Η παρούσα προοπτική ελεγχόμενη κλινική μελέτη διεξήχθη για να ερευνήσει τη συσχέτιση του συνδρόμου αποφολίδωσης με τη νευροαισθητήρια απώλεια ακοής. Τα άτομα της ομάδας μελέτης εμφάνιζαν το σύνδρομο στον ένα ή αμφοτέρους τους οφθαλμούς, ενώ τα άτομα της ομάδας ελέγχου δεν εμφάνιζαν το σύνδρομο σε κανένα οφθαλμό. Κριτήρια αποκλεισμού από τη μελέτη ήταν: προηγηθείσα ωτολογική επέμβαση, οξείες ή χρόνιες ωτολογικές παθήσεις, τραύμα κεφαλής ή ωτός, έκθεση σε θόρυβο, λήψη ωτοτοξικών φαρμάκων, λοίμωξη ανωτέρου αναπνευστικού συστήματος, γλαύκωμα, οφθαλμική υπερτονία και διάφορες συστηματικές παθήσεις. Οι συμμετέχοντες υπεβλήθησαν σε μέτρηση οπτικής οξύτητας, βιομικροσκόπηση, τονομέτρηση, γωνιοσκοπία, βυθοσκόπηση μετά από μυδρίαση, εξέταση οπτικών πεδίων, επισκόπηση και ψηλάφηση ώτων, ωτοσκόπηση, εξέταση ρινοφάρυγγα, εξέταση με τονοδότες και ακοομετρία καθαρών τόνων. Κατά την ακοομετρία υπολογίστηκε για κάθε ους ο ουδός ακοής, για την αέρινη και την οστέινη αγωγή, στις συχνότητες των 0.25, 0.5, 1, 2, 4 και 8kHz. Συνολικά έλαβαν μέρος στη μελέτη 69 άτομα (47 στην ομάδα μελέτης και 22 στην ομάδα ελέγχου). Η μέση ηλικία των συμμετεχόντων ήταν 74,7 ετών και στις δύο ομάδες. Δεν υπήρξαν στατιστικά σημαντικές διαφορές στην κατανομή ηλικιών και φύλων ανάμεσα στις δύο ομάδες. Σε όλους τους εξετασθέντες οι ουδοί ακοής αέρινης και οστέινης αγωγής ήταν ταυτόσημοι για κάθε συχνότητα, γεγονός που υποδήλωνε αμιγή νευροαισθητήρια απώλεια ακοής ή φυσιολογική ακοή. Δεν προέκυψαν κλινικά σημαντικές διαφορές, μεταξύ ουδών ακοής δεξιού και αριστερού ωτός, σε κανένα άτομο. Τα άτομα της ομάδας μελέτης, σε σύγκριση με εκείνα της ομάδας ελέγχου, παρουσίασαν: Α) Σημαντικά υψηλότερα ποσοστά επιπολασμού απώλειας ακοής στις συχνότητες των 1, 2, 4 και 8kHz. Β) Σημαντικά υψηλότερους μέσους ουδούς ακοής και σοβαρότερη απώλεια ακοής στις συχνότητες των 4 και 8kHz. Η μεγαλύτερη διαφορά στη σύγκριση των μέσων ουδών ακοής παρατηρήθηκε στα 8kHz. Τα ανωτέρω αποτελέσματα συνηγορούν υπέρ πολλαπλής συσχέτισης του συνδρόμου αποφολίδωσης με τη νευροαισθητήρια απώλεια ακοής και αφενός επιβεβαιώνουν μαρτυρίες από προηγούμενες έρευνες, αφετέρου παρέχουν ένα εντελώς νέο εύρημα που είναι η στατιστικά σημαντική επίδραση του συνδρόμου στη σοβαρότητα απώλειας ακοής στις υψηλές συχνότητες. Σε σύγκριση με προηγούμενες μελέτες, η παρούσα μελέτη πλεονεκτεί διότι η διερεύνηση της επίδρασης του συνδρόμου στον επιπολασμό και στη σοβαρότητα απώλειας ακοής έγινε με πιο αναλυτική διαδικασία, ετέθησαν λεπτομερέστερα κριτήρια αποκλεισμού υποψηφίων, o ακοομετρικός έλεγχος αφορούσε σε μεγαλύτερο αριθμό συχνοτήτων και αποκλείστηκαν γλαυκωματικοί ασθενείς, ώστε η σχέση μεταξύ συνδρόμου αποφολίδωσης και απώλειας ακοής να εξεταστεί με πιο αντικειμενικό τρόπο. Τα ευρήματα της παρούσας μελέτης επαληθεύουν τη θεωρία ότι το σύνδρομο αποφολίδωσης δεν αποτελεί μόνο οφθαλμολογική πάθηση, αλλά συστηματική διαταραχή με πολυάριθμες επιπλοκές, μία εκ των οποίων αφορά το έσω ους. Συνεπώς, στους ασθενείς με σύνδρομο αποφολίδωσης, εκτός από την οφθαλμολογική εξέταση, συνιστάται η εκτίμηση της ακουστικής ικανότητας με ακοομετρική δοκιμασία. / The present prospective case control clinical study was conducted to investigate the relationship between exfoliation syndrome and sensorineural hearing loss. Study group subjects manifested the syndrome in one or both eyes, whereas control group subjects didn’t manifest the syndrome in either eye. Exclusion criteria from the study were: previous ear surgery, acute or chronic ear diseases, ear or head trauma, noise exposure, oto-toxic drug intake, upper respiratory system infection, glaucoma, ocular hypertension and various systemic diseases. All participants underwent visual acuity measurement, biomicroscopy, tonometry, gonioscopy, dilated fundoscopy, visual field testing, ear inspection and palpation, otoscopy, nasopharyngeal examination, tuning fork testing and pure-tone audiometry. During audiometry the hearing threshold was calculated for every ear, using air and bone conduction, at frequencies of 0.25, 0.5, 1, 2, 4 and 8kHz. A total of 69 subjects participated in the study (47 