Approaches to Medical Therapy

Key Concepts

Therapy is guided by the etiology of the inflammation (infectious versus noninfectious), severity, and anatomic location.
Corticosteroid therapy can be used to quiet acute inflammation, but steroid-sparing therapies must be added if systemic corticosteroids cannot be tapered successfully by 3 months.
It is important to establish goals of therapy and consider further workup or altering therapy if goals of therapy are not achieved.
Patients should be counseled about the goals and side effects of and expectation from immunomodulatory therapy and the need for regular monitoring for potential side effects.

Choosing the best therapy is difficult and should be guided not only by etiology, laterality, associated systemic disease, anatomic location, and disease severity, but also the patient’s general health, concomitant medical problems, current medications, and personal preferences. The decision as to which medications to use, whether it should be local treatment options (e.g., injections or implants) or systemic immunomodulatory agents, is a responsibility shared between the physician and the patient. It is truly a partnership. The more informed the patient is about the goals and potential side effects of treatment, the more likely it is that the individual will be compliant. It is fair to say that enormous advances have occurred in our understanding of how to use many of the drugs under discussion. There has been a shift to the use of intraocular therapy and also to more specific therapies, such as the use of monoclonal antibodies that target specific parts of the immune cascade. Translational studies and animal models have helped improve our understanding of the underlying mechanisms, which has led to a more rational decision-making process. Furthermore, pharmacology is a burgeoning area, with real hope for the future; indeed, other, yet untapped, sources may also provide new immunosuppressive drugs to the growing armamentarium. At present, there may not be any one ideal drug, but treating physicians have some latitude in their choices. However, each of the agents discussed in this chapter is a powerful medication, which must be evaluated with care and expertise.

Goals and Philosophy

In the treatment of uveitis, the decision to intervene by using any therapeutic agent should be based on both a thorough clinical evaluation and philosophic guidelines. In general, the approach to therapy should take into account at least the considerations discussed in the following sections.

Pain, Photophobia, and Discomfort

Symptom relief is an important goal for several reasons. The first and foremost is, of course, the ethical imperative of the physician. However, practical considerations should not be overlooked. Pain relief helps in the establishment of a good patient–physician relationship, which is of primary importance in what is frequently a long therapeutic course with ups and downs. A second practical reason is that once pain relief is obtained, the patient is able to cooperate more readily. The ability to examine the patient’s ocular condition in greater detail and to obtain more reliable test results, particularly visual acuity, is of immeasurable help to the physician.

Degree and Location of Inflammatory Disease

The type and frequency of administration of any therapeutic choice depend on the physician’s evaluation of how “serious” the inflammatory disease is and what ocular structures are being affected. For instance, if the sequela of an intraocular inflammation is limited to the posterior synechiae, then the use of topical mydriatics and corticosteroids may be a reasonable approach to therapy. However, disease that is more posteriorly located would need to be approached by means of quite different strategies. If alternative therapies are available, the physician needs to decide which one to start with. In addition, if vital structures, such as the macula, are involved, more aggressive immunosuppressive therapy may need to be used, even though the potential for side effects may be greater.

Evaluation of Visual Acuity and Prospect of Reversibility

In most cases of inflammatory disease involving the posterior segment, decreased visual acuity is the reason for therapeutic intervention. It is also the major reason that the patient consults the physician, in the hope that therapy will improve vision. It is therefore imperative that the physician attempt to define as clearly as possible why the vision has decreased. On this decision will hinge the therapeutic approach. Patients frequently have multifactorial reasons for vision changes; common causes are macular edema and cataract. The use of various tests in the clinic can aid in this evaluation.

Before embarking on any therapy that has a significant risk for the patient, the physician must weigh this inherent risk against any benefits. It is therefore necessary to decide whether any or all of the visual alterations are caused by irreversible changes. It is difficult to justify starting therapy if no reasonable hope for visual improvement exists. The decision to start therapy is always based on the physician’s belief that the side effects of the therapeutic intervention are outweighed by the potential benefit. It is the physician’s duty to desist from inappropriate therapy as much as it is to institute beneficial treatment.

