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Chew S, Tran T, Sanfilippo P, Lim LL, Sandhu SS, Wickremasinghe S. Elevated aqueous TNF-α levels are associated with more severe functional and anatomic findings in eyes with diabetic macular oedema. Clin Exp Ophthalmol 2024; 52:981-990. [PMID: 39072984 PMCID: PMC11620847 DOI: 10.1111/ceo.14425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 06/24/2024] [Accepted: 07/11/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Intravitreal ranibizumab for diabetic macular oedema (DMO) has been recently shown to modulate levels of aqueous cytokines. This study investigates the associations between changes in aqueous cytokine levels following intravitreal ranibizumab therapy and the corresponding anatomical and functional changes in the eye. METHODS Twenty-five patients comprising 30 eyes diagnosed with DMO were prospectively recruited. All eyes received three loading dose ranibizumab injections at baseline, week 4 and week 8, followed by pro re nata treatment based on best-corrected visual acuity (BCVA) and central macular thickness (CMT) up to week 48. Prior to ranibizumab administration, aqueous samples were collected from all eyes, and subsequent sampling was performed at week 8. Levels of 32 cytokines were assessed at baseline and at week 8. RESULTS At baseline, higher aqueous TNF-α levels were associated with poorer BCVA (p = 0.033), greater macular volume (p = 0.017) and worse diabetic retinopathy (p = 0.047). Higher levels of IL-7 were associated with poorer BCVA and greater macular volume (MV). Following treatment with ranibizumab there was a significant correlation with reduction of aqueous TNF-α and improvements in BCVA and MV, both at 6 months (BCVA [r = -0.558, p = 0.001], MV [r = 0.410, p = 0.024]) and 12-months (BCVA [r = -0.413, p = 0.023], MV [r = 0.482, p = 0.008]). The change in VEGF concentration following ranibizumab treatment did not correlate with either BCVA or MV improvements (p > 0.05). CONCLUSIONS Higher levels of aqueous TNF-α and IL-7 correlated with worse DMO, both anatomically and functionally. Reductions in levels of aqueous TNF-α, but not VEGF, post ranibizumab treatment were associated with improvement in BCVA and MV.
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Affiliation(s)
- Sky Chew
- Centre for Eye Research AustraliaUniversity of MelbourneEast MelbourneVictoriaAustralia
- The Royal Victorian Eye and Ear HospitalEast MelbourneVictoriaAustralia
| | - Tuan Tran
- Centre for Eye Research AustraliaUniversity of MelbourneEast MelbourneVictoriaAustralia
- The Royal Victorian Eye and Ear HospitalEast MelbourneVictoriaAustralia
| | - Paul Sanfilippo
- Centre for Eye Research AustraliaUniversity of MelbourneEast MelbourneVictoriaAustralia
| | - Lyndell L. Lim
- Centre for Eye Research AustraliaUniversity of MelbourneEast MelbourneVictoriaAustralia
- The Royal Victorian Eye and Ear HospitalEast MelbourneVictoriaAustralia
| | - Sukhpal S. Sandhu
- Centre for Eye Research AustraliaUniversity of MelbourneEast MelbourneVictoriaAustralia
- The Royal Victorian Eye and Ear HospitalEast MelbourneVictoriaAustralia
| | - Sanjeewa Wickremasinghe
- Centre for Eye Research AustraliaUniversity of MelbourneEast MelbourneVictoriaAustralia
- The Royal Victorian Eye and Ear HospitalEast MelbourneVictoriaAustralia
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2
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Coughlin BA, Christian B, Trombley B, Mohr S. Interleukin-1 receptor-dependent and -independent caspase-1 activity in retinal cells mediated by receptor interacting protein 2. Front Cell Dev Biol 2024; 12:1467799. [PMID: 39483336 PMCID: PMC11525982 DOI: 10.3389/fcell.2024.1467799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 09/23/2024] [Indexed: 11/03/2024] Open
Abstract
Introduction Inflammation and cell death play an important role in the pathogenesis of diabetic retinopathy. Previously we observed sustained activation of pro-inflammatory caspase-1 in retinas of diabetic animals and patients. In this study, we aimed to look at mechanisms underlying chronic caspase-1 activation in vitro and in vivo. Methods Non-diabetic and diabetic wild type and IL-1 receptor (IL-1R1) knockout mice were used for in vivo experiments. Diabetes was induced using STZ (streptozotocin). Human Müller cells were used for in vitro studies. Cells were treated with either 5 mM or 25 mM glucose or interleukin-1beta (IL-1β) in the presence or absence of IL-1 receptor antagonist (IL-1ra) or siRNA against RIP2 (receptor interacting protein-2) for up to 96 h. Outcome measurements to assess Müller cell functions included measurements of caspase-1 activity using a fluorescence peptide substrate, production of IL-1β by Elisa, and cell death using trypan blue exclusion assays. Results Our in vivo results demonstrate that caspase-1 activation progresses from an IL-1R1 independent mechanism at 10 weeks of diabetes to an IL-1R1 dependent mechanism at 20 weeks indicating that feedback through IL-1R1 is crucial for sustained caspase-1 activity in retinas of mice. A similar hyperglycemia-mediated caspase-1/IL-1β/IL-1R1 feedback signaling was detected in vitro in human Müller cells which was prevented by treatment with IL-1ra. Our data also indicate that hyperglycemia induces caspase-1 activation initially but IL-1β sustains caspase-1 activation via caspase-1/IL-1β/IL-1R1 feedback and we identified RIP2 as mediator for both hyperglycemia- and IL-1β-induced caspase-1 activation. Activation of caspase-1/IL-1β/IL-1R1 feedback signaling caused Müller cell death which was prevented by RIP2 knockdown. Discussion We conclude that any intervention in caspase-1/IL-1β/IL-1R1 feedback signaling presents novel therapeutic options for the treatment of diabetic retinopathy.
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Affiliation(s)
| | | | | | - Susanne Mohr
- Department of Physiology, Michigan State University, East Lansing, MI, United States
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3
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Li J, Zhao T, Sun Y. Interleukin-17A in diabetic retinopathy: The crosstalk of inflammation and angiogenesis. Biochem Pharmacol 2024; 225:116311. [PMID: 38788958 DOI: 10.1016/j.bcp.2024.116311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 05/19/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2024]
Abstract
Diabetic retinopathy (DR) is a severe ocular complication of diabetes which can leads to irreversible vision loss in its late-stage. Chronic inflammation results from long-term hyperglycemia contributes to the pathogenesis and progression of DR. In recent years, the interleukin-17 (IL-17) family have attracted the interest of researchers. IL-17A is the most widely explored cytokine in IL-17 family, involved in various acute and chronic inflammatory diseases. Growing body of evidence indicate the role of IL-17A in the pathogenesis of DR. However, the pro-inflammatory and pro-angiogenic effect of IL-17A in DR have not hitherto been reviewed. Gaining an understanding of the pro-inflammatory role of IL-17A, and how IL-17A control/impact angiogenesis pathways in the eye will deepen our understanding of how IL-17A contributes to DR pathogenesis. Herein, we aimed to thoroughly review the pro-inflammatory role of IL-17A in DR, with focus in how IL-17A impact inflammation and angiogenesis crosstalk.
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Affiliation(s)
- Jiani Li
- Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Tantai Zhao
- Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Yun Sun
- Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China.
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4
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Reddy SK, Devi V, Seetharaman ATM, Shailaja S, Bhat KMR, Gangaraju R, Upadhya D. Cell and molecular targeted therapies for diabetic retinopathy. Front Endocrinol (Lausanne) 2024; 15:1416668. [PMID: 38948520 PMCID: PMC11211264 DOI: 10.3389/fendo.2024.1416668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 05/27/2024] [Indexed: 07/02/2024] Open
Abstract
Diabetic retinopathy (DR) stands as a prevalent complication in the eye resulting from diabetes mellitus, predominantly associated with high blood sugar levels and hypertension as individuals age. DR is a severe microvascular complication of both type I and type II diabetes mellitus and the leading cause of vision impairment. The critical approach to combatting and halting the advancement of DR lies in effectively managing blood glucose and blood pressure levels in diabetic patients; however, this is seldom achieved. Both human and animal studies have revealed the intricate nature of this condition involving various cell types and molecules. Aside from photocoagulation, the sole therapy targeting VEGF molecules in the retina to prevent abnormal blood vessel growth is intravitreal anti-VEGF therapy. However, a substantial portion of cases, approximately 30-40%, do not respond to this treatment. This review explores distinctive pathophysiological phenomena of DR and identifiable cell types and molecules that could be targeted to mitigate the chronic changes occurring in the retina due to diabetes mellitus. Addressing the significant research gap in this domain is imperative to broaden the treatment options available for managing DR effectively.
