ABSTRACT

A 51-year-old man was diagnosed with Behçet’s disease in 2001. The patient was resistant to all immunosuppressive therapies. After 6 months of infliximab therapy, he presented to our clinic with pain and blurred vision in his right eye. The visual acuity was 20/200 and the intraocular pressure was 35 mmHg in the right eye. Biomicroscopic examination revealed corneal dendritic ulcers and 2+ cells in the anterior chamber in the right eye. The herpetic keratouveitis attack was controlled with antiviral therapy but the patient needed another glaucoma surgery. Trabeculectomy with mitomycin C was performed about halfway through an eight-week interval between two doses of infliximab.

Introduction

Behçet’s disease (BD) is a serious sight-threatening clinical entity that involves uveitis accompanied by recurrent oral aphthous ulcers, genital ulcers, skin lesions, and other systemic lesions. Although infliximab, a humanized antibody against tumor necrosis factor-alpha (TNF-α), reduces uveitis attacks in patients with BD, anti-TNF-α therapy increases the risk of infections due to the systemic blockade of TNF-α.^1,2,3

Here, we report herpetic keratouveitis triggered by treatment with the anti-TNF-α antibody infliximab in a uveitis patient with BD and the failure of the previous trabeculectomy during the course of the infection. To our knowledge, this is the first reported case of new-onset herpetic keratouveitis triggered by anti-TNF-α therapy in a patient with BD.

Discussion

Infliximab is a humanized antibody against TNF-α that can greatly reduce ocular inflammatory attacks in uveitic patients affected by BD. However, anti-TNF-α therapy is also associated with a risk of infectious complications due to the systemic blockade of TNF-α. In addition, patients with BD may frequently need ocular surgery. Therefore, intraocular surgery in BD patients under treatment with infliximab may be associated with a higher risk of ocular infections.⁴Moreover, it is unclear if trauma caused by surgery increases disease activity during anti-TNF-α treatment. Trabeculectomy with mitomycin C has provided long-term safety and was effective in reducing intraocular pressure in cases with secondary glaucoma associated with BD.^5,6Trabeculectomy has also been successful in patients with BD receiving infliximab therapy.⁷

In addition to bacterial and fungal infections, biologic treatments may also increase the risk of viral infections; however, previous studies regarding this issue have not been conclusive enough.⁸There are some case reports and studies which reported that herpes zoster infections developed in patients with rheumatologic disease during the biologic treatment course.^{8,9,10,11,12,13}There are also some reported cases of cutaneous herpes simplex virus (HSV) infection following treatment with infliximab.^14,15We are not aware of any published reports of ocular HSV infections associated with use of TNF inhibitors.

In vivo data indicate that TNF-α may have an antiviral effect in HSV-1 infections. In a model in which HSV-1 was reactivated in latently infected mouse cornea, TNF-α and interleukin-6 were the predominant cytokines within the trigeminal ganglion, suggesting a key role for these cytokines in viral clearance.¹⁶Absence of TNF in knockout mice increased susceptibility to primary corneal HSV-1 infections in one study¹⁷and lowered survival rates compared with wild-type mice in another.¹⁸While all three TNF inhibitors used in clinical practice inhibit the actions of TNF-α, their different mechanisms of action may result in a variable susceptibility to HSV-1 infections, although this has not specifically been studied.

In several small placebo-controlled trials, prophylactic use of oral acyclovir in immunocompromised patients was found to be successful in reducing the duration of viral shedding and preventing clinical HSV infections in 80% to 100% of patients.¹⁹The oral doses studied were 600 mg/day for 30 days and 800 mg/day for 180 days. In both studies, there were no additional adverse events compared with placebo. The most frequently reported adverse effects during acyclovir therapy are headache, nausea and abdominal cramping. Although oral acyclovir has a good safety profile, cases of rapidly progressive acute neurological and renal toxicity have been described.²⁰Acyclovir-induced neurotoxicity can present with a variety of symptoms including agitation, delirium and hallucinations.²¹Dose reductions are recommended in patients with renal impairment and in the elderly. Our patient received acyclovir at 800 mg/day for 24 months and a dose reduction was attempted, inflammation in the anterior chamber developed. Although current evidence concerning the optimum duration and dose for long-term prophylaxis is lacking, a decision to continue at this level of therapy was made with the patient because of concerns about infection recurrence.

In our patient, herpetic keratouveitis occurred under infliximab therapy, and the previous trabeculectomy surgery failed due to this attack. The keratouveitis attack was controlled with antiviral therapy but the patient needed repeated glaucoma surgery. The trabeculectomy surgery was risky in this patient because the surgery might have induced both BD and herpetic uveitis; in addition to that, infection was another risk. After the glaucoma surgery under systemic antiviral and infliximab therapy, there were no occurrences of inflammatory or infectious complications.

Conclusion

In conclusion, systemic and ocular infections including HSV infections and reactivations can develop in patients receiving immunosuppressive or biologic agents; therefore, these patients should be monitored closely.