New therapies enrich noninfectious uveitis treatment landscape
Complex, multifactorial and associated with at least 40 different disorders, uveitis is the fifth leading cause of blindness worldwide. With an estimated 30,000 new cases each year, it is responsible for about 10% to 15% of all cases of legal blindness in the United States.
“It is not a negligible percentage,” OSN Retina/Vitreous Board Member Seenu M. Hariprasad, MD, said.
Uveitis is a visually debilitating condition that often recurs and is oftentimes an indication of underlying systemic diseases.
“These patients are burdened with multiple medications having harsh side effects, high copays for visits and testing, and frequent visits to more than one specialist, all of which strongly impact the patient’s life,” he said. “Reducing this burden by preventing recurrences and enhancing the efficacy, durability and safety profile of treatments is a goal we are constantly working toward.”
In the past few years, significant progress has been made in the management of noninfectious uveitis. New options already approved or on track for approval have improved the treatment landscape and enriched the armamentarium of specialists.
“In the past, all that was available were systemic agents and off-label triamcinolone acetonide. Now, we have Humira (adalimumab, AbbVie) for systemic treatment, as well as Ozurdex (dexamethasone intravitreal implant 0.7 mg, Allergan), Yutiq (fluocinolone acetonide intravitreal implant 0.18 mg, EyePoint Pharmaceuticals), Retisert (uocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb) and Xipere (triamcinolone acetonide suprachoroidal injectable suspension, Clearside Biomedical/Bausch + Lomb) as options. They have different indications and durability, and may be complementary to one another,” Hariprasad said.
Differentiating infectious and noninfectious cases
An important first step in patients presenting with signs and symptoms of uveitis is to differentiate between infectious and noninfectious disease.
“Treatment is entirely different, and if we treat infectious uveitis with immunosuppression or steroids, we may cause harm,” Hariprasad said.
Once infectious causes have been ruled out, the exact etiology of the noninfectious form must be determined. From beginning to end, the investigation is a long, difficult challenge and requires an extensive workup.
“There is no easy single test that can be used to differentiate infectious from noninfectious,” Thomas A. Albini, MD, said. “The differentiation is made on the basis of history and risk factors for infections, such as recent hospitalization or surgery. However, endogenous endophthalmitis might be misdiagnosed as noninfectious uveitis. Clinical examination might give some clues to infectious causes, such as toxoplasmosis. But toxoplasmosis sometimes has an unusual presentation and can be difficult to recognize.”
Often, he said, it is imperative to collect a sample of intraocular fluid and perform PCR testing and culture. Serologic testing for syphilis should not be missed.
A future aim is to have better testing methods and more precise diagnostic criteria.
“We have the technology to test smaller and smaller samples of fluid, and yet nothing has really changed in our ability to test for infectious causes of uveitis over the last 20 years,” Albini said.
Current diagnostic criteria for infectious and noninfectious uveitis are based on expert consensus. The Standardization of Uveitis Nomenclature Working Group has been working on the standardization of terminology and has achieved consensus on the definition of several commonly used terms. The same group is using a computer-assisted algorithmic process to identify diagnostic criteria based on real-world cases of the disease.
“AI and computer-based learning might help us develop more accurate diagnostic criteria in the future. However, we don’t have the tens of thousands of cases of uveitis as we do for AMD and DR, for example. AI requires a lot of data,” Albini said.
Multimodal, ultra-widefield imaging plays a crucial role in the diagnosis and management of complex uveitis, according to Sumit Sharma, MD.
“Uveitis is pretty unique in that there is not one disease. There is a combination of 50 or 60 different diseases, and for each patient, a different imaging test is often the ideal. What I try to determine on the first visit is which imaging modality best characterizes the disease of each patient, and then I use that imaging modality even when the disease is inactive to be sure I catch any early sign of recurrence,” he said.
OCT, he said, can be used to detect macular edema and perivascular thickening when there is inflammation. It can also detect damage in the outer retina, the photoreceptor ellipsoid zone and the inner retina. Widefield fluorescein angiography will show areas of active inflammation, active leakage, reactivation of chorioretinal lesions and nonperfusion.
“On fundus autofluorescence, you also look for new areas of chorioretinal lesions, and you can catch active inflammation before it has the chance to show anything on examination. The first thing that will show up on fundus autofluorescence is a hyper- or hypofluorescent area that the patient will perceive as scotoma,” Sharma said.
