Anti-Inflammatory Therapy in Diabetic RetinopathyView this Special Issue
Review Article | Open Access
Katarzyna Zorena, Dorota Raczyńska, Krystyna Raczyńska, "Biomarkers in Diabetic Retinopathy and the Therapeutic Implications", Mediators of Inflammation, vol. 2013, Article ID 193604, 11 pages, 2013. https://doi.org/10.1155/2013/193604
Biomarkers in Diabetic Retinopathy and the Therapeutic Implications
The main problem both in type 1 (T1DM) and type 2 (T2DM) diabetes is the development of chronic vascular complications encompassing micro- as well as macrocirculation. Chronic complications lower the quality of life, lead to disability, and are the cause of premature death in DM patients. One of the chronic vascular complications is a diabetic retinopathy (DR) which leads to a complete loss of sight in DM patients. Recent trials show that the primary cause of diabetic retinopathy is retinal neovascularization caused by disequilibrium between pro- and antiangiogenic factors. Gaining knowledge of the mechanisms of action of factors influencing retinal neovascularization as well as the search for new, effective treatment methods, especially in advanced stages of DR, puts special importance on research concentrating on the implementation of biological drugs in DR therapy. At present, it is antivascular endothelial growth factor and antitumor necrosis factor that gain particular significance.
Dynamic increase in morbidity both for type 1 (T1DM) and type 2 (T2DM) diabetes has reached the state of an epidemic in developed countries and in the developing ones; the incidence of diabetes is increasing at still a quicker pace [1–3]. At present, 284.6 million people are sick with diabetes. According to statistics, in 2030, this number will increase to 438 million, that is, 6.4% of the global population . The main problem both in type 1 (T1DM) and type 2 (T2DM) diabetes is the development of chronic vascular complications encompassing micro- as well as macrocirculation [4–7]. Chronic complications lower the quality of life and lead to disability. Moreover, they shorten life expectancy on average by 16 to 20 years in T1DM patients and by 4 to 6 years in those with type 2 diabetes [8–10]. It is also worth mentioning that the worldwide costs of treating diabetes and its complications are on average 5 to 10% of the overall funds for health service [11–13]. Diabetic retinopathy (DR) is the most common cause of vision loss, and a large number of diabetic patients experience significant vision impairment [10, 14, 15]. Within the first 10 years of living with diabetes, retinopathy can be diagnosed in nearly all T1DM patients and in over 60% of those with T2DM. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), 3.6% of patients with T1DM diagnosed at a younger age and 1.6% of those in whom T2DM developed in a later stage of life were considered blind . Moreover, in the group of T1DM patients, diabetic retinopathy was diagnosed as the cause of blindness in 86% of cases, while in T2DM group of patients, in whom the disease started at an older age and who often suffered from other diseases affecting sight, diabetic retinopathy caused loss of sight in 1/3 of cases .
Pathogenesis of DR is complex, and despite a lot of research, it has not been completely elucidated. The disease process encompasses characteristic changes, namely, thickening of the basement membrane coupled with its increased permeability, loss of pericytes leading to diminished vessel wall tone and development of protruding micro aneurysms, and proliferation of mesangium causing obstruction and obliteration of capillaries. Now, we know that diabetic retinopathy is the effect of genetic, environmental, and immunological factors acting together [16–18]. The main initiating factor for the changes observed in the course of diabetic retinopathy is hyperglycemia. Its metabolic consequences stem from toxic effects of chronically heightened glucose levels in the blood. Numerous trials have demonstrated that chronic, nonphysiologically high blood glucose concentration in diabetic patients causes pericyte damage in the retina, as these cells are the ones most quickly reacting to the glucose overflow. The damaging effect within parietal cells is done by the activation of several metabolic pathways. One of the most important biochemical reactions, which plays an important part in the development of vascular complications in the course of diabetes, is the nonenzymatic glycation of proteins. Its effects are advanced glycation end products (AGEs) [19, 20]. AGEs are permanent, non-reversible products with an ability to produce cross-links between proteins [19–21]. Animal experiments in vitro and in vivo have proven the relationship between AGE concentration and the presence of symptoms characteristic for diabetic retinopathy. The researchers have put particular attention to the enhancement of apoptosis of cells building retinal vessels walls, the formation of cellular capillaries in the retina, and the retinal neovascularization [22, 23]. It is worth noting that the application of AGE inhibitors prevented abnormal pathogenesis [24, 25]. Despite many trials, the mechanisms of enhanced retinal pericytes apoptosis remain unclear. However, numerous pieces of research suggest that such enhanced apoptosis stems from the accumulation of AGE in pericytes. AGEs exert toxic proprieties and may change cellular enzymes’ activity. AGEs accumulating in the basal membranes of the retina modify vascular basal membranes by creating cross-links. As a consequence, pathological changes develop in the retinal vessels [16, 26–28].
Up till now, both our research and the work of other authors show significantly higher AGEs level both in the serum of children with T1DM and late vascular complications [29, 30] and in adults patients with diabetes and PDR [31, 32]. Moreover, in our last research, by applying ROC curve for AGEs, we have determined the reference level for 19.867 pg/mL in the examined group of children and adolescents with T1DM . The end products of advanced glycation influence the cells of many tissues by specific receptors localized on macrophages and endothelial cells which take part in the metabolic turnover of proteins, tissue remodeling, and inflammatory process [23, 24]. The best known receptor linking the advanced glycation end products is the receptor for advanced glycosylation end products (sRAGE). AGE interaction with sRAGE on the surface of monocytes, macrophages, and endothelial cells increases the synthesis and secretion of pro-inflammatory cytokines, such as interleukin 1 (IL1), tumor necrosis factor α (TNF-α) and vascular endothelial growth factor (VEGF), adhesive molecules, and the activation of a nuclear transcription factor NFκB [33–36]. This process encompasses characteristic changes, namely, thickening of the basement membrane coupled with its increased permeability, loss of pericytes leading to diminished vessel wall tone, and development of protruding micro aneurysms, as well as proliferation of mesangium causing obstruction and obliteration of capillaries [16, 21, 23], Figure 1.
Research on the drug which would protect amino groups of proteins exposed to glycation in the first step or prevent the cross-links formation in the third step of the reaction is still ongoing. Drugs preventing the formation of AGE complexes probably block the carbonyl groups of Amadori rearrangement products. This prevents the formation of cross-links with other proteins by binding with their amino groups. Aspirin also exhibits some protecting properties [37, 38]. Another anti-AGE agent, pyridoxamine, also prevented development of DR. However, clinical trials of anti-AGE agents for the treatment of DR have not yet been conducted. Based on those reports, we evaluated the effects of oral aminoguanidine and pyridoxamine on the development of cataract and DR in SDT rats. Authors reported that aminoguanidine prevented accumulation of CML and resulted in almost complete inhibition of DR [39, 40].
