The treatment of uveitis depends largely on the cause, location, and severity of the disease.[59]Smith JR, Rosenbaum JT. Management of uveitis: a rheumatologic perspective. Arthritis Rheum. 2002 Feb;46(2):309-18.
http://www.ncbi.nlm.nih.gov/pubmed/11840433?tool=bestpractice.com
In many cases, the goal of treatment is to control uveitis. All patients should be referred early to an ophthalmologist for management. Any related underlying condition should be managed as appropriate.
Management differs according to infectious or noninfectious etiologies.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
Acute management of noninfectious uveitis
Corticosteroid therapy is first-line for acute noninfectious uveitis; topical ophthalmic formulations are indicated for anterior chamber inflammation.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Management of any underlying disease should occur concurrently.
Effective use of corticosteroid eye drops requires frequent dosing, especially at the beginning of treatment; the most common reason for treatment failure is insufficient dosing. Corticosteroid eye drops may be instilled up to hourly when initiating treatment of acute anterior uveitis, with a subsequent taper depending on the severity of the initial presentation.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Dose and duration is tailored to the patient.
Adverse effects of topical corticosteroids (including elevation of intraocular pressure, posterior subcapsular cataract, and subconjunctival hemorrhage) limit their long-term use.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[61]Mercieca K, Sanghvi C, Jones NP. Spontaneous sub-conjunctival haemorrhage in patients using long-term topical corticosteroids. Eye (Lond). 2010 Dec;24(12):1770-1.
https://www.nature.com/articles/eye2010118
http://www.ncbi.nlm.nih.gov/pubmed/20930855?tool=bestpractice.com
Infectious causes should be ruled out before moving to periocular or intraocular corticosteroid injections, or systemic corticosteroids.
Periocular corticosteroid injections
Periocular (regional) corticosteroid injections may be preferred in a patient who is noncompliant with, or poorly responsive to, topical ophthalmic corticosteroid therapy (that was otherwise safe and well tolerated).[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
In patients responsive to initial topical corticosteroid therapy, periocular corticosteroid therapy can sustain local anti-inflammatory effects. Periocular administration is considered in patients with intermediate or posterior uveitis because it allows the corticosteroid to be delivered close to the site of inflammation.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Adverse effects of periocular corticosteroid injections include:[62]Sen HN, Vitale S, Gangaputra SS, et al. Periocular corticosteroid injections in uveitis: effects and complications. Ophthalmology. 2014 Nov;121(11):2275-86.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4254355
http://www.ncbi.nlm.nih.gov/pubmed/25017415?tool=bestpractice.com
[63]Feldman-Billard S, Du Pasquier-Fediaevsky L, Héron E. Hyperglycemia after repeated periocular dexamethasone injections in patients with diabetes. Ophthalmology. 2006 Oct;113(10):1720-3.
http://www.ncbi.nlm.nih.gov/pubmed/17011953?tool=bestpractice.com
[64]Polski A, Liu KC, Gupta D, et al. Incident glaucoma and ocular hypertension after periocular and intravitreal steroid injections: a claims-based analysis. BMJ Open Ophthalmol. 2023 Dec 22;8(1):e001508.
https://bmjophth.bmj.com/content/8/1/e001508
http://www.ncbi.nlm.nih.gov/pubmed/38135349?tool=bestpractice.com
Intraocular pressure elevation; glaucoma; posterior subcapsular cataract
Hyperglycemia in patients with diabetes (may occur approximately 6 hours after dexamethasone injection)
Injection-site scarring (can complicate repeat injections)
Subconjunctival hemorrhage (avoid injections at the cardinal clock hours [12, 3, 6, 9] to prevent trauma to the anterior ciliary arteries)
Pain: corticosteroid injections can be mixed with a local anesthetic such as lidocaine
Inadvertent penetrating globe trauma
Intraocular corticosteroid injections
Intraocular corticosteroid injections are used for severe posterior uveitis and acute inflammation unresponsive to periocular corticosteroid injections; discussion of risks should be documented in medical notes.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Intraocular corticosteroids may also serve as a bridge to corticosteroid-sparing therapies.
