Exacerbation of human papillomavirus infection with initiation of upadacitinib for atopic dermatitis

Introduction

The treatment landscape for atopic dermatitis (AD) has drastically changed over the past decade, with the introduction and approval of promising new treatments. These include biologic agents, such as dupilumab, an interleukin (IL) 4 and IL-13 inhibitor and tralokinumab, an IL-13 inhibitor, as well as targeted Janus kinase 1 (JAK-1) inhibitor therapies, such as upadacitinib and abrocitinib.¹ These new treatments are recognized for their increased effectiveness and relatively mild side effect profiles compared with traditional systemic immunosuppressive agents, such as corticosteroids, methotrexate, and cyclosporine.¹ Upadacitinib, in particular, was approved for the treatment of moderate-to-severe AD by the Food and Drug Administration in January 2022.² There remains a paucity of literature regarding emerging side effects associated with this second-generation selective JAK-1 inhibitor in the real-world clinical setting. Herein, we present an otherwise healthy young adult with a longstanding history of treatment-resistant AD, who was started on upadacitinib, and 2 months later presented with multiple flat warts distributed diffusely across his face.

Case report

A 20-year-old man was followed by dermatology for management of his longstanding severe AD. His medical history was otherwise unremarkable with no known comorbidities, and at baseline, he had dry skin with skin phototype 4. Given the treatment-resistant nature of his AD, he had initially trialed dupilumab for almost 3 years. Despite notable improvements, he continued to experience intermittent AD flares. During this timeframe, he also briefly developed flat-topped skin-colored verrucous lesions, located exclusively on his face, which were consistent with human papillomavirus (HPV) flat warts. The patient was counseled on ways to limit the spread, including avoiding shaving. The warts were treated with sinecatechins 10% ointment, applied 3 times daily to the affected areas for 16 weeks, and partially resolved. Furthermore, although he had been known for bilateral conjunctivitis prior to receiving dupilumab, he experienced severe worsening of his conjunctivitis while on the biologic, which required monitoring by ophthalmology.

In the context of the incomplete AD resolution and worsened conjunctivitis, a collaborative decision was made with the patient and his ophthalmologist to switch to upadacitinib. As such, he completed the baseline investigations for upadacitinib, which included a complete blood count; electrolytes; creatinine; liver enzymes; QuantiFERON-TB Gold; and hepatitis A, B, and C serologic testing, which were all within normal limits. He had a remote history of shingles on his face twice in the past, and, given the documented risk of developing shingles while receiving upadacitinib, he received 2 doses of the shingles vaccine and was started on a lower dose of upadacitinib 15 mg orally per day. The dupilumab was discontinued on starting upadacitinib. During his first 2 months on upadacitinib, his AD improved notably and his conjunctivitis resolved. However, he developed significant worsening and spread of his HPV flat warts diffusely all over the face (bilateral cheeks, chin, forehead, submental area); prior to starting upadacitinib, he had 3 flat warts in total that were distributed between the right cheek and left side of the chin. He tried applying sinecatechins 10% ointment to the warts every morning and 0.025% tretinoin in an emollient cream base every evening. He was motivated to also continue the upadacitinib, despite the warts, given the dramatic improvement in his AD. The warts continued spreading to his forehead, cheeks, and across his chin (Fig 1), and he was started on imiquimod 5% cream every evening for 8 weeks.

Fig 1.

20-year-old patient with diffusely distributed facial flat warts that developed 2 months after starting upadacitinib around the (A) forehead, (B) left side of the superior aspect of the chin, (C) cheek on the right side, and (D) submental area.

The imiquimod helped improve the smaller warts, but had no effect on larger lesions, so his course of imiquimod was extended by 5 weeks, with limited improvement. He subsequently tried applying tazarotene 0.045% lotion nightly ×2 applications, which remarkably cleared the remaining warts within 5 days, and he has not developed any new warts since then.

Discussion

Sustainable and effective treatment for moderate-to-severe AD has historically been recognized as challenging due to the limited treatment options available. The treatment of AD is further complicated by patients’ increased propensity for systemic comorbidities, including bacterial and viral skin infections.³ Since 2017, the Food and Drug Administration has approved promising new treatments, including biologic agents, such as dupilumab and tralokinumab, and targeted therapies, such as upadacitinib and abrocitinib.¹ Biologics, which target the Th2 cytokine pathway in AD by blocking specific IL signaling, are recognized for particularly mild side effect profiles and improved effectiveness compared with classical systemic treatments.¹ More recently, approved targeted JAK-1 selective inhibitors are powerful agents that inhibit the JAK/STAT pathway to decrease the production of proinflammatory cytokines that contribute to the AD pathogenesis.⁴ JAK-1 inhibitors, when compared with biologics, have been shown to have greater effectiveness but a broader immunosuppressive profile.^4,5 Literature has suggested that JAK-1 inhibitors contribute to impairments in interferon-mediated antiviral responses, which can increase susceptibility to viral infections.⁴ In phase III trials, upadacitinib was more commonly associated with upper respiratory tract infections compared with dupilumab and a small percentage of patients developed eczema herpeticum or herpes zoster.²

Our patient received shingles vaccines prior to starting upadacitinib, given his history of remote shingles infections, and, fortunately, has not developed shingles. However, he experienced an exacerbation of his HPV infection involving flat warts on his face. The clinical examination and patient’s self report suggested that the distribution of warts was limited to his face and he endeavored to limit the spread by avoiding shaving. To our knowledge, HPV outbreaks have not been previously cited as a side effect associated with JAK inhibitors including upadacitinib, abrocitinib, or tofacitinib, nor have they been systematically studied. Although the warts were relatively resistant to several treatments, including sinecatechins 10% ointment, 0.025% tretinoin in an emollient cream base, and imiquimod 5% cream, they responded quickly and completely to tazarotene 0.045%. A greater understanding of the pathogenesis of the upadacitinib-induced HPV exacerbation may help inform more effective and prompt management of the resultant flat warts.

This case highlights the risk of significant spread of HPV flat warts associated with the initiation of upadacitinib. Ongoing research regarding upadacitinib in a clinical setting will be valuable to eliciting the incidence of this side effect and other uncommon side effects to help determine patient suitability for this targeted treatment.

Conflicts of interest

Dr Gavigan has received honoraria from Amgen, AbbVie, Bausch, Beiersdorf, CeraVe, Galderma, Lilly, Medexus Pharma, Novartis, L’Oreal, Pfizer, Sanofi Genzyme, Sun Pharma, UCB, and Valent. Author Seale has no conflicts of interest to declare.