Warts and all
Remedies for warts abound, but high-quality studies are lacking.
Feature
By Jan Bowers, contributing writer, March 1, 2021
Warts, one of the most common skin disorders worldwide, can be easy to treat or maddeningly difficult. Although warts can resolve spontaneously, others readily respond to over-the-counter treatments such as topical salicylic acid or duct tape occlusion. Warts in patients presenting to the dermatologist may require more aggressive therapy, and a stubborn subset, dubbed by one dermatologist the “nine-headed monster,” resist just about every treatment the dermatologist can throw at them.
Cutaneous warts, known as verrucae vulgaris, appear in as many as 30% of the general population and more than 77% of immunocompromised individuals (J Am Acad Dermatol. 2019; 81(5):1127-33). A variety of human papillomavirus (HPV) types can cause warts. Infection can occur at any age, but warts are most common in children and young adults. Although benign, common warts can cause discomfort and emotional distress, and deep plantar warts can be extremely painful.
Dermatologists have a broad range of treatment options to offer their patients, but almost none that are FDA-approved for warts, and very few that are supported by high-quality evidence from clinical trials. As a result, they must rely on their own clinical observations and the advice of their peers, as well as the available literature, to determine the optimal approach for each patient. Given the rate of spontaneous cure, the best approach, particularly in young children, may be non-intervention, said Elaine Siegfried, MD, professor of pediatrics and dermatology at St. Louis University School of Medicine. “I always counsel parents who bring their children for wart treatment about the cause and natural history of warts, as well as spectrum of options. Because none of the treatments are 100% effective, I classify them by degree of associated discomfort, because that is the most important factor for most children. My motto is: Never recommend a treatment that is worse than the disease. I would really like dermatologists to appreciate the risks of treating children, which include emotional trauma.” Patients with widespread, disfiguring warts, including immunocompromised children, are a unique subset that may deserve a more aggressive approach, although efficacy of all options may be lower, she added.
DermWorld spoke with four dermatologists who discussed current therapies for common (non-genital) and plantar warts, their effectiveness, and potential new avenues of treatment.
Topical treatments
Topical therapy for warts encompasses a variety of agents that destroy the infected epithelium, as well as those that stimulate an immune response to attack the virus. Salicylic acid, long considered a first-line treatment, is available over the counter in concentrations up to 40%, and in a 70% preparation available by prescription. Unlike many other wart therapies, its use is supported by some level 1 evidence. In the publication of its 2014 guidelines for the management of cutaneous warts (Br J Dermatol. 2014;171:696-712), the British Association of Dermatologists (BAD) cites a 2011 meta-analysis of five studies showing that warts treated with salicylic acid (all preparations) were 1.6 times more likely to clear than those treated with placebo.
Many dermatologists combine salicylic acid with other topical agents to boost its destructive properties. Paring and/or freezing the wart is the preferred first-line treatment for Stephen K. Tyring, MD, PhD, clinical professor of dermatology at the University of Texas Medical School at Houston and director of the Center for Clinical Studies. But for patients, especially young children, who resist liquid nitrogen, Dr. Tyring starts with an application of cantharidin, which is painless at the time of application. “There’s the regular cantharidin, and then there’s the cantharidin with two other ingredients, salicylic acid and podophyllum,” he said. “So I offer that, and tell them that between visits you can use Dr. Scholl’s salicylic acid patch, or a generic version. Another one of my favorite compounds that’s a little stronger is 5-fluorouracil with salicylic acid.” Dr. Tyring warned that even the stronger topical agents may be of limited efficacy against “the really challenging areas of thick verruca vulgaris or the majority of plantar warts.”
Cantharidin may soon have the distinction of joining salicylic acid as one of the few FDA-approved treatments for warts. Verrica Pharmaceuticals Inc. in late December resubmitted an application for approval of its cantharidin preparation, VP-102, as a treatment for molluscum, and noted in its announcement that it has successfully completed separate Phase 2 studies of VP-102 for the treatment of common warts and external genital warts.
Topical cidofovir often works “when everything else fails,” Dr. Tyring maintained. Compounded in a 3% cream for verrucae vulgaris and 5% for a plantar wart, applied daily for two to four weeks, will generally yield “a dramatic response. It works best if you debulk the wart first; the patient can pare it down between applications at home, as long as they don’t elicit pain or bleeding.” This treatment may be limited by high out-of-pocket costs.