Adverse effects of intraocular corticosteroid injection include those documented for periocular corticosteroid injection. Endophthalmitis, a form of infectious panuveitis, and pseudoendophthalmitis have also been reported.[65]José-Vieira R, Ferreira A, Menéres P, et al. Efficacy and safety of intravitreal and periocular injection of corticosteroids in noninfectious uveitis: a systematic review. Surv Ophthalmol. 2022 Jul-Aug;67(4):991-1013.
http://www.ncbi.nlm.nih.gov/pubmed/34896190?tool=bestpractice.com
[66]Reichle ML. Complications of intravitreal steroid injections. Optometry. 2005 Aug;76(8):450-60.
http://www.ncbi.nlm.nih.gov/pubmed/16150412?tool=bestpractice.com
[67]Jaffe GJ, Martin D, Callanan D, et al. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology. 2006 Jun;113(6):1020-7.
http://www.ncbi.nlm.nih.gov/pubmed/16690128?tool=bestpractice.com
The latter presents as a dense vitritis with hypopyon 1-3 days following intravitreal injection. The anterior chamber will show a dense cellular reaction with almost no flare (as opposed to the fibrinoid reaction characteristic of infectious endophthalmitis). It clears without therapy over 1-8 weeks.
Sustained-release corticosteroid implants may be indicated in patients who fail to respond to, or are intolerant of, intraocular corticosteroid injections.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Implants can be given by intravitreal injection or by surgical fixation to the sclera. Corticosteroid implants are not considered to be first-line therapeutic options.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Adjunctive therapy for the management of acute noninfectious uveitis
Topical cycloplegics (e.g., atropine) are used as adjunct to corticosteroid therapy to reduce pain and minimize spasm to the ciliary body. Cycloplegics can be used if the inflammation is causing synechiae or the uveitis is fibrinous, as can happen with human leukocyte antigen (HLA)-B27-related uveitis or various granulomatous uveitic conditions.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Oral corticosteroids
Oral corticosteroids may be used in severe bilateral or recalcitrant uveitis, or if patients cannot tolerate corticosteroid injections.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
An oral corticosteroid facilitates immediate control, and may be followed by periocular injection (when tolerated in a patient with confirmed immune-mediated uveitis) to minimize systemic adverse effects.
High-dose oral corticosteroid therapy is prescribed initially, and the dose tapered to clinical effect.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
[68]American Academy of Ophthalmology. EyeWiki: treatment of uveitis. Dec 2023 [internet publication].
https://eyewiki.org/Treatment_of_Uveitis
Potential adverse effects associated with prolonged use of oral corticosteroids include hypertension, bone fracture, metabolic issues, and gastrointestinal disturbances.[69]Rice JB, White AG, Scarpati LM, et al. Long-term systemic corticosteroid exposure: a systematic literature review. Clin Ther. 2017 Nov;39(11):2216-29.
https://www.clinicaltherapeutics.com/article/S0149-2918(17)30985-2/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29055500?tool=bestpractice.com
If prolonged oral corticosteroid therapy is anticipated (>3 months), systemic immunomodulatory therapy should be considered.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Intravenous corticosteroids
Intravenous corticosteroids (e.g., high-dose methylprednisolone) are rarely considered, but may be indicated in specific clinical scenarios:[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
[68]American Academy of Ophthalmology. EyeWiki: treatment of uveitis. Dec 2023 [internet publication].
https://eyewiki.org/Treatment_of_Uveitis
Severe, noninfectious posterior uveitis or panuveitis
Intraoperatively, in patients at substantial risk of postoperative inflammation
In patients at imminent danger of visual loss, and/or with extreme pain (usually due to scleritis)
A short course of intravenous corticosteroids may be administered in these circumstances, followed by a gradual taper of an oral corticosteroid.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Supportive care
H2 antagonists or proton-pump inhibitors (PPIs) are recommended to reduce the risk for gastric ulcer among patients receiving high-dose oral corticosteroids, particularly when taking a concomitant systemic nonsteroidal anti-inflammatory drug (NSAID).[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
[68]American Academy of Ophthalmology. EyeWiki: treatment of uveitis. Dec 2023 [internet publication].
https://eyewiki.org/Treatment_of_Uveitis
Postmenopausal or older women maintained on corticosteroid therapy for >3 months should be encouraged to supplement their diet with calcium and vitamin D (to reduce osteoporosis risk), and to perform regular weight-bearing exercise.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Bone mineral density screening is recommended for patients taking corticosteroids >3 months, or for those taking high doses. Bone preservation therapy (e.g., bisphosphonate) should be considered.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Note that bisphosphonates are not typically recommended in individuals age <18 years and in pregnancy; they should be used with caution in women of childbearing age.[70]Losada I, Sartori L, Di Gianantonio E, et al. Bisphosphonates in patients with autoimmune rheumatic diseases: Can they be used in women of childbearing age? Autoimmun Rev. 2010 Jun;9(8):547-52.
