Fluocinolone acetonide 0.19-mg implant for the treatment of noninfectious uveitis with involvement of the posterior segment: a real-world study.

PURPOSE: To evaluate the effectiveness of 0.19-mg fluocinolone acetonide implant (FAi) for preventing inflammatory relapses in noninfectious uveitis with posterior segment involvement in standard clinical practice. Further, to assess the value of remission induction therapy with intraocular and periorbital administered high-dose corticosteroids before FAi. METHODS: A retrospective cohort study in a tertiary referral center specialized in uveitis management. The primary study outcomes were the best-corrected visual acuity (BVCA) and central retinal thickness (CRT) within a 12-month observation period. The secondary outcomes were intraocular pressure (IOP) and intraocular inflammation. The main safety measures were IOP increase and cataract formation. RESULTS: In total, 76 eyes of 57 patients received FAi. Locally administered high-dose corticosteroids were applied in 68.4% of all eyes before FAi. BCVA remained stable within the 12-month observation period (63.21 vs. 62.95, difference 0.26 letters; 95% CI: - 6.31 to 6.84; p > 0.9). Significant CRT reduction upon FAi was sustained after 12 months (362.7 vs. 309.1 µm, difference 53.57 µm; 95% CI: 1.55 to 105.6; p = 0.04). Intraocular inflammation was reduced until 9 months of follow-up (0.82 vs. 0.3, difference 0.53; 95% CI: 0.11 to 0.95; p = 0.007). A mean IOP increase (13.68 vs. 15.6; difference - 1.92; 95% CI: - 3.85 to 0.004; p = 0.0507) and cataract development (20% of all phakic eyes) were noted. CONCLUSION: We observed similar levels of FAi effectiveness for the treatment of noninfectious uveitis in standard clinical practice compared to previous randomized clinical trials. Moreover, remission induction therapy before FAi can benefit patients with increased baseline uveitis activity.

Ocular Involvement in Congenital Infections - TORCH. / Augenbeteiligung bei kongenitalen Infektionen ­ TORCH.

This review summarises the ophthalmological findings in congenital infections. Intrauterine infections are an important cause of childhood blindness. The most common infections are grouped under the acronym TORCH, which stands for Toxoplasma gondii, others, rubella, CMV, and herpes simplex. Overall, these infections are not very common in first-world countries during pregnancy, but are of particular importance because of the threat to vision. Diagnosis of infection or reactivation is a gynaecological challenge. However, ophthalmological examination of newborns can be appropriately targeted if the causative agent is known. The most important therapeutic agents used in the newborn are summarised.

Targeted Medical History and Diagnostic Testing in Uveitis. / Zielgerichtete Anamnese und Diagnostik bei Uveitis.

Uveitis is a collective term for a variety of different intraocular inflammations. The underlying etiologies vary greatly depending on the uveitis subtype, and in particular the anatomical focus. The most common forms of anterior uveitis are acute fibrinous unilateral uveitis, often associated with the HLA-B27 haplotype, and granulomatous inflammation, typically associated with sarcoidosis or herpes infections. Intermediate uveitis is usually idiopathic in nature but can also be associated with multiple sclerosis or sarcoidosis, while vitreoretinal lymphoma must also be considered as a masquerade syndrome in patients aged over 45. Posterior uveitis, on the other hand, as well as retinal vasculitis and panuveitis, have a very broad variety of etiologies; these can, however, be narrowed down through a similar findings-centered approach. Retinitis, for example, is often associated with infections (Toxoplasma gondii and viruses of the herpes group), whereas chorioditis is frequently idiopathic, although infections such as tuberculosis may occur. Therefore, the medical history and laboratory diagnosis should be tailored in patients with uveitis based on the anatomic focus of inflammation (anterior, intermediate, or posterior uveitis, or panuveitis) and the clinical picture (e.g., granulomatous versus nongranulomatous).

Childhood Uveitis. / Uveitis im Kindesalter.

Childhood uveitis is an ophthalmological challenge, since on the one hand it often remains asymptomatic and difficult to detect, and on the other hand it often has a chronic course and is associated with a high risk of complications threatening the vision. The most important risk factors for childhood uveitis are underlying rheumatic diseases; recommendations for ophthalmological monitoring have been developed together with paediatric rheumatologists. Intermediate and posterior uveitis are rare in children. The therapy must effectively control inflammation and at the same time cause only minimal side effects. Since steroids in particular cause side effects frequently, an immunosuppressive therapy must be initiated early in an interdisciplinary cooperation with paediatric rheumatologists and parents with the goal of minimising steroids.

