Exploring Alternative Treatment For Resistant Warts

By Robert Salk, DPM, Kirk Grogan, DPM, Thomas Chang, DPM, and Walter D’Costa, DPM

Plantar warts are generally benign and usually self-limiting lesions, but are often painful and can be quite debilitating. The incidence of plantar warts is 1 to 2 percent in the general population. Warts usually resolve spontaneously within a two-year period in 60 percent of cases. While multiple treatments have been proposed over the years, there is no uniformly effective treatment for warts so therapy can often be difficult and unrewarding. The most common treatment utilized is home therapy with a nonprescription salicylic acid preparation. Unfortunately, certain reports show that only two of five patients have success with salicylic acid.1 In the office, we commonly see patients who have already failed over the counter salicylic acid treatments. Many patients expect an immediate cure and are not interested in repeating salicylic acid. Therefore, it’s important to be aware of the alternative treatments for resistant warts. It is also important to inform patients that a series of treatments and great deal of patience are often required, regardless of the therapy. Patients may favor an individual treatment and may help with the decision-making process. What You Should Know About Salicylic Acid And Cantharidin Salicylic acid. One can apply salicylic acid as a gel, paint or cream in concentrations ranging from 10 to 60 percent. The effectiveness of this treatment varies greatly and is completely dependent on patient compliance and proper debridement of lesions. Using occlusion (moleskin or tape) increases the efficacy. Be sure to confine the application strictly to the wart since salicylic acid does not discriminate between wart and healthy tissue. Complications can occur, especially when treating immunocompromised patients. Creating an aperture in a patch of moleskin and placing it over the wart allows a confined space for the application of the acid. One can subsequently cover the aperture with a bandage. If the area becomes sensitive, decrease the frequency of application from daily to every third day. During the follow-up visit, you should pare the keratotic debris and nonviable tissue in order to determine if there is any remaining viable wart tissue. Nonviable tissue will appear white and macerated, and you should be able to easily debride it from healthy tissue. Salicylic acid treatment can be advantageous with combination therapy (i.e., home use and cryotherapy treatments in the office). We rarely use salicylic acid as a monotherapy in the office unless we have it formulated by a pharmacist at a stronger strength than the 40 percent OTC preparations. However, we would only apply this increased strength in an office setting. Cantharidin. This blistering agent is derived from Spanish fly extract and green blistering beetle, and one would apply it to the debrided wart. Keep in mind that cantharidin initiates an inflammatory response that may take three to six applications to get the desired response. This response often accompanies blistering, erythema and superficial hemorrhaging. This response can be dramatic and painful when it finally occurs so it is important to prepare the patient for this with the right expectations as well as analgesics for mild to moderate pain. Cantharidin is supplied as a solution in a volatile solvent for rapid evaporation and can be applied by regular-sized or microtip cotton swabs, depending on the size of the wart. There will be no changes in the appearance of the wart immediately after application, and it requires simply pressing the soaked swab onto the wart for five to 10 seconds. If a large, tender blister forms, one may drain it with a sterile needle to alleviate the discomfort. Repeat the treatment every one to two weeks with debridement in the clinic. What About The Off-Label Use Of 5-Fluorouracil For Warts? 