http://www.ncbi.nlm.nih.gov/pubmed/20307690?tool=bestpractice.com
Chronic management of noninfectious uveitis: systemic immunomodulatory therapy
Long-term treatment aims to control ocular and systemic disease while minimizing corticosteroid exposure.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Noncorticosteroid systemic immunomodulatory therapy is indicated in the presence of ocular factors (e.g., sight-threatening disease, chronic severe inflammation) and/or therapeutic factors (e.g., failure of regional or systemic corticosteroid therapy, high doses of systemic corticosteroid therapy).[68]American Academy of Ophthalmology. EyeWiki: treatment of uveitis. Dec 2023 [internet publication].
https://eyewiki.org/Treatment_of_Uveitis
[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
Immunomodulatory drugs include:[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
[72]Jabs DA. Immunosuppression for the uveitides. Ophthalmology. 2018 Feb;125(2):193-202.
https://pmc.ncbi.nlm.nih.gov/articles/PMC5794515
http://www.ncbi.nlm.nih.gov/pubmed/28942074?tool=bestpractice.com
Antimetabolites (e.g., methotrexate, azathioprine, mycophenolate)
Calcineurin inhibitors (e.g., cyclosporine, tacrolimus)
Alkylating agents (e.g., cyclophosphamide, chlorambucil)
Biologics (e.g., adalimumab, infliximab, rituximab)
These drugs may be used as corticosteroid-sparing agents. The drug and the regimen should be determined by a specialist.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Patients receiving immunomodulatory therapy require close monitoring.[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
Severe sight-threatening uveitis requires long-term immunomodulatory therapy.
Local corticosteroid therapy may be considered
Alternatives to corticosteroids are preferred for long-term control; however, periocular injections or ocular implants are sometimes used.
Triamcinolone periocular injections: can reduce inflammation for several months. There is a risk of glaucoma and/or cataract after several years of therapy.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Fluocinolone intravitreal implant: reduce severity and frequency of uveitis recurrence, minimizing the use of adjunctive treatment. Effective for 2-3 years. There is a risk of elevated intraocular pressure and cataracts; incisional glaucoma surgery is often required.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
[67]Jaffe GJ, Martin D, Callanan D, et al. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology. 2006 Jun;113(6):1020-7.
http://www.ncbi.nlm.nih.gov/pubmed/16690128?tool=bestpractice.com
Dexamethasone intravitreal implant: preloaded injector releases dexamethasone over 4-6 months.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Systemic immunosuppression and local treatment appear to improve visual outcomes to a similar extent in patients with noninfectious uveitis.[73]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 Oct;118(10):1916-26.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191365
http://www.ncbi.nlm.nih.gov/pubmed/21840602?tool=bestpractice.com
[74]Reddy A, Liu SH, Brady CJ, et al. Corticosteroid implants for chronic non-infectious uveitis. Cochrane Database Syst Rev. 2023 Aug 29;8(8):CD010469.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010469.pub4/full
http://www.ncbi.nlm.nih.gov/pubmed/37642198?tool=bestpractice.com
Seven-year follow-up (nonprespecified) of one randomized controlled trial suggested that systemic therapy may be associated with better visual acuity; however, conclusions are limited by loss to follow-up.[75]Kempen JH, Altaweel MM, Holbrook JT, et al; Writing Committee for the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study Research Group. 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 May 16;317(19):1993-2005.
http://www.ncbi.nlm.nih.gov/pubmed/28477440?tool=bestpractice.com
Chronic management of noninfectious uveitis: initiating immunomodulatory therapy
Evaluation of baseline organ function and screening for active or latent infectious diseases (e.g., tuberculosis, hepatitis) via history, laboratory, and clinically relevant nonocular imaging is recommended before initiation of systemic immunomodulatory therapy.[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
The timing and choice of systemic immunomodulatory therapy is informed by the cause of intraocular inflammation.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
Examples of noninfectious causes necessitating early intervention include sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, Behçet disease, and rheumatoid scleritis.