2. Vascular Endothelial Growth Factor (VEGF)
VEGF, also known as the vascular permeability factor—VPF or vasculotropin, is nowadays considered the main angiogenesis-controlling factor. VEGF is produced by endothelial cells, macrophages, CD4 lymphocytes, plasma cells, myocytes, megakaryocytes, and neoplastic cells . It is a 45 kDa homodimeric glycoprotein belonging to a wide family of growth factors. At present, the VEGF family consists of 6 proteins: VEGF-A,-B,-C,-D,-E, and placental growth factor (PGF) . The best known and most widely used in clinical practice is VEGF-A. We also know several VEGF isoforms: VEGF121, VEGF145, VEGF148, VEGF162, VEGF165, VEGF183, VEGF189, and VEGF206, differing by the length of aminoacids chain, the ability to bind with heparin, mitogenic activity, and the affinity to VEGF receptors [42, 43]. The role of VEGF in the pathogenesis of diabetic retinopathy was first confirmed in 1994 . VEGF stimulates proliferation and migration of endothelial cells and increases vascular permeability. Besides, it induces the production of tissue collagenase and increases macrophage and monocyte chemotaxis. It is also said that VEGF contributes to the increased permeability of blood-retina barrier and that it stimulates the neovascularization process in the advanced retinopathy [43, 45–47]. The increased level of VEGF expression was found already in the early stages of nonproliferative retinopathy in children and adolescents with T1DM [48–50]. It is been suggested that VEGF may play a part in the development of vascular changes in children and adolescents already in the first years of diabetes, when popular and available diagnostic methods would not yet show any changes characteristic of diabetic retinopathy [49, 50]. Moreover, in our other research (Zorena et al. 2010) we have shown that the level of VEGF was higher in patients with T1DM diagnosed with retinopathy, nephropathy, and hypertension as compared with patients with T1DM, retinopathy, and nephropathy but with no hypertension. What is more is that there were also no significant differences in the serum levels of VEGF between the group of patients with T1DM, retinopathy, and nephropathy but no hypertension and the healthy control level. These data show that until the appearance of three complications, VEGF level in children and adolescents with T1DM is not significantly higher as compared with healthy controls . Furthermore, there are numerous works in literature showing increased values of VEGF both in the vitreous humor and in the vitreous body of patients with proliferative diabetic retinopathy or diabetic macular edema (DME) as compared with healthy controls [45–47].
3. Antivascular Endothelial Growth Factor (VEGF) Treatment
Currently, there are four anti-VEGF agents which have been used in the management of diabetic retinopathy, including pegaptanib (Macugen; Pfizer, Inc., New York, USA), ranibizumab (Lucentis; Genentech, Inc., South San Francisco, California, USA), bevacizumab (Avastin; Genentech, Inc.), and VEGF Trap-Eye (Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA).
(Macugen; Eyetech Pharmaceuticals, Inc. and Pfizer Inc., New York) is an aptamer, which was the first of anti-VEGF factors to be approved for the treatment of neovascular AMD, as an inhibitor of the 165 VEGF isomer . A phase 2/3, randomized, double-blind, and 2-year trial has been performed to assess the safety and efficacy of intravitreal pegaptanib sodium 0.3 mg compared with sham injections in subjects with DME, with focal/grid photocoagulation being permitted as needed after week 18. The authors showed that intravitreal pegaptanib sodium 0.3 mg was well tolerated and demonstrated superior efficacy over the sham treatment in the therapy of patients with DME. The proportion of patients with ≥10 letters (or 2 lines) of visual acuity improvement at week 54 was statistically significantly greater in the pegaptanib group versus those in the sham treatment arm .
(Avastin; Genentech, South San Francisco, California) is 93% of a human immunoglobulin Ig1 and 7% of a murine fragment. A specific antibody domain recognises all VEGF-A isoforms [54, 55]. Bevacizumab has recently been used by ophthalmologists in an offlabel use as an intravitreal agent in the treatment of proliferative eye diseases, particularly for choroidal neovascular membrane (CNV) in AMD. Although not currently approved by the FDA for such use, the injection of 0.75 mg–2.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity . Many retina specialists have noted impressive results in the setting of CNV, proliferative diabetic retinopathy, neovascular glaucoma, diabetic macular edema, retinopathy of prematurity, and macular edema secondary to retinal vein occlusions [57, 58]. What is interesting is that in the last work of Suzuki et al. 2013, after bevacizumab injection three days before vitrectomy, apart from VEGF reduction, the authors also showed lower levels of IL-1RA, IL-5, IL-10, IL-12, IL-13 cytokines, and IFN-γ . Research of DRCR.net group continues to analyze the possibility of using bevacizumab in the treatment of diabetic retinopathy [60, 61].
(Lucentis; Genentech, South San Francisco, California) is a humanized antibody fragment directed at all isoforms of VEGF-A and is fabricated specifically for intravitreal use. Ranibizumab is now FDA approved for the treatment of age-related macular degeneration as well as macular edema associated with retinal vein occlusion. For diabetic macular edema, an initial small pilot study showed efficacy of intravitreal injections of ranibizumab in reducing macular thickness and improving visual acuity [62, 63].
In a recent study, authors presented a two-year observation of patients after dosing ranibizumab in diabetic macular edema. After the initial 6 months, all patients were followed up every 2 months. Patients in group 1 could be reinjected if they had persistent or recurrent DME, patients in group 2 could receive either ranibizumab alone or laser only, and patients in group 3 could receive ranibizumab alone or in combination with laser. After 24 months, patients gained 7.7, 5.1, and 6.8 letters in each of the groups, respectively, and the percentage of patients who gained three or more lines of visual acuity was 24, 18, and 26%, respectively . A recent study presented Brown et al. 2013 to report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema . Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, they were eligible to cross over to monthly 0.5 mg ranibizumab. The strong visual acuity (VA) gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Ocular and systemic safety were generally consistent with the results seen at month 24 .
4. Vascular Endothelial Growth Factor Trap-Eye
VEGF Trap is a 115 kDa recombinant fusion protein consisting of the VEGF binding domains of human VEGF receptors 1 and 2 fused to the Fc domain of human IgG1 . The research on the VEGF Trap is now approaching the end of phase II in the treatment of retinal neovascularisation secondary to AMD. Moreover, phase II of the research on using this substance in the treatment of a diabetic eye disease (DED) also starts. A phase I study showed that a single intravitreal injection of VEGF trap-eye exerted biological activity by improving visual acuity and reducing excess retinal thickness in eyes with DME . In this phase II randomized clinical trial, intravitreal VEGF trap-eye was superior to macular laser treatment by the modified ETDRS protocol for the treatment of DME over a 24-week period. VEGF trap-eye resulted in significantly better mean visual acuity outcomes (+8.5 to +11.4 versus +2.5 letters gained) and greater mean reductions in retinal thickness (−127.3 to −194.5 μm versus −67.9 μm) compared with laser alone .
5. Insulin-Like Growth Factor (IGF)
IGF is a polypeptide showing likeness to insulin. There are two such factors: insulin-like growth factor I (IGF-I) and insulin-like growth factor II (IGF-II). IGF-1 polypeptide circulates in the blood as an IGF-binding protein (IGF-BP), probably inhibiting the activity of the free IGF. IGF-I is the main growth factor secreted under the influence of a human growth hormone hGH. In vivo and in vitro studies indicate that IGF-1 acts as an antiapoptotic and anti-inflammatory factor [70, 71]. In ischemic rat kidneys, IGF-I has been shown to exert a protective activity by inhibiting pro-inflammatory cytokines , while in Parkinson’s disease, antiapoptotic IGF-I acted by inhibiting a GSK-3 beta signaling pathway . Protecting IGF-1 action encompasses also central nervous system and cardiac myocytes. Postnatal IGF-1 deficit may also play a part in the development and worsening of neurological deficits in preterm babies . Moreover, in neonates born before term, low IGF-1 concentration is a causative factor for the development of retinopathy of prematurity (ROP) . On the other hand lower IGF-1 levels have been observed in children and adolescents with T1DM and microangiopathy as compared with those with T1DM but no microangiopathy [75, 76]. Moreover, IGF-I concentration was lowest in those children and adolescents with T1DM who had been suffering from diabetes for more than ten years. Interestingly, the same children had higher level of VEGF in serum, and that level had been rising in parallel with the duration of the disease, being highest in patients living with the disease for more than 10 years [48, 75, 77]. In adult patients with PDR, the levels of both IGF-1 and VEGF in the vitreous body were higher than in the control group [78, 79]. It is worth noting that the authors of these studies did not observe differences in IGF-1 or VEGF levels in the serum. On one hand, this effect can be explained by the increase of the IGFBP’s concentrations in the vitreous body, which in turn neutralizes the increased IGF-1 production, and on the other hand, it can be explanied by inhibiting the production of free IGF-1 in the tissues of diabetic patients .