Two goals of treatment
The No. 1 management strategy goal for noninfectious uveitis is to treat the acute phase of the disease.
“A patient who presents in the acute phase, as it often happens, has a very angry-looking eye with severe inflammation and macular edema. So, our first step is to get the acute phase under control, addressing these two manifestations,” Hariprasad said.
The second step is to decrease the rate of recurrence.
“Many patients keep having multiple episodes, and our second goal is to prevent this from happening again,” he said.
A combination of ocular and systemic agents is used to achieve these goals.
“We have a richer armamentarium today and can more confidently manage our patients with a range of FDA-approved options,” he said.
An initial course of oral steroids is the best way of getting inflammation under control, according to Albini. Long-term immunosuppressive therapy is initiated shortly after in specific types of noninfectious uveitis at a high risk for vision loss, such as Behçet’s disease, sympathetic ophthalmia or multifocal choroiditis.
“In other situations, I may just taper off the steroids and start immunosuppression only after there is evidence of recurrent disease,” he said.
The choice of agent is usually either methotrexate, an antimetabolite that has been used off label in ocular inflammatory diseases for many years, or Humira, a recombinant human monoclonal antibody and the first drug to be specifically approved by the FDA for uveitis.
The choice may depend on cost.
“We have no comparative data. We don’t know if Humira is better or worse than the more traditional agents, but the price difference is huge,” Albini said. “Humira is about $5,000 a month in the U.S. and less than half of that in Europe, while methotrexate is $50 a month. So, this is an area where it would be nice to have some data to guide us.”
The appealing aspect of Humira is that it is delivered by subcutaneous injection every 2 weeks, while oral methotrexate is given as multiple small pills taken once weekly. Humira also seems better tolerated in terms of less nausea and fewer side effects and does not require monthly blood testing as methotrexate does.
“The decision is really made with the patient, taking into account the insurance provider because not all insurance reimburses for Humira and discussing the side effects of each treatment, the dosing regimen and the need for lab tests,” Albini said. “That’s the standard. If those drugs don’t work, I use a T-cell inhibitor like tacrolimus as third-line agent.”
As a uveitis specialist, Albini said he feels confident in managing systemic treatment, with the exception of pediatric cases, for which he consults with a pediatric rheumatologist.
Approved sustained-release devices
Local ocular-based therapies have also evolved toward a better risk-benefit profile and decreased treatment burden.
“Retisert, a 0.59 mg fluocinolone acetonide intravitreal surgical implant, was approved in 2005 but is rarely used today because of the high cost (approximately $18,000) and because it requires implantation in the operating room. The procedure is invasive, and the side effect profile of the drug is very poor,” Hariprasad said.
Ozurdex was approved for uveitis in 2010 and was a significant step forward as it was the first FDA-approved steroid administered in the office setting for this condition.
Michael A. Singer, MD, developed a technique that makes Ozurdex injection safer.
“The Ozurdex applicator is a spring that correlates with high speed of pellet insertion. This likely increases the risk of retinal tear and vitreous hemorrhage. In a study, we demonstrated that injection of Ozurdex during a 3-second period significantly reduces the impact velocity and force of pellet insertion. Therefore, we recommend administering Ozurdex injections by rolling the thumb over the length of the button over a period of 3 seconds for a more gentle release of the implant. This is most important in vitrectomized patients but obviously is still a good idea overall,” he said.
Ozurdex is an effective strategy for getting inflammation under control in the acute phase. The drawback is the relatively short duration of action, approximately 4 months, which does not prevent recurrence.
“I feel comfortable using Ozurdex, but the problem is that it should be used several times to control inflammation. After about 4 months, another injection is required,” Singer said.
More recently, Yutiq was approved in 2018. The implant can be injected in the office and is designed to last for up to 3 years. The primary outcome of two parallel phase 3 studies showed a significantly lower recurrence rate compared with sham.
“I don’t use Yutiq as primary treatment; I use it for maintenance. Based on the pharmacokinetics of the medication, Ozurdex effect peaks in the first 2 weeks after the injection and then goes down over time. Yutiq is a much longer and slower dose-release mechanism,” Singer said.
The best strategy, he said, is Ozurdex first to aggressively turn off inflammation, followed by Yutiq when the inflammation is quiet.
