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Vascular endothelial growth factor inhibition in uveitis: a systematic review
  1. Nishi Gulati,
  2. Farzin Forooghian,
  3. Ronni Lieberman,
  4. Douglas A Jabs
  1. Department of Ophthalmology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, USA
  1. Correspondence to Dr Farzin Forooghian, Department of Ophthalmology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1183, New York, NY 10029, USA; farzin.forooghian{at}mssm.edu

Abstract

Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of uveitic complications such as cystoid macular oedema (CMO), choroidal neovasularisation (CNV) and retinal neovascularisation (RNV). The use of intravitreal anti-VEGF therapies, namely bevacizumab and ranibizumab, has recently been described in the treatment of these complications. Evidence describing the use of intravitreal anti-VEGF therapy for these complications consists of case reports and case series, most of which are retrospective and have limitations in design and analysis. As such, the current level of evidence supporting the use of intravitreal anti-VEGF therapy for these complications of uveitis would be rated as very low. Furthermore, blockage of VEGF has not been shown to have an anti-inflammatory effect. Thus, treatment of the underlying inflammatory disease should play a central role in the management of uveitic CMO, CNV and RNV. A two-pronged treatment regimen that focuses on achieving disease quiescence through the use of corticosteroids and/or immunosuppressive agents, while treating complications that arise despite adequate disease quiescence with intravitreal anti-VEGF agents, may be useful. However, further data from prospective controlled trials are needed before the therapeutic role of anti-VEGF therapy in the uveitis treatment regimen can be fully determined.

  • Uveitis
  • treatment
  • VEGF
  • bevacizumab
  • ranibizumab
  • choroidal neovascularisation
  • cystoid macular oedema
  • retina neovascularisation
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Introduction

The use of biological agents targeting vascular endothelial growth factor (VEGF) has emerged as a popular treatment for various ocular diseases. Ranibizumab, a monoclonal antibody fragment that targets VEGF, is now approved by the US Food and Drug Administration (FDA) for the treatment of neovascular age-related macular degeneration (AMD). This agent was approved for use in all types of neovascular AMD after randomised controlled clinical trials documented not only prevention of further visual loss, but also an improvement in visual acuity in a substantial proportion of patients.1 2 Bevacizumab, a monoclonal antibody targeting VEGF that was initially developed for the treatment of metastatic colon cancer, has also demonstrated efficacy in the treatment of neovascular AMD.3 4 The reported success of intravitreal bevacizumab, along with its significantly lower cost compared with ranibizumab, has popularised this agent as an alternative ‘off-label’ anti-VEGF agent in the treatment of neovascular AMD. The superiority of one of these agents over the other has not been established, and is a question being addressed in ongoing clinical trials. The uses of bevacizumab and ranibizumab have gone beyond treating AMD, and these agents have been used on an off-label basis to treat numerous conditions, including diabetic macular oedema,5 6 proliferative diabetic retinopathy,7 neovascular glaucoma,8 central serous chorioretinopathy,9 macular oedema from venous occlusive disease10 and pseudophakic macular oedema.11

Conventionally, one of the mainstays of treatment for uveitis has involved either local or systemic corticosteroids. When corticosteroids alone are ineffective, or a corticosteroid-sparing agent is needed, immunosuppressive therapy typically is indicated.12 When complications such as cystoid macular oedema (CMO), choroidal neovascularisation (CNV) or retinal neovascularisation (RNV) arise despite adequate control of the uveitis, adjunctive treatments sometimes are needed. The use of anti-VEGF agents has recently been reported in the treatment of uveitic complications including CMO, CNV and RNV. In this review, we evaluate the literature on the use of intravitreal anti-VEGF agents (bevacizumab and ranibizumab) for uveitic CMO, CNV and RNV. The evidence in all published reports on this topic will be rated using the GRADE approach (table 1), developed by the Grades of Recommendation, Assessment, Development and Evaluation Working Group and adopted by the Cochrane Collaboration for reviews.13 This method evaluates data based on the underlying methodology used in the study being assessed. It uses a large magnitude of effect, dose–response gradient, and lack of confounding factors to raise, and likelihood of bias, limitations in design, and imprecision or inconsistency of results to reduce the level of the quality of evidence. The resultant level of evidence is then given a quality rating in order to ensure well-informed, evidence-based clinical decision-making.

