Challenges in proliferative vitreoretinopathy: is biological therapy a solution?

KEYWORDS:

• Proliferative vitreoretinopathy
• PVR
• therapeutic challenges
• PVR classification
• methotrexate
• corticosteroids

1. Introduction

Historically, the success of retinal detachment (RD) surgery has been hindered by the presence of proliferative vitreoretinopathy (PVR) with an incidence of 5–10% of all retinal detachment cases [1,2]. Conventional approaches to managing this complication have involved multiple surgeries using different techniques, including retinectomy, sequential surgery and peeling [3]. Surgical intervention still represents the mainstay for treating PVR; however, despite the progress in technology and surgical techniques, a lower rate of success in patients with established PVR has been reported, ranging from 46% to 69% [4,5]. Moreover, PVR is the main cause of failure also in patients without PVR at presentation, accounting for around 75% of the cases [6].

Several clinical risk factors have been enumerated in relation to PVR onset, including the presence of preoperative vitreous hemorrhage, PVR at presentation, aphakia, large retinal break, use of cryopexy, chronic RD, the presence of choroidal detachment preoperatively, horseshoe tear, and the use of silicone oil [7]. A previous retrospective study on the predictive factors of PVR revealed that smoker patients had a significantly higher risk of PVR-induced reattachment in comparison with nonsmokers [8].

This has multiple implications for patients, affecting their functional and anatomical outcomes, as well as for the healthcare system, as these patients often require multiple surgeries, consuming significantly more hospital resources with higher costs than eyes without PVR [9].

The existing limitations of current surgical approaches emphasize the importance of incorporating adjunctive treatments to improve outcomes. Not an easy task, considering the many challenges when faced in dealing with PVR. Beginning with a better understanding of its pathogenic mechanisms to identify specific molecular pathways that can be pharmacologically targeted, an enhanced comprehension of the clinical course of PVR and stratification of risk, and in addition, a revision of the current clinical classification. This comprehension would allow an improved identification of patients who would benefit from adjuvant treatment.

The pathogenesis of PVR involves complex interactions between different cell types, including glial cells, retinal pigment epithelial cells (RPE), Müller glia cells, inflammatory cells, macrophages, and fibroblasts. In addition to multiples cytokines, inflammatory factors, and growth factors [10]. The complex interplay among different cellular components plays a critical role in initiating PVR and maintaining the disease process. This complicated network of cellular interactions and signaling pathways makes the development of effective therapeutic interventions for PVR a challenging task.

In the last years several different pharmacological alternatives have been studied to target distinct pathogenic components of PVR, including inflammation, cell proliferation and fibrosis [11].

2. Pharmacological treatment options

Currently, there are no approved pharmaceutical agents for the adjunctive treatment of PVR.

Corticosteroids, with their large spectrum with anti-inflammatory and anti-proliferative activity, have been investigated in animal models and have shown efficacy in reducing the incidence of PVR-related RD [12]; however, clinical studies on corticosteroids have provided contradictory results, with some reporting no significant differences in outcomes compared to controls [13]. Sustained delivery systems, including dexamethasone intravitreal implant, have also been studied but have not shown significant anatomical and functional results [5].

Currently methotrexate (MTX), an anti-proliferative and anti-inflammatory drug commonly adopted for treating chronic inflammatory disorders and widely used in uveitis, has become a focus of interest for vitreoretinal surgeons. MTX is a folate analogue which inhibits the dihydrofolate reductase activity and, thus, PVR cells are deprived of purine and pyrimidine precursor of DNA and RNA required proliferation [14]. In this regard, in vitro studies of PVR revealed that MTX was effective in inhibiting cell proliferation and regulating apoptosis [15]. Intraoperative single MTX injection, multiple postoperative intravitreal MTX injections and intraoperative MTX infusions have also been investigated with favorable outcomes in terms of retinal reattachment and visual improvement in patients with PVR [16,17]. Despite the promising results with MTX for treating PVR, the low number of studies and quality of evidence, in addition to the lack of randomized clinical trials and some concerns about its possible toxicity do not provide substantial evidence to adopt MTX as a first-line pharmacological agent for the management of PVR. Currently, the GUARD trial is investigating the clinical efficacy and safety of ADX-2191 (MTX 0.8%) administered repeated, weekly intravitreal injections of the drug instead of a single injection at the time of the surgery [18].

