1. INTRODUCTION

Cutaneous warts are common viral skin lesions caused by the infection of the human papillomavirus (HPV). Recalcitrant or recurrent warts may be disfiguring and a source of embarrassment and frustration for patients [1Lipke MM. An armamentarium of wart treatments. Clin Med Res 2006; 4(4): 273-93.

[http://dx.doi.org/10.3121/cmr.4.4.273] [PMID: 17210977] ]. Children and immunocompromised persons tend to be most commonly affected by difficult to treat recalcitrant warts [2Leman JA, Benton EC. Verrucas. Guidelines for management. Am J Clin Dermatol 2000; 1(3): 143-9.

[http://dx.doi.org/10.2165/00128071-200001030-00001] [PMID: 11702295] -4Sterling JC, Handfield-Jones S, Hudson PM. Guidelines for the management of cutaneous warts. Br J Dermatol 2001; 144(1): 4-11.

[http://dx.doi.org/10.1046/j.1365-2133.2001.04066.x] [PMID: 11167676] ] Some lesions may spontaneously disappear but others may persist or even increase in number and size [2Leman JA, Benton EC. Verrucas. Guidelines for management. Am J Clin Dermatol 2000; 1(3): 143-9.

[http://dx.doi.org/10.2165/00128071-200001030-00001] [PMID: 11702295] , 4Sterling JC, Handfield-Jones S, Hudson PM. Guidelines for the management of cutaneous warts. Br J Dermatol 2001; 144(1): 4-11.

[http://dx.doi.org/10.1046/j.1365-2133.2001.04066.x] [PMID: 11167676] , 5Jenson AB, Kurman RJ, Lancaster WD. Tissue effects of and host response to human papillomavirus infection. Dermatol Clin 1991; 9(2): 203-9.

[PMID: 1647900] ]. Although several potential treatment options exist for warts, there is no single treatment that ensures a complete response and lack of recurrence. Treatments may initially be effective but recurrences after treatments are common [4Sterling JC, Handfield-Jones S, Hudson PM. Guidelines for the management of cutaneous warts. Br J Dermatol 2001; 144(1): 4-11.

[http://dx.doi.org/10.1046/j.1365-2133.2001.04066.x] [PMID: 11167676] , 5Jenson AB, Kurman RJ, Lancaster WD. Tissue effects of and host response to human papillomavirus infection. Dermatol Clin 1991; 9(2): 203-9.

[PMID: 1647900] ]. Current treatment options include: topical treatments (commonly salicylic acid), cryotherapy, LASER therapy, photodynamic therapy, surgical excision, immunotherapies, and home remedies such as duct tape or tea tree oil [6Sterling JC, Gibbs S, Haque Hussain SS, Mohd Mustapa MF, Handfield-Jones SE. British Association of Dermatologists’ guidelines for the management of cutaneous warts 2014. Br J Dermatol 2014; 171(4): 696-712.

[http://dx.doi.org/10.1111/bjd.13310] [PMID: 25273231] -8Pazyar N, Yaghoobi R, Bagherani N, Kazerouni A. A review of applications of tea tree oil in dermatology. Int J Dermatol 2013; 52(7): 784-90.

[http://dx.doi.org/10.1111/j.1365-4632.2012.05654.x] [PMID: 22998411] ]. Many of these options are scarring due to their destructive nature while other less invasive options may result in a lack of complete response or an increased chance of recurrence. Some may be painful or cause discomfort for the patient. Additionally, local treatments may be ineffective at treating patients with large lesions or multiple lesions. Furthermore, many of these options have unknown mechanisms of action and varying results among individuals. For this reason, treatment of warts may be challenging and frustrating for both the physician and patient [1Lipke MM. An armamentarium of wart treatments. Clin Med Res 2006; 4(4): 273-93.

[http://dx.doi.org/10.3121/cmr.4.4.273] [PMID: 17210977] ]. Unlike the other various options, immunotherapies target specific lesions and upregulate the immune system to recognize and destroy the lesions at the target site and distant locations. This more systemic approach has shown to be an inexpensive, effective method for treatment of individuals with multiple recalcitrant warts in the literature [9Aldahan AS, Mlacker S, Shah VV, et al. Efficacy of intralesional immunotherapy for the treatment of warts: A review of the literature. Dermatol Ther (Heidelb) 2016; 29(3): 197-207.

[http://dx.doi.org/10.1111/dth.12352] [PMID: 26991521] ]. Although the mechanism has not been completely understood, immunotherapies are believed to work by inducing a systemic T-cell mediated response at the location of contact or injection. It is also suggested that the injection itself may play a role in inducing the immune response [10Nofal A, Salah E, Nofal E, Yosef A. Intralesional antigen immunotherapy for the treatment of warts: current concepts and future prospects. Am J Clin Dermatol 2013; 14(4): 253-60.

