Treatment of Uveitis

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Article initiated by:

Nuno Moura-Coelho, MD, MMedSci, PhD Research Assistant

All contributors:

Rita Pinto Proença MD MMedSci, Marco Dutra-Medeiros MD PhD, Ghazala D. O'Keefe, MD, Nuno Moura-Coelho, MD, MMedSci, PhD Research Assistant, Alan Palestine, MD, Homaira Ayesha Hossain, MD

Assigned editor:

Olivia Lee, MD

Review:

Assigned status Update Pending

 by Homaira Ayesha Hossain, MD on December 31, 2023.

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Contributing Editors:	add

Introduction

The goal of treatment in uveitis is to control inflammation in order to prevent vision loss while also limiting the side effects of therapy. Treatments include medical management with ocular or systemic therapy, as well as surgical interventions for diagnostic or therapeutic purposes and for the treatment of complications of uveitis. Treatment strategies depend on the etiology of inflammation and the disease severity and course. If the underlying etiology is infectious, then this must first be treated with appropriate therapy. If the underlying etiology is idiopathic or associated with systemic autoimmune/inflammatory diseases, then a stepladder approach utilizing anti-inflammatory or immunomodulatory therapy may be necessary, often times in coordination with other specialists.

Mydriatic and Cycloplegic Agents

Mydriatic and cycloplegic agents are utilized in uveitis to relieve symptoms of pain and photophobia (by relieving spasm of the ciliary muscle and pupillary spinchter). They are also used to prevent or break posterior synechiae. The choice of agent and frequency of use is tailored to the severity and course of inflammation. Preparations of short-acting and long-acting agents include:

Agent	Duration
Tropicamide 0.5% and 1%	6 hours
Cyclopentolate 0.5% and 1%	24 hours
Phenylephrine 2.5% and 10%	3 hours (but no cycloplegia)
Homatropine 2%	up to 2 days
Atropine 1%	up to 2 weeks

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

As a primary treatment modality for ocular inflammatory diseases, NSAIDSs are generally ineffective in both local and systemic formulations; however, an exception might be some cases of non-necrotizing anterior scleritis. NSAIDs might also provide some utility as an adjunct to other forms of therapy, such as the use of topical NSAIDs in the treatment of macular edema. The use of systemic NSAIDs with systemic corticosteroids increases the risk of gastric ulcers; therefore, histamine-H₂ receptor antagonists or proton-pump inhibitors should be prescribed to reduce the risk.

Corticosteroids

Corticosteroids are the mainstay of treatment in uveitis and can be administered via multiple routes: topical, local injections (periocular or intraocular), or systemically via oral or intravenous routes.

Topical Steroids

Several steroids exist in topical ophthalmic preparations, and each has unique properties that may provide advantages and disadvantages in specific clinical scenarios. Examples include difluprednate, dexamethasone, prednisolone acetate, fluorometholone, and loteprednol. Generally, topical steroid therapy should be started at high doses and then slowly tapered according to clinical evolution:

• Mild inflammation: administer q6h
• Moderate to severe inflammation: administer q1-2h
  • A loading dose can be considered (e.g. q1min for 5 minutes, then q30min-1h)
  • A steroid ophthalmic ointment given at night can also be considered
• A commonly adopted regimen might consist of :
  • One drop q1h for 3 days, then
  • One drop q2h for 3 days, then
  • One drop q6h for 3 days, then
  • One drop q8h for 7 days, then
  • One drop q12h for 7 days, then
  • One drop qday for 7 days, then stop.

Of note, difluprednate 0.05% four times daily has been found to be equivalent to prednisolone acetate 1% eight times daily in anterior uveitis.

Local Steroid Injections

Periocular or intraocular steroid injections through subconjunctival, transseptal, sub-Tenon, or intravitreal routes can be considered in the following clinical scenarios:

• Severe unilateral uveitis
• Uveitis complicated by cystoid macular edema
• To supplement systemic therapy or when systemic therapy is contraindicated
• Poor patient compliance with topical or systemic therapy

Complications may include subconjunctival or retrobulbar hemorrhage, globe perforation, optic nerve injury, cutaneous changes, orbital fat atrophy, cataract, elevation of intraocular pressure, ptosis, and retinal vascular occlusion.