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Affiliation(s)
- Shivakumar K. Reddy
- Centre for Molecular Neurosciences, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Vasudha Devi
- Department of Pharmacology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Amritha T. M. Seetharaman
- Department of Ophthalmology, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - S. Shailaja
- Department of Ophthalmology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Kumar M. R. Bhat
- Department of Anatomy, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Rajashekhar Gangaraju
- Department of Ophthalmology, The University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Anatomy & Neurobiology, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Dinesh Upadhya
- Centre for Molecular Neurosciences, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
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Muns SM, Villegas VM, Flynn HW, Schwartz SG. Update on current pharmacologic therapies for diabetic retinopathy. Expert Opin Pharmacother 2023; 24:1577-1593. [PMID: 37431888 DOI: 10.1080/14656566.2023.2230139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/16/2023] [Accepted: 06/23/2023] [Indexed: 07/12/2023]
Abstract
INTRODUCTION Diabetic retinopathy is a major cause of visual loss worldwide. The most important clinical findings include diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). AREAS COVERED PubMed was used for our literature review. Articles from 1995 to 2023 were included. Pharmacologic treatment of diabetic retinopathy generally involves the use of intravitreal anti-vascular endothelial growth factor (VEGF) therapy for DME and PDR. Corticosteroids remain important second-line therapies for patients with DME. Most emerging therapies focus on newly identified inflammatory mediators and biochemical signaling pathways involved in disease pathogenesis. EXPERT OPINION Emerging anti-VEGF modalities, integrin antagonists, and anti-inflammatory agents have the potential to improve outcomes with reduced treatment burdens.
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Affiliation(s)
- Sofía M Muns
- Department of Ophthalmology, University of Puerto Rico, San Juan, Puerto Rico
| | - Victor M Villegas
- Department of Ophthalmology, University of Puerto Rico, San Juan, Puerto Rico
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Harry W Flynn
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Stephen G Schwartz
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
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Ramos H, Hernández C, Simó R, Simó-Servat O. Inflammation: The Link between Neural and Vascular Impairment in the Diabetic Retina and Therapeutic Implications. Int J Mol Sci 2023; 24:ijms24108796. [PMID: 37240138 DOI: 10.3390/ijms24108796] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/25/2023] [Accepted: 05/12/2023] [Indexed: 05/28/2023] Open
Abstract
The etiology of diabetic retinopathy (DR) is complex, multifactorial and compromises all the elements of the retinal neurovascular unit (NVU). This diabetic complication has a chronic low-grade inflammatory component involving multiple inflammatory mediators and adhesion molecules. The diabetic milieu promotes reactive gliosis, pro-inflammatory cytokine production and leukocyte recruitment, which contribute to the disruption of the blood retinal barrier. The understanding and the continuous research of the mechanisms behind the strong inflammatory component of the disease allows the design of new therapeutic strategies to address this unmet medical need. In this context, the aim of this review article is to recapitulate the latest research on the role of inflammation in DR and to discuss the efficacy of currently administered anti-inflammatory treatments and those still under development.
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Affiliation(s)
- Hugo Ramos
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Olga Simó-Servat
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
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Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications. Cells 2022; 11:cells11213362. [PMID: 36359761 PMCID: PMC9655436 DOI: 10.3390/cells11213362] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/19/2022] [Accepted: 10/20/2022] [Indexed: 11/24/2022] Open
Abstract
Diabetic retinopathy (DR), with increasing incidence, is the major cause of vision loss and blindness worldwide in working-age adults. Diabetic macular edema (DME) remains the main cause of vision impairment in diabetic patients, with its pathogenesis still not completely elucidated. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of DR and DME. Currently, intravitreal injection of anti-VEGF agents remains as the first-line therapy in DME treatment due to the superior anatomic and functional outcomes. However, some patients do not respond satisfactorily to anti-VEGF injections. More than 30% patients still exist with persistent DME even after regular intravitreal injection for at least 4 injections within 24 weeks, suggesting other pathogenic factors, beyond VEGF, might contribute to the pathogenesis of DME. Recent advances showed nearly all the retinal cells are involved in DR and DME, including breakdown of blood-retinal barrier (BRB), drainage dysfunction of Müller glia and retinal pigment epithelium (RPE), involvement of inflammation, oxidative stress, and neurodegeneration, all complicating the pathogenesis of DME. The profound understanding of the changes in proteomics and metabolomics helps improve the elucidation of the pathogenesis of DR and DME and leads to the identification of novel targets, biomarkers and potential therapeutic strategies for DME treatment. The present review aimed to summarize the current understanding of DME, the involved molecular mechanisms, and the changes in proteomics and metabolomics, thus to propose the potential therapeutic recommendations for personalized treatment of DME.
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8
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Takkar B, Sheemar A, Jayasudha R, Soni D, Narayanan R, Venkatesh P, Shivaji S, Das T. Unconventional avenues to decelerated diabetic retinopathy. Surv Ophthalmol 2022; 67:1574-1592. [PMID: 35803389 DOI: 10.1016/j.survophthal.2022.06.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 02/07/2023]
Abstract
Diabetic retinopathy (DR) is an important microvascular complication of diabetes mellitus (DM), causing significant visual impairment worldwide. Current gold standards for retarding the progress of DR include blood sugar control and regular fundus screening. Despite these measures, the incidence and prevalence of DR and vision-threatening DR remain high. Given its slowly progressive course and long latent period, opportunities to contain or slow DR before it threatens vision must be explored. This narrative review assesses the recently described unconventional strategies to retard DR progression. These include gut-ocular flow, gene therapy, mitochondrial dysfunction-oxidative stress, stem cell therapeutics, neurodegeneration, anti-inflammatory treatments, lifestyle modification, and usage of phytochemicals. These therapies impact DR directly, while some of them also influence DM control. Most of these strategies are currently in the preclinical stage, and clinical evidence remains low. Nevertheless, our review suggests that these approaches have the potential for human use to prevent the progression of DR.
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Affiliation(s)
- Brijesh Takkar
- Srimati Kanuri Santhamma Centre for Vitreoretinal Diseases, L V Prasad Eye Institute, Hyderabad, India; Indian Health Outcomes, Public Health, and Economics Research (IHOPE) Centre, L V Prasad Eye Institute, Hyderabad, India.
| | - Abhishek Sheemar
- Department of Ophthalmology, All India Institute of Medical Sciences, Jodhpur, India
| | | | - Deepak Soni
- Department of Ophthalmology, All India Institute of Medical Sciences, Bhopal, India
| | - Raja Narayanan
- Srimati Kanuri Santhamma Centre for Vitreoretinal Diseases, L V Prasad Eye Institute, Hyderabad, India; Indian Health Outcomes, Public Health, and Economics Research (IHOPE) Centre, L V Prasad Eye Institute, Hyderabad, India
| | - Pradeep Venkatesh
- Dr. RP Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Sisinthy Shivaji
- Prof. Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, India
| | - Taraprasad Das
- Srimati Kanuri Santhamma Centre for Vitreoretinal Diseases, L V Prasad Eye Institute, Hyderabad, India
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9
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Chatziralli I, Touhami S, Cicinelli MV, Agapitou C, Dimitriou E, Theodossiadis G, Theodossiadis P. Disentangling the association between retinal non-perfusion and anti-VEGF agents in diabetic retinopathy. Eye (Lond) 2022; 36:692-703. [PMID: 34408316 PMCID: PMC8956693 DOI: 10.1038/s41433-021-01750-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 07/29/2021] [Accepted: 08/06/2021] [Indexed: 02/07/2023] Open
Abstract
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM) and the leading cause of blindness in patients with DM. In the pathogenesis of DR, chronic hyperglycemia leads to biochemical and structural alterations in retinal blood vessels' wall, resulting in hyperpermeability and non-perfusion. Since vascular endothelial growth factor (VEGF) has been found to play a significant role in the pathogenesis of DR, this review sheds light on the effect of intravitreal anti-VEGF agents on retinal non-perfusion in patients with DR. Based on the existing literature, anti-VEGF agents have been shown to improve DR severity, although they cannot reverse retinal ischemia. The results of the published studies are controversial and differ based on the location of retinal non-perfusion, as well as the imaging modality used to assess retinal non-perfusion. In cases of macular non-perfusion, most of studies showed no change in both fundus fluorescein angiography (FFA) and optical coherence tomography (OCTA) in patients with DR treated with intravitreal anti-VEGF agents, while few studies reported worsening of non-perfusion with enlargement of foveal avascular zone (FAZ). Regarding peripheral ischemia, studies using wide-field-FFA demonstrated an improvement or stability in non-perfusion areas after anti-VEGF treatment. However, the use of wide-field-OCTA revealed no signs of re-perfusion of retinal vessels post anti-VEGF treatment. Further prospective studies with long follow-up and large sample size are still needed to draw solid conclusions.
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Affiliation(s)
- Irini Chatziralli
- grid.5216.00000 0001 2155 08002nd Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece
| | - Sara Touhami
- grid.462844.80000 0001 2308 1657Department of Ophthalmology, Reference Center in Rare diseases, DHU Sight Restore, Hôpital Pitié Salpêtrière, Sorbonne Université, Paris, France
| | - Maria Vittoria Cicinelli
- grid.15496.3f0000 0001 0439 0892School of Medicine, Vita-Salute San Raffaele University, Milan, Italy ,grid.18887.3e0000000417581884Department of Ophthalmology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Chrysa Agapitou
- grid.5216.00000 0001 2155 08002nd Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleni Dimitriou
- grid.5216.00000 0001 2155 08002nd Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece
| | - George Theodossiadis
- grid.5216.00000 0001 2155 08002nd Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Theodossiadis
- grid.5216.00000 0001 2155 08002nd Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece
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10
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Ebrahimi M, Balibegloo M, Rezaei N. Monoclonal antibodies in diabetic retinopathy. Expert Rev Clin Immunol 2022; 18:163-178. [PMID: 35105268 DOI: 10.1080/1744666x.2022.2037420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Diabetic retinopathy (DR), as one of the main complications of diabetes, is among the leading causes of blindness and visual impairment worldwide. AREAS COVERED Current clinical therapies include photocoagulation, vitrectomy, and anti-vascular endothelial growth factor (VEGF) therapies. Bevacizumab and ranibizumab are two monoclonal antibodies (mAbs) inhibiting angiogenesis. Intravitreal ranibizumab and bevacizumab can decrease the rate of blindness and retinal thickness, and improve visual acuity whether as monotherapy or combined with other treatments. They can increase the efficacy of other treatments and decrease their adverse events. Although administered intravitreally, they also might enter the circulation and cause systemic effects. This study is aimed to review our current knowledge about mAbs, bevacizumab and ranibizumab, in DR including superiorities, challenges, and limitations. Meanwhile, we tried to shed light on new ideas to overcome these limitations. Our latest search was done in April 2021 mainly through PubMed and Google Scholar. Relevant clinical studies were imported. EXPERT OPINION Future direction includes detection of more therapeutic targets considering other components of DR pathophysiology and shared pathogenesis of DR and neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, the treat-and-extend regimen, and new ways of drug delivery and other routes of ocular drug administration.
