Uveitis is inflammation within the eye, typically secondary to an immune system response. While the primarily affected area of the eye is the uvea, it typically affects other parts of the eye.
While uveitis and its associated symptoms can resolve quickly, they can reoccur or become a chronic condition and cause permanent vision loss if left untreated.
What is uveitis?
Uveitis can occur secondary to autoimmune processes, such as acquired immunodeficiency syndrome (AIDS), lupus, multiple sclerosis (MS), and rheumatoid arthritis; an infection or condition secondary to an infection such as cytomegalovirus (CMV) retinitis, reactive arthritis, and shingles; and secondary to cancers that affect the eye such as lymphoma.
Uveitis can affect different parts of the eye, with the common subtypes including:
- Anterior: The most common, affecting the iris
- Intermediate: Affecting the ciliary body and vitreous
- Posterior: Affecting the retina and choroid
- Panuveitis: Affecting all three portions of the uvea.1
Common presenting symptoms include pain, redness, and vision loss affecting just one or both eyes.
Drug-induced uveitis: An overview
While the mechanism of drug-induced uveitis is largely unknown, there have been many proposed mechanisms largely grouped into direct, secondary to topical, intravitreal, or intracameral administration, and indirect.
Indirect mechanisms of drug-induced uveitis include:
- Immune complex deposition in uveal tissues
- Immune reaction due to antigens released secondary to antibiotic-induced death of microorganisms
- Alteration of melanin’s ability to act as a scavenger for free radicals
- Suppression of immune checkpoints
- Other mechanisms, including oral contraceptives and topical agents
Some major considerations when treating patients and performing routine exams should be the consideration of the formation of uveitis in select groups, including patients with human immunodeficiency virus (HIV) and those treated with certain systemic medications. Increased observation should be performed for subsets of patients receiving topical treatment for ocular problems or injectables.
Common culprits of drug-induced uveitis
There are several populations that, due to their medication regimen, are prone to developing drug-induced uveitis. These include those being treated for HIV, osteoporosis, urinary tract infection (UTI), toxoplasmosis, inflammatory conditions, and glaucoma.
Cidofovir
The first group of people are those with HIV receiving treatment for HIV-associated infections. In patients with HIV-associated CMV retinitis, cidofovir, a DNA polymerase inhibitor, may be prescribed. While now rarely used due to nephrotoxicity, it has been shown to cause a non-granulomatous anterior in uveitis in 43 to 89% of patients in addition to hypotony.2
It is more commonly seen in patients on concomitant protease inhibitors and less commonly if a patient is simultaneously taking probenecid, as it is believed to inhibit ocular secretion of cidofovir by the ciliary body, thereby minimizing the concentration of the drug intraocularly.3
“The mechanism of action is proposed to be the cumulative toxic effect of the drug itself.”
Ophthalmologists should be especially concerned with patients who present with new onset redness, pain, photophobia, decreased vision, and tearing. On exam, unilateral or bilateral non-granulomatous anterior uveitis can be seen with additional features, including keratic precipitates, posterior synechiae, and hypopyon.
Resolution occurs within months secondary to discontinuation of the drug in addition to aggressive treatment with topical steroids.4
Rifabutin
Rifabutin, an oral bactericide, is typically prescribed as prophylaxis in HIV patients for mycobacterium avium complex. Rifabutin causes anterior uveitis with hypopyon formation;5 however, the likelihood is higher in those with risk factors including low body weight, dosage and duration of therapy, and concomitant with other drugs including clarithromycin and ritonavir.6
The mechanism is likely secondary to direct toxicity or dead microorganisms from the usage of the drug. Symptoms typically present between 2 weeks and 7 months of initiation of therapy and include pain, photophobia, redness, and blurred vision.
On exam, keratic precipitates, conjunctival injection, anterior chamber cell and flare with or without hypopyon, and perivascular retinal infiltrates can be seen.7,8 Symptoms typically resolve within 2 months following treatment with topical steroids and drug discontinuation.
Pamidronate
The second group of those receiving systemic treatment for non-ophthalmologic conditions at risk for the development of uveitis includes those being treated for osteoporosis with bisphosphonates.
The most common bisphosphonate that causes uveitis is intravenous (IV) pamidronate, while oral agents are less commonly precipitants. The proposed mechanism for this class of drugs is thought to be immunologic or toxic reactions secondary to the release of inflammatory cytokines.9
Symptoms that ophthalmologists should be wary of in patients utilizing these medications are those who, within 1 to 6 days of initiating treatment,10 present with unilateral or bilateral redness, pain, photophobia, and blurred vision.
While conjunctivitis is the most common manifestation in the eye, anterior uveitis, scleritis, episcleritis, and iritis also occur. In case reports, some cases were minor and resolved spontaneously, but others noted cases of severe inflammation requiring topical steroids.
Sulfonamides
Another group of patients to be wary of signs are those taking sulfonamides, which are typically prescribed for common infections, including UTIs and toxoplasmosis. Sulfonamides typically cause mild non-granulomatous anterior uveitis.11
The mechanism is thought to be due to the direct immunogenicity of the drug or the result of systemic necrotizing vasculitis.11 In patients with known treatment with a sulfonamide, physicians should be of those presenting within a week of treatment with symptoms of pain, redness, light sensitivity, and vision changes.
On exam, a unilateral or bilateral iritis can be seen. Cessation of the sulfonamide and treatment of any iritis with topical steroids will result in resolution.
