Reggio Emilia (Northern Italy) Interdisciplinary Uveitis Clinic: What We Have Learned in the Last 20 Years.

PURPOSE: To analyze the referral patterns and the clinical and therapeutic features of patients diagnosed with uveitis in an Italian tertiary referral center to provide a comparison with previously published series from the same center. METHODS: Retrospective retrieval of data on all new referrals to the Ocular Immunology Unit in Reggio Emilia (Italy) between November 2015 and April 2022 and comparison with previously published series from the same center. RESULTS: Among the 1557 patients, the male-to-female ratio was 1:1.27. Anterior uveitis was the most common diagnosis (53.7%), followed by posterior (21.6%), pan- (18.5%), and intermediate (6.2%) uveitis. The most identifiable specific diagnoses were anterior herpetic uveitis (18.4%), Fuchs uveitis (12.8%), and tuberculosis (6.1%). Infectious etiologies were the most frequent (34.1%) and were more diffuse among non-Caucasian patients (p < 0.001), followed by systemic disease-associated uveitis (26.5%), and ocular-specific conditions (20%). Idiopathic uveitis accounted for 19.4% of cases. Fuchs uveitis presented the longest median diagnostic delay (21 months). Immunosuppressants were administered to 25.2% of patients. Antimetabolites, calcineurin inhibitors, and biologicals were prescribed to 18.4%, 3%, and 11.4% of cases, respectively. Compared to our previous reports, we observed a significant increase in foreign-born patients and in infectious uveitis, a decrease in idiopathic conditions, and an increasing use of non-biological and biological steroid-sparing drugs. CONCLUSIONS: The patterns of uveitis in Italy have been changing over the last 20 years, very likely due to migration flows. Diagnostic improvements and a more widespread interdisciplinary approach could reduce the incidence of idiopathic uveitis as well as diagnostic delay.

Anterior Segment Optical Coherence Tomography in Uveitis-Glaucoma-Hyphema Syndrome.

PURPOSE: Uveitis-Glaucoma-Hyphema (UGH) syndrome results from contact between the intraocular lens (IOL) and the iris or ciliary body, leading to uveal structure erosion and blood-aqueous barrier breakdown. Treatment involves various drugs, with IOL removal often being necessary. Diagnosis relies on clinical signs, but imaging techniques like ultrasound biomicroscopy (UBM) or anterior segment optical coherence tomography (AS-OCT) are crucial. AS-OCT accurately depicts IOL position and potential contact, emerging as a primary alternative to UBM in the diagnosis. Our study aimed to correlate AS-OCT findings with clinically detectable iris atrophy in pseudophakic patients with IOL-iris chafing and UGH syndrome. METHODS: The study retrospectively analyzed patients diagnosed with UGH syndrome presenting at the Ocular Immunology Unit of Reggio Emilia, Italy, from January 2019 to August 2023. Patients' data were collected. Ophthalmological exams and imaging were performed. The peephole sign in AS-OCT images was evaluated. Statistical analyses were conducted, with a significance level of p ≤ 0.05. RESULTS: The study reviewed 22 eyes of 22 patients with UGH syndrome. Four eyes were excluded, leaving 18 patients (8 females, 10 males). Common misdiagnoses included idiopathic anterior uveitis (55.5%) and herpetic anterior uveitis (16.7%). All patients had iris transillumination defects, mostly focal (77.8%). AS-OCT revealed IOL chafing in all the eyes, with peephole sign correlation. More peephole signs occurred with IOL in the sulcus (p-value = 0.08). CONCLUSION: The study recommends AS-OCT for UGH syndrome confirmation and UBM when IOL-iris chafing is not observed on AS-OCT scans.

Epidemiology of Pediatric Uveitis.

