Should atopic dermatitis patients starting JAK inhibitors take prophylactic acyclovir?

Janus kinases (JAK) are a group of intracellular non-receptor tyrosine kinases involved in the modulation of cytokines which play an integral role in immune and inflammatory processes (1–3). Many autoimmune conditions are precipitated by an imbalance in cytokine function (2). Obstructing this process with JAK inhibiting monoclonal antibodies can be of benefit in the treatment of conditions such as rheumatoid arthritis and inflammatory bowel disease (4). JAK inhibitors repress the signaling of numerous cytokines including IL-4, IL-5, IL-13, IFN-β, and IFN-γ (2,3,5), (Table 1). Interferon gamma (IFN-g) has a key role in preventing viral replication which make it important for limiting infection with and preventing reactivation of viruses, such as herpes viruses (6). Other varieties of monoclonal antibodies target fewer components of the inflammatory pathway. For example, dupilumab, used in atopic dermatitis treatment, inhibits only IL-4 and IL-13, allowing for more targeted immune modulation (7). Thus, dupilumab has a decreased risk of serious infection and no increased risk of overall infection (7,8). While widespread cytokine inhibition by JAK inhibitors allows them to be employed for numerous indications, this advantage is balanced with their less specific immune modulatory effect and increased risk of infection (2,8), (Figure 1).

Figure 1. The widespread inhibition of cytokines by nonselective JAK inhibitors interferes with numerous signaling pathways, as demonstrated above. IFN-β and IFN-γ play key roles in the immune response to viral infections. Suppression of these factors can increase susceptibility to viral infections, such as herpesvirus. Figure adapted from JAK inhibition as a therapeutic strategy for immune and inflammatory diseases (2).

Table 1. JAK inhibitor mechanisms.

	Cytokines	IL-2, IL-4, IL-7, IL-9, IL-15, IL-21	IL-13	IL-3, IL-5, GM-CSF	EPO, TPO, G-CSF, GH, Leptin	IL-6, IL-11, LIF, OSM	IL-12, IL-23	IL-10	IL-19, IL-20, IL-22	IFN-β	IFN-γ
	JAK dimers	JAK1, JAK3	JAK1, JAK2, Tyk2	JAK2	JAK2	JAK1, JAK2, Tyk2	JAK2, Tyk2	JAK1, JAK2, Tyk2	JAK1, JAK2, Tyk2	JAK1, Tyk2	JAK1, JAK2
JAK1 Selective	Filgotinib	+	+	–	–	+	–	+	+	+	+
	Upadacitinib	+	+	–	–	+	–	+	+	+	+
Nonselective	Tofacitinib	+	+	+	+	+	+	+	+	+	+
	Baricitinib	+	+	+	+	+	+	+	+	+	+
	Ruxolitinib	+	+	+	+	+	+	+	+	+	+
	Oclacitinib	+	+	+	+	+	+	+	+	+	+

Outlines the cytokines that are inhibited by different JAK inhibitors. Selective JAK inhibitors only block the signaling of cytokines for which that specific heterodimer is associated. Nonselective JAK inhibitors block the activity of multiple different JAK heterodimers, and thus, interfere with the signaling of numerous cytokines.

JAK inhibitors are associated with an increased risk of herpesvirus infection (9,10). While JAK inhibitors may potentially increase the risk of all herpesviruses due to their modifying effect on the immune system, the literature to-date has largely focused on the risk and incidence of herpes zoster infection in the setting of JAK inhibitor use for an array of autoimmune conditions (11). In the context of rheumatoid arthritis and ulcerative colitis, two of the most common diseases treated with JAK inhibitors, there is an increased risk of herpes zoster during JAK inhibitor therapy (9,10,12,13). The risk of infection associated with JAK inhibitor use and herpes simplex virus 1 and 2 has not been studied as extensively. However, the combined incidences of herpes zoster and herpes simplex virus in rheumatoid arthritis patients treated with tofacitinib was higher than with anti-tumor necrosis factor monoclonal antibodies (14). Patients treated with tofacitinib had crude incidences of 3.87/100 patient-years for herpes zoster and 3.74/100 patient-years for herpes simplex virus, totaling a combined incidence of 7.61/100 patient-years. This was greater than the combined incidence rates for abatacept, rituximab, etanercept, and tocilizumab which ranged from 4.96-6.27/100 patient-years (14). In addition, two case reports have documented herpes simplex virus reactivation in patients on JAK inhibitors, resulting in severe disseminated disease during treatment for myelodysplastic syndrome and rheumatoid arthritis (15,16).

