Pediatric Dermatology Vol. 32 No. 1 85–90, 2015

Examining the Efficacy and Safety of Squaric Acid Therapy for Treatment of Recalcitrant Warts in Children Shaily Pandey, M.D.,* Erin N. Wilmer, M.D.,† and Dean S. Morrell, M.D.* *Department of Dermatology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, †School of Medicine, University of Florida, Gainesville, Florida

Abstract: The objective of the study was to determine the safety and efficacy of squaric acid dibutyl ester (SADBE) therapy on the treatment of recalcitrant warts in children. This retrospective chart review examined 72 patients treated using SADBE from July 2002 to December 2012. Patients were followed for 6 months to 11 years. Patients were treated at a pediatric dermatology outpatient clinic at the University of North Carolina at Chapel Hill. Seventy-two children with verrucae who failed initial treatment for warts were selected for the study. Full long-term follow-up was obtained in 48 patients. Four patients discontinued the use of SADBE because of adverse effects. The primary study outcome was efficacy of SADBE treatment. Adverse effects, dosages administered, type of wart, other cutaneous disease present, and level of immunosuppression were measured. Forty of 48 (83%) patients in whom treatment outcomes could be obtained reported complete resolution of their warts. Seventy percent of patients used a maximum concentration of 0.4% SADBE and 60% of patients reported no adverse effects. The majority of patients treated with SADBE reported complete resolution of warts. Most patients reported no adverse effects even while receiving doses as high as 2% daily. This study shows that SADBE is a safe and effective treatment for recalcitrant warts in children.

Accounting for 8% of all visits annually, warts are one of the most common reasons to visit a dermatologist (1). They affect a significant portion of the population, with prevalences ranging from 7% to 10%. Found primarily in children, they are most commonly diagnosed between the ages of 12 and 16 years (1). Although two-thirds of all warts regress

within 2 years, discomfort and cosmetic concerns cause many people to seek treatment (1). Warts are caused by the human papilloma virus (HPV), with more than 130 different viral subtypes identified. The most common strains that cause cutaneous warts are HPV-1, 2, 3, 4, 27, and 57 (2). Disease arises when there is a break in the skin and the

Address correspondence to Shaily Pandey, M.D., University of North Carolina School of Medicine, Department of Dermatology, 410 Market Street, Suite 400, Chapel Hill, NC 27516, or e-mail: [email protected]. DOI: 10.1111/pde.12387

© 2014 Wiley Periodicals, Inc.

85

None reported Erythema, desquamation, edema, pruritus, burning, pain 100 8 9 6–70

None reported Erythema, pruritus 100 2 2

69 26 29 1.8–40

84 148 188 2–16

31 and 57

Acute contact dermatitis and blisters

Burning, florid sensitization reaction Auto-eczematization

Erythema, pruritus, burning Erythema, pruritus, burning, edema, desquamation Hypopigmentation, pruritus 58 59 61 5–14

0.0003–0.3

Physician

Physician

Hama et al (7)

Dall’Oglio et al (6)

Case series

0.01

Physician Lee and Mallory (5)

Case series

0.5–5

Physician Micali et al (13)

Retrospective

Parent Silverberg et al (3)

Retrospective

0.03–3

Verruca vulgaris Verruca plana, verruca vulgaris Verruca vulgaris, anogenital Verruca vulgaris Anogenital 0.20

Age, years Type of study

Retrospective

Adverse effects Success rate,% Completed treatment, n Enrolled participants, n Type of wart treated SADBE used, % Given by

At the UNC pediatric dermatology clinic, patients with verrucae who fail therapy with multiple agents, including liquid nitrogen, salicylic acid, cantharidin,