Uveitis is uncommon in children and its diagnosis and treatment are challenging. Little is known of the epidemiology of pediatric uveitis. Indeed, population-based studies in the literature are rare. However, there are many tertiary referral center reports that describe the patterns of uveitis in childhood, although few are from developed countries, and their comparison presents some issues. Anterior uveitis is the most frequent entity worldwide, especially in Western countries, where juvenile idiopathic arthritis is diffuse. Most cases of intermediate uveitis do not show any association with infectious or noninfectious systemic diseases. In low- and middle-income countries, posterior uveitis and panuveitis are prevalent due to the higher rates of infectious etiologies and systemic diseases such as Behçet disease and Vogt-Koyanagi-Harada disease. In recent decades, idiopathic uveitis rate has decreased thanks to diagnostic improvements.

Effectiveness of Pegylated Interferon Alpha-2a in Post-Uveitic Macular Edema Previously Responding to Non-Pegylated Interferon.

PURPOSE: To evaluate the efficacy of pegylated interferon (PEG-IFN) alpha-2a to treat post-uveitic relapsing macular edema (ME) after withdrawal of non-PEG IFN alpha-2a or 2b to maintain treatment efficacy. METHODS: This retrospective study investigated subjects with post-uveitic ME who received weekly subcutaneous PEG-IFN alpha-2a injections. Comparisons between baseline central macular thickness (CMT) and best-corrected visual acuity (BCVA) and those at all follow-up visits were made. RESULTS: Six patients (nine eyes) were treated and followed up for six months. CMT (mean [standard deviation]) decreased from 375[117] to 283[39] µm after one month (p < 0.001), remaining significantly lower up to the final follow-up visit at six months (275[38] µm, p = 0.008), and BCVA (0.21[0.16] logMAR at baseline) showed an improvement of 0.12[0.11] logMAR (p = 0.026) at six months. Neither recurrences nor any serious adverse events were recorded. CONCLUSIONS: Post-uveitic ME patients were effectively and safely treated with PEG-IFN alpha-2a.

Could different aqueous humor and plasma cytokine profiles help differentiate between ocular sarcoidosis and ocular tuberculosis?

OBJECTIVE AND DESIGN: A cross-sectional single-center study was conducted to assess cytokine levels in aqueous humor (AH) and plasma of three different uveitis entities: definite ocular sarcoidosis (OS), definite OS associated with QuantiFERON®-TB Gold test positivity (Q + OS) and presumed tubercular uveitis (TBU). SUBJECTS: Thirty-two patients (15 OS, 5 Q + OS, 12 TBU) were included. METHODS: Quantification of selected cytokines was performed on blood and AH samples collected before starting any treatment. Statistical analysis was conducted using the Kruskal-Wallis test, the Mann-Whitney or Fisher test and the Principal Component Analysis (PCA). RESULTS: IL-6, IL-8 and IP-10 levels were higher in AH samples than in peripheral blood. In AH samples, BLC, IL-8 and IP-10 were significantly higher in definite OS than in presumptive TBU. There were no statistically significant differences in terms of cytokine levels between Q + OS and presumptive TBU. PCA showed a similar cytokine pattern in the latter two groups (IFNγ, IL-15, IL-2, IP-10, MIG), while the prevalent expression of BLC, IL-10 and MIP-3 α was seen in definite OS. CONCLUSIONS: The different AH and plasma cytokine profiles observed in OS compared to Q + OS and TBU may help to differentiate OS from TBU in overlapping clinical phenotypes of granulomatous uveitis (Q + OS).

Vogt-Koyanagi-Harada patients show higher frequencies of circulating NKG2Dpos NK and NK T cells.