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Affiliation(s)
- Moein Ebrahimi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA),Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maryam Balibegloo
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA),Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA),Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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11
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Ikeda T, Nakamura K, Kida T, Oku H. Possible roles of anti-type II collagen antibody and innate immunity in the development and progression of diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2022; 260:387-403. [PMID: 34379187 PMCID: PMC8786754 DOI: 10.1007/s00417-021-05342-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 07/19/2021] [Accepted: 07/24/2021] [Indexed: 11/08/2022] Open
Abstract
The pathogenesis of both diabetic retinopathy (DR) and rheumatoid arthritis (RA) has recently been considered to involve autoimmunity. Serum and synovial fluid levels of anti-type II collagen antibodies increase early after the onset of RA, thus inducing immune responses and subsequent hydrarthrosis and angiogenesis, which resemble diabetic macular edema and proliferative DR (PDR), respectively. We previously reported that DR is also associated with increased serum levels of anti-type II collagen antibodies. Retinal hypoxia in DR may induce pericytes to express type II collagen, resulting in autoantibody production against type II collagen. As the result of blood-retinal barrier disruption, anti-type II collagen antibodies in the serum come into contact with type II collagen around the retinal vessels. A continued loss of pericytes and type II collagen around the retinal vessels may result in a shift of the immune reaction site from the retina to the vitreous. It has been reported that anti-inflammatory M2 macrophages increased in the vitreous of PDR patients, accompanied by the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of innate immunity. M2 macrophages promote angiogenesis and fibrosis, which might be exacerbated and prolonged by dysregulated innate immunity.
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Affiliation(s)
- Tsunehiko Ikeda
- Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Takatsuki City, Osaka, Japan.
- Department of Ophthalmology, Osaka Kaisei Hospital, 1-6-10 Miyahara Yodogawa-ku, Osaka City, Osaka, Japan.
| | | | - Teruyo Kida
- Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Takatsuki City, Osaka, Japan
| | - Hidehiro Oku
- Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Takatsuki City, Osaka, Japan
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12
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Szymanska M, Mahmood D, Yap TE, Cordeiro MF. Recent Advancements in the Medical Treatment of Diabetic Retinal Disease. Int J Mol Sci 2021; 22:ijms22179441. [PMID: 34502350 PMCID: PMC8430918 DOI: 10.3390/ijms22179441] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic retinal disease remains one of the most common complications of diabetes mellitus (DM) and a leading cause of preventable blindness. The mainstay of management involves glycemic control, intravitreal, and laser therapy. However, intravitreal therapy commonly requires frequent hospital visits and some patients fail to achieve a significant improvement in vision. Novel and long-acting therapies targeting a range of pathways are warranted, while evidence to support optimal combinations of treatments is currently insufficient. Improved understanding of the molecular pathways involved in pathogenesis is driving the development of therapeutic agents not only targeting visible microvascular disease and metabolic derangements, but also inflammation and accelerated retinal neurodegeneration. This review summarizes the current and emerging treatments of diabetic retinal diseases and provides an insight into the future of managing this important condition.
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Affiliation(s)
- Maja Szymanska
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Daanyaal Mahmood
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Timothy E. Yap
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Maria F. Cordeiro
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
- The Western Eye Hospital, Imperial College Healthcare NHS Trust (ICHNT), London NW1 5QH, UK
- Glaucoma and Retinal Neurodegeneration Group, Department of Visual Neuroscience, UCL Institute of Ophthalmology, London EC1V 9EL, UK
- Correspondence:
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13
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Lindner M, Arefnia B, Ivastinovic D, Sourij H, Lindner E, Wimmer G. Association of periodontitis and diabetic macular edema in various stages of diabetic retinopathy. Clin Oral Investig 2021; 26:505-512. [PMID: 34159405 PMCID: PMC8791870 DOI: 10.1007/s00784-021-04028-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 06/07/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Periodontitis and diabetes are known to have a bidirectional relationship. Diabetic macular edema is a complication of diabetes that is strongly influenced by inflammatory pathways. However, it remains to be established whether inflammation at other locations, such as periodontitis, affects diabetic macular edema. Here, we investigated the prevalence of periodontitis in patients treated for diabetic macular edema. MATERIALS AND METHODS Patients with diabetic macular edema were recruited for this cross-sectional study at the Medical University of Graz. Macular edema was documented by optical coherence tomography. Periodontal status was assessed by computerized periodontal probing and panoramic X-ray imaging. Bleeding on probing, clinical attachment level, probing pocket depth, and plaque index were compared between different stages of diabetic retinopathy. RESULTS Eighty-three eyes of 45 patients with diabetic macular edema were enrolled. Forty-four eyes (53.0%) had early stages of diabetic retinopathy (mild and moderate), and 39 eyes (47.0%) had late stages (severe and proliferative). Patients with mild or moderate DR were more likely to have more severe periodontal conditions than patients with severe or proliferative DR. Fourteen patients with mild DR (82.4%), 7 patients with moderate DR (87.5%), 4 patients with severe DR (100.0%), and 15 patients with proliferative DR (93.8%) had some degree of PD. The periodontal inflamed surface areas and the percentages of tooth sites that bled on probing were significantly higher in patients with early stages of diabetic retinopathy than in those with late stages of the disease (p < 0.05). Patients with periodontal inflamed surface areas of more than 500 mm2 required significantly more intravitreal injections in the last year than those with milder forms of periodontitis (n = 6.9 ± 3.1 versus n = 5.0 ± 3.5, p = 0.03). CONCLUSION In patients with diabetic macular edema, periodontitis is more prevalent in early stages of diabetic retinopathy. We suggest regular dental check-ups for diabetic patients, especially when diabetic macular edema is already present. CLINICAL RELEVANCE Patients with diabetic macular edema should be screened for periodontitis and vice versa, particularly early in the course of diabetes.
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Affiliation(s)
- Marlene Lindner
- Department of Dental Medicine and Oral Health, Medical University of Graz, Billrothgasse 4, 8010, Graz, Austria.
| | - Behrouz Arefnia
- Department of Dental Medicine and Oral Health, Medical University of Graz, Billrothgasse 4, 8010, Graz, Austria
| | - Domagoj Ivastinovic
- Department of Ophthalmology, Medical University of Graz, Auenbruggerplatz 4, 8036, Graz, Austria
| | - Harald Sourij
- Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Ewald Lindner
- Department of Ophthalmology, Medical University of Graz, Auenbruggerplatz 4, 8036, Graz, Austria
| | - Gernot Wimmer
- Department of Dental Medicine and Oral Health, Medical University of Graz, Billrothgasse 4, 8010, Graz, Austria
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14
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Takeda A, Yanai R, Murakami Y, Arima M, Sonoda KH. New Insights Into Immunological Therapy for Retinal Disorders. Front Immunol 2020; 11:1431. [PMID: 32719682 PMCID: PMC7348236 DOI: 10.3389/fimmu.2020.01431] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/03/2020] [Indexed: 12/24/2022] Open
Abstract
In the twentieth century, a conspicuous lack of effective treatment strategies existed for managing several retinal disorders, including age-related macular degeneration; diabetic retinopathy (DR); retinopathy of prematurity (ROP); retinitis pigmentosa (RP); uveitis, including Behçet's disease; and vitreoretinal lymphoma (VRL). However, in the first decade of this century, advances in biomedicine have provided new treatment strategies in the field of ophthalmology, particularly biologics that target vascular endothelial growth factor or tumor necrosis factor (TNF)-α. Furthermore, clinical trials on gene therapy specifically for patients with autosomal recessive or X-linked RP have commenced. The overall survival rates of patients with VRL have improved, owing to earlier diagnoses and better treatment strategies. However, some unresolved problems remain such as primary or secondary non-response to biologics or chemotherapy, and the lack of adequate strategies for treating most RP patients. In this review, we provide an overview of the immunological mechanisms of the eye under normal conditions and in several retinal disorders, including uveitis, DR, ROP, RP, and VRL. In addition, we discuss recent studies that describe the inflammatory responses that occur during the course of these retinal disorders to provide new insights into their diagnosis and treatment.
