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  Maria Vittoria Cicinelli, Francesco Bandello and Giuseppe Querques
  Published on: 23 November 2017
• Early response to ranibizumab predictive of functional outcome after dexamethasone for unresponsive diabetic macular oedema
  Dan CAlugaru, Mihai CAlugaru
  Published on: 23 November 2017

• Published on: 23 November 2017

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  • Maria Vittoria Cicinelli, Ophthalmologist San Raffaele Scientific Institute
  • Other Contributors:
    • Francesco Bandello, Opthalmologist
    • Giuseppe Querques, opththalmologist

  We warmly thank Calugaru D and associates for their correspondence regarding our article entitled " Early response to ranibizumab predictive of functional outcome after dexamethasone for unresponsive diabetic macular oedema".1
  We agree with them about some of the challenges concerning our study. As we have acknowledged in the limitation section of our article, our study is limited by several biases, as its design was retrospective. In particular, patients selection and follow-up represented some of the major flaws in our study. We collected data about patients switched to dexamethasone for different reasons; some patients were treatment-naïve, other had already undergone treatments for diabetic macular edema (DME). No one disclosed any feature of chronic long-standing DME; all of them received prompt therapy after DME diagnosis.
  Some of them showed a good response to ranibizumab loading-dose, with satisfying reduction of macular thickness after the injections. Nevertheless, no patient disclosed a completely dry macula after the anti-vascular endothelial growth factor (VEGF) loading-dose.
  As far as it regards the final functional and anatomical gain at the end of the follow-up, the Authors state that the outcomes of this series were unsatisfactory. However, in the non-responders group, despite initial poor results, the best-corrected visual acuity (BCVA) had improved significantly (p<0.05) and clinically (> 5 letters), as highlighted in the...

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  We warmly thank Calugaru D and associates for their correspondence regarding our article entitled " Early response to ranibizumab predictive of functional outcome after dexamethasone for unresponsive diabetic macular oedema".1
  We agree with them about some of the challenges concerning our study. As we have acknowledged in the limitation section of our article, our study is limited by several biases, as its design was retrospective. In particular, patients selection and follow-up represented some of the major flaws in our study. We collected data about patients switched to dexamethasone for different reasons; some patients were treatment-naïve, other had already undergone treatments for diabetic macular edema (DME). No one disclosed any feature of chronic long-standing DME; all of them received prompt therapy after DME diagnosis.
  Some of them showed a good response to ranibizumab loading-dose, with satisfying reduction of macular thickness after the injections. Nevertheless, no patient disclosed a completely dry macula after the anti-vascular endothelial growth factor (VEGF) loading-dose.
  As far as it regards the final functional and anatomical gain at the end of the follow-up, the Authors state that the outcomes of this series were unsatisfactory. However, in the non-responders group, despite initial poor results, the best-corrected visual acuity (BCVA) had improved significantly (p<0.05) and clinically (> 5 letters), as highlighted in the text.
  The analysis of central macular thickness (CMT) at 12 months on optical coherence tomography disclosed that the poor and good responders reached CMT of 363 microns and of 359 microns, respectively. Despite being more than the cutoff for the upper level of normal CMT, as suggested by the Authors, for DME eyes a CMT of ~350um should be considered as a good outcome, as values inferior to this cut-off would indicate impending atrophy of the neurovascular tissue. As a validation of our approach, we referred to the latest Diabetic Retinopathy Clinical Research Network (DRCR.net) guidelines about persistent macular thickening after ranibizumab treatment, according to which CMT appeared to be a less important prognostic factor in DME outcomes. In fact, persistent macular edema was associated with similar long-term improvement in visual acuity showed by patients in which DME did not persist.2 Finally, we would like to specify that we analyzed data of included patients until 12-months follow-up; these patients did not conclude treatment for DME, and most of them continued to receive injections for their condition.
  We perfectly agree that, along with CMT, other OCT biomarkers (as disorganization of the retinal inner layers, integrity of the ellipsoid zone and of the cone outer segment tips, presence of taut internal limiting membrane or epiretinal membrane, and vitreomacular traction) should be analyzed in order to predict the prognostic outcome of diabetic patients.3-4 A specific analysis of these parameters was beyond our purposes, but we will include them in a future more complete stepwise linear regression analysis of the data presented in the present study.
  We listed the complications of treatment experienced by patients who underwent dexamethasone (DEX) implant, with particular attention to intraocular pressure increase as well as cataract worsening. These two are well-known side-effects of dexamethasone implant and their rate did not exceed the expectations in our study.5 Despite these complications, intravitreal steroids have shown a good safety profile in long-term prospective studies, especially in those cases when anti-VEGF are contraindicated, or fewer intravitreal injections regimen is required.
  In conclusion, we kindly disagree with the conclusion of the Authors and we further demonstrated the usefulness of switching the therapeutic drug in diabetic patients non-responders to anti-VEGF the by replying to this letter.