[http://dx.doi.org/10.1007/s40257-013-0018-8] [PMID: 23813361] ]. The immunotherapies, thereby, help the body recognize the lesions and destroy them. Several specific antigens have been used for contact (topical) and intralesional immunotherapy treatments for cutaneous warts. Some contact immunotherapy antigens and contact allergens include: diphenylcyclopropenone (DPCP), Imiquimod 5% Cream, Bacillus Calmette-Guerin (BCG), dinitrochlorobenzene (DNCB), tuberculin jelly, and squaric acid dibutylester (SADBE). The most commonly studied intralesional immunotherapy antigens include: Candida albicans, measles-mumps-rubella (MMR) vaccine, tuberculin PPD, killed Myobacterium w, recombinant alpha-2 interferon, and Trichophyton. Bleomycin, an intralesional cytotoxic agent, is also commonly studied. Both intralesional immunotherapy approaches and contact immunotherapy approaches have been shown to be effective in the treatment of warts.

1.1. Efficacy of Contact Immunotherapies and Contact Allergens

Each contact immunotherapy antigen has shown to have varying, but promising, efficacies in the treatment of recalcitrant warts. Suh et al. performed an uncontrolled, open-label study which showed DPCP to have a clearance rate as high as 82.9% [11Suh DW, Lew BL, Sim WY. Investigations of the efficacy of diphenylcyclopropenone immunotherapy for the treatment of warts. Int J Dermatol 2014; 53(12): e567-71.

[http://dx.doi.org/10.1111/ijd.12688] [PMID: 25427069] ]. Imiquimod was shown to have a success rate of 44%, ranging from 27% to 89% in an evidence-based review performed by Ahn and Huang [12Ahn CS, Huang WW. Imiquimod in the treatment of cutaneous warts: an evidence-based review. Am J Clin Dermatol 2014; 15(5): 387-99.

[http://dx.doi.org/10.1007/s40257-014-0093-5] [PMID: 25186654] ]. In a study on children performed by Salem et al., BCG was shown to have a complete response on 65% of children with common warts and 45% of children with plantar warts [13Salem A, Nofal A, Hosny D. Treatment of common and plane warts in children with topical viable Bacillus Calmette-Guerin. Pediatr Dermatol 2013; 30(1): 60-3.

[http://dx.doi.org/10.1111/j.1525-1470.2012.01848.x] [PMID: 22958215] ]. One study exploring the efficacy and safety of SADBE for the treatment of recalcitrant warts in children found that 83% of patients experienced complete clearance. However, only 60% reported no adverse side effects [14Pandey S, Wilmer EN, Morrell DS. Examining the efficacy and safety of squaric acid therapy for treatment of recalcitrant warts in children. Pediatr Dermatol 2015; 32(1): 85-90.

[http://dx.doi.org/10.1111/pde.12387] [PMID: 25040421] ]. SADBE is limited because it can cause irritation when treating warts in the genital region [15Dall’ Oglio F, Nasca MR, D’Agata O, Micali G. Adult and paediatric contact immunotherapy with squaric acid dibutylester (SADBE) for recurrent, multiple, resistant, mucocutaneous anogenital warts. Sex Transm Infect 2002; 78(4): 309-10.

[http://dx.doi.org/10.1136/sti.78.4.309-a] [PMID: 12181482] ]. There are some reports of contact dermatitis and blistering as well, especially when treated with higher concentrations [15Dall’ Oglio F, Nasca MR, D’Agata O, Micali G. Adult and paediatric contact immunotherapy with squaric acid dibutylester (SADBE) for recurrent, multiple, resistant, mucocutaneous anogenital warts. Sex Transm Infect 2002; 78(4): 309-10.

[http://dx.doi.org/10.1136/sti.78.4.309-a] [PMID: 12181482] , 16Lee AN, Mallory SB. Contact immunotherapy with squaric acid dibutylester for the treatment of recalcitrant warts. J Am Acad Dermatol 1999; 41(4): 595-9.

[PMID: 10495383] ]. DNCB, although shown to be effective in the treatment of warts, is a known mutagenic and relatively expensive in comparison to other antigens. For this reason, DNCB although effective, is not often chosen because of the vast other antigens available for use immunotherapy. It has since been largely replaced by DPCP and SADBE, which are considered much safer options [17Singh G, Prakash B. Topical Immunotherapy: Role in Dermatology. Recent Advances in Dermatology 2014; 3: 126.]. Tuberculin Jelly, no longer largely studied as a potential wart therapy, had shown variable efficacy in the literature. Tuberculin PPD intralesional immunotherapy appears to have replaced tuberculin jelly because of its shorter treatment response and strength [17Singh G, Prakash B. Topical Immunotherapy: Role in Dermatology. Recent Advances in Dermatology 2014; 3: 126., 18Elela IM, Elshahid AR, Mosbeh AS. Intradermal vs intralesional purified protein derivatives in treatment of warts. Golf J Deramatol Venereol 2011; 18: 21-6.]. Contact immunotherapies present as an effective treatment for recalcitrant therapy for the treatment of recalcitrant warts. Of the contact immunotherapies, DPCP and SADBE are two of the most commonly used therapies because of their high success rates in achieving a complete response to treatment.

1.1.1. Efficacy of Intralesional Immunotherapies and Intralesional Cytotoxic Agents Intralesional immunotherapies have been the focus of several studies found in the literature. The interest in intralesional approaches may be the result of shorter treatment times, strength, and lesser adverse side effects with promising results. Additionally, intralesional immunotherapies elicit a response of warts at locations distant to the injection site. The injection itself may also help to induce an immune response at the target site. Several antigens have presented as effective options for use in intralesional immunotherapy approaches to treat warts. In a two year study at Mayo Clinic, 80% of patients had a response to Candida antigen with 39% having a complete response to treatment. It was also found that 7 of 8 immuno-compromised patients showed a partial or complete response to the antigen [19Alikhan A, Griffin JR, Newman CC. Use of Candida antigen injections for the treatment of verruca vulgaris: A two-year mayo clinic experience. J Dermatolog Treat 2016; 27(4): 355-8.

[http://dx.doi.org/10.3109/09546634.2015.1106436] [PMID: 26558635] ]. Another study, which used higher doses of Candida antigen, reported complete response rates as high as 82% [20Kim KH, Horn TD, Pharis J, et al. Phase 1 clinical trial of intralesional injection of Candida antigen for the treatment of warts. Arch Dermatol 2010; 146(12): 1431-3.

[http://dx.doi.org/10.1001/archdermatol.2010.350] [PMID: 21173332] ]. MMR vaccine has shown complete response rates as high as 75% in one study and 81% in another study. Both studies showed low recurrence among patients, but some patients (<30%) experienced flu-like symptoms during treatment [21Zamanian A, Mobasher P, Jazi GA. Efficacy of intralesional injection of mumps-measles-rubella vaccine in patients with wart. Adv Biomed Res 2014; 3: 107.

[http://dx.doi.org/10.4103/2277-9175.129701] [PMID: 24804181] -29Nofal A, Nofal E, Yosef A, Nofal H. Treatment of recalcitrant warts with intralesional measles, mumps, and rubella vaccine: a promising approach. Int J Dermatol 2015; 54(6): 667-71.

[http://dx.doi.org/10.1111/ijd.12480] [PMID: 25070525] ]. In a study performed by Saoji et al., tuberculin PPD showed a complete response rate of 76% in four treatments with very minimal adverse reactions to the antigen [22Saoji V, Lade NR, Gadegone R, Bhat A. Immunotherapy using purified protein derivative in the treatment of warts: An open uncontrolled trial. Indian J Dermatol Venereol Leprol 2016; 82(1): 42-6.

[http://dx.doi.org/10.4103/0378-6323.171650] [PMID: 26728809] ]. Myobacterium w vaccine showed complete response rates as high as 89% in a study performed by Gupta et al. and 93% in a study performed by Garg and Baveja [23Gupta S, Malhotra AK, Verma KK, Sharma VK. Intralesional immunotherapy with killed Mycobacterium w vaccine for the treatment of ano-genital warts: an open label pilot study. J Eur Acad Dermatol Venereol 2008; 22(9): 1089-93.

[http://dx.doi.org/10.1111/j.1468-3083.2008.02719.x] [PMID: 18484970] , 30Amirnia M, Khodaeiani E, Fouladi DF, Masoudnia S. Intralesional immunotherapy with tuberculin purified protein derivative (PPD) in recalcitrant wart: A randomized, placebo-controlled, double-blind clinical trial including an extra group of candidates for cryotherapy. J Dermatolog Treat 2016; 27(2): 173-8.

[http://dx.doi.org/10.3109/09546634.2015.1078871] [PMID: 26295565] ]. Another antigen, Alpha 2- interferon, has shown 50-70% complete response rates in genital warts, specifically. One major downside to interferon is that it has a much higher costs than other potential antigens for intralesional immunotherapies [24Kirby PK, Kiviat N, Beckman A, Wells D, Sherwin S, Corey L. Tolerance and efficacy of recombinant human interferon gamma in the treatment of refractory genital warts. Am J Med 1988; 85(2): 183-8.

[http://dx.doi.org/10.1016/S0002-9343(88)80339-5] [PMID: 2840824] ]. As a result, other antigens are preferred over interferon. Bleomycin, a relatively costly cytotoxic agent, has shown complete response rates ranging from 14-99% in the literature [25Lewis TG, Nydorf ED. Intralesional bleomycin for warts: a review. J Drugs Dermatol 2006; 5(6): 499-504.

[PMID: 16774100] ]. Studies using Trichophyton alone were not readily found, but Trichophyton was found to increase response rates when combined with other antigens in several studies. Trichophyton combined with other antigens MMR and Candida showed a complete response rate of 71% in a study performed Johnson and Horn [26Johnson SM, Horn TD. Intralesional immunotherapy for warts using a combination of skin test antigens: a safe and effective therapy. J Drugs Dermatol 2004; 3(3): 263-5.

[PMID: 15176159] ]. As shown above, various antigens for intralesional immunotherapies have shown extremely high response rates in the literature and may provide a reliable, effective option for patients in the treatment of difficult warts in the clinical setting.