in study group and 22 in control group). Mean age of participants was 74.7 years in both groups. Differences in age and gender distribution between the two groups were not statistically significant. Hearing thresholds were identical for both air and bone conduction, in all examined subjects at each frequency, signifying pure sensorineural hearing loss or normal hearing. No clinically significant differences were found, between hearing thresholds of left and right ear, in any subject. Compared to control group, study group subjects displayed: A) Significantly higher prevalence rates of hearing loss at frequencies of 1, 2, 4 and 8kHz. B) Significantly higher mean hearing thresholds and more severe hearing loss at frequencies of 4 and 8kHz. The greatest difference in the comparison of mean hearing thresholds was observed at 8kHz. The above results advocate for a multiple association between exfoliation syndrome and sensorineural hearing loss and on the one hand support evidence from previous research, on the other hand provide a totally new finding, that is the statistically significant effect of the syndrome on severity of hearing loss at high frequencies. Compared to previous studies, the present study has advantages because the syndrome effect on prevalence and severity of hearing loss was investigated in a more thorough manner, the candidate exclusion criteria were more detailed, audiometric testing involved a greater number of frequencies and glaucomatous patients were excluded, in order the relationship between exfoliation syndrome and hearing loss to be examined in a more objective way. The findings of the present study verify the theory that exfoliation syndrome is not only an ocular disease, but also a systemic disorder with numerous complications, one of which concerns the inner ear. Consequently, in patients with exfoliation syndrome, besides the ophthalmologic examination, an assessment of hearing ability with audiometric testing is recommended.

INTRODUÇÃO: O pênfigo foliáceo (PF) caracteriza-se pela síntese de autoanticorpos contra a desmogleína 1 (Dsg1) com acantólise na epiderme superior. As lesões na face e tronco podem evoluir para eritrodermia (PFE), cuja patogênese é pouco conhecida. Estudos prévios sugerem a participação do fator de crescimento endotelial vascular (VEGF) e da endoglina (Eng). OBJETIVOS: Avaliar dados demográficos, expressão tecidual e níveis séricos do VEGF e Eng, bem como o perfil dos imunocomplexos no PFE. PACIENTES, MATERIAIS E MÉTODOS: Foram selecionados pacientes de PFE (n=31) e indivíduos controles com pênfigo vulgar (PV; n=10), psoríase (PSO; n=10) e saudáveis (CS; n=14) com amostras de soro e pele armazenadas. Os níveis séricos do VEGF, receptor solúvel do VEGF (sVEGFR-1), anti-Dsg1 e -Dsg3 foram avaliados por meio da técnica de ELISA, e a presença do VEGF, Eng, e imunocomplexos in situ foi determinada por imuno-histoquímica (IH) em plataforma automatizada (n=19). Após digitalização das lâminas, a reatividade aos anticorpos supracitados foi classificada manualmente em: 0 (ausente), 1 (discreta-moderada) e 2 (intensa), e analisada por software. RESULTADOS: PFE ocorreu no início da doença em 25/31 pacientes (80,6%), com média de idade de 42,7 anos e predomínio feminino (23/31; 74,2%). Os pacientes foram hospitalizados em média por 41,2 dias; infecção bacteriana foi a principal complicação (30/31; 96,8%), com bacteremia em 10/31 (32,3%) causada por Staphylococcus aureus em 7/10 (70%) dos pacientes. Infecção pelo vírus do herpes simples (HSV) em 11/31 (35,5%) doentes determinou internação prolongada. Valores de imunofluorescência indireta, e anti-Dsg1 e VEGF séricos (ELISA) foram superiores no PFE vs. PF não-eritrodérmico (PFNE) (p < 0,05). Níveis do sVEGFR-1 foram semelhantes no PFE e PFNE, e correlacionaram-se fracamente com a anti-Dsg1 no PFNE (p=0,034). A avaliação manual da IH com anti-VEGF no PFE foi estatisticamente diferente do PFNE (p=0,042) e CS (p=0,004), e similar ao PV (p=0,667) e PSO (p=0,667). Já no PFNE, a expressão do VEGF foi estatisticamente diferente do PV (p=0,049) e PSO (p=0,049) e semelhante ao CS (p=0,247). A contagem automatizada dos vasos marcados com anti-Eng no PFE foi similar ao PFNE (p=0,700) e PSO (p=0,133), e diferente do PV (p=0,0009) e CS (p=0,0009). A avaliação de 6 espécimes de PFE mostrou depósitos de imunocomplexos: intercelulares intraepidérmicos com IgG e C3 (n=6), IgA (n=5) e IgM (n=1); nas células inflamatórias com IgG e C3 (n=6), IgM e IgA (n=1); nos vasos com IgG, C3 e IgA (n=6), e IgM (n=5); e nos anexos com IgG e C3 (n=6), IgA (n=3) e IgM (n=1). CONCLUSÕES: O PFE predomina no início da doença e em mulheres, com maior risco de infecção. O aumento do VEGF sérico e tecidual sugere uma resposta reparadora ao dano tecidual causado pelos níveis elevados de autoanticorpos no PFE. A menor expressão de Eng no PFE indica uma desregulação da angiogênese na eritrodermia. De forma pioneira, a IH automatizada demonstrou a presença de imunocomplexos intraepidérmicos e nas estruturas dérmicas / BACKGROUND: Pemphigus foliaceus (PF) is characterized by the production of autoantibodies against desmoglein 1 (Dsg1), triggering superficial acantholysis. Lesions on the face and trunk may evolve to erythroderma (PFE). The pathogenesis of PFE is not fully understood. Previous studies suggest the role of vascular endothelial growth factor (VEGF) and endoglin (Eng). OBJECTIVES: To evaluate demographic data, VEGF and Eng expression, and immune complexes deposition in patients with PFE. METHODS: This study included patients with PFE (n=31) and controls with pemphigus vulgaris (PV; n=10), psoriasis (PSO; n=10), and health individuals (CS; n=14) that had serum and skin samples stored. Serum levels of VEGF, soluble VEGF receptor (sVEGFR-1), anti-Dsg1 and Dsg3 were measured by ELISA, and the in situ expression of VEGF, Eng, and immune complexes was evaluated utilizing an automated immunohistochemistry (IH) platform (n=19). After digitalizing the slides, the reactivity was manually classified as 0 (negative), 1 (mild-to-moderate) and 2 (intense), and also analyzed by software. RESULTS: PFE occurred at the onset of the disease in 25/31 (80.6%) patients, with a mean age of 42.7 years and a female predominance (23/31; 74.2%). Patients were hospitalized with an average length of stay of 41.2 days. Bacterial infection was the main complication (30/31; 96.8%), with bacteremia in 10/31 (32.3%) due to Staphylococcus aureus in 7/10 (70%) patients. Herpes simplex virus infection in 11/31 (35.5%) PFE patients caused prolonged hospitalization. Indirect immunofluorescence titers and serum anti-Dsg1 and VEGF (ELISA) were increased in PFE vs. non-erythrodermic PF (PFNE) (p < 0.05). Serum levels of sVEGFR-1 were similar in PFE and PFNE, and weakly correlated with anti-Dsg1 in PFNE (p=0.0342). Manual analysis of anti-VEGF positivity in PFE was statistically different from PFNE (p=0.042) and CS (p=0.004), and similar to PSO (p=0.667) and PV (p=0.667). VEGF expression in PFNE was statistically different from PSO (p=0.049) and PV (p=0.049) and similar to CS (p=0.247). The automated positive vessel count with anti-Eng was similar between PFE and PFNE (p=0.700) and PSO (p=0.133), but different from PV (p=0.0009). Immune complex deposits were evaluated in 6 specimens obtained during PFE and exhibited: intraepidermal intercellular deposits with IgG and C3 (n=6), IgA (n=5) and IgM (n=1); reactivity to inflammatory cells with IgG e C3 (n=6), IgM and IgA (n=1); vascular deposits with IgG, C3 and IgA (n=6), and IgM (n=5); and adnexal positivity with IgG and C3 (n=6), IgA (n=3) and IgM (n=1). CONCLUSIONS: Erythroderma predominates at the onset of PF, especially in women, with higher infectious risk. Increased expression of serum and in situ VEGF suggests that healing processes are triggered in response to the tissue damage caused by high levels of circulating autoantibodies in PFE. The reduced expression of Eng in PFE demonstrates a dysregulated angiogenesis during erythroderma. To the best of our knowledge, this is the first study that showed intraepidermal and dermal deposits of multiple immune complexes utilizing automated IH analysis