Approach
The treatment of uveitis depends largely on the cause, location, and severity of the disease.[23] In many cases, the goal of treatment is to control, not cure, uveitis. All patients should be referred early to an ophthalmologist for management. Any related underlying condition should also be managed as appropriate.
Noninfectious uveitis
The therapeutic goals for the management of noninfectious uveitis are based on establishing both immediate and long-term control, choosing drugs based on their efficacy and tolerability. Drug classes that are well suited for immediate control may not be appropriate for long-term control, and vice versa. Immediate control refers to the immediate elimination of active inflammation, using therapy that may not be sustainable for the long term - often high-dose corticosteroids in some form. Immediate control is the essential first step in the management of ocular inflammation. Long-term control involves preventing inflammation from reactivating after it has been rendered inactive. It is made difficult by the fact that corticosteroids, which are almost always the therapy used to achieve immediate control, have numerous side effects that make them unsuitable for long-term use. Long-term control therefore requires finding the therapy that has the fewest side effects but is still able to prevent disease recurrence. This may include low-dose corticosteroids, corticosteroid injections, corticosteroid implants, or immunosuppressive drugs.[24] Most practitioners find long-term control to be the most challenging part of uveitis management.
Achieving immediate control
Corticosteroids achieve immediate control of inflammation rapidly and effectively. They decrease the production and migration of most immune cells via the inhibition of phospholipase A2, decreasing both prostaglandin and leukotriene production, and are the first-choice drug for patients who present with ocular inflammation that is not believed to be infectious. Various formulations can be used, including eye drops, periocular injections, oral preparations, or (much more rarely) intravenous infusions. The key to successful use of corticosteroid eye drops is very frequent administration initially; the most common reason for failure to control inflammation with these drugs is insufficient dosing. Generally they are started hourly for acute anterior uveitis, with a subsequent taper depending on the severity of the initial presentation.
Topical corticosteroids have numerous side effects, which ultimately limit their usefulness for long-term control, including:
Intraocular pressure elevation, which can occur at any time but most commonly starts somewhere after 1 month of therapy. The increase almost invariably resolves when the drops are stopped.
Posterior subcapsular cataracts, which generally do not progress after the drops are stopped.
Subconjunctival hemorrhages, which should be expected in patients using corticosteroid eye drops chronically. They usually involve one vessel that ruptures continually, such that a patient has repeated hemorrhages in the same spot until it scars over.
Once topical corticosteroids have been found to be effective and safe in a particular patient, a periocular corticosteroid injection can be considered. This modality of administration is useful for a more sustained local anti-inflammatory effect. Patients should be made fully aware that the use of corticosteroids for periocular injection is off-label. These drugs are produced for the treatment of other diseases, and their use in ophthalmology is not approved by the US Food and Drug Administration (FDA). This discussion should be documented in the medical records.
Side effects of periocular corticosteroid injections include:
Intraocular pressure elevation.
Posterior subcapsular cataracts. For this reason, repeat injections may be avoided in children, particularly in the amblyogenic age group (under the age of 10 years).
Hyperglycemia in patients with diabetes, which will persist for approximately 24 hours after dexamethasone injection or slightly more than 48 hours after triamcinolone injection. For patients in whom systemic absorption should be minimized, subconjunctival injections are superior to peribulbar injections.
Injection site scarring, which may complicate repeat injection in the same spot.
Subconjunctival hemorrhage, especially using the subtenon or subconjunctival approach. The “cardinal clock hours” (12, 3, 6, 9) should be avoided when giving periocular injections, since trauma to branches of the anterior ciliary arteries that run in these clock hours can cause marked hemorrhage. In particular, dexamethasone injections cause subconjunctival hemorrhages and patients should be warned beforehand to expect this.
Pain, when injecting dexamethasone or betamethasone. These drugs need to be mixed with lidocaine when injected. Non-preserved triamcinolone may be slightly more uncomfortable than the standard commercially available formulation.
Inadvertent penetrating globe trauma.
Intraocular corticosteroid injections are used for severe posterior uveitis. Patients should be made fully aware of the risks associated with this form of treatment, and this discussion should be documented in medical notes.
Side effects of intraocular corticosteroid injections include:
Intraocular pressure elevation, which is seen in about one third to one half of patients. It almost always resolves as the drug dissolves, which takes anywhere between 2 and 10 weeks in non-vitrectomized eyes. This effect occurs much less in vitrectomized eyes, because the drug washes out of the eye much more quickly, usually after 2 weeks.
