Aflibercept for choroidal neovascularizations secondary to pseudoxanthoma elasticum: a prospective study

Pseudoxanthoma elasticum (PXE, OMIM #264800) is a rare multi-system disease with autosomal recessive inheritance. PXE is caused by biallelic mutations in the ABCC6 gene which codes for a transmembrane protein that is mainly expressed in the liver [1]. Lack or reduced function of ABCC6 leads to increased calcification of tissue rich in elastic fibers, hence explaining the major manifestations of the disease, i.e., whitish-yellowish skin changes, early-onset arteriosclerosis, and characteristic ocular changes driven by calcification of Bruch’s membrane [2]. Decreased pyrophosphate levels are thought to play an important role in the disease process, but the exact pathogenic pathways are still unknown [3, 4].

The ocular phenotype is characterized by so-called peau d’orange which marks the transition zone between the centrally calcified and peripheral uncalcified Bruch’s membrane, peripheral chorioretinal atrophic spots (comet lesions), and angioid streaks which represent breaks within the thickened and brittle Bruch’s membrane [5‐7]. At later stages, macular atrophy may develop, or the disease course may be complicated by choroidal neovascularizations (CNV) that typically originate from angioid streaks [7‐9].

The risk for developing CNV is already significant in the 5th decade and increases further with age [8]. If left untreated, PXE patients with CNV may develop rapid and irreversible loss of central vision [10]. Among PXE-related morbidities, visual impairment most severely affects the patients’ quality of life [11, 12].

The development of intravitreal anti-vascular endothelial growth factor (VEGF) agents has significantly improved the visual prognosis of patients with PXE-related CNV. Good evidence exists for the efficacy of intravitreal bevacizumab and ranibizumab [10]. Another intravitreal VEGF inhibitor is aflibercept, which is a fusion protein of the extracellular domains of the VEGF receptor 1 and 2 and the Fc fragment of human IgG potentially blocking all isoforms of VEGF A and placental growth factor [13, 14]. The efficacy of intravitreal aflibercept is proven for CNV secondary to AMD [15] and myopia [16]. Evidence for efficacy for the treatment of CNV secondary to angioid streaks in PXE patients is limited to few case reports [17‐20]. In addition, there is one small prospective study on ranibizumab-pretreated patients with a CNV secondary to angioid streaks reporting favorable outcomes, which, however, was not specific for PXE patients [21]. Therefore, it was the aim of this study to prospectively investigate the use of intravitreal aflibercept for treatment-naïve and pretreated CNV in patients with PXE.

In this prospective study, treatment with 2 mg intravitreal aflibercept improved or stabilized BCVA in the majority of patients with PXE-associated CNV during a review period of 12 months. Concurrently, central retinal thickness decreased, leakage from active CNV was reduced, and retinal sensitivity on microperimetry improved. No uncommon or unexpected adverse event was observed. Accordingly, these results indicate that intravitreal aflibercept may be a treatment option for CNV associated with angioid streaks in PXE patients.

To our knowledge, this represents the first prospective study using aflibercept for CNV exclusively in patients with PXE. The results are in accordance with few previous case reports [17‐20] as well as with one small prospective study on CNV secondary to angioid streaks [21] and indicate comparable efficacy and safety as intravitreal bevacizumab and ranibizumab, which are widely used for the treatment of PXE related CNV [10].

At first glance, the results of this study with a mean gain of 4.3 ETDRS letters might seem less favorable compared with previous studies using other anti-VEGF agents. One comparable prospective study using monthly intravitreal ranibizumab injections for PXE-associated CNV reported an improvement of 12 ETDRS letters over a period of 12 month [23]. In addition, the randomized, placebo-controlled MINERVA study, which investigated the efficacy of intravitreal ranibizumab for the treatment of CNV due to other causes than AMD or myopia, included a subgroup of 27 eyes with angioid streak-related CNV that gained 11 EDTRS letters after 2 intravitreal injections [24]. However, baseline BCVA in these studies was worse (61 and 62 ETDRS letters) compared with the study reported herein (75 ETDRS letters). Patients with good BCVA were not excluded from participating in the current study in order to match the real-world situation, hence explaining differences of baseline BCVA compared with other studies. Of note, patients enrolled herein with lower baseline BCVA also had the largest improvement. Inclusion of eyes with BCVA of up to 20/20 results in less potential improvement (ceiling effect). Moreover, regression to the mean may additionally favor larger vision gains when preselecting eyes with worse vision. Both effects may also need to be considered when interpreting the higher effect sizes of eyes with lower baseline BCVA in this study.

Another confounder in this study was that both, treatment-naïve and pretreated eyes were included. Although visual acuity gain was comparable, treatment-naïve eyes had the overall better baseline and final BCVA. Treatment-naïve eyes with their favorable baseline characteristics received fewer injections indicating overall less diseases activity in this subgroup.

Cardiovascular complications such as stroke or cardiac infarction are a well-known complication of PXE [25]. Therefore, particular attention needs to be paid to cardiovascular adverse events when using anti-VEGF drugs in patients with PXE. One patient in this study experienced an asymptomatic ST-elevation on ERG examination followed by an uneventful intracardiac catheter examination, which was, however, graded as not likely associated with the study medication/procedure. Hence, although no definitive conclusions can be drawn due to small sample size and limited review period, the safety profile of intravitreal aflibercept in PXE patients seems comparable with other intavireal anti-VEGF drugs and in favor of treatment.

There are some limitations of this study. The relatively small sample size due to the rareness of the disease, and the heterogeneous cohort due to high phenotypic variability of PXE-related retinopathy may limit general conclusions [26]. Various parameters including the severity of disease manifestation in the fellow eye, dark adaptation, or contrast vision were not considered in this study, but may have influenced the outcome of the vision-related quality of life assessment [27]. Furthermore, although prospective, the study had no control group, e.g., with placebo treatment. This was based on the following considerations: First, withholding treatment in a control group can be associated with irreversible loss of vision, and some treatment options (e.g., photodynamic therapy) may result in significantly worse outcomes, which would both not be acceptable for a control group from an ethical point of view [10]. Second, the current gold standard for treatment are intravitreal anti-VEGF agents, but the only randomized, placebo-controlled study using ranibizumab had not been published at the time our study was conducted [24]. However, we speculate that any potential difference in a head-to-head trial with another anti-VEGF agent would have been unlikely to be detected due to the low number of patients included in this study. Third, the study included patients with BCVA of 20/20 minimizing treatment effects detectable using BCVA as primary outcome measure.

Overall, the results of this study indicate that intravitreal aflibercept is a treatment option for CNV associated with PXE. This expands the spectrum of available treatment options in patients with PXE which may be of particular value in cases with poor response to other treatment options.