Vogt-Koyanagi-Harada (VKH) is an autoimmune disease characterized by inflammation in tissues that contain melanocytes. We aimed to increase the knowledge regarding immunological pathways deregulated in VKH disease. We compared the percentages of circulating natural killer (NK), NK T and T cells expressing the activatory markers: CD16, CD69, NK group 2D (NKG2D), natural cytotoxicity triggering receptor 3 (Nkp30), natural cytotoxicity triggering receptor 1 (Nkp46) and the inhibitory marker: NK group 2 member A (NKG2A) in 10 active VKH patients, 20 control subjects (CTR) and seven patients with Behçet disease (BD) by flow cytometry. Cytotoxic potential of NK cells was determined through the degranulation marker CD107a expression after contact with K562 cells by flow cytometry. Moreover, plasmatic levels of 27 cytokines were determined with a multiplex bead-based assay. VKH patients showed higher percentages of NKG2Dpos NK and NK T cells versus CTR. The cytotoxic potential of NK cells induced by K562 cells was comparable between VKH patients and CTR. Finally, higher concentrations of interleukin (IL)-4, IL-5, IL-7, IL-17 and platelet-derived growth factor-subunits B (PDGF-bb) were detected in plasma of VKH patients versus CTR. The immune profile of VKH patients was similar to that of BD patients.

Interferon Alpha-2a Treatment for Post-Uveitic Refractory Macular Edema.

Purpose: To assess the efficacy of interferon (IFN) alpha-2a in the treatment of post-uveitic refractory macular edema (ME).Methods: Retrospective cohort of patients with post-uveitic refractory ME, who received subcutaneous IFN alpha-2a injections for at least 3 months. Baseline central macular thickness (CMT) and best-corrected visual acuity (BCVA) were compared with those at follow-up visits up to 12 months.Results: Thirty-seven patients were included. Treatment duration (median [interquartile range]) was 14[8-24] months with a follow-up of 17[10-38] months. CMT (mean [standard deviation]) decreased from 438[140] to 335[119] µm after 1 month (p < 0.0001) and remained significantly lower up to 12 months (286[98] µm, p = 0.001). BCVA (0.48[0.33] logMAR at baseline) improved by 0.26[0.33] logMAR (p = 0.001) at 12 months. There were 14 recurrences. Seven patients had treatment side effects, without serious adverse events.Conclusions: IFN alpha-2a was effective, safe, and well tolerated in treating post-uveitic refractory ME.

The Role of Gene Therapy in the Treatment of Retinal Diseases: A Review.

BACKGROUND: Gene therapy represents the therapeutic delivery of nucleic acid polymers into patient cells with the aim of treating an underlying disease. Over the past 2 decades this new therapy has made substantial progress owing to better understanding of the pathobiologic basis of various diseases coupled with growth of gene transfer biotechnologies. The eye, in particular, represents a suitable target for such therapy due to the immune privilege provided by the blood-ocular barrier, the ability to directly visualize, access and locally treat the cells and the minimal amount of vector needed given the size of this organ. It is not surprising therefore that several clinical trials are now ongoing in this field. OBJECTIVE: The purpose of this review was to provide an update on gene therapy for retinal diseases, discussing differences in treatment strategies, vector designs and surgical techniques. METHOD: Research was performed on PubMed, ClinicalTrials.gov, and Home Genetic Reference. We additionally utilized the internet database for genetics of retinal diseases, the portal for rare diseases and orphan drugs and the NCBI database Online Mendelian Inheritance in Man. No restriction was applied on the language of publications. RESULTS: We present the available results of current active clinical trials for inherited retinal disease such as Leber's congenital amaurosis type 2, choroideremia, Stargardt disease, achromatopsia and juvenile X-linked retinoschisis. We also illustrate a new approach of this therapy for the treatment of much more common ocular diseases such as age-related macular degeneration and diabetic retinopathy. CONCLUSION: Gene therapy represents an emerging and promising therapeutic approach for the treatment not only of rare inherited retinal diseases but also much more common retinal pathologies.

Use of anteromedial thigh perforator flap and immunological implications of Gorlin-Goltz syndrome: a case study.

