Uveitis: Treatment

INTRODUCTION — Intraocular inflammation (ie, uveitis) results from many causes. The approach to therapy depends upon the etiology, severity of the inflammation, and location within the eye [1]. The management of a patient with uveitis will require consultation with an ophthalmologist or other specialist in uveal eye disease. Ideally, therapy should be initiated within 24 hours of the onset of acute anterior uveitis, and infectious causes of uveitis should be treated promptly.

This topic will focus primarily on the treatment of uveitis that is not related to an active infection. Treatment of uveitis that is due to infection or systemic rheumatic disease is discussed in more detail in the topics on management of the underlying condition. The etiology, clinical manifestations, and diagnostic approach to a patient with a painful red eye and uveitis are presented separately. (See "The red eye: Evaluation and management" and "Uveitis: Etiology, clinical manifestations, and diagnosis".)

TERMINOLOGY — The uvea is the middle portion of the eye. The anterior portion of the uvea includes the iris and ciliary body. The pars plana is the tissue just posterior to the ciliary body and just anterior to the retina. The posterior portion of the uvea is known as the choroid (figure 1).

●Anterior uveitis – Inflammation of the anterior uveal tract is called anterior uveitis and is synonymous with iritis. When the adjacent ciliary body is also inflamed, the process is known as iridocyclitis.

●Intermediate uveitis – The presence of inflammatory cells in the vitreous humor posterior to the lens is termed intermediate uveitis, even though the vitreous humor is not technically part of the uveal tract.

●Posterior uveitis – Terms used to describe uveitis posterior to the lens include vitreitis, intermediate uveitis, pars planitis, choroiditis, retinitis, chorioretinitis, or retinochoroiditis.

●Panuveitis – Panuveitis refers to simultaneous inflammation in the anterior chamber, vitreous humor, and choroid or retina.

These definitions are in keeping with those outlined by expert consensus [2].

URGENCY OF TREATMENT — Patients with uveitis should be treated promptly because there is some risk of vision loss. Timely diagnosis and treatment can be challenging due to the variable clinical presentations of uveitis, which depend both on the location of inflammation and the related condition. As an example, anterior uveitis is often associated with acute-onset eye pain and redness but may be insidious with minimal symptoms in patients with juvenile idiopathic arthritis. Generally, acute anterior uveitis should be treated within 24 hours of the onset of symptoms, and infectious uveitis should likewise be treated immediately upon diagnosis.

MULTIDISCIPLINARY CARE — All patients with uveitis require regular follow-up with an ophthalmologist or other specialist in uveal eye disease. (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'When to refer to an ophthalmologist'.)

Other subspecialist care may be required depending on the etiology of uveitis, including infectious disease specialists (eg, treatment of cytomegalovirus retinitis) and rheumatologists (eg, treatment of uveitis related to psoriatic arthritis). Additionally, rheumatology and ophthalmology often work together to help manage patients with noninfectious uveitis that is unrelated to a systemic rheumatic disease but requires systemic immunosuppression.

SUPPORTIVE MEASURES FOR ALL PATIENTS — Patients with uveitis may benefit from supportive measures like applying warm compresses to a closed eye and wearing sunglasses when exposed to bright light. Such measures are never sufficient for treatment and must always be combined with more specific therapies outlined below. Oral analgesics (eg, nonsteroidal antiinflammatory drugs [NSAIDs], acetaminophen) may also be used.

INFECTIOUS UVEITIS — Treatment of uveitis due to infection depends on the type of infection. Infectious causes of uveitis are shown in the table (table 1). (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Infectious causes'.)

Treatment of underlying infection — Patients should be given targeted antiviral, antimicrobial, antifungal, and antiparasitic treatments when these are available. Generally, the treatment for infectious uveitis due to a particular pathogen is similar to the treatment of other types of infections caused by those pathogens. However, patients who are immunocompromised may require longer courses of therapy. Other treatment considerations specific to uveitis are outlined below:

●Viral infections – The most common causes of viral uveitis are cytomegalovirus (CMV), herpes zoster, and herpes simplex. Infection with herpes simplex or herpes zoster may cause retinal destruction (acute retinal necrosis), which may progress rapidly without appropriate therapy. Antiviral therapy is especially important in the setting of retinitis to limit retinal damage. CMV retinitis is rare in immunocompetent patients, while herpes simplex and herpes zoster may affect both immunocompetent and immunocompromised patients. Immunosuppressed patients are at greater risk for acute retinal necrosis. These infections require prompt treatment with appropriate antiviral agents, as discussed in the appropriate topic reviews:

•(See "Treatment of herpes zoster", section on 'Ocular disease'.)

•(See "Treatment of AIDS-related cytomegalovirus retinitis".)

•(See "Herpes simplex keratitis", section on 'Management'.)

●Bacterial and spirochetal infections – Bacterial infections that can cause uveitis in the immunocompetent host include syphilis and, less commonly, cat scratch disease, tuberculosis, Lyme disease, and leprosy. All bacterial causes of uveitis require prompt treatment with appropriate targeted therapy, as discussed in the specific topic reviews. Additional considerations for bacterial uveitis due to syphilis, cat scratch disease, and tuberculosis are discussed separately:

•(See "Syphilis: Treatment and monitoring", section on 'Treatment of neuro/ocular/otic syphilis'.)

•(See "Treatment of cat scratch disease", section on 'Neurologic and ocular manifestations'.)

•(See "Tuberculosis and the eye", section on 'Treatment'.)

