KR102455767B1 - Method for predicting early recurrence of diabetic macular edema refractory - Google Patents

Abstract

The present invention relates to a predicting method of inveterate diabete macular edema early recurrence and, more specifically, to a predicting method of early recurrence of an edema in an inveterate diabete macular edema patient who has undergone intravitreal dexamethasone implant implantation using optical coherence tomography.

Description

{Method for predicting early recurrence of diabetic macular edema refractory}

The present invention relates to a method for predicting early recurrence of diabetic macular edema, an intractable disease. More specifically, the present invention relates to a method for predicting early recurrence of edema in a patient with intractable diabetic macular edema who underwent intravitreal dexamethasone implantation using optical coherence tomography.

Diabetic retinopathy (DME) is one of the most common causes of blindness worldwide. Diabetic macular edema is caused by increased retinal ischemia and increased vascular endothelial growth factor as diabetic retinopathy progresses. This increase in vascular endothelial growth factor damages the blood retinal barrier, abnormally enhances vascular permeability, and induces an increase in interstitial fluid, leading to retinal edema [1,2].

Vascular endothelial growth factor (VEGF) is an essential endogenous mediator of diabetic macular edema, and anti-VEGF is effective in improving visual acuity and is generally regarded as the first-line therapy for diabetic macular edema [3]. However, there are many patients who do not respond well to anti-VEGF, and there is a problem that the degradation of body fluid is temporary and not complete [4-6]. Because it is known that the cause of diabetic macular edema is not only an increase in vascular endothelial growth factor but also several types of inflammatory cytokines, it is advantageous in the treatment of refractory diabetic macular edema patients who do not respond to anti-VEGF treatment. Intracorporeal steroid injection may be an alternative choice [7,8].

Dexamethasone (DEX) implants (Ozurdex®, Allergan, Inc., Irvine, CA, USA) are known to exist in the vitreous for up to 6 with one insertion [9,10], but in actual clinical environment In this study, more frequent administration of dexamethasone implant is required due to early recurrence of diabetic macular edema. The maximum effect of dexamethasone implant occurs at 3 months, and tends to decrease slowly at 4-6 months, and the average interval between additional dexamethasone administrations is variously reported to be about 3 to 7 months [11- 14].

On the other hand, spectral-domain optical co-herence tomography (SD-OCT) is widely used as a non-invasive tool to obtain high-resolution images of each layer constituting the retina and objectively measure the thickness, The hyperreflective foci (HRF) observed in optical coherence tomography have been reported in various diseases such as diabetic retinopathy, macular degeneration, and branch retinal vein occlusion [15-17].

[Prior literature]

[Non-patent literature]

[1] J. H. Kempen, B. J. O’Colmain, M. C. Leske et al., “The prevalence of diabeticretinopathy amongadults in the United States,” JAMA Ophthalmology, vol. 122, no. 4, pp. 552-563, 2004.

[2] J. W. Y. Yau, S. L. Rogers, R. Kawasaki et al., “Global prevalence and major risk factors of diabetic retinopathy,” Diabetes Care, vol. 35, no. 3, pp. 556-564, 2012.

[3] B. Bahrami, T. Hong, M. C. Gilles, and A. Chang, “Anti-VEGF therapy for diabetic eye diseases,” Asia-Pacific Journal of Ophthalmology, vol. 6, no. 6, pp. 535-545, 2017.

[4] L. M. Jampol, N. M. Bressler, and A. R. Glassman, “Revolution to a new standard treatment of diabetic macular edema,” Jama, vol. 311, no. 22, pp. 2269-2270, 2014.

[5] M. J. Elman, N. M. Bressler, H. Qin et al., “Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinoloneplus promptlaserfordiabeticmacularedema,” Ophthalmology, vol. 118, no. 4, pp. 609-614, 2011.

[6] R. Rajendram, S. Fraser-Bell, A. Kaines et al., “A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data : report 3,” JAMA Ophthalmology, vol. 130, no. 8, pp. 972-979, 2012.

[7] H. Funatsu, H. Noma, T. Mimura, S. Eguchi, and S. Hori, “Association of vitreous inflammatory factors with diabetic macular edema,” Ophthalmology, vol. 116, no. 1, pp. 73-79, 2009.

