Rafael S. Grajewski

Favourable outcome after cataract surgery with IOL implantation in uveitis associated with juvenile idiopathic arthritis

Purpose:  Management of uveitic cataract in patients with juvenile idiopathic arthritis (JIA) is challenging, and intraocular lens (IOL) implantation is controversial. This study investigated the outcome after minimally invasive surgery with IOL implantation.

Anti-inflammatory treatment of uveitis with biologicals: new treatment options that reflect pathogenetic knowledge of the disease

BackgroundEndogenous uveitis is a sight-threatening disease. In addition to corticosteroids, immunosuppressive agents are commonly used to treat patients with severe course. Immunosuppressive drugs act nonspecifically, rather than providing a specific interaction with the critical pathogenetic pathways of uveitis. Better knowledge of the basic mechanisms underlying uveitis and of the molecules that are important for regulating inflammation has helped to create new and more specific treatment approaches. Biological therapy for inflammatory diseases employs substances that interfere with specific molecules or pathways induced in the body during the inflammatory process.MethodsThis review gives an overview on molecules that play a critical role in the pathogenetic process of uveitis, as has been observed in patients or the respective animal models, and summarizes the current experience with biologicals for the treatment of uveitis refractive to conventional immunosuppressives.

Spectrum of Uveitis in A German Tertiary Center: Review of 474 Consecutive Patients

Abstract Purpose: To analyze the spectrum of uveitis at a German tertiary center. Patients and methods: A total of 474 consecutive patients with uveitis were classified according to the primary anatomic site of inflammation, examined for laterality of disease, and screened for etiologies. Results: Out of the total, 253 patients (53%) had anterior uveitis, 90 patients (19%) had intermediate uveitis, 100 patients (21%) had posterior uveitis, and 31 patients (7%) had panuveitis. Fifty-six percent of the patients had bilateral involvement, predominantly in intermediate uveitis (ratio 4:1) and panuveitis (ratio 3.4:1). Regarding the etiology of all uveitis cases we found 17% infectious, 23% specific clinical entities, 20% associated with systemic disease (most commonly sarcoidosis with 11%), and 41% idiopathic uveitis. Conclusions: Anterior uveitis was the most common anatomic site of intraocular inflammation. Using a tailored approach, screening for systemic etiologies is recommended, since 20% of all patients had associated systemic diseases.

The Trojan Horse Tale Revisited: An Eye on Metastatic Spread of Carcinoma Cells

Macrophages expressing tumor markers were detected in the blood and eye of a patient with parotid gland carcinoma. These “Trojan horses” may transport tumor cells to distant organs, where carcinomas could grow and establish metastases in new environments. The metastatic spread of carcinoma cells is not fully understood. Here, we compare the peripheral blood mononuclear cells (PBMC) and intraocular metastatic cells in parotid gland carcinoma with the PBMCs of healthy donors by immunohistochemistry and flow cytometry. We found Ber-EP4 tumor marker–positive carcinoma cells in the aqueous humor of the patients right eye and a CD45 and Ber-EP4–expressing PBMC population in his blood. These Ber-EP4–expressing cells exhibited a monocytic-myeloid phenotype with coexpression of CD11b, CD115, and the macrophage marker CD172a (SIRP-α). Uptake of pHrodogreen revealed their phagocytic activity. Our findings suggest that the tumor cells in the anterior chamber originally derived from cell fusions between tumor cells and myeloid cells in the peripheral blood. Thus, metastases of a solid malignancy could use monocytes–macrophages as the Trojan horse to enter the eye. Cancer Immunol Res; 4(2); 92–94. ©2015 AACR.

Predictive value of serum markers for pulmonary involvement in ocular sarcoidosis

including the ganglion cell layers (Fig. 1A,B). The ganglion cell count in the retina did not differ between eyes in different groups. No picnotic nuclei were found. An analysis with the Dual Fluorescence Apoptosis Detection Kit showed the absence of apoptosis in the RPE and in all retinal layers (Fig. 1C,D). To our knowledge, the safety of intraocular clenbuterol injection has never been reported. This study indicates that 0.08 lg clenbuterol administered intravitreally in rabbit eyes did not display ocular toxicity. The dosage used was threefold higher than the targeted therapeutic level and was shown to be free of side-effects. However, the limitations of this study include the lack of electrophysiological testing, the short follow-up period and the number of rabbits used. Further studies will be required to clearly determine the effective dose of intravitreal clenbuterol and to monitor retinal function using electroretinography. In conclusion, our preliminary study suggests that a 0.08 lg dose of intravitreally injected clenbuterol may be safe for rabbit eyes. Therefore, if proven to be safe by further studies, intraocular clenbuterol might be considered a possible treatment for patients with persistent subfoveal fluid accumulation after retinal detachment surgery.