●Parasitic infections – Toxoplasmosis gondii can cause chorioretinitis in immunocompetent and immunocompromised adults; treatment in patients with human immunodeficiency virus (HIV) infection requires higher doses and a longer duration of therapy. (See "Toxoplasmosis: Ocular disease" and "Toxoplasmosis in patients with HIV", section on 'Chorioretinitis'.)

Adjunctive glucocorticoids — Adjunctive glucocorticoids are frequently used for patients with anterior infectious uveitis and can also be used in select patients with posterior uveitis, especially those with involvement of the pars plana or intermediate region. The formulation, dose, and timing of glucocorticoids varies with the type of infection and severity of inflammation. These are discussed separately in the respective treatment topics. (See 'Treatment of underlying infection' above.)

Dilating drops for anterior uveitis — For patients with anterior uveitis, a dilating drop such as cyclopentolate (1 percent) can relieve pain due to spasm of the muscles controlling the pupil and will also help prevent the formation of posterior synechiae that may interfere with the function of the pupil. It is typically dosed as one drop to each affected eye three times daily for adults. Cyclopentolate drops may blur near vision due to difficulty accommodating. They can also increase intraocular pressure and should be used with caution in patients who have or who are at risk for narrow-angle glaucoma.

NONINFECTIOUS UVEITIS — The approach to treating noninfectious uveitis varies depending upon the location of the inflammation, because topical therapies are not able to penetrate all portions of the eye adequately. Topical therapies are most effective for anterior uveitis.

Initial treatment — Local agents used to treat uveitis include various forms of glucocorticoids. depending on the location of inflammation, as well as dilating drops for patients with anterior uveitis. Certain patients may also benefit from systemic immunosuppressive therapy as part of their initial treatment. The approach to initial treatment of noninfectious uveitis is summarized in the algorithm (algorithm 1).

Locally administered glucocorticoids for most patients — In most patients with noninfectious uveitis, we give locally administered glucocorticoids in the form of drops or injections as part of the initial treatment strategy. The optimal delivery method for local glucocorticoid therapy depends on the location of inflammation (eg, anterior versus posterior uveitis). Potential complications include increased intraocular pressure and cataractogenesis; therefore, these treatments may not be appropriate for patients with glaucoma, especially when delivered by local injection. Also, due to the potential for adverse drug effects with cumulative glucocorticoid exposure, we generally do not give long-acting injectable forms of glucocorticoids as part of the initial therapy.

●Eye drops – Different forms of glucocorticoid drops may be more effective for anterior versus posterior uveitis.

•Anterior uveitis – Noninfectious causes of anterior uveitis are generally treated with topical glucocorticoids such as prednisolone acetate (1 percent). The frequency of administration depends upon the intensity of the inflammation. As an example, patients with mild ocular inflammation may be treated four times a day, while those with more severe inflammation may require hourly drops.

•Posterior uveitis – Uveitis that is primarily posterior to the lens is generally not responsive to topical medication, although some experts are increasingly using difluprednate (0.05 percent) [3]. Difluprednate has better vitreous humor penetration for inflammation posterior to the lens compared with other topical corticosteroids, but it also has a greater tendency to raise intraocular pressure and to cause cataracts. As with other forms of topical glucocorticoids, the dosing frequency depends on the extent of inflammation.

●Injections for panuveitis, intermediate uveitis, and posterior uveitis – Additional options for initial treatment of posterior uveitis, as well as treatment of panuveitis or intermediate uveitis, include treatment with periocular or intraocular injection of a glucocorticoid such as triamcinolone. There are various types of periocular injections including subconjunctival, subtenon, suprachoroidal, or peribulbar. Intraocular injection of glucocorticoids entails more risk than a periocular injection, but this approach can also provide more potent and sustained benefit. The US Food and Drug Administration (FDA) has approved glucocorticoids for intraocular injection, including a formulation of triamcinolone and polymers that slowly release either fluocinolone acetonide or dexamethasone. Some patients may decline glucocorticoid injection.

The preference for initially using locally administered glucocorticoids over systemic ones is based on the premise that, for most patients, locally administered forms should provide the same clinical benefit with a lower risk of systemic adverse drug effects. Clinical features and systemic conditions that should prompt consideration of systemic immunosuppression as part of the initial therapy, including the addition of systemic glucocorticoids, are discussed below. (See 'Indications for systemic immunosuppression' below.)

Dilating drops for anterior uveitis — As with infectious uveitis, dilating drops such as cyclopentolate may help reduce pain and the risk of developing posterior synechiae in patients with anterior uveitis. (See 'Dilating drops for anterior uveitis' above.)

Indications for systemic immunosuppression — Systemic treatment is generally reserved for patients who remain symptomatic despite local therapies. However, it may be reasonable to start systemic agents as part of the initial treatment strategy in certain groups of patients, including those with the following features or conditions:

●Severe disease with profoundly limited vision or risk of significant vision loss, including those with macular edema

●Bilateral posterior uveitis

●Comorbid glaucoma precluding the use of local glucocorticoid injections

●Certain systemic diseases including Behçet syndrome and serpiginous choroiditis

The choice of systemic therapy and indications to start systemic therapy for refractory disease are detailed below. (See 'Systemic glucocorticoids for most patients' below and 'Addition of glucocorticoid-sparing immunosuppression' below.)

Treatment of resistant disease — We define resistant disease as patients with ongoing inflammation (eg, presence of inflammatory cells, retinal vasculitis, vitreitis) despite initial therapy or patients who are dependent on any form of glucocorticoids to maintain quiescence for a period of three months or more. These patients often require systemic glucocorticoids and/or other immunosuppressive agents. Additional courses or intensification of locally administered glucocorticoids may also be helpful.