Table 1

Quality of evidence based on the grades of recommendation, assessment, development and evaluation working group

The pathogenic role of VEGF in the complications of uveitis

Through its promotion of angiogenesis and increased vascular permeability, VEGF plays an important role in the inflammatory process. As such, the expression of VEGF is intimately linked to that of major cytokines in the inflammatory cascade. Nuclear factor-κβ (NF-κβ) is a transcription factor that is crucial in the inflammatory response. In addition to inducing the expression of numerous inflammatory mediators, NF-κβ also induces the expression of VEGF.14 Several inflammatory cytokines, including interleukin (IL)-1β,15 16 tumour necrosis factor (TNF)-α,15 17 IL-6,18 IL-819 and TGF-β215 can upregulate VEGF production through various molecular pathways. In patients with uveitis, aqueous humour VEGF levels are increased in eyes with CMO.20 In patients with neovascular AMD, aqueous humour VEGF levels are related to CNV disease activity.21 Similarly, the role of VEGF in promoting RNV has been well established.22 The importance of VEGF in the development of CMO, CNV and RNV, as well as its involvement in the inflammatory cascade, suggests that its inhibition may have therapeutic potential when these complications occur in the setting of uveitis. While VEGF inhibition seems reasonable to treat uveitis complications such as CMO, CNV and RNV (which are secondary to angiogenesis and increased vascular permeability), the role of anti-VEGF therapy to treat inflammation is less clear. Whether inhibition of VEGF has any anti-inflammatory effect in addition to its anti-angiogenic and anti-permeability actions is not known and needs to be explored.

The corticosteroid triamcinolone acetate has been widely used as a local therapy for treatment of uveitis and its complications such as CMO, CNV and RNV. Its mechanism of action remains to be fully elucidated, but it is thought to involve the inhibition of prostaglandin and leukotriene synthesis, as well as downregulation of cell adhesion and major histocompatibility molecules.23 In animal models of hypoxia triamcinolone decreases retinal levels of IL-1β, TNF-α, NF-κβ and VEGF.24 In contrast to anti-VEGF agents that are very specific, corticosteroids are more non-specific with respect to their mechanism of action. Which therapeutic strategy, specific versus non-specific, is superior in the treatment of uveitic complications is not clear. It can be speculated that when only one mediator is specifically inhibited, compensatory mechanisms may exist to adapt to its removal by increasing the production of other mediators. Compensatory elevations of angiogenic and inflammatory factors following VEGF inhibition have been described.25 26 Recently, elevations of several inflammatory cytokines following intravitreal bevacizumab injection have been described in the setting of proliferative diabetic retinopathy.27 The significance of this in the setting of uveitis and the treatment of its complications is not known, but deserves further investigation.

VEGF inhibition for the treatment of uveitic CMO

To date, nine reports regarding the use of intravitreal bevacizumab or ranibizumab for the treatment of uveitic CMO have been published.28–36 Seven of these were case series, three prospective28 30 35 and five retrospective,29 32–34 36 and one was an isolated case report.31 All published reports included small numbers of patients, ranging from one to 27, with the follow-up period ranging from 1 week to 1 year. The majority of cases reported were of non-infectious uveitis, although two reports included patients with infectious uveitis.34 Only one of the articles described the use of ranibizumab for uveitic CMO.30 36 Only one study28 reported the use of Early Treatment of Diabetic Retinopathy Study (ETDRS) charts to record visual acuity. Four articles reported a statistically significant improvement in visual acuity at the end of the follow-up period,28 30 34 35 and four articles reported no change in visual acuity.29 32 33 36 Five of the case series found a statistically significant decrease in central retina thickness as measured by optical coherence tomography (OCT),28–30 33 34 while three series observed no change in central retinal thickness.32 35 36 Both visual acuity and OCT thickness were noted to improve in the isolated case report.31 Several reports included patients requiring multiple injections to maintain the transient response.28–31 34–36 When reporting retrospective data from clinical series of patients with variable follow-up, the reporting of proportions or means can be misleading. It is more appropriate to report rates, or use statistical analyses that incorporate the variable follow-up times.37 However, this was only done in two of three retrospective case series where variable follow-up was present.33 36