Posterior subcapsular cataracts are common. Corticosteroid responders are much more likely to develop cataracts.
Endophthalmitis, which is a form of infectious panuveitis and a potential complication of all intraocular procedures, although the risk is under 1%.[25]
Pseudoendophthalmitis, which presents as a dense vitritis with hypopyon 1 to 3 days following intravitreal injection. The examiner can recognize it because 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 to 8 weeks.
Pain. Difficulty achieving local anesthesia should be anticipated when repeating pars plana injections in the same clock hour. For this reason, the injection site should be rotated around different clock hours when administering repeat injections.
Subconjunctival hemorrhage at the injection site, which tends to be mild.
Acute damage to the intraocular structures during the injection procedure.
Oral corticosteroids may be used in severe bilateral or recalcitrant uveitis, or if patients cannot tolerate corticosteroid injections. It is also sometimes necessary or helpful to confirm that a patient’s uveitis is in fact immune-mediated (i.e., not infectious), and therefore treatable with corticosteroids, before corticosteroid injections are administered. In such cases, a trial of a short course of oral corticosteroids is useful for establishing this, without incurring the long-term risks associated with corticosteroid injections to prove corticosteroid efficacy.
Oral corticosteroids cause adrenal suppression after 1 week of therapy, so after 7 days the dose should be lowered gradually to avoid this. The speed of the taper depends on the clinical circumstances, but a rapid taper would involve decreasing the dose by 10 mg/day (e.g., 50 mg one day, 40 mg the next, etc.) until discontinuation. This approach is common when oral corticosteroids have been used to achieve immediate control, and a periocular injection is then given for longer-term control. An example of a slower taper would be decreasing the daily prednisone dose by 10 mg every week, while monitoring to see how far the dose can be lowered before the inflammation recurs.
If it is anticipated that oral corticosteroid therapy will be continued at any dose for longer than 1 month, concomitant bisphosphonate therapy is often added. It should be noted that bisphosphonates are contraindicated in girls and in women of childbearing age.
In light of the many side effects of oral corticosteroids, their use for prolonged periods should be approached with great caution. If it is anticipated that longer than 8 weeks of therapy will be needed, periocular depot injections, systemic immunomodulatory therapy, or both should generally be used.
It is important to document consideration of the side effects. It is wise to avoid prescribing automatic refills of oral corticosteroid prescriptions, and patients' side effects and tolerance should be reviewed with every prescription renewal.
Intravenous corticosteroids are to be considered an extreme therapy, and only used for uveitis in certain circumstances:
Intraoperatively in patients at substantial risk of postoperative inflammation
In cases of imminent danger of visual loss and/or extreme pain (usually due to scleritis).
Infectious causes should be ruled out before moving to systemic, periocular, or intravitreal corticosteroids.
Cycloplegics can be used if the inflammation is causing synechiae or the uveitis is fibrinous in nature, as can happen with human leukocyte antigen (HLA)-B27-related uveitis or various granulomatous uveitic conditions.
Maintaining long-term control
The primary goal of long-term treatment is to achieve control of both ocular and associated systemic disease, while minimizing exposure to corticosteroids in order to avoid corticosteroid-related side effects. While long-term therapy is not required in most cases, there is a group of patients with severe, sight-threatening uveitis who require long-term immunomodulatory therapy.
When considering long-term therapy, alternatives to corticosteroids are typically preferred, although local therapy with periocular injections or ocular implants is sometimes used.
Local therapy:
Periocular triamcinolone injections can reduce inflammation in an eye for several months. Patients may undergo periodic injections as needed to maintain long-term control. It may be expected that such patients might require treatment of cataracts and glaucoma after a few years.
Fluocinolone implants have been found to be very effective in reducing the frequency and severity of uveitis recurrences and the amount of adjunctive treatment needed. Typically the duration of action is about 2 to 3 years. More than half of recipients sustain an increase in IOP more than 10 mmHg, and cataracts can invariably be expected to worsen over time.[26] Incisional glaucoma surgery is frequently required in patients who have the implant.
A dexamethasone intravitreal implant is also available. The implant is biodegradable and releases dexamethasone over a 4- to 6-month period. It is injected using a preloaded injector.
Corticosteroid eye drops are generally used for immediate disease control, rather than long-term therapy.
