Introduction
The goal of uveitis therapy is to suppress intraocular inflammation to zero or minimal activity and then maintain quiescence. In other words, excellent, enduring control is the goal. If we can achieve this, then patients are spared the multiple structural complications of uveitis that ultimately lead to vision loss, be they mild or severe: band keratopathy, synechiae, glaucoma, cyclitic membranes, hypotony, macular edema, epiretinal membranes, chorioretinal scarring or atrophy, and optic neuropathy, to name a few.
The field has indeed come a long way in just a half-century. As recently as the 1960s, the only systemic therapies available to ophthalmologists were systemic corticosteroids and methotrexate. The latter was used sparingly because of the bugaboo of the label “chemotherapy,” terrifying patients and perhaps even doctors alike. Before that, fever chambers were used to induce pyrexia in uveitis patients, sometimes treating the disease but also sometimes killing the patient. We now know that low-dose antimetabolites and other systemic immunomodulatory therapies (IMTs), although possessing the potential for serious adverse effects, are preferred compared with the ravages of undertreated severe, chronic uveitic diseases. Today, we have a plethora of systemic IMT agents, biologic agents, and local drugs and implants with which to treat these diseases. There are still many challenging and refractory cases, but we have come a long way from the 1960s, and longer still from the days of the fever chamber.
This chapter will briefly review the standard systemic and local therapies for noninfectious uveitis (NIU) and, more importantly, will discuss the approach to therapy. When is local therapy sufficient? When should one consider systemic therapy and systemic IMT and, if so, how does one combine the various agents we now have at our disposal?
General Guidelines: Local Versus Systemic Therapy
Assuming one has identified active uveitis with the potential to cause structural damage, the first decision is whether to treat locally or systemically. There are several broad rules to guide the initial route of therapy in many cases. Like all guidelines, there will be many exceptions, but they should bring a measure of order to one’s thinking, especially for the novice. Recalling the Standardization of Uveitis Nomenclature’s (SUN) variables for categorizing uveitis (anatomy, course, laterality) is particularly helpful here.
First, anterior uveitis can typically be treated with topical therapy, whereas NIU involving the posterior segment (NIU-PS) typically requires locally injected or systemic therapy. Second, unilateral disease can often be treated locally, whereas bilateral disease is more often treated systemically. Third, chronic disease warrants chronic therapy, be it chronic (or frequently repeated) local therapy or chronic systemic therapy. Because ocular adverse effects with chronic local corticosteroid therapy are serious (glaucoma being usually the most concerning), the authors generally prefer systemic therapy in these cases, particularly for aggressive disease.
Exceptions immediately come to mind. For instance, acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a bilateral NIU involving the posterior segment but is generally self-limited and requires no treatment. Then there are other cases where some variables favor systemic therapy and others favor local. For instance, bilateral, chronic, anterior uveitis associated with juvenile idiopathic arthritis (JIA) has two variables in favor of systemic treatment (bilaterality and chronicity) but one variable in favor of topical therapy (anterior anatomic location). In this case, the specific systemic disease association has added key information. It has been well established by multiple studies that JIA-associated anterior uveitis is generally best treated with aggressive systemic therapy. Similarly, a patient with biopsy-proven sarcoidosis could also have chronic, bilateral anterior uveitis. Again, the systemic disease association provides valuable information. Sarcoidosis is usually highly corticosteroid responsive. In a mild case, a patient could be maintained on one drop of topical corticosteroids daily with good control, sparing her the potentially adverse effects of systemic IMT. If the patient is already pseudophakic and/or has shown little sign of corticosteroid response with increased intraocular pressure (IOP), this becomes an even more sensible treatment plan.
Thus knowledge of the individual patient and of the specific uveitic entity are critical. One of the goals of this book is to familiarize the reader with the latter via its case-based format.
Systemic Therapy: Corticosteroids and Systemic Immunomodulatory Therapy
Corticosteroids
The fourth general rule is that acute episodes of inflammation should be treated with corticosteroids, whereas chronic inflammation is better treated with corticosteroid-sparing therapy. Corticosteroids have a plethora of effects on the immune response, a full discussion of which is beyond the scope of this book. For acute, systemic treatment, the authors will typically use prednisone 0.75 to 1 mg/kg up to 80 mg PO daily. There are exceptions to this dosing. Vogt–Koyanagi–Harada syndrome and sympathetic ophthalmia may require very large doses of systemic corticosteroids (e.g., prednisone 100 mg PO daily) to gain adequate initial control. Intravenous (IV) methylprednisolone can also be used if particularly large doses are required to control intraocular inflammation. Once quiescence has been established, the prednisone is tapered. The author uses the following tapering schedule: 70 mg PO daily×1 week, then 60 mg PO daily×1 week, 50 mg PO daily×1 week, 40 mg PO daily×1 week, 30 mg PO daily×1 week, 20 mg PO daily×2 weeks, 15 mg PO daily×2 weeks, 10 mg PO daily × 2 weeks, then hold at 5 to 7.5 mg PO daily×3 months before resuming the taper ( Box 3.1 ).
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0.75–1 mg/kg up to 80 mg daily×2 weeks, then
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70 mg daily×1 week
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60 mg daily×1 week
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50 mg daily×1 week
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40 mg daily×1 week
- •
30 mg daily×1 week
- •
20 mg daily×2 weeks
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15 mg daily×2 weeks
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10 mg daily×2 weeks
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Hold at 5 or 7.5 mg×3 months before resuming taper
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≤5 mg, taper by 1 mg every 2–4 weeks
Other uveitis specialists endorse other tapering regimens, but the authors feel this program strikes a good balance between the competing goals of efficacious therapy tapered slowly and the many adverse effects of systemic corticosteroid therapy, which usually become much more tolerable at a dose of approximately 10 mg PO daily. Holding prednisone at a low dose before resuming the taper is helpful to prevent recurrences, but there is no high-level evidence for this recommendation.