Follow-Up Procedures and Standardization of Observations

It is imperative that a reasonable time be allotted to evaluate whether a specific therapy is effective. For most medications, up to 3 months is a reasonable period in which to evaluate whether an acute problem will improve. One should remember that ocular changes caused by uveitis may resolve slowly, and the observer must use changes sometimes subtle in the ocular examination to determine whether to continue therapy. The patient should adhere to a regular follow-up schedule and should know who to contact if an emergency arises. Depending on the severity of disease, initially frequent—as frequent as weekly—visits may be needed both to ensure improvement and to evaluate potential side effects from therapy. The physician needs to preset the definition of a therapeutic “success” and adhere to these criteria. Just as it is unwise to stop or alter therapy too soon, it is not reasonable to continue therapy if the minimal criteria for success are not met. Such criteria may include symptoms and/or findings, such as an increase in vision, a decrease in the amount of vitreous haze, a decrease in the number of cells in the anterior chamber, or a decrease in the photophobia the patient is experiencing.

With regard to the criteria that determine successful treatment, there is a presupposition that tests are performed in a standard manner and that test results reflect a change in the ocular status rather than the variability inherent in the test. Standardization of observations is critical to the successful evaluation of the condition in these patients.

Disease Laterality

In patients with unilateral uveitis and no underlying systemic disease, use of local therapy is preferred over systemic drugs. In our experience, it is rare that unilateral disease justifies long-term therapy, but it certainly happens. In the patient with sight remaining in only one eye, a judgment as to the use of local therapy before systemic therapy needs to be made.

General Health and Age of Patient

The very basic considerations of patient health and age must play a role in deciding what sort of therapy to use. We thoroughly evaluate all patients and examine all therapeutic alternatives before starting systemic therapy, especially in children. The secondary effects of systemic immunosuppressive agents, such as steroids, can have a major and lifelong effect on a growing child. A diagnosis of diabetes may be a relative contraindication for systemic corticosteroid therapy, whereas uncontrolled hypertension or renal disease may make cyclosporin a poor therapeutic choice. The physician must be always aware that most of these therapies can have significant systemic and local effects.

Patient Reliability, Preferences, and Understanding

Sufficient time should be spent with the patient, who deserves an explanation of ocular (and systemic) findings, the seriousness of these findings, the type of therapy warranted, and the possible positive and adverse effects. A fully informed patient provides invaluable aid to the treating physician. Obtaining informed written consent may be a requirement under certain circumstances, such as with experimental therapies. Patients with uveitis usually require long-term care, and the more the patient understands the medical concerns, uncertainties, and possible therapeutic alternatives early on, the easier is the treating physician’s task.

Nonsurgical Therapeutic Options

Corticosteroids

The corticosteroid family of medications has been the mainstay of therapy for ocular inflammatory disease since its introduction by Gordon in the early 1950s. Its use in ophthalmology began soon after its introduction into the medical armamentarium. The synthetic compounds usually used by the physician are variations of the compounds normally found in the body, and they profoundly affect many aspects of the organism’s physiology. The synthetic preparations available to the physician were developed because of their particularly effective mediation of one aspect of these hormones’ effects: immunosuppression. The treating physician should be totally at ease with the various therapeutic strategies available.

Mode of action

In humans, corticosteroids are not considered to be cytotoxic agents. Human immune cells are not susceptible to lysis by corticosteroid administration, even at the higher dosages usually employed, unlike some of the other agents covered in this chapter. Mice, rats, and rabbits are considered to be corticosteroid-sensitive animals, with their lymphocytes showing a marked tendency toward lysis after the administration of corticosteroids. Therefore extrapolation from animal experiments must take place only after careful evaluation.

The mechanism of entry into the cell by steroids has been evaluated by means of several systems. The underlying point for the action of all the steroid hormones is a need for cellular receptors. The steroid is met at the cell surface by the appropriate receptor and then complexes with it in the cytoplasm of the cell. This complex then migrates to the nucleus, where it exerts its effect on deoxyribonucleic acid (DNA) transcription, leading to changes in ribonucleic acid (RNA) production. These RNA alterations result in changes in protein production and cell function. In steroid-sensitive animals, such as rats, cells with steroid receptors will be lysed. However, this is not the case in humans.