Systemic immunomodulatory therapy:
While some patients may achieve disease quiescence following an initial corticosteroid taper, those with chronic or potentially sight-threatening disease often benefit from corticosteroid-sparing immunomodulatory drugs.[27] These drugs can eliminate the need for a prolonged corticosteroid use, which is often fraught with an even greater side-effect profile and more immunosuppression than the immunomodulatory drugs. Immunomodulatory drugs include antimetabolites (e.g., methotrexate, azathioprine, mycophenolate), calcineurin inhibitors (e.g., cyclosporine, tacrolimus), alkylating agents (e.g., cyclophosphamide, chlorambucil), and biologic response modifiers (e.g., adalimumab, infliximab, rituximab).
The selection of the appropriate immunomodulatory therapy is an inexact science, and experienced practitioners often disagree about what is the “correct” first line agent for a given disease. Overall, however, antimetabolites are usually the drug class of choice as they have the advantage of oral dosing, manageable adverse effects, and minimal monitoring requirements. However, specific drug selection varies between practitioners as there are no large prospective clinical trials, and the use of these agents in uveitis is off-label (apart from adalimumab). Methotrexate and mycophenolate are the most common first-line antimetabolites; there is no clear difference in efficacy between these drugs for controlling inflammation in adults with noninfectious uveitis.[28] Where there is incomplete disease control with antimetabolites, calcineurin inhibitors are occasionally added to the regimen. Tumor necrosis factor (TNF)-alpha inhibitors are used as a next step in many cases either in place of or in addition to antimetabolites. In many cases, patients are treated with monotherapy, but combination therapy may be effective in recalcitrant cases.[29] The use of alkylating agents is falling out of favor now that biologic agents are increasingly being used.
Once a patient is started on an immunomodulatory drug, the initial corticosteroid dose (eye drops or oral corticosteroid started at initial presentation) is generally gradually tapered (e.g., over 1 to 2 months) and the patient’s response monitored.
There are some conditions where TNF-alpha inhibitors would be considered first line (e.g., HLA B27+ uveitis with ankylosing spondylitis). Adalimumab is approved in the US and Europe for the treatment of noninfectious intermediate and posterior uveitis and panuveitis.[30][31][32] In case reports, adalimumab has been associated with severe thrombocytopenia.[33]
In cases of treatment failure with these agents, other options include returning to corticosteroid treatment, using an alternative immunomodulatory drug, or switching to another biologic agent either within the same class or to another class altogether. Rituximab, a monoclonal antibody against CD20, is particularly useful in associated conditions such as rheumatoid arthritis, granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), or systemic lupus erythematosus-associated vasculitis.
General principles of treatment with immunomodulatory drugs
Immunomodulation can be considered in 3 different scenarios:
Corticosteroid intolerance, usually due either to intraocular pressure elevation or to cataract formation.
Disease in multiple organ systems, such as children with juvenile idiopathic (juvenile rheumatoid) arthritis who have iritis and arthritis, or patients with sarcoid uveitis who have active pulmonary (or any bodily) inflammation.
Certain very severe uveitic entities, which are an indication for strong immunomodulatory therapy (sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, Behçet disease, rheumatoid scleritis).[34]
Practitioners vary in their approach to choosing immunosuppressive agents and when to use which drug. Nearly all, however, would agree that 4 factors merit consideration:
Severity of the inflammation
Type of inflammation (i.e., uveal tract inflammation, vasculitis, or scleritis/keratitis)
Associated systemic diseases or, in idiopathic inflammation, laboratory findings that may point toward treatment for one or another sort of systemic disease
Childbearing potential and family planning issues.
Patients are reasonable candidates for these agents if they are capable of adhering to sometimes complicated treatment and laboratory regimens, they understand the risks and benefits of therapy, and they want to take the drug.
The pros and cons of immunomodulatory therapy versus corticosteroids must be carefully considered. While the patient can avoid the side effects of corticosteroids by using this therapy, these drugs all carry their own side effects, they take weeks to months to show an effect, and they are less reliably effective than corticosteroids. Choice of therapy also depends on any associated conditions. For example, some severe diseases (e.g., uveitis associated with granulomatosis with polyangiitis, polyarteritis nodosa, lupus sympathetic ophthalmia) necessitate immediate treatment with corticosteroids and immunomodulatory therapy, while other less serious conditions may be initially treated with a corticosteroid and an immunomodulatory drug considered if the corticosteroid cannot be tapered or there are disease flare-ups. One randomized controlled trial (RCT) and one Cochrane review found no significant difference between fluocinolone implants and systemic immunosuppression in terms of efficacy.[35][36]
[ 
]
Seven-year follow-up (non-prespecified) of the RCT suggested that systemic therapy may be associated with better visual acuity; however, conclusions are limited by loss to follow-up.[37]
In cases of juvenile idiopathic arthritis (JIA)-associated anterior uveitis, immunomodulatory therapy is employed to improve long-term visual prognosis and to reduce the risk of ocular complications. In children ages <11 years, chronic corticosteroid use causes heightened concern about cataract and glaucoma development.[38][39][40] While methotrexate remains part of the treatment armamentarium for JIA uveitis, TNF-alpha inhibitors - especially adalimumab - are being increasingly used with or without concurrent methotrexate to achieve disease remission.[39][40] The FDA has approved adalimumab for the treatment of pediatric uveitis in children ages ≥2 years.[41]
Immunomodulatory therapy should be used only with the full support, understanding, and consent of the patient, after clearly discussing risks and the underlying evidence base.