Intraocular glucocorticoids for posterior or intermediate uveitis — Intraocular formulations of glucocorticoids can provide a longer duration of local glucocorticoid treatment for patients with refractory posterior or intermediate uveitis. In these patients, we typically use longer-lasting intraocular glucocorticoids rather than frequent local short-acting glucocorticoid injections. While there are no data directly comparing these approaches, more frequent short-acting glucocorticoids may be more burdensome for patients and may make patients more vulnerable to breakthrough flares.

The most commonly used long-acting intraocular glucocorticoid is fluocinolone, which can be injected or surgically implanted. Examples of ideal candidates for intraocular fluocinolone include:

●A patient without a systemic disease who has no other indication for immunosuppression

●A patient with a systemic disease that is otherwise well controlled with a stable immunosuppressive regimen

●Patients who have had prior cataract surgery and no history of glucocorticoid-associated increased intraocular pressure

Many patients and ophthalmologists prefer the injectable approach and reserve the surgically implanted device for the patient with severe disease, but there are other factors that may also influence the choice. As an example, we avoid intraocular depot glucocorticoid injection in aphakic patients due to the risk of the glucocorticoid pellet migrating into the anterior chamber, where it can cause glaucoma and/or corneal decompensation.

●The dose of intravitreal injection of fluocinolone acetonide in adults is 0.18 mg and lasts for up to 36 months.

●The surgically implanted intraocular fluocinolone device (0.59 mg) continuously delivers glucocorticoid into the vitreous humor for approximately 2.5 years [4].

Randomized trials support the use of intraocular fluocinolone, particularly the intraocular implants. In a meta-analysis of two trials, intraocular glucocorticoid-releasing implants reduced the risk of uveitis recurrence at 24 months by 54 percent (relative risk 0.46, 95% CI 0.35-0.60) and led to an improvement in best corrected visual acuity (mean difference 0.22 logMAR, 95% CI 0.13-0.31) [5]. In one study, visual acuity was better in patients initially allocated to receive systemic immunosuppressive therapy compared with patients who had fluocinolone implants after seven years of extended follow-up, although the study was limited by 30 percent loss to follow-up in both groups [6].

The fluocinolone implant carries a slight risk of surgical complications, including endophthalmitis. Cataract and glaucoma are common complications of intraocular glucocorticoid-releasing implants, but they do not cause systemic toxicity. Almost all patients who have not had prior cataract surgery develop a cataract, and approximately 30 percent of patients require additional surgery for glaucoma. The safety of multiple implantations and continuous glucocorticoid exposure beyond 2.5 years requires additional study.

Systemic glucocorticoids for most patients — We most commonly use systemic glucocorticoids in the following clinical scenarios:

●As part of the initial treatment of patients with severe vision loss (ie, visual acuity of 20/200 or worse) or bilateral posterior uveitis

●As part of the treatment of refractory bilateral uveitis that has not responded to topical medications and that is interfering with the activities of daily living (eg, due to impaired visual acuity)

●As a therapeutic bridge for patients with refractory uveitis who are starting glucocorticoid-sparing therapies, since such treatments commonly take months to become fully effective

The clinician should strive to use the lowest dose of glucocorticoids that provides acceptable benefit for the shortest amount of time (table 2). The dose varies based on the underlying disease, disease severity, patient profile, and clinician and patient preferences. A common initial dose in adults is the equivalent of 40 to 60 mg of prednisone daily. Rarely, high-dose intravenous methylprednisolone (1000 mg daily for three consecutive days) may be given before transitioning to oral glucocorticoids in patients with severe disease with profound visual impairment or risk of significant vision loss [7]. Glucocorticoids are gradually tapered to the lowest dose that controls inflammation. If remission has been achieved for 6 to 12 months, the maintenance dose of oral glucocorticoid may be gradually discontinued. A sample of how oral glucocorticoids might be given and tapered is provided in the table (table 3).

A risk-benefit ratio must be considered for any therapeutic decision. The threshold for using oral glucocorticoids will vary as some patients function well with a visual acuity of 20/70, while others are functionally impaired with a visual acuity of 20/25. Toxicity related to oral glucocorticoid use may limit acceptance by patients and requires monitoring (eg, body weight, blood pressure) (table 4). Certain glucocorticoid-related toxicities are cumulative; care should be taken to limit the dose and duration as much as possible, especially when patients have uveitis related to a chronic condition that may cause recurrent flares. (See "Major adverse effects of systemic glucocorticoids".)

The use of systemic glucocorticoids for the above scenarios is generally consistent with the approach outlined by expert panels of ophthalmologists and rheumatologists [8-10].

Addition of glucocorticoid-sparing immunosuppression — Glucocorticoid-sparing immunosuppression is frequently required for the treatment of refractory uveitis. It may also be needed as part of the initial treatment strategy for patients with certain clinical features, comorbidities, and/or underlying conditions. (See 'Indications for systemic immunosuppression' above.)

Pretreatment testing — Patients should be screened appropriately for chronic infections prior to starting systemic immunosuppression, which depends on the agent used but frequently includes blood tests for hepatitis B, hepatitis C, and tuberculosis. Patients starting systemic immunosuppression should also be counseled about preventive vaccinations. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)

Choice of agent and treatment strategies — Uveitis associated with systemic disease may respond best to certain types of immunosuppressive agents (eg, tumor necrosis factor [TNF]-alpha inhibitors are first-line therapy for uveitis related to Behçet syndrome), which are outlined below. (See 'Patients with systemic inflammatory or autoimmune disease' below.)

