Uveitis: Treatment

INTRODUCTION — Intraocular inflammation (ie, uveitis) results from many causes. The approach to therapy depends upon the etiology, location, and severity of the inflammation [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. A general approach to evaluation and treatment of the patient presenting with a painful red eye is discussed separately. Treatment of uveitis that is due to infection is discussed in more detail in topic reviews that address management of the specific infection. The etiology, clinical manifestations, and diagnostic approach to a patient with uveitis are presented separately. (See "The red eye: Evaluation and management" and "Uveitis: Etiology, clinical manifestations, and diagnosis".)

DEFINITIONS — 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).

●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.

●Terms used to describe uveitis posterior to the lens include vitritis, intermediate uveitis, pars planitis, choroiditis, retinitis, chorioretinitis, or retinochoroiditis. Panuveitis refers to inflammation in the anterior chamber, vitreous humor, and choroid or retina simultaneously. 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.

UVEITIS DUE TO INFECTION — Infectious causes of uveitis are shown in the table (table 1).

●Viral infections may cause either anterior or posterior uveitis. The most common viruses causing uveitis are cytomegalovirus (CMV), herpes zoster, and herpes simplex. These infections should be treated promptly with appropriate antiviral agents. As indicated by a study from Singapore, CMV is being increasingly recognized in some populations from southeast Asia as a cause of a chronic, unilateral anterior uveitis associated with elevated intraocular pressure [2]. Fuchs heterochromic iridocyclitis, a form of chronic unilateral, primarily anterior uveitis, is now considered to be most often secondary to a remote infection with rubella [3]. In herpetic infection of the retina, retinal destruction (acute retinal necrosis) may progress rapidly without appropriate therapy. Although immunosuppressed patients are at greater risk for acute retinal necrosis, it may also occur in patients with an intact immune system.

CMV retinitis is seen only rarely in immunocompetent patients, while herpes simplex and herpes zoster may affect both immunocompetent and immunocompromised patients.

●In addition to treating the underlying infection, patients with anterior uveitis due to an infection are often treated with topical glucocorticoids after initiation of antiviral medication. Treatment of ocular involvement due to these viral infections is discussed in the appropriate topic reviews. (See "Treatment of AIDS-related cytomegalovirus retinitis" and "Herpes simplex keratitis" and "Treatment of herpes zoster", section on 'Ocular disease'.)

●Treatment of chorioretinitis due to Toxoplasmosis gondii in patients with HIV infection and in immunocompetent adults is discussed separately. Higher doses and longer duration of treatment are generally used in patients with HIV infection. (See "Toxoplasmosis in patients with HIV", section on 'Chorioretinitis' and "Toxoplasmosis: Ocular disease".)

Other treatable infectious causes of uveitis in the immunocompetent host include syphilis, and, less commonly, cat scratch fever, tuberculosis, leprosy, and Lyme disease. (See "Uveitis: Etiology, clinical manifestations, and diagnosis".)

NONINFECTIOUS UVEITIS — The approach to treating noninfectious uveitis varies depending upon the location of the inflammation. There are limited available data from controlled trials. The following strategies are generally consistent with the approach advocated by a consensus panel of both ophthalmologists and rheumatologists that convened in 2000, prior to any extensive testing of biologic therapies, such as tumor necrosis factor (TNF) inhibitors, for uveitis [4]. Expert panels have subsequently summarized the role of biologic therapies in the treatment of uveitis [5,6]. These are potentially complex decisions that require consultation and ongoing care with an ophthalmologist or other specialist in uveitis.

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'.)

Initial treatment — Noninfectious causes of anterior uveitis are generally treated with topical glucocorticoids such as prednisolone acetate (1 percent). The frequency for the drops depends upon the intensity of the inflammation. A dilating drop such as cyclopentolate (1 percent) can relieve pain due to spasm of the muscles controlling the pupil and will also help to prevent the formation of posterior synechiae that may interfere with the function of the pupil.

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) [7]. 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 or to cause a cataract. Additional options for initial treatment of intermediate or posterior uveitis, or of panuveitis, include observation only in selected cases, or treatment with periocular injection of a glucocorticoid such as triamcinolone (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 more sustained benefit. Some patients, however, may decline a periocular or intraocular injection. 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. Complications from glucocorticoid injections in or around the eye include glaucoma and cataractogenesis.