Therapeutic response to systemic immunomodulatory therapy varies greatly; patients require continued treatment with a corticosteroid (topical or systemic) until immunomodulatory therapy is effective, and the corticosteroid can then be tapered.[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
Efficacy and toxicity of the immunomodulatory drug is monitored at 6- to 8-week intervals via blood work (e.g., complete blood count, renal function tests, liver function tests), and ancillary tests as required. Rheumatologist or hematologist input may be required.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
Initial choice of therapy
Antimetabolites are commonly used, are dosed orally, and have manageable adverse effects.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
Methotrexate and mycophenolate are first-line antimetabolites.[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
One systematic review and meta-analysis found that methotrexate may be slightly more effective at controlling inflammation, including achievement of corticosteroid-sparing control, than mycophenolate in patients with noninfectious intermediate, posterior, and panuveitis (follow-up 0-6 months).[76]Edwards Mayhew RG, Li T, McCann P, et al. Non-biologic, steroid-sparing therapies for non-infectious intermediate, posterior, and panuveitis in adults. Cochrane Database Syst Rev. 2022 Oct 31;10(10):CD014831.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD014831.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/36315029?tool=bestpractice.com
Azathioprine is less commonly used in some territories, including the US.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
Results from one small clinical trial found that patients randomized to azathioprine required significantly higher average corticosteroid doses than those randomized to cyclosporine.[77]Cuchacovich M, Solanes F, Díaz G, et al. Comparison of the clinical efficacy of two different immunosuppressive regimens in patients with chronic Vogt-Koyanagi-Harada disease. Ocul Immunol Inflamm. 2010 Jun;18(3):200-7.
http://www.ncbi.nlm.nih.gov/pubmed/20482399?tool=bestpractice.com
In meta-analysis, however, cyclosporine plus a corticosteroid was not found to be superior to azathioprine plus a corticosteroid with respect to efficacy or safety (low‐ or very low‐certainty evidence).[76]Edwards Mayhew RG, Li T, McCann P, et al. Non-biologic, steroid-sparing therapies for non-infectious intermediate, posterior, and panuveitis in adults. Cochrane Database Syst Rev. 2022 Oct 31;10(10):CD014831.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD014831.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/36315029?tool=bestpractice.com
Risk for ocular complications with azathioprine and cyclosporine appears to be similar (very uncertain).[76]Edwards Mayhew RG, Li T, McCann P, et al. Non-biologic, steroid-sparing therapies for non-infectious intermediate, posterior, and panuveitis in adults. Cochrane Database Syst Rev. 2022 Oct 31;10(10):CD014831.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD014831.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/36315029?tool=bestpractice.com
Observational data suggest that azathioprine may be associated with a higher rate of treatment-related adverse effects than methotrexate or mycophenolate in patients with ocular inflammation (with uveitis accounting for the majority of diagnoses).[78]Galor A, Jabs DA, Leder HA, et al. Comparison of antimetabolite drugs as corticosteroid-sparing therapy for noninfectious ocular inflammation. Ophthalmology. 2008 Oct;115(10):1826-32.
http://www.ncbi.nlm.nih.gov/pubmed/18579209?tool=bestpractice.com
Alternative options
Where there is incomplete disease control with antimetabolites, calcineurin inhibitors are occasionally added to the regimen.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Cyclosporine is widely used; major risks include bone marrow suppression and renal toxicity.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Tacrolimus may also be considered.[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
In one small randomized open-label trial, tacrolimus appeared to have a more favorable safety profile than cyclosporine with comparable efficacy.[79]Murphy CC, Greiner K, Plskova J, et al. Cyclosporine vs tacrolimus therapy for posterior and intermediate uveitis. Arch Ophthalmol. 2005 May;123(5):634-41.
https://jamanetwork.com/journals/jamaophthalmology/fullarticle/417021
http://www.ncbi.nlm.nih.gov/pubmed/15883282?tool=bestpractice.com
However, the trial was underpowered.
Alkylating agents are rarely used due to associated toxicity and the increasing use of biologics.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Cyclophosphamide and chlorambucil may be considered for severe, stubborn, or refractory uveitis when other treatments are not tolerated or are contraindicated.
Chronic management of noninfectious uveitis: adjustment of systemic immunomodulatory therapy
Adjustment of systemic immunomodulatory therapy may be clinically indicated in certain circumstances including: deterioration of visual function, anterior chamber cells or flare, vitreous haze, chorioretinal or retinal vascular lesions, macular or optic nerve involvement.[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
Before therapy is changed, exclude treatment nonadherence, infections (e.g., syphilis, tuberculosis), and masquerade syndromes (e.g., intraocular malignancy, retinal degeneration) as factors in a patient with inadequate response to therapy.[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
Consideration may then be given to dose escalation to the maximum tolerated therapeutic dose.