For patients with uveitis who do not have a related systemic disease, there is no strong evidence to support using one type of systemic immunosuppressive therapy over another. Therefore, the choice of agent is often based on multiple factors, including the following:

●Etiology of the uveitis

●Severity of inflammation

●The cause of any visual loss (eg, macular edema)

●Adverse effects of and contraindications to specific therapies

●Regulatory or insurance restrictions and drug cost to the patient

●Patient and provider preference

We most commonly use glucocorticoid-sparing immunosuppressive therapy in the following clinical scenarios:

●As part of the initial treatment of patients with a contraindication to glucocorticoids or with uveitis related to certain systemic diseases (see 'Patients with systemic inflammatory or autoimmune disease' below)

●As part of the treatment of refractory uveitis, including patients with chronic uveitis (≥3 months' duration), those who do not tolerate or fail to respond to oral glucocorticoids (eg, ongoing inflammation after two to four weeks), and those who cannot reduce glucocorticoids (eg, requiring ≥10 mg or more of prednisone for three months)

Commonly used options for immunosuppressive therapies to treat noninfectious uveitis include antimetabolites (eg, methotrexate [MTX], azathioprine [AZA], mycophenolate mofetil [MMF]) and TNF-alpha inhibitors. Initially, we start an antimetabolite and proceed if needed to a TNF-alpha inhibitor in patients with resistant disease due to concerns regarding cost and adverse effects of biologic agents. (See 'Antimetabolites' below.)

In patients who are resistant to first-line systemic immunosuppressive therapies, subsequent therapeutic options include the following:

●Adding local or oral glucocorticoids, usually on a temporary basis (see 'Locally administered glucocorticoids for most patients' above and 'Systemic glucocorticoids for most patients' above)

●Switching to a different antimetabolite or combining an antimetabolite with a calcineurin antagonist (see 'Antimetabolites' below)

●Adding or substituting a TNF-alpha inhibitor (eg, adalimumab) (see 'Tumor necrosis factor-alpha inhibitors' below)

If the above approaches are likewise unsuccessful, other biologic agents may be considered (eg, interleukin 6 [IL-6] inhibitors, anti-CD-20 therapies). In very rare cases, cyclophosphamide may be used to treat severe and/or refractory uveitis. (See 'Other therapies' below.)

Studies examining the efficacy of various immunosuppressive agents for treatment of uveitis are primarily observational; there are also limited data from controlled trials on some of the newer biologic agents (eg, TNF-alpha inhibitors). Our approach to immunosuppressive treatment is generally aligned with the guidance issued by a consensus panel of ophthalmologists and rheumatologists in 2000 (notably prior to any extensive testing of biologics) [8] and subsequent expert panel recommendations (which include the role of biologics) [9,10].

Antimetabolites — Antimetabolites that may be used to treat refractory uveitis include MTX, MMF, and AZA. Doses are generally similar to those used for other conditions requiring immunosuppressive therapy. These medications should be used with appropriate caution and careful monitoring. There should be no specific contraindication to the therapy, such as active liver disease when using MTX. AZA may be less well tolerated than MTX and MMF [11]. More information about drug dosing, contraindications, adverse effects, and monitoring for these agents is provided separately:

●(See "Use of methotrexate in the treatment of rheumatoid arthritis".)

●(See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

●(See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

Evidence directly comparing various types of antimetabolites is very limited; however, MTX and MMF appear to have similar clinical effectiveness. In a trial of 216 adults with noninfectious uveitis (intermediate, posterior, or panuveitis), patients who were randomly assigned to receive MTX (25 mg weekly by mouth) versus those assigned to MMF (3 g daily) had similar rates of successful treatment at six months (defined as resolved inflammation on ≤7.5 mg of prednisone daily and ≤2 drops of prednisone acetate 1% daily). Specifically, 67 percent of patients taking MTX and 57 percent of patients taking MMF had treatment success, and most participants maintained this response at 12 months. Prior studies and smaller trials suggested that MMF may be superior, but notably the dosing of MTX was suboptimal in several studies [11-15]. Further trials are needed to confirm whether responses differ between uveitis subgroups and in patients with more severe disease.

Evidence supporting these various therapies is primarily observational and includes the following:

●Methotrexate – A few observational studies have supported the use of MTX in noninfectious uveitis [14,16,17]. In an observational study of 384 patients with noninfectious ocular inflammation who were taking MTX as the single glucocorticoid-sparing immunosuppressive therapy, 58.4 percent had controlled inflammation on low-dose glucocorticoids (≤10 mg daily of prednisone) by 12 months; rates varied by location of inflammation, ranging from 69 percent of patients with intermediate uveitis to 39 percent of patients with posterior or panuveitis [14]. Within a year, therapy was stopped in 13 percent of patients due to lack of benefit and in 16 percent of patients due to adverse effects.

●Mycophenolate mofetil – Several observational studies suggest that MMF is moderately effective in treating noninfectious uveitis [12,13,18,19]. As an example, in a study of 60 patients with noninfectious uveitis, 72 percent of patients had successful control of inflammation on low-dose glucocorticoids (≤10 mg daily of prednisone) by 12 months [19]. Therapy was discontinued due to lack of efficacy in 17 percent of patients and due to adverse effects in another 6 percent.