[8] S. Rangasamy, P. G. McGuire, and A. Das, “Diabetic retinopathy andinflammation: noveltherapeutictargets,” Middle East African Journal of Ophthalmology, vol. 19, no. 1, pp. 52-59, 2012.

[9] Y. Yang, C. Bailey, A. Loewenstein, and P. Massin, “Intravitreal corticosteroids in diabetic macular edema,” Retina, vol. 35, no. 12, pp. 2440-2449, 2015.

[10] J.-E. Chang-Lin, M. Attar, A. A. Acheampong et al., “Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant,” Investigative Opthalmology & Visual Science, vol. 52, no. 1, pp. 80-86, 2011.

[11] A. Malcl'es, C. Dot, N. Voirin et al., “Real-life study in diabetic maculare dema treated with dexamethasone implant,” Retina, vol. 37, no. 4, pp. 753-760, 2017.

[12] S. Zandi, T. Lereuil, F. Freiber et al., “Long-term intravitreal dexamethasone treatment in eyes with pretreated chronic diabeticmacularedema,” Journal of Ocular Pharmacology and Therapeutics, vol. 33, no. 8, pp. 620-628, 2017.

[13] C. Bucolo, L. Gozzo, L. Longo, S. Mansueto, D. C. Vitale, and F. Drago, “Long-term efficacy and safety profile of multiple injections of intravitreal dexamethasone implant to manage diabetic macular edema: a systematic review of real-world studies,” Journal of Pharmacological Sciences, vol. 138, no. 4, pp. 219-232, 2018.

[14] I. Aknin and L. Melki, “Longitudinal study of sustained-release dexamethasone intravitreal implant in patients with diabetic macular edema,” Ophthalmologica, vol. 235, no. 4, pp. 187-188, 2016.

[15] M. Bolz, U. Schmidt-Erfurth, G. Deak, G. Mylonas, K. Kriechbaum, and C. Scholda, “Optical coherence tomographic hyperreflective foci,” Ophthalmology, vol. 116, no. 5, pp. 914-920, 2009.

[16] S. Omri, F. Behar-Cohen, Y. de Kozak et al., “Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy,” The American Journal of Pathology, vol. 179, no. 2, pp. 942-953, 2011.

[17] S. Vujosevic, T. Torresin, S. Bini et al., “Imaging retinal inflammatory biomarkers after intravitreal steroid and anti VEGF VEGF treatment in diabetic macular oedema,” Acta Ophthalmologica, vol. 95, no. 5, pp. 464-471, 2017.

Therefore, the present inventors tried to predict the early recurrence of edema in patients with intractable diabetic macular edema who underwent intravitreal dexamethasone implant insertion. By identifying that diabetic macular edema can recur more quickly after transplantation, the present invention has been completed.

The present invention provides an early recurrence of refractory diabetic macular edema after intravitreal dexamethasone implantation, comprising analyzing a hyperreflective foci (HRF) observed in Optical Coherence Tomography (OCT) obtained from a subject. The purpose of the present invention is to provide a method for predicting the prognosis of

The present invention also provides an early stage of refractory diabetic macular edema after intravitreal dexamethasone implant insertion, including analyzing hyperreflective foci (HRF) observed in Optical Coherence Tomography (OCT) obtained from a subject. An object of the present invention is to provide a method for providing information for predicting the prognosis of recurrence.

As used herein, the term “hyperreflective foci (HRF)” refers to particles having a reflectance equal to or higher than the retinal pigment epithelium (RPE) band of SD-OCT and a diameter of 20 to 40 μm.

As used herein, the term “early recurrence” refers to a case in which the central subfield thickness (CST) increases by 50 μm or more after 3 months compared to the first month after implantation of the intravitreal DEX implant.

The method for predicting the prognosis of early recurrence of refractory diabetic macular edema after intravitreal dexamethasone implant insertion using optical coherence tomography (OCT) according to the present invention is that HRF is independent in the early recurrence of refractory diabetic macular edema. Since it can be used as a predictive factor for intractable diabetic macular edema, it is possible to accurately predict the prognosis of early recurrence of intractable diabetic macular edema, and provide information to determine the appropriate treatment direction according to the predicted prognosis.

Hereinafter, various examples are presented to help the understanding of the invention. The following examples are provided for easier understanding of the invention, and the protection scope of the invention is not limited to the following examples.