Ocular ischaemic complications in giant cell arteritis: CHADS2-score predicts risk of permanent visual impairment.

OBJECTIVES: To identify independent risk factors for permanent visual loss (PVL) in patients with giant cell arteritis (GCA), with a special focus on sonographic findings of the temporal, carotid and subclavian/axillary arteries, and on established scoring systems of ischaemia risk assessment. METHODS: Consecutive patients with a diagnosis of GCA between 2002 and 2013 were retrospectively identified from a prospectively maintained database. Data on clinical characteristics including ophthalmological findings, laboratory values, and sonographic findings of the temporal, carotid an axillary arteries were extracted. CHADS2- and CHA2DS2-VASc-score were calculated. Clinical, laboratory and sonographic characteristics of patients with and without PVL were compared. Multiple logistic regression models were calculated to identify variables independently associated with PVL. RESULTS: One-hundred-fifty-two patients were included in the analysis. PVL occurred in 30.2% of patients, with anterior ischaemic optic neuropathy as predominant underlying cause (91.3%). The frequency of PVL was strongly dependent on the age at diagnosis, with a significant increase after the age of 70 years. In multivariate analysis, axillary artery vasculitis with an odds ratio (OR) of 0.3 and constitutional symptoms with an OR of 0.1 were negatively associated with PVL. A CHADS2-score of 1 (OR 10.7) or ≥2 (OR 25) was associated with a significantly increased risk of PVL. CONCLUSIONS: The risk of PVL secondary to GCA increases with age but is lower in patients presenting with constitutional symptoms and/or exhibiting axillary artery involvement. The CHADS2-score may help to discriminate patients with low vs. high risk of PVL.

Management of dupilumab-associated conjunctivitis in atopic dermatitis.

Since September 2017, the monoclonal antibody dupilumab (Dupixent® ) has been approved in the EU for the treatment of moderate-to-severe atopic dermatitis. By blocking IL-4 and IL-13 signaling pathways, dupilumab improves both objective signs and subjective symptoms of the disease. Blocking of the IL-4aRα subunit leads to improvement of the skin's barrier function and reduction in Th2-mediated inflammation. While the rate of adverse events on dupilumab is generally low, mild-to-moderate conjunctivitis associated with redness as well as a burning and foreign body sensation has been reported in up to 28 % of patients. Treatment options include topical corticosteroids and topical calcineurin inhibitors. The present review highlights the clinical presentation of dupilumab-associated conjunctivitis and addresses pharmacological and non-pharmacological options available for the treatment of this clinically highly relevant condition.

Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells.

BACKGROUND: Uveitis is a potentially blinding inflammatory disease of the inner eye with a high unmet need for new therapeutic interventions. Here, we wanted to investigate the suppressive effect of the intraocular application of the small molecule dihydroorotate dehydrogenase (DHODH)-inhibitor PP-001 on experimental relapsing rat uveitis and furthermore determine its effect on proliferation and cytokine secretion of human peripheral blood lymphocytes (PBL) and human retinal pigment epithelial (RPE) cells in vitro. METHODS: Spontaneously relapsing uveitis was induced in rats by immunization with interphotoreceptor retinoid-binding protein (IRBP) peptide R14. PP-001 was injected intravitreally after resolution of the primary disease to investigate further relapses. Proliferation and metabolic activity of phytohemagglutinin (PHA)-stimulated human peripheral lymphocytes with and without PP-001 and cytokine secretion were determined by XTT assay and bioplex bead assay. The RPE cell line ARPE-19 as well as primary human RPE cells treated with PP-001 or anti-vascular endothelial growth factor (VEGF) antibody bevacizumab were also investigated for metabolic activity and cytokine/chemokine secretion. RESULTS: Injection of PP-001 into rat eyes reduced the number of relapses by 70%, from 20 relapses (57% of the rats affected) in the control group to 6 relapses (33% of the rats) in the treatment group. In human PBL cultures, PP-001 reduced the proliferation in a dose-dependent manner. The secretion of several cytokines such as IL-17, IFN-γ, and VEGF was suppressed by PP-001, as previously observed with rat T cells in the experimental autoimmune uveitis (EAU) model. In contrast, human RPE cells were not affected by PP-001, while the anti-VEGF antibody bevacizumab severely impaired the secretion of various cytokines including VEGF. CONCLUSIONS: For the first time, intravitreal injection of PP-001 demonstrated an effective, but transient reduction of relapses in the rat EAU model. In vitro PP-001 suppressed proliferation and cytokine/chemokine secretion of human lymphocytes, while neither human RPE cell line ARPE-19 nor primary RPE cells were affected.

