In this research, combination of intravitreal Bevacizumab and IFN alpha-2b eye drops has been investigated. It has been found that combination of IVB and IFN alpha − 2b significantly enhances visual acuity and results in a better disease outcome compared to IVB monotherapy. Furthermore, combination therapy significantly reduced macular thickness, meaning that the BRB in patients who received adjunctive IFN alpha 2b attained more optimal functionality.
Pro-inflammatory mechanisms and pathways, including tissue growth factors, tumor necrosis factor alpha (TNF alpha), various interleukins, cellular infiltration, in addition to chemotaxis triggered by VEGF upregulation, provokes an inflammatory state in the retinal tissue [3, 11]. Inflammation, along with VEGF production and hyperglycemic state, subsequently triggers reactive angiogenesis, cytotoxic and vasogenic edema and as a result, disruption in the function of retina [12]. Research has found that IFN alpha levels in the aqueous humor of patients with DR are substantially reduced [13]. This finding suggests that imbalance in IFN alpha expression might play a role in DME development. Presence of immune-mediated and Inflammatory constituents in the pathophysiology of DR and DME, prompts ophthalmologists to utilize immunomodulatory and anti-inflammatory agents to halt the disease progression and achieve more optimal results. Several adjunctive anti-inflammatory treatments have been investigated. These include conventional anti-inflammatory drugs, such as steroids [14] and non-steroidal anti-inflammatory drugs [15], along with newly discovered agents, such as TNF antagonists [16].
Topical and injective forms of IFN alphas have been employed in a wide range of ophthalmic pathologies, including ocular surface, uveal, and retinal disorders. Anti-neoplastic and anti-viral effects of IFN alpha have granted its use in various ocular neoplasms, including ocular conjunctival papillomatosis and MALT lymphomas [17, 18]. IFN alpha has also shown to be effective in vernal keratoconjunctivitis treatment [19]. Application of IFN alpha, including IFN alpha 2a, in refractory DME has shown promising results [20]. Data on the applicability of IFN alpha 2b utilization in DME treatment remains extremely limited.
Interferon alpha 2b has been shown to effectively enhance the function of BRB by improving tissue stability and reducing endothelial permeability [21]. By suppression of VEGF gene transcription and repressing interleukin(IL)-8, IFN alpha inhibits angiogenesis [10, 22]. Additionally, IFN-alpha exhibits an antagonizing effect on TNF-alpha, which is a key inflammatory pathway involved in DME development [23,24,25]. Concentration of several pro-inflammatory cytokines, including IL-6 and IFN gamma, are markedly increased in the aqueous humor of patients with DR [13, 26]. A review by Kalliolias and Ivashkiv states that type 1 interferons (including IFN alphas) downregulate pro-inflammatory cytokines, such as IL-6 and IFN gamma, therefore act as inflammatory modulators [27]. It is worth noting that IVB itself, by suppressing VEGF receptors 1 and 2, contributes in the modulation of the inflammatory state [11].
Aside from minor side-effects such as irritative conjunctivitis and vision haziness, topical IFN-alpha2b has not generally caused serious complications [8]. No adverse effect was observed in patients who received IFN-alpha2b eye drops in this study; However, long-term safety of topical IFN therapy requires further investigation. Close follow-up of patients who receive topical IFN alpha is advised.
In a previous trial by Afarid et al. [10], adjunctive topical IFN alpha2b improved patients’ BCVA; despite that, changes in CMT measures were not statistically significant. Furthermore, the standard treatment of patients was not pre-determined and patients randomly received intravitreal Bevacizumab or focal laser. In our study, a larger sample size, by reaching a higher statistical power, enabled us to demonstrate that adjunctive therapy with IFN alpha2b significantly reduces macular thickness, in addition to further confirming its enhancing effect on patients’ visual acuity. Additionally, our study was the first trial on adjunctive IFN alpha2b with a fixed, pre-determined standard treatment (IVB), enabling us to introduce a possible therapeutic regimen for DME treatment.
In a study by Faghihi et al. [28], additive injection of sub-tenon IFN-alpha2b was compared with the topical form in patients with refractory DME. In that study, both routes of additive IFN administration, along with monotherapy with IVB, were relatively unsuccessful among patients with CMT over 400 microns. At the third month follow-up, additive IFN eye drops only enhanced patients’ visual acuity but failed to reduce patients’ macular thickness significantly. While the results of the previous study can be attributed to the refractory state of their patients’ condition, a relatively small sample size might also play a role. Moreover, continuous administration of topical IFN for three months in this trial (compared to the one-time injection of sub-tenon IFN in the previous trial) possibly contributed to a more optimal response. Further research is warranted regarding adjunctive therapy with IFN alpha2b in refractory cases of DME.
Intriguingly, in this study, post-treatment IOP was markedly lower in patients who received IFN + IVB than in patients who received IVB only. This finding was also observed in the previous trial by Afarid et al. [10]. It can be explained by the balancing effect of IFN alpha on pro-inflammatory cytokines, which potentially contribute to trabecular meshwork dysfunction and disruptions in aqueous humor circulation [29]. Higher IOP levels, by triggering cytokine production, may contribute to the worsening of the inflammatory state [30]. Additionally, anti-VEGF therapies might increase IOP, resulting in ocular hypertension, which is a sight-threatening condition [31]. Therefore, employing an additional agent that lowers the IOP appears to be rational.
Leave a Reply