According to the first embodiment,

the present invention

(A) obtaining an image by optical coherence tomography (OCT) from the retina of the subject; and

(B) Disclosed is a method for predicting the prognosis of early recurrence of intractable diabetic macular edema, comprising the step of analyzing a hyperreflective foci (HRF) in the retina through the obtained image.

In the method for predicting the prognosis of early recurrence of refractory diabetic macular edema according to the present invention, the method also includes (C) an early stage of refractory diabetic macular edema when the HRF value obtained in step (B) is 8 or more as a result of HRF analysis. It is characterized in that it further comprises a step of determining that the likelihood of recurrence is high.

In the method for predicting the prognosis of early recurrence of refractory diabetic macular edema according to the present invention, the method also includes (C) an early stage of refractory diabetic macular edema when the HRF value obtained in step (B) is less than 8 as a result of HRF analysis. It is characterized in that it further comprises a step of determining that the likelihood of recurrence is low.

In the method for predicting the prognosis of early recurrence of intractable diabetic macular edema according to the present invention, the subject is characterized in that the subject has undergone intravitreal dexamethasone implantation.

In the method for predicting the prognosis of early recurrence of refractory diabetic macular edema according to the present invention, the early recurrence has a central subfield thickness (CST) of 50 μm or more after 3 months compared to the first month after intravitreal DEX implant implantation. characterized by an increase.

According to the second embodiment,

the present invention

(A) obtaining an image by optical coherence tomography (OCT) from the retina of the subject; and

(B) Disclosed is a method for providing information for prognostic prediction of early recurrence of intractable diabetic macular edema, comprising the step of analyzing hyperreflective foci (HRF) in the retina through the obtained image.

In the method of providing information for predicting the prognosis of early recurrence of intractable diabetic macular edema according to the present invention, the method also includes (C) when the HRF value obtained in step (B) is 8 or more as a result of HRF analysis, intractable diabetes mellitus. It is characterized in that it further comprises a step of determining that the possibility of early recurrence of macular edema is high.

In the method of providing information for predicting the prognosis of early recurrence of intractable diabetic macular edema according to the present invention, the method also includes (C) when the HRF value obtained in step (B) is less than 8 as a result of HRF analysis, intractable diabetes mellitus. It is characterized in that it further comprises the step of determining that the possibility of early recurrence of macular edema is low.

In the method for providing information for predicting the prognosis of early recurrence of intractable diabetic macular edema according to the present invention, the subject is characterized in that the subject has undergone intravitreal dexamethasone implantation.

In the method of providing information for predicting the prognosis of early recurrence of intractable diabetic macular edema according to the present invention, the early recurrence has a central subfield thickness (CST) of 3 compared to the first month after intravitreal DEX implantation. It is characterized by an increase of 50 μm or more after months.

<Example>

1. Target and Method

Patients with DME refractory to bevacizumab who underwent intravitreal DME implant implantation and 12-month follow-up at Chungbuk National University Hospital from March 2015 to June 2017 were included. The criteria for inclusion are as follows:

(1) refractory DME to bevacizumab; and

(2) Completely cured refractory DME after intravitreal DEX implant implantation.

Worse or SD of Best Corrected Visual Acuity (BCVA) by ETDRS (Early Treatment Diabetic Retinopathy Study) line twice after injection compared to before the first treatment among patients who received 3 or more previous anti-VEGF injection treatments - If the decrease in retinal thickness was less than 10% in the measurement using OCT, it was defined as intractable DME. Patients who received intraocular corticosteroid therapy within 6 months, patients with other intraocular conditions impairing the VA except for cataract surgery, and patients with other eye diseases causing macular edema were excluded.

Before the procedure, BCVA and intraocular pressure were measured using the Snellen visual acuity test, and slit lamp microscopy, fundus examination, and fluorescein angiography were performed. In addition, central macular thickness (CMT) was measured using SD-OCT, and the test was performed at each revisit.