Neue Therapieansätze bei entzündlichen Augenerkrankungen durch Modulation von Lymphangiogenese und zellulärer Immunität: Die DFG-Forschergruppe 2240 stellt sich vor

Background Ophthalmology, principally, is a very successful subdiscipline in medicine. Nonetheless, there are still unmet medical needs which necessitate translational research. Methods The funding instrument of a Research Unit (RU) of the German Research Foundation (DFG) is presented as exemplified by the RU 2240 at the Department of Ophthalmology at the University of Cologne. Results The Research Unit integrates different research groups working on pathologic ocular inflammation, macrophages/microglia and (lymph)angiogenesis to collaborate in a synergistic way. Rotation positions allow young clinicians to rotate into research labs for a defined period of time. A Research Unit is also a powerful strategic tool to strengthen clinical and experimental ophthalmology at individual medical faculties. Conclusions The funding instrument of a Research Unit is highly suitable for fostering translational research in a medical subdiscipline such as ophthalmology, supporting the next generation of (clinician) scientists in ophthalmology and finding new cures for our patients.

The Phenotype of Monocytes in Anterior Uveitis Depends on the HLA-B27 Status

HLA-B27 is the allele most frequently associated with human anterior uveitis. The majority of HLA-B27-positive [acute anterior uveitis (AAU)] patients develop clinically distinct symptoms with acute symptomatic onset of flare and a recurrent disease course characterized by a massive cellular ocular infiltrate during uveitis relapse. By contrast, uveitis in HLA-B27-negative [idiopathic anterior uveitis (IAU)] patients tends to develop a clinically less fulminant, more chronic, and typically asymptomatic disease course. To analyze systemic immune responses in the different uveitis entities, we analyzed peripheral blood cells by flow cytometry. In addition, as a pro-inflammatory biomarker serum, S100A8/A9 levels were quantified by ELISA from patients with AAU (n = 27) and IAU (n = 21), and in healthy controls (n = 30). Data were obtained either during active uveitis flare or after 3 months of inactivity. IAU patients showed a transiently increased frequency of CD56- and CD163-positive monocytes and of both granulocytic myeloid-derived suppressor cells and Th17 cells during active uveitis. By contrast, AAU patients showed an elevated frequency of monocytes, activated T cells, and elevated S100A8/A9 serum levels during clinically quiescent disease. The differentially regulated response of both innate and adaptive immune cells in the blood may be related to the clinically distinct characteristics of the two different uveitis entities.

Analysis of the impact of allergy and atopy on new onset of uveitis

The inappropriate immune response to harmless foreign and self‐antigens is a common feature of allergy, atopy and autoimmune disease. The influence of environmental factors in the initiation of autoimmunity is not well understood. It is conceivable that immune responses to allergens may also serve as a trigger of bystander immune reactions, including autoimmunity such as uveitis. Therefore, we wanted to investigate the prevalence of allergies and atopy in patients with different types of uveitis in comparison to a control cohort.

Macular thickening of uveitic eyes in the absence of macular oedema and epiretinal membranes