JAK inhibitors are emerging as a treatment for atopic dermatitis, a chronic inflammatory condition of the skin (17,18). Patients with atopic dermatitis have an increased risk of infection due to skin defects, immune dysregulation, predominant staphylococcus aureus colonization, and decreased commensal bacteria of the skin flora (19). The herpesviridae family of viruses are of particular concern, with an increased risk of herpes zoster in patients with severe atopic dermatitis (20). One of the most common and severe microbial infections associated with atopic dermatitis is disseminated infection with herpes simplex virus resulting in eczema herpeticum (21). Instead of being confined to a single area, eczema herpeticum presents with diffuse vesicular rash, fever, and lymphadenopathy (22). Eczema herpeticum occurs in approximately 3% of patients with atopic dermatitis, and this condition has a mortality rate of up to 10% when left untreated or when it occurs in immunocompromised individuals (23–25). An increased risk of herpes virus infections also occurs in patients being treated with JAK inhibitors for atopic dermatitis (26,27). Baricitinib increases the risk of herpes zoster and herpes simplex when used in the treatment of atopic dermatitis (26–29). Although the exact magnitude of the risk is not well characterized, cases of eczema herpeticum have occurred in multiple JAK inhibitor therapy trials (30–33). While JAK inhibitors are highly effective treatments for atopic dermatitis, the increased risk of infection or reactivation of latent disease including herpes virus outbreaks may be of particular importance in this population due to the propensity of patients with severe atopic dermatitis to develop eczema herpeticum (12,34,35). Thus, there may be utility in the preventative use of antivirals during the treatment of atopic dermatitis with JAK inhibitors in order to decrease morbidity and mortality from this condition.

Outbreaks of eczema herpeticum are typically treated with acyclovir or valacyclovir. Valacyclovir is a prodrug of acyclovir that enhances its bioavailability and is rapidly converted to acyclovir when ingested orally (36). Acyclovir is a DNA polymerase inhibitor that treats eczema herpeticum, oral and genital herpes simplex virus infections, and herpes zoster (37). Mild cases of eczema herpeticum can be treated with oral acyclovir or valacyclovir for 7 to 21 days which typically results in an improvement in symptoms and healing of their lesions. Severe cases or outbreaks in those who are significantly immunocompromised receive intravenous acyclovir or valacyclovir until lesions start to crust, after which point they can be transitioned to an oral formulation (38).

In addition to being effective treatment, valacyclovir and acyclovir are safe and well-tolerated drug with no associated toxicities and minimal adverse effects aside from crystalluria and increased creatinine levels (37,39,40). The risk of these side effects can be mitigated with fluid administration prior to taking acyclovir and adjustment in acyclovir dosage according to renal function (41). An ability to prevent reactivation of herpes simplex virus and herpes zoster coupled with this tolerability make valacyclovir and acyclovir options for prophylaxis in patients needing long-term suppression due to severe or recurrent outbreaks or extreme immunosuppression (39,40,42,43). The use of valacyclovir or acyclovir for prophylaxis in patients at risk of eczema herpeticum specifically has not yet been studied. Valacyclovir and acyclovir are equally efficacious in the treatment and prophylaxis of herpes simplex virus, but valacyclovir requires less frequent dosing due to the increased bioavailability (44–46). Twice daily dosing of 500 mg of valacyclovir effectively prevents herpes simplex virus reactivation (47,48). A 15-day supply of this dosage could be obtained for $11 (49). Prophylaxis to prevent eczema herpeticum in patients with atopic dermatitis being treated with a JAK inhibitor may only be needed until clinical improvement occurs (reducing the risk of eczema herpteticum), which may occur in as little as four weeks depending on the agent used and the patient’s response (50).

Given the increased risk of herpes virus infection associated with JAK inhibitor use, the potentially devastating effect a case of eczema herpeticum could have in patients with atopic dermatitis, the effectiveness of acyclovir in preventing herpes simplex virus outbreaks, and the relatively benign side effect profile associated with acyclovir, prophylactic use of acyclovir (or valacyclovir) in patients with atopic dermatitis may be considered when beginning therapy with JAK inhibitors. This may be especially beneficial for patients that already have an established history of herpes simplex virus infection with recurrent and/or severe outbreaks.

Disclosure statement

Dr. Feldman has received research, speaking and/or consulting support from a variety of companies including Galderma, GSK/Stiefel, Almirall, Leo Pharma, Boehringer Ingelheim, Mylan, Celgene, Pfizer, Valeant, Abbvie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate and National Psoriasis Foundation. He is founder and majority owner of www.DrScore.com and founder and part owner of Causa Research, a company dedicated to enhancing patients’ adherence to treatment. Milaan Shah, Katherine Beuerlein, and Dr. Joseph Jorizzo have no conflicts to disclose.