In this study, we discovered that the combination treatment improved BCVA and decreased CMT in both the naïve and refractory patient groups, with the naïve group showing greater improvement in BCVA and no increase in complications. With the growing emphasis on anti-VEGF and anti-inflammatory combination therapy for RVO-ME, the treatment modality proposed in this study is an excellent addition to the investigation of combination treatment strategies. To the best of our knowledge, this is the first study to compare the efficacy of combination treatment in naïve patients versus refractory patients.
RVO-ME is thought to be caused by a breakdown of the blood-retinal barrier (BRB) with complicated pathogenesis [22]. At first, in RVO patients, hypoxia and ischemia increase VEGF expression, which leads to an increase in endothelial cell proliferation, vascular permeability, and angiogenesis. It promotes actin filament reorganization in the cytoplasm, which leads to angiogenesis[23, 24]. However, evidence suggests that retinal ischemia cannot fully explain the pathophysiology of RVO-related macular edema. VEGF levels, for example, are not particularly high in nonischemic CRVO patients[25, 26]. RVO-ME patients have elevated levels of inflammatory cytokines, growth factors, chemokines, adhesion molecules, and other substances. Inflammatory factors such as interleukin-1α, interleukin − 6, interleukin − 8, monocyte chemoattractant protein-1, and platelet-derived growth factor-AA all play important roles in the pathogenesis of RVO, according to previous researches [27–30]. Some inflammatory factors, such as serum amyloid A, are present throughout the disease's acute and chronic phases [31]. These pathological processes in RVO-ME suggest that anti-inflammatory therapy, in addition to anti-VEGF therapy, is important.
The results of clinical trials heavily influence the treatment modality chosen for RVO-ME. Anti-VEGF therapy is commonly used in the treatment of RVO-ME. Ranibizumab has been shown in clinical trials, whether randomized controlled trials (e.g., BRAVO study) [32] or real-world studies (e.g., LUMINOUS study) [33], to improve patients' vision while reducing macular edema. Simultaneously, the GENEVA study demonstrated the efficacy of Dex-I on RVO-ME [16]. According to a recent expert consensus, intravitreal anti-VEGF should be used as first-line therapy, followed by other anti-VEGF agents or DEX in cases of persistent or recurrent ME [34]. However, there have been reports of patients who did not respond to either treatment. Despite being the first-line treatment, anti-VEGF has a high rate of non-response. The rate of non-response to anti-VEGF treatment in randomized controlled trials was 15–20% [35], and in the real world, the rate of non-response to anti-VEGF treatment for vision was up to 27.9% at 4 months and 30.2% at 12 months. In addition, 75% remained nonresponsive after one year in patients who did not respond to early treatment [36]. In other words, persistence does not guarantee success. The results of previous studies that switched from DEX-I to anti-VEGF or vice versa were not ideal. Failure to respond to anti-VEGF or DEX-I monotherapy may be due to a variety of factors. On the one hand, a single molecule may only partially address the pathogenesis of ME, especially when many components have been implicated. Tachyphylaxis or tolerance may develop after repeated administration of the same medicine [18, 37]. Therefore, combined anti-VEGF and anti-inflammatory treatment modalities have been investigated in recent years.
The use of anti-VEGF combined with DEX-I in RVO-ME eyes has been reported less frequently [17, 18, 21, 38], and the few available studies did not use the same treatment paradigm. The investigation of RVO-ME treatment options is ongoing, and combination therapy is being tried more frequently, but the timing of combination therapy is not yet conclusive. Previous research has shown that when compared to anti-VEGF monotherapy, combination therapy significantly prolongs treatment duration, restores the anatomy and improves visual acuity, and reduces the number of anti-VEGF treatments [21, 38]. After one year of combination therapy, Giuffrè et al. discovered refractory RVO-ME patients with significant improvement in CMT but not in BCVA [18]. Therefore, we conducted this prospective study to determine whether initial combination therapy was superior to delayed combination therapy in terms of functional and anatomical improvement and whether naïve patients had better BCVA outcomes. The benefit of BCVA was lower in the refractory group, which could be attributed to irreversible photoreceptor and RPE damage caused by prolonged macular edema. According to the studies, sudden ischemia can cause a surge of VEGF and inflammatory factors in a short period of time [30], so an initial combined treatment can rapidly inhibit the release of VEGF and inflammatory factors, slow the progression of the disease, and maintain better visual outcomes. On the contrary, as the macular edema disease course was prolonged in refractory patients, the macular structure appeared to be continuously damaged, and patients' visual prognosis remained poorer even after the combination treatment was administered.
IVR was performed concurrently as DEX-I in this study, which simplified the treatment process and reduced the treatment burden on patients. Patients in this study were admitted to the operating room less frequently when compared to alternate or sequential treatments. The mean number of co-injections during the follow-up period was 2.52 ± 0.58 in the naïve patients' group and 2.33 ± 0.55 in the refractory patients' group, which is lower than previously reported [39]. Retreatment occurred around every 4 months in either group, which is much longer than monthly injection. Approximately 42% of patients, according to previous reports, expect to reduce the number of injections while maintaining efficacy [40]. The reduction in the number of injections in this study, compared to the refractory patients' group, not only reduced the incidence of injection-related complications such as vitreous hemorrhage and retinal detachment objectively but also reduced the financial burden on patients in the context of the Covid-19 pneumonia epidemic.
The most common side effects of DEX-I treatment were increased IOP and cataract risk [16]. This study also demonstrated that the initial combination treatment was safe, with cataract and high IOP side effects roughly comparable to previously reported results [22]. In this study, IOP elevation was generally moderate, and no patients required surgery to control IOP. The small sample size is the study's main limitation, and longer follow-up clinical studies with larger sample sizes are expected in the future.