Uveitis: a practical guide for ophthalmologists and optometrists

Uveitis is uncommon, but it causes a disproportionate share of visual morbidity. In the Northern California Epidemiology of Uveitis Study, which covered a population of 731,898, the incidence was 52.4 per 100,000 person-years and the prevalence was 115.3 per 100,000 persons. Both rates were highest in patients aged 65 years or older.¹

This report sheds light on this group of vision-threatening diseases that will be the focus of Inflammatory Eye Disease Awareness Week from October 19-25.

The visual stakes are high. In a tertiary referral series of 315 consecutive patients, 69.95% had reduced vision (6/18 or worse), and 22% met criteria for legal blindness at some point during follow-up.² Cystoid macular edema, cataract, or the combination of the two explained the vision loss in 64.5% of patients.² Outcomes were worse in patients with panuveitis or bilateral disease, in older patients, and in those whose vision stayed reduced for longer.²

Classification and diagnosis

Step 1: Classification based on anatomic location.The SUN Working Group recommended an anatomic framework, in which uveitis is categorized by the location of the ocular inflammation rather than by any resultant complications.³ The group also agreed on the following common conventions for clinical reporting³: a shared scale for grading anterior chamber cells, flare, and vitreous haze; uniformity in the documentation of the structural complications; agreed-upon meanings for outcome such as inactive inflammation, improvement, worsening, and corticosteroid sparing; and consistency in the reporting of visual acuity results. Using the grades provides a consistent baseline for evaluating treatment response and communicating with clinicians managing patients.

Step 2: Characterization of the uveitis along several dimensions. Jabs and Busingye described a structured diagnostic approach to the 30 diseases that comprise the uveitides.⁴ Each case is characterized along the following dimensions: course, ie, inflammatory onset and pattern over time; ocular laterality; anatomic location; morphology; presence or absence of active infection; and host age and presence of a systemic disease.

The authors noted that using these features usually results in a one candidate diagnosis or a short list.⁴

Step 3: Order laboratory tests selectively. According to the authors, testing is carried out both to identify an infection, because that changes treatment and to identify a systemic disease that affects the patient's general health.⁴ Laboratory screening tests are ordered for every patient, so they are limited to conditions that can produce any form of uveitis. Targeted tests are ordered only when specific clinical features point toward a particular disease.⁴

When no established diagnosis fits, the authors call the uveitis "undifferentiated" rather than idiopathic and describe it by its course, laterality, and location.⁴ They believe that this approach identifies the specific disease in most patients while keeping laboratory testing to a minimum.⁴

Management

Management has three arms: ruling out infection first because its presence changes the treatment⁴; determining when to choose immunosuppressive drugs over corticosteroids⁵ to address severe disease and side effects from corticosteroids; and control of disease that requires high systemic doses associated with complications.⁵ In light of the risks, tailoring therapy to each patient and monitoring patients on a regular schedule are advised.⁵

The 2018 FOCUS initiative updated this guidance to include biologics.⁶ The guidelines covered when to begin administering biologic or nonbiologic immunomodulatory drugs, the baseline information to gather before starting therapy, advice on when to change/stop treatment, guidance on choosing treatments agents based on each drug's benefits and risks, and decision-making that includes patients, coordinating among clinicians, and safety surveillance.

Treatments

The following are the treatment effects with the various approaches.

Local corticosteroids

• Dexamethasone implant 0.7 mg (Ozurdex, AbbVie) (HURON study): reduced inflammation and improved vision through 6 months; peak rates of IOP ≥25 mmHg did not differ significantly from sham (7.1% vs 4.2%).⁷
• Fluocinolone acetonide insert 0.18 mg (Yutiq, Alimera Sciences, now ANI Pharmaceuticals): recurrence at 12 months was 38% vs 98% with sham (P < 0.001), with less need for add-on systemic (19% vs 40%) and local (7% vs 62%) therapy. Cataract was more frequent, but use of intraocular pressure (IOP)-lowering medication was similar.⁸
• Intravitreal triamcinolone and the dexamethasone implant (which was noninferior to intravitreal triamcinolone) (POINT study) for uveitic macular edema each gained five more letters at 8 weeks than periocular triamcinolone, at a modestly higher risk of IOP of 24 mmHg or higher.⁹ In the MERIT study, the dexamethasone implant reduced persistent or recurrent edema more than intravitreal methotrexate (P < 0.01) or ranibizumab (P = 0.018) and was the only arm with a significant best-corrected visual acuity increase (4.86 letters); IOP increases were more frequent, but few reached 30 mmHg or higher.¹⁰ In the PEACHTREE study, suprachoroidal triamcinolone reduced the central subfield thickness by 153 μm vs 18 μm with sham treatment, with elevated IOP in 11.5% vs 15.6%.¹¹

