Real‐life treatment of cutaneous warts with cantharidin podophyllin salicylic acid solution

Abstract Patients often request treatment of their burdensome cutaneous warts. However, a safe and effective treatment for cutaneous warts is lacking. This study evaluates treatment outcome, side effects, and patient satisfaction after topical application of cantharidin 1% podophyllin 2% salicylic acid 30% (CPS1) solution in a large series of children and adults with cutaneous warts. Fifty‐two children and 83 adults with warts, treated with CPS1 solution between October 2012 and October 2014, were included. Complete clearance of warts occurred in 86.5% of children and 62.7% of adults treated with CPS1 solution (p < .01). Resolution of warts was partial in 3.9 and 24.1% and absent in 9.6 and 13.2% of children and adults respectively. Side effects were present in 41.2% of children and 46.3% of adults (p = .7). Most common side effects were blistering, pain, and burning sensation. No serious adverse events occurred. On a 10‐point scale, median patient satisfaction score was 9.0 (interquartile range 7.8–10.0) and 8.0 (interquartile range 5.1–9.7) for children and adults respectively (p < .01). CPS1 solution is a safe and promising treatment modality with a high clearance and high patient satisfaction rate for the management of cutaneous warts, particularly in children.


| INTRODUCTION
Warts are a common viral infection of the skin caused by certain types of the human papillomavirus (HPV; Bruggink et al., 2012). As a result of natural immunity, without treatment, warts tend to resolve spontaneously within months to years (Sterling, Gibbs, Haque Hussain, Mohd Mustapa, & Handfield-Jones, 2014). Prior research demonstrated that 52% of warts in children cleared within 1 year and two thirds of the warts resolved within 2 years, regardless of treatment of the warts Massing & Epstein, 1963). An expectant approach is often advised for the management of the cutaneous warts.
However, patients often request treatment of warts due to pain, discomfort, and/or social stigma. Treatment of warts is often painful, labor intensive, time-consuming, and expensive. A safe and effective treatment for cutaneous warts is still lacking (Sterling et al., 2014).

| Treatment and definitions
Treatments were performed by trained health care professionals at our outpatient clinic, under the supervision of a physician. Selfapplication of CPS1 solution was not allowed due to its toxicity and potential misuse, as it can be fatal if ingested (Torbeck et al., 2014).
Excessive callus was removed by using a curette or scalpel. The treatment regimen consisted of topical application of cantharidin 0.7% solution followed by subsequent applications with CPS1 solution. For the first treatment, cantharidin 0.7% solution was applied in order to carefully assess the extent of blister formation and other side effects.
The solution was applied to the wart with a 1-mm surrounding rim of normal skin. Treated warts were covered with occlusive tape. Patients were advised to rinse the solution off the treated warts 4-8 hr after application (in accordance with the product instruction), once a tingling/burning sensation, or blister appeared. Application of the solutions was performed at intervals of 3-4 weeks until complete clearance of all treated warts had occurred. Complete clearance was defined as resolution of all treated warts, noted by physician and/or patient. Clearance was considered partial when a section of treated warts had disappeared or if treated warts became smaller compared to baseline, based on patient's experience. Warts that initially cleared with treatment, but reoccurred at the same location within 3 years of treatment with CPS1 solution were noted as recurrences.

| Data collection
Data were collected from a combination of electronic patient records and a survey. The physician judged clearance of the warts during regular check-ups. In case of discrepancies between the electronic patient records and the survey, the information from the electronic patient records was used to minimize recall bias. Patients were approached by post or telephone to complete the survey. solution somewhat enhanced resolution of the warts. However, this relatively modest increase in clearance rate did come at a cost. The studies using CPS2 solution reported significantly more severe side effects and higher toxicity than our study, using CPS1 solution (Becerro de Bengoa Vallejo et al., 2008;Coskey, 1984;Kaçar et al., 2012;López López et al., 2016;López-López et al., 2015). One study reported cellulitis in 3.3% of children treated with topical application of CPS2 solution followed by an occlusion period of 24 hr (Coskey, 1984   Erythema 6 (11.8) 4 (4.9) 10 (7.5) Pigmentation of skin 2 (3.9) 5 (6.1) 7 (5. Note: Data are n (%). Abbreviations: CPS1, cantharidin 1% podophyllin 2% salicylic acid 30%; n, total number of patients; NC, not calculable due to multiple answer options; #, data obtained from patients' electronic record and survey;^, Multiple answers are possible. and hemorrhagic bulla in 26.7, 60, and 13.3% of the patients (Ghonemy, 2017). We adhered to the product instruction of CPS1 solution, which advised an occlusion period of 4-8 hr. Our study reported only mild side effects, no secondary infections, or serious adverse events. Furthermore, these mild side effects in our study also coincided with a high patient satisfaction rate. Therefore, we consider topical application of CPS1 solution followed by an occlusion period of 4-8 hr as an effective, safe, and well-tolerated treatment for cutaneous warts, especially in children.
This was the first study evaluating treatment outcomes after topical application of CPS1 solution for the management of cutaneous warts in children versus adults. As this study shows, children more often than adults seek treatment for warts due to social and cosmetic inconveniences. Children are more difficult to treat as painful treatments are poorly tolerated and should preferably be avoided (Sterling et al., 2014). In daily practice, this can be challenging for both doctor and patient. Therefore, a distinction between children and adults is crucial in evaluating and choosing an adequate, satisfactory, and effective topical treatment for cutaneous warts Sterling et al., 2014). A review of the management of cutaneous warts in children proposed salicylic acid 25-35% as the preferred treatment for children with large, multiple, or periungual warts due to easy daily application at home and mild side effects. Cryotherapy was viewed as another simple and easy treatment, however often poorly tolerated by children due to pain, scarring and post-inflammatory hyper-or hypopigmentation. They also considered cantharidin to be a valuable option for the treatment of cutaneous warts in children (Gerlero & Hernández-Martín, 2017).
The current study shows that CPS1 solution is a safe, rather quick, well tolerated and highly appreciated treatment for warts in children.
However, application of the CPS1 solution by trained health care professionals is mandated (Torbeck et al., 2014 study included a large non-selected sample of patients with burdensome recalcitrant warts in a single center secondary hospital.
Limitations of this study include its retrospective nature, lack of a placebo group, and potential recall bias due to long follow-up period.
In this study, we tried to limit the recall bias by relying on electronic patients' records in case of discrepancies. Selection bias might also have been present, as it was probable that patients with painful or recalcitrant warts were more frequently referred to our secondary hospital than treated in primary care. These results might underestimate the true clearance rate, if the CPS1 solution were to be applied in patients with warts in a primary care setting. Additionally, previous research established that the HPV type in warts can also predict the response to certain treatments . In this retrospective study, the HPV types in warts were not tested and therefore the role of HPV type on clearance of warts in this study population remains unknown.

| CONCLUSION
This study established topical application of CPS1 solution as a safe, effective, and promising treatment modality for the management of cutaneous warts, especially in children. A large prospective (placebo controlled) randomized trial is indicated to further assess this promising safe and effective treatment for cutaneous warts.