Intravitreal Sirolimus for Noninfectious Uveitis: A Phase III Sirolimus Study Assessing Double-masKed Uveitis TReAtment (SAKURA).

PURPOSE: To evaluate the efficacy and safety of intravitreal sirolimus in the treatment of noninfectious uveitis (NIU) of the posterior segment (i.e., posterior, intermediate, or panuveitis). DESIGN: Phase III, randomized, double-masked, active-controlled, 6-month study with intravitreal sirolimus. PARTICIPANTS: Adults with active NIU of the posterior segment (intermediate, posterior, or panuveitis), defined as a vitreous haze (VH) score >1+. Subjects discontinued NIU medications before baseline, except for systemic corticosteroids, which were allowed only for those already receiving them at baseline and were rapidly tapered after baseline per protocol. METHODS: Intravitreal sirolimus assigned 1:1:1 at doses of 44 (active control), 440, or 880 µg, administered on Days 1, 60, and 120. MAIN OUTCOME MEASURES: The primary efficacy outcome was the percentage of subjects with VH 0 response at Month 5 (study eye) without use of rescue therapy. Secondary outcomes at Month 5 were VH 0 or 0.5+ response rate, corticosteroid tapering success rate (i.e., tapering to a prednisone-equivalent dosage of ≤5 mg/day), and changes in best-corrected visual acuity (BCVA). Adverse events during the double-masked treatment period are presented. RESULTS: A total of 347 subjects were randomized. Higher proportions of subjects in the intravitreal sirolimus 440 µg (22.8%; P = 0.025) and 880 µg (16.4%; P = 0.182) groups met the primary end point than in the 44 µg group (10.3%). Likewise, higher proportions of subjects in the 440 µg (52.6%; P = 0.008) and 880 µg (43.1%; P = 0.228) groups achieved a VH score of 0 or 0.5+ than in the 44 µg group (35.0%). Mean BCVA was maintained throughout the study in each dose group, and the majority of subjects receiving corticosteroids at baseline successfully tapered off corticosteroids (44 µg [63.6%], 440 µg [76.9%], and 880 µg [66.7%]). Adverse events in the treatment and active control groups were similar in incidence, and all doses were well tolerated. CONCLUSIONS: Intravitreal sirolimus 440 µg demonstrated a significant improvement in ocular inflammation with preservation of BCVA in subjects with active NIU of the posterior segment.

Fast and Successful Management of Intraocular Inflammation with a Single Intravitreal Dexamethasone Implant.

Purpose: To investigate the efficacy and safety of a single dexamethasone intravitreal implant (Ozurdex®, 700 µg). Methods: In this prospective noncomparative case series, 84 patients (54 females) received a dexamethasone intravitreal implant. At weeks 4, 12 and 24 after the injection, vitreous haze, macular thickness and best corrected visual acuity (BCVA) were assessed and adverse events reported. Results: Clearance of vitreous haze could be achieved after 4 weeks in 61% of all eyes (p < 0.001) and remained significant until week 24 (p < 0.001). This was paralleled by a reduction of central retinal thickness after 4 (p < 0.001), 12 (p < 0.001) and 24 weeks (p < 0.006). Significant and fast improvement of BCVA was already achieved after 4 weeks (p < 0.001) but vanished by week 24. Intraocular pressure reached ≥35 mm Hg in 3 eyes and was significantly more frequent in intermediate uveitis compared to posterior uveitis (p < 0.016). Conclusions: The dexamethasone implant is effective in controlling intraocular posterior segment inflammation and reduces central retinal thickness fast and effectively. © 2014 S. Karger AG, Basel.

Severe Visual Impairment Following CAR T-Cell Therapy in Two Individuals with Malignant Optic Nerve Infiltration.

We report two patients who displayed evidence of localized ocular inflammation after CAR T-cell infusion. To manage the resulting severe visual impairment, systemic corticosteroids were administered to both patients. This treatment led to a reduction in local inflammation and restored vision in one of the patients.

[Ocular side effects of modern oncological therapy : Immunological checkpoint and MEK/BRAF signal transduction inhibitors]. / Okuläre Nebenwirkungen moderner onkologischer Therapie : Immunologische Checkpoint- und MEK/BRAF-Signaltransduktionsinhibitoren.