2. Optical coherence tomography analysis

Heidelberg Spectralis® (Spectralis; Heidelberg Engineering, Heidelberg, Germany) OCT was used to evaluate and analyze CST, ellipsoidal area (EZ) and outer limiting membrane (ELM) status, presence of subretinal fluid (SRF) and HRF. The CST was automatically calculated as the average retinal thickness within the central circle with a radius of 500 μm, and the extent of damage to the EZ and EML was measured within the range of 1500 μm in diameter based on the B-scan passing through the central fovea. HRF was defined as discrete, well-enclosed particles with a diameter of 20 to 40 μm with a reflectance equal to or higher than that of the retinal pigment epithelium (RPE) band of SD-OCT. The number of HRFs within an area with a radius of 1500 μm centered on the fovea in a horizontal raster scan was manually calculated using ImageJ software ( http://imagej.nih.gov/ij) . HRF was subdivided according to retinal layers: inner retina (between inner limiting membrane and inner nuclear layer), outer retina (between outer plexiform layer and outer limiting membrane) and whole retina (between inner limiting membrane and outer limiting membrane). The photoreceptor layer, RPE and subretinal space were excluded because their naturally high reflectivity prevented the evaluation of HRF. Calculation and classification were analyzed by two retinologists. If the discrepancy in the number of HRFs between retinologists exceeds 20%, the difference was resolved through discussion, and the average of the two investigators was used for analysis.

3. Statistical analysis

Statistics were performed using SPSS version 22.0 software (SPSS Inc, Chicago, IL, USA). program was used. The Mann-Whitney U test was used for groups with a non-normal distribution or unequal distribution. Comparisons between categorical variables were performed using Fisher's exact test. Multivariate logistic regression analysis was performed to identify independent criterion factors associated with early recurrence. Receiver Operating Characteristic (ROC) analysis was performed to determine the accuracy of prediction for early recurrence of DME. It was judged to be statistically significant only when the p-value was less than 0.05.

<Experimental example>

In 38 eyes of 36 patients, intravitreal DEX implants for bevacizumab treatment for refractory DME were implanted. Finally, 29 eyes of 26 patients were analyzed. Of the other 9 patients, 9 eyes were excluded from the analysis due to prior vitreous surgery (1 eye), retinal disease (5 eyes), and follow-up period within 12 months (4 eyes).

Experimental Example 1. Confirmation of early and late recurrence of DME

According to the recurrence time of macular edema after intravitreal DEX implantation, the group in which the central subfield thickness (CST) increased by 50 µm or more at 3 months compared to the first month after intravitreal DEX implantation was classified as an early recurrence group, and the rest were classified as late recurrence. classified into groups. As a result, 16 eyes (55.2%) out of 29 eyes were classified as early recurrence group and 13 eyes were classified as late recurrence group, and the results of sintering and OCT between the two groups are shown in Table 1 below.

Characteristic early relapse group
(n = 16) late relapse group
(n = 13) p value Age, mean±SD (years) 60.2±10.7 56.0±6.8 0.233 Gender, Male/Female (%) 6/9 (40/60) 6/5 (55/45) 0.467 Diabetes type, type 1 / 2 (%) 0/16 (0/100) 2/11 (15/85) 0.104 Hemoglobin A _1C , mean±SD (%) 9.0±1.7 8.2±1.7 0.300 High blood pressure (%) 6 (40) 5 (45) 0.781 Diabetic retinopathy type NPDR/PDR (%) 11/5 (69/31) 7/6 (54/46) 0.274 Lens status, phakic/pseudophakic (%) 8/8 (50/50) 9/4 (69/31) 0.451 Panretinal photocoagulation (%) 11 (69) 10 (77) 0.697 Number of previous intravitreal bevacizumab injections, mean±SD 4.1±1.7 4.8±2.5 0.417 Duration of treatment with intravitreal bevacizumab injection, mean±SD (months) 5.3±2.7 7.9±6.4 0.190 Best corrected visual acuity (log MAR), mean±SD 0.68±0.39 0.79±0.45 0.464 Central retinal thickness, mean±SD (μm) 604.9±191.4 577.3±172.5 0.690 subretinal fluid 5 (31) 1 (8) 0.119 Number of HRFs, mean±SD entire retina 11.38±3.07 7.54±3.60 0.006 inner retina 5.44±1.50 4.08±1.70 0.034 outer retina 5.94±2.74 3.46±2.30 0.013 ELM damage length, mean±SD (μm) 86.20±69.28 78.46±108.23 0.440 EZ damage length, mean±SD (μm) 268.87±77.34 199.00±132.16 0.072