  References:

  1. Cicinelli MV, Cavalleri M, Querques L, et al. Early response to ranibizumab predictive of functional outcome after dexamethasone for unresponsive diabetic macular oedema. Br J Ophthalmol 2017; http:/ dx. doi. org/ 10.1136/bjophthalmol-2017-310242.

  2. Bressler SB, Ayala AR, Bressler NM, Melia M, Qin H, Ferris FL 3rd, Flaxel CJ, Friedman SM, Glassman AR, Jampol LM, Rauser ME; Diabetic Retinopathy Clinical Research Network. Persistent Macular Thickening After Ranibizumab Treatment for Diabetic Macular Edema With Vision Impairment. JAMA Ophthalmol. 2016 Mar;134(3):278-85. doi: 10.1001/jamaophthalmol.2015.5346.

  3. Sun JK, Lin MM, Lammer J, Prager S, Sarangi R, Silva PS, Aiello LP. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA Ophthalmol. 2014 Nov;132(11):1309-16.

  4. Iacono P, Parodi MB, Scaramuzzi M, Bandello F. Morphological and functional changes in recalcitrant diabetic macular oedema after intravitreal dexamethasone implant. Br J Ophthalmol. 2016 Sep 13. pii: bjophthalmol-2016-308726. doi: 10.1136/bjophthalmol-2016-308726.

  5. Boyer DS, Yoon YH, Belfort R Jr, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. 2014;121:1904-1914.

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2017

  Early response to ranibizumab predictive of functional outcome after dexamethasone for unresponsive diabetic macular oedema

  • Dan CAlugaru, Ophthalologist Univ of Medicine Cluj-Napoca/Romania
  • Other Contributors:
    • Mihai CAlugaru, Professor of Ophthalmology

  Early response to ranibizumab predictive of functional outcome after dexamethasone for unresponsive diabetic macular oedema
  Dan Calugaru, Mihai Calugaru
  Department of Ophthalmology, Univ of Medicine Cluj-Napoca/Romania

  Re: Early response to ranibizumab predictive of functional outcome after dexamethasone for unresponsive diabetic macular oedema. Cicinelli et al. Br J Ophthalmol 2017; http: /dx.doi. org/ 10.1136/bjophthalmol-2017-310242.

  Dear Editor
  We would like to address several challenges that have arisen from the study by Cicinelli et al (1), which can be specifically summarized below.
  1. The study was retrospectively conducted, with a selection bias attributable to the heterogeneity of the patients included, for example, six patients were affected by the type 1 diabetes mellitus; eighteen eyes were phakic; twenty seven eyes underwent cataract extraction and intraocular lens implant; and thirteen eyes received grid macular photocoagulation for diabetic macular oedema (DME) prior to ranibizumab (RNB).
  2. After undergoing three loading-dose intravitreal injections of RNB performed at fixed 4-week intervals for the first 12 weeks, all the patients regardless of functional and anatomical characteristics, were shifted to dexamethasone implant (DEX implant 0.7 mg; Ozurdex; Allergan, Irvine, California, USA) continued at 4-month intervals until stable best-corrected visual acuity (BCVA) was reached. However, nothing was...

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  Early response to ranibizumab predictive of functional outcome after dexamethasone for unresponsive diabetic macular oedema
  Dan Calugaru, Mihai Calugaru
  Department of Ophthalmology, Univ of Medicine Cluj-Napoca/Romania

  Re: Early response to ranibizumab predictive of functional outcome after dexamethasone for unresponsive diabetic macular oedema. Cicinelli et al. Br J Ophthalmol 2017; http: /dx.doi. org/ 10.1136/bjophthalmol-2017-310242.