Although there is no consensus on the best treatment for uveitic CMO, most studies support aggressive treatment of the underlying inflammatory disease as an important component of the treatment regiment.38 39 In patients with multifocal choroiditis, use of systemic immunosuppressive therapy is associated with a reduction in the development of CMO.40 Adjunctive treatment with anti-VEGF treatments may be appropriate in cases of uveitis where CMO persists despite adequate control of the inflammatory process. In some reports, the level of uveitis activity was not defined.28 31 Standardised criteria for defining disease activity have been established by the Standardization of Uveitis Nomenclature (SUN) working group.41 In many reports where anti-VEGF therapy was used for refractory CMO in the setting of inactive uveitis, the definition of ‘inactive’ was not stated.32 33 35 Hence, it is difficult to know if the inflammation was truly inactive in these cases. The SUN criteria define inactive uveitis as grade 0 cells in the anterior chamber, or less than 1 cell per high power field (HPF).41 CMO is considered a structural complication of uveitis, and is not considered in the definition disease activity.41 The presence of grade 0.5–1+ cells implies activity, and thus does not represent inactive disease. However, in two reports describing the use of anti-VEGF in the setting of inactive uveitis, the definition of inactive allowed up to grade 0.5–1+ cells to be present.29 30 One study included patients with active uveitis, but ‘active’ was not defined.36 Furthermore, in some studies patients were concurrently treated with intravitreal triamcinolone.28 34 The ability to determine if anti-VEGF therapy was beneficial is thus confounded by these issues, which suggest that there may have been active inflammation still present that, if treated with corticosteroids and/or immunosuppression, would have resulted in resolution of the CMO.

Based on the GRADE approach,13 the level of quality of evidence for anti-VEGF therapy in the treatment of uveitic CMO would be rated as very low. Given the multiple confounding issues noted amongst the various studies in the literature, there is no clear-cut evidence supporting the routine use of intravitreal anti-VEGF therapy in uveitic CMO. Treatment of uveitic CMO should be focused on controlling the underlying inflammation, and steroids and/or immunosuppressive agents are the gold standard at this time.12 Although the relative efficacy of intravitreal anti-VEGF compared with intravitreal triamcinolone as adjunctive therapies for uveitic CMO is not known, cases that were unresponsive to intravitreal bevacizumab but responded to intravitreal triamcinolone have been described.28 Based on the available data in the literature, further data from prospective controlled trials are warranted in order to fully determine the role of intravitreal anti-VEGF agents in the treatment of uveitic CMO. At this point, however, it seems reasonable to consider intravitreal anti-VEGF therapy on a case-by-case basis in patients with refractory uveitic CMO in the setting of inactive uveitis and in which intravitreal triamcinolone is contraindicated.

VEGF inhibition for the treatment of uveitic CNV

Multiple reports have been published on the use of intravitreal anti-VEGF agents in the management of uveitic CNV. To date, there have been 11 reports describing intravitreal anti-VEGF in the treatment of CNV secondary to non-infectious uveitis; one study was prospective,42 whereas the remaining were retrospective, non-comparative case series.36 43–51 Sample sizes varied from two to 96 patients, while follow-up periods ranged from 1 to 24 months. In addition to non-infectious uveitis, many series also included patients with CNV secondary to infectious uveitis or other non-uveitic causes.36 42 48–51 Five of these studies were restricted to only patients with non-infectious uveitic CNV.43–47 Most studies involved bevacizumab, with only one report describing the use of ranibizumab.45 Only six studies performed a statistical analysis, and all of these reported an improvement in visual acuity and/or a decrease in OCT thickness.36 42 47 49–51 In addition, two of the 10 reports used ETDRS charts for measurement of visual acuity, but these charts were used only on some of the patients.50 51 Several reports described the need for multiple injections to maintain the therapeutic response.36 42 45–51 In some retrospective studies where statistical analysis was performed, the analyses did not account for the variable follow-up of the patients.47 49–51

Analogous to the treatment of uveitic CMO, the treatment of CNV secondary to uveitis should include control of the underlying inflammation. This approach is supported by evidence suggesting that treatment with systemic prednisone or immunosuppressive therapy may be of benefit in the treatment of CNV secondary to uveitis.40 52–54 Some of the reports describing the use of intravitreal anti-VEGF therapy for uveitic CNV included patients with active uveitis,36 50 51 while others did not comment on or define the activity of uveitis at the time of CNV presentation using standardised criteria.42–49 Furthermore, in some studies patients were treated with concurrent intravitreal triamcinolone.36 46 49 Thus, it is not possible to know how much the activity of the underlying inflammatory disease was contributing to the development of CNV and the need for intravitreal bevacizumab/ranibizumab. Interestingly, one of the studies reported that the angiographic regression pattern correlated with the presence of active uveitis, with complete regression occurring in a higher percentage of patients with inactive uveitis.50

