Drug-induced uveitis is a relatively rare condition in which systemically or topically administered drugs trigger intraocular inflammation. It accounts for 0.38–1.4% of all uveitis cases 1) and less than 0.5% in tertiary referral uveitis clinics.
It became widely recognized in the 1990s following case reports of rifabutin and cidofovir in AIDS patients. 1) In recent years, reports have increased due to the widespread use of intravitreal injections, immune checkpoint inhibitors, and vaccines.
The following criteria are useful for establishing a drug causality relationship.
Not all criteria need to be met, but consider discontinuing the suspected drug and switching to an alternative.
Depending on the causative drug, the condition can present with various manifestations, from anterior uveitis to panuveitis. The most common is anterior uveitis (84.7%), followed by posterior (10.2%) and intermediate (2.6%). 2)
Yes, uveitis has been reported with topical ophthalmic medications such as brimonidine (glaucoma eye drops) and prostaglandin analogs. In particular, brimonidine can develop from several weeks up to 5 years after initiation, and may be missed if the patient does not report using eye drops. 1)
The pathogenesis of drug-induced uveitis is broadly divided into direct mechanisms and indirect mechanisms. 1)
Direct mechanism: Direct toxicity of the drug, metabolite, or excipient disrupts the blood-ocular barrier (BAB/BRB), allowing inflammatory cells to infiltrate. Onset usually occurs within 24 to 48 hours.
Indirect mechanisms (three main pathways):
Drug-induced uveitis is a diagnosis of exclusion. Infectious uveitis (e.g., HSV, VZV, cytomegalovirus, toxoplasma) and autoimmune uveitis must be ruled out.
For vasculitis and posterior uveitis, additional testing includes vasculitis screening (ANCA, ANA, ENA, dsDNA). 1)
Discontinuation of the causative drug is the most important treatment. However, in cancer immunotherapy, life-prolonging effects may outweigh the risk of uveitis. Consultation with the prescribing physician (oncology, rheumatology, etc.) is necessary before discontinuation.
Anterior uveitis: Usually manageable with topical steroid eye drops. Posterior uveitis/retinal vasculitis: Requires systemic steroids or local steroid injection.
If re-administration is planned, an ophthalmology visit within 1–2 weeks after administration is recommended. 1)
Bisphosphonates (most common)
Drug examples: Zoledronic acid, Alendronic acid, Pamidronic acid
Incidence: Acute anterior uveitis 0.8–1.1% with zoledronic acid1)
Onset: 1–7 days after IV (mean 5 days), 15–21 days after oral administration
Treatment: Drug discontinuation + topical steroids (anterior uveitis); systemic steroids (scleritis)
Note: Accounts for more than two-thirds of all drug-induced uveitis1)
Rifabutin (MAC treatment drug)
Drug example: Mycobutin®
Onset: 2 weeks to 7 months after starting
Features: Anterior uveitis with hypopyon. Risk increases when combined with CYP450 inhibitors1)
Treatment: Discontinue rifabutin + topical steroids and cycloplegics
Prognosis: Resolves within 1–2 months after discontinuation
Anti-VEGF drugs (intravitreal injection)
Brolucizumab: Uveitis risk 4.6% (retinal vasculitis 3.3%)1)
Faricimab: Uveitis incidence 0.87%, vitritis 0.63%1)
Aflibercept/Bevacizumab/Ranibizumab: 0.02–0.16% sterile endophthalmitis1)
Treatment: Intensive topical steroids. Systemic steroids for severe cases. In mild cases, continuation of the same drug may be possible, but discontinuation or switching is often required.
Vancomycin (intracameral injection)
Complications: Hemorrhagic occlusive retinal vasculitis (HORV)
Onset: Average 9 days after intravitreal vancomycin1)
Symptoms: Painless blurred vision and peripheral scotoma. Minimal anterior chamber/vitreous inflammation
Prognosis: 56% develop neovascular glaucoma within 1–2 months1)
Treatment: Steroids, panretinal photocoagulation, anti-VEGF therapy
A large retrospective study of 67,517 glaucoma patients compared the incidence of uveitis by topical glaucoma medication, with the following results. 2)
| Drug class | Uveitis incidence | Odds ratio vs. PGA |
|---|---|---|
| PGA (prostaglandin analogs) | 0.32% | Reference |
| Beta-blockers | 1.95% | 6 times higher |
| Alpha agonists | 1.63% | 5 times higher |
| Carbonic anhydrase inhibitor | 1.68% | 6 times higher |
The common belief that PGA causes uveitis has been disproven by large-scale data.2) Even in patients with a history of uveitis, no increase in inflammatory flares was observed with PGA.