Continued inadequate response may warrant switching to an alternative immunomodulatory drug or the introduction of an alternative treatment (e.g., biologics, surgery [vitrectomy, cryotherapy], or local or regional therapies). Consider individualized therapy based on history, cause of uveitis, and patient preference.[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
If a patient is not benefiting adequately from immunomodulatory therapy (i.e., suppression of ocular inflammation; achieving inactive disease or drug-induced remission) the diagnosis should be reconsidered.
Chronic management of noninfectious uveitis: biologics
The tumor necrosis factor (TNF)-alpha inhibitors adalimumab and infliximab are the most commonly used biologics used in the treatment of noninfectious uveitis.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
[80]Jaffe GJ, Dick AD, Brézin AP, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016 Sep 8;375(10):932-43.
https://www.nejm.org/doi/10.1056/NEJMoa1509852
http://www.ncbi.nlm.nih.gov/pubmed/27602665?tool=bestpractice.com
[81]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 Sep 17;388(10050):1183-92.
http://www.ncbi.nlm.nih.gov/pubmed/27542302?tool=bestpractice.com
[82]National Institute for Health and Care Excellence. Adalimumab and dexamethasone for treating non-infectious uveitis. Jul 2017 [internet publication].
https://www.nice.org.uk/guidance/ta460
They are typically considered in patients who are intolerant of, or who do not respond to, more traditional immunosuppressants. Meta-analysis indicates that infliximab and adalimumab have similar therapeutic efficacy and corticosteroid-sparing effect in patients with noninfectious uveitis.[83]Liu W, Bai D, Kou L. Comparison of infliximab with adalimumab for the treatment of non-infectious uveitis: a systematic review and meta-analysis. BMC Ophthalmol. 2023 May 29;23(1):240.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10226205
http://www.ncbi.nlm.nih.gov/pubmed/37248486?tool=bestpractice.com
TNF-alpha inhibitors are used in the management of autoimmune inflammatory diseases. Adalimumab and infliximab may, therefore, be of particular value for the treatment of uveitis associated with Behçet disease and HLA-B27+ ankylosing spondylitis.[84]Renton WD, Jung J, Palestine AG. Tumor necrosis factor (TNF) inhibitors for juvenile idiopathic arthritis-associated uveitis. Cochrane Database Syst Rev. 2022 Oct 14;10(10):CD013818.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013818.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/36239193?tool=bestpractice.com
In patients with Behçet uveitis, adalimumab may be superior to infliximab with respect to ocular inflammation remission, drug retention, and the incidence of severe infusion or injection reactions.[85]Guan X, Zhao Z, Xin M, et al. Long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha treatment for patients with Behcet's uveitis: a systematic review and meta-analysis. Int J Rheum Dis. 2024 Feb;27(2):e15096.
http://www.ncbi.nlm.nih.gov/pubmed/38402428?tool=bestpractice.com
Adalimumab is approved in the US and Europe for the treatment of noninfectious intermediate, posterior, and panuveitis. Infliximab is not licensed in the US or Europe for the treatment of uveitis. Infliximab has, however, been studied in refractory uveitis including Behçet disease and idiopathic uveitis.[71]Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-73.
https://www.aaojournal.org/article/S0161-6420(17)32446-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/29310963?tool=bestpractice.com
[86]Busto-Iglesias M, Rodríguez-Martínez L, Rodríguez-Fernández CA, et al. Perspectives of therapeutic drug monitoring of biological agents in non-infectious uveitis treatment: a review. Pharmaceutics. 2023 Feb 25;15(3):766.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10051556
http://www.ncbi.nlm.nih.gov/pubmed/36986627?tool=bestpractice.com
Rituximab, an anti-CD20 monoclonal antibody, may be of benefit for patients with uveitis associated with rheumatoid arthritis, granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), or systemic lupus erythematosus-associated vasculitis.[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
[87]Ng CC, Sy A, Cunningham ET Jr. Rituximab for non-infectious uveitis and scleritis. J Ophthalmic Inflamm Infect. 2021 Aug 16;11(1):23.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8364894
http://www.ncbi.nlm.nih.gov/pubmed/34396463?tool=bestpractice.com
[88]Miserocchi E, Modorati G, Berchicci L, et al. Long-term treatment with rituximab in severe juvenile idiopathic arthritis-associated uveitis. Br J Ophthalmol. 2016 Jun;100(6):782-6.