“I don’t wait for the inflammation to return before I start the Yutiq because I believe that it does a great job controlling it,” he said. “By analogy, in order to put out a fire, initially you need a fire hose. In order to keep the fire controlled when it is just embers, you can use something like a sprinkler system.”
New site of administration
Xipere is a preservative-free suspension of triamcinolone acetonide prepackaged in a syringe with a special needle for injection in the suprachoroidal space.
“It has the theoretical advantage of a higher concentration of steroids at the source of inflammation, which is the choroid and retina, minimizing concentration anteriorly. This should result in higher efficacy and lower rate of side effects such as IOP elevation and cataract compared with intravitreal injections,” Sharma said.
A head-to-head comparison would be necessary to confirm this theoretical advantage, which could represent a breakthrough in uveitis treatment with less concern about side effects.
Sharma was involved in the Xipere clinical trials and said there is a short learning curve to doing the procedure, but it is something that all retina specialists will be able to perform.
According to Hariprasad, Xipere is an important new addition to uveitis treatment because it is specifically indicated for macular edema, which is the No. 1 cause of vision loss associated with uveitis.
“In the setting of uveitis, people don’t lose vision because of the inflammation but because of the edema,” he said.
The durability of Xipere is in the range of Ozurdex, between 4 and 8 months, but this still has to be determined, and FDA approval is pending.
“A systemic approach is still the mainstay of treatment for noninfectious uveitis, and I use the sustained-release drugs only in specific cases, such as in patients with diabetes or hypertension and in pregnant or potentially pregnant women, to avoid the side effects of steroids,” Albini said.
Another subset of patients is those who are against systemic treatment in general.
“Patients can really be prejudiced in either way. Some would rather do anything to avoid any type of surgery or injection to the eye, and others would rather do anything to the eye but avoid being on a systemic agent and being exposed to systemic side effects. The choice between systemic and local therapy is really made on a patient-to-patient basis. On the other hand, in patients who have glaucoma, you want to avoid local therapies that increase IOP, and in children you would not use them either because of the risk of cataract,” he said.
Hariprasad said he uses the intravitreal sustained-delivery steroid option as first-line treatment in bilateral noninfectious disease.
“My first experience with a ‘wow’ effect, back in 2011, was a young woman with bilateral noninfectious uveitis treated with Ozurdex. She had such a beautiful response, and this is when I first realized the potential of sustained-delivery steroid technology. Additionally, I have done many Yutiq injections, and it has been life-changing for these patients. A young woman, a schoolteacher, who had at least two recurrences this past year has done spectacularly with Yutiq. She now has 20/25 vision with no recurrences, which has been life-changing for her personally and professionally. As far as Xipere is concerned, we have high expectations,” he said.
Hariprasad is confident that acceptance of these new options will grow with the publication of further data and expert discussion.
“The community is still learning about these treatments. Since these technologies are not inexpensive, a lot of clinicians are waiting to hear the experience of colleagues before implementing them,” he said.
Children are a subset of patients in whom uveitis treatment is an even greater challenge. Topical steroids cause cataract and glaucoma, which are more devastating for children than adults, and systemic steroids are associated with growth retardation.
“I can always tell a child with juvenile idiopathic arthritis because they are typically smaller,” Lisa J. Faia, MD, said.
Adalimumab is approved for patients aged 2 years and older, and the citrate-free formulation, which makes injections less painful, means administration is easier in pediatric patients.
“It is amazing what it can do for children. With an injection every 2 weeks, they start running and playing again. They are doing so much better,” Faia said.
Due to the risk for glaucoma and cataract, sustained-release drugs are still not indicated.
“Cataract surgery in a child means staying aphakic for about 1 year because of the inflammatory response. It is too big of a deal. Glaucoma procedures may be of limited utility due to the scarring because children have a robust inflammatory response. I would love to be able to use local therapies, but the risk profile is still too high,” Faia said.
Diverse options for diverse disease
The holy grail of noninfectious uveitis treatment would be a sustained-release drug that does not cause IOP elevation and cataract formation that could be delivered locally with an in-office procedure.
“Cataract formation with steroids is universal. If you give enough steroids for enough time, you will get a cataract, and IOP rise occurs in about a third of patients overall,” Sharma said.
However, what is available now is a significant advance compared with what was available 5 years ago.
“Slowly but surely, we are adding more treatments, and hopefully we will eventually have a treatment that has the anti-inflammatory effect of corticosteroids but avoids the side effects,” he said.