Inferior Transseptal Approach

1. Topical anaesthesia (e.g., tetracaine)
2. Disinfection of the skin of the lower eyelid and maxillary area (e.g., povidone-iodine 5%)
3. Shake the vial containing the steroid
4. Draw 1 mL steroid (triamcinolone acetonide or methylprednisolone acetate 40 mg/mL) into a 2 mL syringe
5. Replace the drawing-up needle with a 25-gauge needle
6. Instruct the patient to look straight ahead
7. Insert the 25-gauge needle through the skin at the junction of the other third and the inner two-thirds of the lower orbital rim, entering close to the bony margin whilst clearing the margin itself (note: some authors inject via the conjunctiva)
8. Advance the needle slowly and tangentially to the globe
9. Slightly withdraw the plunger to ascertain no blood enters the syringe, and inject the full 1 mL of steroid in a slow fashion
10. Withdraw the needle carefully

Posterior Sub-Tenon Approach

1. Topical anaesthesia (e.g., tetracaine)
2. Place a small cotton pledget impregnated with an anaesthetic agent (e.g., tetracaine, lidocaine 2% gel) in the superior fornix at the site of injection for 2 minutes
3. Shake the vial containing the steroid
4. Draw 1 mL steroid (triamcinolone acetonide or methylprednisolone acetate 40 mg/mL) into a 2 mL syringe
5. Replace the drawing-up needle with a 25-gauge needle
6. Instruct the patient to look in the nasal inferior direction (i.e., the direction opposite to the superotemporal injection site)
7. Penetrate the bulbar conjunctiva with the needle tip, bevel towards the eye globe
8. Slowly insert the needle posteriorly, following the contour of the globe, making side-to-side motions to prevent globe penetration
9. Slightly withdraw the plunger to ascertain no blood enters the syringe, and inject the full 1 mL of steroid in a slowly fashion
10. Withdraw the needle carefully

Intravitreal Steroid Injections

There are several options of intravitreal steroid delivery utilized in the treatment of uveitis:

Implant	Medication and Dosage	Duration
Triesence	triamcinolone acetonide intravitreal suspension, 40 mg/mL	3 months
Ozurdex	dexamethasone intravitreal implant, 0.7mg	6 months
Yutiq	fluocinolone acetonide intravitreal implant, 0.18mg	36 months
Retisert	fluocinolone acetonide intravitreal implant, 0.59mg	30 months

The use of intravitreal steroids is effective in the treatment of of uveitis and uveitic macular edema (see below).

Systemic Steroids

Systemic steroid therapy may be indicated in cases of vision-threatening uveitis, when there is poor response to topical or local steroid therapy, and in cases of bilateral or systemic involvement. Treatment should consist of high dosage initially and then tapering according to clinical effect. In cases of severe uveitis, intravenous methylprednisolone may be considered (typically 1g/day for three days). Initial dosing of oral prednisone is typically 1-1.5 mg/kg/day. Too rapid tapering or early discontinuation of systemic steroids may lead to disease recurrence. If steroid therapy is continued at a dose of more than 7.5mg/day for a duration of more than 3 months, then steroid-sparing agents should be considered. A typically adopted steroid tapering schedule is as follows:

Prednisone dose (mg/day)	Decrement (mg/day)	Taper Interval
		RAPID	STANDARD
60-30	10	2 days	weekly
30-15	5	2 days	weekly
15-7.5	2.5	2 days	weekly
< 7.5	2.5-1	2-7 days	weekly-monthly

Side Effects of Corticosteroid Therapy

Side effects of corticosteroid therapy are related to the route of administration and relative potency of the drugs. Ocular side effects include cataract, elevation of intraocular pressure (IOP), and glaucoma. Systemic side effects of corticosteroid therapy include diabetes, hypertension, peptic ulcer, insomnia, osteoporosis, and others. Patients on long-term steroid treatment should receive calcium and vitamin D supplementation to prevent osteoporosis.

Given the safety profile of this class of drugs and the risks of ocular and systemic complications, relative potencies (as established compared to the reference of hydrocortisone) must also be taken into account. Corticosteroids are presented in decreasing order of relative potency in the table below:

Relative potencies of corticosteroids
Corticosteroid	Systemic Equivalent (mg)	Relative Potency
Bethamethasone	0.6	33.0
Dexamethasone	0.75	26.0
Methylprednisolone	4	5.0
Triamcinolone	4	5.0
Prednisolone	4	5.0
Prednisone	5	4.0
Hydrocortisone	20	1.0
Cortisone	25	0.8

Immunomodulatory Therapy (IMT)

An important goal in the treatment of uveitis is to minimize the use of corticosteroids and its myriad ocular and systemic adverse effects. The use of immunomodulatory therapy is an essential treatment strategy in the management of noninfectious uveitis (NIU). The Fundamentals of Care for Uveitis (FOCUS) International Consensus Group of uveitis specialists (both ophthalmologists and rheumatologists) outlined the following indications for noncorticosteroid systemic immunomodulatory therapy (NCSIT):