Reference

METHODS

TABLE 1. Previous Squaric Acid dibutyl ester (SADBE) Studies

virus invades the epidermis to infect the basal keratinocytes (3). Disease clearance occurs when an inflammatory response, usually marked by erythema at the lesion, is generated through T-cell activation or HPV-directed antibodies (3). Biopsies of involuting warts, which show a dense inflammatory infiltrate, demonstrate this immunologic response (1). Initial wart therapy involves physical destruction through cryotherapy, salicylic acid, cantharidin, and paring or excision, although immunotherapy is also effective, presumably by stimulating the immune system into eradication. Common first-line topical immunotherapeutics are 5-fluorouracil, imiquimod, and intralesional antigens (1,4,5). Treatment of recurrent or recalcitrant warts in children is a challenge since the surgical and destructive options are painful and potentially frightening. Contact immunotherapy offers a less painful approach than destructive measures. Over the last 15 years, contact sensitizers such as squaric acid dibutyl ester (SADBE) have been used with increasing frequency in wart treatment. Acting by induction of a type IV delayed hypersensitivity reaction, SADBE stimulates a cell-mediated response against the hapten-bound viral proteins on antigen-presenting cells, which can ultimately lead to wart resolution (5). Warts not directly treated using SADBE can also resolve during treatment of a distant wart, suggesting stimulation of a systemic immune response as well (6,7). Its use in the treatment of alopecia areata has demonstrated the long-term safety of SADBE in children (8–12). Although SADBE therapy, first used clinically in 1979, has been heavily studied in alopecia areata, few studies have evaluated its efficacy in the treatment of warts in children. The results of these studies, including case series and retrospective examination of cohorts, are shown in Table 1 (1,3,5,7,13,14). Treatment methodologies vary between institutions. Reported efficacy varies from 58% to 84% (1,3,5,7,13,14). The therapeutic regimen, including pretreatment with salicylic acid, dosing, and frequency of administration, differs in these studies. The purpose of our study was to retrospectively evaluate the efficacy of SADBE in the treatment of warts in children seen in the University of North Carolina (UNC) dermatology clinic.

Adverse effects leading to discontinuation of treatment

86 Pediatric Dermatology Vol. 32 No. 1 January/February 2015

Pandey et al: Squaric Acid Efficacy and Safety 87

candida antigen, imiquimod, and fluorouracil cream, are considered for treatment with SADBE. Patients are sensitized with 2% SADBE to a quarter-sized area on the upper inner arm, which is then covered with an occlusive dressing. Patients remove the dressing at home the next day and wash the area with soap and water. Two weeks after this treatment, the patients’ parents are instructed to apply 0.4% SADBE three times a week to the warts. Over the ensuing weeks, the patients’ parents slowly increase the frequency (an additional day per week until using daily) to elicit a mild dermatitis. If mild dermatitis is not seen by the next follow-up clinic visit, the physician increases the concentration of medication prescribed. Additionally, to prevent self-sensitization, parents are instructed to wear gloves and use cotton-tipped swabs when applying the solution. Patients are seen monthly to ensure that the proper reaction is being elicited and to make changes in the concentration of solution or frequency of SADBE (1). Permission from the institutional review board was granted from the UNC School of Medicine to conduct a retrospective chart review examining the efficacy of SADBE on recalcitrant warts. From July 2002 to December 2012, 72 consecutive patients treated with SADBE for multiple warts were identified. Demographic and clinical information on age, sex, duration of warts, types of warts, anatomic sites, number of lesions at each visit, prior therapies, concomitant therapies, presence of a positive sensitization reaction, immunosuppression status, other skin diseases, whether therapy was completed, whether there was complete resolution, time to initial response, maximum weekly dose used, time to complete resolution or duration of therapy, adverse effects, and the presence of any other warts not directly treated and whether they resolved was extracted from the chart. The medical chart was also examined to see whether SADBE therapy was reinitiated at any time after the initial therapy was completed. Follow-up was attempted between January and June 2013 through telephone communication and mailed surveys. The following questions were asked: Did the warts go away? Did the warts return? Would you attribute the resolution of warts to squaric acid? Would you try squaric acid therapy again? Data were analyzed to determine the efficacy of treatment with SADBE and any factors that influenced its efficacy. Stata version 12.1 (StataCorp, College Station, TX) was used to perform analyses for all statistics. Descriptive analyses of demographic variables, treatment frequencies, adverse effects, concomitant skin diseases, time to initial treatment,

duration of treatment, follow-up duration, type of wart treated, and resolution status were performed. Questions asked over the telephone and through surveys were also analyzed descriptively. Differences in frequencies were deemed statistically significant at p < 0.05. A series of chi-square analyses were also conducted to determine whether there was a correlation between the variables measured and wart resolution after treatment. RESULTS Seventy-two consecutive patients treated with SADBE for warts were studied. The baseline characteristics of the patient population are summarized in Table 2; 38 patients treated (mean age 9.7 years) were female (53%) and 34 were male (47%). Of the 72

