Randomized Study of Intravitreal Injection of Bevacizumab in the Treatment of Persistent Uveitic Macular Edema

    

    

    Figure 3: Patient 6 who developed MEM during follow-up.
    

Central macular thickness (CMT) in μm

A statistically significant change in CMT was noted during follow-up:

At 1 year of follow-up, 65% of patients had a CMT of less than 300 μm and 55% had a CMT of less than 250μm.

2 patients had increased and stable macular thickness after 1 year of follow-up (Patients 14 and 17 who had a CMT of 1122 μm and 935 μm respectively) (Figures 41,44)

The average CMT was initially 546.55 μm. After 1 year of follow-up, the CMT was 369.95 μm

The improvement in CMT was statistically significant at 3 months and 1 year of follow-up.

After 3 months of follow-up, there was a reduction of at least 60 μm, and after 1 year of follow-up, the reduction in CMT was at least 100μm and this affected 65% of patients.

Our results show a reduction in CMT from 60 μm to 100 μm or more with a significant improvement in VA of 0.4 logMAR or 3 lines on the Monoyer scale after 1 year of follow-up.

VA was not completely correlated with CMT. We take the example of patients 2, 19, and 20 who had a normal CMT, while their VA (0.2; 0.2 and 0.1 logMAR, respectively) remained below 0 logMar or 10/10 in Monoyer.

Favorable responses to Bevacizumab in the following patients: 1,2, 4, 5, 11, 13, 16, 18, 19, 20.

No significant ocular or systemic side effects were observed with Bevacizumab IVT in our study. No patient developed ocular hypertension or endophthalmitis after injection.

There was no evidence of recurrence of uveitis after Bevacizumab IVT. In addition, no thromboembolic events were recorded in our patients during the follow-up period.

VA and CME results were favorable in younger patients (Patient 1, for example), and/or in patients with cystoid macular edema whose thickness did not exceed 400 μm and whose the integrity of the photoreceptor line was respected.

Discussion

The response of uveitic macular edema (VA + CMT) to treatment with Bevacizumab injection differs according to the authors. The different responses to anti-VEGF therapy can be explained by the different variations in the etiopathogenesis of uveitic macular edema [9].

Cordero Coma and al. treated 13 eyes of 13 patients with ME secondary to uveitis, resulting in significant loss of visual acuity, persistent to medical treatments. The use of intravitreal injection of Bevacizumab showed promising results, with improved VA and CMT in 62% of patients after a single injection. The chance of VA improvement increased gradually by week 6, reaching 81% by week 14 [9].

According to the same authors, the injection of Bevacizumab in uveitic ME is more advantageous than injection of corticosteroids, as well as less likely to cause glaucoma or cataract. Bevacizumab is prepared from a preservative-free solution and also contains no known retinal damaging ingredients. None of the patients in this study had myodesopsias with Bevacizumab [9]. Nevertheless, it has several drawbacks, including a shorter half-life and reduced anti-inflammatory effect in the vitreous. Although no patients required repeat injections in this study, the small number of patients included and the short follow-up limit the ability to judge the need for reinjection [9].

Fine and al showed in a study the relationship between uveitic ME and the concentration of angiogenic factors in the aqueous humor (HA) and blood of patients. In this cross-sectional study, VEGF levels were measured by enzyme-linked immunosorbent assays in the HA of patients with uveitis. Therefore, these authors found that VEGF is a potential target in the management of uveitic ME [10].

K Weiss and al studied 11 eyes in 9 patients with uveitic ME treated with 1.25 mg Bevacizumab injection into the vitreous. The 1.25 mg dose was used because the vitreous VEGF concentrations observed by K. Weiss in patients with uveitis were similar to those in patients with exudative AMD. 1.25 mg is the most commonly used dose [11].

He concluded that the beneficial effects of intravitreal Bevacizumab were transient. While 9 eyes showed at least 2 lines of visual enhancement during the first 2 weeks, only 3 eyes maintained this visual enhancement during the follow-up period. Favorable responses to retreatment indicate that the effect of Bevacizumab is insufficient. According to the same author, the main limitation of this study is that it included a small number of patients and a larger study is needed [11].

