to HLA-B*51.

Consensus classification criteria for paediatric Behçet's disease from a prospective observational cohort: PEDBD.

BACKGROUND: We aimed to describe the main features of Behçet's disease (BD) in children in the largest prospective cohort to date and to propose a classification. METHODS: An international expert consensus group was formed to define a data set of minimal symptoms for the inclusion of patients. Patients were entered prospectively during 66 months. Experts classified patients on a consensus basis. The concordance of two international classifications was analysed in confirmed patients with BD. Comparisons of subgroups of patients helped define consensus criteria. BD-associated clinical manifestations were also investigated in three control diseases extracted from an independent data set (Eurofever). FINDINGS: In total, 42 centres from 12 countries included 230 patients; data for 219 (M/F ratio=1) could be analysed. The experts classified 156 patients (71.2%) as having confirmed BD. Males more often than females showed cutaneous, ocular and vascular symptoms and females more often genital aphthosis. Age at disease onset and skin and vascular involvement were lower for European than non-European children. Oral aphthosis was the presenting sign for 81% (179/219) of patients. The mean delay to the second symptom was 2.9±2.2 years. International classifications were not concordant with the expert classification. Our paediatric classification contains six categories, a minimum of three signs (each in a distinct category) defining paediatric BD. Three clinical signs discriminated our cohort from the Eurofever cohorts. INTERPRETATION: We present a comprehensive description of a large cohort of patients from both European and non-European countries and propose the first classification of paediatric BD for future therapeutic trials.

Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease.

Genome-wide association studies (GWAS) are a powerful means of identifying genes with disease-associated common variants, but they are not well-suited to detecting genes with disease-associated rare and low-frequency variants. In the current study of Behçet disease (BD), nonsynonymous variants (NSVs) identified by deep exonic resequencing of 10 genes found by GWAS (IL10, IL23R, CCR1, STAT4, KLRK1, KLRC1, KLRC2, KLRC3, KLRC4, and ERAP1) and 11 genes selected for their role in innate immunity (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4) were evaluated for BD association. A differential distribution of the rare and low-frequency NSVs of a gene in 2,461 BD cases compared with 2,458 controls indicated their collective association with disease. By stringent criteria requiring at least a single burden test with study-wide significance and a corroborating test with at least nominal significance, rare and low-frequency NSVs in one GWAS-identified gene, IL23R (P = 6.9 × 10(-5)), and one gene involved in innate immunity, TLR4 (P = 8.0 × 10(-4)), were associated with BD. In addition, damaging or rare damaging NOD2 variants were nominally significant across all three burden tests applied (P = 0.0063-0.045). Furthermore, carriage of the familial Mediterranean fever gene (MEFV) mutation Met694Val, which is known to cause recessively inherited familial Mediterranean fever, conferred BD risk in the Turkish population (OR, 2.65; P = 1.8 × 10(-12)). The disease-associated NSVs in MEFV and TLR4 implicate innate immune and bacterial sensing mechanisms in BD pathogenesis.

Uveitis as a prognostic factor in multiple sclerosis.

Uveitis is occasionally encountered in multiple sclerosis (MS) patients. The objective of this report is to investigate whether uveitis has a prognostic impact on the clinical course of MS. Several clinical and demographic features were compared between 41 MS patients with uveitis and 100 randomly selected MS patients without uveitis. While there were no significant differences by means of gender, age of MS onset, oligoclonal band positivity and disease duration, EDSS and progression index (PI) scores of MS patients with uveitis were significantly lower than those without uveitis (p = 0.004 and <0.001, respectively). Our results suggest that uveitis might be used as a good prognostic factor.

Natural killer cells dominate a Th-1 polarized response in Behçet's disease patients with uveitis.

OBJECTIVES: Behçet's disease (BD) is a systemic inflammatory disorder of unknown etiology, characterised by recurring relapses and remissions. BD manifestations have been thought to be associated with the immunological abnormalities triggered by environmental factors in genetically susceptible individuals. Natural killer (NK) cells are important members of innate immunity with their cytotoxic activity and also cytokine secretions. They have the capacity to induce or dampen immune responses. Different study groups have reported conflicting results about NK cell activity in the BD pathogenesis, however, contribution of NK cells to BD is still unclear. METHODS: NK cells from BD patients with uveitis (n=11) as well as age- and gender-matched healthy controls (n=9) were purified and intracytoplasmic cytokine levels of TNF-α, IFN-γ, IL-2, IL-4, IL-10, IL-12 and IL-13 were determined. RESULTS: Increased TNF-α, IFN-γ and IL-2 in relapse period and increased IL-4 as well as a slight increase of IL-10 in remission period were observed. CONCLUSIONS: Our results show that NK cells are the contributors of BD pathogenesis with their NK1 profile in relapse periods, and also with their NK2 profile in remission periods, in BD patients with uveitis. An increase in IL-10 observed in remission periods may be linked to the regulatory potential of NK cells in the recurrent nature of BD manifestations.