Conventional immunosuppression

• Methotrexate vs mycophenolate (FAST study): among 216 adults, mycophenolate 3 g daily was not superior to methotrexate 25 mg weekly overall, but results varied by subtype (P for interaction = 0.004).¹² Methotrexate succeeded more often in posterior uveitis or panuveitis (74.4% vs 55.3%; P = 0.02), whereas mycophenolate trended better in intermediate uveitis (63.6% vs 33.3%; P = 0.07). Elevated liver enzymes were the most common nonserious laboratory adverse event (13.0% vs 7.4%).¹²

Biologics: adalimumab (Humira, AbbVie)

• Active disease (VISUAL I study): halved the risk of treatment failure in 217 adults (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.36-0.70).¹³
• Inactive disease during steroid taper (VISUAL II study): treatment failure was 39% vs 55% with placebo (HR 0.57; 95% CI, 0.39-0.84).¹⁴
• Pediatric juvenile idiopathic arthritis-associated uveitis (SYCAMORE study): added to stable methotrexate, it lowered treatment failure (HR 0.25; 95% CI, 0.12-0.49).¹⁵
• Versus conventional drugs (ADVISE study): provided greater corticosteroid sparing than antimetabolites or calcineurin inhibitors at 6 months (69% vs 54%) and more successful steroid discontinuation at 12 months (55% vs 40%; P = 0.028).¹⁶
• Safety: Adverse and serious adverse events were more frequent with adalimumab in the VISUAL I and SYCAMORE trials.^13,15

Outcomes and complications

Causes of vision loss

In a cohort followed for a mean of 36.7 months, the main causes of vision loss were²: cystoid macular edema alone 26.8%, cataract alone 17.7%, and combination of both 20%. The mean duration of visual loss was 21 months. Among 148 patients with panuveitis, 84.45% had reduced vision.²

Local vs systemic therapy: the MUST trial

The MUST trial randomized 255 patients with intermediate, posterior, or panuveitis to a fluocinolone acetonide implant or to systemic corticosteroids plus immunosuppression. At 24 months, visual acuity did not differ significantly between the two approaches.¹⁷

• Active inflammation persisted in fewer patients who received an implant than in patients treated systemically: 12% vs 29%, respectively (P = 0.001).
• Eyes in the implant group were more likely to need cataract surgery (80%; HR 3.3), IOP-lowering treatment (61%; HR 4.2), and glaucoma care (17%; HR 4.2).
• Patients on systemic therapy had more infections requiring a prescription (0.60 vs 0.36 per person-year), but these caused no meaningful lasting harm.

At 7 years, the 215 patients who consented to extended follow-up showed a different picture.¹⁸

• The mean visual acuity favored systemic therapy by 7.2 letters (95% CI, 2.1-12). The minimal clinically important difference was seven letters.
• Most cumulative systemic adverse outcomes were below 10% in both groups.
• Exceptions (implant vs systemic) were hyperlipidemia (6.1% vs 11.2%, respectively), hypertension (9.8% vs 18.4%), osteopenia (41.5% vs 43.1%), fractures (11.3% vs 18.6%), hospitalization (47.6% vs 42.3%), and antibiotic-treated infection (57.4% vs 72.3%).

The investigators cautioned that patients lost to follow-up make the 7-year findings less certain.¹⁸

Safety signals with biologics

The VISUAL I study reported more adverse events with adalimumab than with placebo: 1,052.4 vs 971.7 per 100 person-years. Serious adverse events were 28.8 vs 13.6 per 100 person-years.¹³

The VISUAL II study recorded no opportunistic infections in either arm (not counting oral candidiasis and tuberculosis), and overall adverse event rates were comparable between arms.¹⁴

In the SYCAMORE study, children receiving adalimumab had more adverse events (10.07 vs 6.51 per patient-year) and more serious adverse events (0.29 vs 0.19 per patient-year).¹⁵

Key points

• Classify every case by anatomic location, and grade cells, flare, and vitreous haze with the SUN system.³

• Characterize course, laterality, location, morphology, infection, and host. Use laboratory screening only for diseases that can present as any type of uveitis, and target other tests.⁴

• Consider immunosuppression when disease is severe, when corticosteroid side effects occur, or when control requires corticosteroid doses likely to cause complications.^5,6