●Azathioprine – A small number of observational studies have supported the use of AZA in noninfectious uveitis [20,21]. In one involving 145 patients with noninfectious ocular inflammation, rates of successful control of inflammation after six months of therapy with AZA varied based on the location of inflammation, ranging from 69 percent of those with intermediate uveitis to 24 percent of those with anterior uveitis [20]. Within the first year, therapy was stopped in 17 percent of patients due to lack of benefit and in 24 percent due to adverse effects.

Tumor necrosis factor-alpha inhibitors — TNF-alpha inhibitors may be used to treat refractory uveitis and are also sometimes used as initial therapy for those with macular edema. Adalimumab is the TNF-alpha inhibitor with the most supportive evidence for treating uveitis, leading to its approval by both the European Medicines Agency (EMA) and the FDA in 2016 for treating noninfectious intermediate, posterior, and panuveitis [22,23]. By contrast, etanercept is generally not effective for uveitis [24,25]. Other key differences between TNF-alpha inhibitors, including route of administration and frequency of dosing, are summarized in a table (table 5).

●Dosing – Dosing of TNF-alpha inhibitors is generally similar to that used for other systemic autoimmune and autoinflammatory diseases and is often given with a loading dose. As an example, in adult patients, adalimumab may be given as an 80 mg subcutaneous initial injection, followed one week later by 40 mg subcutaneously and then 40 mg every other week.

In patients with intermediate uveitis/pars planitis, we obtain baseline brain magnetic resonance imaging (MRI) before starting a TNF-alpha inhibitor because of the association between these manifestations and demyelinating diseases (eg, multiple sclerosis).

●Adverse effects – Adverse effects of TNF-alpha inhibitors include immunosuppression, infusion or injection-site reactions, cytopenias, demyelinating disease, and heart failure. They should be used with caution in patients with preexisting heart failure, and adults with moderate or severe heart failure should receive doses of infliximab of 5 mg/kg or less. TNF-alpha inhibitors are associated with an increased risk of forming neutralizing drug antibodies and autoantibodies, as well as developing autoimmune diseases (eg, drug-induced lupus). While one prospective study of patients with uveitis being treated with infliximab noted an unusual increase in adverse effects, including drug-induced lupus [26], this has not been observed in subsequent studies. Adverse effects of TNF-alpha inhibitors are discussed in more detail elsewhere. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)

●Evidence – Two well-designed, randomized trials showed that adalimumab was effective in the treatment of noninfectious intermediate, posterior, and panuveitis [27,28]. In these trials, adalimumab significantly improved the time-to-treatment failure in patients with uveitis who followed a tapering schedule for oral glucocorticoids. An open-label extension of these trials further supports the efficacy of adalimumab for the treatment of noninfectious intermediate, posterior, or panuveitis [29]. Prospective studies suggest that infliximab has similar efficacy for treating noninfectious uveitis, especially the subtype related to Behçet syndrome [30,31]. Additional evidence supporting the use of TNF-alpha inhibitors for noninfectious uveitis has been derived from trials of patients with uveitis related to systemic conditions, such as juvenile idiopathic arthritis, Behçet syndrome, and ankylosing spondylitis. Data to support the use of TNF-alpha inhibitors as initial therapy for patients with macular edema are very limited, as the trials above did not include a sub-analysis for this specific patient group [32]. (See "Oligoarticular juvenile idiopathic arthritis", section on 'Treatment' and 'Patients with systemic inflammatory or autoimmune disease' below.)

The safety and tolerability of TNF-alpha inhibitors for treatment of noninfectious ocular inflammatory disease (including uveitis and scleritis) was evaluated in an eight-year prospective cohort study of 43 patients [33]. Serious adverse effects requiring discontinuation of the TNF-alpha inhibitor or hospitalization were noted in four patients (9 percent). Over 90 percent of patients had a sustained remission of disease after a median of 1.2 years taking a TNF-alpha inhibitor, although over half experienced at least one relapse.

Adalimumab and infliximab appear to have similar efficacy in controlling inflammation and preventing flares of noninfectious uveitis based on several observational studies [34,35]. However, one observational study of 107 patients with noninfectious uveitis (intermediate, posterior, or panuveitis) found that those taking infliximab had lower corticosteroid doses at the last follow-up visit and a lower frequency of uveitic macular edema compared with those taking adalimumab [34].

Other therapies — Other agents that have relatively less supportive evidence for the treatment of refractory noninfectious uveitis include calcineurin inhibitors, IL-6 inhibitors, anti-CD-20 agents, cyclophosphamide, and interferon alpha.

●Calcineurin inhibitors – Calcineurin inhibitors (eg, cyclosporine and tacrolimus) may be used as the primary glucocorticoid-sparing agent or be combined with other types of immunosuppressive therapy (eg, antimetabolites or TNF-alpha inhibitors) in patients with refractory uveitis. Doses are generally similar to those used for other conditions requiring immunosuppressive therapy. Patients should be carefully monitored and should not have any specific contraindication to the therapy (eg, hypertension or kidney disease when using cyclosporine). More information about drug dosing, contraindications, adverse effects, and monitoring for these agents is provided separately. (See "Pharmacology of calcineurin inhibitors".)

Evidence supporting the use of calcineurin inhibitors is primarily observational and includes the following:

•Cyclosporine – In an observational study of 373 patients with noninfectious ocular inflammation (including 345 with uveitis), 36 percent of patients using cyclosporine had successful control of inflammation on low-dose glucocorticoids (≤10 mg daily of prednisone) by 12 months; adverse effects were three times more common in patients who were 55 years of age or older [36].

