These new agents have few clear-cut ocular side effects but there are areas of concern, with causation yet to be determined. Smith et al (2001) reported 60 cases of etanercept and optic neuritis. Symptoms develop within 1–14 months after starting therapy with a mean development time of 9.5 months. Nine patients had positive dechallenges and three had positive rechallenges. Tauber et al (2005) and Noguera-Pons et al (2005) also reported an association of this drug with optic neuritis. Fooroozan et al (2002), Mejico (2004), ten Tusscher et al (2003), Strong et al (2004) and Tran et al (2005) suggested an association of optic or retrobulbar neuritis with infliximab usage. Chung et al (2006) reported two cases of optic neuritis associated with adalimumab use. Winthrop et al (2013) in a retrospective, population-based cohort study of 61,227 patients did not find a higher incidence of optic neuritis among anti–tumor necrosis factor alpha therapy. It is unproven whether these agents cause optic neuritis. Positive rechallenge data suggests perhaps a small subject who may be hypersensitive to these agents.

These agents continue to indicate a possible association with demyelinating diseases such as optic and retrobulbar neuritis. While there are a number of reports in the literature with many authors feeling a positive association, there are many compounding factors. Many cases are associated with uveitis and other demyelinating diseases. However, a positive cause-and-effect relationship, although possible, has yet to be proven.

The question of whether these agents cause intraocular inflammation is confused by the fact that the diseases that the drugs are used to treat might also cause uveitis. There are two cases in the literature (Reddy et al 2003) and a case in the National Registry showing uveitis occurring each time etanercept was started and clearing each time the drug was stopped. Taban et al (2006) reported a case of positive double rechallenge of etanercept exacerbating anterior uveitis. Hashkes et al (2003) reported sarcoid-related uveitis occurring during etanercept therapy. De Vos et al (1995) have shown exacerbation of uveitis with anti–tumor necrosis factor in animals. It is possible one may find a subset of patients for which etanercept may cause or aggravate uveitis. Infliximab seems to be free of causing uveitis.

Data suggests that this class of drugs may cause autoimmune diseases such as sarcoid and lupus. These diseases may cause uveitis or the drug, primarily etanercept, is the cause. It seems that etanercept, a soluble receptor, whereas infliximab, a monoclonal antibody, may explain why uveitis develops after etanercept and recovers after infliximab (Kakkassery et al 2010).

While there are a few reports in the literature of retinal abnormalities occurring shortly after starting infliximab, compounding factors makes one suspect normal background noise.

While some suggest etanercept as a treatment for scleritis, there are three cases in the National Registry where this drug is implicated as causing or exacerbating scleritis. Because the disease these drugs are used to treat can also cause scleritis, at this time a drug-induced effect is only suspect. Because these drugs can cause a dry mouth, they may aggravate ocular sicca. Reports of these drugs causing systemic vasculitis and suppression of the hemopoetic systems possibly support occasional reports of retinal vascular abnormalities and vitreous hemorrhage.

Single cases of possible retinal toxicity causing visual field changes with etanercept (Clifford et al 2004), orbital myositis (Caramaschi et al 2003) and orbital cellulitis (Roos et al 2006) have been reported. There are no cases of any of these in the National Registry.

Low-dosage intravitreal infliximab injections in humans were not well tolerated (Giganti et al 2010).

Generic Names:

1. Auranofin; 2. aurothioglucose; 3. sodium aurothiomalate (gold sodium thiomalate).

Proprietary Names:

1. Ridaura; 2. Solganal; 3. Aurolate, Myocrysine.

Primary use

These heavy metals are used in the treatment of active rheumatoid arthritis and nondisseminated lupus erythematosus.

Patients taking any of the gold agents may show one of two patterns of ocular chrysiasis. The more common pattern is where gold salts are deposited in the conjunctiva, all layers of the cornea and the crystalline lens. Gold deposition in the cornea may take a Hudson-Stähli line distribution or a vortex distribution, not unlike Fabry disease. The gold deposits tend to be increased in areas of corneal scarring. Deep corneal deposition is usually in the posterior half of the cornea and denser inferiorly, while the superior cornea and perilimbal areas are more often spared. Lopez et al (2003), using confocal microscopy, found gold deposits most frequently in the anterior and mid corneal stroma. Lens deposits of gold are much less frequent than corneal deposits and are of little to no clinical importance. These deposits are reversible after stopping gold therapy but may take 3–12 months, and in some cases many years, to resolve. Visual acuity is unaffected, and deposition of gold in the cornea or lens is not an indication for cessation of therapy. In general, a total of over 1 g of gold deposited is needed before corneal changes are seen. In total dosages of 1.5 g, 40–80% of patients will have gold deposition in the cornea. While lens deposits have previously been considered rare, 55% of patients on daily dosages over 1 g for three or more years has been reported to develop lens deposits. Corneal deposits may be seen as early as one month after starting therapy. It has been suggested that gold deposits in the cornea and lens are secondary to metal from the aqueous fluid or perilimbal blood vessels.

The second variant of ocular chrysiasis is much less common. This type presents as an inflammatory response secondary to gold, including corneal ulceration, subepithelial white perilimbal infiltrates, brush-like perilimbal stromal vascularization and interstitial keratitis (Arffa 1991; McCormick et al 1985). Corneal ulceration is more often marginal, crescent shaped and possibly 2–3 mm in length. This response is felt to be an idiosyncratic allergic reaction, may be unilateral or bilateral, and is an indication in most patients to stop therapy. Zamir et al (2001) point out that, in patients presenting with marginal keratitis, this variant of chrysiasis should be considered. Stopping gold therapy along with looking for systemic toxicity is often warranted. Patients must be continuously followed because stromal inflammation may reoccur even after gold is stopped.