Systemic treatment is generally reserved for resistant inflammation and may be indicated in patients with glaucoma who cannot be treated with local injection. In addition, patients with bilateral disease are often treated with systemic therapy. Some specific forms of inflammation such as Behçet syndrome or serpiginous choroiditis are more likely to require systemic therapy. The approach to therapy is generally not affected by the etiology of the uveitis, but there are important exceptions. As examples, Behçet syndrome is especially responsive to infliximab [8-11]; Vogt-Koyanagi-Harada disease may benefit from intravenous methylprednisolone when the illness first begins, and pars planitis is often managed just by observation or periocular glucocorticoid injections to treat the complication of macular edema. One study found that interferon beta was more effective than methotrexate (MTX) in controlling macular edema associated with intermediate uveitis [12].

Disease resistant to initial treatment — Patients with ongoing inflammation, regardless of anatomic location, may require systemic glucocorticoid therapy or additional antiinflammatory or immunosuppressive agents, such as an antimetabolite and/or a calcineurin antagonist (eg, cyclosporine). In patients with uveitis who are resistant to such therapy, subsequent therapeutic options include a TNF inhibitor, such as adalimumab; a switch to a different antimetabolite; a glucocorticoid, either regionally or orally, usually on a temporary basis; or the combination of an antimetabolite with a calcineurin antagonist. The choice between these options depends on many variables such as patient and provider preference, etiology of the uveitis, severity of inflammation, patient cost and regulatory or insurance restrictions, and the cause of any visual loss. (See 'Oral glucocorticoids' below and 'Antimetabolites, calcineurin antagonists, or cytotoxic agents' below and 'Anti-tumor necrosis factor-alpha' below and 'Long-acting intraocular glucocorticoids' below.)

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 [13]. 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.

Oral glucocorticoids — Oral glucocorticoids are generally reserved for patients with bilateral disease that has not responded to topical medications and that is interfering with the activities of daily living. A risk-benefit ratio must be considered for any therapeutic decision. 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. Body weight, blood pressure, blood glucose, bone mineral density, and lipids should be monitored if patients require chronic oral glucocorticoid therapy. (See "Major adverse effects of systemic glucocorticoids".)

The goal of glucocorticoid therapy is not to cure but to limit the inflammation. Many forms of uveitis that are severe enough to warrant oral glucocorticoid or other immunosuppressive drugs are chronic, such as sarcoidosis. Thus, the clinician should strive to use the lowest dose of medication that provides acceptable benefit. The dose of oral glucocorticoid varies based on the underlying disease, the disease severity, the patient profile, and the clinician and patient preference. A common initial dose is the equivalent of 40 to 60 mg of prednisone per day, with gradual tapering after response to the lowest dose that controls inflammation.

If remission has been achieved for 6 to 12 months, the maintenance dose of glucocorticoid may be gradually discontinued. A shorter course of therapy is usually sufficient in patients with severe iritis associated with the human leukocyte antigen (HLA)-B27 spectrum of spondyloarthritis. It is rarely necessary to treat such patients with oral therapy for more than two weeks because the eye inflammation generally remits spontaneously.

Antimetabolites, calcineurin antagonists, or cytotoxic agents — A small percentage of patients with uveitis may require immunosuppressive medications. Indications for their use include bilateral disease, active inflammation, failure to respond to oral glucocorticoid therapy, or severe disease that interferes with activities of daily living. Additionally, patients who require a daily dose of 10 mg or more of prednisone to control their ocular inflammation may benefit from a glucocorticoid-sparing agent, such as an antimetabolite, as a safer long-term alternative. This recommendation is consistent with the consensus of a group of international experts on uveitis management [14].

Initially, we prefer MTX, azathioprine, mycophenolate mofetil (MMF), or a calcineurin antagonist, such as cyclosporine or tacrolimus, rather than a TNF inhibitor because of concerns regarding cost and toxicity of the biologic agent. Severe uveitis associated with Behçet syndrome is an exception for which a TNF inhibitor could be considered for initial therapy. (See "Treatment of Behçet syndrome", section on 'Ocular disease'.)

