Overview
A thorough review of medications should be conducted in evaluation of every uveitis patient
Mechanisms of drug-induced uveitis are poorly understood, but may include direct medication toxicity, breakdown of blood-aqueous and blood-retina barriers, and immune-mediated vasculitis
Using the 10 criteria proposed by Naranjo et al., the causative relationship between a medication and an adverse reaction can be quantitatively assessed
Systemic Medications
Bisphosphonate
A group of medications used to treat osteoporosis or to prevent fractures in bone malignancy
Conjunctivitis, anterior uveitis, episcleritis, and scleritis may occur within 24 hours of administration
Mechanism: release of inflammatory cytokines
Cidofovir
Given intravenously or intraocularly for CMV retinitis; rarely used today due to irreversible nephrotoxicity
Nongranulomatous anterior uveitis and hypotony, especially after multiple intraocular injections
May require aggressive topical or periocular steroids, cycloplegia, and discontinuation of cidofovir; oral probenecid reduces incidence of uveitis and hypotony
Rifabutin
Used for Mycobacterium avium complex prophylaxis in immunocompromised patients
Characteristic hypopyon anterior uveitis, though intermediate uveitis with dense vitritis, panuveitis, and retinal vasculitis can occur as well
Incidence is dose and duration dependent (5.6% incidence with 300 mg daily dose, but quadruples with 600 mg)
Uveitis may be accompanied by arthralgia, jaundice, pseudojaundice, or transient rash
Uveitis resolves after 1–2 months with intensive topical or systemic corticosteroids and discontinuation of rifabutin
Sulfonamides “Sulfa Drugs”
Trimethoprim-sulfamethoxazole (Bactrim): bilateral nongranulomatous anterior uveitis. Retinal hemorrhages may appear within a week of taking medication. The trimethoprim component, a non-sulfa drug, can lead to uveitis as well
Topiramate (Topamax): bilateral anterior uveitis with, uveal effusion. Secondary angle closure may classically result from the effusion displacing the lens/iris diaphragm forward, and anterior rotation of ciliary body
TNF-Alpha Inhibitors
Etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) have all been implicated – particularly etanercept – in paradoxical autoimmune reactions, including uveitis, biopsy-proven sarcoidosis (as well as ocular sarcoidosis), lupus-like syndrome, interstitial lung disease, and autoimmune hepatitis
Most reported cases occur within 1 year of therapy start and most resolve after discontinuation of TNF-alpha inhibitors
Mechanism: auto-antibody formation and subsequent immune complex deposition
Fluoroquinolones
Acute, bilateral anterior uveitis, often within 3–4 weeks of exposure. May have significant pigment dispersion, endothelial dusting, iris atrophy, posterior synechiae, and possible IOP elevation
Iris transillumination defect and mydriasis may persist after acute episode
Immune Checkpoint Inhibitors (ICPIs): Ipilimumab, Pembrolizumab, Nivolumab
Tumor cells evade the immune system by activating inhibitory receptors, including CTLA-4 and PD-1, on the surface of tumor-specific T lymphocytes
- Ipilimumab (Yervoy) binds CTLA-4, while Pembrolizumab (Keytruda) and Nivolumab (Opdivo) bind PD-1 to prevent such inactivation by tumor cells:
Ipilimumab indicated for metastatic cutaneous melanoma
Pembrolizumab and nivolumab indicated for a variety of malignancies in addition to melanoma
All 3 ICIPs have been associated with bilateral uveitis, most commonly anterior but also intermediate, posterior and panuveitis. Posterior segment presentation can be highly VKH-like
Typical onset: 6–12 weeks after ICPI infusion
Uveitis accounts for about 1% of all adverse events associated with ICPIs, while colitis accounts for up to 60%. Other systemic manifestations include vitiligo, hearing loss, poliosis, headache, arthritis, rash, autoimmune hepatitis, interstitial nephritis, pneumonitis
Topical, regional, or systemic corticosteroid may need to be maintained if ICPI needs to be continued
Mechanisms: T-cell activation and, in cases of cutaneous and choroidal melanomas, tumor lysis result in melanin and melanin-associated protein release into bloodstream, which in turn activate primed T-cells in the uveal tract
BRAF Inhibitors (Vemurafenib, Dabrafenib) and MEK Inhibitors (Trametinib)
Inhibit signaling pathways that lead to tumor proliferation
Indicated for metastatic cutaneous melanoma
All 3 have been associated with bilateral uveitis, most commonly anterior
Topical Medications
Brimonidine
Granulomatous anterior uveitis with IOP elevation, conjunctival hyperemia, and follicular conjunctivitis
Usually occurs after 1+ year of use
When used bilaterally, uveitis onset in each eye can be asynchronous, with a long delay in fellow eye involvement
Mechanism: unknown
Metipranolol
Granulomatous anterior uveitis
Mechanism: unknown
Prostaglandin Analogues
Latanoprost, travoprost, and bimatoprost have all been associated with anterior uveitis, with latanoprost most frequently implicated
Mechanisms: breakdown of blood-aqueous barrier, increased production of inflammatory mediators such as IL-1, IL-6, and eicosanoids
Other side effects of prostaglandin analogues: conjunctival hyperemia, eyelash growth, iris darkening, periocular skin pigmentation, CME, and reactivation of HSV keratitis
We find this class of glaucoma drops to have effective IOP-reducing effect and do not lead to increased flare-ups in our uveitis patients, as long as disease is controlled with systemic IMT
Intraocular Medications
Anti-VEGF
Acute intraocular inflammation with severe complications has been reported especially with bevacizumab
Symptoms of decreased vision and floaters that often start within 24 hours of injection
Patients respond to systemic or topical corticosteroid treatment with a slow but persistent recovery
Pain may be the only symptom that distinguishes true infectious endophthalmitis from a sterile intraocular inflammation secondary to anti-VEGF
Triamcinolone Acetonide
Sterile endophthalmitis similar to that seen with anti-VEGF
Likely due to preservatives, as introduction of preservative-free formulation (Triesence) has greatly reduced incidence
Vaccines
BCG (definite)
Influenza (probable)
MMR (probable)
Hepatitis B (probable)
HPV (probable)
Varicella (possible)
Drug-Induced TINU Syndrome
Flubiprofen
Goreisan (a Chinese herb)
Paracetamol
Codeine phosphate
Lamotrigine
Smoking synthetic cannabinoid