• Ocular factors such as acute sight-threatening disease, chronic persistent inflammation, exudative retinal detachment, posterior and macular involvement, and binocular sight-threatening disease
• Therapeutic needs such as failure of regional or systemic steroid therapy, high dosage of systemic steroid therapy, relapse after reduction of systemic steroid therapy, and steroid intolerance or need for steroid-sparing effect

Immunomodulatory therapies for the treatment on NIU include the following:

Class	Name
Antimetabolites	Azathioprine
	Methotrexate
	Mycophenolate Mofetil
Calcineurin Inhibitors	Cyclosporine
	Tacrolimus
Alkylating Agents	Chlorambucil
	Cyclophosphamide

Additionally, biologic therapies for the treatment of NIU include the following:

Class	Name
Anti-TNFα	Infliximab
	Adalimumab
	Golimumab
	Certolizumab
Anti-IL-1β	Anakinra
	Canakinumab
Anti-IL-2	Daclizumab
Anti-IL-6	Tocilizumab
	Sarilumab
Anti-IL-17A	Secukinumab
Anti-IL-12/ IL-23	Ustekinumab
Anti-CD20	Rituximab
Selective co-stimulator modulator	Abatacept
Interferons	IFN α-2a
	IFN α-2b
	IFN β
Janus kinase inhibitors	Tofacitinib
	Baricitinib
Other	Intravenous immunoglobulin

The FOCUS Initiative Group has provided information on the level of evidence for each NCSIT available for the treatment of intermediate and posterior NIU, excluding biologics. An adapted version is showed below:

Evidence levels of NCSITs in the treatment of noninfectious uveitis
SYSTEMIC NCSITs	LEVEL OF EVIDENCE FOR NIU	RECOMMENDATION LEVEL	CLINICAL EFFECTS
MYCOPHENOLATE MOFETIL	2B	B	Control of inflammation, steroid-sparing, improved VA
AZATHIOPRINE	2B	C	Control of inflammation, steroid-sparing
METHOTREXATE	2B	B	Control of inflammation, steroid-sparing, improved VA
CYCLOSPORINE	2B	B	Control of inflammation, steroid-sparing, improved VA
TACROLIMUS	2B	B	Control of inflammation, steroid-sparing, improved VA
CYCLOPHOSPHAMIDE	4	C	Control of inflammation, steroid-sparing
CHLORAMBUCIL	4 (for panuveitis in sympathetic ophthalmia)	C	Control of inflammation, steroid-sparing, improved VA

In addition, the FOCUS Initiative group has provided information regarding the level of evidence supporting the use of biologics in uveitis. A simplified version is presented below:

Evidence Levels of biologic agents in the treatment of noninfectious uveitis
BIOLOGIC AGENTS	LEVEL OF EVIDENCE FOR NIU	RECOMMENDATION LEVEL	CLINICAL EFFECTS
ADALIMUMAB	1B	A	Control of inflammation, steroid-sparing, improved VA
INFLIXIMAB	2B	B-C	Control of inflammation, steroid-sparing, improved VA
ETANERCEPT	4	C	Not recommended (EL2B)
ANAKINRA	4 (for Behçet’s disease)	C	Control of inflammation
GEVOKIZUMAB	2B (for Behçet’s disease)	C	Control of inflammation
DACLIZUMAB	2B	B	Control of inflammation, steroid-sparing, improved VA
TOCILIZUMAB	4	C	Control of inflammation, improved VA
RITUXIMAB	2B (for Behçet’s disease)	C	Control of inflammation
ALEMTUZUMAB	2B (for Behçet’s disease)	C	Control of inflammation, steroid-sparing
INTERFERON-ALFA	2B	B	Control of inflammation, steroid-sparing, improved VA
INTERFERON-BETA	2B (IU or MS-related uveitis)	C	Control of inflammation, improved VA

The choice of IMT must be individualized taking into account the patients’s history, cause of uveitis, and comorbidities.

Major Studies in the Treatment of Uveitis

The Multicenter Uveitis Steroid Treatment (MUST) Trial demonstrated that systemic therapy (including corticosteroid-supplemented immunomodulatory therapy and biologic agents) improved visual outcomes, controlled inflammation, and reduced macular edema similarly to local treatment using sustained-release intravitreal fluocinolone acetonide implant in patients with noninfectious intermediate uveitis, posterior uveitis, or panuveitis. The implant was slightly better for the first 5 years, after which they were similar with uveitis control in 87% of patients at 7 years. Data from the MUST studies suggest that oral corticosteroids and immunosuppression can be administered relatively safely for at least 7 years. Interestingly, a Cochrane systematic review was unable to conclude that the implants are superior to traditional systemic therapy for the treatment of noninfectious uveitis, and findings regarding safety outcomes suggest increased risks of post-implant surgery for cataract and elevated intraocular pressure compared with standard-of-care systemic therapy including corticosteroids.