TABLE 2. Baseline Patient Characteristics Characteristic

Value

Age, years, mean (range) Duration of warts, months, mean (range) Immune status, n (%) Immunocompromised Not immunocompromised Type of warts, n (%) Verruca vulgaris Verruca plana Location, n (%) Leg Periungual Plantar Hand Arm Digit Face Chest Genitals Neck Previous treatments, n (%) Liquid nitrogen Salicylic acid Fluorouracil cream Candida antigen Imiquimod Cantharidin Duct tape Paring Tretinoin Laser Tazarotene Excision Cimetidine Dichloroacetic acid Electrodesiccation and curettage Garlic Methylene blue Bleomycin Famotidine Vinegar

9.7 (3–18) 8 (6–10) 5 (7) 67 (93) 64 (89) 3 (4) 23 20 20 13 12 8 7 2 1 1

(32) (28) (28) (18) (17.) (11) (10) (3) (1) (1)

55 48 23 22 17 9 6 5 5 3 3 2 2 1 1 1 1 1 1 1

(76) (67) (32) (31) (24) (13) (8) (7) (7) (4) (4) (3) (3) (1) (1) (1) (1) (1) (1) (1)

88 Pediatric Dermatology Vol. 32 No. 1 January/February 2015

treated patients, 89% had common warts (verruca vulgaris) and 4% had flat warts (verruca plana). The type of wart was not documented in the medical record of 7% of patients. As seen in Table 3, although a smaller percentage of periungual warts resolved with the use of SADBE therapy, this was not statistically significantly different from the success rate observed at other wart locations. All patients had failed prior (non-SADBE) treatments and 16 (33%) were concomitantly treated with other therapies, including cryotherapy, 5-flurouracil cream, salicylic acid, candida antigen injection, cimetidine, and vinegar, as shown in Table 4. In the 48 patients for whom treatment outcome is known, the presence of simul-

TABLE 3. Clearance of Warts Patients with clearance, n (percentage of population resolution)

Characteristic Age, years 3–7 9–13 14–18 Immune status Immunosuppressed Not immunosuppressed Type of wart Verruca vulgaris Verruca plana Location Leg Periungual Plantar Hand Arm Face Chest Genital Neck Strength of treatment 0.2% daily 0.4% once to 0.4% daily 1% three times a week to 2% daily Duration of treatment 1–4 mos 6–12 mos >1 yr

14 (82) 18 (90) 7 (64) 4 (80) 35 (81) 39 (83) 1 (100) 16 (84) 9 (75) 12 (100) 10 (77) 11 (92) 3 (100) 0 (0) 0 (0) 0 (0) 1 (100) 26 (79) 12 (86) 8 (50) 18 (100) 6 (86)

