KR102455767B1 - Method for predicting early recurrence of diabetic macular edema refractory - Google Patents
Method for predicting early recurrence of diabetic macular edema refractory Download PDFInfo
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Abstract
Description
본 발명은 난치병 당뇨황반부종 조기 재발의 예측 방법에 관한 것이다. 보다 구체적으로, 본 발명은 빛간섭단층촬영을 이용한 유리체강내 덱사메타손 임플란트 삽입술을 받은 난치성 당뇨황반부종 환자에서 부종의 조기 재발의 예측 방법에 관한 것이다. 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.
당뇨망막병증 (Diabetic Macular Edema, DME)은 전 세계적으로 실명의 가장 흔한 원인 중 하나로, 시력저하를 일으키는 주된 원인은 당뇨망막병증 환자의 약 20% 정도에서 발생하는 황반부종으로 알려져 있다. 당뇨황반부종은 당뇨망막병증이 진행되면서 망막허혈이 심해지고, 혈관내피성장인자가 증가하게 되어 발생한다. 이러한 혈관내피성장인자의 증가는 혈액망막장벽을 손상시켜 비정상적으로 혈관의 투과성을 항진시키고 세포 간질액의 증가를 유발하여 망막부종을 유발한다[1,2]. 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].
혈관내피성장인자 (VEGF)는 당뇨황반부종의 필수 내인성 매개자로서, 항-VEGF는 시력 개선에 효과적이며 일반적으로 당뇨황반부종의 1차 요법으로 간주되고 있다[3]. 그러나, 항-VEGF에 잘 반응하지 않는 환자가 많으며 체액의 분해가 일시적이며 완전하지 않다는 문제점이 존재한다[4-6]. 당뇨황반부종을 일으키는 원인은 혈관내피성장인자의 증가뿐만 아니라 여러 종류의 염증성 사이토카인이 관여하고 것으로 알려져 있기 때문에, 항-VEGF 치료에 반응하지 않는 난치성(refractory) 당뇨황반부종 환자의 치료에 있어서 유리체내 스테로이드 주사가 대안으로 선택될 수 있다 [7,8].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].
덱타메타손 (Dexamethasone, DEX) 임플란트 (Ozurdex®, Allergan, Inc., Irvine, CA, USA)는 한 번의 삽입술로 최대 6 까지 유리체내에 존재하며[9,10]하는 것을 알려져 있으나, 실제 임상 환경에서는 당뇨황반부종의 조기 재발로 인하여 덱타메타손 임플란트의 더 빈번한 투여가 요구되고 있다. 덱타메타손 임플란트의 최대 효과는 3 개월에 발생하며, 4 ~ 6 개월에서 천천히 감소하는 경향이 있으며, 추가 덱타메타손 튜여 사이의 평균 간격은 약 3 ~ 7 개월로 다양하게 보고되고 있다[11-14].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].
한편, 스펙트럼영역 빛간섭단층촬영(spectral-domain optical co-herence tomography, SD-OCT)은 망막을 구성하는 각 층별형태의 고해상도 영상을 얻고 두께를 객관적으로 측정하는 비침습적 도구로 널리 이용되고 있으며, 이러한 빛간섭단층촬영에서 관찰되는 고반사점 (hyperreflective foci, HRF))이 당뇨망막병증, 황반변성, 망막분지정맥폐쇄 등 여러 질환들에서 보고되고 있다[15-17]. 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].
[선행문헌][Prior literature]
[비특허문헌][Non-patent literature]
[1] J. H. Kempen, B. J. O’Colmain, M. C. Leske et al., “The prevalenceofdiabeticretinopathyamongadultsintheUnited States,” JAMA Ophthalmology, vol. 122, no. 4, pp. 552-563, 2004. [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. [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,andA.Chang,“Anti-VEGF therapy for diabetic eye diseases,” Asia-Pacific Journal of Ophthalmology, vol. 6, no. 6, pp. 535-545, 2017. [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,andA.R.Glassman,“Revolution to a new standard treatment of diabetic macular edema,” Jama, vol. 311, no. 22, pp. 2269-2270, 2014. [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 triamcinolonepluspromptlaserfordiabeticmacularedema,” Ophthalmology, vol. 118, no. 4, pp. 609-614, 2011. [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. [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. [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 retinopathyandinflammation:noveltherapeutictargets,”Middle East African Journal of Ophthalmology, vol. 19, no. 1, pp. 52-59, 2012. [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. [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. [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. Voirinetal.,“Real-life study in diabetic maculare dema treated with dexamethasone implant,”Retina, vol. 37, no. 4, pp. 753-760, 2017. [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.Freiberget al.,“Long-term intravitreal dexamethasone treatment in eyes with pretreated chronic diabeticmacularedema,”JournalofOcularPharmacologyand Therapeutics, vol. 33, no. 8, pp. 620-628, 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. [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. [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. [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. [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. [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.