  Dear Editor
  We would like to address several challenges that have arisen from the study by Cicinelli et al (1), which can be specifically summarized below.
  1. The study was retrospectively conducted, with a selection bias attributable to the heterogeneity of the patients included, for example, six patients were affected by the type 1 diabetes mellitus; eighteen eyes were phakic; twenty seven eyes underwent cataract extraction and intraocular lens implant; and thirteen eyes received grid macular photocoagulation for diabetic macular oedema (DME) prior to ranibizumab (RNB).
  2. After undergoing three loading-dose intravitreal injections of RNB performed at fixed 4-week intervals for the first 12 weeks, all the patients regardless of functional and anatomical characteristics, were shifted to dexamethasone implant (DEX implant 0.7 mg; Ozurdex; Allergan, Irvine, California, USA) continued at 4-month intervals until stable best-corrected visual acuity (BCVA) was reached. However, nothing was stated as to whether there were patients with complete retinal dryness at week 12 and if so, why they were switched to dexamethasone implant.
  3. In the assessment of the final results of this study we considered the current assertion that evaluation of outcomes has to be guided by anatomical measure data with visual changes as a secondary guide [2]. Accordingly, the final outcomes of this series were unsatisfactory. Specifically, despite a significant mean gain of 5.6 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in BCVA score in poorly responding patients and an insignificant improvement of 2.1 ETDRS letters in patients with good visual response, the central macular thickness (CMT) decreased significantly to 363.6 microns and reduced insignificantly to 359 microns, in the poor and good responders, respectively. Of note, the both CMT values were more than the cutoff for the upper level of normal CMT [3], highlighting unresolved DME. Moreover, seven eyes developed intraocular pressure =/> 20 mm Hg, cataract progression was observed in nine among the phakic eyes (50%) during the study period, and two patients underwent cataract extraction after the dexamethasone implant. Importantly, persistence of unresolved macular oedema can permanently damage the outer retinal layers, leading to retinal fibrosis and macular atrophy, indicating that the disease process is still active and progressive, requiring further treatment with antiangiogenic agents.
  4. As far as the potential prognosticatours of clinical outcome after dexamethasone implant are concerned, the following baseline characteristics should have been considered and included in a stepwise linear regression analysis along with those already presented, namely the subfoveal choroidal thickness, the qualitative status of the 4 outer retinal layers, the vitreoretinal interface abnormalities (vitreomacular adhesion/traction and epiretinal membrane), the diabetic retinopathy severity, the presence of macular ischemia on fluorescein angiography, and the duration of DME prior to therapy.
  5. The specific anti-VEGF drugs (bevacizumab [Avastin; Genentech, South San Francisco, California, USA)/ranibizumab [Lucentis, Genentech]/aflibercept [Eylea; Regeneron Pharmaceuticals Inc, Tarrytown, New York, USA]) represent the front-line therapy for the treatment of DME but only the VEGF inhibition may not be sufficient to decrease inflammatory response. Therefore, addition of a non-specific anti-VEGF substance, ie. a corticosteroid implant, is mandatory. Both groups of anti-VEGF substances provide similar rates of vision improvement but with superior anatomic outcomes and fewer injections in the corticosteroid implant-treated eyes. However, more patients receiving the corticosteroid implant lose vision mainly due to cataract [4].
  Altogether, the results of this study can not be validated and extrapolated because a stepwise linear regression analysis of the potential predictors of functional outcome was not carried out. Regardless of the anti-VEGF agents employed (bevacizumab/ranibizumab/aflibercept/ corticosteroid), the efficacy of therapy depends primarily on the promptness of the therapy after DME diagnosis [4,5].

  References
  1. Cicinelli MV, Cavalleri M, Querques L, et al. Early response to ranibizumab predictive of functional outcome after dexamethasone for unresponsive diabetic macular oedema. Br J Ophthalmol 2017; http:/ dx. doi. org/ 10.1136/bjophthalmol-2017-310242.
  2. Freund KB, Korobelnik JF, Devenyi R, et al. Treat-and-extend regimens with anti-VEGF agents in retinal diseases. Retina 2015;35(8):1489-1506.
  3. Gover S, Murthy RK, Brar VS, Chalam KV.Normative data for macular thickness by high-definition spectral-domain optical coherence tomography (spectralis). Am J Ophthalmol 2009;148(2):266-271.
  4. Calugaru D, Calugaru M. Real-world outcomes of ranibizumab treatment for diabetic macular edema in a United Kingdom National Health Service setting. Am J Ophthalmol 2017;174(2):175-176.
  5. Calugaru D, Calugaru M. Comments to: Long-term efficacy and safety of intravitreal dexamethasone implant for the treatment of diabetic macular edema. Eur J Ophthalmol 2016;26(6):171-172.

  Conflict of interest:
  None declared

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  Conflict of Interest:
  None declared.

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