The effects of steroids on the immune system are both local and systemic. Essentially, all cellular components are affected. On the systemic level, a profound change is seen particularly with neutrophils and lymphocytes ( Fig. 8.1 ). Clamen and Fauci showed that a large number of the lymphocytes in the intravascular space continuously recirculate with the extravascular lymphocyte pool in organs, such as bone marrow, the spleen, and lymph nodes. The addition of steroids induces a change in the recirculation pattern, with a large number of T cells, particularly the helper T (Th cells) subset, sequestered out of the intravascular circulation. This phenomenon results in a break in the recruitment of immunoreactive cells to the site of the inflammatory reaction. The effect on neutrophils appears to be quite striking as well. Steroid therapy induces a larger number of neutrophils to be produced by bone marrow. In addition to this increased production, the circulating half-life of these cells on reaching the intravascular space is prolonged. Concomitant with these effects is an impeding of neutrophil migration from this space to the site of inflammation. Decreases in the number of circulating monocytes, eosinophils, and basophils have also been observed.

Fig. 8.1, Anti-inflammatory effects of corticosteroids.

Although the changes in the immune system are profound, it is important to remember that they are temporary. Fauci demonstrated that T-cell subsets return to essentially the presteroid ingestion state after about 24 hours. This observation is most important in developing a strategy for the treatment of an acutely active inflammatory condition, whether in the eye or elsewhere.

Profound effects on cell function have been noted with the addition of a steroid. The effects on the various immune cell populations include a decrease in bactericidal activity, delayed hypersensitivity reactions, lymphokine production, and changes in immediate hypersensitivity reactions. In addition, steroid administration has a profound effect on local resident cells in an organ, particularly the vascular endothelium. A reduction in the leakage of fluid during an inflammatory episode from the capillary endothelium results from steroid administration, thereby reducing tissue swelling. Furthermore, during an inflammatory response, there is a decrease in the amount of intracellular fluid taken in by cells, thereby reducing cell swelling and avoiding the resultant decrease in function and ultimate lysis. The effect of steroids on lysosome membranes, thought at one time to be an important stabilizing factor, now remains unclear.

Preparations, dosage schedules, and complications

Many steroid preparations are available and they have varying potencies. Therefore the dosages to be used are different for each ( Table 8.1 and Fig. 8.2 ).

TABLE 8.1

Relative Potencies of Corticosteroids

Preparation	Systemic Equivalent (mg)	Anti-inflammatory Potency
Hydrocortisone	20	1.0
Cortisone	25	0.8
Prednisolone	5	4.0
Prednisone	5	4.0
Dexamethasone	0.75	26
Methylprednisolone	4	5
Triamcinolone	4	5
Betamethasone	0.6	33

Fig. 8.2, Structures of more commonly used corticosteroids.

Topical application of corticosteroids is an excellent way to treat certain uveitides. Prednisolone acetate formulations have been commonly used for anterior uveitis. Although studies do show differences in corneal penetration between phosphate and acetate preparations of steroids, it is not clear whether there is any difference in clinical efficacy between the two preparations in treating active inflammation. When the diagnosis is made, it is imperative that initial treatment of uveitis be aggressive. In severe cases, hourly administration (while the patient is awake) and even beginning therapy with administration of a drop every 15 minutes for the first hour, as a “loading dose,” could be considered. Once a dosing schedule has been found to be effective, as evidenced by a reduction in the flare and cells in the eye, we then see the patient often (every 2–3 days to once a week) and begin a very slow tapering of the drops. The schedule for tapering is unique to each patient, but persons who have had numerous attacks may need to continue one or two drops a day for weeks or even months.