6. Pigment Epithelium Derived Factor (PEDF)
PEDF is a 50 kDa protein with neuroprotective, neurotrophic, and antiangiogenic activities [81, 82]. Pigment epithelium-derived factor is a glycoprotein that belongs to the superfamily of serine protease inhibitors. It was first purified from a conditioned media of human retinal pigment epithelial cells with neuronal differentiating activity . Recently, PEDF has been shown to be the most potent inhibitor of angiogenesis in the mammalian eye; it inhibited retinal endothelial cell growth and migration and suppressed ischemia-induced retinal neovascularization [83–85]. In studies on mice without PEDF, gene Doll et al. have shown that lack of this gene results in serious disturbances both in cell differentiation and in retina architecture . The hypothesis that PEDF may inhibit angiogenesis by directly diminishing the expression of the vascular endothelial growth factor gene first appeared in 2003 . PEDF also inhibits the production of reactive oxygen species (ROS) and the monocyte chemotactic protein (MCP-1). It also neutralizes harmful effects of the glycation end products. Newest data confirm that PEDF exhibits also a direct effect on vascular endothelial growth factor receptor 1 (VEGFR-1) by increasing the gamma-secretase complex activity . Other research suggests the role of a transcription factor NF-κb and a Fas ligand, a cytokine belonging to the TNF and its receptor (FasFas/CD95) superfamily, by PEDF action. Volpert et al. have proven that anti-FasL antibodies and the use of caspase inhibitors inhibit PEDF. So, PEDF can prevent cell apoptosis by activating transcription factor NF-κb, as well as activate programmed cell death by increasing the expression of a Fas ligand . In experimental studies, it is been shown that PEDF inhibits neoangiogenesis when oxygen concentration in the blood is normal but promotes it when oxygen is scarce . In the vitreous body of diabetic patients with PDR, the level of a soluble vascular endothelial growth factor receptor-1 (sVEGF-R1) has been significantly higher, and the level of PEDF was lower as compared to the control group of patients with diabetes but no signs of retinopathy .
PEDF may exhibit antiangiogenic effect through its antioxidant action. The authors have shown that by its antioxidant effects PEDF can block the effects of proangiogenic factors [91, 92]. In animal models, it is been shown that the administration of PEDF may alleviate characteristic changes in diabetic retinopathy . In recent studies, Ishibashi et al. (2013) demonstrated for the first time that PEDF could block the AGE-induced apoptotic cell death of podocytes by suppressing RAGE expression and subsequent ROS generation partly via PPARγ activation .
7. Transforming Growth Factor Beta (TGFβ)
TGF-β belongs to the family of transforming growth factors with immunoregulatory properties . In humans, transforming growth factor β (TGF-β) is present in three inactive isoforms bound with latent associated protein (LAP) and latent TGF-beta binding protein (LTBP). TGF-β1 is present in endothelial cells, hemopoietic cells, and connective tissue cells, TGF-β2 in epithelial tissue and in neurons, and TGF-β3 in connective tissue cells. The activation takes place with the use of plasmin or cathepsin D, after cleavage from nonactive complex. It exerts its action through type I, II, and III TGF-β receptors and in conjunction with a specific SMAD protein present in the cytoplasm [94–96]. Its biological role consists of stimulating mesenchymal cell division which in turn enhances angiogenesis and chondrogenesis. TGF-β inhibits proliferation of T and B lymphocytes, NK cells and the expression of class II MHC particles as well as the formation of cytotoxic T-lymphocytes . Moreover, it stimulates, for example, posttraumatic regenerative processes by increasing the production of proteins, collagen, fibronectin, and integrin in fibroblasts. TGF-β can inhibit enzymes that take part in the degradation of these proteins—heparinase, collagenase, and stromelysin. Moreover it increases the production of tissue inhibitors of metalloproteinases (TIMP). The increased level of TGF-β1 has been found in the idiopathic pulmonary fibrosis, diabetic retinopathy, and glaucoma [97–99]. Among the drugs currently in clinical use, the few that have anti-TGF-activity include tranilast, losartan, glitazones, and imatinib mesylate [100, 101]. These drugs have been found to block the production, activation, or biological activity of TGF-β. Moreover, in the presence of trans-resveratrol showed inhibition of TGF-β1 and VEGF, COX-2, IL-6 and IL-8 . However, the total blockade of TGF-β function can have adverse effects, such as the exposure of intraocular tissue to the damaging effects of local and systemic immune responses. Therefore, a new anti-TGF-β therapy is to selectively block its activation at sites where excess TGF-activation occurs, without affecting its basic function .
8. Interleukin 12 (IL12)
IL-12 is a multipurpose cytokine and in physiological conditions, it is produced mainly by macrophages, dendritic cells, keratinocytes, granulocytes, and mast cells . It stimulates proliferation, activation, and cytotoxicity of lymphocytes T and NK (natural killer) cells, as well as the production of INFγ and TNF-α by these cells. On one hand, IL-12 contributes to the development of autoimmunological diseases, such as rheumatoid arthritis, multiple sclerosis, and type 1 diabetes [103, 104]; on the other, in vitro and in vivo studies have shown that this cytokine has strong antineoplastic activities . Few studies conducted recently indicate that IL-12 may have antiangiogenic properties . In vitro studies have shown that maintaining the equilibrium between pro- and anti-inflammatory mediators allows for maintaining physiological angiogenesis, while disturbing this equilibrium in favor of the first leads to pathological angiogenesis [107, 108]. In our studies (Zorena et al.), we have shown that in the group of children with T1DM and retinopathy the serum level of TNF-α was significantly higher and the level of IL-12 was significantly lower than in the control group without the symptoms of diabetic retinopathy . Obtained results suggest that increased TNF-α production may be the result of insufficient IL-12 level. Maybe the balance between the pro- and antiangiogenic cytokines is one of the factors preventing the development of diabetic nephropathy and retinopathy in those children. It has been shown that, in T1DM patients, IL-12 serum concentration was the highest in subgroup with > or = 3 mg/L hsCRP () . Moreover, a significantly higher concentration of proinflammatory cytokine IL-12 has been found in the aqueous humor of nontreated diabetic retinopathy patients in comparison with diabetic patients treated for retinopathy, without retinopathy, or with healthy individuals . The attempts of therapy with rhIL-12 antibodies (ustekinumab) have been performed in patients with Crohn’s disease and psoriatic arthritis [111, 112].
9. Tumor Necrosis Factor-Alpha (TNF-α)
TNF-α is one of the main inflammatory response cytokines. It is produced mainly by monocytes and macrophages and interacts with them by endo-, para-, and autocrine mode of action. It acts chemotactically on monocytes and neutrophils and activates them as macrophages. It enhances the cytotoxicity of monocytes and macrophages, being at the same time one of the mediators of this cytotoxicity. Biological effects largely depend on the quantity and intensity of TNF secretion . TNF-α is one of the cytokines inducing the interruption of the blood-retina barrier by loosening tight junctions between individual endothelial cells of the retina and also between the cells of the retinal pigment epithelium. Apart from taking part in the inflammatory processes, TNF-α plays an important role in neovascularisation and vasomotor reactions [114, 115]. Factors significantly enhancing the secretion of the cytokine are hypoxia and methylglyoxal-modified proteins, which increase the level of mRNA TNF-α expression. This cytokine fulfills its numerous duties thanks to the ability to stimulate the synthesis of other cytokines, functionally connected with TNF-α, extracellular matrix proteins, modulation of monocyte, and macrophage chemotaxis, as well as the effect on the expression of adhesion molecules in the retinal vessels . TNF-α has been found in the serum of children and adolescents with T1DM and NPDR [49, 116]. The same authors have shown that out of the examined proinflammatory factors, serum TNF-α level can be an independent predictive factor for NPDR development in children with T1DM . Similarly higher level of serum TNF-α have been found in adult patients with T1DM and PDR [117, 118]. Increased levels of TNF-α has also been found in the vitreous body of patients with T2DM and PDR as compared with the control group .
