Therapeutic Options for Uveitis
Thanks to a plentiful number of choices available and in the pipeline, the future looks promising for patients with this condition.
Uveitis is an inflammatory condition associated with visual impairment, blindness, and reduced quality of life. The condition often affects patients in their most active and economically productive years.1 Uveitis has been demonstrated to cause between 5% and 20% of cases of legal blindness in the United States and the European Union, and up to 25% of cases of legal blindness in developing countries.2
AT A GLANCE
• Uveitis is a debilitating condition causing between 5% and 20% of legal blindness in the United States and the European Union.
• Immunomodulatory therapy is essential in controlling chronic inflammation, with decreased risks compared with chronic corticosteroid use.
• Numerous agents are in the pipeline for treatment of uveitis, including long-acting steroid delivery systems, local nonsteroidal agents, systemic therapies, gene therapies, and more.
Immunomodulatory therapy is essential in controlling chronic noninfectious inflammation, with decreased risks compared with chronic corticosteroid use. Steroid-sparing immunomodulatory therapy, such as antimetabolites (methotrexate and mycophenolate), T-cell inhibitors, alkylating agents, and, more recently, biologics, are commonly used to manage uveitis. This article is an overview of newer available treatments for uveitis and therapies under clinical investigation (see Table below).
Treatment guidelines discourage use of systemic corticosteroids at doses higher than 10 mg daily due to complications associated with prolonged use. However, local steroids, especially sustained-delivery options, have had increasing importance in the management of uveitis.
Fluocinolone Acetonide Intravitreal Implant 0.59 mg
The fluocinolone acetonide intravitreal implant 0.59 mg (Retisert, Bausch + Lomb) was approved by the US Food and Drug Administration (FDA) in 2005. It is surgically implanted to treat noninfectious intermediate uveitis, posterior uveitis, or panuveitis and releases drug for approximately 3 years.3-7
Preclinical studies demonstrated that the implant is well tolerated, with no measurable systemic drug absorption. In a multicenter trial, the implant effectively controlled inflammation for 34 weeks, preserved vision (87% stabilized or improved), reduced cystoid macular edema (CME), and decreased the need for adjunctive therapy.5 The implant reduced uveitis recurrence (no more than one for any patient in the study) and the need for adjunctive therapy.3,5
The MUST trial demonstrated statistically significantly better control of uveitis in the implant group (88% vs. 71%).7,8 Associated adverse events included increased intraocular pressure (IOP), cataract, hypotony, and suture exposure.3,4 The implant is contraindicated in active viral, bacterial, mycobacterial, and fungal eye infection.7
A follow-up study of the patients in the MUST trial concluded that patients treated with systemic therapy had better visual acuity outcomes than those in the implant group. However, in the second half of the 7-year study period, less than 30% of patients in the implant arm had had an implant placed, dampening the strength of this conclusion. The implant appears to work as well as systemic therapy while it releases drug (ie, the first 3 years after implantation). Patients with chronic inflammation may need to have the implant replaced every 30 months for optimum results.
Other Fluocinolone Acetonide Intravitreal Implants
The fluocinolone acetonide intravitreal implant 0.19 mg (Iluvien, Alimera Sciences) was FDA-approved in 2014 to treat eyes with diabetic macular edema.3,6 The implant is inserted intravitreally with a 25-gauge needle.3,6,7 In July, Alimera secured the rights to pursue a secondary indication for posterior uveitis in the European Union, the Middle East, and Africa.9
Jaffe et al3 found that the visual acuity of eyes with noninfectious intermediate uveitis, posterior uveitis, or panuveitis treated with the injectable fluocinolone acetonide implant stabilized or improved after 1 year. All 11 eyes in the study remained quiet and required less adjunctive therapy during 24 months of follow-up.3 There was evidence of resolution of anterior chamber cells; reduced vitreous haze; decreased macular thickness and volume and decreased retinal nerve fiber layer thickness on optical coherence tomography (OCT); and absence of recurrences. Adverse effects included increased IOP and cataract progression.3,6
The fluocinolone acetonide intravitreal implant 0.18 mg (Durasert, pSivida) is currently under investigation for use in posterior segment noninfectious uveitis. Phase 3 pivotal trials of 3-year treatment with this implant have met their primary endpoint with a favorable safety profile, but results have not been published.10,11
The dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan) is a sustained-release, injectable, biodegradable steroid implant approved in the United States and Europe for the treatment of noninfectious uveitis affecting the posterior segment.6,7 Implanted with a 22-gauge injector, the device releases dexamethasone in a biphasic manner over a 6-month period. After the first 2 months, the steroid concentration declines until month 4, when it maintains a lower concentration until month 6.
The HURON study compared the safety and efficacy of two doses (0.7 mg and 0.35 mg) of the dexamethasone intravitreal implant for the treatment of noninfectious intermediate or posterior segment uveitis over 6 months.12 Both doses were effective in controlling vitreous inflammation and improving visual acuity with reduction in CME, but the higher dose had a longer duration of action without a significant increase in side effects. A total of 47% of patients treated with the 0.7 mg implant achieved the primary outcome measure—a vitreous haze score of zero at 8 weeks.7,8 Observed side effects included raised IOP and cataract progression. The implant has also been shown to be effective in reducing macular thickness and increasing visual acuity in uveitic macular edema in vitrectomized eyes and in pediatric uveitis.6
The dexamethasone intravitreal implant 0.7 mg is contraindicated in patients with periocular infections and advanced glaucoma and in patients whose posterior lens capsule is not intact, due to a risk of implant migration into the anterior chamber, seen especially in vitrectomized eyes.7
Suprachoroidal Triamcinolone Acetonide
Triamcinolone acetonide (CLS-TA, Clearside Biomedical) is in development as a single suprachoroidal 4.0 mg or 0.8 mg injection for treatment of macular edema associated with noninfectious uveitis.
In the Dogwood trial, the primary endpoint of reducing retinal thickness was successfully achieved at 8 weeks after single treatment. The secondary endpoint of improving best corrected visual acuity (BCVA) was also achieved.13 Although data are limited, the hope is that suprachoroidal injection will maximize triamcinolone’s effect on the retina while minimizing its effect on the lens and trabecular meshwork.
LOCAL NONSTEROIDAL AGENTS
Sirolimus (Opsiria, Santen) is a macrolide compound derived from Streptomyces hygroscopicus. It has potent immunosuppressive and antineoplastic activity that depends on its binding to specific cytosolic proteins (immunophilins) to generate an immunosuppressive complex.14 Sirolimus inhibits the activity of the serine/threonine protein kinase of mammalian target of rapamycin (mTOR).
Oral administration of sirolimus demonstrated complete inhibition of autoimmune uveitis in preclinical models.2,15 However, this delivery route requires laboratory and clinical monitoring for systemic toxicity (anemia and hyperlipidemia). Bimonthly intravitreal sirolimus was effective at a dose of 440 µg without systemic side effects in a phase 1 study.14 At the 6-month and 12-month primary endpoints of the SAVE study, sirolimus reduced vitreous haze and the need for systemic corticosteroids in patients with uveitis.15
The phase 3 SAKURA 1 and 2 studies reported significant improvement in reducing ocular inflammation in patients with active noninfectious uveitis and successful tapering of corticosteroid dose (<5 mg/d). The results suggest that intravitreal injection of sirolimus can effectively resolve ocular inflammation, often without concomitant use of other local or systemic immunoregulators.2,14-16 The most often encountered adverse event was worsening of inflammation, with minimal ocular hypertension or cataract progression over 2 years.15
Systemic sirolimus (Rapamune, Pfizer) is approved for several indications. The ophthalmic formulation of sirolimus has been accepted for review by the FDA.
Adalimumab (Humira, Abbvie) is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody specific for tumor necrosis factor-alpha (TNF-alpha). Adalimumab binds TNF-alpha and blocks its interaction with its two known receptors. It is FDA-approved for the treatment of noninfectious intermediate uveitis, posterior uveitis, and panuveitis. Adalimumab is administered subcutaneously at a typical dose of 40 mg every other week.6,17-20
Suhler et al showed that adalimumab was safe and effective in 68% of refractory uveitis patients 10 weeks after initial dose, and the effect was maintained in 39% after 1 year.18 Jaffe et al reported that patients who received adalimumab had a significantly lower risk of treatment failure, defined as increased vitreous haze, new active inflammatory lesions, anterior chamber cell grade, or worsening of BCVA.17 After discontinuation of immunomodulatory therapy, adalimumab achieved early and sustained disease control, reducing inflammation and visual impairment. Its use is associated with significant reduction of macular thickness relative to baseline and with resolution of macular edema.17,18,20 17,20
Before initiation of treatment, baseline laboratory screening should be completed, consisting of complete blood count; comprehensive metabolic panel including liver function, renal function, and electrolytes; and screening for tuberculosis by tuberculin skin test and/or interferon gamma release assay.17,19 Contraindications include any evidence of active infection, lymphoproliferative disorder diagnosed or treated within the previous 5 years, moderate or severe heart failure, chronic hepatitis B or C, presence of any demyelinating disorders, pneumonitis, or use in the perioperative period (1 week before and 1 week after surgery).19
Tocilizumab (Actemra, Genentech) is a humanized monoclonal IgG1 antibody interleukin-6 receptor (IL-6R) synthesized by recombinant DNA technology. It is approved in the United States and other countries for treatment of several autoimmune disorders and is being studied for treatment of refractory uveitis-related macular edema.6,14,21,22 Tocilizumab blocks IL-6–mediated signaling by binding both soluble and transmembrane IL-6 receptors. The drug consequently reduces T-cell activation, Th17 differentiation, antibody secretion, and hepatic acute phase protein production.