The newer topical corticosteroid preparation 0.05% difluprednate (Durezol) is indicated for the treatment of inflammation and pain associated with ocular surgery and the treatment of endogenous anterior uveitis. It is considered twice as potent as prednisolone acetate 1% ophthalmic suspension and is started typically at a dosage of four times a day and tapered based on clinical response. Durezol was found to be as effective as 1% prednisolone acetate ophthalmic suspension in treating subjects with endogenous anterior uveitis in two randomized, double-masked active controlled trials, in which patients were treated with either Durezol four times daily or 1% prednisolone acetate ophthalmic suspension eight times daily for 14 days. The mean intraocular pressure (IOP) values in both groups remained less than 21 mm Hg throughout the study. A high rate of steroid-induced IOP elevation and cataract formation has been observed in pediatric uveitis cases ^,

A second option is to inject the corticosteroids periocularly. This method, which permits a relatively high concentration of the drug to be given rapidly, is an effective way to treat particularly severe inflammatory conditions. There is the general choice between long-acting preparations (in a depot vehicle) and shorter-acting soluble preparations. These injections can be given as frequently as every 1 to 2 weeks for short periods. In addition to treatment of severe anterior segment inflammation in general, this is a useful approach for unilateral disease, for perioperative management of a uveitic eye, and for patients in whom the systemic steroids are contraindicated. It is an effective way to treat both active inflammation and cystoid macular edema (CME), even in children, although the procedure may require general anesthesia in young children.

Several approaches to periocular injections have been suggested, and it probably is best to use the approach that one feels the most comfortable with. The approach from the superotemporal aspect of the globe, as described by Schlaegel, is thought to reduce the possibility of penetration of the globe and to place the medication under the Tenon capsule and in the region of the macula. Freeman et al. demonstrated that the temporal approach is efficient for injecting the steroid close to the macula. Topical anesthetics are liberally used, and the area in which the injection is to be given (e.g., superotemporal aspect of the globe) is further anesthetized with a cotton swab soaked in topical anesthetic (either 4% lidocaine or cocaine). Triamcinolone 40 mg in 1 mL injectable suspension is the preferred depot steroid formulation (preservative-free formulation used for intraocular injection). An alternative approach is to inject the steroid preparation directly through the lower lid or the inferior fornix (using a 25-gauge needle) while the patient looks upward and is known as the orbital floor injection. Periocular injections can be performed in 4- to 12-week intervals, in a series of two to four injections before considering this method ineffective ( Fig. 8.3 ).

Fig. 8.3, (A) Temporal approach to giving periocular injection. (B) Inferior fornix approach. (Courtesy Dr. Roxana Ursea.) (C) Although the possibility is markedly reduced if precautions are taken, perforation of the globe can occur, as seen here.

Periocular injection of corticosteroids has been shown to be effective in treating active intraocular inflammation and CME. In a large retrospective cohort study of greater than 900 patients, 73% of eyes achieved complete control of inflammation, and 50% showed improvement in vision. Within 12 months, ocular hypertension was seen in 15% to 34%, glaucoma surgery was performed in 2.4%, and cataract surgery was performed in 13.8% of eyes. An additional local approach is the intraocular administration of corticosteroids. To date, this route of administration has been achieved by using several approaches. The most common is direct injection, usually of preservative-free triamcinolone suspension (Triesence) (2–4 mg), into the vitreous fluid. There are newer intravitreal corticosteroid formulations in the form of 0.7 mg dexamethasone intravitreal implant (Ozurdex), 0.18 mg fluocinolone acetonide intravitreal implant (Yutiq), and 0.59 mg fluocinolone intravitreal implant (Retisert); the last is implanted surgically, whereas others are injectable. These sustained release formulations are discussed in more detail below. Surgical or in-office placement of a slow-release fluocinolone acetonide-containing implant into the eye is another option.

Intravitreal steroid injections have been reported to be effective in treating many intraocular problems, including choroidal neovascularization, CME secondary to uveitis, diabetes, central vein occlusion, and pseudophakia ( Fig. 8.4 ). In a 40-patient randomized study, which compared orbital floor injection of steroid and intravitreal injections for CME, foveal thickness increased with orbital floor injections; however, it decreased with intravitreal injections, with CME improving in 50% of patients. However, at 6 months, there was no difference in the best corrected vision (BCVA) between the two groups. This perhaps underlines the issue that repeat injections are necessary for a sustained effect.

