Treatment for recalcitrant plantar warts can be time-consuming and the options for treatment have differing levels of success. Accordingly, the authors share pearls and case studies from their clinical experience as well as insights from the literature on modalities ranging from topical agents and surgical excision to oral therapies and pulsed dye lasers.
The treatment of warts can be very challenging. Wart treatment is indicated for numerous reasons including irritation, pain, cosmetic embarrassment and risk of transmission. Many warts fail to respond to conventional treatment and after several months are considered recalcitrant. Recalcitrant warts require a more aggressive and focused treatment approach.
Accordingly, let us take a closer look at current and emerging modalities for recalcitrant warts.
Warts (verrucae) involve the epithelium of the skin and are caused by infection with the human papillomavirus (HPV). Warts are the most common viral infection of the skin, affecting 7 to 10 percent of the general population.1 Plantar warts are benign proliferations of epithelial cells on the soles of the feet. Plantar warts are most often caused by infection by HPV types 1, 2, 4, 60 or 63.1 The human papillomavirus thrives in warm, moist environments, such as public swimming pools and locker rooms, and transmits by direct contact, possibly through small cuts or abrasions in the stratum corneum layer of the skin.
Verrucae can spread locally by autoinoculation to develop at adjacent sites of viral infection. The spread of the virus is related to the patient’s immune status with more advanced lesions occurring in children and immunocompromised adults. There are several different types of plantar warts. Multiple, shallow, widespread lesions can coalesce to form mosaic warts. Myrmecia are deeply burrowing epidermal lesions that extend far below the skin surface and tend to be very painful. The hypothesis is that the lesions develop secondary to pressure on the skin surface.
There is no specific definition of recalcitrance but typically, recalcitrant warts are those that persist following several months of conventional treatment. Up to one-third of non-genital warts, especially plantar and periungual warts, become recalcitrant.2 Given that premalignant and malignant skin disorders, including squamous cell carcinoma and verrucous carcinoma, can present with characteristics similar to verrucae, one should perform a punch biopsy for histopathological diagnosis of any suspicious lesions or lesions that fail to respond to standard treatment regimens.
The treatment of plantar warts tends to be time consuming, costly and painful. Indeed, some modalities can lead to scar tissue formation. There is no single wart treatment that is 100 percent effective. There is a vast array of treatment modalities and the success rates vary significantly. Conventional treatment of warts frequently involves several ablative modalities including debridement, topical keratolytics (salicylic acid) and cantharone. These ablative agents often have the aid of occlusive dressings. Several treatment modalities, including topical medications, oral medication, nutritional supplements, intralesional injections and surgical excision, exist for the treatment of verrucae that fail to respond to conventional treatment.
Imiquimod (Aldara, Medicis). Imiquimod is an immunomodulatory agent that acts to enhance cell mediated immunity. The drug previously received approval for the treatment of several conditions including basal cell carcinoma, superficial squamous cell carcinoma and anogenital warts. Two studies have shown the effectiveness of imiquimod for the treatment of recalcitrant cutaneous warts.3,4 These studies showed daily application for five days per week for up to 16 weeks resulted in complete clearance of verrucae in 80 percent of immunocompetent patients.
5-fluorouracil (Efudex, Valeant Pharmaceuticals). Fluorouracil is an antineoplastic drug that inhibits thymidylate synthase causing cell death due to a lack of thymidine triphosphate, an essential precursor to DNA replication.5 Studies have demonstrated that fluorouracil has cure rates for cutaneous warts ranging from 50 to 95 percent.6,7 A meta-analysis of randomized controlled studies showed that the combination of 5-fluorouracil with 10% salicylic acid led to a threefold improvement in the cure rate of warts.8 The recommended use is 5% Efudex cream applied to verrucae two to three times daily for up to 12 weeks.
Bleomycin sulphate. Bleomycin is a glycopeptide produced by the bacteria Streptomyces verticillus, which has antiviral and antineoplastic actions. In their review of intralesional bleomycin for wart treatment, Lewis and Nydorf showed bleomycin cure rates ranging from 14 to 99 percent.9 The majority of studies show bleomycin to be an effective treatment in over two-thirds of reported cases with minimal side effects.9 The recommended dosage is 0.1-2.0 IU per lesion via an intralesional injection every two to four weeks.
