<scp>JAK</scp> inhibitors: Unveiling varicella and herpes risks in atopic dermatitis

Advances in understanding the pathogenesis of inflammatory and immune-mediated diseases have opened new doors for therapeutic interventions. Among the most important discoveries is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, which plays a central role in the signaling mechanisms of inflammatory cytokines and various growth factors. The Food and Drug Agency approved the first JAK inhibitor, ruxolitinib, in 2011, followed by tofacitinib in 2012. Since then, numerous JAK inhibitors have received approval, expanding treatment options for rheumatological, oncological, gastroenterological, and dermatological conditions, among them, many inflammatory dermatological conditions. Beginning with rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease, the use of JAK inhibitors has rapidly expanded, now including emerging indications such as vitiligo, pyoderma gangrenosum, hidradenitis suppurativa, and refractory dermatomyositis besides atopic dermatitis (AD), psoriasis, and alopecia areata.1-5 The occurrence of severe and opportunistic infections in patients treated with JAK inhibitors represents a significant drawback of JAK inhibitors. JAKs facilitate signaling for various cytokines and hormones. They phosphorylate STAT proteins upon activation, causing them to dimerize and enter the nucleus to regulate target gene transcription. JAK inhibitors block this signaling pathway.2 Because of their immunomodulatory effect, JAK inhibitors have been implicated in adverse effects such as increased infection risk and cytopenia.1, 2 Although the mechanisms are not fully understood, JAK inhibitors impede T helper 1 maturation, which is crucial for immunity against intracellular pathogens.1 In this issue, Ireland et al.1 present key data on infection risks derived from meta-analyses of studies comparing JAK inhibitors to placebo. Their meta-analysis, which includes 40 randomized controlled trials, indicates no higher risk of serious or opportunistic infections with JAK inhibitors compared to a placebo. However, the findings suggest an increased risk of upper respiratory infections and varicella zoster infections in patients on JAK inhibitors, with no significant difference observed between agents and herpes simplex infections in individuals treated for AD (Figure 1).1 Previous studies indicated that impaired skin barrier and immune dysregulation in AD predispose patients to herpes zoster infections, regardless of biologic therapies, potentially placing them at greater risk when treated with JAK inhibitors.3 Consequently, the authors recommend vaccinating patients with non-live recombinant varicella zoster vaccine prior to or during treatment with JAK inhibitors.1, 4 They advise to remain alert for herpes simplex infections in patients with AD, particularly concerning Kaposi varicelliform eruption.1 Additionally, ordering baseline laboratory investigations before starting JAK inhibitor therapy is generally recommended to identify potential risks and adverse events.4 As the use of JAK inhibitors expands in treating various dermatological conditions, maintaining awareness of the risk of infections, especially in AD patients, is essential. Timely vaccination for varicella zoster, monitoring for herpes simplex infections, particularly in patients with AD, and regular follow-ups could help mitigate infection risks and enhance therapy with JAK inhibitors.