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Affiliation(s)
- Atsunobu Takeda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Ophthalmology, Clinical Research Institute, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | - Ryoji Yanai
- Department of Ophthalmology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Yusuke Murakami
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mitsuru Arima
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koh-Hei Sonoda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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15
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Specialized pro-resolving mediators in diabetes: novel therapeutic strategies. Clin Sci (Lond) 2019; 133:2121-2141. [DOI: 10.1042/cs20190067] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 10/07/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023]
Abstract
AbstractDiabetes mellitus (DM) is an important metabolic disorder characterized by persistent hyperglycemia resulting from inadequate production and secretion of insulin, impaired insulin action, or a combination of both. Genetic disorders and insulin receptor disorders, environmental factors, lifestyle choices and toxins are key factors that contribute to DM. While it is often referred to as a metabolic disorder, modern lifestyle choices and nutrient excess induce a state of systemic chronic inflammation that results in the increased production and secretion of inflammatory cytokines that contribute to DM. It is chronic hyperglycemia and the low-grade chronic-inflammation that underlies the development of microvascular and macrovascular complications leading to damage in a number of tissues and organs, including eyes, vasculature, heart, nerves, and kidneys. Improvements in the management of risk factors have been beneficial, including focus on intensified glycemic control, but most current approaches only slow disease progression. Even with recent studies employing SGLT2 inhibitors demonstrating protection against cardiovascular and kidney diseases, kidney function continues to decline in people with established diabetic kidney disease (DKD). Despite the many advances and a greatly improved understanding of the pathobiology of diabetes and its complications, there remains a major unmet need for more effective therapeutics to prevent and reverse the chronic complications of diabetes. More recently, there has been growing interest in the use of specialised pro-resolving mediators (SPMs) as an exciting therapeutic strategy to target diabetes and the chronic complications of diabetes.
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16
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Akhtar-Schäfer I, Wang L, Krohne TU, Xu H, Langmann T. Modulation of three key innate immune pathways for the most common retinal degenerative diseases. EMBO Mol Med 2019; 10:emmm.201708259. [PMID: 30224384 PMCID: PMC6180304 DOI: 10.15252/emmm.201708259] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
This review highlights the role of three key immune pathways in the pathophysiology of major retinal degenerative diseases including diabetic retinopathy, age‐related macular degeneration, and rare retinal dystrophies. We first discuss the mechanisms how loss of retinal homeostasis evokes an unbalanced retinal immune reaction involving responses of local microglia and recruited macrophages, activity of the alternative complement system, and inflammasome assembly in the retinal pigment epithelium. Presenting these key mechanisms as complementary targets, we specifically emphasize the concept of immunomodulation as potential treatment strategy to prevent or delay vision loss. Promising molecules are ligands for phagocyte receptors, specific inhibitors of complement activation products, and inflammasome inhibitors. We comprehensively summarize the scientific evidence for this strategy from preclinical animal models, human ocular tissue analyses, and clinical trials evolving in the last few years.
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Affiliation(s)
- Isha Akhtar-Schäfer
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - Luping Wang
- Department of Ophthalmology, University of Bonn, Bonn, Germany
| | - Tim U Krohne
- Department of Ophthalmology, University of Bonn, Bonn, Germany
| | - Heping Xu
- Centre for Experimental Medicine, The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, Belfast, UK
| | - Thomas Langmann
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany .,Center for Molecular Medicine, University of Cologne, Cologne, Germany
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17
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Semeraro F, Morescalchi F, Cancarini A, Russo A, Rezzola S, Costagliola C. Diabetic retinopathy, a vascular and inflammatory disease: Therapeutic implications. DIABETES & METABOLISM 2019; 45:517-527. [PMID: 31005756 DOI: 10.1016/j.diabet.2019.04.002] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 04/04/2019] [Accepted: 04/07/2019] [Indexed: 12/13/2022]
Abstract
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in the working-age population in the Western world. Diabetic macular oedema (DME) is one of the major complications of DR. Therapy with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs has become the gold standard treatment for DR and its complications. However, these drugs have no effect on the pathogenesis of DR and must be administered frequently via invasive intravitreal injections over many years. Thus, there is a pressing need to develop new therapeutic strategies to improve the treatment of this devastating disease. Indeed, an increasing volume of data supports the role of the inflammatory process in the pathogenesis of DR itself and its complications, including both increased retinal vascular permeability and neovascularization. Inflammation may also contribute to retinal neurodegeneration. Evidence that low-grade inflammation plays a critical role in the pathogenesis of DME has opened up new pathways and targets for the development of improved treatments. Anti-inflammatory compounds such as intravitreal glucocorticoids, topical non-steroidal anti-inflammatory drugs (NSAIDs), antioxidants, inflammatory molecule inhibitors, renin-angiotensin system (RAS) blockers and natural anti-inflammatory therapies may all be considered to reduce the rate of administration of antineovascularization agents in the treatment of DR. This report describes the current state of knowledge of the potential role of anti-inflammatory drugs in controlling the onset and evolution of DR and DME.
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Affiliation(s)
- F Semeraro
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
| | - F Morescalchi
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
| | - A Cancarini
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
| | - A Russo
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
| | - S Rezzola
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
| | - C Costagliola
- Department of Medicine and Health Sciences 'V. Tiberio', University of Molise, Via Francesco De Sanctis 1, 86100 Campobasso, Italy.
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18
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de Gaetano M, McEvoy C, Andrews D, Cacace A, Hunter J, Brennan E, Godson C. Specialized Pro-resolving Lipid Mediators: Modulation of Diabetes-Associated Cardio-, Reno-, and Retino-Vascular Complications. Front Pharmacol 2018; 9:1488. [PMID: 30618774 PMCID: PMC6305798 DOI: 10.3389/fphar.2018.01488] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 12/05/2018] [Indexed: 12/18/2022] Open
Abstract
Diabetes and its associated chronic complications present a healthcare challenge on a global scale. Despite improvements in the management of chronic complications of the micro-/macro-vasculature, their growing prevalence and incidence highlights the scale of the problem. It is currently estimated that diabetes affects 425 million people globally and it is anticipated that this figure will rise by 2025 to 700 million people. The vascular complications of diabetes including diabetes-associated atherosclerosis and kidney disease present a particular challenge. Diabetes is the leading cause of end stage renal disease, reflecting fibrosis leading to organ failure. Moreover, diabetes associated states of inflammation, neo-vascularization, apoptosis and hypercoagulability contribute to also exacerbate atherosclerosis, from the metabolic syndrome to advanced disease, plaque rupture and coronary thrombosis. Current therapeutic interventions focus on regulating blood glucose, glomerular and peripheral hypertension and can at best slow the progression of diabetes complications. Recently advanced knowledge of the pathogenesis underlying diabetes and associated complications revealed common mechanisms, including the inflammatory response, insulin resistance and hyperglycemia. The major role that inflammation plays in many chronic diseases has led to the development of new strategies aiming to promote the restoration of homeostasis through the "resolution of inflammation." These strategies aim to mimic the spontaneous activities of the 'specialized pro-resolving mediators' (SPMs), including endogenous molecules and their synthetic mimetics. This review aims to discuss the effect of SPMs [with particular attention to lipoxins (LXs) and resolvins (Rvs)] on inflammatory responses in a series of experimental models, as well as evidence from human studies, in the context of cardio- and reno-vascular diabetic complications, with a brief mention to diabetic retinopathy (DR). These data collectively support the hypothesis that endogenously generated SPMs or synthetic mimetics of their activities may represent lead molecules in a new discipline, namely the 'resolution pharmacology,' offering hope for new therapeutic strategies to prevent and treat, specifically, diabetes-associated atherosclerosis, nephropathy and retinopathy.
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Affiliation(s)
- Monica de Gaetano
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Caitriona McEvoy
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
- Renal Transplant Program, University Health Network, Toronto, ON, Canada
| | - Darrell Andrews
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Antonino Cacace
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Jonathan Hunter
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Eoin Brennan
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Catherine Godson
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
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19
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Rübsam A, Parikh S, Fort PE. Role of Inflammation in Diabetic Retinopathy. Int J Mol Sci 2018; 19:ijms19040942. [PMID: 29565290 PMCID: PMC5979417 DOI: 10.3390/ijms19040942] [Citation(s) in RCA: 504] [Impact Index Per Article: 72.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 03/09/2018] [Accepted: 03/17/2018] [Indexed: 02/07/2023] Open
Abstract
Diabetic retinopathy is a common complication of diabetes and remains the leading cause of blindness among the working-age population. For decades, diabetic retinopathy was considered only a microvascular complication, but the retinal microvasculature is intimately associated with and governed by neurons and glia, which are affected even prior to clinically detectable vascular lesions. While progress has been made to improve the vascular alterations, there is still no treatment to counteract the early neuro-glial perturbations in diabetic retinopathy. Diabetes is a complex metabolic disorder, characterized by chronic hyperglycemia along with dyslipidemia, hypoinsulinemia and hypertension. Increasing evidence points to inflammation as one key player in diabetes-associated retinal perturbations, however, the exact underlying molecular mechanisms are not yet fully understood. Interlinked molecular pathways, such as oxidative stress, formation of advanced glycation end-products and increased expression of vascular endothelial growth factor have received a lot of attention as they all contribute to the inflammatory response. In the current review, we focus on the involvement of inflammation in the pathophysiology of diabetic retinopathy with special emphasis on the functional relationships between glial cells and neurons. Finally, we summarize recent advances using novel targets to inhibit inflammation in diabetic retinopathy.
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Affiliation(s)
- Anne Rübsam
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
| | - Sonia Parikh
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
| | - Patrice E Fort
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, USA.