Fig. 8.4, Intravitreal injection in a phakic patient. Following topical anesthesia, betadine application, (A) and marking of injection site at 4 mm using calipers, (B) intravitreal injection is performed at 90 degrees to the sclera aiming the center of the globe (C).

Since 2009 longer-acting slow-release formulations of injectable intravitreal corticosteroids have become available. A 0.7 mg dexamethasone in a solid polymer drug delivery system (Ozurdex) is currently approved by the U.S. Food and Drug Administration (FDA) for treating posterior segment uveitis. The implant is placed in the vitreous fluid by using a 22-gauge applicator, and the biodegradable polymers break down into water (H ₂ O) and carbon dioxide (CO ₂ ) as dexamethasone is released over a period of approximately 6 months. The efficacy of dexamethasone implant was assessed in a masked randomized study of 153 patients with noninfectious posterior segment uveitis receiving a single injection. By 8 weeks, 47% of patients receiving the implant reached a vitreous haze score of 0 versus 12% of those receiving the sham treatment. There was a significant improvement in central macular thickness in the dexamethasone implant treated eyes compared with sham. The percent of patients achieving a 3-line improvement from baseline vision was 43% for patients receiving implant versus 7% for those receiving the sham treatment. Overall, the response peaked at week 8 and was maintained through week 26. Side effects in initial sham-controlled 6-month studies were increased IOP in 25%, and it peaked at week 8, with only 1% requiring glaucoma surgery, and cataract in 5% of eyes. Cataract rates were higher at 54% to 68% in 2-year observational and 3-year sham-controlled studies (package insert). A randomized controlled trial (RCT) comparing the effectiveness of three regional corticosteroid injections for uveitic macular edema over 6 months (POINT Trial) showed that intravitreal triamcinolone acetonide and the intravitreal dexamethasone implant (Ozurdex) were superior to periocular triamcinolone acetonide. The intravitreal approaches were associated with higher incidence of IOP increase compared with periocular injection. In our group, we prefer periocular injection for mild, injection naive cases and intravitreal steroid injections-triessence or ozurdex-for more severe or recalcitrant cases.

The fluocinolone acetonice 0.18 mg implant (Yutiq) is a sterile nonbioerodible intravitreal implant that releases drug over 36 months; it is preloaded into a single-dose applicator and is designed to release fluocinolone acetonide at an initial rate of 0.25 μg/day. In a 3-year double-masked RCT of patients with chronic recurrent posterior segment uveitis, 6-month and 12-month uveitis recurrence rates were significantly lower with the fluocinolone acetonide insert (28% and 38%) and the sham treatment (91% and 98%), respectively. Incidence of 15-letter decrease or greater in BCVA and adjunctive systemic treatment was reduced by 50% among eyes injected with fluocinolone acetonide. IOP increase and cataract were more common in eyes that received 0.18 mg fluocinolone intravitreal implant (Yutiq) injection; by 12 months 33% versus 5% of eyes receiving fluocinolone acetonide versus the sham injection required cataract surgery. We typically use Yutiq for long term management.