Mesquida et al21 reported a statistically significant reduction in central foveal thickness beginning the first month after initiation of therapy and continued and sustained through 24 months, associated with visual improvement.6 A phase 1/2 clinical trial of tocilizumab in juvenile idiopathic arthritis (JIA)-associated uveitis has begun.6 The multicenter, randomized STOP-UVEITIS study assessing the safety, tolerability, and bioactivity of two doses of tocilizumab in intermediate, posterior, and panuveitis is under way in the United States.6,23
Tocilizumab appears to be effective in reducing macular edema, controlling inflammation, and maintaining or improving visual acuity as long as patients are receiving infusions.22,24 The adverse events reported are infections (including tuberculosis), infusion reactions, increased risk of gastrointestinal perforation, laboratory abnormalities (hyperlipidemia, elevated transaminases, neutropenia), augmented risk of neurologic disorders, and malignancies.21,22
Sarilumab (Kevzara, Sanofi Genzyme) is a subcutaneously administered fully human monoclonal antibody directed against the alpha subunit of the IL-6 receptor complex. It is indicated for the treatment of rheumatoid arthritis and is undergoing clinical trials for use in the management of posterior segment noninfectious uveitis.25-27 In the SATURN study, in patients with noninfectious uveitis, reductions in vitreous haze and steroid dosing were seen in treated patients.25 Visual acuity and central macular thickness also improved with a 200-mg dose administered subcutaneously every 2 weeks. This drug targets a specific inflammatory mediator, and it has been associated with fewer side effects than other available therapies.25,27 Neutropenia and elevated alanine aminotransferase levels were reported as adverse events.26
Repository corticotropin injection (Acthar, Mallinckrodt Pharmaceuticals) is delivered by subcutaneous or intramuscular injection and targets melanocortin receptors. It is FDA-approved for a range of severe acute and chronic allergic and inflammatory ophthalmic conditions, including diffuse posterior uveitis. Little has been published on corticotropin’s clinical efficacy in the treatment of patients with uveitis,28,29 but the drug may be able to reduce inflammation with less systemic effects than steroids.
EYS606 (Eyevensys) is a nonviral gene therapy that uses a proprietary electrotransfection injection system to deliver plasmids encoding for the production of anti–TNF-alpha into the ciliary muscle of the eye. TNF-alpha is a cytokine that has been shown to play a pivotal role in mediating intraocular inflammation in noninfectious uveitis. EYS606 is being investigated in an open-label phase 1b study in the United Kingdom that is expected to be completed toward the end of this year.30
OTHER TREATMENT OPTIONS
EGP-437 (Eyegate Pharmaceuticals) is a dexamethasone phosphate solution that is delivered to targeted ocular tissues using transscleral iontophoresis. Iontophoresis is a noninvasive method in which low electrical current is applied to an ionizable substance to increase its mobility across a surface through electrochemical repulsion.1,14,31,32
EGP-437 has been shown to have a prolonged duration of action and to be more effective compared with other delivery routes. In 2012, Cohen et al reported that EGP-437 was well tolerated and extremely effective, achieving anterior cell chamber scores of zero within 28 days after one treatment in 60% of participants with noninfectious anterior uveitis.31 The most commonly reported adverse effects were conjunctival hyperemia, punctate keratitis, conjunctival edema, eye pain, and erythema and edema of the eyelid.32
NS2 (Aldeyra Therapeutics) is an aldehyde-binding small molecule that traps aldehydes, neutralizing toxic aldehyde species that can lead to inflammation via activation of the nuclear factor kappa B pathway. Once the aldehyde is trapped, the aldehyde complex is degraded and aldehyde levels are diminished, which potentially reduces toxicity and inflammation.