The VISUAL I, II, and III Trials demonstrated the efficacy of adalimumab in the control of inflammation in patients with noninfectious intermediate uveitis, posterior uveitis, or panuveitis. The percentage of patients showing quiescence increased from 34% at week 0 to 85% at week 150, and the average daily dose of systemic steroids decreased from 9.4 ± 17.1 mg/day at week 0 to 1.5 ± 3.9 mg/day at week 150. Infections were the most commonly reported adverse event. The SYCAMORE Trial demonstrated that combined use of adalimumab with methotrexate in children with juvenile idiopathic arthritis associated uveitis decreased the likelihood of treatment failure over the use of methotrexate alone. Patients on adalimumab were more likely to report adverse events than those on palcebo.

The long-term safety of immunosuppression was addressed by the Systemic Immunosuppressive Therapy for Eye Disease (SITE) Cohort Study, which evaluated 9250 patients with ocular inflammation with up to 30 years of follow-up. Alkylating agents did not have a significantly increased risk of overall mortality but had a borderline significant increased risk of cancer-related mortality. The study found no increased malignancy risk with antimetabolites or calcineurin inhibitors in patients without an inherent increased risk, nor increased risk of mortality or cancer mortality.

Surgical Interventions in the Treatment of Uveitis

Surgical interventions may also be necessary in the treatment of complications of uveitis. This can include the treatment of calcific band keratopathy with chelation therapy with disodium ethylene diamine tetraacetic acid (EDTA), cataract surgery, glaucoma surgery, surgical interventions for hypotony, pars plana vitrectomy and membrane peel for epiretinal membrane, retinal detachment repair, and others.

Selected Uveitis-Related Complications

Uveitic Macular Edema

Macular edema is a frequent complication and a major cause of vision loss in patients with uveitis, and treatment includes both control of intraocular inflammation as well as treatments directed towards macular edema. The Periocular Versus Intravitreal Corticosteroids for Uveitic Macular Edema (POINT) Trial demonstrated that periocular triamcinolone acetonide, intravitreal triamcinolone acetonide, and the intravitreal dexamethasone implant reduced central subfield thickness by 23%, 39%, and 46% (respectively) at 8 weeks compared to baseline in patients with uveitic macular edema. Although the MUST trial suggested that 0.59 mg implants provided no significantly increased efficacy compared to systemic treatment, a few studies have shown implanted eyes have improved uveitic macular edema.

Several studies have also examined the impact of intravitreal anti-VEGF injections in the treatment of uveitic macular edema. Repeat bevacizumab injections appear to improve visual acuity and reduce macular thickness in refractory uveitic macular edema. Ranibizumab injections have been studied in the PROMETHEUS trial to evaluate its efficacy in patients with macular edema from causes other than diabetic retinopathy, retinal vein occlusion, or neovascular age-related macular degeneration. At 12 months, ranibizumab showed superiority in visual acuity gain over sham, reaching + 5.45 letters of visual acuity treatment effect in the inflammatory or post-uveitis macular edema subgroup. To date, no large studies have been conducted to evaluate the clinical results of intravitreal aflibercept in UMO, and very little evidence available in the literature is derived from anecdotal case reports.

Uveitic Choroidal and Retinal Neovascularization

Intravitreal anti-VEGF injections have also been utilized in the treatment of uveitic choroidal and retinal neovascularization Most studies involve bevacizumab, and a few involve ranibizumab, while the use of aflibercept is scarce, with only one small case series suggesting clinical benefit from a switch strategy from ranibizumab to aflibercept in refractory uveitic CNV. The MINERVA study was designed to evaluate the efficacy of ranibizumab in patients with CNV from uncommon causes, including inflammatory disease. In the postinflammatory CNV subgroup, a treatment effect of +6.5 letters at month 2 was noted in the ranibizumab treatment group.

Conclusions

Uncontrolled uveitis is a leading cause of vision loss in the United States and worldwide. These data reinforce the importance of prompt and aggressive treatment of uveitis. The management of the uveitis patient represents a challenge for both the patient and the clinician; therefore, referral to a uveitis specialist should be considered early in the course of the disease. The ultimate goals of treatment of uveitis are to preserve vision, prevent significant vision-related morbidity, and prevent the iatrogenic effects of local and systemic therapies. Finally, treatment of the uveitis patient must always consider the underlying systemic disease. Thus, close collaboration with infectious disease specialists, autoimmune disease specialists, and other medical specialties dedicated to these diseases is of utmost importance.