9.1. Etanercept (Enbrel, Pfizer, New York, NY, USA)
It is a fusion (hybrid?) protein composed of a TNF receptor and the Fc fragment of human IgG antibody. It inhibits the binding of TNF-α and TNF-β to the surface TNF receptors, inactivating TNF and suppressing neutrophil migration and proinflammatory cytokine synthesis. Clinical studies have been indeterminate regarding the efficacy of etanercept for the treatment of ocular inflammation [120–122].
9.2. Infliximab (Remicade, Janssen, Beerse, Belgium)
It is an IgG1 chimeric monoclonal antibody with a constant human region and a variable murine one. This agent binds both the soluble and the cell-bound TNF-α but not TNF-β . It has shown encouraging responses in patients with treatment-resistant ocular inflammation including Behçet’s disease, Wegener’s granulomatosis, sarcoidosis, and juvenile inflammatory arthritis . However, recently, the illustrated paper demonstrates a rare extraintestinal manifestation of Crohn’s disease, orbital myositis, and its temporal relationship to the discontinuance of infliximab therapy and its successful treatment, without recurrence with tapering prednisone and adalimumab .
9.3. Adalimumab (Humira, Abbott)
It is a fully humanized IgG1 monoclonal antibody, specifically directed against TNF-α, which binds both its soluble and cell-bound forms . Adalimumab has been used with increasing frequency and found to be effective for treatment of birdshot retinochoroidopathy, juvenile inflammatory arthritis, Behçet’s disease, and diabetic macular edema [127, 128].
9.4. Rituximab (Rituxan, Biogen Idec, Weston, MA)
It is a chimeric monoclonal antibody that binds to CD20 antigen on the surface of B cells and suppresses B-cell differentiation resulting in reduced IgG and IgM production . It has been found to be effective in treatment of systemic lupus erythematosus, Behçet’s disease, Wegener’s granulomatosis uveitis, and retinal vasculitis [130, 131].
9.5. SIMPONI (Golimumab, Janssen Biotech, Inc.)
It is a human monoclonal antibody forming stable complexes with high affinity to the soluble and transmembrane form of human tumor necrosis factor (TNF-α), preventing TNF-α binding with its receptors. Human TNF binding by golimumab neutralizes TNF-α-induced expression of adhesive selectin E particles, vascular cell adhesion molecules (VCAM-1), and intercellular adhesion molecules (ICAM-1) on the surface of endothelial cells. In in vitro studies, golimumab inhibits the TNF-induced secretion of interleukin IL-6, IL-8 and the granulocyte-macrophage colony stimulating factor (GM-CSF). In patients receiving golimumab, there was an improvement in C-reactive protein concentration, which in turn significantly decreased concentrations of interleukin 6 (IL-6), ICAM-1 particles, metalloproteinase (MMP-3), and vascular endothelial growth factor (VEGF). Moreover, in patients with RA or ankylosing spondylitis, it was the TNF-α concentration that decreased, while in those with psoriatic arthritis, it was the IL-8 concentration that decreased [132–134]. However, it should be noted that the above-mentioned administration of monoclonal antibodies may bind to ocular complications [135, 136].
The search for new, efficient treatment methods, especially in advanced stages of diabetic retinopathy, makes the research on biological drugs especially important. Conducted studies suggest that among known factors, both pro-angiogenic (such as TNF-α or VEGF) and antiangiogenic, PEDF is a good material for study; although at present, the success of monoclonal antibody therapy can be judged to be merely moderate. The administration of all the above mentioned drugs is associated with many complications, drugdependent as well as linked with the method of drug administration itself. The latter can give transient complications, such as subconjunctival hemorrhage, the feeling of a foreign body under the eyelid, and increased intraocular pressure. Serious complications, with about 0.05% frequency, encompass the intraocular inflammation, retinal detachment, damage to the lens, or hemorrhage into the vitreous body. However, ongoing energetic studies in many centers around the world suggest that most probably in the near future we will achieve therapeutic success in preventing loss of sight in DM patients.
Conflict of Interests
The authors do not have any conflict of interests.
This study was financed by the Medical University of Gdańsk Grant (ST-56).
- E. Ginter and V. Simko, “Global prevalence and future of diabetes mellitus,” Advances in Experimental Medicine and Biology, vol. 771, pp. 35–41, 2012.
- M. J. Magee and K. M. Narayan, “Global confluence of infectious and non-communicable diseases—the case of type 2 diabetes,” Preventive Medicine, vol. 57, no. 3, pp. 149–151, 2013.
- P. Jarosz-Chobot, J. Polanska, A. Szadkowska et al., “Rapid increase in the incidence of type 1 diabetes in Polish children from 1989 to 2004, and predictions for 2010 to 2025,” Diabetologia, vol. 54, no. 3, pp. 508–515, 2011.
- P. Romero-Aroca, I. Mendez-Marin, M. Baget-Bernaldiz, J. Fernández-Ballart, and E. Santos-Blanco, “Review of the relationship between renal and retinal microangiopathy in diabetes mellitus patients,” Current Diabetes Reviews, vol. 6, no. 2, pp. 88–101, 2010.
- R. Pant, R. Marok, and L. W. Klein, “Pathophysiology of coronary vascular remodeling: relationship with traditional risk factors for coronary artery disease,” Cardiology in Review. In press.
- H. Hamasaki, S. Moriyama, and H. Yanai, “A crosstalk between macroangiopathy and microangiopathy in type 2 diabetes,” International Journal of Cardiology, vol. 168, no. 1, pp. 550–551, 2013.
- P. P. C. de Almeida Salgado, I. N. Silva, E. C. Vieira, and A. C. S. E. Silva, “Risk factors for early onset of diabetic nephropathy in pediatric type 1 diabetes,” Journal of Pediatric Endocrinology and Metabolism, vol. 23, no. 12, pp. 1311–1320, 2010.
- M. Trento, P. Passera, M. Trevisan et al., “Quality of life, impaired vision and social role in people with diabetes: a multicenter observational study,” Acta Diabetologica, 2013.
- T. Skrivarhaug, H. J. Bangstad, L. C. Stene, L. Sandvik, K. F. Hanssen, and G. Joner, “Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway,” Diabetologia, vol. 49, no. 2, pp. 298–305, 2006.
- A. M. Jacobson, B. H. Braffett, P. A. Cleary, R. A. Gubitosi-Klug, M. E. Larkin, and The DCCT/EDIC Research Group, “The long-term effects of type 1 diabetes treatment and complications on health-related quality of life: a 23-year follow-up of the diabetes control and complications/epidemiology of diabetes interventions and complications cohort,” Diabetes Care, vol. 36, no. 10, pp. 3131–3138, 2013.
- M. B. Gomes, A. S. de Mattos Matheus, L. E. Calliari et al., “Economic status and clinical care in young type 1 diabetes patients: a nationwide multicenter study in Brazil,” Acta Diabetologica, 2012.
- L. Govan, O. Wu, A. Briggs et al., “Inpatient costs for people with type 1 and type 2 diabetes in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group,” Diabetologia, vol. 54, no. 8, pp. 2000–2008, 2011.
- P. Kawalec and A. Pilc, “A cost-effectiveness analysis of treatment of diabetic complications in 2002,” Journal of the Diabetes Poland, vol. 1, pp. 9–14, 2004.
- J. M. Tarr, K. Kaul, K. Wolanska, E. M. Kohner, and R. Chibber, “Retinopathy in diabetes,” Advances in Experimental Medicine and Biology, vol. 771, pp. 88–106, 2012.