Based on the GRADE approach,13 the level of quality of evidence for anti-VEGF therapy in the treatment of uveitic CNV would be rated as very low. However, given what is known about the important contribution of VEGF to the pathophysiology of CNV development, the use of intravitreal bevacizumab/ranibizumab may be a viable option in cases of uveitic CNV. However, more data from prospective controlled studies will be required before the role of these agents in treatment of uveitic CNV can be fully known. Until that time, a two-pronged approach to treatment of uveitic CNV may be considered; while the acute complication of CNV is being treated with anti-VEGF therapy, attention should also be focused on treatment of the underlying inflammatory disease. It should be noted that treatment of the underlying disease based on published guidelines12 will likely reduce the likelihood of recurrent CNV and reduce the need for repeated anti-VEGF treatment.

VEGF inhibition for the treatment of uveitic RNV

RNV can occur in uveitis secondary to peripheral retinal ischaemia from occlusive vasculitis. Cases of RNV (as well as neovascularisation of the disc, or NVD) were included in reported case series that included predominantly cases of uveitic CNV.50 51 In addition, there has been one report of RNV included with a case of CNV as well as two reports describing three patients with Eales' disease.44 55 56 Only one report included a subanalysis of eyes with RNV/NVD, and this report did not demonstrate any statistically significant gain in visual acuity following intravitreal bevacizumab.51 In three cases the authors reported complete regression of the neovascular complex, which had persisted despite retinal laser photocoagulation, following a single injection of intravitreal bevacizumab.44 55 56 Other series reported complete regression of some cases and partial regression of others.50 51 Based on the available reports, the quality of data supporting a role for intravitreal bevacizumab in the treatment of uveitis RNV would be classified as very low using the GRADE approach,13 and more data are needed. The treatment of uveitic RNV should focus on treatment of the underlying inflammatory disease, as well as laser photocoagulation to areas of ischaemic retina. If RNV persists despite these efforts, intravitreal bevacizumab may be an option. However, the limited data concerning use of intravitreal bevacizumab in the setting of uveitic RNV, as well as reports of tractional retinal detachment following intravitreal bevacizumab in patients with proliferative diabetic retinopathy,57 need to be carefully considered.

Conclusions

The use of intravitreal anti-VEGF therapy has expanded tremendously in recent years, and intravitreal anti-VEGF agents are now used to manage complications from various diseases of the posterior segment. The utilisation of anti-VEGF agents is a novel approach to the management of the complications of uveitis such as CMO, CNV and RNV. The rationale for the use of these agents is based on the fact that they target an important pathophysiological step in the development of these complications. Evidence on the use of intravitreal bevacizumab/ranibizumab to treat the complications of uveitis is limited, and caution must be used when interpreting the results of these reports. More long-term data on the efficacy and safety of intravitreal anti-VEGF for the treatment of uveitic CMO, CNV and RNV are needed. Furthermore, while anti-VEGF therapies may inhibit angiogenesis and decrease vascular permeability, it is not known if they have any anti-inflammatory effect. Despite the lack of strong evidence, anti-VEGF treatments may play a role in the management of uveitic CMO, CNV and RNV in cases with inactive uveitis41 that are refractory to standard therapy. While intravitreal anti-VEGF therapy may serve as a useful adjunctive treatment, attention should not be drawn away from treatment of the underlying inflammatory disease. The short-term control of the complications of uveitis with intravitreal anti-VEGF must be considered along with the long-term goal of disease remission using standard practice guidelines.12 Uveitic complications are often secondary to persistent underlying inflammation, and aggressive control of this inflammation is important in the management of these complications. When these complications arise attention should be focused on controlling any residual inflammation, while considering intravitreal anti-VEGF therapy as a possible adjunctive therapy. Further data from prospective studies are needed to fully determine the role of intravitreal anti-VEGF therapy for the uveitic complications of CMO, CNV and RNV.

References

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Footnotes

  • Funding Mount Sinai School of Medicine.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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