29 eyes of 27 patients with uveitic macular edema complicating uveitis of various causes were studied and analyzed according to RENE A and al, with a follow-up of one year. 13 patients had a single intravitreal injection of Bevacizumab, 6 patients required a 2^nd injection, with a mean logMAR visual acuity of 0.42. The average CMT decreased from 383.66 μm to 294.32 μm over the course of one year. The success of Bevacizumab injection in the treatment of uveitic ME is related to the fact that uveitis was in a lull in all patients before ME treatment [12].

LOTT and al. also retrospectively analyzed the effect of intravitreal injection of Bevacizumab on 13 eyes of 11 patients, with an average follow-up of 13 months. Each patient received between one and four IVTs (average of 2). After 6 months, 40% of patients improved in VA, 20% had no change, and 40% had worsening VA [13].

MACKENSEN and al. conducted a study involving 11 eyes of 10 patients, with 72% of patients having a favorable response 1 month after Bevacizumab injection and a significant reduction in CMT, while 4 patients had no improvement in VA [14].

Mirshahi and al. treated 12 patients with uveitic ME resistant to one or two IVTs of Bevacizumab but only in Behçet’s disease, with a mean follow-up of 4 months. VA improved in 58% of patients, remained stable in the remaining cases, while there was no significant change in CMT before and after treatment [15].

FARIBA GHASSEMI studied 19 patients and followed them for 6 months. 15 of them had ME due to Behçet’s disease and received an average of 3 IVT of Bevacizumab without statistically significant improvement in visual acuity and central macular thickness [16].

In our study, we collected 20 eyes of 20 patients with persistent uveitic ME. These patients constitute a cohort at a tertiary referral center, usually representing the most severe form of uveitis.

Our current study evaluates the short- and medium-term efficacy of Bevacizumab IVT in 20 patients with refractory uveitic ME, with or without the need for repeated injections.

All patients received at least one IVT of Bevacizumab, 8 eyes received a 2^nd injection, and only 5 who needed 3 IVT to restore macular structure and visual function. The criterion for retreatment is a CMT maintained > at 250 μm.

We showed significant improvement in VA and CMT during a 1-year follow-up time. 80% of our patients showed at least 2 lines of VA gain, with the achievement of better VA gain and a mean LogMar VA of 0.57 at 1 year follow-up. The decrease in ME can explain the visual improvement in most cases. Indeed, 65% of the patients had a CMT <300 μm with a mean CMT that decreased from 546.55 μm to 369.95 μm after 1 year of follow-up.

VA is not always correlated with CMT, some authors report a moderate to strong correlation, and others like MACKENSEN show a very weak correlation [14]. In our study, the VA did not correlate with the CMT in 3 patients; the latter had a normal CMT with a VA that remained deteriorated.

4 of the patients (20%), showed no improvement in VA or CMT throughout the follow-up period.

Our results are consistent with those of the following studies: Cordero Coma [9] and RENE A [12].

These initial data suggest that Bevacizumab injection may be an attractive complementary option for the treatment of refractory uveitic ME.

Our results find that the off-label use of Bevacizumab in the treatment of uveitic ME is well justified and tolerated. Early initiation of treatment, before the onset of retinal fibrosis, is recommended to prevent irreversible photoreceptor damage.

The strengths of our study are the number of patients included and the follow-up period (1 year). However, longer studies with a much longer follow-up period are warranted. Further randomized controlled trials on this topic with comparative statistical measurements of functional and anatomical data on macular OCT are recommended. We emphasize the critical importance of remission of uveitis for all patients who have received such treatment for refractory uveitic ME.

Conclusion

ME is the 1st cause of blindness in patients with uveitis. It remains a redoutable complication and very difficult to manage despite the many therapeutic strategies available.

Uveitic ME may persist despite remission of uveitis. The numerous adverse effects associated with the chronic use of ocular corticosteroids (local and/or systemic) for the treatment of uveitic macular edema have led to the search for new therapeutic options.

The mechanism by which anti-VEGF monoclonal antibodies might be effective in the treatment of uveitic macular edema is a matter of speculation. Intravitreal Bevacizumab appears to be a useful and advantageous alternative in the treatment of persistent uveitic macular edema. This therapeutic alternative has the advantage of fewer side effects but has the disadvantage of a short duration of action, hence the need for repeated injections. In addition to the risks associated with any IVT, such as endophthalmitis and systemic passage of Bevacizumab.

Assessment and measurement of intravitreal VEGF levels in patients with uveitic macular edema provides a basis for determining intravitreal VEGF-A concentrations and justifies the treatment and injection doses of Bevacizumab.

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