이에 본 발명자들은 유리체강내 덱사메타손 임플란트 삽입술을 받은 난치성 당뇨황반부종 환자에서 부종의 조기 재발을 예측하고자 노력한 결과, 빛간섭단층촬영에서 관찰되는 고반사점을 분석하여 고반사점의 수가 많을수록 유리체내 덱타메타손 임플란트 이식 후 당뇨황반부종이 더 빨리 재발할 수 있음을 규명함으로써, 본 발명을 완성하기에 이르렀다.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.
본 발명은 대상체로부터 수득한 빛간섭단층촬영(Optical Coherence Tomography, OCT)에서 관찰되는 고반사점 (hyperreflective foci, HRF)를 분석하는 것을 포함하는, 유리체강내 덱사메타손 임플란트 삽입술을 받은 난치성 당뇨황반부종의 조기 재발의 예후를 예측하는 방법을 제공하는 것을 목적으로 한다. 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
본 발명은 또한 대상체로부터 수득한 빛간섭단층촬영(Optical Coherence Tomography, OCT)에서 관찰되는 고반사점 (hyperreflective foci, HRF)를 분석하는 것을 포함하는, 유리체강내 덱사메타손 임플란트 삽입술을 받은 난치성 당뇨황반부종의 조기 재발의 예후 예측을 위한 정보를 제공하는 방법을 제공하는 것을 목적으로 한다. 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.
본 명세서에서 사용된 용어 “고반사점 (hyperreflective foci, HRF)”은 SD-OCT의 망막색소상피 (retinal pigment epithelium, RPE) 밴드와 같거나 더 높은 반사율을 직경 20 내지 40 μm의 입자를 의미한다. 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.
본 명세서에서 사용된 용어 “조기 재발”은 중심망막두께 (central subfield thickness, CST)가 유리체내 DEX 임플란트 이식 후 첫 달에 비해 3개월 후에 50μm 이상 증가한 경우를 의미한다. 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.
본 발명에 따른 빛간섭단층촬영(Optical Coherence Tomography, OCT)을 이용한 유리체강내 덱사메타손 임플란트 삽입술을 받은 난치성 당뇨황반부종의 조기 재발의 예후를 예측하는 방법은 HRF가 난치성 당뇨황반부종의 조기 재발에 있어서 독립적인 예측 인자로 사용될 수 있기 때문에 난치성 당뇨황반부종의 조기 재발 예후를 정확하게 예측하여, 예측된 예후에 따른 적절한 치료방향을 결정할 수 있도록 정보를 제공할 수 있다. 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.
이하, 발명의 이해를 돕기 위해 다양한 실시예를 제시한다. 하기 실시예는 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐 발명의 보호범위가 하기 실시예에 한정되는 것은 아니다. 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.
제1구현예에 따르면, According to the first embodiment,
본 발명은 the present invention
(A) 대상체의 망막으로부터 빛간섭단층촬영(Optical Coherence Tomography, OCT)에 의한 이미지를 얻는 단계; 및(A) obtaining an image by optical coherence tomography (OCT) from the retina of the subject; and
(B) 상기 얻어진 이미지를 통해 망막 내 고반사점 (hyperreflective foci, HRF)을 분석하는 단계를 포함하는 난치성 당뇨황반부종의 조기 재발의 예후를 예측하는 방법을 개시한다. (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.
본 발명에 따른 난치성 당뇨황반부종의 조기 재발의 예후를 예측하는 방법에 있어서, 상기 방법은 또한 (C) 상기 단계 (B)에서 얻어진 HRF 분석 결과 HRF의 값이 8 이상인 경우 난치성 당뇨황반부종의 조기 재발 가능성이 높은 것으로 판단하는 단계를 추가로 포함하는 것을 특징으로 한다. 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.