Other antiproliferative drugs have been scrutinized for PVR, including 5-fluoruracil (5-FU), daunorubicin, paclitaxel and colchicine. In particular, 5-FU is a thymidylate synthase inhibitor, which leads to disruption of DNA and RNA synthesis in PVR cells [19]. Differently, daunorubicin is a topoisomerase II inhibitor, which prevents DNA and RNA production by intercalating DNA strands [20]. 5-FU and daunorubicin have shown convincing results in animal models; however, inconsistent outcomes were reproduced in clinical studies [21,22].

Furthermore, paclitaxel and colchicine still need to be tested in clinical trials despite the good results in preclinical studies [11].

Recent studies have highlighted the role of growth factors, specifically the vascular endothelial growth factor (VEGF) and the placental growth factor (PIGF), in the pathogenesis of PVR [23]. Animal models have shown that ranibizumab, an anti-VEGF biological drug, effectively reduced PVR incidence in rabbits [24]; nevertheless, clinical studies have demonstrated poorer outcomes, with no significant differences in visual acuity, retinal reattachment rate, or epiretinal membrane formation between bevacizumab-treated patients and controls [25]. A meta-analysis of multiple studies also concluded that intravitreal bevacizumab injection during vitrectomy did not effectively lower retinal redetachment rates or improve visual acuity in PVR-related RD cases [26].

Other biological agents are currently being investigated for the treatment of PVR. In vitro studies showed the connective tissue growth factor (CTGF), one of the downstream mediators of transforming growth factor-beta (TGF-beta), among others is involved in the development of fibrosis in PVR. Rho-kinase inhibitors, which display an inhibitory effect on CTGF gene expression and have anti-fibrotic properties have been indicated as new molecular target drugs for PVR [27]. However, only their application in pre-clinical and clinical trials may show whether rho-kinase inhibitors will be an effective alternative or adjunct treatment option for treating PVR.

In humans, the ongoing, randomized FIXER study (NCT04891991) is studying the clinical efficacy and safety of intravitreal infliximab, an anti-tumor necrosis factor- α (TNF- α), given at the dose of 1 mg/0.05 ml by the end of vitrectomy in patients with PVR. Intravitreal infliximab has been proven in previous studies to reduce levels of proinflammatory cytokines in the vitreous and therefore preventing fibroblastic cell formation in proinflammatory conditions [28]. Results from this large, randomized trial will provide more evidence on the possible role of this biological agent for preventing and treating PVR.Another ongoing randomized, pilot study (NCT03727776) is currently examining the clinical efficacy in preventing PVR of subcutaneous injection of adrenocorticotropic hormone (ACTH), self-administered by the patients starting on post-operative day 1 and then twice a week for 8 weeks. The primary endpoint is the analysis of mean aqueous levels of albumin (marker of inflammation) [29]. Results from this study will elucidate the effectiveness of ACTH in reducing inflammation after surgery and its potential role in treating PVR.

3. Expert opinion

Several treatment options have been investigated as adjunctive pharmacological agents in the prevention and management of PVR, including corticosteroids, MTX and other anti-proliferative agents; however, in spite of some promising results, the existing data does not provide conclusive evidence due to the inconsistent outcomes in terms of clinical effectiveness and the predominantly non-randomized and small-scale nature of these studies [11]. In this direction, novel interesting therapeutic targets are currently being investigated, including TGF-beta, TNF- α, ACTH and others. Results from these early-phase clinical trials will shed light on the most promising pathogenic pathway to be targeted in the treatment of PVR.

Beside the research of novel therapeutic targets, some other challenges need to be further overcome with the present evidence. In fact, one of the primary issues associated with the conducted studies is the heterogeneous case selection. This problem arises from the current classification of PVR, which is purely descriptive, it does not provide information on the activity of the process and there is no estimation of repeated risk of PVR formation after surgery hindering the progress in comprehending the underlying causes and consequently the prognosis [30]. Thus, it becomes imperative to revise the existing classification of PVR, to facilitate the development of new treatment approaches.

This problem stems from the current classification of PVR, which is purely descriptive and focuses on anatomical features, does not provide information on the activity of the process and does not estimate the risk of recurrence of PVR formation after surgery, hindering progress in understanding the underlying causes and consequently the prognosis. It is therefore imperative to revise the existing classification of PVR to facilitate the development of new treatment approaches.

In conclusion, to develop appropriate therapeutic strategies for PVR several obstacles should still be overcome including a better understanding of the pathogenic processes and molecular pathways involved in this disorder. A revision of the current clinical classification of PVR, appropriate risk stratification and patient selection in clinical trials will be a major step forward in the search for a definitive solution to this important medical issue.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.