The 0.59 mg fluocinolone acetonide sterile implant (Retisert) is designed to release ﬂuocinolone acetonide between 0.3 and 0.6 μg/day over approximately 30 months and is FDA approved for treating posterior segment uveitis. It is surgically implanted into the posterior segment of the eye through a pars plana incision. 0.59 mg fluocinolone acetonide implant has been evaluated in mainly two multicenter RCTs. In a 3-year, multicenter, randomized, historically controlled trial of the 0.59-mg fluocinolone acetonide intravitreous implant in 110 patients and the 2.1-mg fluocinolone acetonide intravitreous implant in 168 patients, uveitis recurrence was reduced from 62% in the preimplantation period to 4%, 10%, and 20% during the 1-, 2-, and 3-year postimplantation periods for the 0.59-mg implant. An improvement in vision occurred more in implanted eyes than in nonimplanted eyes. As indicated by the results of clinical trials with 0.59 mg fluocinolone acetonide implant, during the 3-year postimplantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. IOP-lowering medications to lower IOP were required in approximately 77% of patients; filtering surgeries were required to control IOP in 37% of patients. The Multicenter Uveitis Steroid Treatment (MUST) trial was a phase IV RCT comparing the fluocinolone acetonide implant and standard systemic therapy in patients with vision-threatening noninfectious intermediate uveitis, posterior uveitis, or panuveitis. The results of the MUST trial at 2 years showed that among the 255 patients (479 eyes with uveitis) randomized to implant or systemic therapy, both the implant and the systemic therapy groups had an improvement in visual acuity (+6.0 and +3.2 letters, respectively), and there was no difference between the treatment groups. However, fluocinolone acetonide implant therapy was associated with faster and more frequent control of inflammation and a greater quantitative improvement in central macular thickness. Long-term results also showed that spontaneous dissociation of the implant occurred in 22 of the 250 implanted eyes between 4.8 and 8.6 years. The cumulative risk of dissociation over 6 years was 4.8%, and the risk of both spontaneous dissociation and surgery-related dissociation increased with longevity of the implants. Therefore it is recommended that the physician periodically monitor the integrity of the implant by visual inspection.

A novel suprachoroidal injection platform that delivers triamcinolone acetonide suspension (CLST-TA) has been shown to be effective in treating uveitic macular edema in a phase 3 randomized clinical trial (PEACCHTREE Trial). Among the 160 patients visual acuity improvement by 15 or more ETDRS letters was seen in 47% of patients that received the suprachoroidal injection versus 16% in the control arm (P < 0.001). As of late 2020 an NDA filing for triamcinolone acetonide ophthalmic suspension for Suprachoroidal Injection (Xipere) based on the results of the PEACHTREE trial was accepted by the FDA.

Secondary effects

The topical application of steroid induces an increase in IOP in a significant number of patients. This should be monitored closely. The reactivation of corneal herpes simplex infection can occur with topical steroid therapy.

Regional injection of steroid has secondary effects unique to the procedure as well: (1) Although steroid injections are an effective therapy for childhood uveitis, general anesthesia may be required, with potential inherent side effects. (2) Possible penetration of the globe during periocular (sub-Tenon or orbital floor) injection is a concern. (3) Repeated periocular injections can induce orbital problems, such as proptosis of the globe and fibrosis of the extraocular muscles. (4) Retinal and choroidal vascular occlusions after posterior sub-Tenon injections given to treat CME have been reported. (5) Severe or intractable glaucoma can occur after periocular or intravitreal injections. This can become particularly problematic when a depot injection has been used. In such cases, the depot may need to be removed surgically, and this is sometimes a major undertaking. (6) Reactions to the vehicle in which the steroid injection was placed can also occur; this is, however, less of a concern with newer preservative-free triamcinolone formulations. (7) In patients with scleritis and ocular toxoplasmosis, periocular injections can be problematic. (8) Endophthalmitis is a rare, but potentially severe, complication of intravitreal steroid injections and has been reported in 0.13% of patients receiving intravitreal steroid injections.

Systemic corticosteroids remain the initial drug of choice for most patients with severe bilateral endogenous sight-threatening uveitis. When initiating systemic steroid therapy, one should keep in mind several considerations. It is imperative that the treating physician (to the best of his or her ability) rule out the possibility of infection or malignant disease as a cause of the intraocular inflammation. Uppermost is the clinical impression, based on the ocular examination, that there is an inflammatory response that requires systemic therapy. It is also important for the practitioner to set standards to determine whether the therapy is successful or not. A detailed discussion that includes duration of therapy, goals, and side effects should occur with the patient before starting therapy. The duration of treatment varies, depending on the individual patient and the clinical scenario. Each patient’s requirements, capacities, and willingness to undergo treatment are very unique.