Bleomycin injection can cause moderate to severe pain, secondary to the intralesional nature of the injection and due to the bleomycin compound itself. A local anesthetic block is recommended prior to the intralesional injection of bleomycin.
Candida antigen. Candida antigen intralesional immunotherapy is a newer modality for the treatment of recalcitrant warts that works by using the ability of the immune system to recognize fungal antigens. The hypothesis is that intralesional injection of Candida antigen creates a delayed type hypersensitivity reaction that increases the immune system’s ability to recognize and clear HPV.
Success rates range from 47 to 70 percent for intralesional immunotherapy with Candida antigen.10,11 Studies on the use of Candida antigen for the treatment of warts have additionally shown regression of warts at sites distant to the initial intralesional injection.10 This is a unique benefit that you don’t see with other treatment modalities. The recommended treatment is to administer the Candida skin test as a local injection every three to four weeks for an average of three treatments. Side effects include pain localized to the injection site and rare influenza-like symptoms.12
Interferon-alpha. Interferons are proteins that cells release in response to pathogens such bacteria, viruses or parasites. These proteins facilitate communication between cells to activate the immune system to eliminate the offending pathogen. Leukocytes produce interferon-alpha and it is involved in the immune response against viral infection. Researchers have shown that sublesional interferon-alpha injection is an effective treatment for verrucae. Aksakal and colleagues showed a single sublesional dose of 4.5 MU interferon-alpha is an effective treatment for plantar verruca lesions.13
Retinoids. Retinoids are a class of chemical compounds that are chemically related to vitamin A. As a wart treatment, retinoids are useful due to their ability to alter keratinization and induce irritant dermatitis. A study conducted by Gelmetti showed an 80 percent success rate of acitretin (Soriatane, Stiefel Laboratories) for the treatment of extensive warts in children.14 The recommended treatment for acitretin is 1 mg/kg per day for no more than three months.
In addition to the use of oral retinoids, there is fair evidence to support the use of topical retinoids for the treatment of recalcitrant warts.15,16 Gupta showed that weekly debridement and application of adapalene 0.1% gel (Differin, Galderma Laboratories), a topical retinoid, under occlusion resulted in complete resolution of plantar verrucae in an average of 39 days.17 Ilaria and coworkers and Rami and coworkers showed successful use of acitretin for the treatment of resistant viral warts.18,19
Cimetidine. Cimetidine is a histamine H2-receptor antagonist that inhibits stomach acid production. Clinicians most commonly use cimetidine for the treatment of gastroesophageal reflux disease and peptic ulcers. Research has demonstrated that cimetidine exhibits immunomodulatory activity through increased mitogen-induced lymphocyte proliferation and inhibition of T-cell function at histamine receptor sites.20 Orlow and Paller first showed the successful use of cimetidine to eliminate multiple warts in a study population of 36 children.21 In 2005, Mullen and colleagues showed an 84.3 percent success rate with the use of oral cimetidine (25-40 mg/kg per day) for the treatment of pedal verrucae.22
Diindolylmethane. Diindolylmethane is a natural phytochemical found in cruciferous vegetables. Diindolylmethane is a natural indole and research has shown it to have in vitro as well as in vivo efficacy in the treatment of HPV-related conditions.23,24 The hypothesis is that diindolylmethane prevents or reduces the growth of warts by promoting apoptosis activity in HPV-transformed keratinocytes.23 An orally active, absorbable formulation of pure diindolylmethane (BioResponse DIM, BioResponse) is commercially available as a dietary supplement. Useful clinical responses to formulated diindolylmethane have occurred in individuals with recurrent respiratory papillomatosis and HPV-related conditions of the airway epithelium.25
The recommended dosage of Bioresponse DIM is 6 mg/kg twice per day. Side effects include gastrointestinal upset and discoloration of urine. A study conducted in our clinic showed diindolylmethane to be a well-tolerated treatment modality for recalcitrant plantar verrucae with a 94 percent cure rate.26 The mean time first response to diindolylmethane was 2.3 months and the mean time to resolution was 4.1 months.26
The pulsed dye laser selectively targets hemoglobin and dermal blood vessels within the wart tissue. The laser heats the hemoglobin and dissipates thermal energy to surrounding tissues, causing cauterization and leading to a necrotic wart that eventually sloughs off. The pulsed dye laser causes significantly less tissue damage than a standard CO2 laser.