taneous treatment with another agent was not related to treatment outcome (p > 0.05). Eighty-two percent of the 72 patients treated had no other skin diseases documented in the chart. Five (7%) had acne and two (3%) also had atopic dermatitis and keratosis pilaris. One subject each had a congenital nevus, epidermolysis bullosa, molluscum contagiosum, tinea corporis, and tuberous sclerosis. Based on chi-square analysis, the presence of other skin diseases was not related to treatment response. Of the 48 patients in whom resolution status could be determined, the majority used 0.4% SADBE at frequencies ranging from three times a week to daily. One patient only needed to use 0.2% SADBE daily to achieve results. Sixteen patients (29%) used higher concentrations, varying from 1% three times a week to 2% daily to achieve results. There was no statistical difference in the maximum possible dose and response to treatment. Forty of 48 patients (83%) reported resolution of their warts treated using SADBE. Of 44 patients surveyed, 37 (84%) attributed their wart resolution to SADBE. Of the patients who exhibited resolution, the average time to an initial decrease in warts was 2.6 months after sensitization, and patients continued treatment for a mean of 8 months. The average length of follow-up, including follow-up by telephone and surveys, was 34 months. When asked, 23 of 34 patients (68%) would repeat SADBE treatment if they had another wart. One patient never initiated therapy after sensitization because of a severe reaction to 2% SADBE leading to cutaneous erosions. To our knowledge, this patient had no prior history of SADBE sensitization. Sixty percent of the 52 patients who were asked about adverse effects and whose response was documented in the chart did not report any adverse effects. In those who experienced adverse effects, the most frequently reported were erythema, pruritus, dermatitis, irritation, and blisters. Individual patients reported bleeding and burning. These results are summarized in Table 5. The presence or absence of adverse effects did not affect response to treatment. Although 63% of

TABLE 4. Concomitant Treatments

TABLE 5. Adverse Effects

Treatment

Treated, n (% reporting resolution)

Adverse effect

n (%)

None 5-flurouracil cream Salicylic acid Candida Liquid nitrogen Cimetidine Vinegar

32 9 6 4 3 2 1

None Erythema Symptomatic dermatitis Pruritus Blisters Bleeding Burning

31 (60) 9 (17) 8 (15) 5 (10) 2 (4) 1 (2) 1 (2)

(84) (89) (67) (100) (100) (50) (100)

Pandey et al: Squaric Acid Efficacy and Safety 89

patients did not report a reaction at the sensitization site, there was no difference in resolution based on this variable. In this study, the warts of four of five immunosuppressed patients resolved with SADBE use. This percentage was not significantly different from the proportion of immunocompetent patients whose warts resolved. DISCUSSION The findings of our study show that SADBE is a safe and effective treatment for recalcitrant warts in children, even at higher concentrations than previously described. Parents of patients can safely administer the medication at home for prolonged periods of time. The age and sex distribution of this study mirrored previous studies and supports previous findings that there may be no difference in wart resolution based on age, sex, or type of wart treated (5,13,15). On average, patients in this study experienced resolution of warts later than in previous studies and continued treatment for longer than in previous studies. Treatment adherence can affect the efficacy of therapy. In the majority of previous studies, physicians applied the treatment in the office setting up to twice weekly and demonstrated success rates as high as 84%. Our study, with a resolution rate of 83%, demonstrates that SADBE can be appropriately and effectively applied at home with no effect upon patient safety. The average initial response to treatment seen in this study (2.6 mos) was later than the earliest time frame for a decrease in warts, reported to be 2 weeks by Silverberg et al (3). Micali et al (13) discontinued treatment for responders after 2.5 months, having seen an initial decrease in lesions at approximately 3.3 weeks. The finding of delayed initial response in our chart review suggests that early nonresponders should receive prolonged treatment and potentially higher concentrations. Furthermore, our patients were seen only once a month, so the time of onset of treatment effect may have been artificially delayed if not reported by the patient and then documented in the clinic note. Still, the duration of therapy seen in our study, on average 8 months, was longer than in previous studies, which reported treatment discontinuation ranging from 7 weeks to 7 months (3,5,13). As patients anecdotally mentioned in telephone surveys, treatment efficacy may also have motivated patients to continue treatment for newly arising warts. This study verified findings previously reported on our treatment protocol (1).