Brimonidine eye drops: Can cause granulomatous anterior uveitis. Onset occurs from 1 week to up to 5 years after initiation.1) Prognosis is good with discontinuation plus topical steroids, but recurrence occurs upon rechallenge.
Mepranolol (beta-blocker): The most common beta-blocker to cause uveitis. Resolves 3–5 weeks after discontinuation.
Large-scale studies have shown that PGAs have the lowest incidence of uveitis compared to other glaucoma medications (beta-blockers, alpha-agonists, carbonic anhydrase inhibitors), and no increased risk of recurrence was found even in patients with a history of uveitis. Avoiding PGAs due to uveitis concerns may result in missing the opportunity to receive the most effective intraocular pressure-lowering therapy. 2)
Immune checkpoint inhibitors (anti-PD-1, anti-CTLA-4, etc.): Uveitis occurs due to T cell activation. It can range from anterior to panuveitis and retinal vasculitis. Cytokine storms involving TNF-α, IL-17, and IL-2 cause tissue damage and disruption of the blood-ocular barrier. 1) The decision to continue or discontinue the drug should be made through multidisciplinary discussion, considering the life-prolonging effects of cancer therapy.
TNF inhibitors (etanercept, etc.): These often suppress uveitis in patients with arthritis, but there are also reports of inducing uveitis. For etanercept-induced uveitis, switching to adalimumab or infliximab is an option. 1)
BRAF and MEK inhibitors: Used for melanoma treatment. There is a risk of uveitis. 1)
Drug-induced tubulointerstitial nephritis and uveitis (TINU) syndrome is an independent disease entity presenting with acute interstitial nephritis + bilateral anterior uveitis. It has been reported after use of drugs such as flurbiprofen, antibiotics (commonly used for respiratory infections: 24% of cases), and nonsteroidal anti-inflammatory drugs. Treatment: discontinuation of the causative drug + topical steroids (systemic steroids in severe cases).
:::caution Note Drug-induced uveitis is a diagnosis of exclusion. In immunocompromised patients, infectious uveitis (especially CMV and tuberculosis) should be ruled out before diagnosis. Be aware of potential reactivation of latent tuberculosis even after discontinuation of TNF inhibitors.1) :::
The final common pathway of drug-induced uveitis is disruption of the blood-ocular barrier. The mechanism of BRB disruption varies by drug.3)
| Drug | Mechanism of action | BRB disruption mechanism |
|---|---|---|
| Brimonidine | Selective α2 agonist | Increased production of inflammatory cytokines |
| Bisphosphonates | Osteoclast function inhibition | Idiosyncratic immune reaction (T cell activation) |
| Brolucizumab | Anti-VEGF | Type IV hypersensitivity reaction (increase in inflammatory cytokines such as CCL2, IL-6, IL-8, ICAM-1)3) |
| Immune checkpoint inhibitors | Blockade of immunosuppressive receptors | Increased autoimmune reaction rate |
In the case of brolucizumab, it has been confirmed that after intravitreal injection, CD4+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ histiocytes accumulate in the vitreous, exacerbating inflammation. 3)
HORV is thought to be a type III hypersensitivity reaction (deposition of antigen-antibody complexes on vessel walls), but histologically, it has also been suggested that non-granulomatous choroiditis may be a primary choroidal process leading to retinal vascular necrosis. 1)
In recent years, reports of uveitis following COVID-19 mRNA vaccination have increased. Three mechanisms have been proposed: (1) direct infection from live attenuated vaccines, (2) accumulation of adjuvants/additives in uveal tissue, and (3) immune cross-reactivity with ocular structures due to molecular mimicry. 1)
With the widespread use of novel anticancer drugs, the scope of drug-induced uveitis is expanding. Most evidence comes from case reports and retrospective studies; prospective studies and registries are needed to quantify incidence and outcomes. 1)
Collaboration among ophthalmologists, oncologists, rheumatologists, general practitioners, and pharmacists is essential for early recognition and appropriate management of drug-induced uveitis. Pharmacists and optometrists often serve as the first point of contact, and their role in early recognition is significant. 1)
:::danger Disclaimer This article is educational content intended to provide medical information. For diagnosis and treatment of individual patients, please consult your primary care physician or specialist. Please refrain from self-diagnosis or self-treatment based on the information in this article. In particular, if you are using anticancer drugs such as immune checkpoint inhibitors, do not discontinue medication on your own without consulting your doctor, even if symptoms of uveitis appear. :::