본 발명에 따른 난치성 당뇨황반부종의 조기 재발의 예후를 예측하는 방법에 있어서, 상기 방법은 또한 (C) 상기 단계 (B)에서 얻어진 HRF 분석 결과 HRF의 값이 8 미만인 경우 난치성 당뇨황반부종의 조기 재발 가능성이 낮은 것으로 판단하는 단계를 추가로 포함하는 것을 특징으로 한다. 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.
본 발명에 따른 난치성 당뇨황반부종의 조기 재발의 예후를 예측하는 방법에 있어서, 상기 대상체는 유리체강내 덱사메타손 임플란트 삽입술을 받은 것을 특징으로 한다. 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.
본 발명에 따른 난치성 당뇨황반부종의 조기 재발의 예후를 예측하는 방법에 있어서, 상기 조기 재발은 중심망막두께 (central subfield thickness, CST)가 유리체내 DEX 임플란트 이식 후 첫 달에 비해 3개월 후에 50μm 이상 증가한 것을 특징으로 한다. 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.
제2구현예에 따르면, According to the second embodiment,
본 발명은 the present invention
(A) 대상체의 망막으로부터 빛간섭단층촬영(Optical Coherence Tomography, OCT)에 의한 이미지를 얻는 단계; 및(A) obtaining an image by optical coherence tomography (OCT) from the retina of the subject; and
(B) 상기 얻어진 이미지를 통해 망막 내 고반사점 (hyperreflective foci, HRF)을 분석하는 단계를 포함하는 난치성 당뇨황반부종의 조기 재발의 예후 예측을 위한 정보를 제공하는 방법을 개시한다. (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.
본 발명에 따른 난치성 당뇨황반부종의 조기 재발의 예후 예측을 위한 정보를 제공하는 방법에 있어서, 상기 방법은 또한 (C) 상기 단계 (B)에서 얻어진 HRF 분석 결과 HRF의 값이 8 이상인 경우 난치성 당뇨황반부종의 조기 재발 가능성이 높은 것으로 판단하는 단계를 추가로 포함하는 것을 특징으로 한다. 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.
본 발명에 따른 난치성 당뇨황반부종의 조기 재발의 예후 예측을 위한 정보를 제공하는 방법에 있어서, 상기 방법은 또한 (C) 상기 단계 (B)에서 얻어진 HRF 분석 결과 HRF의 값이 8 미만인 경우 난치성 당뇨황반부종의 조기 재발 가능성이 낮은 것으로 판단하는 단계를 추가로 포함하는 것을 특징으로 한다. 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.
본 발명에 따른 난치성 당뇨황반부종의 조기 재발의 예후 예측을 위한 정보를 제공하는 방법에 있어서, 상기 대상체는 유리체강내 덱사메타손 임플란트 삽입술을 받은 것을 특징으로 한다. 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.
본 발명에 따른 난치성 당뇨황반부종의 조기 재발의 예후 예측을 위한 정보를 제공하는 방법에 있어서, 상기 조기 재발은 중심망막두께 (central subfield thickness, CST)가 유리체내 DEX 임플란트 이식 후 첫 달에 비해 3개월 후에 50μm 이상 증가한 것을 특징으로 한다. 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.
<실시예> <Example>
1. 대상 및 방법1. Target and Method
2015년 3월부터 2017년 6월까지 충북대학교병원에서 유리체내 DME 임플란트 이식 및 12개월 추적 관찰을 받은 베바시주맙 (bevacizumab)에 대한 난치성 DME 환자를 대상으로 하였으며, 포함 기준은 다음과 같다: 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) 베바시주맙에 대한 난치성 DME; 및(1) refractory DME to bevacizumab; and
(2) 유리체내 DEX 임플란트 이식 후 완전히 치료된 난치성 DME.(2) Completely cured refractory DME after intravitreal DEX implant implantation.
이전에 항-VEGF 주사 치료를 3회 이상 받았던 환자들 중 첫 치료 전과 비교하여 주사 후 2회 ETDRS (Early Treatment Diabetic Retinopathy Study) 라인에 의한 최대교정시력 (Best Corrected Visual Acuity, BCVA)의 악화 또는 SD-OCT를 이용한 측정에서 망막두께의 감소가 10% 미만인 경우 난치성 DME로 정의하였다. 6개월 이내에 안내 코르티코스테로이드 치료를 받은 환자, 백내장 수술을 제외한 VA를 손상시키는 다른 안내 병증이 있는 환자, 및 황반부종을 야기하는 다른 안질환을 가진 환자는 제외하였다. 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.