Other topical agents that have shown some success against warts include off-label use of hydrogen peroxide, imiquimod, retinoic acid, and compounded contact sensitizers such as squaric acid dibutyl ester and diphenylcyclopropenone (DCP). Dr. Siegfried uses DCP in her young patients who resist cryotherapy and have widespread or persistent warts. “DCP is relatively inexpensive, about $70 a bottle in my area, which will last for several months. Also, it’s not photolabile, like squaric acid,” she noted. Sensitizer treatment is associated with minimal discomfort; the major risk is a blistering reaction, which can be avoided with careful use. “I saw a recent patient who had developed severe blistering after daily application as advised by his inexperienced dermatologist. DCP triggers a delayed hypersensitivity response so it is generally applied only about once a week. Because this is not an FDA-approved, commercially available product, safe and effective use is generally learned from clinician mentors and honed over time. Like surgical skills, it is not learned by reading a textbook.”
Paging Dr. Scholl: Do OTC remedies really work?
Patients have been self-treating their warts for centuries with creative, sometimes highly complex folk remedies. Today, patients can turn to homeopathic and over-the-counter treatments before consulting a physician for their warts, but evaluating the effectiveness of those treatments is difficult, said John Barbieri, MD. “The most common over-the-counter treatments, like salicylic acid, do work about 20-60% of the time, depending on the study, but many warts get better on their own, which poses a challenge in evaluating the effectiveness of any wart treatment: You don’t know if the treatment did it or they just got better because they were going to anyway.”
Salicylic acid, cryotherapy, and duct tape occlusion are commonly used over-the-counter remedies for warts. Pediatric dermatologist Elaine Siegfried, MD, recommends salicylic acid to patients who prefer not to undergo in-office cryotherapy. “If they refuse cryotherapy, and have few warts, I recommend over-the-counter salicylic acid,” she said, adding that proper use is critical to success. “Most people who we see in the office who have used over-the-counter salicylic acid haven’t used it frequently enough or for long enough to get the full benefit. Most don’t read the fine print on the directions.”
Dr. Barbieri remarked that salicylic acid is “a great over-the-counter treatment, and it never hurts to start with that,” but he doesn’t encourage patients to try OTC cryotherapy treatments “because they don’t get cold enough. Our in-office freezing treatments are -200˚C and many OTC ones are closer to -10˚C to -25˚C. They’re not as strong and they don’t work as well as the in-office ones.”
Another home-based remedy, covering a wart with duct tape, has yielded inconsistent results in clinical trials. An early trial of duct tape occlusion (Arch Pediatr Adolesc Med. 2002; 156: 971-4) compared the efficacy of common silver duct tape applied to the wart for a maximum of two months with that of cryotherapy (10-second treatments every two to three weeks, with a maximum of six treatments). Of the 51 patients completing the study, 22 of the 26 treated with duct tape (85%) and 15 of the 25 treated with cryotherapy (60%) had complete resolution of their warts. The British Association of Dermatologists (BAD) guidelines cite a number of studies with widely varying results, remarking that “although these studies have not confirmed a definite effect of occlusion on warts, there is the possibility that an effect may occur in children.”
Finally, Dr. Siegfried discusses certain natural remedies with her patients “because they’re cheap, easy, and safe. My recent favorite has been garlic, which has been used for centuries in traditional Chinese medicine. Cut a clove of garlic in half and rub it on the wart every night. Tape occlusion may help, but be sure to caution patients about the risk of local inflammation or even erosion. Hold treatment for a few days if it hurts.”
Cryotherapy
Like Dr. Tyring, many dermatologists turn to freezing the wart as their first-line therapy. “I think it’s the basic mainstay of treatment, especially when combined with salicylic acid, either over the counter or compounded with 5-FU,” said John Barbieri, MD, dermatology research fellow at the Perelman School of Medicine at the University of Pennsylvania. “That tends to work for about 50-80% of patients, and the key is persistence. It often takes multiple sessions, and if you get the wart 90% better but don’t completely cure it, it may come back.”
The BAD guidelines note that factors such as freeze time, mode of application, and intervals between treatment can vary among different practitioners, adding that “paring before cryotherapy can improve results in plantar warts, but not hand warts.” The guidelines note that evidence of cryotherapy’s effectiveness from randomized trials “is highly variable, ranging from 0% to 69% with a mean of 49%.” Two recently published trials comparing cryotherapy with salicylic acid indicate that cryotherapy “gave equivalent or improved rates of cure when compared with salicylic acid.”
Intralesional treatment
Another method of attacking a wart involves injecting a therapeutic agent into or near the lesion, an approach usually reserved for recalcitrant warts. Bleomycin, a cytotoxic agent used in chemotherapy, has been used to treat warts for 40 years, according to the BAD guidelines. The guidelines note that open studies of injected bleomycin “have suggested clearance rates of approximately 20-90% of treated warts with one or more treatments, with most reporting a patient response rate of approximately 65-85%.” Dr. Tyring remarked that bleomycin “is quite painful, and when over-injected it can cause necrosis of a lot of normal skin; therefore, it has to be used very conservatively and carefully.”