As can be seen from Table 1 above, there was no significant difference in the number of prior intravitreal bevacizumab injections and duration of injection treatment between the early and late recurrence groups, and also in the length of CST, EZ, and ELM injuries. It was confirmed that there was no significant difference between the two groups. On the other hand, it was confirmed that the number of HRF for SD-OCT of the inner retina and the outer retina was significantly higher in the early recurrence group than in the late recurrence group. In the early relapse group, the mean total retinal HRF number was 11.38 ± 3.07 (inner retina 5.44 ± 1.50 and outer retina 5.94 ± 2.74), whereas in the late relapse group, the mean total retinal HRF number was 7.54 ± 3.60 ( Inner retina 4.08 ± 1.70 and outer retina 3.46 ± 2.30) were identified.

Experimental Example 2. Relationship between early recurrence of DME and clinical data

After intravitreal DEX implantation, logistic regression analysis was performed to confirm the baseline risk factors of the eye accompanying early recurrence of DME, and the results are shown in Table 2 below.

variable (n=29) Univariate Logistic Regression Multivariate Logistic Regression Whole Retinal HRF Inner Retinal HRF Outer retinal HRF odds ratio
(95% confidence interval) p odds ratio
(95% confidence interval) p odds ratio
(95% confidence interval) p odds ratio
(95% confidence interval) p age 0.052 (0.965-1.155) 0.268 1.056
(0.960-1.162) 0.264 1.056
(0.959-1.163) 0.271 1.051
(0.957-1.154) 0.302 gender, male 1.667 (0.116-2.277) 0.323 0.424
(0.056-3.223) 0.407 0.342
(0.047-2.477) 0.288 0.662
(0.105-4.180) 0.660 BCVA,
log MAR 0.496 (0.080-3.091) 0.453 - - - - - - Hemoglobin A _1C 1.322 (0.790-2.213) 0.289 - - - - - - PDR 0.390 (0.085-1.779) 0.224 - - - - - - Intravitreal bevacizumab injection
duration of treatment 0.876 (0.724-1.060) 0.174 - - - - - - CST 1.001 (0.997-1.005) 0.678 - - - - - - SFR 5.455
(0.548-54.276) 0.148 - - - - - - Number of HRFs throughout the retina 1.424 (1.076-1.886) 0.014 1.518
(1.095-2.103 0.012 - - - - Number of HRFs in the inner retina 1.712 (1.022-2.866) 0.041 - - 2.058
(1.087-3.897) 0.027 - - Number of HRFs in the outer retina 1.578 (1.046-2.380) 0.030 - - - - 1.610
(1.049-2.470) 0.029 ELM damage length 1.001 (0.992-1.010) 0.813 - - - - - - EZ Damage Length 1.007 (0.998-1.016) 0.117 - - - - - -

As can be seen from Table 2 above, according to univariate logistic regression analysis, it was confirmed that the number of HRFs in the inner retina, outer retina, and total retina is a very important factor in the early recurrence of DME. In addition, according to the results of multivariate regression analysis adjusted for age and sex, it was confirmed that the number of HRFs in the inner retina, outer retina, and total retina was correlated with early recurrence of DME after intravitreal DEX implantation.

As the specific parts of the present invention have been described in detail above, for those of ordinary skill in the art, these specific descriptions are only preferred embodiments, and it is clear that the scope of the present invention is not limited thereby. something to do. Accordingly, it is intended that the substantial scope of the present invention be defined by the appended claims and their equivalents.

Claims (5)

In the method of predicting the prognosis of early recurrence of intractable diabetic macular edema performed by a computing device executing an image analysis program,
(A) receiving an image by optical coherence tomography (OCT) obtained from the retina of a subject who has undergone intravitreal dexamethasone implant insertion;
(B) analyzing a hyperreflective foci (HRF) in the retina through the received image;
(C) As a result of the HRF analysis obtained in step (B), if the HRF value is 8 or more, the possibility of early recurrence of intractable diabetic macular edema is high, and if the HRF value is less than 8, the possibility of early recurrence of intractable diabetic macular edema is Determining that the likelihood of late recurrence is low and high;
The early recurrence is characterized by an increase in central subfield thickness (CST) of 50 μm or more after 3 months compared to the first month after implantation of intravitreal DEX implants,
A method for predicting the prognosis of early recurrence of intractable diabetic macular edema.

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