Patients taking immunosuppression should receive killed influenza vaccines, and any other vaccines they receive must also be killed. These patients should never receive live vaccines.
Both male and female patients taking these drugs should be using birth control. This discussion and the method of birth control being used should be documented in the medical records. Patients should wait 3 months after stopping these drugs before attempting to conceive.
Standard baseline laboratory tests for immunosuppression are a complete blood count and hepatic and renal function tests, regardless of the agent used. Tests to exclude latent tuberculosis (TB) and hepatitis should also be performed. For cyclophosphamide, a urinalysis should also be performed. For cyclosporine and tacrolimus, blood pressure should be assessed before treatment is started.
The patient’s internist or primary care doctor should always be kept well informed about the use of these drugs, and these doctors will almost always need to be involved if the patient develops drug-related complications.
Patients who have even minor infections while taking immunosuppressive drugs should stop the drug until their symptoms have resolved. Internist and pediatrician colleagues should be involved in getting these ailments monitored and treated promptly.
Corticosteroids in pregnancy
In practice, ocular inflammation in pregnant women is rare, and many women with long histories of chronic uveitis observe that their disease becomes inactive during pregnancy and returns afterwards.[42]
During pregnancy, systemic immunomodulatory therapy is typically avoided. In severe cases of sight-threatening disease, certain options can be discussed with the patient’s obstetric clinicians, including oral corticosteroids, adalimumab, and locally delivered corticosteroids.[42][43][44] Options for locally delivered corticosteroids include intravitreal triamcinolone, dexamethasone intravitreal implant, and fluocinolone intravitreal implant.[42]
If immediate control of inflammation is necessary, prednisolone is generally safe to use. Dexamethasone and betamethasone are the only corticosteroids that cross the placenta. However, betamethasone is not commonly used in the management of uveitis. Although the amount of daily systemic corticosteroid exposure to the mother and fetus from a dexamethasone sustained-release implant that releases its dose over 90 days is very small, corticosteroid intravitreal implants should only be used if the potential benefits outweigh the risks to the fetus.
For long-term control:
Inflammation limited to the anterior segment can be controlled indefinitely with prednisolone eye drops.
Posterior segment inflammation, however, cannot be controlled with topical medications, and periocular triamcinolone injections are not universally acknowledged to be safe in pregnancy. However, intravitreal triamcinolone can be used; it is considered safer than periocular triamcinolone, since the volume of drug is much less and the drug is limited to the interior of the eye. Dexamethasone intravitreal implant and fluocinolone intravitreal implant may also be considered.[42] Corticosteroid implants should only be used if the potential benefits outweigh the risks to the fetus.
Infective uveitis
Uveitis secondary to an infection should be treated urgently, as it is often more aggressive and may lead to permanent blindness long term. Numerous infectious agents can result in uveitis, including HIV-associated opportunistic infections (e.g., cytomegalovirus [CMV], Pneumocystis carinii, TB, toxoplasmosis, candida), sexually transmitted infections (e.g., syphilis, gonorrhea, herpes simplex virus [HSV], chlamydia), congenital infections (TORCH: Toxoplasmosis, Other agents, Rubella, CMV, HSV), and infections related to occupational/leisure (e.g., leptospirosis, brucellosis, toxoplasmosis, Bartonella henselae [cat scratch disease]), geographic (e.g., histoplasmosis, coccidioidomycosis, Borrelia burgdorferi [Lyme disease], TB, malaria, leprosy), or environmental (e.g., TB) exposure. The treatment of infective uveitis depends on the causative organism and, due to the aforementioned array of potential infective etiologies, specialist advice should be sought regarding appropriate management.
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