• Methotrexate and mycophenolate performed similarly overall, but results differed by anatomic subtype.¹² Adalimumab outperformed placebo in the VISUAL I, VISUAL II, and SYCAMORE trials, and outperformed conventional immunosuppression for corticosteroid sparing in the ADVISE study.^13-16

• For uveitic macular edema, intravitreal corticosteroids outperformed periocular triamcinolone (POINT study), and the dexamethasone implant outperformed intravitreal methotrexate and ranibizumab (MERIT study).^9,10

• Local implants control inflammation but raise the risk of cataract and elevated IOP. In the MUST trial, visual acuity favored systemic therapy at 7 years.^17,18

References
1. Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study. Ophthalmology. 2004;111:491-500. doi:10.1016/j.ophtha.2003.06.014

2. Durrani OM, Tehrani NN, Marr JE, et al. Degree, duration, and causes of visual loss in uveitis. Br J Ophthalmol. 2004;88(9):1159-62. doi:10.1136/bjo.2003.037226

3. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140:509-16. doi:10.1016/j.ajo.2005.03.0574. Jabs DA, Busingye J. Approach to the diagnosis of the uveitides. Am J Ophthalmol. 2013;156:228-36. doi:10.1016/j.ajo.2013.03.027

5. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492-513. doi:10.1016/s0002-9394(00)00659-0

6. Dick AD, Rosenbaum JT, Al-Dhibi HA, et al; Fundamentals of Care for Uveitis International Consensus Group. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018;125:757-73. doi:10.1016/j.ophtha.2017.11.017

7. Lowder C, Belfort R Jr, Lightman S, et al; Ozurdex HURON Study Group. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011;129:545-53. doi:10.1001/archophthalmol.2010.339

8. Jaffe GJ, Foster CS, Pavesio CE, et al. Effect of an injectable fluocinolone acetonide insert on recurrence rates in chronic noninfectious uveitis affecting the posterior segment: twelve-month results. Ophthalmology. 2019;126:601-10. doi:10.1016/j.ophtha.2018.10.033

9. Thorne JE, Sugar EA, Holbrook JT, et al; Multicenter Uveitis Steroid Treatment Trial Research Group. 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;126:283-95. doi:10.1016/j.ophtha.2018.08.021

10. Acharya NR, Vitale AT, Sugar EA, et al; Multicenter Uveitis Steroid Treatment Trial (MUST) Research Group, Writing Committee. Intravitreal therapy for uveitic macular edema—ranibizumab versus methotrexate versus the dexamethasone implant: the MERIT trial results. Ophthalmology. 2023;130:914-23. doi:10.1016/j.ophtha.2023.04.011

11. Yeh S, Khurana RN, Shah M, et al; PEACHTREE Study Investigators. Efficacy and safety of suprachoroidal CLS-TA for macular edema secondary to noninfectious uveitis: phase 3 randomized trial. Ophthalmology. 2020;127:948-55. doi:10.1016/j.ophtha.2020.01.006

12. Rathinam SR, Gonzales JA, Thundikandy R, et al; FAST Research Group. Effect of corticosteroid-sparing treatment with mycophenolate mofetil vs methotrexate on inflammation in patients with uveitis: a randomized clinical trial. JAMA. 2019;322:936-45. doi:10.1001/jama.2019.12618

13. Jaffe GJ, Dick AD, Brézin AP, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016;375:932-43. doi:10.1056/NEJMoa1509852

14. Nguyen QD, Merrill PT, Jaffe GJ, et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet. 2016;388:1183-92. doi:10.1016/S0140-6736(16)31339-3

15. Ramanan AV, Dick AD, Jones AP, et al; SYCAMORE Study Group. Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med. 2017;376:1637-46. doi:10.1056/NEJMoa1614160

16. Jabs DA, Sugar EA, Burke AE, et al; Adalimumab versus Conventional Immunosuppression for Uveitis Trial Research Group. Adalimumab versus Conventional Immunosuppression for Uveitis (ADVISE) Trial. Ophthalmology. 2026;133:310-25. doi:10.1016/j.ophtha.2025.10.004

17. Kempen JH, Altaweel MM, Holbrook JT, et al; Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Ophthalmology. 2011;118:1916-26. doi:10.1016/j.ophtha.2011.07.027
18. Writing Committee for the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study Research Group; Kempen JH, Altaweel MM, Holbrook JT, et al. Association between long-lasting intravitreous fluocinolone acetonide implant vs systemic anti-inflammatory therapy and visual acuity at 7 years among patients with intermediate, posterior, or panuveitis. JAMA. 2017;317:1993-2005. doi:10.1001/jama.2017.5103