5-fluorouracil (Efudex, Carac Cream). One may utilize 5-fluorouracil as a cream with two existing forms, Efudex 5% cream and Carac 0.5% cream. The agent 5-fluorouracil is chemotherapeutic and is FDA-approved for actinic keratoses and basal cell carcinomas.2 However, there has been a great deal of interest in its off-label use for the HPV virus. We typically use Efudex in our treatment course for warts as it is has 10 times the strength of Carac cream. However, Carac cream is known to supply the 5-fluorouracil over an extended period of time. While the exact mechanism is unknown, this agent does inhibit DNA synthesis.2 By inhibiting DNA synthesis with 5-fluorouracil, we eradicate the wart because the wart is a DNA virus. We are currently conducting a controlled randomized trial with the use of Efudex cream. Prior to the study, we have utilized 5-fluorouracil as a first-line treatment for plantar warts with excellent success. In the clinic, you would apply the medication to the debrided lesion and occlude it with tape. This treatment course is simple both for the clinician and patient. If pinpoint bleeding occurs with debridement, you must establish hemostasis before applying 5-fluorouracil and tape (waterproof tape, duct tape). The choice of tape is open as long as it has strong adhesive properties and is waterproof. In order to maintain a high concentration of the 5-fluorouracil for the wart, emphasize to the patient that he or she should apply it twice a day and perform debridement with a pumice stone at home. It is extremely important to see the patient every one or two weeks in the clinic in order to pare nonviable tissue. Doing so allows maximum contact and penetration of the medication to the wart. Since 5-fluorouracil has the tendency to affect the wart exclusively, there is not as much of an issue of containing the medicine. Unlike salicylic acid, 5-fluorouracil has great affinity to the wart without affecting surrounding tissues. Many patients will have extensive maceration of the warts within two weeks. As the weeks go by and with diligent treatment at home, the wart will actually begin to ulcerate. This is normal as the wart is simply destroyed at a faster rate than it can be replaced with healthy skin. These ulcerations are superficial, minimally painful and are harbingers of complete destruction of the wart. When you can see skin lines running right to the edge of the ulcer, have the patient continue the treatment for one to two more weeks. At the end of this period, follow up with the patient, discontinue the 5-fluorouracil and allow the lesion to heal. The typical treatment course for 5-fluorouracil will be from eight to 10 weeks. A Closer Look At Using Imiquimod For Plantar Warts Imiquimod (Aldara cream). Imiquimod is an immune enhancer that induces interferon-alpha after it is applied topically.3 This cytokine is produced by keratinocytes. The cells respond as though they have been infected and this action clears the warts. In response to the viral infection, interferon-alpha induces keratinocytes to produce enzymes and other factors that block viral replicatory pathways.3 Imiquimod is FDA approved for anogenital warts but it can be successful in its off-label use for plantar warts. Instruct patients to apply the medication daily before bedtime with tape occlusion. They should repeat this process until the wart clears. Close follow-up visits in the clinic are necessary to ensure proper debridement of the verruca and hyperkeratotic tissue. Keep in mind that patients may experience local skin reactions such as erythema, erosion, excoriation/flaking and edema at the site of application or surrounding areas. If this occurs, tell the patients to discontinue the medication until the symptoms subside. Can Bleomycin Injections Make A Difference? Bleomycin. Bleomycin is a cytotoxic polypeptide with antitumor, antibacterial and antiviral properties. It was initially isolated from the soil fungus Streptomyces verticellus. The mechanism of action is inhibition of DNA synthesis. We reserve intralesional bleomycin for recalcitrant warts, considering the pain that is often associated with the injection. When using these injections, employ local anesthesia and prepare the patient for the potential pain involved with the treatment. One may prescribe analgesics for moderate pain. Our standard injection technique utilizes a 27-gauge needle and a 3-ml syringe with a 1.0- to 1.5-U/ml solution of bleomycin. One can prepare this by adding 10 to 15 ml of 0.5% marcaine with epinephrine to 15 units of bleomycin. Doing so produces an activity of 1 to 1.5 units of bleomycin per milliliter of prepared solution. Bleomycin is typically supplied in 15- or 30-unit vials of sterile lyophilized material and must be refrigerated. In a review of the literature, authors commonly utilized a 1.0-U/ml solution with sterile saline or water.4-6 The authors believe that the increase in strength from 1.0-U/ml to 1.5-U/ml can make a significant difference in cure rates without affecting safety. A 1-cm lesion will usually receive 0.5 to 0.75 ml of this solution. One should inject the bleomycin strictly into the wart without going deep into subcutaneous tissue. You