In recent years, checkpoint inhibitors have revolutionized the treatment of previously untreatable malignant tumors, significantly improving the life expectancy as well as quality of life in many cases. Checkpoint inhibitors comprise a group of drugs with different mechanisms of action. These include immunological checkpoint inhibitors (iCPI) and intracellular signal transduction inhibitors; however, both substance classes can cause inflammatory or toxic ocular side effects. The frequency of intraocular inflammation (uveitis) is reported to be ca. 1-2%, toxic side effects were observed in up to more than 50% of the patients treated with signal transduction inhibitors. In the following article the main mechanisms of these forms of treatment are characterized. Furthermore, this article presents the currently most frequently used therapeutic agents and their typical ophthalmological side effects to increase awareness and to draw attention to these still rare but increasingly more frequent findings.

Pathogenesis of Bacterial Uveitis.

PURPOSE: To describe the pathogenesis and the general immune mechanisms of the most frequent causes of bacterial uveitis. METHODOLOGY: Narrative review. RESULTS: Both extra- and intracellular bacteria can induce uveitis, whereas intracellular bacteria are generally transported into the inner eye via cells of the innate immune system, mainly macrophages. Systemic adaptive immunity is usually induced before the bacteria are localized to the inner eye, and once T and B cells have detected the pathogens behind the blood-eye barriers they elicit an acute and/or chronic inflammatory response deteriorating visual acuity that can severely affect the non-regenerating, intraocular tissues. CONCLUSIONS: An understanding of pathogenic mechanisms, and its correlation with clinical and imaging features, can facilitate early recognition of microbial factors and institution of appropriate therapy.

Long-Term Results of 0.19mg Fluocinolone Acetonide Insert for Treatment of Non-Infectious Uveitis in Clinical Practice.

PURPOSE: To evaluate the long-term outcomes of patients with non-infectious uveitis treated with 0.19 mg fluocinolone acetonide insert (FAi) for up to 36 months in clinical practice. METHODS: A retrospective study conducted at a single uveitis center. RESULTS: Fifty eyes of 39 patients were included. Mean best corrected visual acuity (BCVA) and central retinal thickness (CRT) remained stable until month 36 after FAi implantation (61.04 vs. 70.25 letters and 370.8 vs. 332.5 µm, respectively). The recurrence rate was 34% (17 eyes) after 36 months, of which 82% (14 eyes) received high-dose corticosteroids before FAi. Mean intraocular pressure (IOP) remained unchanged (13.38 vs. 15.74 mmHg), while most phakic eyes (13 of 14 eyes) required cataract surgery. CONCLUSIONS: We show that FAi effectively prevents recurrences of non-infectious uveitis for up to three years in clinical practice, comparable with randomized clinical trials. Patients who received high-dose corticosteroids before FAi have an increased risk for early recurrence and should be considered for scheduled re-treatment.

A new small molecule DHODH-inhibitor [KIO-100 (PP-001)] targeting activated T cells for intraocular treatment of uveitis - A phase I clinical trial.

Uveitis is a T cell-mediated, intraocular inflammatory disease and one of the main causes of blindness in industrialized countries. There is a high unmet need for new immunomodulatory, steroid-sparing therapies, since only ciclosporin A and a single TNF-α-blocker are approved for non-infectious uveitis. A new small molecule inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme pivotal for de novo synthesis of pyrimidines, has a high potency for suppressing T and B cells and has already proven highly effective for treating uveitis in experimental rat models. Systemic and intraocular application of KIO-100 (PP-001) (previously called PP-001, now KIO-100) could efficiently suppress rat uveitis in a preventive as well as therapeutic mode. Here we describe the outcome of the first clinical phase 1 trial comparing three different doses of a single intraocular injection of KIO-100 (PP-001) in patients with non-infectious posterior segment uveitis. No toxic side effects on intraocular tissues or other adverse events were observed, while intraocular inflammation decreased, and visual acuity significantly improved. Macular edema, a sight-threatening complication in uveitis, showed regression 2 weeks after intraocular KIO-100 (PP-001) injection in some patients, indicating that this novel small molecule has a high potential as a new intraocular therapy for uveitis. Clinical trial registration: [https://www.clinicaltrials.gov/ct2/show/NCT03634475], identifier [NCT03634475].