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20
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Current Advances in Pharmacotherapy and Technology for Diabetic Retinopathy: A Systematic Review. J Ophthalmol 2018; 2018:1694187. [PMID: 29576875 PMCID: PMC5822768 DOI: 10.1155/2018/1694187] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 10/12/2017] [Accepted: 11/07/2017] [Indexed: 01/01/2023] Open
Abstract
Diabetic retinopathy (DR) is classically defined by its vascular lesions and damage in the neurons of the retina. The cellular and clinical elements of DR have many features of chronic inflammation. Understanding the individual cell-specific inflammatory changes in the retina may lead to novel therapeutic approaches to prevent vision loss. The systematic use of available pharmacotherapy has been reported as a useful adjunct tool to laser photocoagulation, a gold standard therapy for DR. Direct injections or intravitreal anti-inflammatory and antiangiogenesis agents are widely used pharmacotherapy to effectively treat DR and diabetic macular edema (DME). However, their effectiveness is short term, and the delivery system is often associated with adverse effects, such as cataract and increased intraocular pressure. Further, systemic agents (particularly hypoglycemic, hypolipidemic, and antihypertensive agents) and plants-based drugs have also provided promising treatment in the progression of DR. Recently, advancements in pluripotent stem cells technology enable restoration of retinal functionalities after transplantation of these cells into animals with retinal degeneration. This review paper summarizes the developments in the current and potential pharmacotherapy and therapeutic technology of DR. Literature search was done on online databases, PubMed, Google Scholar, clinitrials.gov, and browsing through individual ophthalmology journals and leading pharmaceutical company websites.
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21
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Systemic factors related to soluble (pro)renin receptor in plasma of patients with proliferative diabetic retinopathy. PLoS One 2017; 12:e0189696. [PMID: 29240802 PMCID: PMC5730163 DOI: 10.1371/journal.pone.0189696] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 11/30/2017] [Indexed: 11/19/2022] Open
Abstract
(Pro)renin receptor [(P)RR], a new component of the tissue renin-angiotensin system (RAS), plays a crucial role in inflammation and angiogenesis in the eye, thus contributing to the development of proliferative diabetic retinopathy (PDR). In this study, we investigated systemic factors related to plasma levels of soluble form of (P)RR [s(P)RR] in patients with PDR. Twenty type II diabetic patients with PDR and 20 age-matched, non-diabetic patients with idiopathic macular diseases were enrolled, and plasma levels of various molecules were measured by enzyme-linked immunosorbent assays. Human retinal microvascular endothelial cells were stimulated with several diabetes-related conditions to evaluate changes in gene expression using real-time quantitative PCR. Of various systemic parameters examined, the PDR patients had significantly higher blood sugar and serum creatinine levels than non-diabetic controls. Protein levels of s(P)RR, prorenin, tumor necrosis factor (TNF)-α, complement factor D (CFD), and leucine-rich α-2-glycoprotein 1 (LRG1) significantly increased in the plasma of PDR subjects as compared to non-diabetes, with positive correlations detected between s(P)RR and these inflammatory molecules but not prorenin. Estimated glomerular filtration rate and serum creatinine were also correlated with plasma s(P)RR, but not prorenin, levels. Among the inflammatory molecules correlated with s(P)RR in the plasma, TNF-α, but not CFD or LRG1, application to retinal endothelial cells upregulated the mRNA expression of (P)RR but not prorenin, while stimulation with high glucose enhanced both (P)RR and prorenin expression. These findings suggested close relationships between plasma s(P)RR and diabetes-induced factors including chronic inflammation, renal dysfunction, and hyperglycemia in patients with PDR.
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22
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Coughlin BA, Feenstra DJ, Mohr S. Müller cells and diabetic retinopathy. Vision Res 2017; 139:93-100. [PMID: 28866025 PMCID: PMC5794018 DOI: 10.1016/j.visres.2017.03.013] [Citation(s) in RCA: 241] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 03/27/2017] [Accepted: 03/30/2017] [Indexed: 12/17/2022]
Abstract
Müller cells are one of the primary glial cell types found in the retina and play a significant role in maintaining retinal function and health. Since Müller cells are the only cell type to span the entire width of the retina and have contact to almost every cell type in the retina they are uniquely positioned to perform a wide variety of functions necessary to maintaining retinal homeostasis. In the healthy retina, Müller cells recycle neurotransmitters, prevent glutamate toxicity, redistribute ions by spatial buffering, participate in the retinoid cycle, and regulate nutrient supplies by multiple mechanisms. Any disturbance to the retinal environment is going to influence proper Müller cell function and well being which in turn will affect the entire retina. This is evident in a disease like diabetic retinopathy where Müller cells contribute to neuronal dysfunction, the production of pro-angiogenic factors leading to neovascularization, the set up of a chronic inflammatory retinal environment, and eventual cell death. In this review, we highlight the importance of Müller cells in maintaining a healthy and functioning retina and discuss various pathological events of diabetic retinopathy in which Müller cells seem to play a crucial role. The beneficial and detrimental effects of cytokine and growth factor production by Müller cells on the microvasculature and retinal neuronal tissue will be outlined. Understanding Müller cell functions within the retina and restoring such function in diabetic retinopathy should become a cornerstone for developing effective therapies to treat diabetic retinopathy.
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Affiliation(s)
- Brandon A Coughlin
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Derrick J Feenstra
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Susanne Mohr
- Department of Physiology, Michigan State University, East Lansing, MI, USA.
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Kocabora MS, Telli ME, Fazil K, Erdur SK, Ozsutcu M, Cekic O, Ozbilen KT. Serum and Aqueous Concentrations of Inflammatory Markers in Diabetic Macular Edema. Ocul Immunol Inflamm 2015; 24:549-54. [DOI: 10.3109/09273948.2015.1034804] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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24
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Zaidi FH, Ansari E. New treatments for diabetic macular edema. World J Ophthalmol 2015; 5:45-54. [DOI: 10.5318/wjo.v5.i2.45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Revised: 02/10/2015] [Accepted: 04/07/2015] [Indexed: 02/06/2023] Open
Abstract
This work comprehensively reviews the latest treatment options for diabetic macular edema (DME) used in its management and presents further work on the topic. Diabetic retinopathy is an important and increasingly prevalent cause of preventable blindness worldwide. To meet this increasing burden there has recently been a proliferation of pharmacological therapies being used in clinical practice. A variety of medical treatment options now exist for DME. These include non-steroidal anti-inflammatory drugs such as nepafenac, as well as intravitreal steroids like triamcinolone (kenalog). Long-term results up to 7 years after commencing treatment are presented for triamcinolone. Studies are reviewed on the use of dexamethasone (ozurdex) and fluocinolone (Retisert and Iluvien implants) including the FAME studies. A variety of anti-vascular endothelial growth factor (anti-VEGF) agents used in DME are considered in detail including ranibizumab (lucentis) and the RESTORE, RIDE, RISE and Diabetic Retinopathy Clinical Research Network (DRCR.net) studies. Bevacizumab (avastin) and pegaptinib (macugen) are also considered. The use of aflibercept (eylea) is reviewed including the significance of the DA VINCI, VISTA-DME, VIVID-DME and the DRCR.net studies which have recently suggested potentially greater efficacy when treating DME for aflibercept in patients with more severely reduced visual acuity at baseline. Evidence for the anti-VEGF agent bevasiranib is also considered. Studies of anti-tumour necrosis factor agents like infliximab are reviewed. So are studies of other agents targeting inflammation including minocycline, rapamycin (sirolimus) and protein kinase C inhibitors such as midostaurin and ruboxistaurin. The protein kinase C β inhibitor Diabetic Macular Edema Study is considered. Other agents which have been suggested for DME are discussed including cyclo-oxygenase-2 inhibitors like celecoxib, phospholipase A2 inhibitors, recombinant erythropoietin, and monoclonal anti-interleukin antibodies such as canakinumab. The management of DME in a variety of clinical scenarios is also discussed - in newly diagnosed DME, refractory DME including after macular laser, and postoperatively after intraocular surgery. Results of long-term intravitreal triamcinolone for DME administered up to seven years after commencing treatment are considered in the context of the niche roles available for such agents in modern management of DME. This is alongside more widely used treatments available to the practitioner such as anti-VEGF agents like aflibercept (Eylea) and ranibizumab (Lucentis) which at present are the mainstay of pharmacological treatment of DME.
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Abstract
This is a summary of current and emerging pharmacologic therapies utilized in the treatment of diabetic retinopathy (DR). Current therapies, such as ranibizumab, bevacizumab, triamcinolone acetonide, and fluocinolone acetonide, inhibit angiogenesis and inflammation and may be used alone or in combination with laser treatment. Emerging therapies aim to reduce oxidative stress or inhibit other signal transduction pathways, including the protein kinase C cascade and aldose reductase pathway. Future therapies may target other molecules crucial to the pathogenesis of DR, including hepatocyte growth factors and matrix metalloproteinase 9. Finally, the emergence of novel mechanisms of medication delivery may also be on the horizon.