http://www.ncbi.nlm.nih.gov/pubmed/26396026?tool=bestpractice.com
[89]Ahmed A, Foster CS. Cyclophosphamide or rituximab treatment of scleritis and uveitis for patients with granulomatosis with polyangiitis. Ophthalmic Res. 2019;61(1):44-50.
http://www.ncbi.nlm.nih.gov/pubmed/29635229?tool=bestpractice.com
[90]You C, Ma L, Lasave AF, et al. Rituximab induction and maintenance treatment in patients with scleritis and granulomatosis with polyangiitis (Wegener's). Ocul Immunol Inflamm. 2018;26(8):1166-73.
http://www.ncbi.nlm.nih.gov/pubmed/28628344?tool=bestpractice.com
Pregnancy
Ocular inflammation in pregnant women is rare, and many women with chronic uveitis observe disease remission during pregnancy, with recurrence postpartum.[91]Chiam NP, Lim LL. Uveitis and gender: the course of uveitis in pregnancy. J Ophthalmol. 2014;2014:401915.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3941965
http://www.ncbi.nlm.nih.gov/pubmed/24683491?tool=bestpractice.com
All patients should be referred early to an ophthalmologist for management.
Systemic immunomodulatory therapy is typically avoided during pregnancy. For severe, sight-threatening disease, treatment options may include intravitreal or oral corticosteroids, and adalimumab.[91]Chiam NP, Lim LL. Uveitis and gender: the course of uveitis in pregnancy. J Ophthalmol. 2014;2014:401915.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3941965
http://www.ncbi.nlm.nih.gov/pubmed/24683491?tool=bestpractice.com
[92]Bandoli G, Palmsten K, Forbess Smith CJ, et al. A review of systemic corticosteroid use in pregnancy and the risk of select pregnancy and birth outcomes. Rheum Dis Clin North Am. 2017 Aug;43(3):489-502.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604866
http://www.ncbi.nlm.nih.gov/pubmed/28711148?tool=bestpractice.com
[93]Chambers CD, Johnson DL, Xu R, et al. Birth outcomes in women who have taken adalimumab in pregnancy: a prospective cohort study. PLoS One. 2019;14(10):e0223603.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799916
http://www.ncbi.nlm.nih.gov/pubmed/31626646?tool=bestpractice.com
Infective uveitis
Uveitis secondary to an infection is often aggressive and may lead to permanent blindness. Seek specialist advice.
Treatment of the infection may be regional and/or systemic. Antiviral, antimicrobial, antifungal, and antiparasitic treatment is considered depending on etiology.[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[49]Gueudry J, Muraine M. Anterior uveitis. J Fr Ophtalmol. 2018 Jan;41(1):e11-21.
http://www.ncbi.nlm.nih.gov/pubmed/29290458?tool=bestpractice.com
[60]Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016 Jan-Feb;61(1):1-17.
http://www.ncbi.nlm.nih.gov/pubmed/26164736?tool=bestpractice.com
Numerous infectious agents can result in uveitis. These may include:[3]Burkholder BM, Jabs DA. Uveitis for the non-ophthalmologist. BMJ. 2021 Feb 3;372:m4979.
http://www.ncbi.nlm.nih.gov/pubmed/33536186?tool=bestpractice.com
[94]Ngathaweesuk Y, Hendrikse J, Groot-Mijnes JDF, et al. Causes of infectious pediatric uveitis: a review. Surv Ophthalmol. 2024 May-Jun;69(3):483-94.
https://www.surveyophthalmol.com/article/S0039-6257(23)00172-8/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/38182040?tool=bestpractice.com
HIV-associated opportunistic infections (e.g., cytomegalovirus [CMV], Pneumocystis carinii, tuberculosis [TB], toxoplasmosis, candida)
Sexually transmitted infections (e.g., syphilis, gonorrhea, herpes simplex virus [HSV], chlamydia)
Congenital infections (TORCH: Toxoplasmosis, Other agents, Rubella, CMV, HSV)
Infections related to occupation/leisure (e.g., leptospirosis, brucellosis, toxoplasmosis, Bartonella henselae [cat-scratch disease])
Geography-specific infections (e.g., histoplasmosis, coccidioidomycosis, Borrelia burgdorferi [Lyme disease], TB, malaria, leprosy)
Environment-specific infection (e.g., TB) exposure[49]Gueudry J, Muraine M. Anterior uveitis. J Fr Ophtalmol. 2018 Jan;41(1):e11-21.
http://www.ncbi.nlm.nih.gov/pubmed/29290458?tool=bestpractice.com