Immunosuppressive agents that may be employed include antimetabolites, such as azathioprine [15], MMF [16], and MTX [17]; calcineurin inhibitors, such as cyclosporine and tacrolimus; and, rarely, alkylating agents, such as cyclophosphamide. These medications should be used with appropriate caution and careful monitoring. Doses are generally similar to those used for other conditions requiring immunosuppressive therapy. As an example, for azathioprine, the usual dose is 1.5 mg/kg daily (typically 100 to 200 mg daily); the maximum dose can be up to 4 mg/kg daily but should not exceed 250 mg daily. There should be no specific contraindication to the therapy, such as active liver disease when using methotrexate, or hypertension or renal disease when using cyclosporine. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents" and "Pharmacology of cyclosporine and tacrolimus" and "General principles of the use of cyclophosphamide in rheumatic diseases".)

MTX (25 mg weekly by mouth) had similar or better efficacy and safety than MMF (3 g daily) as a glucocorticoid-sparing treatment to control inflammation in a randomized trial involving 216 patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis [18], despite prior studies and smaller trials suggesting MMF superiority that sometimes used suboptimal MTX doses [16,19-22]. Treatment success, which included control of inflammation in both eyes and limited glucocorticoid use (no greater than 7.5 mg daily of oral prednisone and 2 drops daily of topical prednisone acetate 1 percent), was achieved at six months with MTX and MMF in 67 and 57 percent of patients, respectively, and maintained in most patients at 12 months. Elevated liver function tests were seen in 13 and 7 percent of patients, respectively. Further trials are needed to confirm whether responses differ between uveitis subgroups and in patients with more severe disease.

Anti-tumor necrosis factor-alpha — In patients with uveitis who are resistant to therapy with antimetabolites and/or a calcineurin antagonist such as cyclosporine, one major option is the use of a TNF inhibitor such as adalimumab (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 inhibitor because of the association of such findings with demyelinating disease.

Two well-designed, randomized trials showed that adalimumab was effective in the treatment of noninfectious intermediate, posterior, and pan-uveitis [23,24]. In these trials, adalimumab significantly improved the time-to-treatment failure in patients with uveitis who followed a tapering schedule for oral glucocorticoids. In mid-2016, both the European Medicines Agency (EMA) and the FDA recommended approval of adalimumab for adults with these forms of uveitis [25,26]. An open-label extension of these trials further supports the efficacy of adalimumab for the treatment of intermediate, posterior, or pan, noninfectious uveitis [27].

Additional evidence supporting the use of TNF inhibitors for uveitis includes:

●In patients with juvenile idiopathic arthritis, the SYCAMORE trial demonstrated benefit from the addition of adalimumab to ongoing therapy with methotrexate in children with active uveitis [28]. In this 18-month trial involving 90 patients, therapy with methotrexate was continued, and patients were randomly assigned to also receive adalimumab or placebo. The addition of adalimumab delayed the time to treatment failure (hazard ratio [HR] 0.25, 95% CI 0.12-0.49), which was less frequent in the adalimumab-treated patients (27 versus 60 percent). The median time to failure was not reached in the adalimumab group during the trial period but was 24.1 weeks with placebo. Enrollment in the trial was stopped early due to the degree of benefit. Serious adverse events were more common in patients receiving adalimumab (0.29 versus 0.19 events per patient-year). In the United States, adalimumab is approved for the treatment of children with uveitis.

●The response of uveitis associated with Behçet syndrome to infliximab has been encouraging in observational studies [8-11,29-31]. For example, in an open-label observational study of 43 patients, 33 patients responded to conventional therapy (oral glucocorticoids, cyclosporine, azathioprine, or methotrexate) [11]. Ten patients who failed to respond were subsequently treated with infliximab (5 mg/kg) every two weeks for a total of six doses. Patients treated with infliximab had fewer relapses and longer remissions than patients who were treated conventionally. Infliximab has been approved in Japan to treat Behçet syndrome, which is a relatively common cause of uveitis in that country.

●Several reports suggest that infliximab may be more effective than etanercept for the treatment of uveitis [32,33]. An unusual increase in adverse effects, including drug-induced lupus, was reported in one prospective study using infliximab to treat uveitis [34].

●Several biologics including etanercept, adalimumab, certolizumab, golimumab, infliximab, and possibly secukinumab [35] appear to reduce the risk of developing eye inflammation in patients with ankylosing spondylitis, a disease frequently associated with acute anterior uveitis [36,37].

