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Integrated analysis of clinical, structural and functional parameters in the acute and non-acute phases of Vogt-Koyanagi-Harada disease: a prospective study

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Viviane Mayumi Sakata
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
Defense date:
Examining board members:
Joyce Hisae Yamamoto; Mauro Goldbaum; Rubens Belfort Mattos Junior; Fernando Oréfice; Hisashi Suzuki
Advisor: Joyce Hisae Yamamoto

OBJECTIVES: To describe the course of Vogt-Koyanagi-Harada disease (VKHD) prospectively, integrating clinical, structural and functional parameters. METHODS: Patients with VKHD in the acute (part I) and non-acute (more than 12 months from diagnosis) phases (part II) were included. Patients in the acute phase received a standard treatment with methylprednisolone pulsetherapy followed by high-dose oral corticosteroids with slow tapering during 15 months. Evaluations included clinical exams, fluorescein (FA) and indocyanine green (ICGA) angiographies and optical coherence tomography (OCT). In part I, they were performed at inclusion, then after 1,2,4,6,9,and 12 months; in part II, they were performed at inclusion then every 3 months for up to 12 months. Functional evaluation using electroretinography (ERG) was performed at inclusion and every 6 months in part I and at inclusion and at 12 months in part II. Two non-blinded readers analyzed the imaging exams in part I. In part II, three trained and blinded-readers performed the imaging exams analysis. For study`s purpose, at least two concordant readings were considered. Imaging exams utilized the Spectralis® (HRA+OCT, Heidelberg engineering). Inflammatory signs detected on FA, ICGA and OCT were denominated as subclinical signs. Additional treatment with high doses of corticosteroids or more intensive systemic immunosuppression was indicated in cases with clinical signs of inflammation, with subclinical signs on FA or with two consecutive worsening > 30% on ERG. RESULTS: Nine patients (7F/2M) were included in part I; median age was 33 years old and median time elapsed from onset of symptoms to treatment was 13 days. At disease presentation, classic signs (choroiditis, anterior uveitis, serous retinal detachment, optic disc hyperemia and extraocular manifestations) were observed; they improved in 30 days after treatment. Subclinical signs improved in variable periods of time: subfoveal choroidal thickness (CT) decreased to a median value of 347 ?m, 30 days after the beginning of treatment, dark dots diminished during the follow-up but they were still observed at 12 months. Relapse (worsening of inflammation) was noticed in 17 of 18 eyes at a median follow up time of seven months, when tapering schedule corticosteroid dosage reached the mean dose of 0.3mg/kg/d of prednisone. Dark dots, fuzzy vessels and choroid thickening were the most frequent subclinical signs. Relapses in 10 of 17 eyes were concomitant with worsening on ERG. Three patterns of evolution could be delineated: no signs of inflammation (pattern A, 1 eye), only subclinical signs of inflammation (pattern B, 11 eyes) and clinical signs of inflammation (pattern C, 6 eyes). CT>=506 ?m 30 days after the beginning of treatment was more than 80% sensitive and specific to detect more severe cases (pattern C). ERG parameters at 24 months were subnormal as compared to the control group, despite improvement during follow-up. Further long-term results after 24 month demonstrated stabilization of ERG parameters in patients that had received additional treatment, whereas there was worsening in those patients who had not received additional treatment (p<0.001). Moreover, pattern B patients without additional treatment had a further decrease on ERG values compared to results observed in pattern C or B patients with additional treatment (p<0.001). In Part II, 20 patients (17F/3M) were included; median age at diagnosis was 31 years old, median lag time from onset of symptoms and treatment was 19 days and median time after diagnosis was 55 months. The interobserver agreement for CT reading was substantial (kappa 0.8), whereas for angiographic signs was slight (kappa < 0.2). Recurrences, clinically (pattern C, 11 cases) or subclinically (pattern B, 6 cases) detected, were observed in 85% of cases. Concomitant inflammation of posterior segment detected by subclinical signs was present in 64% of cases with cells in anterior chamber. Simultaneous signs of subclinical inflammation of posterior segment and anterior uveitis were also observed in part I. CT change was the main subclinical sign observed in pattern B patients. ERG evaluation was performed in 13 cases. Pattern C cases (7 patients) presented worse results than pattern B cases (5 patients). Further analysis depicted that pattern B patients who had an additional treatment had better results than pattern B non-treated and pattern C (p<0.001). CONCLUSION: Three patterns of evolution were observed in VKHD patients during this prospective study, 94% (part I) and 85% (part II) presented recurrence/worsening with clinical (pattern C) or subclinical (Pattern B) signs of inflammation. In part I, worsening was observed at seven months after treatment start when reaching mean dose of 0.3mg/Kg/d of prednisone even after initial high-dose of corticosteroids followed by slow tapering. At day 30 after treatment, CT >= 506 ?m had a greater than 80% sensitivity and specificity to detect cases with pattern C evolution. Considering subclinical signs, CT increase reliably detected recurrence, whereas angiographic signs required cautious interpretation. Sequential analysis was more conclusive than an isolated exam. Anterior chamber cells seemed to be the \"tip of the iceberg\" of a more diffuse inflammation. ERG analysis was subnormal even after 24 months of follow up since disease onset; additional treatment could prevent functional worsening in patients with subclinical signs of inflammation. Worse retinal function in patients with clinical recurrences (pattern C) in part II and subclinical recurrences (pattern B) in parts I and II suggest that ideal treatment of recurrences should be further pursued (AU)

FAPESP's process: 11/19194-4 - Vogt-Koyanagi-Harada disease: parameters for effective treatment on acute phase and long-standing disease
Grantee:Viviane Mayumi Sakata
Support type: Scholarships in Brazil - Doctorate (Direct)