Gorlin-Goltz syndrome is mainly characterised by the development of numerous multicentric and relapsing cutaneous basal cell carcinomas (BCCs). A major problem for patients with Gorlin-Goltz syndrome is the large amount of BCCs that can invade the deep underlying structures, especially the face. Here, we describe the case of a 23-year-old male affected by Gorlin-Goltz syndrome. He had recurrent BCCs on a hairless scalp and dorsum since he was 17 years old and underwent four surgical procedures to excise BCCs, including a reconstruction with anteromedial thigh perforator flap. For each of the surgical procedures, a phenotypic study on peripheral blood mononuclear cells using flow cytometry was performed on the same day of surgery, and on days 7, 14 and 21 after surgery. The role of the tumour-specific cytolytic immune response as a potential future treatment of syndromic BCCs and its trend in relation to surgical ablation of large portions of tumour tissue was examined, and the cosmetic and therapeutic results are shown.

Microenvironment and microbiology of skin wounds: the role of bacterial biofilms and related factors.

Wound healing is a systemic response to injury that impacts the entire body and not just the site of tissue damage; it represents one of the most complex biological processes. Our knowledge of wound healing continues to evolve and it is now clear that the wound microenvironment plays a crucial role. The interactions between cells and the surface microenvironment, referred to as the "biofilm," contributes to skin homeostasis and healing. Understanding the functional complexity of the wound microenvironment informs how various factors such as age, ischemia, or bacterial infections can impair or arrest the normal healing processes, and it also allows for the possibility of acting therapeutically on healing defects with microenvironment manipulation. Microbes represent a particularly important factor for influencing the wound microenvironment and therefore wound healing. Moreover, the role of infections, particularly those that are sustained by biofilm-forming bacteria, is mutually related to other microenvironment aspects, such as humidity, pH, metalloproteinases, and reactive oxygen species, on which the modern research of new therapeutic strategies is focused. Today, chronic wounds are a rapidly growing health care burden and it is progressively understood that many non-healing wounds might benefit from therapies that target microorganisms and their biofilm communities. There is no doubt that host factors like perfusion impairments, venous insufficiency, pressure issues, malnutrition, and comorbidities strongly impact the healing processes and therefore must be targeted in the therapeutic management, but this approach might be not enough. In this article, we detail how bacterial biofilms and related factors impair wound healing, the reasons they must be considered a treatment target that is as important as the host's local and systemic pathologic conditions, and the latest therapeutic strategies derived from the comprehension of the wound microenvironment.

Paraplegia in a patient with Von Hippel Lindau syndrome: surgical and reconstructive treatment of Marjolin's ulcer. A case report.

STUDY DESIGN: Marjolin's ulcer is a squamous cell carcinoma that develops in posttraumatic scars and chronic wounds. Suspicion of such lesions should be raised in chronic wounds demonstrating characteristic changes. We have reported the peculiar phenomenon of malignant transformation of chronic pressure sores that occurred in a paraplegic patient. OBJECTIVES: The aim of this study was to cover the extensive defects by a last resort reconstructive option. SETTING: Department of Plastic and Reconstructive Surgery, Università Politecnica delle Marche, Ancona, Italy. METHODS AND RESULTS: A 40-year-old paraplegic man, with multiple hemangioblastomas of the brain and spinal cord due to Von Hippel Lindau syndrome developed pressure ulcers with unstable healing over the sacral, trochanteric, bilateral, and ischiatic areas after 15 years from neurosurgery. The biopsy result showed an invasive squamous carcinoma. Carcinomas in pressure sores are highly aggressive, and they need to be treated more radically. In our case we opted for a demolitive surgical treatment including musculocutaneous rotational flap harvested from total left thigh to cover the extensive defects. The limb was previously disarticulated. CONCLUSION: In Marjolin's ulcer, multiple biopsies are the first-line modality for the early diagnosis as they are a safe method with high rate of accuracy. First-line treatment is surgery consisting of radical excision with lymph node dissection, if they are involved. Adjuvant radiation therapy may be used in selected patients. Management of massive pelvic defects can be a challenging problem. The pedicled lower limb flap offers a technique that can be considered as a last resort procedure for extensive defects where other options are insufficient or not available anymore. In our case the patient is disease-free after 2 years of follow-up.