Approach

The treatment of uveitis depends largely on the cause, location, and severity of the disease.[59] 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]

Acute management of noninfectious uveitis

Corticosteroid therapy is first-line for acute noninfectious uveitis; topical ophthalmic formulations are indicated for anterior chamber inflammation.[3][60]​​​ 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]​ 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][61]

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]​ 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]

Adverse effects of periocular corticosteroid injections include:[62][63][64]​​​​

  • 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]​ 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][66][67]​​​​​ 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][60]​ 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]

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]

Oral corticosteroids

Oral corticosteroids may be used in severe bilateral or recalcitrant uveitis, or if patients cannot tolerate corticosteroid injections.[60] 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][68]

Potential adverse effects associated with prolonged use of oral corticosteroids include hypertension, bone fracture, metabolic issues, and gastrointestinal disturbances.[69] If prolonged oral corticosteroid therapy is anticipated (>3 months), systemic immunomodulatory therapy should be considered.[60] 

Intravenous corticosteroids

Intravenous corticosteroids (e.g., high-dose methylprednisolone) are rarely considered, but may be indicated in specific clinical scenarios:[60][68]

  • 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]

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][68]

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]

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]​ 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]

Chronic management of noninfectious uveitis: systemic immunomodulatory therapy

Long-term treatment aims to control ocular and systemic disease while minimizing corticosteroid exposure.[3][60]​​

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][71]

Immunomodulatory drugs include:[3][60][71]​​​​[72]

  • 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]​ Patients receiving immunomodulatory therapy require close monitoring.[71] 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][60]​​

  • 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][60]​​[67]

  • Dexamethasone intravitreal implant: preloaded injector releases dexamethasone over 4-6 months.[3][60]​​

Systemic immunosuppression and local treatment appear to improve visual outcomes to a similar extent in patients with noninfectious uveitis.[73][74]​ 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]

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]

The timing and choice of systemic immunomodulatory therapy is informed by the cause of intraocular inflammation.[60][71]​​​ 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]

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][71]

Initial choice of therapy

Antimetabolites are commonly used, are dosed orally, and have manageable adverse effects.[3][60][71] Methotrexate and mycophenolate are first-line antimetabolites.[71] 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]

Azathioprine is less commonly used in some territories, including the US.[3]​ Results from one small clinical trial found that patients randomized to azathioprine required significantly higher average corticosteroid doses than those randomized to cyclosporine.[77] 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]​ Risk for ocular complications with azathioprine and cyclosporine appears to be similar (very uncertain).[76]​ 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]

Alternative options

Where there is incomplete disease control with antimetabolites, calcineurin inhibitors are occasionally added to the regimen.[60]​ Cyclosporine is widely used; major risks include bone marrow suppression and renal toxicity.[60] Tacrolimus may also be considered.​[71] In one small randomized open-label trial, tacrolimus appeared to have a more favorable safety profile than cyclosporine with comparable efficacy.[79]​ However, the trial was underpowered.

Alkylating agents are rarely used due to associated toxicity and the increasing use of biologics.[3][60]​​​ 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] 

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] 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] 

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][71]​​​​​[80][81][82]​ 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]

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]​ 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]

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][86]

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][87][88][89][90]

Pregnancy

Ocular inflammation in pregnant women is rare, and many women with chronic uveitis observe disease remission during pregnancy, with recurrence postpartum.[91]​ 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][92][93]

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][49][60]​​

Numerous infectious agents can result in uveitis. These may include:[3][94]

  • 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]

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