- R. Klein, B. E. K. Klein, S. E. Moss, and K. J. Cruickshanks, “The wisconsin epidemiologic study of diabetic retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes,” Ophthalmology, vol. 105, no. 10, pp. 1801–1815, 1998.
- K. Zorena, D. Raczyńska, and K. Raczyńska, “Immunological risk factors for the development and progression of diabetic retinopathy,” in Diabetic Retinopathy, pp. 137–162, InTech, Rijeka, Croatia, 2012.
- A. M. A. El-Asrar, M. I. Nawaz, D. Kangave, M. M. Siddiquei, and K. Geboes, “Angiogenic and vasculogenic factors in the vitreous from patients with proliferative diabetic retinopathy,” Journal of Diabetes Research, vol. 2013, Article ID 539658, 9 pages, 2013.
- S. Kastelan, M. Tomić, J. Salopek-Rabatić et al., “The association between the HLA system and retinopathy development in patients with type 1 diabetes mellitus,” Collegium Antropologicum, vol. 37, supplement 1, pp. 65–70, 2013.
- A. Bierhaus, M. A. Hofmann, R. Ziegler, and P. P. Nawroth, “AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept,” Cardiovascular Research, vol. 37, no. 3, pp. 586–600, 1998.
- S. Y. Goh and M. E. Cooper, “The role of advanced glycation end products in progression and complications of diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 4, pp. 1143–1152, 2008.
- M. Chen, T. M. Curtis, and A. W. Stitt, “Advanced glycation end products and diabetic retinopathy,” Current Medicinal Chemistry, vol. 44, no. 6, pp. 1397–1407, 2013.
- L. Wang, Q. Q. Deng, X. H. Wu, J. Yu, X. L. Yang, and Y. M. Zhong, “Upregulation of glutamate-aspartate transporter by glial cell line-derived neurotrophic factor ameliorates cell apoptosis in neural retina in streptozotocin-induced diabetic rats,” CNS Neuroscience and Therapeutics, 2013.
- H. Zong, M. Ward, A. Madden et al., “Hyperglycaemia-induced pro-inflammatory responses by retinal Müller glia are regulated by the receptor for advanced glycation end-products (RAGE),” Diabetologia, vol. 53, no. 12, pp. 2656–2666, 2010.
- Z. Sun, J. Liu, X. Zeng et al., “Protective actions of microalgae against endogenous and exogenous advanced glycation endproducts (AGEs) in human retinal pigment epithelial cells,” Food and Function, vol. 2, no. 5, pp. 251–258, 2011.
- Y. Zhu, T. Shu, Y. Lin et al., “Inhibition of the receptor for advanced glycation endproducts (RAGE) protects pancreatic β-cells,” Biochemical and Biophysical Research Communications, vol. 404, no. 1, pp. 159–165, 2011.
- A. W. Stitt and T. M. Curtis, “Advanced glycation and retinal pathology during diabetes,” Pharmacological Reports, vol. 57, supplement, pp. 156–168, 2005.
- N. C. Chilelli, S. Burlina, and A. Lapolla, “AGEs, rather than hyperglycemia, are responsible for microvascular complications in diabetes: a “glycoxidation-centric” point of view,” Nutrition, Metabolism and Cardiovascular Diseases, 2013.
- G. Mohammad, M. M. Siddiquei, A. Othman, M. Al-Shabrawey, and A. M. A. El-Asrar, “High-mobility group box-1 protein activates inflammatory signaling pathway components and disrupts retinal vascular-barrier in the diabetic retina,” Experimental Eye Research, vol. 107, pp. 101–109, 2013.
- K. Zorena, M. Kula, E. Malinowska, D. Raczyńska, M. Myśliwiec, and K. Raczyńska, “Threshold serum concentrations of tumour necrosis factor α (TNFα) as a potential marker of the presence of microangiopathy in children and adolescents with type 1 diabetes mellitus (T1DM),” Human Immunology, vol. 74, no. 1, pp. 75–81, 2013.
- J. Kostolanská, V. Jakuš, and L. Barák, “HbA1c and serum levels of advanced glycation and oxidation protein products in poorly and well controlled children and adolescents with type 1 diabetes mellitus,” Journal of Pediatric Endocrinology and Metabolism, vol. 22, no. 5, pp. 433–442, 2009.
- M. Kerkeni, A. Saïdi, H. Bouzidi, S. B. Yahya, and M. Hammami, “Elevated serum levels of AGEs, sRAGE, and pentosidine in Tunisian patients with severity of diabetic retinopathy,” Microvascular Research, vol. 84, no. 3, pp. 378–383, 2012.
- E. Sato, T. Nagaoka, H. Yokota, A. Takahashi, and A. Yoshida, “Correlation between plasma pentosidine concentrations and retinal hemodynamics in patients with type 2 diabetes,” The American Journal of Ophthalmology, vol. 153, no. 5, pp. 903.e1–909.e1, 2012.
- A. M. A. El-Asrar, M. I. Nawaz, M. M. Siddiquei, A. S. Al-Kharashi, D. Kangave, and G. Mohammad, “High-mobility group box-1 induces decreased brain-derived neurotrophic factor-mediated neuroprotection in the diabetic retina,” Mediators of Inflammation, vol. 2013, Article ID 863036, 11 pages, 2013.
- S. F. Yan, R. Ramasamy, and A. M. Schmidt, “Receptor for AGE (RAGE) and its ligands-cast into leading roles in diabetes and the inflammatory response,” Journal of Molecular Medicine, vol. 87, no. 3, pp. 235–247, 2009.
- Y. Matsumoto, M. Takahashi, and M. Ogata, “Relationship between glycoxidation and cytokines in the vitreous of eyes with diabetic retinopathy,” Japanese Journal of Ophthalmology, vol. 46, no. 4, pp. 406–412, 2002.
- M. Kula, K. Zorena, and J. Myśliwska, “Transcription factor NF-κB—its role in inflammation in diabetes type 1,” Family Medicine and Primary Care Review, vol. 13, no. 3, pp. 592–595, 2011.
- P. Urios, A. M. Grigorova-Borsos, and M. Sternberg, “Aspirin inhibits the formation of pentosidine, a cross-linking advanced glycation end product, in collagen,” Diabetes Research and Clinical Practice, vol. 77, no. 2, pp. 337–340, 2007.
- P. Urios, A. Grigorova-Borsos, and M. Sternberg, “Flavonoids inhibit the formation of the cross-linking AGE pentosidine in collagen incubated with glucose, according to their structure,” European Journal of Nutrition, vol. 46, no. 3, pp. 139–146, 2007.
- D. Luo, Y. Fan, and X. Xu, “The effects of aminoguanidine on retinopathy in STZ-induced diabetic rats,” Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 13, pp. 4386–4390, 2012.
- A. H. M. El Shazly, A. M. Mahmoud, and N. S. Darwish, “Potential prophylactic role of aminoguanidine in diabetic retinopathy and nephropathy in experimental animals,” Acta Pharmaceutica, vol. 59, no. 1, pp. 67–73, 2009.
- N. Ferrara, H. Gerber, and J. LeCouter, “The biology of VEGF and its receptors,” Nature Medicine, vol. 9, no. 6, pp. 669–676, 2003.
- L. P. Aiello and J. S. Wong, “Role of vascular endothelial growth factor in diabetic vascular complications,” Kidney International Supplements, vol. 58, no. 77, pp. S113–S119, 2000.
- N. Ferrara, “Role of vascular endothelial growth factor in regulation of physiological angiogenesis,” The American Journal of Physiology—Cell Physiology, vol. 280, no. 6, pp. C1358–C1366, 2001.
- A. P. Adamis, J. W. Miller, M. T. Bernal et al., “Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy,” The American Journal of Ophthalmology, vol. 118, no. 4, pp. 445–450, 1994.