•Tacrolimus – In an observational study of 62 patients with noninfectious uveitis, patients taking tacrolimus (median total daily dose of 3 mg) had an 85 percent probability of being able to taper prednisone to 10 mg daily after 14 months [37]. Another observational study examined the effect of adding tacrolimus for 32 patients with noninfectious intermediate, posterior, or panuveitis who remained dependent on glucocorticoids for disease control despite the use of an antimetabolite (either MTX or MMF) [38]. After six months, 75 percent of patients were able to achieve inactive disease on a low dose of glucocorticoids (≤7.5 mg daily of prednisone).

Based on observational data, cyclosporine and tacrolimus appear to have similar clinical effectiveness but different rates of tolerability. In a trial of 37 patients with refractory noninfectious posterior segmental intraocular inflammation, patients who were randomly assigned to receive cyclosporine (2.5 to 5 mg/kg daily) versus tacrolimus (0.03 to 0.08 mg/kg daily) had similar rates of treatment response (68 versus 67 percent respectively) [39]. However, more patients taking cyclosporine experienced adverse effects compared with those taking tacrolimus; adverse effects included fatigue, gum hypertrophy, palpitations, and increases in mean arterial pressure and serum cholesterol level.

●Interleukin 6 inhibitors – Tocilizumab, a type of IL-6 inhibitor, is sometimes used for the treatment of noninfectious uveitis. Dosing is generally the same as when it is used for other types of inflammatory conditions. Dosing, adverse effects, and monitoring are discussed in detail elsewhere. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab'.)

Data to support the use of tocilizumab are limited. In a prospective trial, 37 patients with intermediate, posterior, or panuveitis who were randomly assigned to one of two doses of tocilizumab (4 mg/kg or 8 mg/kg every four weeks) showed improvements after six months in multiple outcomes (visual acuity, vitreous haze, and central macular thickness) [40-42].

●Anti-CD-20 agents – Anti-CD-20 agents, specifically rituximab, have also been used for treatment of noninfectious uveitis that has been refractory to multiple other systemic therapies. Various doses and administration schedules have been reported, including protocols that are used for rheumatologic and oncologic conditions [43]. More information on rituximab dosing, adverse effects, and the prevention of infusion reactions is provided separately. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

Several retrospective reviews suggest that rituximab may be beneficial in treating refractory noninfectious uveitis [43-45]. As an example, in a literature review that identified 108 patients with noninfectious uveitis who received rituximab, 84 percent had a positive response to therapy [43].

●Cyclophosphamide – Cyclophosphamide is very rarely used for patients with severe uveitis or uveitis that is refractory to multiple other therapies. Drug dosing, contraindications, and monitoring are outlined separately, including a discussion of reproductive health counseling. (See "General principles of the use of cyclophosphamide in rheumatic diseases".)

Data supporting the use of cyclophosphamide for treatment of uveitis comes from several observational studies [46-48]. As an example, a retrospective study of 44 patients with uveitis who were taking oral or intravenous cyclophosphamide found that 81 percent of patients were in remission at 12 months [48]. In addition, 65 percent of patients were able to be maintained on less than 10 mg of prednisone daily.

●Interferon alpha – Alpha interferon is used (primarily in Europe) for posterior uveitis or Behçet syndrome that are refractory to other agents. It has also been used to treat persistent cystoid macular edema, a common complication of uveitis that can limit visual acuity. Cystoid macular edema usually responds to control of the underlying inflammation or to the local injection of glucocorticoids [49]. Alpha interferon requires frequent injections and is associated with flu-like symptoms and depression, which may limit its use. (See "Treatment of Behçet syndrome", section on 'Posterior uveitis'.)

In a randomized trial of 19 adults with intermediate uveitis and macular edema, patients who were randomly assigned to receive interferon beta therapy had greater improvements in visual acuity at three months compared with those taking subcutaneous MTX [50].

●Investigational approaches – Multiple other immunosuppressive agents have been tested for the treatment of noninfectious uveitis:

•Interleukin 17 inhibitors – An antibody to IL-17 was tested in several randomized trials with disappointing results [51], although a smaller randomized trial showed efficacy for anti-IL-17 in treating uveitis if the antibody was given intravenously [52].

•Janus kinase inhibitors – Filgotinib, a type of Janus kinase inhibitor, was tested in a multicenter randomized trial (results pending); however, the manufacturer is not pursuing this indication.

•Sirolimus – An intravitreal injection of sirolimus showed benefit at the lower of two dosages tested in one randomized trial [53].

Tapering therapy — The optimal time to taper therapy and the speed of tapering depend on the severity of uveitis, the type of therapy being used, and potential associated systemic conditions (eg, spondylarthritis).

Glucocorticoids may generally be tapered once uveitis has resolved. The optimal frequency to taper glucocorticoids is variable and primarily depends on the oral dose or frequency of topical drops that was required to control disease. A sample taper for oral glucocorticoids is provided in the table (table 3). Patients who have been on chronic oral glucocorticoids are at risk of developing iatrogenic adrenal insufficiency. More information about glucocorticoid withdrawal is provided separately. (See "Glucocorticoid withdrawal".)

When glucocorticoid-sparing immunosuppressive therapies are required, whether and when to taper therapy depends on the indication. As an example, patients with a related systemic condition will need to have treatment adjusted based on all of the disease manifestations. Typically, for patients with uncomplicated noninfectious uveitis who do not have a related systemic condition, we consider tapering systemic immunosuppression after patients have been in remission for at least 12 months without requiring topical or systemic glucocorticoids.