Editor, M acular oedema is a common and vision-threatening complication of all types of uveitis (Onal et al. 2014). Therefore, spectral-domain optical coherence tomography (SD-OCT) has become a standard tool in the examination of uveitis patients. Macular oedema is accompanied by macular thickening, which has been described in acute anterior uveitis (Traill et al. 2007), and can be further promoted by epiretinal membrane formation. Little is known about macular central retinal thickness (CRT) and macular volume (MV) in uveitic eyes without macular oedema or epiretinal membranes. Therefore, we are interested to compare CRT and MV between uveitis-affected eyes and unaffected healthy fellow eyes. Between 1 January 2012 and 31 December 2014, 774 consecutive patients with anterior, intermediate, posterior and panuveitis underwent standardized clinical examination (Grajewski et al. 2015) as well as macular SD-OCT measurement of both eyes. Inclusion criteria for this prospective, non-randomized, single-centre study were (1) confirmed diagnosis of unilateral uveitis before treatment and (2) absence of cystoid macular oedema (CME), diffusemacular oedema (DME, defined by presence of small low-reflective areaswith spongelike appearance), serous retinal detachment (SRD), epiretinal membrane with (ERM+) and without (ERM ) retinal surface wrinkling, as defined elsewhere (Onal et al. 2014). Patients with bilateral uveitis, isolated keratitis, isolated (epi-) scleritis, isolated retinal vasculitis, and isolated optic neuritis, one-eyed patients as well as patients with significant opacities of at least one eye disabling SDOCT measurement were excluded. Altogether, a total of 136 patients were identified (Table 1) and enrolled in this clinical study performed in conformance with the Declaration of Helsinki and approved by the institutional review board. In uveitic as well as non-affected fellow eyes of all 136 patients, MV and CRT were measured using highresolution SD-OCT (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany). Commercial software (SPSS version 21.0; SPSS, Inc., Chicago, IL, USA) was used for all statistical analyses. Comparisons between uveitic and non-affected fellow eyes were performed using Wilcoxon and Kruskal–Wallis tests. A p-value of less than 0.05 was considered statistically significant. Uveitic eyes revealed significantly higher MV as well as CRT values than the non-affected fellow eyes (p < 0.001, respectively; Table 1). Regarding the anatomical location of inflammation, MV and CRT were significantly higher in uveitic than in non-affected fellow eyes for anterior (p < 0.001, respectively), intermediate (p = 0.027 and p = 0.028, respectively) and posterior uveitis (p = 0.012 and p = 0.024, respectively). The different uveitis localizations showed no statistically significant differences between each other regarding CRT and MV. There was no significant association with the clinical characteristics, including age, gender, ethnicity, onset, duration and course of uveitis, type of inflammation, visual acuity as well as aetiology of uveitis. CRTof fellow eyeswas similar to previously reported CRT of normal healthy eyes (Song et al. 2010). This study demonstrates macular thickening in all types of uveitis in the absence of macular oedema and epiretinal membranes. Interestingly, this finding was not dependent on the type of uveitis or clinical characteristics, despite the presence of a high proportion of infectious causes. The precise mechanisms that lead to macular oedema are still unknown, but during inflammation cytokines are released that contribute to breakdown of blood–retinal barriers and consecutive leakage of retinal vessels resulting in macular oedema development (Klaassen et al. 2013). As cytokine molecules can diffuse within intraocular fluids, they can reach the macular region and contribute to macular oedema in all types of uveitis, independently of the anatomic location of inflammation. Similarly, retinal thickening of uveitic eyes may represent a precursor state of macular oedema, representing a gradual transition of a morphologically normal appearing ‘thicker’ retina to a macular oedema. Therefore, careful monitoring of uveitis patients using SD-OCT is recommended.

Topische antiinflammatorische Therapieoptionen

Inflammatorische Prozesse des Auges gehören zu den häufigsten Entitäten in der Augenheilkunde. Die Anwendung antientzündlicher Substanzen ist daher für den Behandler eine zentrale therapeutische Option. Hierbei kommen zumeist aufgrund der guten Zugänglichkeit des Auges topische Applikationen zur Anwendung. Substanzgruppen wie Antiallergika, nichtsteroidale Antirheumatika, Glukokortikoide, Calcineurininhibitoren, Serumaugentropfen sowie neuere, noch in der Entwicklung befindliche Substanzen werden spezifisch sowohl in schmalen als auch in breiten Indikationsspektren eingesetzt, weshalb die Kenntnis der Wirkmechanismen und der potenziellen Nebenwirkungen von großer Bedeutung ist. Dieser Artikel soll einen Überblick über die derzeitig verfügbaren antiinflammatorisch wirksamen Substanzen geben, die topisch verabreicht werden können. Hierbei wird auf eine detaillierte Anwendungsbeschreibung (Dosis, Applikationshäufigkeit, Dauer usw.) in Bezug auf die einzelnen Krankheitsbilder bewusst verzichtet. Ziel ist es, dem Leser pharmakologisches Basiswissen mit direktem ophthalmologischen Bezug zu vermitteln.