- R. Simó, E. Carrasco, M. García-Ramírez, and C. Hernández, “Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy,” Current Diabetes Reviews, vol. 2, no. 1, pp. 71–98, 2006.
- B. Wirostko, T. Y. Wong, and R. Simó, “Vascular endothelial growth factor and diabetic complications,” Progress in Retinal and Eye Research, vol. 27, no. 6, pp. 608–621, 2008.
- G. Mohammad and R. A. Kowluru, “Diabetic retinopathy and signaling mechanism for activation of matrix metalloproteinase-9,” Journal of Cellular Physiology, vol. 227, no. 3, pp. 1052–1061, 2012.
- F. Chiarelli, A. Spagnoli, F. Basciani et al., “Vascular endothelial growth factor (VEGF) in children, adolescents and young adults with type 1 diabetes mellitus: relation to glycaemic control and microvascular complications,” Diabetic Medicine, vol. 17, no. 9, pp. 650–656, 2000.
- M. Myśliwiec, A. Balcerska, K. Zorena, J. Myśliwska, P. Lipowski, and K. Raczyńska, “The assessment of the correlation between vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), glycaemic control (HbA1c) and the development of the diabetic retinopathy in children with diabetes mellitus type 1,” Klinika Oczna, vol. 109, no. 4–6, pp. 150–154, 2007.
- K. Zorena, J. Myśliwska, M. Myśliwiec, A. Balcerska, P. Lipowski, and K. Raczyńska, “Interleukin-12, vascular endothelial growth factor and tumor necrosis factor-α in the process of neoangiogenesis of diabetic retinopathy in children,” Klinika Oczna, vol. 109, no. 4–6, pp. 155–159, 2007.
- K. Zorena, J. Myśliwska, M. Myśliwiec et al., “Association between vascular endothelial growth factor and hypertension in children and adolescents type I diabetes mellitus,” Journal of Human Hypertension, vol. 24, no. 11, pp. 755–762, 2010.
- M. Lu and A. P. Adamis, “Molecular biology of choroidal neovascularization,” Ophthalmology Clinics of North America, vol. 19, no. 3, pp. 323–334, 2006.
- M. B. Sultan, D. Zhou, J. Loftus, T. Dombi, and K. S. Ice, “A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema,” Ophthalmology, vol. 118, no. 6, pp. 1107–1118, 2011.
- M. S. Gordon and D. Cunningham, “Managing patients treated with bevacizumab combination therapy,” Oncology, vol. 69, no. 3, pp. 25–33, 2005.
- M. E. van Meter and E. S. Kim, “Bevacizumab: current updates in treatment,” Current Opinion in Oncology, vol. 22, no. 6, pp. 586–591, 2010.
- L. Benhmidoune, A. McHachi, M. Boukhrissa et al., “Use of bevacizumab in the treatment of complicated proliferative diabetic retinopathy,” Journal Français d'Ophtalmologie, 2013.
- J. F. Arevalo, J. Fromow-Guerra, J. G. Sanchez et al., “Primary intravitreal bevacizumab for subfoveal choroidal neovascularization in age-related macular degeneration: results of the Pan-American collaborative retina study group at 12 months follow-up,” Retina, vol. 28, no. 10, pp. 1387–1394, 2008.
- O. Tokgöz, A. Sahin, A. Tüfek et al., “Inhalation anesthesia with sevoflurane during intravitreal bevacizumab injection in infants with retinopathy of prematurity,” BioMed Research International, vol. 2013, Article ID 435387, 4 pages, 2013.
- Y. Suzuki, K. Suzuki, Y. Yokoi, Y. Miyagawa, T. Metoki, and M. Nakazawa, “Effects of intravitreal injection of bevacizumab on inflammatory cytokines in the vitreous with proliferative diabetic retinopathy,” Retina, 2013.
- S. Gangaputra, T. Almukhtar, A. R. Glassman et al., “Comparison of film and digital fundus photographs in eyes of individuals with diabetes mellitus,” Investigative Ophthalmology and Visual Science, vol. 52, no. 9, pp. 6168–6173, 2011.
- B. J. Thomas, G. Shienbaum, D. S. Boyer, and H. W. Flynn Jr., “Evolving strategies in the management of diabetic macular edema: clinical trials and current management,” Canadian Journal of Ophthalmology, vol. 48, no. 1, pp. 22–30, 2013.
- Q. D. Nguyen, S. Tatlipinar, S. M. Shah et al., “Vascular endothelial growth factor is a critical stimulus for diabetic macular edema,” The American Journal of Ophthalmology, vol. 142, no. 6, pp. 961.e4–969.e4, 2006.
- D. V. Do, Q. D. Nguyen, S. M. Shah et al., “An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular oedema,” The British Journal of Ophthalmology, vol. 93, no. 2, pp. 144–149, 2009.
- Q. D. Nguyen, S. M. Shah, A. A. Khwaja et al., “Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study,” Ophthalmology, vol. 117, no. 11, pp. 2146–2151, 2010.
- D. M. Brown, Q. D. Nguyen, D. M. Marcus et al., “Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE,” Ophthalmology, 2013.
- M. W. Stewart and F. J. Rosenfeld, “Predicted biological activity of intravitreal VEGF Trap,” The British Journal of Ophthalmology, vol. 92, no. 5, pp. 667–668, 2008.
- D. V. Do, Q. D. Nguyen, D. Boyer et al., “One-year outcomes of the DA VINCI study of VEGF trap-eye in eyes with diabetic macular edema,” Ophthalmology, vol. 119, no. 8, pp. 1658–1665, 2012.
- F. G. Holz, W. Amoaku, J. Donate et al., “Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study,” Ophthalmology, vol. 118, no. 4, pp. 663–671, 2011.
- M. Englander, T. C. Chen, E. I. Paschalis, J. W. Miller, and I. K. Kim, “Intravitreal injections at the Massachusetts eye and ear infirmary: analysis of treatment indications and postinjection endophthalmitis rates,” The British Journal of Ophthalmology, vol. 97, no. 4, pp. 460–465, 2013.
- S. Sukhanov, Y. Higashi, S. Y. Shai et al., “IGF-1 reduces inflammatory responses, suppresses oxidative stress, and decreases atherosclerosis progression in ApoE-deficient mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 12, pp. 2684–2690, 2007.
- X. Sun, L. Huang, M. Zhang, S. Sun, and Y. Wu, “Insulin like growth factor-1 prevents 1-mentyl-4-phenylphyridinium-induced apoptosis in PC12 cells through activation of glycogen synthase kinase-3β,” Toxicology, vol. 271, no. 1-2, pp. 5–12, 2010.
- N. Goes, J. Urmson, D. Vincent, V. Ramassar, and P. F. Halloran, “Effect of recombinant human insulin-like growth factor-1 on the inflammatory response to acute renal injury,” Journal of the American Society of Nephrology, vol. 7, no. 5, pp. 710–720, 1996.
- C. Löfqvist, E. Engström, J. Sigurdsson et al., “Postnatal head growth deficit among premature infants parallels retinopathy of prematurity and insulin-like growth factor-1 deficit,” Pediatrics, vol. 117, no. 6, pp. 1930–1938, 2006.
- A. Pérez-Muñuzuri, J. R. Fernández-Lorenzo, M. L. Couce-Pico, M. J. Blanco-Teijeiro, and J. M. Fraga-Bermúdez, “Serum levels of IGF1 are a useful predictor of retinopathy of prematurity,” Acta Paediatrica, vol. 99, no. 4, pp. 519–525, 2010.
- J. Peczyńska, M. Urban, B. Urban, B. Głowińska, and B. Florys, “Assessment of growth factor levels in adolescents with type 1 diabetes mellitus and the beginning of diabetic microangiopathy,” Pediatric Endocrinology, Diabetes and Metabolism, vol. 10, no. 1, pp. 41–48, 2004.