Generic Names:

1. Celecoxib; 2. etodolac; 3. nimesulide; 4. rofecoxib; 5. valdecoxib.

Proprietary Names:

1. Celebrex; 2. Lodine; 3. Ainex; 4. Vioxx; 5. Bextra.

Primary use

These nonsteroidal anti-inflammatory drugs are selective inhibitors of cyclooxygenase-2 and are used in various forms in the treatment of arthritis, acute pain and dysmenorrhea.

The above-mentioned side effects are extremely rare. Fraunfelder et al (2006) reported blurred vision and conjunctivitis with multiple cases of positive rechallenge. The onset may occur within a few hours to days; and, if the drug is discontinued, it resolves within 72 hours. Meyer et al (2006) made known a possible association of thrombotic events in selected patients. These findings include central retinal vein or other retinal venous occlusions. Recchia et al (2008) reviewed 111 consecutive retinal venous occlusion patients with 321 controls and could not find a significantly higher rate of retinal venous occlusive disease in COX-2 inhibitor users. Meyer et al (2006) pointed out that the US FDA strongly associates the use of COX-2 inhibitors with Stevens-Johnson syndrome and toxic epidermal necrolysis. Coulter et al (2004) reported a case of temporary blindness and another with bilateral jelly-bean–shaped loss of central vision. Lund et al (2001) reported a case of orange spots in both visual fields. All signs and symptoms are fully reversible. The mechanism of action is postulated as inhibition of synthesis of prostaglandins that control blood flow. Also, most of these agents are sulfonamides with known drug-induced transient myopia.

Generic Name:

Fenoprofen calcium.

Proprietary Name:

Nalfon.

Primary use

This nonsteroidal anti-inflammatory agent is used in the management of rheumatoid arthritis.

Ibuprofen is one of the largest selling antiarthritic agents in the world. The adverse ocular event most commonly associated with this drug is transient blurred vision. In those patients who have experienced a drug rechallenge, refractive error changes, diplopia, photophobia, dry eyes and decrease in color vision appear to be well documented. A typical vortex kera­topathy with deposition limited to the corneal epithelium has been described. Once the drug was stopped, this resolved within three weeks. Other nonsteroidal anti-inflammatories such as indometacin and naproxen can also cause corneal epithelial deposition. While sicca has been attributed to this drug, one suspects that this in part is secondary to the drug being in the tears and aggravating an already dry eye. Palungwachira et al (2005) described a case of periorbital edema due to ibuprofen, and there is one case of this in the National Registry as well. Nicastro (1989) described three young females who were long-term ibuprofen users who possibly developed macular edema with vision in the 20/30–20/50 range. Once the drug was stopped, vision returned to 20/20. Reversible toxic amblyopia has been reported (Ravi et al 1986; Clements et al 1990).

This drug can cause other CNS changes, including aseptic meningitis with secondary effects on the visual system. If ibuprofen is not discontinued, permanent visual loss may result. For a drug so commonly used in combination with other agents, it is not possible to implicate this agent specifically. However, many of the cases are outside the usual multiple sclerosis age group and occur shortly after starting this medication. Patients on this drug should therefore be told to stop this medication if a sudden decrease in vision occurs. If there is an unexplained decrease in vision that occurs while on ibuprofen, tests to rule out optic nerve abnormalities should be considered. There may be a rare idiosyncratic optic nerve response associated with the use of this drug. The typical sequence is that after a few months of therapy, a unilateral or bilateral marked decrease in visual acuity occurs, with vision receding to the 20/80–20/200 range. Visual fields may show various types of scotomas. If the medication is stopped, visual acuity usually returns to normal in 1–3 months, but it may take up to 8 months for color vision to return to normal.

Ibuprofen, as well as other nonsteroidal anti-inflammatories, may possibly cause intracranial hypertension. This is more common if used in combination with other antiarthritic agents, which can also induce this side effect.

Generic Name:

Indometacin (indomethacin).

Proprietary Names:

Indocin, Indocin SR, Indo-Lemmon, Indomethegan G.

Indometacin has been used for over four decades with few ocular side effects unless the drug is used for prolonged periods in high doses. Its most serious side effect is retinal pigmentary retinopathy, with macular atrophy and a waxy disk (Burns 1968; Henkes et al 1972). This is associated with depressed ERG and constricted visual fields. While blurred vision may occur after starting this agent, seldom is it of clinical significance. The drug is probably secreted in the tears, thereby causing corneal deposits, irritation and occasionally keratitis. Intracranial hypertension and optic neuritis have been reported with indometacin use.

Keratorefractive surgery has brought topical ocular indometacin back into clinical use in large part because it has fewer side effects than steroids. Its main use is as a local anesthetic, showing less damage to the corneal epithelium (Badalá et al 2004) in the immediate postoperative period. Sheehan et al (1989) reported a case of possible acute asthma due to topical ocular indometacin. Gueudry et al (2010) reported eight patients who developed corneal ulceration, descemetocele or perforation after topical ocular 0.1% indometacin 3–4 times daily primarily after clear cornea cataract extraction. Most patients were on other topical ocular medications as well. They state “even though our study does not prove a causal relationship between the use of indometacin and the development of corneal complications, their onsets were temporally associated with the start of NSAIDs use.”

Generic Name:

Ketoprofen.

Proprietary Name:

Oruvail.

Primary use

This nonsteroidal anti-inflammatory drug with antipyretic and analgesic properties is used in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout.