Acute anterior uveitis is a general term for uveitis primarily involving acute inflammation of the anterior segment of the eye. When inflammatory cells are present in the anterior chamber, it is called iritis; when inflammation also extends to the anterior vitreous, it is called iridocyclitis.
Acute anterior uveitis is the most common type of uveitis1). In Western countries, it accounts for about 50% of all uveitis cases, whereas in Japan its frequency is around 2.5–6%, showing regional differences. It is more common in young men, and onset in HLA-B27-positive individuals is characteristic. The B27 positivity rate among Japanese patients with acute anterior uveitis has been reported to range from 4% to 63%.
The main etiologies of acute anterior uveitis are broadly divided into four categories: idiopathic, rheumatic disease-related, Fuchs heterochromic iridocyclitis, and herpetic uveitis1). Many cases resolve with appropriate anti-inflammatory therapy, but recurrence is not uncommon. If inflammation does not recur for three months after stopping treatment, it is considered a “limited period” of inflammation.
QIs acute anterior uveitis a common disease in Japan?
A
In Western countries, it is a very common disease accounting for about 50% of all uveitis, but in Japan it accounts for only 2.5–6%, showing regional differences. In Japan, infectious uveitis (e.g., cytomegalovirus), Vogt-Koyanagi-Harada disease, and Behçet’s disease are relatively more common.
The following findings are confirmed by slit-lamp examination:
Conjunctival and ciliary injection: Severe injection seen throughout the anterior segment.
Anterior chamber inflammation: Numerous inflammatory cells, intense flare, and fibrin are observed. Fibrin may adhere to the iris or anterior lens capsule and cover the pupillary area.
Hypopyon: Inflammatory cells and fibrin accumulate in the lower anterior chamber. It is viscous and poorly mobile (in contrast to the thin hypopyon in Behçet’s disease).
Keratic precipitates (KP) and Descemet’s membrane folds: Inflammatory cells deposit on the corneal endothelium.
Posterior synechiae: Occur frequently. If circumferential, they cause iris bombé and lead to acute angle-closure glaucoma.
Intraocular pressure changes: Usually, intraocular pressuredecreases due to reduced ciliary body function. It may increase due to aqueous outflow obstruction from posterior synechiae or trabecular meshwork blockage by inflammatory cells.
Mild vitreous opacities: Observed when inflammation extends to the anterior vitreous.
In HHV-6A-associated acute anterior uveitis, severe findings such as eyelid edema, massive fibrinous exudate in the anterior chamber, and intraocular pressure exceeding 50 mmHg have been reported 1). Zoledronic acid-induced acute anterior uveitis is characterized by rapid onset within 24–36 hours after administration, presenting with dusty keratic precipitates, anterior chamber flare, and fibrin exudation 2).
Acute anterior uveitis is classified into three groups based on etiology: non-infectious (autoimmune/inflammatory), infectious, and drug-induced.
Non-infectious
HLA-B27-associated: The most common systemic association. It is linked to spondyloarthritis including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and inflammatory bowel disease. Approximately half of patients with ankylosing spondylitis develop acute anterior uveitis.
Sarcoidosis: Presents as granulomatous anterior uveitis.
Behçet’s disease: Presents as anterior uveitis with hypopyon.
Juvenile idiopathic arthritis: Causes chronic, often asymptomatic, bilateral anterior uveitis in children.
IgG4-related disease: A rare cause presenting as hypertensive granulomatous anterior uveitis. Serum IgG4 is markedly elevated 8).
Infectious and Drug-induced
Herpes viruses (HSV, VZV, CMV): Present as ocular herpes with keratitis and iritis.
HHV-6A: Cases have been reported where HHV-6A DNA was detected in aqueous humor by mNGS 1).
Syphilis: Can mimic any uveitis pattern, so it must always be ruled out.
Zoledronic acid (bisphosphonate): The incidence of acute anterior uveitis after the first intravenous dose is approximately 1.1%, with a mean onset time of 3 days (range 2–4 days) 2). This is significantly higher than the annual incidence of 0.029% with oral alendronate.
COVID-19 vaccine: An increased risk of acute anterior uveitis after vaccination has been reported. With the Pfizer-BioNTech vaccine, there have been cases of ipsilateral onset 5 days after the first dose and 3 days after the second dose 4).
Regarding the risk of acute anterior uveitis due to zoledronic acid, the WHO pharmacovigilance database (VigiBase) reported 195 cases of uveitis among 48,990 reports, with a relative risk of 1.45 (95% CI: 1.25–1.68) for the first bisphosphonate administration 3). Even in patients tolerating long-term oral alendronate, the risk of developing acute anterior uveitis after intravenous zoledronic acid cannot be excluded 2). Since 19.2–50% of patients with HLA-B27-associated acute anterior uveitis have ankylosing spondylitis, evaluation of spinal and joint symptoms is important in addition to ocular symptoms.
QIf I develop uveitis after COVID-19 vaccination, should I avoid the next dose?
A
Vaccine-related acute anterior uveitis is transient and often improves with topical steroid eye drops. Current evidence does not support discontinuing vaccination 4)5)6). However, if it occurs, it is advisable to receive ophthalmologic treatment and consult with your doctor about continuing vaccination.
Slit-lamp microscopy is the most important diagnostic tool. It evaluates inflammatory cells in the anterior chamber, flare, keratic precipitates (KP), fibrin, hypopyon, iris nodules, and posterior synechiae. At the initial visit, dilate the pupil and perform fundus examination to determine the direction of differential diagnosis based on the presence or absence of posterior segment inflammation.
The following systemic tests are useful for diagnosis.
Syphilis screening: Should be performed in all patients.
HLA-B27 typing: Performed for recurrent acute anterior uveitis.
Chest X-ray: Performed to rule out sarcoidosis in bilateral or granulomatous disease.
ACE and lysozyme tests: Their usefulness as ancillary tests for sarcoidosis is debated.
Broad, non-targeted “uveitis screening panels” are not recommended due to low predictive value.
Aqueous humor PCR: Used to confirm viral etiologies such as HSV, VZV, and cytomegalovirus.
Metagenomic next-generation sequencing (mNGS): Useful for identifying pathogens such as HHV-6A that are not detected by conventional PCR1). In HHV-6A cases, HHV-6A DNA was detected in both aqueous humor and blood1).
Herpesvirus-related acute anterior uveitis: Combine topical steroids with antiviral agents.
HHV-6A-associated acute anterior uveitis: A reported regimen: intravenous foscarnet (3 g/12 h) plus ganciclovir (0.45 g/12 h) for 2 weeks, followed by oral ganciclovir (1 g three times daily) tapered over 35 days1). Corrected visual acuity improved to 20/50 at 2 months and 20/22 at 5 months after antiviral treatment.
Zoledronic acid-induced acute anterior uveitis: Tobramycin/dexamethasone eye drops 4 times/day plus atropine sulfate eye ointment 2 times/day are effective. If accompanied by high intraocular pressure, add brinzolamide eye drops2). Topical antibiotics alone are ineffective and may worsen the condition2). The average duration of steroid eye drop treatment is 26±10 days (range 17–44 days), and vision usually recovers without sequelae2)3).
QWhat eye drops are used in the treatment of acute anterior uveitis?
A
Standard treatment in Japan is a combination of steroid eye drops (Rinderon 0.1%: starting every 1–2 hours depending on inflammation severity, then tapering) and mydriatic eye drops (Mydrin P 3 times daily). Mydriatics are always used together to prevent posterior synechiae and reduce pain. For severe inflammation, subconjunctival injection or short-term oral steroids may be added.
When infectious exposure is added to genetic predisposition (HLA-B27 positivity), molecular mimicry is thought to cause cross-reactivity with ocular-specific antigens, triggering iritis. TNF-α has been detected at the gene and protein levels in the affected sacroiliac joints of ankylosing spondylitis, playing a central role in the pathogenesis of AS and its associated uveitis. Animal studies also suggest that the gut microbiome may be involved in the development of HLA-B27-related diseases.
Mechanism of zoledronic acid-induced acute anterior uveitis
Nitrogen-containing bisphosphonates inhibit the mevalonate pathway, suppressing the synthesis of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP)3). This leads to accumulation of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which activate γδ T cells and release inflammatory cytokines such as IL-1, IL-6, TNF-α, and IFN-γ2)3).
Jin et al. (2021) considered this acute anterior uveitis as part of the acute phase response (APR) because it appears simultaneously with fever, myalgia, and arthralgia2). Patients with 25(OH)D < 30 ng/mL have a significantly higher risk of developing APR, and it has also been suggested that secretion of bisphosphonates into tears may trigger intraocular inflammation2).
Zoledronic acid mechanism
Mevalonate pathway inhibition: Suppresses FPP and GGPP synthesis.
IPP and DMAPP accumulation: Strongly activates γδ T cells.
Inflammatory cytokine release: IL-1, IL-6, TNF-α, and IFN-γ are released.
Uveitis onset: Acute onset as local ocular inflammation.
Vaccine-related mechanisms
Molecular mimicry: Viral components structurally resemble self-antigens, causing B and T cells to cross-react4)5)6).
Bystander activation: Non-specific excessive immune response creates a local inflammatory environment6).
HHV-6 interacts with CD46 (a complement regulatory protein) via viral glycoprotein H (gH), leading to cell fusion and entry1). Since CD46 is present on all nucleated cell membranes, HHV-6 can infect various cell types including T lymphocytes, fibroblasts, epithelial cells, and endothelial cells1). HHV-6A exhibits higher virulence than HHV-6B and induces CD46-dependent cell fusion without viral replication via the gH/gL/gQ1/gQ2 tetrameric complex1). The detection rate of HHV-6 DNA in normal intraocular fluid is less than 2%, so a positive result in intraocular fluid is important as it suggests active infection1).
QWhy does uveitis occur after zoledronic acid injection?
A
Zoledronic acid inhibits the mevalonate pathway, leading to accumulation of IPP and DMAPP, which activates γδ T cells and releases large amounts of inflammatory cytokines such as IL-6 and TNF-α. Uveitis is thought to develop in the eye as part of this systemic inflammatory response (acute phase reaction)2)3).
Only 9 cases have been reported in the literature where HHV-6 was confirmed as the sole pathogen of intraocular inflammation, of which 4 were healthy individuals without any underlying disease 1). HHV-6A-related acute anterior uveitis limited to the anterior segment is an extremely rare report.
Ma et al. (2024) detected HHV-6A, which was not detected by conventional PCR, from both aqueous humor and blood using mNGS 1). After antiviral treatment with intravenous foscarnet plus ganciclovir, corrected visual acuity improved to 20/50 at 2 months and 20/22 at 5 months. The response to treatment provided evidence of active infection and was also useful for differentiation from chromosomally integrated HHV-6 (ciHHV-6).
mNGS is attracting attention as a promising technique for pathogen identification in acute anterior uveitis of unknown cause, and its future diagnostic application is expected 1).
Risk management of zoledronic acid-induced acute anterior uveitis
A review of 34 case reports showed that most cases developed unilaterally within 7 days after the first dose and improved without sequelae with topical steroids 3). Current osteoporosis treatment guidelines do not list zoledronic acid-induced acute anterior uveitis as an absolute contraindication, and data on the risk of recurrence upon re-administration remain limited 2)3).
Findings from large population studies are accumulating that the risk of uveitis increases after the first vaccination. Anterior uveitis is the most common, and most cases resolve with topical steroids 4)5).
Sanjay et al. (2022) reported 41 cases of post-vaccine acute anterior uveitis as a multicenter study 5). The mean onset was 5.5 days (range 1–14 days) after vaccination, most cases occurred after the Pfizer vaccine, and they improved with topical steroids. Cases occurring even during immunosuppressive therapy (methotrexate 25 mg/week) were shown.
In a patient with chronic graft-versus-host disease after hematopoietic stem cell transplantation, acute anterior uveitis (cell 4+) with hypopyon developed 3 days after Moderna vaccination, and a refractory case that improved 6 months after onset with intravitreal dexamethasone 0.5 mg injection has also been reported 7). Although it is not considered a reason to discontinue vaccination, special attention is needed in immunocompromised patients.
IgG4-related eye disease and acute anterior uveitis
Reports of IgG4-related disease presenting with anterior uveitis alone are rare 8). Elevated serum IgG4 (1381 mg/dL; normal range 1–123 mg/dL) was a clue to diagnosis 8). There are case reports that rituximab is effective for refractory and recurrent cases, and large-scale studies are expected in the future 8).
Ma H, Wang X, Chen Y, et al. Human Herpesvirus 6A Infection-Associated Acute Anterior Uveitis. J Inflamm Res. 2024;17:11577-11585.
Jin X, Shou Z, Shao Y, Bian P. Zoledronate-induced acute anterior uveitis: a three-case report and brief review of literature. Arch Osteoporos. 2021;16(1):104.
Vernaza Trujillo DA, Osorio Escorcia PM, Sierra Castillo S, et al. Two Case Reports of Zoledronic Acid-Induced Acute Anterior Uveitis. Cureus. 2024;16(10):e72689.
Alhamazani MA, Alruwaili WS, Alshammri B, et al. A Case of Recurrent Acute Anterior Uveitis After the Administration of COVID-19 Vaccine. Cureus. 2022;14(3):e22911.
Sanjay S, Yathish GC, Singh Y, et al. COVID-19 vaccination and recurrent anterior uveitis. Indian J Ophthalmol. 2022;70(12):4445-4448.
Sanjay S, Kawali A, Mahendradas P. COVID-19 vaccination, dengue hepatitis, and recurrent unilateral anterior uveitis. Indian J Ophthalmol. 2023;71(5):2269-2272.
Lin CY, Chien HJ. Acute exacerbation of ocular graft-versus-host disease and anterior uveitis after COVID-19 vaccination. BMC Ophthalmol. 2023;23(1):360.
Chen JL, Men M, Naini BV, Tsui E. IgG4-related hypertensive granulomatous anterior uveitis. Am J Ophthalmol Case Rep. 2022;26:101465.
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