Uveitis has multiple consequences, including macular edema (ME), which can continue even with control of the overlying inflammation. Although intravitreal steroids are a common treatment choice, other options have also been considered, including anti-VEGF agents and methotrexate. To evaluate these, the Macular Edema Ranibizumab vs Intravitreal Anti-Inflammatory Therapy (MERIT) Trial compared intravitreal dexamethasone implants vs intravitreal ranibizumab and intravitreal methotrexate. 

MERIT was a multicenter, randomized, parallel treatment trial. It included patients with anterior, intermediate, posterior, and panuveitis divided in a 1:1 fashion. Included patients were over the age of 18 and had inactive or minimally inactive uveitis with ME. Patients were treated with intravitreal dexamethasone (0.7 mg implant, Ozurdex; Allergan/AbbVie), ranibizumab (0.5 mg in 0.05 mL, Lucentis; Genentech), or methotrexate (400 mg in 0.1 mL). Ultimately, intravitreal dexamethasone provided the most control of ME, with a reduction in central subfield thickness of 35%, as compared to ranibizumab (22%) and methotrexate (11%).¹ Below, we discuss the results of the trial with 2 of the lead authors, Douglas A. Jabs, MD, MBA, and Nisha Acharya, MD, MS.

Sruthi Arepalli, MD: What was a motivating interest for comparing these 3 agents?

Douglas A. Jabs, MD, MBA: The MUST trial showed that even with systemic therapy that controls the inflammation, almost two-thirds of patients with uveitic ME need at least 1 adjunctive regional corticosteroid injection.² Another thing we learned was that at about 2 years, 40% of patients had persistent ME. The question arises whether to give those patients additional corticosteroid injections or do something else. A third observation from the MUST trial was that over time, ME did go away in almost 90% of patients, but about 40% had a relapse. So, there is both persistent uveitic ME and relapsed uveitic ME among uveitis patients receiving systemic medications. Some preliminary data have suggested that after an initial regional corticosteroid injection, a second one adds added benefit, so that’s a viable option. Preliminary pilot data from Dr. Acharya suggested that anti-VEGF, namely intravitreal ranibizumab, may have value in this situation,³ and we know that in conditions such as vein occlusion, anti-VEGF is probably better than corticosteroids.⁴ There were also some data from the United Kingdom suggesting that intravitreal methotrexate was very useful for noninfectious intermediate posterior and panuveitis with benefits for ME. So, we now have 3 options available for regional treatment of persistent or recurrent uveitic ME, and that led to the MERIT trial, which evaluated the comparative effectiveness of intravitreal ranibizumab vs intravitreal methotrexate vs the intravitreal dexamethasone implant for persistent or recurrent uveitic ME.¹

SA: What were some of the biggest takeaways from this study?

Nisha Acharya, MD, MS: The biggest takeaway is that for patients with persistent or recurrent uveitic ME who have controlled inflammation, intravitreal steroids is a superior choice to ranibizumab or to intravitreal methotrexate for reduction of ME and for improvement in visual acuity (VA), which is the most important clinical outcome in this patient population. Visual acuity gain was clearly superior in patients with the dexamethasone implant. 

There was also concern about repeated intravitreal steroid use causing more adverse events in terms of pressure elevation. This trial did show that patients who received the dexamethasone implant had greater increases in intraocular pressure compared to the other 2 treatment groups. However, these were relatively mild overall and there was not a significant difference at the 30 mmHg or higher threshold. No patients needed glaucoma surgery. Overall, the results support the use of intravitreal corticosteroids for uveitic ME that is persistent or recurrent.

DJ: Only intravitreal corticosteroids improved VA. The other 2 treatments had no significant VA improvement at 12 weeks. As Dr. Acharya said, the clear winner in this trial was repeat intravitreal corticosteroids. 

NA: It’s also important to note that the improvement was clinically meaningful at 1 line of improvement on the ETDRS chart with the dexamethasone group, and it was also statistically significant.

SA: Did anything about this surprise you given the results of the paper?

NA: Given prior studies,⁵ I was surprised especially by the lack of response with methotrexate, which was very striking. Ranibizumab did show some improvement in macular thickness, but not in VA. Methotrexate showed no benefit anatomically or in VA. One potential reason for this lack of response may be that the prior studies published on intravitreal methotrexate included patients with active uveitis and some with uveitic ME. In MERIT, however, patients had to have minimally active or inactive uveitis with persistent or recurrent ME. This difference might explain the results, but it still was surprising. These results point to the importance of doing randomized clinical trials to definitively compare treatments.

We were also surprised by the duration of effect of the dexamethasone implant. The POINT trial, another NIH/NEI funded trial that Dr. Jabs led prior to MERIT, compared intravitreal to periocular corticosteroids.⁶ Based on the registration clinical trial data, dexamethasone was expected to last up to 6 months, but in the POINT trial, the peak efficacy was closer to 8 weeks. That bore out again in the MERIT trial, but at 12 weeks, dexamethasone was still superior to the other treatments. That’s why these kinds of trials are important. This is a different patient population than the clinical trials that led to approval of the dexamethasone implant and that has practical implications for how the drug is used. These results indicate that ophthalmologists may need to inject intravitreal dexamethasone more frequently to maintain the effect.