Systemic Immunomodulatory Therapy: When to Start
The decision to start IMT is driven by an understanding of the severity, laterality, and chronicity of the patient’s intraocular inflammation; the status of the patient’s fellow eye in cases of unilateral uveitis; the adverse effects incurred by local and/or systemic treatment with corticosteroids; and the patient’s ability to adhere to the frequent laboratory and clinical follow-up necessary for all patients on IMT. If this sounds complex, it can be. However, a few straightforward guidelines can help to make the decision ( Box 3.2 ).
- 1.
Chronic bilateral uveitis
- 2.
Chronic unilateral uveitis, particularly in a monocular patient
AND
- A.
Inability to control inflammation with local and/or systemic corticosteroids, or
- B.
Unacceptable adverse effects of local and/or systemic corticosteroids
- A.
- 3.
Acute, recurrent, or chronic uveitis with highly damaging inflammation, unilateral or bilateral
First, any patient with active, bilateral, chronic uveitis despite prednisone 10 mg or greater should typically be on IMT. Chronic doses of 10 mg or more have been shown to significantly increase the risk of osteoporosis and cardiac disease with long-term treatment. Chronic unilateral uveitis requiring ≥10 mg is a different situation, as local therapies, detailed later, may allow for disease quiescence with an acceptable level of local adverse effects and for tapering of prednisone to <10 mg PO daily.
Second, and in a similar vein, some patients with either chronic unilateral or bilateral uveitis may achieve quiescence with a combination of low doses of systemic prednisone (<10 mg PO daily) and local therapies (e.g., intravitreal or periocular triamcinolone, fluocinolone implants, etc.) but incur unacceptable adverse effects. Whereas a cataract is easily managed with a safe and effective surgical procedure, glaucoma can be more difficult to control in certain patients. Patients with severe and prolonged increases in IOP with local corticosteroid therapy are also candidates for IMT.
In a monocular patient, one has a heightened sensitivity both to ocular adverse effects and the damaging impact of uveitis flares that may arise as the effects of local therapy wane. Thus in monocular patients with chronic unilateral uveitis, the authors have a lower threshold (though not absolute indication) to start IMT.
Finally, an understanding of the severity of a patient’s disease and the potential for irreversible damage with any flare is critical, not simply in monocular patients but in all patients. Certain uveitic syndromes are highly vision-threatening and present strong indications for nearly immediate initiation of IMT ( Box 3.3 ), almost simultaneous with high-dose corticosteroid therapy. Other cases are less clear-cut and highly specific to the individual patient. These can present a challenging and somewhat subjective assessment for the clinician. For instance, some patients with recurrent HLA-B27–associated anterior uveitis experience severe flares, albeit in one eye, causing profound inflammation and hypotony from which it can take many months to recover. Every flare is a prolonged physical and psychological ordeal for these patients. Moreover, one worries about the potential for cyclitic membranes to develop with multiple severe flares, a condition that portends a poor prognosis. Thus even if the patient only flares once a year, for instance, IMT may be a reasonable management plan based on the history of extremely severe flares.
- 1.
Behçet disease
- 2.
Sympathetic ophthalmia
- 3.
Serpiginous or ampiginous choroiditis
- 4.
ANCA-positive scleritis or retinal vasculitides
- 5.
Necrotizing scleritis
Systemic Immunomodulatory Therapy: Types
Broadly speaking, there are four classes of IMT agents: antimetabolites, T-cell inhibitors, alkylating agents, and biologics. Each of these will be briefly reviewed to shed light on their strengths and weaknesses. An adverse effect common to all systemic IMT agents is that they increase susceptibility to infection, although to varying degrees, particularly with regard to certain pathogens. This will be detailed later. Another is increased incidence of cancer, particularly nonmelanoma skin cancer. Therefore all patients on any of these agents should avoid sunbathing and must not receive vaccinations using live organisms.
Antimetabolites
Methotrexate and mycophenolic acid are two of the mainstays of steroid-sparing IMT and are commonly used as first-line steroid-sparing agents. Azathioprine has also shown efficacy in uveitis, though it is now less commonly employed.
Methotrexate has been used for decades and is a familiar drug to uveitis specialists. It is the antimetabolite of choice in children, but is also readily used in adults. Although it is an antimetabolite, it has multiple different mechanisms of action, including inhibition of folate metabolism, which reduces T-cell proliferation and induces activated T-cell apoptosis; an increase in adenosine signaling, which has antiinflammatory effects; and changes to the cytokine profile of helper T cells. The contribution of each to the control of ocular inflammation remains unclear. The authors commonly start the drug at the very low dose of 5 mg PO every week (the subcutaneous route is also readily available) and add 2.5 mg per week (typically 2.5 mg in a tablet) to a minimum dose of 15 mg every week in the effort to improve gastrointestinal (GI) tolerability of the drug. Other initial dosing regimens are used by other specialists. In general, uveitis requires higher doses than rheumatologic diseases. Methotrexate is no exception, as the minimum efficacious dose in adults is 15 mg in contrast to rheumatoid arthritis, for instance, where 7.5 mg is a common dose. The maximum dose is 25 mg every week ( Table 3.1 ). Folic acid supplementation (1–2 mg PO daily or folinic acid 5–7.5 mg PO every week) is essential. Adverse effects include hepatotoxicity, stomatitis, GI distress and ulcers, hair loss, cytopenias, and, less commonly, pneumonitis. Patients should not drink any alcohol while on the drug.