Uveitis in Tumor Patients Treated with Immunological Checkpoint- and Signal Transduction Pathway-Inhibitors.

PURPOSE: New tumor therapies like immune checkpoint inhibitors and small molecule inhibitors of MEK and BRAF have increased the patient's survival rate but can be burdened with severe side-effects including uveitis. Here, we show the spectrum, treatment, and outcome of uveitis types induced by tumor treatment. METHODS: In this retrospective study, we have included 54 patients from different centers who were developing uveitis under tumor therapy. A 16-item questionnaire was analyzed for type, treatment, and outcome of uveitis and type of tumor treatment, which we have correlated here. RESULTS: Irrespective of the tumor treatment, most patients developed anterior uveitis. All patients received corticosteroids and some additional immunosuppressive treatments. Cessation of tumor therapy was necessary only in a minority of cases. CONCLUSIONS: Ocular autoimmunity should be differentiated from toxic effects of cancer treatment and timely recognized since it can be generally well controlled by anti-inflammatory treatment, preserving the patient's vision without cessation of the tumor treatment.

Posterior subcapsular cataracts are a late effect after acute exposure to 0.5 Gy ionizing radiation in mice.

PURPOSE: The long-term effect of low and moderate doses of ionizing radiation on the lens is still a matter of debate and needs to be evaluated in more detail. MATERIAL AND METHODS: We conducted a detailed histological analysis of eyes from B6C3F1 mice cohorts after acute gamma irradiation (60Co source; 0.063 Gy/min) at young adult age of 10 weeks with doses of 0.063, 0.125, and 0.5 Gy. Sham irradiated (0 Gy) mice were used as controls. To test for genetic susceptibility heterozygous Ercc2 mutant mice were used and compared to wild-type mice of the same strain background. Mice of both sexes were included in all cohorts. Eyes were collected 4 h, 12, 18 and 24 months after irradiation. For a better understanding of the underlying mechanisms, metabolomics analyses were performed in lenses and plasma samples of the same mouse cohorts at 4 and 12 h as well as 12, 18 and 24 months after irradiation. For this purpose, a targeted analysis was chosen. RESULTS: This analysis revealed histological changes particularly in the posterior part of the lens that rarely can be observed by using Scheimpflug imaging, as we reported previously. We detected a significant increase of posterior subcapsular cataracts (PSCs) 18 and 24 months after irradiation with 0.5 Gy (odds ratio 9.3; 95% confidence interval 2.1-41.3) independent of sex and genotype. Doses below 0.5 Gy (i.e. 0.063 and 0.125 Gy) did not significantly increase the frequency of PSCs at any time point. In lenses, we observed a clear effect of sex and aging but not of irradiation or genotype. While metabolomics analyses of plasma from the same mice showed only a sex effect. CONCLUSIONS: This article demonstrates a significant radiation-induced increase in the incidence of PSCs, which could not be identified using Scheimpflug imaging as the only diagnostic tool.

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

BACKGROUND: Endogenous 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. METHODS: This 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.

Uveitis in a patient treated with Bacille-Calmette-Guérin: possible antigenic mimicry of mycobacterial and retinal antigens.

PURPOSE: To investigate the cellular immune response in uveitis developing after intravesical Bacille-Calmette-Guérin (BCG) applications. DESIGN: Experimental study. PARTICIPANTS: A 72-year-old HLA-B27-negative patient with bilateral granulomatous anterior uveitis that developed during the third cycle of intravesical BCG applications she was receiving for treatment of bladder carcinoma. METHODS: The patient's peripheral T cell reactivity to ocular autoantigens was compared with the response to purified protein derivative (PPD) from Mycobacterium tuberculosis. T-cell proliferation and cytokine and chemokine secretion were measured in vitro. MAIN OUTCOME MEASURES: Anterior uveitis was treated successfully with topical corticosteroids and cycloplegics. RESULTS: The following were demonstrated: proliferation to PPD, interphotoreceptor retinoid-binding protein (IRBP), and IRBP-peptide R16, as well as secretion of proinflammatory cytokines in response to PPD, retinal soluble antigen (S-Ag), IRBP, cellular retinal-binding protein (CRALBP), and some S-Ag and IRBP peptides. CONCLUSIONS: These data indicate the generation of a polyclonal autoimmune reaction elicited by BCG. Amino acid sequence alignments revealed homologies between proteins from M. tuberculosis, BCG, and retinal antigens, suggesting antigenic mimicry as a potential cause of uveitis in this patient.