Long-acting intraocular glucocorticoids — Intraocular fluocinolone formulations that provide long duration of local glucocorticoid are a potential option for patients with refractory posterior uveitis. We reserve use of the intraocular fluocinolone for patients with noninfectious posterior or intermediate uveitis that would otherwise require frequent local short-acting glucocorticoid injections.

Examples of ideal candidates 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

Intraocular fluocinolone can be surgically implanted or injected. The surgically implanted intraocular fluocinolone device (0.59 mg) delivers a glucocorticoid into the vitreous humor continuously for approximately 2.5 years [38]. Fluocinolone acetonide (0.18 mg) can be delivered by an intravitreal injection that also provides local glucocorticoid for a long duration. Many patients and ophthalmologists prefer the injectable approach and reserve the surgically implanted device for the patient with severe disease. There are other factors that may also influence the choice of surgically implanted versus injectable fluocinolone (eg, avoiding intraocular depot glucocorticoid injection in an aphakic patient).

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) [39]. In one study, after seven years of extended follow-up, visual acuity was better in patients initially allocated to receive systemic therapy, although the study was limited by 30 percent loss to follow-up in both groups [40].

The 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.

Investigational approaches — An antibody to IL-17 was tested in several randomized trials with disappointing results [41]; although a smaller randomized trial showed efficacy for anti-IL-17 in treating uveitis if the antibody was given intravenously [42]. An intravitreal injection of sirolimus showed benefit at the lower of two dosages tested in one randomized trial [43]. The Janus kinase (JAK) inhibitor, filgotinib, was tested in a multicenter randomized trial (results pending), but the manufacturer is not pursuing this indication.

Alpha interferon is used, primarily in Europe, for refractory posterior uveitis or Behçet syndrome, if the response to other agents is inadequate. 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 [44]. Alpha interferon requires frequent injections and its use is associated with flu-like symptoms and depression. (See "Treatment of Behçet syndrome", section on 'Posterior uveitis'.)

Prevention of recurrent episodes — Several small studies have found that sulfasalazine can help prevent attacks of HLA-B27-associated iritis [45,46]. This prophylactic approach is appropriate for patients whose attacks are especially frequent or severe. TNF inhibitors are highly effective in reducing the frequency of HLA-B27-associated iritis, but the risk and cost usually do not justify their use if the purpose is solely to prevent iritis. Some evidence also indicates that methotrexate [47] or oral nonsteroidal antiinflammatory drugs (NSAIDs) [48] might reduce the frequency of iritis attacks.

PROGNOSIS — Prognosis varies depending upon the etiology and severity of the uveitis. 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 [49].

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

●The optimal management of a patient with uveitis will require consultation with an ophthalmologist or other specialist in eye disease. Ideally, therapy should be initiated within 24 hours of the onset of acute, anterior uveitis, and most infectious causes of uveitis should be treated promptly. (See 'Introduction' above.)

●Treatment of uveitis due to an infectious agent is directed toward the responsible organism. Infection with herpes simplex or herpes zoster may cause retinal destruction (acute retinal necrosis). Antiviral therapy is especially important in the setting of retinitis in order to limit retinal damage. (See 'Uveitis due to infection' above.)

●Uveitis is generally classified as anterior, intermediate, posterior, or panuveitis (involving all anatomic segments of the uveal tract). Anterior uveitis not due to infection is treated with topical glucocorticoids. Dilating ophthalmic drops are indicated if ciliary spasm is causing pain or if there is risk for posterior synechiae. Posterior or intermediate uveitis and panuveitis are generally not responsive to topical treatment. Initial management of uveitis posterior to the lens usually includes observation, as well as periocular and, occasionally, intraocular glucocorticoid injections. (See 'Initial treatment' above.)

●Oral glucocorticoids are frequently recommended for patients with uveitis that is resistant to topical therapy. Other immunomodulatory agents are suggested in patients who have active inflammation that interferes with activities of daily living and who have one of the following indications (see 'Disease resistant to initial treatment' above):

•Refractory uveitis

•Drug-related adverse effects from systemic glucocorticoids or persistent requirement for a dose of prednisone greater than 10 mg/day or equivalent

●An intraocular fluocinolone-releasing implant offers an alternative to systemic therapy, but it may necessitate multiple surgeries for its complications (cataract and glaucoma). Long-lasting intravitreally injected glucocorticoids are gaining in popularity over surgically implanted fluocinolone. (See 'Long-acting intraocular glucocorticoids' above.)

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