can accomplish this by turning the needle bevel up away from the skin while inserting the needle at the edge of the wart. Make sure the insertion is as flush to the skin as possible in order to avoid too deep a penetration. Proceed to fan the needle across the wart through one puncture site in order to prevent the medication from seeping from multiple holes. Using the appropriate injection technique will allow you to see the needle through the transparency of the epidermis. There will be a hemorrhagic blister from the injection. This is normal. You should debride the blister during a return visit from the patient one or two weeks after the injection. Studies have reported success rates up to 99.23 percent via one to three injections of bleomycin into 1,052 warts at an Australian Air Force Base.4-6 Studies have also shown success with infiltration of bleomycin via a multiple puncture using a vaccination needle.4-6 Other Modalities That May Merit Consideration Candida antigen. A new and under-studied treatment for warts involves the intralesional injection of Candida skin test antigen.7 With the injection of the wart, 74 percent had complete clearing in the pilot study.7 The remarkable aspect of this study is that 78 percent of those with resolution also had resolution of anatomically distant, untreated warts. This suggests an HPV-directed immunity in some patients. In using this treatment approach, one would deliver the antigen with a needle and syringe, using the same concentration as with allergy testing, into the base of the wart. Then you would proceed to puncture the wart aggressively to help initiate an immune response. Keep in mind that this process is uncomfortable and may require a prescribed analgesic for the patient. One should follow up with the patient in one to two weeks. Duct tape. A fitting conclusion to the myriad of non-surgical therapies is the use of duct tape. In one study by Focht, et. al., on warts in children, 85 percent of those treated with duct tape had resolution while 60 percent of those treated with cryotherapy had resolution.8 This study shows the importance of the simple act of occluding the wart, which creates a macerating and keratolytic environment not unlike salicylic acid. This therapy does require the use of a pumice stone at home and clinical debridement in the office. Still, this may be a simple and painless treatment course for the pediatric patient. Results are not as promising with tape occlusion alone in the adult population. A preliminary result from a study we are conducting shows only 10 percent resolution in adult patients with tape occlusion alone. However, the majority of patients have had substantial reduction in size of their lesions after 12 weeks of treatment. By incorporating combination therapy with tape and a topical medication (i.e. 5-fluorouracil, imiquimod), we expect better results. A Closer Look At The Etiology And Diagnosis Of Warts Plantar warts are epidermal lesions caused by an infection by the human papilloma virus (HPV). Over 100 subtypes of HPV have been identified. The subtypes commonly found in plantar warts are HPV 1, 2, 4 and 10. The HPV virus is transmitted between hosts through direct contact. For infection and replication to take place, the virus requires a compromised skin surface with epithelial cells in an advanced state of differentiation. The virus attacks the granulosum and keratin layers of the epidermis. The viral DNA and protein production occur in the upper spinous layer with final virus assembly occurring in the granular layer.11 HPV is a non-enveloped, double-stranded DNA virus that replicates in all epithelial cell layers. However, viral replication is associated with excessive proliferation of all of the epidermal layers except the basal layer. This process produces acanthosis, parakeratosis and hyperkeratosis. There is also a deepening of the rete ridges, which produces the typical papillomatous architecture that produces pinpoint bleeding with debridement of the lesion. Plantar warts occur most frequently in children and young adults. One study suggests that the persistence of disease may be attributable to a lack of Langerhans’ cells at the site of the lesion, leading to decreased stimulation of cell-mediated immune response.12 Minor trauma at the site of inoculation may be important as there could be an abrasion of the skin that allows penetration of the wart into the epidermis. Warts will frequently be present in high-pressure or high-friction areas that are often otherwise occupied by calluses. Though one can