- A. Wȩdrychowicz, H. Dziatkowiak, J. Nazim, and K. Sztefko, “Insulin-like growth factor-1 and its binding proteins, IGFBP-1 and IGFBP-3, in adolescents with type-1 diabetes mellitus and microalbuminuria,” Hormone Research, vol. 63, no. 5, pp. 245–251, 2005.
- F. Santilli, A. Spagnoli, A. Mohn et al., “Increased vascular endothelial growth factor serum concentrations may help to identify patients with onset of type 1 diabetes during childhood at risk for developing persistent microalbuminuria,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 8, pp. 3871–3876, 2001.
- R. Simó, A. Lecube, R. M. Segura, J. García Arumí, and C. Hernández, “Free insulin growth factor-I and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy,” The American Journal of Ophthalmology, vol. 134, no. 3, pp. 376–382, 2002.
- M. E. Hartnett, N. Tinkham, L. Paynter et al., “Aqueous vascular endothelial growth factor as a predictor of macular thickening following cataract surgery in patients with diabetes mellitus,” The American Journal of Ophthalmology, vol. 148, no. 6, pp. 895.e1–901.e1, 2009.
- R. Burgos, C. Mateo, A. Cantón, C. Hernández, J. Mesa, and R. Simó, “Vitreous levels of IGF-I, IGF binding protein 1, and IGF binding protein 3 in proliferative diabetic retinopathy: a case-control study,” Diabetes Care, vol. 23, no. 1, pp. 80–83, 2000.
- C. Hernández and R. Simó, “Neuroprotection in diabetic retinopathy,” Current Diabetes Reports, vol. 12, no. 4, pp. 329–337, 2012.
- V. Vigneswara, M. Berry, A. Logan, and Z. Ahmed, “Pigment epithelium-derived factor is retinal ganglion cell neuroprotective and axogenic after optic nerve crush injury,” Investigative Ophthalmology and Visual Science, vol. 54, no. 4, pp. 2624–2633, 2013.
- J. Tombran-Tink, “PEDF in angiogenic eye diseases,” Current Molecular Medicine, vol. 10, no. 3, pp. 267–278, 2010.
- J. A. Doll, V. M. Stellmach, N. P. Bouck et al., “Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas,” Nature Medicine, vol. 9, no. 6, pp. 774–780, 2003.
- S. Yamagishi, S. Amano, Y. Inagaki, T. Okamoto, M. Takeuchi, and H. Inoue, “Pigment epithelium-derived factor inhibits leptin-induced angiogenesis by suppressing vascular endothelial growth factor gene expression through anti-oxidative properties,” Microvascular Research, vol. 65, no. 3, pp. 186–190, 2003.
- D. W. Dawson, O. V. Volpert, P. Gillis et al., “Pigment epithelium-derived factor: a potent inhibitor of angiogenesis,” Science, vol. 285, no. 5425, pp. 245–248, 1999.
- J. Cai, L. Wu, X. Qi et al., “PEDF regulates vascular permeability by a γ-secretase-mediated pathway,” PLoS ONE, vol. 6, no. 6, Article ID e21164, 2011.
- O. V. Volpert, T. Zaichuk, W. Zhou et al., “Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor,” Nature Medicine, vol. 8, no. 4, pp. 349–357, 2002.
- P. Subramanian, S. E. Crawford, and S. P. Becerra, “Assays for the antiangiogenic and neurotrophic serpin pigment epithelium-derived factor,” Methods in Enzymology, vol. 499, pp. 183–204, 2011.
- N. Matsunaga, Y. Chikaraishi, H. Izuta et al., “Role of soluble vascular endothelial growth factor receptor-1 in the vitreous in proliferative diabetic retinopathy,” Ophthalmology, vol. 115, no. 11, pp. 1916–1922, 2008.
- X. Shen, B. Xie, Y. Cheng, Q. Jiao, and Y. Zhong, “Effect of pigment epithelium derived factor on the expression of glutamine synthetase in early phase of experimental diabetic retinopathy,” Ocular Immunology and Inflammation, vol. 19, no. 4, pp. 246–254, 2011.
- Y. Ishibashi, T. Matsui, K. Ohta et al., “PEDF inhibits AGE-induced podocyte apoptosis via PPAR-γ activation,” Microvascular Research, vol. 85, pp. 54–58, 2013, Erratum in Microvascular Research, vol. 87, p. 100, 2013.
- V. V. Orlova, Z. Liu, M. Goumans, and P. T. Dijke, “Controlling angiogenesis by two unique TGF-β type I receptor signaling pathways,” Histology and Histopathology, vol. 26, no. 9, pp. 1219–1230, 2011.
- I. Pot, S. Patel, L. Deng et al., “Identification of a novel link between the protein kinase NDR1 and TGFβ signaling in epithelial cells,” PLoS ONE, vol. 8, no. 6, Article ID e67178, 2013.
- D. Yang, J. M. Baumann, Y. Y. Sun et al., “Overexpression of vascular endothelial growth factor in the germinal matrix induces neurovascular proteases and intraventricular hemorrhage,” Science Translational Medicine, vol. 5, no. 193, Article ID 193ra90, 2013.
- A. Weiss and L. Attisano, “The TGFβ superfamily signaling pathway,” Wiley Interdisciplinary Reviews: Developmental Biology, vol. 2, no. 1, pp. 47–63, 2013.
- I. V. Yang, “Epigenomics of idiopathic pulmonary fibrosis,” Epigenomics, vol. 4, no. 2, pp. 195–203, 2012.
- K. Zorena, E. Malinowska, D. Raczyńska, M. Myśliwiec, and K. Raczyńska, “Serum concentrations of transforming growth factor-β 1 in predicting the occurrence of diabetic retinopathy in juvenile patients with type 1 diabetes mellitus,” Journal of Diabetes Research, vol. 2013, Article ID 614908, 6 pages, 2013.
- K. Zorena, D. Raczyńska, P. Wiśniewski et al., “Relationship between serum transforming growth factor β 1 (TGF-β1) concentrations and the duration of type 1 diabetes mellitus (T1DM) in children and adolescents,” Mediators of Inflammation. In press.
- R. Agarwal and P. Agarwal, “Future target molecules in antiglaucoma therapy: TGF-β may have a role to play,” Ophthalmic Research, vol. 43, no. 1, pp. 1–10, 2009.
- J. N. Losso, R. E. Truax, and G. Richard, “Trans-resveratrol inhibits hyperglycemia-induced inflammation and connexin downregulation in retinal pigment epithelial cells,” Journal of Agricultural and Food Chemistry, vol. 58, no. 14, pp. 8246–8252, 2010.
- M. Majewska-Szczepanik, S. Paust, U. H. von Andrian, P. W. Askenase, and M. Szczepanik, “Natural killer cell-mediated contact sensitivity develops rapidly and depends on interferon-α, interferon-γ and interleukin-12,” Immunology, vol. 140, no. 1, pp. 98–110, 2013.
- H. Rothe, V. Burkart, A. Faust, and H. Kolb, “Interleukin-12 gene expression is associated with rapid development of diabetes mellitus in non-obese diabetic mice,” Diabetologia, vol. 39, no. 1, pp. 119–122, 1996.
- B. Y. Kang and T. S. Kim, “Targeting cytokines of the interleukin-12 family in autoimmunity,” Current Medicinal Chemistry, vol. 13, no. 10, pp. 1149–1156, 2006.
- D. G. Duda, M. Sunamura, L. Lozonschi et al., “Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12,” Cancer Research, vol. 60, no. 4, pp. 1111–1116, 2000.
- F. Ghiringhelli, C. Ménard, F. Martin, and L. Zitvogel, “The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression,” Immunological Reviews, vol. 214, no. 1, pp. 229–238, 2006.
