Rapid Resolution of Diffuse Warts Following Initiation of Dupilumab for Severe Atopic Dermatitis

In this featured article with The Dermatologist, Dr Ilka Netravali shared insights from her study, “Rapid Resolution of Diffuse Warts Following Initiation of Dupilumab for Severe Atopic Dermatitis.”¹

Ilka Arun Netravali, MD, PhD, FAAD, is a dual board-certified dermatologist and pediatric dermatologist at Pediatric Dermatology of North Texas. She works alongside Dr Fred Ghali to direct the nation’s only multi-location exclusively pediatric dermatology practice and also serves as the Director of Clinical and Translational Research.

How commonly are cutaneous warts found to co-occur with other diseases of immune dysfunction such as atopic dermatitis (AD)?
 

Cutaneous warts caused by human papillomavirus (HPV) are a relatively common viral infection, but there is surprisingly limited epidemiologic data regarding their occurrence, with studies in children in the United States and globally suggesting a prevalence of about 3% to 4% in most data sets, and with a peak at 9 to 10 years of age. 

It is conventionally accepted that the combination of immune dysfunction and barrier disruption that characterize AD increases the propensity for skin infections, including Staphylococcus aureus, molluscum contagiosum, and eczema herpeticum. One would, therefore, also expect patients with AD to be predisposed to developing cutaneous warts. European cohort studies, however, have actually demonstrated a lower prevalence of warts in children with active AD vs those without AD. Interestingly, a more recent large-scale, US population-based survey indicated a higher prevalence of warts in children with AD and other atopic disorders, such as asthma, hay fever, and food allergy, compared with those without AD, but a slightly lower prevalence in patients with AD alone. It seems then that AD may increase propensity for wart infection but, in particular, when co-occurring with additional atopic disease. In the same investigation, the subset of children with AD and warts also had a higher number of extracutaneous infections and increased rates of other atopic disorders, implying that the presence of warts in patients with AD may be linked to additional immune aberrancy and barrier impairment in these patients. 

Cutaneous warts typically resolve within 2 years regardless of therapy, and AD does not appear to impact time to resolution. However, having severe or recalcitrant warts, such as failure to respond to 5 treatments over a period of 6 months, should raise suspicion for immunodeficiency, and especially for defects in the T-cell and NK-cell compartments that are instrumental in the host defense against HPV. This includes in the setting of infection, as with HIV, immunosuppression following organ transplantation, and inborn errors of immunity (IEI). 

Some key IEIs in which cutaneous warts are among the defining features include rare genodermatoses, such as epidermodysplasia verruciformis (EV); warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome; and hyper-IgE syndrome (HIES). EV is characterized by mutations in EVER transmembrane proteins that restrict HPV viral replication and gene expression. At least 19 different HPV genotypes have been found in affected patients who classically develop generalized warts in infancy, and at least one-third have malignant transformation into squamous cell carcinomas. In WHIM syndrome, there is a defect in neutrophil release from the bone marrow, and the clinical hallmark is numerous warts along with recurrent bacterial pulmonary, gastrointestinal, and cutaneous infections. Deficiency of DOCK8 in some patients with HIES leads to T-cell homing, polarization, and activation defects, which manifests as recurrent sinopulmonary infections, staphylococcal skin abscesses, AD, and severe cutaneous viral infections, with 62% of patients afflicted with significant warts. These patients also have increased risk of lymphomas and squamous cell carcinomas. 

What is the mechanism of action behind dupilumab, as an IL-4 receptor alpha-blocking monoclonal antibody, used to treat severe AD and diffuse filiform warts?
The pathogenesis of AD is multifactorial, instigated by epidermal barrier dysfunction that ultimately promotes T helper 2 (T_H2) inflammation, which is the immunologic hallmark of disease. T_H2 cells produce key cytokines, IL-4 and IL-13, that are instrumental in mediating key processes that drive allergic and atopic responses, including immunoglobulin class-switching to IgE and mast cell priming. Dupilumab selectively blocks the common alpha subunit of IL-4 and IL-13 receptors, which translates to effective suppression of atopic disease. 

While AD is characterized by T_H2 pathway activation, a productive antiviral immune response against warts necessitates the activation of T helper 1 (T_H1) and cytoxic T-cell function. Concurrent with dupilumab’s attenuation of the T_H2 axis, there may be skewing toward T_H1 function. In recent ex vivo studies, T-cells from patients with AD treated with dupilumab have been shown to produce increased levels of the prototypical T_H1 antiviral cytokine IFNɣ compared to those from healthy controls. Interestingly, this is most pronounced within the first 4 weeks of treatment, which also corresponds to when patients first note improvement in AD symptoms, such as decreased xerosis, implying an improved barrier function. It is therefore possible that dupilumab augments the host defense against cutaneous warts not only by facilitating the T_H1 immune response, but also by restoring epithelial integrity to thwart HPV entry. 

Of note, a recent case report showed resolution of untreated warts in a pediatric patient with AD after 16 weeks of dupilumab. The patient in our case had significantly more rapid improvement with full clearance at 6 weeks, but had also received additional treatments for her warts. We had administered 1 dose of intralesional Candida antigen 2 weeks after her first dupilumab injection and also recommended oral cimetidine, although she was poorly compliant with the latter. Studies of intralesional Candida antigen suggest it takes approximately 3 to 4 injections at 3-week intervals to achieve appreciable wart clearance, while randomized controlled trials of cimetidine have been underwhelming. Both intralesional Candida antigen and cimetidine are thought to promote T_H1 activation, however, and it is possible that dupilumab potentiated these effects to foster the remarkably brisk and complete wart resolution in our patient. 