“I am very glad to see the development in this landscape, from having one off-label therapy with no clinical trial data to support its use to having two good FDA-approved agents and another awaiting approval, hopefully this year. From a management standpoint, it is a very good time for patients with these very burdensome inflammatory diseases,” Hariprasad said.
No magic bullet that works for every case of uveitis has been discovered so far, but uveitis is a diverse disease and it is good to have a diverse set of treatment options, according to Albini.
“The more options we have, the better off we are, and we can predict that we will become much more successful in controlling this inflammatory condition over time as we develop more and more targeted therapies,” he said. – by Michela Cimberle
- Albini TA, et al. Dev Ophthalmol. 2016;doi:10.1159/000431131.
- Albini TA, et al. Ocul Immunol Inflamm. 2020;10.1080/09273948.2018.1560476.
- Bessette AP, et al. Ophthalmol Retina. 2017;doi:10.1016/j.oret.2017.02.005.
- Chen TH, et al. Ophthalmic Surg Lasers Imaging Retina. 2018;doi:10.3928/23258160-20181101-02.
- Cunningham ET Jr, et al. Ocul Immunol Inflamm. 2015;doi:10.3109/09273948.2015.1114778.
- Gritz DC, et al. Ophthalmology. 2004;doi:10.1016/j.ophtha.2003.06.014.
- Jabs DA, et al. Am J Ophthalmol. 2005;doi:10.1016/j.ajo.2005.03.057.
- Krambeer CJ, et al. Ophthalmic Surg Lasers Imaging Retina. 2019;doi:10.3928/23258160-20190129-14.
- Oliver GF, et al. Ophthalmology. 2017;doi:10.1016/j.ophtha.2017.03.009.
- Ong DN, et al. Clin Exp Ophthalmol. 2019;doi:10.1111/ceo.13694.
- Pichi F, et al. Prog Retin Eye Res. 2017;doi:10.1016/j.preteyeres.2017.04.005.
- Refere-Linero C, et al. Ocul Immunol Inflamm. 2019;doi:10.1080/09273948.2019.1578380.
- Sharma S, et al. Ophthalmology. 2015;doi:10.1016/j.ophtha.2015.02.032.
- Testi I, et al. Ther Deliv. 2019;doi:10.4155/tde-2019-0051.
- Tomkins-Netzer O, et al. Ophthalmology. 2015;doi:10.1016/j.ophtha.2015.07.036.
- Yeh S, et al. Retina. 2019;doi:10.1097/IAE.0000000000002279.
- For more information:
- Thomas A. Albini, MD, can be reached at Bascom Palmer Eye Institute, 900 NW 17th St., Room 264, Miami, FL 33136; email: email@example.com.
- Lisa J. Faia, MD, can be reached at Beaumont Neuroscience Center Building, 3555 W. 13 Mile Road, Suite LL-20, Royal Oak, MI 48073; email: firstname.lastname@example.org.
- Seenu M. Hariprasad, MD, can be reached at University of Chicago Medicine and Biological Sciences, 5841 S. Maryland Ave., MC 2114, Chicago, IL 60637; email: email@example.com.
- Sumit Sharma, MD, can be reached at Cleveland Clinic, Desk i32, 9500 Euclid Ave., Cleveland, OH 44195; email: firstname.lastname@example.org.
- Michael A. Singer, MD, can be reached at Medical Center Ophthalmology Associates, 11900 Crownpoint Drive, #140, San Antonio, TX 78233; email: email@example.com.
Disclosures: Albini reports he is a consultant for Allegro Ophthalmics, EyePoint Pharmaceuticals, Allergan, Beaver-Visitec, Adverum Biotechnologies, Novartis, Santen, Genentech, Valeant, Notal Vision, Janssen Biotech, RegenxBio and Clearside Biomedical. Faia reports she is a consultant for AbbVie, Santen and Genentech and is on the speaker bureau for AbbVie, Allergan and Genentech. Hariprasad reports he is a consultant for Graybug, Allergan, Novartis, OD-OS, EyePoint, Alimera Sciences, Spark and Regeneron. Sharma reports he is a consultant for EyePoint, Clearside, Genentech, Roche, Regeneron, Allergan, Alimera and Bausch + Lomb. Singer reports he is a consultant for Allergan and EyePoint.
Click here to read the Point/Counter "Which treatment paradigm — local or systemic therapy — best treats bilateral noninfectious uveitis?"