Prevention of recurrent episodes — In patients who have recurrent episodes of uveitis that are frequent (eg, ≥3 episodes/year) or severe, it may be reasonable to continue longitudinal glucocorticoid-sparing immunosuppressive therapy to try to prevent future attacks. We generally use the same type of glucocorticoid-sparing therapy that induced remission and decrease the dose when possible.

Multiple observational studies have suggested that various therapies may reduce the risk of recurrent noninfectious uveitis; there are no strong data to support the superiority of one agent over another. Several small studies have found that sulfasalazine can help prevent attacks of acute anterior recurrent uveitis, including in patients with associated spondylarthritis and human leukocyte antigen B27 (HLA-B27) positivity [54,55]. Some evidence also indicates that MTX [56] or oral nonsteroidal antiinflammatory drugs (NSAIDs) [57] might reduce the frequency of iritis attacks.

Many types of TNF-alpha inhibitors, IL-17 inhibitors, and Janus kinase inhibitors appear to reduce the risk of developing eye inflammation in patients with ankylosing spondylitis, a disease frequently associated with acute anterior uveitis [58-61]. However, the risk and cost usually do not justify their use if the purpose is solely to prevent iritis.

FOLLOW-UP EVALUATION — The frequency of follow-up examinations will depend on the severity of uveitis, associated visual impairment, and intraocular pressure as well as the therapies being used.

SPECIAL POPULATIONS

Patients with systemic inflammatory or autoimmune disease — Noninfectious uveitis is sometimes driven by an underlying systemic inflammatory or autoimmune disease. Generally, the initial treatment strategy for such patients involves locally-administered agents as well as systemic therapy (see 'Initial treatment' above). For certain underlying conditions, there is evidence to support specific types of therapy as outlined below:

●Conditions related to HLA-B27 positivity – A shorter course of oral glucocorticoids is usually sufficient to treat severe iritis in patients with a positive human leukocyte antigen B27 (HLA-B27) and a related condition (eg, spondyloarthritis, psoriasis, psoriatic arthritis, inflammatory bowel disease). It is rarely necessary to treat such patients with oral therapy for more than two weeks because the eye inflammation generally remits rapidly. The same guidance is generally applicable for patients who have a condition that is often associated with HLA-B27 positivity but who are themselves negative for the antigen.

In patients who have frequent flares of uveitis but who are not taking systemic therapy for their underlying condition, it may be reasonable to start a tumor necrosis factor (TNF)-alpha inhibitor. (See 'Tumor necrosis factor-alpha inhibitors' above and 'Prevention of recurrent episodes' above.)

●Juvenile idiopathic arthritis – The screening, treatment, monitoring, and complications of uveitis in patients with juvenile idiopathic arthritis is described in detail separately. (See "Oligoarticular juvenile idiopathic arthritis", section on 'Uveitis'.)

●Behçet syndrome – The treatment of uveitis related to Behçet syndrome is discussed in detail elsewhere. (See "Treatment of Behçet syndrome", section on 'Ocular disease'.)

●Sarcoidosis – Patients with uveitis related to sarcoidosis may only require locally administered and/or systemic glucocorticoids for treatment. For patients who require glucocorticoid-sparing systemic immunosuppression, methotrexate (MTX) and TNF-alpha inhibitors are commonly used; dosing is similar to when these agents are used for other manifestations of sarcoidosis [62]. (See "Treatment of pulmonary sarcoidosis: Initial approach".)

●Vogt-Koyanagi-Harada syndrome – Patients with Vogt-Koyanagi-Harada syndrome (VKH) may benefit from intravenous methylprednisolone when the illness first begins, followed by a taper of oral prednisone [63]. More information about VKH is provided separately. (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Systemic inflammatory diseases'.)

Many other systemic conditions are associated with uveitis; the approach to management is discussed in the respective disease-specific topics, including the following:

●Systemic lupus erythematosus (see "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Management')

●Sjögren's disease (see "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Efficacy of specific therapeutic agents')

●Relapsing polychondritis (see "Treatment of relapsing polychondritis")

●Blau syndrome (see "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Blau syndrome')

●Kawasaki disease (see "Kawasaki disease: Initial treatment and prognosis")

●Tubulointerstitial nephritis and uveitis syndrome (see "Tubulointerstitial nephritis and uveitis (TINU syndrome)", section on 'Management and prognosis')

●Multiple sclerosis (see "Overview of disease-modifying therapies for multiple sclerosis")

●Primary angiitis of the central nervous system (see "Primary angiitis of the central nervous system in adults", section on 'Treatment')

Drug-associated uveitis — Patients who have had uveitis related to a drug or hypersensitivity reaction should generally avoid the offending medication in the future, except in the case of potentially life-saving interventions (eg, immunotherapy for patients with metastatic malignancy). Treatment of noninfectious uveitis related to immune checkpoint inhibitor therapy is outlined elsewhere; otherwise, treatment of uveitis is the same as outlined for other causes of noninfectious uveitis. (See "Ocular side effects of systemically administered chemotherapy", section on 'Immune checkpoint inhibitors' and 'Noninfectious uveitis' above.)

Pregnancy and lactation — Safety of medications during pregnancy and lactation is another important consideration for any patient who is or may become pregnant. Treatment of infectious uveitis may need to be adjusted depending on the antiviral or antibiotic used, as discussed in the respective treatment topics. Among the immunosuppressive therapies for noninfectious uveitis, MTX, mycophenolate mofetil (MMF), and cyclophosphamide are contraindicated in patients who are interested in becoming or who are pregnant, and cyclophosphamide can also reduce future fertility. Azathioprine (AZA) and calcineurin inhibitors can often still be used with appropriate monitoring. One type of TNF-alpha inhibitor, certolizumab, has minimal transfer across the placenta. These issues are discussed in more detail elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation" and "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Reproductive health counseling'.)