Tumor necrosis factor (TNF)-alpha inhibitors
A third medication that has been demonstrated to cause uveitis is TNF-alpha inhibitors, a proinflammatory cytokine typically prescribed to treat various inflammatory conditions. These agents have been used to treat autoimmune-associated ocular inflammation as well as being used for the off-label treatment of uveitis and scleritis.
Of the three TNF inhibitors, etanercept is the most implicated. While the mechanism underlying uveitis is unknown, the relationship between the TNF inhibitors and pro-inflammatory cytokine interferon may promote the activation of immune cells, immune complex deposition, and auto-antibody formation, ultimately leading to the development of autoimmune disease.12
Oral fluoroquinolones
The final major class of systemic antibiotics prescribed by other physicians that ophthalmologists should be vigilant to screen for is the development of uveitis in those taking oral fluoroquinolones. While most of the typical fluoroquinolones can cause uveitis, moxifloxacin is most likely.
The exact mechanism is unknown, but it is believed that phototoxicity, concurrent viral infection, or autoimmune predisposition to disorders, demonstrated by the findings of HLA-B27 and HLA-B51 haplotypes in 20 and 40% of patients, respectively, underly the condition. Another proposed, though less likely, mechanism is concurrent viral infection.13
“Uveitis typically develops within 20 days after drug initiation with bilateral ocular pain and visual impairment symptoms.”
Examination often will reveal fine, pigmented keratic precipitates with prominent pigment in the anterior chamber with only minimal non-pigmented cells.14 Of note, in patients treated with moxifloxacin, uveitis should be suspected in those with pigment dispersion and iris transillumination. Cessation of the drug will treat the uveitis.
Metipranolol
Another major subset to be vigilant in our patients with glaucoma managed by topical drops. Uveitis is a side effect that should be considered when deciding on drug class and should be kept in mind when selecting the appropriate pharmacological treatment.
Metipranolol, a nonselective topical beta blocker, can cause the formation of granulomatous anterior uveitis, most commonly seen with the 0.6% dose. While the initial mechanism of uveitis formation is improper sterilization of multiuse bottles, the issue has persisted with new single-dose bottles and new sterilization methods.15
Physicians should be concerned in patients that present as early as 7 months but up to 31 months with unilateral or bilateral granulomatous or non-granulomatous anterior uveitis with keratic precipitates, anterior chamber cell and flare, or iris nodules, and in a select population, posterior synechiae.16,17
Iritis typically resolves within 3 to 5 weeks of treatment with cycloplegic agents and topical steroids. Uveitis also resolves within 3 to 5 weeks following the discontinuation of the drug and initiation of topical steroids.
Brimonidine
Brimonidine, a selective alpha 2 receptor agonist, is a fairly safe medication in the treatment of glaucoma; however, there are case reports that describe granulomatous anterior uveitis and elevated intraocular pressure (IOP) when used chronically.18
Uveitis typically manifests only in the treated eye in patients on the drug for at least 11 months who were additionally over 75. Symptoms include redness, photopia, blurred vision, and keratic precipitates, iris nodules, anterior chamber cell and flare, and posterior synechiae on the exam.
Resolution of symptoms was achieved with cessation of the drug and treatment with topical steroids and cycloplegic agents for inflammation. However, rebound was a noted issue if the drug was re-started.
Prostaglandin analogs
Prostaglandin analogs work to treat glaucoma via increasing uveoscleral outflow, resulting in lowered IOP. These drugs are believed to precipitate uveitis by stimulating downstream proinflammatory eicosanoids.19
Isolated iritis has also been reported in patients without a previous history of uveitis but resolved following cessation of the drug.20 Symptoms ophthalmologists should be aware of that indicate the development of uveitis include redness, pain, and decreased vision, in addition to mild anterior chamber reactions on exam.
Topical steroids
Topical steroids can cause the development of uveitis or aggravation of already existing uveitis following withdrawal. A common cause is dexamethasone sodium phosphate 0.1%. However, corticosteroid withdrawal-associated uveitis has been described with different topical formulations.21
While the mechanism is unknown, there has been a noted association with positive treponemal antibody absorption.22 Symptoms resolved rapidly following treatment with a topical mydriatic agent.
Intraocular medications
Finally, intraocular medications should be carefully considered in the development of uveitis, including intravitreal triamcinolone, a corticosteroid used typically to treat noninfectious uveitis and macular edema.
However, the mechanism by which uveitis is caused is believed to potentially migrate to the anterior chamber before forming a pseudo-hypopyon. Of note, this reaction is seen mainly in the preserved formulations and is uncommon in the preservative-free form.4
Injected anti-vascular endothelial growth factor (VEGF), which is used off-label for retinal pathologies such as age-related macular degeneration (AMD) and diabetic retinopathy, can incite an aseptic endophthalmitis.
This has especially been implicated in bevacizumab, but ranibizumab can also induce sterile reactions. The mechanism underlying the formation of uveitis is believed to be due to the size of the bevacizumab molecule, making it more immunogenic than ranibizumab.23
Conclusions
While there are multiple mechanisms by which various systemic, topical, and injected drugs can precipitate uveitis, it is important that clinicians be vigilant when starting patients on new medications or in patients they see in clinic who present with new medications.
Although cessation of the offending drug will typically result in the resolution of the symptoms, it is crucial to ensure that the patient’s symptoms and clinical signs resolve, occasionally requiring topical steroids as well.