Injection of Candida and other antigens, such as vaccines for tuberculosis, mumps, and Hepatitis B, are forms of immunotherapy that are non-specific to the HPV. “Candida can be like magic; when it works, it’s really amazing and helpful,” said Dr. Barbieri. “The problem is, for many patients it doesn’t work; it just doesn’t trigger an immune response to help fight the wart.” Intralesional cidofovir also works “like magic,” with a response rate bordering on 100%, Dr. Barbieri said. He and his colleagues conducted a retrospective study of patients with recalcitrant warts treated with intralesional cidofovir at the University of Pennsylvania, finding that most patients’ warts resolved after three to four treatment sessions. In his own experience, Dr. Barbieri said he’s found cidofovir to be effective in immunosuppressed patients with multiple warts and in patients with difficult, refractory palmoplantar warts. The downside, he pointed out, is that cidofovir is expensive, difficult to procure, and available only in a large vial (enough to treat 25 patients) but it is only single-use. The shelf life of an opened vial, he said, is unknown since it is not intended to be stored that way. “These treatments can be really helpful; they’re just difficult,” he said. “My hope is that we can make it more accessible to patients in the future, maybe by getting it packaged more appropriately for use in the dermatology clinic.”
Surgical and laser treatments
In a Medscape article on non-genital warts, dermatologist Philip D. Shenefelt, MD, writes that “although electrodesiccation and curettage may be more effective than cryosurgery, it is painful, more likely to scar, and HPV can be isolated from the plume. Avoid using surgical excision in most circumstances because of the risks of scarring and recurrence.”
Pulsed dye, carbon dioxide, and Nd:YAG lasers are also used to destroy warts. A recent study comparing treatment with the long-pulsed Nd:YAG laser with cryotherapy concluded that the overall therapeutic effects of LP-Nd:YAG laser were similar to cryotherapy, but laser may be more effective in treating relatively recalcitrant warts and may be associated with shorter time to clearance of warts. In Dr. Barbieri’s view, “it’s just a more expensive, ‘fancier’ way to do what freezing does, with the potential risk of creating a plume of the wart virus.”
Looking ahead
The development of a vaccine for nine HPV types (none of which are linked to common or plantar warts) may point the way to more effective immunotherapy for warts, said Dr. Tyring. He noted that in testing the vaccine, Gardasil® 9, “some people who got the vaccine got rid of their non-genital verrucae vulgaris, and probably rarely, of plantar warts. These are more case reports than trials.” If the manufacturer would sponsor a trial “where we could administer the vaccine a little closer to the verrucae vulgaris and see if we could elicit an elimination of the warts in reproducible numbers that would make it statistically significant, it would be worthwhile doing,” he maintained. “But so far I haven’t gotten them to sponsor such a trial, and I don’t think anyone else has either.” Dr. Tyring said he is also interested in testing the adjuvant in Gardasil 9 by treating an equal number of patients with a similar number of warts, “half getting the adjuvant and half getting the vaccine. Because it may be just the adjuvant that’s helping the body recognize that HPV is there.”
Another promising path for research lies in better understanding how warts evade the immune system. Wesley Yu, MD, assistant professor of dermatology at Oregon Health & Science University School of Medicine, was motivated as a resident to investigate the recalcitrant warts that drove patients to endure painful treatments for years. “We decided to look at immune checkpoints because that’s become extremely relevant for cancer treatment,” Dr. Yu explained. “We thought: maybe HPV is hijacking the same system that cancers do in order to evade the immune system.”
With Drs. Timothy Berger, Jarish Cohen, Jeffrey North, and Zoltan Laszik at the University of California, San Francisco, Dr. Yu examined 44 biopsies of cutaneous warts (30 common warts, 14 myrmecia). “We stained for PD-1, PD-L1, and immune cell markers, and found that PD-L1 was expressed by a majority of warts, and that seems to be a signal that the lymphocytes were responding to, because they were expressing the receptor to PD-L1.” If warts are in fact using PD-L1 to escape the immune system, he pointed out, “we might be able to use things like topical immune checkpoint inhibitors or develop ways to block PD-L1 expression upstream without using a checkpoint inhibitor in order to help the immune system recognize these warts.”
Topical PD-L1 inhibitors aren’t yet available, Dr. Yu noted, “but there are some labs that are working on developing them. It’s a tough subject to research, but there are some real nuggets in there that hopefully will help us crack not only viruses, but also cancer immune activation.” Commenting on Dr. Yu’s research in Medscape, Graeme M. Lipper, MD, wrote that “given the exorbitant price and potential systemic toxicity of checkpoint inhibitors, such as pembrolizumab and nivolumab, these drugs won’t find practical use treating warts in the immediate future. Nevertheless, as new and hopefully cheaper and safer (topical?) drugs are developed to exploit the immune checkpoint pathway, we may gain a powerful new weapon to slay the nine-headed wart monster.”