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Affiliation(s)
- Vaidehi S. Dedania
- Department of Ophthalmology, Albany Medical Center, Lions Eye Institute, Albany, NY 12208, USA
| | - Sophie J. Bakri
- Department of Ophthalmology, Mayo Clinic, Rochester, MN 55905, USA
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Myśliwska J, Ryba-Stanisławowska M, Smardzewski M, Słomiński B, Myśliwiec M, Siebert J. Enhanced apoptosis of monocytes from complication-free juvenile-onset diabetes mellitus type 1 may be ameliorated by TNF-α inhibitors. Mediators Inflamm 2014; 2014:946209. [PMID: 25053869 PMCID: PMC4099355 DOI: 10.1155/2014/946209] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 04/28/2014] [Accepted: 05/01/2014] [Indexed: 01/17/2023] Open
Abstract
Diabetes mellitus type 1 is associated with an enhanced apoptosis of different cells and tissues, accelerating occurrence of diabetic microvascular complications. The aim of our study was to determine spontaneous apoptotic potential of the monocyte subsets in juvenile-onset complication-free diabetes mellitus type 1 and to compare them with the corresponding values of the healthy. Moreover, we wanted to assess effects of TNF-R1 blocking agents and those of general TNF-α blocker (Infliximab) on spontaneous apoptosis of monocytes. Sixty randomly selected DM1 patients (14.5 ± 3.2 years) and 30 healthy (13.5 ± 2.8 years) volunteers were enrolled in the study. Our results indicate that three monocyte subsets are distinguishable in the groups of young diabetic patients and the healthy, similarly to in the blood of adults. DM1 patients were characterized by higher values of apoptotic monocytes than the healthy. The manipulation with drugs inhibiting TNF-R1 expression diminished the pool of CD16(+) apoptotic monocytes. Infliximab reduced the apoptotic CD16(-) cells. In conclusion, diabetes mellitus type 1 is associated with greater apoptosis of three monocyte subsets which may contribute to the development of microvascular complications. TNF-α modifiers appear to ameliorate monocyte apoptosis. They may be useful for controlling excessive monocyte apoptosis in diabetic patients.
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Affiliation(s)
- Jolanta Myśliwska
- Department of Immunology, Medical University of Gdańsk, Ulica Dębinki 1, 80-211 Gdańsk, Poland
| | | | - Marcin Smardzewski
- Department of Immunology, Medical University of Gdańsk, Ulica Dębinki 1, 80-211 Gdańsk, Poland
| | - Bartosz Słomiński
- Department of Immunology, Medical University of Gdańsk, Ulica Dębinki 1, 80-211 Gdańsk, Poland
| | - Małgorzata Myśliwiec
- Academic Clinic of Pediatrics, Hematology, Oncology and Endocrinology, Medical University of Gdańsk, Ulica Dębinki 7, 80-211 Gdańsk, Poland
| | - Janusz Siebert
- Department of Family Medicine, Medical University of Gdańsk, Ulica Dębinki 2, 80-211 Gdańsk, Poland
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Reply. Correspondence to: Intravitreal tumor necrosis factor inhibitors in the treatment of refractory diabetic macular edema: a pilot study from the Pan-American Collaborative Retina Study Group. Retina 2013; 33:1287-90. [PMID: 23624521 DOI: 10.1097/iae.0b013e31828bcb2f] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Inflammation and pharmacological treatment in diabetic retinopathy. Mediators Inflamm 2013; 2013:213130. [PMID: 24288441 PMCID: PMC3830881 DOI: 10.1155/2013/213130] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 09/17/2013] [Indexed: 01/23/2023] Open
Abstract
Diabetic retinopathy (DR), the most common microvascular complication of diabetes mellitus, is estimated to be the leading cause of new blindness in the working population of developed countries. Primary interventions such as intensive glycemic control, strict blood pressure regulation, and lipid-modifying therapy as well as local ocular treatment (laser photocoagulation and pars plana vitrectomy) can significantly reduce the risk of retinopathy occurrence and progression. Considering the limitations of current DR treatments development of new therapeutic strategies, it becomes necessary to focus on pharmacological treatment. Currently, there is increasing evidence that inflammatory processes have a considerable role in the pathogenesis of DR with multiple studies showing an association of various systemic as well as local (vitreous and aqueous fluid) inflammatory factors and the progression of DR. Since inflammation is identified as a relevant mechanism, significant effort has been directed to the development of new concepts for the prevention and treatment of DR acting on the inflammatory processes and the use of pharmacological agents with anti-inflammatory effect. Inhibiting the inflammatory pathway could be an appealing treatment option for DR in future practices, and as further prospective randomized clinical trials accumulate data, the role and guidelines of anti-inflammatory pharmacologic treatments will become clearer.
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Sun C, Li XX, He XJ, Zhang Q, Tao Y. Neuroprotective effect of minocycline in a rat model of branch retinal vein occlusion. Exp Eye Res 2013; 113:105-16. [PMID: 23748101 DOI: 10.1016/j.exer.2013.05.018] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Revised: 05/01/2013] [Accepted: 05/21/2013] [Indexed: 01/06/2023]
Affiliation(s)
- Chuan Sun
- Department of Ophthalmology, People's Hospital, Peking University, Beijing, China
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30
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Klaassen I, Van Noorden CJF, Schlingemann RO. Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions. Prog Retin Eye Res 2013; 34:19-48. [PMID: 23416119 DOI: 10.1016/j.preteyeres.2013.02.001] [Citation(s) in RCA: 502] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Revised: 12/19/2012] [Accepted: 02/01/2013] [Indexed: 12/16/2022]
Abstract
Breakdown of the inner endothelial blood-retinal barrier (BRB), as occurs in diabetic retinopathy, age-related macular degeneration, retinal vein occlusions, uveitis and other chronic retinal diseases, results in vasogenic edema and neural tissue damage, causing loss of vision. The central mechanism of altered BRB function is a change in the permeability characteristics of retinal endothelial cells caused by elevated levels of growth factors, cytokines, advanced glycation end products, inflammation, hyperglycemia and loss of pericytes. Subsequently, paracellular but also transcellular transport across the retinal vascular wall increases via opening of endothelial intercellular junctions and qualitative and quantitative changes in endothelial caveolar transcellular transport, respectively. Functional changes in pericytes and astrocytes, as well as structural changes in the composition of the endothelial glycocalyx and the basal lamina around BRB endothelium further facilitate BRB leakage. As Starling's rules apply, active transcellular transport of plasma proteins by the BRB endothelial cells causing increased interstitial osmotic pressure is probably the main factor in the formation of macular edema. The understanding of the complex cellular and molecular processes involved in BRB leakage has grown rapidly in recent years. Although appropriate animal models for human conditions like diabetic macular edema are lacking, these insights have provided tools for rational design of drugs aimed at restoring the BRB as well as for design of effective transport of drugs across the BRB, to treat the chronic retinal diseases such as diabetic macular edema that affect the quality-of-life of millions of patients.
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Affiliation(s)
- Ingeborg Klaassen
- Ocular Angiogenesis Group, Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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31
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Arevalo JF, Serrano MA, Wu L. Combined inhibition of tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF) for the treatment of macular edema of various etiologies: a short-term pilot study. Eye (Lond) 2013; 27:569-71. [PMID: 23328798 DOI: 10.1038/eye.2012.301] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
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33
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Andriankaja OM, Galicia J, Dong G, Xiao W, Alawi F, Graves DT. Gene expression dynamics during diabetic periodontitis. J Dent Res 2012; 91:1160-5. [PMID: 23103632 DOI: 10.1177/0022034512465292] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Diabetes impairs the resolution of periodontal inflammation. We explored pathways altered by inflammation in the diabetic periodontium by using ligatures to induce periodontitis in type-2 diabetic Goto-Kakizaki rats. Ligatures were removed after 7 days, and rats were then treated with TNF inhibitor (pegsunercept) or vehicle alone and euthanized 4 days later. RNA was extracted from periodontal tissue, examined by mRNA profiling, and further analyzed by functional criteria. We found that 1,754 genes were significantly up-regulated and 1,243 were down-regulated by pegsunercept (p < 0.05). Functional analysis revealed up-regulation of neuron-associated and retina-associated gene clusters as well as those related to cell activity and signaling. Others were down-regulated by TNF inhibition and included genes associated with host defense, apoptosis, cell signaling and activity, and coagulation/hemostasis/complement. For selected genes, findings with microarray and rt-PCR agreed. PPAR-α was investigated further by immunohistochemistry due to its anti-inflammatory function and was found to be up-regulated in the gingiva during the resolution of periodontal inflammation and suppressed by diabetes. The results indicate that diabetes-enhanced inflammation both up- and down-regulates genes involved in cellular activity and cell signaling, while it predominantly up-regulates genes involved in the host response, apoptosis, and coagulation/homeostasis/complement and down-regulates mRNA levels of neuron, retina, and energy/metabolism-associated genes.
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Affiliation(s)
- O M Andriankaja
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
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34
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Das UN. Lipoxins, resolvins, and protectins in the prevention and treatment of diabetic macular edema and retinopathy. Nutrition 2012; 29:1-7. [PMID: 22677359 DOI: 10.1016/j.nut.2012.02.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2011] [Revised: 01/17/2012] [Accepted: 02/10/2012] [Indexed: 10/28/2022]
Abstract
Diabetic macular edema and retinopathy are low-grade inflammatory conditions. Infusions of antitumor necrosis factor-α (anti-TNF-α) antibody and antivascular endothelial growth factor (anti-VEGF) antibody have been shown to be at least partly effective in the treatment of diabetic macular edema and proliferative diabetic retinopathy. Intravitreal therapy of diabetic macular edema by the anti-TNF-α antibody has been found to produce significant side effects and anti-VEGF therapy to be ineffective. Nevertheless, these studies have indicated that the suppression of TNF-α and other proinflammatory cytokines and VEGF could be of benefit in diabetic macular edema and retinopathy. The retina is rich in polyunsaturated fatty acids, especially in ω-3, and several studies have shown that polyunsaturated fatty acids prevent diabetic retinopathy. Lipoxins, resolvins, and protectins derived from various polyunsaturated fatty acids possess anti-inflammatory actions and suppress the production of interleukin-6, and TNF-α and VEGF have antiangiogenic actions. In view of these evidences, I propose that lipoxins, resolvins, and protectins could be of significant benefit in the prevention and management of diabetic macular edema and retinopathy.