대상 환자들에 대해 시술 전 스넬렌시표(Snellen visual acuity test)를 이용하여 BCVA과 안압을 측정하였으며, 세극등 현미경검사, 안저검사, 형광안저촬영을 시행하였다. 또한 SD-OCT를 이용하여 중심황반두께(central macular thickness, CMT)를 측정하였으며, 재 방문시마다 상기 검사를 수행하였다. 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. 빛간섭단층촬영 분석2. Optical coherence tomography analysis
Heidelberg Spectralis® (Spectralis; Heidelberg Engineering, Heidelberg, Germany) OCT를 이용하여 CST, 타원체 영역 (EZ) 및 외부 제한 막 (ELM) 상태, 망막 하액 (SRF)의 존재 및 HRF를 평가하고 분석하였다. CST는 반경이 500 μm인 중심원 내의 평균 망막 두께로 자동적으로 계산하였으며, EZ 및 EML의 손상 범위는 망막중심오목을 통과하는 B-스캔을 기준으로 1500 μm 직경의 범위 내에서 측정하였다. HRF는 SD-OCT의 망막색소상피 (retinal pigment epithelium, RPE) 밴드와 같거나 더 높은 반사율을 갖는 이산적이고 잘-둘러싸인 직경 20 내지 40 μm의 입자로 정의하였다. 수평 래스터 스캔에서 중심와를 중심으로 반경 1500 μm 영역 내의 HRF의 수는 ImageJ 소프트웨어 (http://imagej.nih.gov/ij)를 사용하여 수동으로 계산하였다. HRF는 망막 층에 따라: 내부 망막 (내부 제한 막과 내부 핵층 사이), 외부 망막 (외부 플렉시폼 층과 외부 제한 막 사이) 및 전체 망막 (내부 제한 막과 외부 제한 막 사이)으로 세분화되었다. 광수용체 층, RPE 및 망막하 공간은 이들의 자연적으로 높은 반사율이 HRF의 평가를 방해하기 때문에 제외하였다. 계산과 분류는 망막분과전문의 2명이 분석하였으며, 망막전문의 사이의 HRF 수의 불일치가 20%를 초과하는 경우에는 논의를 통해 차이를 해결하고, 두 조사자의 평균을 분석에 사용하였다. 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. 통계분석3. Statistical analysis
통계는 SPSS version 22.0 소프트웨어 (SPSS Inc, Chicago, IL,USA)를 이용하였다. 프로그램을 이용하였다. 비정규분포 또는 불균등 분산을 가진 군에 대해서는 Mann-Whitney U test를 이용하였다. 범주의 변수 사이의 비교는 Fisher’s exact test를 이용하여 수행하였다. 다변량 로지스틱 회귀 분석을 수행하여 조기 재발과 관련된 독립적인 기준 인자를 식별하였다. DME의 조기 재발에 대한 예측의 정확성을 결정하기 위하여 ROC (Receiver Operating Characteristic) 분석을 수행하였다. p값이 0.05 미만인 경우에 한하여 통계학적으로 유의하다고 판단하였다.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.
<실험예><Experimental example>
36명의 환자 중 38안에 난치성 DME에 대한 베바시주맙 치료에 대한 유리체내 DEX 임플란트를 이식하였으며, 최종적으로 26명의 환자 중 29안에 대하여 분석하였다. 그 외의 9명의 환자 중 9안에 대해서는 이전의 유리체 수술 (1안), 망막 질환 (5안) 및 12개월 이내의 추적 기간 (4안)을 이유로 분석에서 제외하였다. 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).
실험예 1. DME의 조기 재발 및 후기 재발 확인Experimental Example 1. Confirmation of early and late recurrence of DME
유리체내 DEX 임플란트 이식 후 황반부종의 재발 시간에 따라, CST (central subfield thickness)가 유리체내 DEX 임플란트 이식 후 첫 달에 비해 3개월에 50μm 이상 증가한 군을 조기 재발 군으로 분류하고, 나머지는 후기 재발 군으로 분류하였다. 그 결과, 29안 중에서 16안 (55.2 %)이 조기 재발 군으로 분류되었고 13 안이 후기 재발 군으로 분류되었으며, 상기 두 군 사이의 소결 및 OCT 결과를 하기의 표 1에 나타내었다. 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.