Children — There are additional therapeutic considerations for pediatric patients with noninfectious uveitis. MTX-induced nausea is more common in children than adults and can have a significant impact on quality of life (eg, ability to regularly attend school) [64]. Oral glucocorticoids more commonly cause cataracts in children compared with adults and may also lead to growth impairment. (See "Cataract in children", section on 'Glucocorticoids' and "Causes of short stature", section on 'Glucocorticoid therapy'.)

PROGNOSIS — Prognosis varies depending upon the etiology and severity of the uveitis. In one study of patients with noninfectious uveitis, over half of the patients required a change in treatment after their initial course of systemic therapy [65]. Disease in a large majority of these patients was effectively controlled with a switch to a different immunosuppressive drug or the use of combinations of immunosuppressive agents. In patients with new-onset anterior uveitis, factors associated with a lower rate of medication-free remission and persistent inflammation include diagnosis with juvenile idiopathic arthritis, Behçet syndrome, bilateral uveitis, history of cataract surgery, and findings at presentation of either 1+ or greater vitreous cells or visual acuity of 20/200 or worse [66].

Potential complications from uveitis vary on the location of inflammation but may include permanent vision loss, glaucoma, cataracts, and damage to the optic nerve and/or retina [67]. Of note, some problems, such as cataracts and glaucoma, may result from both uveitis and the glucocorticoids that are used for treatment.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uveitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Uveitis (The Basics)" and "Patient education: Chorioretinitis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Urgency of treatment – Both infectious and noninfectious uveitis have the potential to cause vision loss and should be treated immediately upon diagnosis. (See 'Urgency of treatment' above.)

●Infectious uveitis – Patients should be given targeted antiviral, antimicrobial, antifungal, and antiparasitic treatments when these are available. Patients who are immunocompromised may require longer courses of therapy. Adjunctive glucocorticoids are frequently used for patients with anterior infectious uveitis and can also be used in select patients with posterior uveitis (eg, involvement of the pars plana or intermediate region). The timing, type, and dose of glucocorticoids varies with the type of infection and severity and location of inflammation. (See 'Treatment of underlying infection' above and 'Adjunctive glucocorticoids' above.)

●Noninfectious uveitis

•Initial treatment – The algorithm summarizes the initial treatment of noninfectious uveitis (algorithm 1). For most patients with noninfectious uveitis, we suggest locally administered, short-acting glucocorticoids rather than systemic or long-acting injectable forms (Grade 2C). The optimal glucocorticoid formulation (eg, drops, intraocular injection) depends on the location of inflammation. However, in patients with one of the following, we also add systemic immunosuppression:

-Severe disease with profoundly limited vision or risk of significant vision loss

-Patients with bilateral posterior uveitis

-Patients with glaucoma who cannot be treated with local glucocorticoid injections

-Patients with certain systemic diseases

•Treatment of resistant disease – We define resistant disease as patients with ongoing inflammation (eg, presence of inflammatory cells, retinal vasculitis, vitreitis) despite initial therapy or patients who are dependent on any form of glucocorticoids to maintain quiescence for ≥3 months. These patients often require systemic therapy with glucocorticoids and other immunosuppressive agents and may also benefit from additional courses or intensification of locally administered glucocorticoids. (See 'Treatment of resistant disease' above.)

-Systemic immunosuppression – In most patients with refractory uveitis unrelated to a related systemic disease, we suggest an antimetabolite (ie, methotrexate [MTX], mycophenolate mofetil [MMF], or azathioprine [AZA]) plus systemic glucocorticoids rather than starting an alternative immunosuppressive agent or using systemic glucocorticoids alone (Grade 2C). Certain types of glucocorticoid-sparing agents may be preferable to antimetabolites when patients have underlying systemic disease (eg, tumor necrosis factor [TNF]-alpha inhibitors for Behçet syndrome). In those with contraindications to antimetabolites or who have persistent symptoms despite one, we use a TNF-alpha inhibitor. (See 'Systemic glucocorticoids for most patients' above and 'Addition of glucocorticoid-sparing immunosuppression' above.)

-Intraocular glucocorticoids for posterior or intermediate uveitis – For patients with refractory posterior or intermediate uveitis, we suggest long-acting intraocular glucocorticoids rather than frequent local short-acting glucocorticoid injections (Grade 2C). (See 'Intraocular glucocorticoids for posterior or intermediate uveitis' above.)

•Tapering therapy – The optimal time to taper therapy and the speed of tapering depend on the severity of uveitis, the type of therapy being used, and potential associated systemic conditions (eg, spondylarthritis). Generally, glucocorticoids may be tapered once uveitis has resolved and glucocorticoid-sparing immunosuppressive therapy may be tapered after a period of sustained remission (≥12 months) without requiring topical or systemic glucocorticoids. (See 'Tapering therapy' above.)

●Patients with systemic inflammatory or autoimmune disease – For patients with noninfectious uveitis related to an underlying systemic inflammatory or autoimmune disease, initial treatment generally involves locally administered agents as well as systemic glucocorticoid-sparing immunosuppressive therapy; the optimal immunosuppressive agent often varies by condition. (See 'Patients with systemic inflammatory or autoimmune disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James T Rosenbaum, MD, who contributed to earlier versions of this topic review.