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Affiliation(s)
- Undurti N Das
- School of Biotechnology, Jawaharlal Nehru Technological University, Kakinada, India.
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35
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Costa GN, Vindeirinho J, Cavadas C, Ambrósio AF, Santos PF. Contribution of TNF receptor 1 to retinal neural cell death induced by elevated glucose. Mol Cell Neurosci 2012; 50:113-23. [PMID: 22522145 DOI: 10.1016/j.mcn.2012.04.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Revised: 03/16/2012] [Accepted: 04/02/2012] [Indexed: 12/31/2022] Open
Abstract
Diabetic retinopathy (DR), a leading cause of vision loss and blindness among working-age adults, holds several hallmarks of an inflammatory disease. The increase in cell death in neural retina is an early event in the diabetic retina, preceding the loss of microvascular cells. Since tumor necrosis factor-α (TNF-α) has been shown to trigger the death of perycites and endothelial cells as well as the breakdown of the blood-retinal barrier, we set out to investigate whether TNF-α acting through tumor necrosis factor receptor 1 (TNFR1), the major receptor responsible for mediating TNF-induced cell death, could also be responsible for the early neuronal cell death observed in DR. We used retinal neural cell cultures exposed to high glucose conditions, to mimic hyperglycaemia, and evaluated the contribution of TNFR1 in neural cell death. TNFR1 was found to be present to a great extent in retinal neurons and the levels of this receptor were found to be altered in cells cultured in high glucose conditions. High glucose induced an early decrease in cell viability, an increase in apoptosis and a higher immunoreactivity for the cleaved caspase-3, indicating a high glucose-induced caspase-dependent cell death. These observations were correlated with an increase in TNF-α expression. Nonetheless, inhibiting the activation of TNFR1 was sufficient to prevent the decrease in cell viability and the increase in retinal cell death by apoptosis. In conclusion, our data indicate that TNF-α acting through TNFR1 is responsible for the high glucose-induced cell death and that blocking the activity of this receptor is an adequate strategy to avoid cell loss in such conditions.
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Affiliation(s)
- G N Costa
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
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36
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Myśliwska J, Smardzewski M, Marek-Trzonkowska N, Myśliwiec M, Raczyńska K. Expansion of CD14+CD16+ monocytes producing TNF-α in complication-free diabetes type 1 juvenile onset patients. Cytokine 2012; 60:309-17. [PMID: 22484242 DOI: 10.1016/j.cyto.2012.03.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2011] [Revised: 02/14/2012] [Accepted: 03/08/2012] [Indexed: 12/20/2022]
Abstract
We concentrated on the complication-free phase of juvenile onset type 1 diabetes mellitus (T1DM) searching for associations between concentration of inflammatory factors TNF-α, CRP and VEGF and two monocyte subsets the CD14(++)CD16(-) and CD14(+)CD16(+). We analysed a randomly selected group of 150 patients without complications (disease duration 2.74 ± 2.51 years) at the start of the project and 5 years later. They were compared with 24 patients with retinopathy (6.53 ± 3.39 years of disease) and 30 healthy volunteers. Our results indicate that in the complication-free period the concentration of TNF-α significantly increased and continued to increase after retinopathy was established. After 5 years the percentage and absolute number of CD14(+)CD16(+) monocytes doubled in complication-free patients. Our study indicates that the size of CD14(+)CD16(+) monocyte subset may be used alternatively to CRP values as an indicator of inflammation grade. Our results imply the necessity of trials using anti-TNF-α therapy in the complication-free phase of the disease.
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Affiliation(s)
- Jolanta Myśliwska
- Department of Immunology, Medical University of Gdańsk, Gdańs, Poland.
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Emerging pharmacotherapies for diabetic macular edema. EXPERIMENTAL DIABETES RESEARCH 2012; 2012:548732. [PMID: 22474425 PMCID: PMC3299388 DOI: 10.1155/2012/548732] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2011] [Revised: 10/27/2011] [Accepted: 10/27/2011] [Indexed: 12/20/2022]
Abstract
Diabetic macular edema (DME) remains an important cause of visual loss in patients with diabetes mellitus. Although photocoagulation and intensive control of systemic metabolic factors have been reported to achieve improved outcomes in large randomized clinical trials (RCTs), some patients with DME continue to lose vision despite treatment. Pharmacotherapies for DME include locally and systemically administered agents. We review several agents that have been studied for the treatment of DME.
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38
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Zhang W, Liu H, Al-Shabrawey M, Caldwell RW, Caldwell RB. Inflammation and diabetic retinal microvascular complications. J Cardiovasc Dis Res 2011; 2:96-103. [PMID: 21814413 PMCID: PMC3144626 DOI: 10.4103/0975-3583.83035] [Citation(s) in RCA: 132] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Diabetic retinopathy (DR) is one of the most common complications of diabetes and is a leading cause of blindness in people of the working age in Western countries. A major pathology of DR is microvascular complications such as non-perfused vessels, microaneurysms, dot/blot hemorrhages, cotton-wool spots, venous beading, vascular loops, vascular leakage and neovascularization. Multiple mechanisms are involved in these alternations. This review will focus on the role of inflammation in diabetic retinal microvascular complications and discuss the potential therapies by targeting inflammation.
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Affiliation(s)
- Wenbo Zhang
- Vascular Biology Center, Georgia Health Sciences University, Augusta, Georgia, USA
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39
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Zhang W, Liu H, Rojas M, Caldwell RW, Caldwell RB. Anti-inflammatory therapy for diabetic retinopathy. Immunotherapy 2011; 3:609-28. [PMID: 21554091 DOI: 10.2217/imt.11.24] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Diabetic retinopathy (DR) is one of the most common complications of diabetes. This devastating disease is a leading cause of blindness in people of working age in industrialized countries and affects the daily lives of millions of people. Despite tight glycemic control, blood pressure control and lipid-lowering therapy, the number of DR patients keeps growing and therapeutic approaches are limited. Moreover, there are significant limitations and side effects associated with the current therapies. Thus, there is a great need for development of new strategies for prevention and treatment of DR. Studies have shown that DR has prominent features of chronic, subclinical inflammation. This article focuses on the role of inflammation in DR and summarizes the progress of studies of anti-inflammatory strategies for DR.
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Affiliation(s)
- Wenbo Zhang
- Vascular Biology Center, Georgia Health Sciences University, Augusta, GA 30912-2500, USA.
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40
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intravitreal tumor necrosis factor inhibitors in the treatment of refractory diabetic macular edema: a pilot study from the Pan-American Collaborative Retina Study Group. Retina 2011; 31:298-303. [PMID: 21099452 DOI: 10.1097/iae.0b013e3181eac7a6] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE The purpose of this study was to report the short-term visual and anatomical outcomes after intravitreal injections of two different tumor necrosis factor α inhibitors in eyes with refractory diabetic macular edema. METHODS An interventional, retrospective, multicenter study of 39 eyes with refractory diabetic macular edema that were injected with adalimumab (n = 5 for 2 mg) or infliximab (n = 15 for 1 mg; n = 19 for 2 mg). The main outcome measures were the best-corrected visual acuity and the central macular thickness at 3 months of follow-up. RESULTS In the 1-mg infliximab group, the logarithm of the minimal angle of resolution best-corrected visual acuity improved from 1.49 ± 0.58 at baseline to 1.38 ± 0.56 at 3 months (P = 0.6991). In the 2-mg infliximab group, the logarithm of the minimal angle of resolution best-corrected visual acuity worsened from 0.76 ± 0.54 to 1.03 ± 0.69 at 3 months (P = 0.5995). In the adalimumab group, the logarithm of the minimal angle of resolution best-corrected visual acuity improved from 1.44 ± 0.77 to 1.08 ± 0.85 at 3 months (P = 0.2500). The central macular thickness in the 1-mg infliximab group decreased from 459 ± 125 μm at baseline to 388 ± 131 μm at 3 months (P = 0.1178). In the 2-mg infliximab group, the central macular thickness remained unchanged from 378 ± 97 μm at baseline to 349 ± 118 μm at 3 months (P = 0.2162). In the adalimumab group, the central macular thickness remained unchanged from 521 ± 163 μm at baseline to 526 ± 390 μm at 3 months (P = 0.1250). There were no systemic side effects reported in any of the patients. However, laboratory markers for autoimmunity were not done. None of the eyes injected with either adalimumab or 1 mg of infliximab had adverse ocular events. In the 2-mg infliximab group, 42% (8 of 19) of eyes developed severe uveitis. Three of these eyes (37.5%) required pars plana vitrectomy. The uveitis in the remaining five eyes resolved with topical steroid therapy. CONCLUSION Both intravitreal adalimumab and infliximab do not appear to benefit eyes with refractory diabetic macular edema. Intravitreal injections of infliximab may elicit a severe intraocular inflammatory reaction.