In a randomized, multicenter, investigator-masked, comparator-controlled, parallel-group phase 2 clinical trial, topical NS2 reduced anterior chamber cell count in patients with noninfectious uveitis.33 Anterior chamber cell count was reduced 53% in those receiving NS2 after 8 weeks of treatment. The drug showed effectiveness equal to that of topical corticosteroids without IOP elevation or cataract production. No serious adverse events were reported.
Uveitis can be a debilitating condition, and it affects a significant percentage of the population. As the research outlined above demonstrates, much work is being done in many centers to find more and better ways to safely and effectively treat and manage uveitis.
1. Babu K, Mahendradas P. Medical management of uveitis – current trends. Indian J Ophthalmol. 2013;61(6):277-283.
2. Nguyen QD, Merrill PT, Clark L, et al; Sirolimus study assessing double-masked uveitis treatment (SAKURA) study group. Intravitreal sirolimus for noninfectious uveitis: a phase III sirolimus study assessing double-masked uveitis treatment (SAKURA). Ophthalmology. 2016;123(11):2413-2423.
3. Jaffe GJ, Lin P, Keenan RT, Ashton P, Skalak C, Stinnett SS. Injectable fluocinolone acetonide long-acting implant for noninfectious intermediate uveitis, posterior uveitis, and panuveitis. Two years results. Ophthalmology. 2016;123(9):1940-1948.
4. Jaffe GJ, Ben-Nun J, Guo H, et al. Fluocinolone acetonide sustained drug delivery device to treat severe uveitis. Ophthalmology. 2000;107(11):2024-2033.
5. Jaffe GJ, Martin D, Callanan D, Pearson A, Levy B, Comstock T; for the Fluocinolone Acetonide Uveitis Study Group. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis thirty-four–week results of a multicenter randomized clinical study. Ophthalmology. 2006;113(6):1020-1027.
6. Barry RJ, Nguyen QD, Lee RW, Murray PI, Denniston AK. Pharmacotherapy for uveitis: current management and emerging therapy. Clin Ophthalmol. 2014;8:1891-1911.
7. Cabrera M, Yeh S, Albini TA. Sustained-release corticosteroid options. J Ophthalmol. 2014;164692.
8. Relhan N, Yeh S, Albini TA. Intraocular sustained-release steroids for uveitis. Int Ophthalmol Clin. 2015;55(3):25-38.
9. Alimera Sciences to expand Iluvien indication in Europe for posterior uveitis [press release]. Alimera Sciences. July 10, 2017. Accessed September 18, 2017.
10. pSivida’s Durasert three-year treatment for posterior segment uveitis successfully achieves primary efficacy endpoint in second phase 3 study [press release]. pSivida. June 13, 2017. http://investors.psivida.com/releasedetail.cfm?ReleaseID=1029974. Accessed September 18, 2017.
11. Safety and efficacy of an injectable fluocinolone acetonide intravitreal insert. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT01694186. Updated December 22, 2016. Accessed September 18, 2017.
12. Lowder C, Belfort R Jr, Lightman S, et al; for the Ozurdex HURON Study Group. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011;129(5):545-553.
13. Clearside Biomedical, Inc. announces positive topline data from phase 2 clinical trial for the treatment of macular edema associated with noninfectious uveitis [press release]. Clearside Biomedical. www.businesswire.com/news/home/20160105005447/en/Clearside-Biomedical-Announces-Positive-Topline-Data-Phase. Accessed September 18, 2017.
14. Maya JR, Sadiq MA, Zapata LJ, et al. Emerging therapies for noninfectious uveitis: what may be coming to the clinics. J Ophthalmol. 2014;2014:310329.
15. Ibrahim MA, Sepah YJ, Watters A, et al. One-year outcomes of the SAVE study: sirolimus as a therapeutic approach for uveitis. Transl Vis Sci Technol. 2015;4(2):4.
16. Nguyen QD, Ibrahim MA, Watters A, et al. Ocular tolerability and efficacy of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis: primary 6-month results of the SAVE study. J Ophthalmic Inflamm Infect. 2013;3:32.
17. Jaffe GJ, Dick AD, Brézin AP, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016; 375(10):932-943.
18. Suhler EB, Lowder CY, Goldstein DA, et al. Adalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trial. Br J Ophthalmol. 2013;97(4):481-486.
19. Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN. Expert panel recommendations for the use of anti–tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology. 2014;121(3):785-796.
20. Díaz-Llopis M, Salom D, Garcia-de-Vicuña C, et al. Treatment of refractory uveitis with adalimumab: a prospective multicenter study of 131 patients. Ophthalmology. 2012;119(8):1575-1581.
21. Mesquida M, Molins B, Llorenç V, et al. Twenty-four month follow-up of tocilizumab therapy for refractory uveitis-related macular edema [published online ahead of print May 16, 2017]. Retina.
22. Mesquida M, Molins B, Llorenç V, et al. Long term effects of tocilizumab therapy for refractory uveitis related macular edema. Ophthalmology. 2014;121(12):2380-2386.
23. Study of the safety, tolerability, and bioactivity of tocilizumab on patients with non-infectious uveitis: the Stop-Uveitis Study (STOP-Uveitis). Clinicaltrails.gov. https://clinicaltrials.gov/ct2/show/NCT01717170. Updated April 26, 2017. Accessed September 18, 2017.
24. Adán A, Mesquida M, Llorenç V, et al. Tocilizumab treatment for refractory uveitis-related cystoid macular edema. Graefes Arch Clin Exp Ophthalmol. 2013;251(11):2627-2632.
25. Nguyen QD, Sundaram PA, Erickson K, et al; for the SATURN Study Group. The SATURN study (SARIL-NIU): sarilumab for the treatment of posterior segment non-infectious uveitis (NIU). Paper presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 3-7, 2015; Denver, CO.
26. Heissigerova J, Sundaram PA, Erickson K, et al. Sarilumab for the treatment of posterior segment non-infectious uveitis (NIU): the SATURN (SARIL-NIU) study. Acta Ophthalmol. 2015;93(S255):1755-3768.2015.0577.
27. Nguyen QD, Sundaram PA, Erickson K, Varona R, Vinet L, Valerie Corp-dit-Genti, Robert Vitti, Marc D de Smet; Interim results from the SATURN Study: Sarilumab in Non-infectious Uveitis (SARIL-NIU). Invest Ophthalmol Vis Sci. 2016;57(12):1894.
28. Agarwal A, Hassan M, Sepah YJ, Do DV, Nguyen QD. Subcutaneous repository corticotropin gel for non-infectious panuveitis: reappraisal of an old pharmacologic agent. Am J Ophthalmol Case Rep. 2016;4:78-82.
29. Ahmad KT, Sukumaran S, Brown KL, Ali TK. Use of corticotropin hormone for treatment of refractory uveitis secondary to juvenile idiopathic arthritis. Poster presented at: 9th International Symposium on Uveitis; August 20, 2016; Dublin, Ireland.
30. Eyevensys announces series A extension bringing total capital raised to €9 million [press release]. Eyevensys. September 15, 2016. www.eyevensys.com/news/7/115/Eyevensys-Announces-Series-A-Extension-Bringing-Total-Capital-Raised-to-9-Million.html. Accessed September 18, 2017.
31. Cohen AE, Assang C, Patane MA, et al; Avion Study Investigators. Evaluation of dexamethasone phosphate delivered by ocular iontophoresis for treating noninfectious anterior uveitis. Ophthalmology. 2012;119(1):66-73.
32. Iontophoresis delivery of dexamethasone phosphate for noninfectious, non-necrotizing anterior scleritis, phase 1 dose-varying study. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT01059955. Updated April 20, 2016. Accessed September 18, 2017.
33. Aldeyra Therapeutics announces positive results from phase II clinical trial in subjects with noninfectious anterior uveitis [press release]. Aldeyra Therapeutics. May 9, 2016. http://ir.aldeyra.com/releasedetail.cfm?ReleaseID=969829. Accessed September 18, 2017.
Thomas Albini, MD
• associate professor of clinical ophthalmology at Bascom Palmer Eye Institute, University of Miami, Fla.
• member of the Retina Today editorial advisory board
• financial disclosures: consultant for Abbvie, Allergan, Bausch + Lomb, Mallinkrodt, and Santen
Andrea Arriola López, MD, MSc
• uveitis fellow at Bascom Palmer Eye Institute, University of Miami, Fla.
• financial interest: none acknowledged
Dr. Arriola would like to thank the Pan-American Ophthalmological Foundation and the Retina Research Foundation for funding her fellowship at Bascom Palmer Eye Institute.