Introduction

Erythema multiforme (EM) is an immune-driven condition that affects the skin and mucous membranes. It is typically recognised by target lesions featuring three concentric zones, resembling a bull’s eye. EM can be categorised as EM minor or EM major based on the location of the target lesions. 

Furthermore, EM is commonly triggered by the body’s overresponse to Herpes Simplex Virus (HSV), a condition called Herpes-Associated Erythema Multiforme (HAEM). Usually, HAEM is a self-limiting condition that affects someone once in their life, as the body develops antibodies against HSV. In some cases, HAEM can be recurrent; approximately 20-25% of people affected by HAEM may continue to have recurring episodes.. To help manage this and prevent any reactivation of the virus, doctors may prescribe antiviral medication.¹ 

Continue reading to learn more about the use of antiviral therapy in recurrent herpes-associated erythema multiforme.

Pathophysiology of HSV-associated EM 

What is the mechanism behind HAEM? 

Studies have shown that the pathogenesis of HAEM is similar to a delayed hypersensitivity reaction. This reaction starts when DNA fragments of the herpes simplex virus are carried by immune cells in the blood. These immune cells are called CD34+ cells, which are the early form of skin immune cells, and they interact with the skin’s keratinocytes. Keratinocytes are the majority of cells found in the outermost layer of the skin. This foreign HSV DNA attracts HSV-specific immune cells (CD4+ T helper 1 cells), which release interferon-γ, a signalling protein. This leads to the immune response being amplified in the body,activating  CD8+ cytotoxic T cells to directly attack keratinocytes with HSV proteins. The direct killing of the CD8+ cells causes skin damage and the formation of the classic target lesions seen in EM.²

Why do recurrences occur in HAEM?

Recurrences occur because of HSV’s nature. HSV can present as an active infection, a latent infection, or even reactivation. The most noticeable stage of the virus occurs during active infection, when the virus copies DNA, makes proteins, and assembles new virus particles inside the host cell. This process is halted by the immune system as described earlier, leading to the formation of EM target lesions. However, when HSVislatent, it remains dormant within certain cells in the body. In HSV-1, this is usually the sensory ganglia, where nerves connect to the skin and mucous membranes. Due to the lack of assembly of virus particles, the immune system does not recognise the virus. This means the latent virus can reactivate. Certain triggers, such as stress, UV light, or immunosuppression, may reactivate the virus, restarting the process of damage. The virus never leaves the body in some people with HSV, leading to an endless cycle of latency and activation, causing recurrent episodes of HAEM.³

Management of erythema multiforme 

In EM, management depends on the symptoms and severity of the rash. In practice, a doctor usually investigates the causes of the target lesions appearing. For example, if it were due to an infection, such as HSV, and there is specific treatment for that infection, it can be given. Or if it was due to a specific outweigh the risks. To manage the rash’s symptoms (i.e., itching, discomfort, or pain), other medications may be given. These conventional management approaches include:⁴

• Pain relief medications 
• Moisturisers
• Antihistamines 
• Topical steroids 
• Hospital admission for fluids and electrolyte restoration
• Ophthalmologic assessment 
• Antiviral medication

Management of recurrent HAEM 

The management of recurrent herpes-associated erythema multiforme emphasises that the herpes simplex virus (HSV) operates through cycles of latency and activation. This understanding supports the long-term use of prophylactic antiviral medications to help control outbreaks. 

In the following sections, we will explore the rationale for using antivirals, review available antiviral options, discuss their limitations, and highlight new and emerging therapies in the field.

What is the rationale for antivirals?

HSV reactivation triggers the body's immune response, specifically activating CD8+ T cells that target and destroy the HSV DNA fragments present in skin cells. This process results in the manifestation of EM. Consequently, each time HSV reactivates, EM flare-ups occur. Antiviral medications can help reduce the replication of HSV DNA fragments. The goal of long-term antiviral treatment is to continuously suppress HSV activity, prevent recurrences, and minimise the virus's impact on the quality of life of those affected.⁵

Antiviral therapy

Antiviral therapy for HAEM includes acyclovir, valacyclovir, and famciclovir. These medications can be administered orally, either in a continuous or episodic regimen.⁶ A randomised controlled trial conducted in 1995 indicated that the most effective approach is a continuous oral antiviral therapy lasting longer than six months. The findings also showed that the treatment was particularly effective for patients with a clear connection to HSV.⁷ It is recommended that individuals with recurrent herpes associated EM who respond well to treatment continue the medication for a minimum of one to two years before considering discontinuation. If the patient remains unresponsive to the initial treatment, it may be appropriate to double the antiviral dosage. Alternatively, switching to a different antiviral therapy could enhance efficacy.

Limitations of antivirals 

Unfortunately, some individuals with recurrent HAEM find it challenging to maintain long-term remission, even with treatment. A study showed that among patients receiving six months of continuous antiviral therapy, only 4 out of 15 sustained remission after stopping the medication. ⁷ This indicates that the effectiveness of such treatment is not uniform. Consequently, recurrent HAEM that does not respond to prophylactic antiviral therapy may require alternative treatments.

Emerging and adjunctive therapies

Recurrent HAEM that is resistant to antiviral therapy may lead to the use of other alternative treatments, such as immunomodulators. Immunomodulators are substances that can stimulate or suppress the immune system and, therefore, influence the body's response to HSV. Emerging therapies, including medications like azathioprine, dapsone, and thalidomide, can have adverse side effects and need more validation through controlled trials. ⁶ 

A critical aspect of managing HSV is the connection between lifestyle factors and the virus's reactivation. Various triggers, such as heightened stress levels, trauma, and UV exposure, can significantly influence this process.⁸ The complexity of individual circumstances can affect the efficacy of treatments, making the behaviour of HSV unpredictable from one person to another. This situation underscores the importance of incorporating lifestyle and trigger management strategies, advocating for a more biopsychosocial and holistic approach to treatment. 

FAQs

Can antiviral therapy cure HSV?

No. Antiviral therapy does not cure HSV; it only helps stop the virus from replicating. This reduces symptom duration and severity and lowers the risk of recurrence and transmission to others.

Why do some people get EM once, while others have recurrent HAEM? 

This is due to differences in people’s immune systems. Some may experience EM once due to an exaggerated immune response to HSV, but following that ‘one-off’ event, their immune system no longer reacts in the same way. In others, every HSV reactivation triggers a hypersensitivity response, causing HAEM. This can be due to several factors, such as genetics, the frequency of HSV reactivation, differences in immune system regulation, and environmental factors.

Is recurrent HAEM contagious?

The EM rash is not contagious, meaning it cannot be spread from person to person. However, the herpes simplex virus (HSV), which can trigger EM, is contagious and can be transmitted during active outbreaks. Direct contact with HSV blisters, whether through oral contact or skin-to-skin contact, can spread the virus. Therefore, it is advisable to take precautions.

Conclusion

In conclusion, recurrent herpes-associated EM is a challenging condition that can significantly impact quality of life; however, it is manageable. Antivirals serve as the primary first-line therapy for HSV-associated EM presentations and can also be used prophylactically in the long term, not only to suppress flare-ups but also to induce remission in some cases. Despite the available treatments, there are limitations for recurrent HAEM, highlighting the need for more personalised approaches and further research.