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41
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Karampetsou MP, Liossis SNC, Sfikakis PP. TNF-α antagonists beyond approved indications: stories of success and prospects for the future. QJM 2010; 103:917-28. [PMID: 20802008 DOI: 10.1093/qjmed/hcq152] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Tumour necrosis factor alpha (TNF-α) is a key molecule of the inflammatory response and data derived from studies in experimental animal models and humans suggest that TNF-α may be implicated in the pathogenesis of various autoimmune and non-infectious inflammatory conditions. Over the past decade pharmaceutical agents directed against TNF-α (infliximab, adalimumab and etanercept) have been widely and successfully employed for the management of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis, psoriatic arthritis, juvenile idiopathic arthritis and inflammatory bowel disease, whereas two novel anti-TNF-α agents, golimumab and certolimumab pegol, recently entered the market for the treatment of RA, AS, Crohn's disease and psoriasis. Encouraged by the positive results obtained from the use of TNF-α antagonists in terms of efficacy and safety and due to the increasingly accumulating evidence regarding the implication of TNF-α in the pathogenesis of numerous disorders, anti-TNF-α agents have been considered for the management of diseases other than the ones they were initially approved for. Although in the case of multiple sclerosis and chronic heart failure the outcome from the administration of TNF-α blockers had been less than favourable, in other cases of non-infectious inflammatory conditions the response to TNF-α inhibition had been fairly beneficial. More specifically, according to well-documented clinical trials, anti-TNF-α agents exhibited favourable results in Behçet's disease, non-infectious ocular inflammation, pyoderma gangrenosum and hidradenitis suppurativa. In this review we discuss the successful outcomes as well as the prospects for the future from the off-label use of TNF-α antagonists.
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Affiliation(s)
- M P Karampetsou
- Department of Medicine, University of Patras, 26504, Patras, Greece
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42
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Affiliation(s)
- Francesco Boscia
- Department of Ophthalmology and Otolaryngology, University of Bari, Bari, Italy.
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Jo DH, Kim JH, Kim JH. How to overcome retinal neuropathy: the fight against angiogenesis-related blindness. Arch Pharm Res 2010; 33:1557-65. [PMID: 21052933 DOI: 10.1007/s12272-010-1007-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Revised: 08/23/2010] [Accepted: 08/24/2010] [Indexed: 12/22/2022]
Abstract
The retina consists of neuronal cells of high metabolic activity that are supplied by an abundant vasculature. It is a main theme of ophthalmologic research, because retinopathies are common causes of blindness in all age groups: age-related macular degeneration in the elderly, diabetic retinopathy in the middle aged, and retinopathy of prematurity and retinoblastoma in children. Interestingly, angiogenesis underlies the pathogenesis of all these diseases, and breakdown of the blood-retinal barrier is also thought to play an important role before and throughout the process of new vessel formation. However, so far, most treatments have targeted angiogenesis only, especially vascular endothelial growth factor. Consideration of the restoration of the blood-retinal barrier should be required. In this review, we discuss the clinical manifestation, pathogenesis, and current treatment options for angiogenesis-related blindness. In addition, because of the recent introduction of novel strategies, we describe pathogenesis-based treatment options to treat angiogenesis-related blindness.
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Affiliation(s)
- Dong Hyun Jo
- Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, Korea
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44
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Kachi S, Kobayashi K, Ushida H, Ito Y, Kondo M, Terasaki H. Regression of macular edema secondary to branch retinal vein occlusion during anti-TNF-alpha therapy for rheumatoid arthritis. Clin Ophthalmol 2010; 4:667-70. [PMID: 20689780 PMCID: PMC2915850 DOI: 10.2147/opth.s10532] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2010] [Indexed: 11/26/2022] Open
Abstract
A patient with macular edema secondary to a branch retinal vein occlusion (BRVO) was treated with intravenous injections of infliximab, an antitumor necrosis factor (TNF)-α antibody, for her rheumatoid arthritis (RA). Before the injection, the thickness of the right fovea, determined by optical coherent tomography, was 629 μm and the best-corrected visual acuity (BCVA) was 20/50. After eight injections of infliximab and 10 months after the first injection, her foveal thickness was decreased to 293 μm and the visual acuity improved to 20/20. There was no recurrence of macular edema during the infliximab injections. However, the infliximab injection was stopped because the patient developed pneumonia. Eight months after stopping the infliximab injection, her foveal thickness increased to 494 μm. To treat the RA, her orthopedists began weekly subcutaneous injections of etanercept, a fusion protein of a section of the TNF receptor and immunoglobulin. Five months later, the foveal thickness had decreased to 260 μm, and the visual acuity remained at 20/25+. Because TNF-α is known to break down the blood–retinal barrier, the improvements in our case suggest that TNF-α plays a role in the pathogenesis of macular edema in some patients with BRVO.
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Affiliation(s)
- Shu Kachi
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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45
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Sfikakis PP, Grigoropoulos V, Emfietzoglou I, Theodossiadis G, Tentolouris N, Delicha E, Katsiari C, Alexiadou K, Hatziagelaki E, Theodossiadis PG. Infliximab for diabetic macular edema refractory to laser photocoagulation: a randomized, double-blind, placebo-controlled, crossover, 32-week study. Diabetes Care 2010; 33:1523-8. [PMID: 20413522 PMCID: PMC2890353 DOI: 10.2337/dc09-2372] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Because many patients with diabetic macular edema (DME) do not respond to focal/grid laser photocoagulation, the only currently approved treatment, alternatives are needed. Based on encouraging preliminary findings, we aimed to assess efficacy and safety of the anti-tumor necrosis factor (TNF) monoclonal antibody infliximab in this condition. RESEARCH DESIGN AND METHODS This was a single-center, double-blind, randomized, placebo-controlled, crossover study. Eleven patients with sight-threatening DME persisting after two sessions of laser photocoagulation received infliximab (5 mg/kg) intravenously at weeks 0, 2, 6, and 14, followed by placebo at weeks 16, 18, 22, and 30, or vice versa. Blinding was maintained to week 32, when the final assessments were performed. Best corrected visual acuity evaluated by a mixed-models approach for imbalanced crossover design using the percentage difference as the outcome variable was the primary study end point. Data were analyzed on an intention-to-treat basis. RESULTS Early Treatment of Diabetic Retinopathy Study (ETDRS) scores dropped from 31.6 +/- 5.1 (mean +/- SD) letters read at baseline to 28.8 +/- 11.6 letters read at week 16 in six placebo-treated eyes and improved to 35.4 +/- 11.2 letters read after infliximab. In contrast, visual acuity improved from 23.5 +/- 10.3 at baseline to 30.4 +/- 13.4 letters read at week 16 in eight infliximab-treated eyes and was sustained at completion of placebo treatment (31.4 +/- 12.1 letters read). The excess visual acuity in infliximab-treated eyes was greater by 24.3% compared with that in placebo-treated eyes (95% CI 4.8-43.7; P = 0.017). Infliximab treatment was well tolerated. CONCLUSIONS The positive results of this small phase III study suggest that larger and longer term trials should be conducted to assess the efficacy of systemic or intravitreal anti-TNF agent administration for primary treatment of DME.
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Affiliation(s)
- Petros P Sfikakis
- First Department of Propaedeutic and Internal Medicine, Laiko General Hospital, Athens, Greece.
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More questions than answers: a call for a moratorium on the use of intravitreal infliximab outside of a well-designed trial. Retina 2010; 30:1-5. [PMID: 20061905 DOI: 10.1097/iae.0b013e3181cde727] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Abstract
PURPOSE The purpose of this study was to investigate the stability of reconstituted infliximab solutions and determine whether infliximab is suitable for compounding for potential intravitreal use. METHODS Infliximab was reconstituted, and the solution was aliquoted and stored refrigerated. On each day of testing, an aliquot was serially diluted to concentrations ranging from 50,000 pg/mL to 69 pg/mL. Each dilution was assayed by microsphere immunoassay daily for 5 days and weekly for a total of 6 weeks. The outcome measure was median fluorescence intensity measured by dual laser flow analysis of fluorochrome-labeled secondary antibodies to infliximab bound to tumor necrosis factor-alpha-coated microspheres. RESULTS There was an increasing median fluorescence intensity for increasing infliximab concentration in a sigmoidal dose-response curve with a variable slope that was equivalent for each time point. Each respective concentration of infliximab showed nearly equivalent median fluorescence intensity for every time point over the 6-week period. CONCLUSION The authors found that the immunoreactivity of 2 different concentrations of infliximab stored at 4 degrees C over a 6-week period remained stable. Infliximab is suitable for compounding and could be a cost-effective intravitreal medication for use in clinical practice if further study supports its safety and efficacy.
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Abstract
BACKGROUND Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) continue to cause significant visual loss among patients with diabetes mellitus. In some patients unresponsive to standard laser techniques, as well as improved control of blood pressure and blood sugar, pharmacologic treatment may be beneficial. Although no agent is now approved by the FDA for this purpose, many agents are now being studied in randomized clinical trials (RCTs). OBJECTIVE To review concisely the chief pharmacotherapies for diabetic retinopathy available at present. METHODS Literature review and synopsis. RESULTS Used alone, intravitreal triamcinolone acetonide (IVTA) seems to have some short-term efficacy against DME, but longer-term outcomes (< or = 3 years) using IVTA monotherapy showed a lesser benefit than focal/grid laser treatment in a prospective RCT done by the Diabetic Retinopathy Clinical Research Network. Intravitreal anti-VEGF agents have demonstrated some short-term efficacy against DME, and continuing RCTs will evaluate combination therapies (anti-VEGF and laser) for both DME and PDR. Other agents are being evaluated in pilot studies and Phase II RCTs. CONCLUSION Pharmacotherapies for DME and PDR have potential for vision stabilization or improvement. Continuing RCTs will provide evidence-based data on their role in clinical practice. A potential role for pharmacotherapy in the prevention of DME and PDR is also emerging.
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Affiliation(s)
- Stephen G Schwartz
- University of Miami Miller School of Medicine, Bascom Palmer Eye Institute, 311 9th Street North, #100, Naples, FL 34102, USA.
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