- M. P. Colombo and G. Trinchieri, “Interleukin-12 in anti-tumor immunity and immunotherapy,” Cytokine and Growth Factor Reviews, vol. 13, no. 2, pp. 155–168, 2002.
- K. Zorena, J. Myśliwska, M. Myśliwiec, A. Balcerska, P. Lipowski, and K. Raczyńska, “Interleukin-12 and tumour necrosis factor-α equilibrium is a prerequisite for clinical course free from late complications in children with type 1 diabetes mellitus,” Scandinavian Journal of Immunology, vol. 67, no. 2, pp. 204–208, 2008.
- M. Wegner, A. Araszkiewicz, A. Pioruńska-Mikołajczak, D. Zozulińska-Ziółkiewicz, B. Wierusz-Wysocka, and M. Pioruńska-Stolzmann, “The evaluation of IL-12 concentration, PAF-AH, and PLA(2) activity in patients with type 1 diabetes treated with intensive insulin therapy,” Clinical Biochemistry, vol. 42, no. 16-17, pp. 1621–1627, 2009.
- A. G. Antunica, K. Karaman, L. Znaor, A. Sapunar, V. Buško, and V. Puzović, “IL-12 concentrations in the aqueous humor and serum of diabetic retinopathy patients,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 250, no. 6, pp. 815–821, 2012.
- Y. Zhu, C. Hu, M. Lu et al., “Population pharmacokinetic modeling of ustekinumab, a human monoclonal antibody targeting IL-12/23p40, in patients with moderate to severe plaque psoriasis,” Journal of Clinical Pharmacology, vol. 49, no. 2, pp. 162–175, 2009.
- J. Buckland, “Therapy: ustekinumab therapeutic effects-more than skin deep,” Nature Reviews Rheumatology, vol. 9, no. 8, p. 445, 2013.
- J. Bigda, I. Beletsky, C. Brakebusch et al., “Dual role of the p75 tumor necrosis factor (TNF) receptor in TNF cytotoxicity,” Journal of Experimental Medicine, vol. 180, no. 2, pp. 445–460, 1994.
- R. Arita, S. Nakao, T. Kita et al., “A key role for ROCK in TNF-α-mediated diabetic microvascular damage,” Investigative Ophthalmology and Visual Science, vol. 54, no. 3, pp. 2373–2383, 2013.
- K. Zorena, M. Myśliwiec, K. Rybarczyk et al., “Proangiogenic effects of tumor necrosis factor-α (TNF-α) in diabetes mellitus children,” Family Medicine and Primary Care Review, vol. 10, no. 3, pp. 745–748, 2008.
- K. Zorena, J. Myśliwska, M. Myśliwiec et al., “Serum TNF-α level predicts nonproliferative diabetic retinopathy in children,” Mediators of Inflammation, vol. 2007, Article ID 92196, 5 pages, 2007.
- C. Gustavsson, E. Agardh, B. Bengtsson, and C. Agardh, “TNF-α is an independent serum marker for proliferative retinopathy in type 1 diabetic patients,” Journal of Diabetes and its Complications, vol. 22, no. 5, pp. 309–316, 2008.
- D. N. Koleva-Georgieva, N. P. Sivkova, and D. Terzieva, “Serum inflammatory cytokines IL-1β, IL-6, TNF-α and VEGF have influence on the development of diabetic retinopathy,” Folia medica, vol. 53, no. 2, pp. 44–50, 2011.
- J. Adamiec-Mroczek and J. Oficjalska-Młyńczak, “Assessment of selected adhesion molecule and proinflammatory cytokine levels in the vitreous body of patients with type 2 diabetes—role of the inflammatory-immune process in the pathogenesis of proliferative diabetic retinopathy,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 246, no. 12, pp. 1665–1670, 2008.
- A. Reiff, “Long-term outcome of etanercept therapy in children with treatment-refractory uveitis,” Arthritis and Rheumatism, vol. 48, no. 7, pp. 2079–2080, 2003.
- P. P. Sfikakis, “Behçet's disease: a new target for anti-tumour necrosis factor treatment,” Annals of the Rheumatic Diseases, vol. 61, supplement 2, pp. ii51–ii53, 2002.
- L. L. Lim, F. W. Fraunfelder, and J. T. Rosenbaum, “Do tumor necrosis factor inhibitors cause uveitis? A registry-based study,” Arthritis and Rheumatism, vol. 56, no. 10, pp. 3248–3252, 2007.
- L. H. Calabrese, “Molecular differences in anticytokine therapies,” Clinical and Experimental Rheumatology, vol. 21, no. 2, pp. 241–248, 2003.
- A. Yoshida, T. Kaburaki, K. Okinaga, M. Takamoto, H. Kawashima, and Y. Fujino, “Clinical background comparison of patients with and without ocular inflammatory attacks after initiation of infliximab therapy,” Japanese Journal of Ophthalmology, vol. 56, no. 6, pp. 536–543, 2012.
- S. Verma, K. I. Kroeker, and R. N. Fedorak, “Adalimumab for orbital myositis in a patient with Crohn's disease who discontinued infliximab: a case report and review of the literature,” BMC Gastroenterology, vol. 13, article 59, 2013.
- M. Benucci, G. Saviola, M. Manfredi, P. Sarzi-Puttini, and F. Atzeni, “Tumor necrosis factors blocking agents: analogies and differences,” Acta Bio Medica, vol. 83, no. 1, pp. 72–80, 2012.
- I. K. Petropoulos, J. D. Vaudaux, and Y. Guex-Crosier, “Anti-TNF-α therapy in patients with chronic non-infectious uveitis: the experience of Jules Gonin Eye Hospital,” Klinische Monatsblatter fur Augenheilkunde, vol. 225, no. 5, pp. 457–461, 2008.
- L. Wu, E. Hernandez-Bogantes, J. A. Roca, J. F. Arevalo, K. Barraza, and A. F. Lasave, “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, vol. 31, no. 2, pp. 298–303, 2011.
- N. R. Biswas, G. K. Das, and A. K. Dubey, “Monoclonal antibodies in ophthalmology,” Nepal Medical College Journal, vol. 12, no. 4, pp. 264–271, 2010.
- K. J. Donnithorne, R. W. Read, R. Lowe, P. Weiser, R. Q. Cron, and T. Beukelman, “Retinal vasculitis in two pediatric patients with systemic lupus erythematosus: a case report,” Pediatric Rheumatology Online Journal, vol. 11, no. 1, p. 25, 2013.
- C. S. Foster, P. Y. Chang, and A. R. Ahmed, “Combination of rituximab and intravenous immunoglobulin for recalcitrant ocular cicatricial pemphigoid. A preliminary report,” Ophthalmology, vol. 117, no. 5, pp. 861–869, 2010.
- E. Shono, “Effectiveness of golimumab in clinical management of patients with rheumatoid arthritis,” Drugs in R&D, vol. 13, no. 1, pp. 95–100, 2013.
- D. Owczarek, D. Cibor, M. Szczepanek, and T. Mach, “Biological therapy of inflammatory bowel disease,” Polish Archives of Internal Medicine, vol. 119, no. 1-2, pp. 84–88, 2009.
- A. Beck, T. Wurch, and J. M. Reichert, “6th annual European antibody congress 2010: November 29–December 1, 2010, Geneva, Switzerland,” MAbs, vol. 3, no. 2, pp. 111–132, 2011.
- P. Marticorena-Álvarez, M. Chaparro, A. Pérez-Casas, A. Muriel-Herrero, and J. P. Gisbert, “Probable diffuse retinopathy caused by adalimumab in a patient with Crohn's disease,” Journal of Crohn's and Colitis, vol. 6, no. 9, pp. 950–953, 2012.
- M. Mesquida, B. Molins, V. Llorenç et al., “Current and future treatments for Behçet's uveitis: road to remission,” International Ophthalmology, 2013.
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