## 4 Discussion  
Affibercept, also known as \"VEGF-Trap Eye\", is a human recombinant glycoprotein designed by combining portions of VEGF receptor (VEGF) and human IgG1 Fc region [10]. Due to its characteristic molecular structure, affibercept has the ability to bind VEGF-A, VEGF-B, PIGF-1, and PIGF-2, whereas the other three anti-VEGF agents approved for the treatment of nAMD--ranibizumab, bevacizumab and brolucizumab--can only bind VEGF-A [13,14]. It has been proven that repeated intravitreal injections of affibercept can lead to its accumulation in serum. [PERSON] et al. revealed that the maximum serum concentration (Cmax) of affibercept was 0.45 nM after the first dose of 2 mg/0.05 mL, and then after the third monthly injection Cmax this increased to 0.58 nM [15]. Two main routes for drug entry into systemic circulation after intravitreal injection are known. The first pathway is based on the mechanism of the diffusion of drug molecules into the anterior chamber of the eye and the outflow, along with the aqueous humor, further into the systemic circulation [16]; the second pathway involves the interaction between drug molecules with fragments of Fc molecules in their structure and Fc receptors located in the blood-retina barrier (BRB). According to current knowledge, this interaction is responsible for the penetration into the systemic circulation of affibercept and bevacizumab, anti-VEGF agents with an Fc domain fragment in their structure, as well as a much smaller systemic exposure of intravitreal ranibizumab lacking the Fc domain in its structure [8]. VEGF-A, along with PIGF, belongs to the platelet-derived growth factor (PDGF) supergene family [10]. Pathological conditions, such as inflammation, hypoxia, ischemia and injury, result in increased VEGF expression [6,10]. It has been proven that both VEGF and PIGF are key factors regulating the process of abnormal angiogenesis, and also play an important role in inflammatory [8] and autoimmune [9] processes--these three components are suspected of being the main contribution to the still not fully understood pathophysiology of nAMD [1]; hence, the current therapeutic strategies for nAMD are based on monoclonal antibodies inactivating VEGF-A (bevacizumab, ranibizumab) or VEGF-A, VEGF-B and PIGF (aflibercept) [15]. Our study showed a significant decrease in systemic PIGF levels after the third monthly intravitreal administration of affibercept in patients with nAMD, compared to the serum PIGF levels determined before the first injection. [PERSON] et al. reported a counterregulatory increase in systemic PIGF, but not VEGF-A, one week and four weeks after a single intravitreal injection of afflibercept [17]. An increase in systemic PIGF after a week, but not after four weeks, associated with only a single intravitreal injection of afflibercept, was observed by [PERSON] et al. in patients with diabetic macular edema (DME) [18]. Interestingly, in our study, negligible changes in serum VEGF-A levels were observed. Contrary to our results, in previous studies a significant decrease in systemic VEGF levels measured after 3 h [15,19], 1 day [20] or 7 days [21, 22, 23] was observed, which persisted over one month after intravitreal afflibercept administration [15,19, 20, 21, 23, 22]. In studies that also evaluated the effect of three monthly afflibercept injections on systemic VEGF levels, the results were comparable with those obtained after the first injection [15,19]. We suggest that further studies with longer monitoring of serum VEGF-A concentration are necessary to fully assess the possibility of the occurrence of long-term VEGF-A-mediated pro-angiogenic response after the initial loading phase of intravitreal afflibercept. Among the IL-17 family, six specific cytokines have been distinguished--IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F, respectively. These cytokines affect target cells through specific receptors located on the surface of the cell membrane [24].