We generally find it advisable to begin therapy with prednisone 1 mg/kg/day or 60 mg/day, whichever is lower ( Table 8.2 ). The high doses of corticosteroids should be maintained until a clinical effect is seen or for 4 weeks. If it is determined that the corticosteroids are having a beneficial effect, then a slow reduction of the therapeutic dose needs to be established. As a general tapering schedule, if the dose of prednisone is greater than 40 mg/day, then the daily dose can be reduced by 10 mg/day every 1 to 2 weeks; if the dose is between 20 and 40 mg/day, the dose can be reduced by 5 mg/day every 1 to 2 weeks; if the dose is between 10 and 20 mg/day, the dose can be reduced by 2.5 mg/day every 1 to 2 weeks; and if the dose is less than 10 mg, the dose can be reduced by 1 to 2.5 mg/day every 1 to 2 weeks. As soon as it is clear that long-term (i.e., >3 months) therapy will be needed, addition of a second agent should be considered.

TABLE 8.2

Common Agents Used to Control Intraocular Inflammatory Disease

Agent	Usual Dosage ^a
Prednisone	Oral: 1–2 mg/kg/day
Methylprednisolone	Intravenous pulse: 1 g over 1–2 hours
Intraocular triamcinolone ^b	Intravitreal: 2–4 mg
Periocular triamcinolone	Subtenon or periorbital injection: 20–40 mg
Fluocinolone acetonide intravitreal implant (Retisert)	0.59 mg (sustained release for 30 months; surgical implantation)
Fluocinolone acetonide intravitreal implant (Yutiq)	0.18 mg (sustained release for 36 months; in office injection)
Dexamethasone intravitreal implant (Ozurdex)	0.7 mg (sustained release for 6 months; in office injection)
Antimetabolites
Methotrexate	Oral: 7.5–25 mg weekly; can be given intramuscularly
Azathioprine	Oral: 50–150 mg daily, 1–1.5 mg/kg/day, but up to 2.5 mg/kg/day
Mycophenolate mofetil	Oral: 1 g twice per day
Alkylating Agents
Cyclophosphamide	Oral: 50–100 mg daily, up to 2.5 mg/kg body weight/day
Cyclophosphamide	Intravenous pulse: 750 mg/m ² (adjusted to kidney function and white blood cell count)
Chlorambucil	Oral: 0.1–0.2 mg/kg/day
Calcineurin Inhibitors
Cyclosporin	Oral: Up to 5 mg/kg/day, usually given with prednisone, 10–20 mg/day
Tacrolimus	Oral: 0.15–0.30 mg/kg/day
Biologics
Adalimumab ^c	Subcutaneous: 40 mg per injection
Infliximab	Intravenous: 3–10 mg/kg, usually 5 mg/kg per infusion given at 4–8 week intervals
Interferon-α	Subcutaneous: 3–6 × 10 ⁶ units four times daily × 1 month, then every 6 hours; 3 × 10 ⁶ units three times per week

a It is important to note that the dosages should ultimately be determined by a treating physician with experience using these medications on the basis of the medical state of the patient in question. Furthermore, not all of these medications (or the route of therapy indicated) have been approved by various governmental agencies (i.e., U.S. Food and Drug Administration [FDA]) for use in patients with uveitis. Therefore the physician needs to inquire about their specific use.

b For intraocular administration preservative free Triesence is used.

c Adalimumab is currently the only biologic approved for the treatment of uveitis at the following dose schedule: Induction dose is 80 mg followed by 40 mg 1 week later. Maintenance dosing is 40 mg every 2 weeks.

Antacids or proton pump inhibitors can be considered on a case-by-case basis. Calcium and vitamin D supplements should be prescribed to patients, particularly those receiving long-term therapy. We recommend 800 units of vitamin D and 1500 mg of calcium daily to minimize the risk of steroid-induced osteoporosis, which mostly occurs in the first 6 months of treatment.