diagnose warts with a high degree of certainty based on their clinical appearance, a biopsy may be required for a definitive diagnosis. If a lesion is chronic, aggressive, irregular and resistant to multiple therapies, be cautious of possible malignancy. In rare cases, warts may degenerate into verrucous carcinomas.13 In Conclusion The key to success for treating the recalcitrant wart is combination therapy. It’s also essential for patients to take an active role in their treatment. We will commonly incorporate a home therapy of 5-fluorouracil cream with tape occlusion and thorough debridement both in the office and by the patient with a pumice stone. Additionally, we will commonly prescribe cimetidine 400 mg TID and educate patients to take vitamin A and zinc supplements daily. Patients should expect to take these medications for at least three months. A study by Orlow and Pallor showed an 81 percent success rate in eradicating warts in children with cimetidine alone in three months.9 A similar study revealed only a 30 percent success rate among adults.10 When using the above treatment modalities and combination therapy, we infrequently need to implement more aggressive treatments like surgical excision and laser treatments. Furthermore, the aforementioned conservative modalities do not have as much pain and morbidity associated with them. Although there is a certain place for surgical curettage and laser treatments, there are times when these approaches are impractical. In conclusion, we have had great success with a conservative approach in treating the recalcitrant wart by employing combination therapy. Dr. Salk is the Director of Research at the Northern California Foot and Ankle Center. He is in private practice in San Francisco and Santa Rosa, Ca. Dr. Chang is Chief of the Department of Podiatric Medicine and Surgery at the Sutter Medical Center in Santa Rosa, Ca. He is a Clinical Professor at the California School of Podiatric Medicine at Samuel Merritt College. He is a Fellow of the American College of Foot and Ankle Surgeons and is a faculty member of the Podiatry Institute. Dr. Grogan is a Research and Surgical Fellow at the Northern California Foot and Ankle Center, and practices in San Francisco and Santa Rosa, Ca. Dr. D’Costa is Chief of Staff-Elect at the Sutter Medical Center in Santa Rosa, Ca., and is in private practice in Santa Rosa, Ca.



References 1. Bunney, MH, Nolan, MW, Williams, DA. An assessment of methods of treating viral warts by comparative treatment trials based on a standard design. Br J Dermatol 94:667-679, 1976. 2. Diasio R, Harris B. Clinical Pharmacology of 5-fluorouracil. Clinical Pharmacokinetics 1989:16:215-237. 3. Dahl M. Imiquimod: An Immune Response Modifier. J Am Acad Dermatology. July 2000:S1-S5. 4. Templeton S, et al. Intradermal Bleomycin Injections Into Normal Human Skin. Arch Derm. 1994:130:577-583. 5. Amer M, et al. Therapeutic Evaluation for Intralesional Injection of Bleomycin Sulfate in 143 Resistant Warts. J Am Acad Derm. 1988;18:1313-1316. 6. Shelly W, et al. Intralesional Bleomycin Sulfate Therapy for Warts. Arch Derm. 1991;127:234-236. 7. Johnson S, et al. Intralesional Injection of Mumps or Candida Skin Test Antigens. Arch Derm. 2001;137:451-455. 8. Focht DR, et al. The Efficacy of Duct Tape vs Cryotherapy in the Treatment of Verruca Vulgaris (The Common Wart). Arch Pedi Adolesc Med. 2002;156:971-974. 9. Orlow SJ, Paller A. Cimetidine Therapy For Multiple Viral Warts In Children. J Am Acad Dermatol. 1993; 28(5), 794-5. 10. Rogers CJ, Gibney MD, et. al. Cimetidine therapy for recalcitrant warts in adults: is it any better than placebo? J Am Acd Dermatol 1999; 41:123-7. 11. Stoler MH, Broker TR. In situ hybridization detection of human papillomavirus DNAs and messenger RNAs in genital condylomas and cervical carcinoma. Hum Pathol. 1986;17:1250-1258. 12. Arany I, Tyring SK. Status of local cellular immunity in interferon-responsive and -nonresponsive human papillomavirus-associated lesions. Sex Transm Dis 1996;23:475. 13. Schwartz RA. Verrucous carcinoma of the skin and mucosa. J Am Acad Dermatol. 1995;32:121. Additional References 14. Stehr-Green PA, Hewer P, Meekin GE, et al. The aetiology and risk factors for warts among poultry processing workers. Int J Epidemiol. 1993;22:294-298. 15. Keefe M, Al-Ghamdi A, Coggon D, et al. Cutaneous warts in butchers. Br J Dermatol. 1994;130:9-14. 16. Gibbs S, Harvey I. Local treatments for cutaneous warts: systematic review. Br Medical Journal. 2002:325:461-464.


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