(n = 16)early relapse group
(n = 16)
(n = 13)late relapse group
(n = 13)
상기 표 1로부터 알 수 있듯이, 조기 재발 군 및 후기 재발 군 사이에는 이전의 유리체내 베바시주맙 주사 횟수 및 주사 치료 기간에서의 유의적인 차이는 없었으며, 또한 CST, EZ, 및 ELM 손상 길이에 있어서도 두 군 사이에서의 유의적인 차이는 없는 것으로 확인되었다. 반면, 내부 망막 및 외부 망막의 SD-OCT에 대한 HRF의 수에 있어서 후기 재발 군 보다 조기 재발 군에서 유의적으로 높은 것으로 확인되었다. 초기 재발 군의 경우, 망막 전체의 평균 HRF 수는 11.38±3.07 (내부 망막 5.44±1.50 및 외부 망막 5.94±2.74)으로 측정된 반면, 후기 재발 군의 경우 망막 전체의 평균 HRF 수는 7.54±3.60 (내부 망막 4.08±1.70 및 외부 망막 3.46±2.30)으로 확인되었다. 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.
실험예 2. DME의 조기 재발과 임상 데이터와의 관계Experimental Example 2. Relationship between early recurrence of DME and clinical data
유리체내 DEX 임플란트 이식 후 DME의 조기 재발을 동반한 눈의 기준 위험 인자를 확인하기 위하여 로지스틱 회귀 분석을 수행하고, 그 결과를 하기의 표 2에 나타내었다. 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.
(95% 신뢰구간)odds ratio
(95% confidence interval)
(95% 신뢰구간)odds ratio
(95% confidence interval)
(95% 신뢰구간)odds ratio
(95% confidence interval)
(95% 신뢰구간)odds ratio
(95% confidence interval)
(0.960-1.162)1.056
(0.960-1.162)
(0.959-1.163)1.056
(0.959-1.163)
(0.957-1.154)1.051
(0.957-1.154)
(0.056-3.223)0.424
(0.056-3.223)
(0.047-2.477)0.342
(0.047-2.477)
(0.105-4.180)0.662
(0.105-4.180)
log MARBCVA,
log MAR
치료 기간Intravitreal bevacizumab injection
duration of treatment
(0.548-54.276)5.455
(0.548-54.276)
(1.095-2.1031.518
(1.095-2.103
(1.087-3.897)2.058
(1.087-3.897)
(1.049-2.470)1.610
(1.049-2.470)
상기 표 2로부터 알 수 있듯이, 단변량 로지스틱 회귀분석에 따르면, 내부 망막, 외부 망막 및 전체 망막에서의 HRF의 수가 DME의 조기 재발에 있어서 매우 중요한 인자임이 확인되었다. 또한, 연령 및 성별을 조정한 다변량 회귀 분석 결과에 따르면, 내부 망막, 외부 망막 및 전체 망막에서의 HRF의 수가 유리체내 DEX 임플란트 이식 후 DME의 조기 재발과 상관관계가 있음이 확인되었다.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.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시태양일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.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)
(A) 유리체강내 덱사메타손 임플란트 삽입술을 받은 대상체의 망막으로부터 얻은 빛간섭단층촬영(Optical Coherence Tomography, OCT)에 의한 이미지를 수신하는 단계;
(B) 상기 수신한 이미지를 통해 망막 내 고반사점(hyperreflective foci, HRF)을 분석하는 단계;
(C) 상기 단계(B)에서 얻어진 HRF 분석 결과 HRF의 값이 8 이상인 경우 난치성 당뇨황반부종의 조기 재발 가능성이 높은 것으로 판단하고, HRF의 값이 8 미만인 경우 난치성 당뇨황반부종의 조기 재발 가능성은 낮고 후기 재발 가능성은 높은 것으로 판단하는 단계를 포함하고,
상기 조기 재발은 중심망막두께 (central subfield thickness, CST)가 유리체내 DEX 임플란트 이식 후 첫 달에 비해 3개월 후에 50μm 이상 증가한 것을 특징으로 하는 것인,
난치성 당뇨황반부종의 조기 재발의 예후를 예측하는 방법.
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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