Intravenously administered “pulse” corticosteroid therapy can also be employed. This approach is typically used in patients who have a severe bilateral process that needs to be treated as rapidly as possible with 1 g methylprednisolone intravenously and repeated daily for 3 days. It is not yet clear whether this method, indeed, renders better results compared with a high dose of oral prednisone, such as 80 mg/day, but in our experience, it certainly reverses an acute process very rapidly. This approach has been used to treat imminently vision-threatening manifestations of Vogt-Koyanagi-Harada (VKH) syndrome and Behçet disease.

Those administering the medications should be familiar with the potential side effects of corticosteroids. Notable side effects are hyperglycemia and diabetes mellitus, osteoporosis, hyperlipidemia, weight gain, hypertension, and mood and sleep changes. Avascular necrosis of weight-bearing joints is a rare, but well-recognized, complication. Some of the more common secondary problems are listed in Box 8.1 . Other adverse reactions have included nonketotic hyperosmolar coma, in young patients without diabetes receiving systemic corticosteroids for a short time, and central serous retinopathy.

BOX 8.1

Secondary Effects of Corticosteroid Therapy

Fluids, Electrolytes

Sodium retention, potassium loss
Fluid retention
Hypokalemic alkalosis
Hyperosmolar coma

Musculoskeletal

Muscle weakness
Steroid myopathy
Osteoporosis
Aseptic necrosis of femoral and humeral heads
Tendon rupture

Gastrointestinal

Nausea
Increased appetite
Peptic ulcer
Perforation of small and large bowel
Pancreatitis

Dermatologic

Poor wound healing
Easy bruisability
Increased sweating

Neurologic

Convulsions
Headaches
Hyperexcitability
Moodiness
Psychosis

Endocrine

Menstrual irregularities
Cushingoid state
Suppression of growth in children
Hirsutism
Suppression of adrenocortical pituitary axis
Diabetes

Ophthalmic

Cataracts
Glaucoma
Central serous retinopathy
Activation of herpes (topical)

Other

Weight gain
Thromboembolism

The effects of long-term corticosteroid administration are a constant concern, particularly in children. Polito et al. studied growth in 10 boys with glomerulonephritis who received prednisone (1.2 mg/kg) every other day for at least 2 consecutive years. They found that in six patients, the peak growth velocity was delayed after age 15 years. However, after age 16 years, growth velocity was significantly higher than expected, permitting these patients to reach their genetic height potential.

A question that must be constantly asked is whether the desired effect warrants the potential or real side effects. There is no easy answer, and a dialogue between the patient and the physician is the only way this question can be addressed. Although corticosteroids remain the mainstay of therapy for uveitis, in some patients, the condition is resistant to steroids. For those receiving long-term steroid therapy, the risk of unacceptable side effects at the dosages that need to be given to control the disease are real. In those patients, other immunomodulatory agents are added as steroid-sparing agents so that lower steroid doses (≤10 mg daily) can be used or none at all. When needed, a daily maintenance dose of 10 mg or less of steroid is considered acceptable. The combination of steroids with these agents provides reasonable and effective regimens for some patients and is discussed next. Although we may often begin therapy with corticosteroids, we add a steroid-sparing agent if significant amounts of steroids (>10 mg) for longer than 3 to 4 months are needed to control the ocular inflammation.

Cytotoxic Agents

Although mustard gas was synthesized earlier, its use during World War I, with the resultant lymphopenia and lymphoid aplasia, led to the evaluation of this family of agents for therapeutic purposes. On a practical basis, two major categories of cytotoxic agent are used in the treatment of ocular inflammatory disease: alkylating agents, such as chlorambucil and cyclophosphamide ( Fig. 8.5 ), and antimetabolites, such as azathioprine and methotrexate (see Fig. 8.8 later in the chapter). They have been used by physicians for several decades, but their true efficacy in many ocular disorders remains unclear; however, more knowledge has been gained with regard to their use for other putative autoimmune diseases. The physician treating severe sight-threatening diseases should be aware of these agents and how they may fit into the general scheme of nonsurgical therapy for uveitis. Although, when viewed as a group, cytotoxic agents are associated with serious side effects, the role they play as steroid-sparing or steroid-replacing agents cannot be denied. ^,

Alkylating Agents

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