What should physicians consider when treating patients with AD and cutaneous warts?
AD and cutaneous warts are both common pediatric dermatologic conditions. As alluded to earlier, warts may occur more frequently in some patients with AD, specifically when the weakened epithelial barrier of AD is accompanied by additional atopic disease, such as asthma, allergic rhinitis, or food allergy. 

However, when warts are widespread, recurring, or recalcitrant, it is important to consider whether a patient may have additional immune dysfunction such as in the form of IEIs, which are often genetic disorders diagnosed in childhood. In these individuals, it is crucial to conduct a thorough history and physical examination. This includes assessing for frequent and severe infections, with particular attention to the type of pathogen, for example, bacterial, viral, fungal, or opportunistic, and location of disease, such as sinopulmonary, gastrointestinal, or dermatologic, as well as for autoimmunity, malignancy, and atopy. 

Regarding the latter, eczematous rashes and warts co-occur in specific IEIs, including Netherton syndrome (NS), Wiskott-Aldrich syndrome (WAS), and DOCK8-deficient HIES. NS is an autosomal recessive disorder distinguished by the combination of congenital ichthyosiform erythroderma, trichorrhexis invaginata (bamboo hair), and atopy, along with increased susceptibility to viral warts. WAS is an X-linked IEI identified by the triad of eczema, thrombocytopenia, and pyogenic infections, and less commonly, with intractable warts. Our patient who presented with abundant atopic disease in the form of AD, asthma, allergic rhinoconjunctivitis, and food allergies, as well as with numerous warts, raised concern for DOCK8-deficient HIES. 

For patients with suspected IEI, the next step is focused laboratory and genetic testing to help identify the specific disease and immune defect. Laboratory studies may include serum immunoglobulin levels, complete blood cell count with differential to enumerate immune cell types, T-cell stimulation assays to evaluate T-cell function, complement studies, and flow cytometry to quantify B- and T-cell subsets. The results will help guide genetic testing and confirm a diagnosis. 

Expeditiously diagnosing IEIs is critical to allow for initiation of tailored care, which is often optimized with help from our infectious disease and allergy/immunology colleagues. Doing so helps reduce the morbidity and mortality of these diseases, which are often associated with failure to thrive and long-term risk of malignancy.

Are there any tips or insights you would like to share with your dermatologist colleagues regarding dupilumab utilized for AD and cutaneous warts?
The skin of patients with AD is often dry, pruritic, cracked, eroded, and inflamed. As a result, when these patients develop warts, and especially when the warts overlap eczematous lesions, it becomes difficult to tolerate many of the typically employed therapies. These interventions are largely destructive and include chemical treatments, such as salicylic acid and 5-fluorouracil, and physical modalities such as cryotherapy. They work by inducing epidermal damage, but also cause pain, burning, and blistering, and frequently require multiple treatment sessions, which is particularly untenable when there are multiple lesions to treat, and even more so in the context of the already weakened epithelial barrier of AD. 

In these patients, I consider immunotherapy, for example, intralesional Candida antigen, as was initiated in the patient from our case. It is important, however, to make sure patients understand that this approach often takes 3 to 4 treatment sessions spaced roughly 3 weeks apart; it is not superior to the destructive therapies; and as with destructive therapies, efficacy is not 100%. 

And so, with all of my patients with cutaneous warts, the discussion starts with whether to pursue treatment, and focuses on weighing the pain, functional impairment, and emotional distress associated with cutaneous warts with the discomfort and lack of guaranteed success associated with therapeutic intervention. I also emphasize that nonintervention and an expectant approach to management are reasonable, especially in immunocompetent individuals, in whom spontaneous resolution often occurs within 2 years. 

For patients with severe AD who want to proceed with treatment for their cutaneous warts, but are not candidates for destructive therapy, our case in which rapid resolution of warts occurred 6 weeks after dupilumab initiation is certainly noteworthy. It is an isolated report, however, and dupilumab’s effects on wart clearance, which may be mediated through skewing from a T_H2 to T_H1 immunological response, as well as through an improvement in skin barrier function, remains to be fully elucidated. Randomized, placebo-controlled studies to further explore the nature, efficacy, and safety of dupilumab in this context, both with and without adjunctive therapies, are clearly warranted. It will also be interesting to investigate how the numerous other immunomodulating therapies being employed for AD, including injectable biologics targeting IL-13, like tralokinumab, as well as topical and oral Janus kinase inhibitors, such as ruxolitinib, abrocitinib, and upadacitinib, may impact warts. Without such data regarding dupilumab, however, it is difficult to recommend it outright solely for the treatment of cutaneous warts. That being said, for patients with severe or recalcitrant AD or other conditions for which dupilumab is indicated, having concomitant cutaneous warts, may make dupilumab an ideal treatment choice.

Reference
1. Netravali IA, Sockler PG, Heimall J, Treat JR. Rapid resolution of diffuse warts following initiation of dupilumab for severe atopic dermatitis. Pediatr Dermatol. Published online September 8, 2023. doi:10.1111/pde.15414