The average maximum concentration used was in the range of previously reported concentrations; a significant portion of patients used concentrations of 0.4% SADBE from once a week to daily. Still, in our cohort, more than 28% of patients used SADBE at doses of 1% or higher, and additional adverse effects were not experienced. All patients in this study had previously failed firstline (non-SADBE) treatments in our clinical setting, which defined their warts as recalcitrant. Only one other study reported treatment of recalcitrant warts and a resolution rate of 69% with physician office applications (5). In our study, 83% of the 44 who could be reached for follow-up reported resolution of their warts. Overall, prior reports of SADBE wart treatment documented response rates ranging from 58% to 84% (1,3,5,13,14). The highest reported success rate with SADBE treatment included pretreatment of warts with 70% salicylic acid under occlusion for 2 days, with a resolution rate of 84%; a similar rate was seen in our limited patient population (40 of 48 patients) who were available for follow-up (13). Our study noted concurrent skin diseases in patients, as they are occasionally cited as a reason for lack of treatment response. One study mentioned immunosuppression and atopic dermatitis as reasons for nonresponse (14). Even in our limited patient population, our study suggests no association between atopic dermatitis and response (1). Our study emphasized that therapy was effective even with concurrent common skin diseases such as acne and atopic dermatitis as well as with uncommon conditions such as epidermolysis bullosa and tuberous sclerosis and in immunocompromised patients. The majority of our patients experienced no adverse effects, confirming the safety of SADBE treatment. According to previous studies, effects observed at the initial sensitization site include erythema, edema, hyperpigmentation, and blistering. Adverse effects of direct treatment of the wart include mild erythema, desquamation, pruritus, and burning (4,5,13). In this study, adverse effects leading to treatment discontinuation were seen in three patients and included severe urticarial reactions and dermatitis. Other studies reported isolated adverse effects also seen here, including erythema, pruritus, desquamation, burning, and dermatitis (3–5,13). Hypopigmentation and persistent sensitization are also reported in the literature, but no patient reported that in our study (5). In conclusion, our SADBE treatment approach confirms the efficacy and safety of home use in

90 Pediatric Dermatology Vol. 32 No. 1 January/February 2015

recalcitrant pediatric warts. The treatment is effective for the majority of patients at 0.4% applied at a frequency ranging from once a week to daily. If needed, patients can safely go over the previously reported maximum dose of 1%. Furthermore, the topical medication can be administered at home with minor adverse effects over 8 months. The treatment dose and frequency may need to be optimized over a period of 2 to 3 months before results are observed. Patients should therefore be encouraged to follow up monthly, and the concentration of SADBE should be increased regularly to achieve therapeutic effect. This therapy can be used successfully in immunosuppressed patients as well as with patients with other skin conditions.

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6. Dall’Oglio F, Nasca MR, D’Agata O et al. Adult and paediatric contact immunotherapy with squaric acid dibutylester (SADBE) for recurrent, multiple, resistant, mucocutaneous anogenital warts. Sex Transm Infect 2002;78:309–310. 7. Hama N, Hatamochi A, Hayashi S et al. Usefulness of topical immunotherapy with squaric acid dibutylester for refractory common warts on the face and neck. J Dermatol 2009;36:660–662. 8. Orecchia G, Marelli MA, Perfetti L et al. Alopecia areata: more on topical sensitizers. Dermatologica 1990;180:57–59. 9. Orecchia G, Malagoli P, Santagostino L. Treatment of severe alopecia areata with squaric acid dibutylester in pediatric patients. Pediatr Dermatol 1994;11: 65–67. 10. Tosti A, Guidetti MS, Bardazzi F et al. Long-term results of topical immunotherapy in children with alopecia totalis or alopecia universalis. J Am Acad Dermatol 1996;35:199–201. 11. Valsecchi R, Cainelli T, Tornaghi A et al. Squaric acid dibutylester treatment of alopecia areata. Clin Exp Dermatol 1985;10:233–238. 12. van der Steen PHM, Boezeman JBM, Happle R. Topical immunotherapy for alopecia areata: reevaluation of 139 cases after an additional follow-up of 19 months. Dermatology 1992;184:198–201. 13. Micali G, Nasca M, Tedeschi A et al. Use of squaric acid dibutylester for cutaneous warts in children. Pediatr Dermatol 2000;17:315–318. 14. Micali G, Dall’Oglio F, Tedeschi A et al. Treatment of cutaneous warts with squaric acid dibutylester: a decade of experience. Arch Dermatol 2000;136:557–558. 15. Silverberg JI, Silverberg NB. Adjunctive trichloroacetic acid therapy enhances squaric acid response to verruca vulgaris. J Drugs Dermatol 2012;11:1228–1230.

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