Patients generally tolerate the treatment well and local anesthesia is not required. Typically, one to three treatments are required for clinical resolution. Researchers have reported success rates of 76 to 89 percent with the use of the pulsed dye laser for treatment of recalcitrant warts.27,28
Pringle and Helms showed that blunt surgical dissection can have a 90 percent cure rate for warts.29 This surgical technique involves administering a local anesthetic block with subsequent, standard surgical skin preparation of the skin. Then one would circumscribe the margins of the lesion with a curette or scalpel to create a plane of dissection from the surrounding normal skin. Blunt dissection then continues along the cleavage plane, eventually removing the wart in a single piece.
Physicians should take care not to enter the dermis on dissection due to the potential to create painful scar tissue with healing. One can then apply electrocautery to the wound bed following excision.
We have found that evaluating the wart size, number, depth and response to prior treatment modalities are key factors in the treatment of recalcitrant warts. In our practice, we have found that solitary, recalcitrant lesions respond well to a single injection of 0.1-2.0 IU of bleomycin. We have found that painful myrmecia lesions respond well to surgical excision. Diindolylmethane supplementation is a well-tolerated, successful adjunctive treatment when multiple wart lesions are present.
Clinicians should obtain a punch biopsy for histopathological diagnosis if there is a suspicion for underlying malignancy or if any lesion shows resistance for several months to multiple treatment modalities.
A 51-year-old female presented to our clinic with a complaint of multiple painful plantar warts of three years in duration. Past treatment included seven cryotherapy treatments and topical 40% salicylic acid for 15 weeks. The physical exam showed a cluster of plantar verrucae measuring 2.0 cm x 1.5 cm to the plantar midfoot with numerous immediate satellite lesions, two solitary verrucae to the distal forefoot near the third and fourth metatarsal heads, and two lesions to the plantar hallux, all on the right foot. Additionally, there was a single plantar verruca to the left forefoot.
Our treatment consisted of debridement, cantharidin (Cantharone, Dormer Laboratories) treatment under occlusive dressing and diindolylmethane supplementation of six 150 mg capsules per day in divided dosage. At four weeks, there was a decrease in the size and number of verrucae. We increased the diindolylmethane dosage to eight 150 mg capsules per day to enhance the response to diindolylmethane and repeated debridement and the use of cantharidin. Five weeks later at her third office visit, there was complete resolution of all verrucae.
A 17-year-old male swimmer and wrestler presented to our clinic with recurrent verrucae to his heel of several months duration. Past treatment included multiple cryotherapy treatments. The physical exam revealed a large plantar verruca on the left heel measuring 10 mm x 19 mm with multiple smaller satellite lesions. His initial two office visits to our clinic one month apart consisted of debridement of the skin lesion and application of cantharidin under occlusion followed by daily home applications of 60% salicylic acid.
The lesions persisted so we recommended diindolylmethane supplementation of six 150 mg capsules per day in divided dosage, which the patient started one month after his second office treatment. At his third office visit two months later, there was complete resolution of the verrucae lesions.
When it comes to the treatment of recalcitrant warts, there are numerous modalities including topical treatment, intralesional injections, oral medication/supplementation, laser treatment and surgical excision. We recommend a punch biopsy for confirmed histopathological diagnosis for all suspicious lesions and lesions that fail to respond to conventional treatment modalities.
Dr. Weber is a Fellow of the American College of Foot and Ankle Surgeons. She is in private practice in Boulder, Colo.
Dr. Hoffman is in private practice in Boulder, Colo.
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