This study aimed to identify the retinal vascular conditions associated with the reactivation of ROP after ranibizumab monotherapy, the key aspects that should be monitored during follow-up, and whether repeat ranibizumab treatment is effective in reactivated ROP.
The study findings are summarized as follows: 1) In all infants with reactivated ROP, it took more than 1 week for the resolution of plus disease. 2) After the first ranibizumab injection, retina vascular formation in the peripheral area was slower in the reactivated ROP group than in the non-reactivated ROP group. Eight weeks after injection, 90% of the reactivated ROP group showed retinal vascularization within 1 DF from the original lesion. 3) All recurrent lesions occurred in posterior zone II, and the formation of retinal blood vessels in zone II occurred at an average of 18.9 ± 5.2 weeks after the first injection. 4) In the absence of vitreous traction, reinjection of ranibizumab is effective in the treatment of reactivated ROP.
The reported recurrence rate after ranibizumab treatment ranges from 4.3–52%19. In the RAINBOW study11, 22 eyes (15%) in the ranibizumab 0.2 mg group and 26 eyes (17%) in the ranibizumab 0.1 mg group received additional treatment due to ROP recurrence. The RAINBOW study6 recommends the use of 0.2 mg ranibizumab, but in real-world settings, ranibizumab is used in various doses from 0.15 mg to 0.3 mg11,15,20. A US multicenter study15 found no significant difference in the retreatment rate between the low-dose and high-dose ranibizumab groups. In this study, the retreatment rate due to recurrence of ROP treated with 0.2 mg injection of ranibizumab was approximately 25%.
The risk period for recurrence after intravitreal bevacizumab monotherapy is from 45 to 55 weeks PMA, which is the critical 10-week “recurrence window”; in rare cases, recurrence may occur up to 65 weeks PMA21. In the BEAT-ROP study, the mean time to recurrence after bevacizumab monotherapy was 16.0 ± 4.6 weeks5.
There are differences in the recurrence rate and duration of ROP depending on the anti-VEGF agent used, which may be related to their different pharmacokinetic properties. In the study by Chan et al.22, ROP recurred at an average of 7.6 weeks after the administration of ranibizumab. Gunay et al.16 reported that recurrence occurred at an average interval of 8.75 ± 1.5 weeks after treatment with ranibizumab, whereas the average interval was considerably longer after treatment with bevacizumab (14 ± 2.65 weeks). According to a meta-analysis of ROP study20, retreatment in the intravitreal ranibizumab group (9.29 ± 4.47 weeks) was earlier than that in the bevacizumab group (11.36 ± 4.31 weeks) or aflibercept group (12.96 ± 2.24 weeks). Consistent with the previous studies, the time of retreatment in the present study was 39 to 53 weeks PMA, and the average retreatment interval after the first injection was 9.0 ± 3.3 weeks (range 4–16).
The typical clinical course after anti-VEGF injection is that the plus disease typically begins to regress within 1 week and the ROP lesion regresses in 2 to 4 weeks11,17. In the present study, it took more than 1 week for the plus disease to disappear in all cases in the reactivated ROP group. This may be attributable to a higher VEGF concentration before injection in cases with reactivated ROP. Moreover, the time required for ROP regression was longer in the reactivated ROP group than in the non-reactivated ROP group (3.4 vs 2.0 weeks).
ROP treated with anti-VEGF injections has a higher risk of recurrence when retinal vascularization beyond the avascular area is very slow or halted and the ischemic retinal area becomes very large over time23–25. A question arises: To what extent should retinal blood vessels form after anti-VEGF injection to reduce the risk of ROP recurrence? This is an important issue in follow-up after anti-VEGF therapy. The area from the optic disc to 2 DF corresponds to Zone I, the area from 2 DF to 3 DF corresponds to posterior Zone II, and the area from 3 DF to 4 DF corresponds to Zone II18. Mintz-Hittner et al.21 reported that the anterior extent of retinal vascularization in recurrent ROP after bevacizumab monotherapy was 1.76 disc diameters and the rate of vascularization was 0.23 disc diameters/week. Wu et al.26 reported that retinal vascularization of 4 DF from the optic disc to the temporal retina and 3.3 DF to the nasal retina after ranibizumab monotherapy can be considered a safe indicator of reactivation after ranibizumab therapy. In this study, the extent of vascularization at 4 weeks after primary ranibizumab injection in the recurrent ROP group was less than 0.5 DF from the original lesion in all cases, and the extent of vascularization at 8 weeks after injection was less than 1 DF in 90% of cases. Additionally, all recurrence areas were in the posterior Zone II, including the advanced edge or the original lesion.
It is important to assess whether ROP has regressed well or is at risk of recurrence until 55 weeks of PMA, but continuous checkups thereafter are a burden for both the baby and their guardian. So, what is the optimal duration of follow-up retinal examination for premature infants who have received anti-VEGF injection treatment? Toy et al.23 suggested that ROP should be monitored until retinal vessels have formed within 2 disc diameter of the ora serrata. Therefore, if retinal vascularization is safely formed up to Zone II, the risk of ROP recurrence can be considered low.
The present study suggests that it is important to carefully check the following aspects during follow-up after ranibizumab administration. First, did the plus disease disappear within 1 week after the first injection? Second, did the ROP lesion regress within 4 weeks? In most cases, when regression occurs within 2 weeks, recurrence is unlikely to occur. Additionally, if regression does not occur within 4 weeks, it can be considered as incomplete regression. Third, have more than 1 DF of vascular progression formed at 8 weeks after injection? Fourth, were retinal blood vessels formed up to zone 2 after injection?
Most cases of ROP require only one or two anti-VEGF injections.11,15,21,27 A third injection is rarely required. Martínez-Castellanos et al.28 recommended that anti-VEGF injection should be repeated if ROP worsens due to inadequate technique, if elevation of ridge with new vessels is observed, and if flat new blood vessels are observed; however, vitrectomy should be performed if vitreous traction is observed above the ridge. In the Korea multicenter study10, laser treatment was preferred over anti-VEGF reinjection in cases requiring additional treatment. However, when anti-VEGF injections were selected, they tended to be administered at a dose equal to or higher than the first injection. In the present study, Infant #1 had a reactivated lesion with vitreous traction (blue arrow) that progressed to focal retinal detachment after reinjection. Therefore, in cases with vitreous traction over a ridge or extraretinal vascular proliferation, re-injection of ranibizumab may lead to tractional retinal detachment.
Some limitations of this study should be considered. This was a retrospective singer-center study. In addition, we did not use the vascular severity score (an objective indicator of the changes in plus disease) and fluorescein angiography (to delineate the retinal vascular abnormalities and peripheral retinal state). However, unlike other studies, this study provides valuable insights for the follow-up of ROP patients after ranibizumab monotherapy. It is important to check whether regression is occurring up to 4 weeks after injection and to check whether retinal vascularization is well formed at least 1DF from the original lesion at 4 to 8 weeks. Moreover, this study is meaningful in that few studies have reported clinical outcomes after re-injection of ranibizumab.
In conclusion, we performed serial fundus photography and fundus examination to identify the characteristics of retinal blood vessels associated with ROP reactivation. Our findings suggest that ROP recurrence is more likely to occur if retinal vascular development is slow even more than 8 weeks after injection. In the absence of vitreous traction, ranibizumab reinjection is considered effective in treating recurred ROP. However, further fluorescein angiography studies will help standardize the follow-up guidelines after anti-VEGF therapy and treatment protocols for reactivated ROP.