DJ: I agree with Dr. Acharya about the surprising results, but we often seem to forget that the dexamethasone implant has a biphasic release — a very high initial release followed by a lower sustained release. We saw a maximum benefit at about 8 weeks, right after the high initial release, which was followed by a somewhat lesser but still significantly beneficial effect at 12 weeks, during the steady-state release. This suggests that the intravitreal dexamethasone implant may need to be administered every 3 to 4 months for uveitic ME rather than every 6 months, as we saw in the original HURON study of the dexamethasone implant for uveitis.⁷ 

SA: Are there any instances in which you would consider the other 2 therapies, methotrexate or ranibizumab, over the dexamethasone implant in uveitic ME?

DJ: The lack of effect of methotrexate in MERIT suggests it really does not have a role in the management of uveitic ME. Ranibizumab probably doesn’t have a role in uveitic ME either, because of the lack of effect on VA and the very modest effect on ME. The one caveat here is that these are just the 12-week results, so it is conceivable that there might be a late improvement in VA. However, based on the data we have now, I would not use it.

NA: I agree with Dr. Jabs. Some might suggest the other drugs for patients who have high pressure or very little optic nerve reserve. However, the goal is to treat the ME, so it does not make sense to treat with alternative therapies if they won’t work. Even in those patients with high intraocular pressure, the strategy would be to use the steroids and to enlist the help of glaucoma specialists to control pressure, because the goal is to treat the ME. 

I’ve also heard people say that they would consider other therapies when a patient has a compromised posterior capsule, because a dexamethasone implant could migrate anteriorly. That is a reason not to inject the implant, but that doesn’t mean using the other 2 therapies studied in MERIT is the only option, because there are other intravitreal steroid formulations that are comparable to the dexamethasone implant. The POINT trial showed that intravitreal triamcinolone is comparable to intravitreal dexamethasone.⁶ That would be fine in a patient with a compromised capsule. 

SA: Anything else you’d like to add?

NA: These kinds of trials are a huge collaborative effort, with people around the world working together. The results of MERIT show the power of collaboration to answer clinically relevant questions that weren’t addressed by the initial studies conducted on these therapies.

DJ: It’s also important to recognize that although Dr. Acharya was a protocol chair and I’m the research group chair, we’re just the spokespeople for the entire research group. This work can’t be done without everyone’s participation. RP

Sruthi Arepalli, MD, is an assistant professor in the vitreoretinal and uveitis service at Emory University in Atlanta, Georgia. Dr. Arepalli reports consultancy to EyePoint Pharmaceuticals.

Douglas A. Jabs, MD, MBA, is a uveitis and ocular oncology specialist with Johns Hopkins Medicine in Baltimore, Maryland. He reports no relevant disclosures.

Nisha Acharya, MD, MS, is the director of the uveitis and ocular inflammatory disease service and the uveitis fellowship at the F.I. Proctor Foundation of the University of California, San Francisco. She reports consultancy to Roche.
Drs. Jabs and Acharya report that Genentech donated the ranibizumab for use in the MERIT trial.

References

1. Multicenter Uveitis Steroid Treatment Trial (MUST) Research Group Writing Committee, Acharya NR, Vitale AT, et al. Intravitreal therapy for uveitic macular edema-ranibizumab versus methotrexate versus the dexamethasone implant: the MERIT trial results. Ophthalmology. 2023;130(9):914-923. doi:10.1016/j.ophtha.2023.04.011
2. Tomkins-Netzer O, Lightman SL, Burke AE, et al. Seven-year outcomes of uveitic macular edema: the Multicenter Uveitis Steroid Treatment Trial and follow-up study results. 2021;128(5):719-728. doi:10.1016/j.ophtha.2020.08.035
3. Acharya NR, Hong KC, Lee SM. Ranibizumab for refractory uveitis-related macular edema. Am J Ophthalmol. 2009;148(2):303-309.e2. doi:10.1016/j.ajo.2009.03.028
4. Ming S, Xie K, Yang M, He H, Li Y, Lei B. Comparison of intravitreal dexamethasone implant and anti-VEGF drugs in the treatment of retinal vein occlusion–induced oedema: a meta-analysis and systematic review. BMJ Open. 2020;10(6):e032128. doi:10.1136/bmjopen-2019-032128
5. Taylor SR, Habot-Wilner Z, Pacheco P, Lightman SL. Intraocular methotrexate in the treatment of uveitis and uveitic cystoid macular edema. Ophthalmology. 2009;116(4):797-801. doi:10.1016/j.ophtha.2008.10.033
6. Thorne JE, Sugar EA, Holbrook JT, et al. Periocular triamcinolone vs intravitreal triamcinolone vs intravitreal dexamethasone implant for the treatment of uveitic macular edema: the PeriOcular vs INTravitreal corticosteroids for uveitic macular edema (POINT) Trial. Ophthalmology. 2019;126(2):283-295. doi:10.1016/j.ophtha.2018.08.021
7. Lowder C, Belfort R Jr, Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011;129(5):545-553. doi:10.1001/archophthalmol.2010.339