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The Effectiveness of Cutaneous Wart Resolution with Current Treatment Modalities

Abstract Non-venereal warts are a frequent dermatological presentation with potential spontaneous regression in immunocompetent adults and children within 2 years. Evidence shows that conventional wart treatments are not a guaranteed treatment modality and can carry concerns regarding safety. The aim of this literature review was to identify the most effective treatments for wart resolution to guide clinical practice while identifying areas for further research. A systematic literature review was performed to determine the current treatment modalities for non-anogenital cutaneous warts in immunocompetent individuals and their effectiveness. Articles were categorized into one of eight groups depending on anatomical location, population age, or recalcitrant status with ranked levels of evidence. This literature review highlights a variety of treatments for non-venereal warts shown to be effective. In this instance where optimal evidence-based treatments are not available, clinical experience determines the most appropriate clinical practice. Further reproducible immunotherapy research on wart resolution is required to enable clear comparisons of these treatment modalities to conventional methods. Future clinical practice will require the human papillomavirus type to target the wart treatment accordingly; however, further research is required to determine these correlations.


IntroductIon
Verruca lesions are strategically named depending on their location: face, shins and dorsum of hands (verruca plana), soles of feet (verruca plantaris), common warts (verruca vulgaris), and surrounding nails (periungual verruca). Verruca lesions are caused by a localized infection of the keratinocytes by the human papillomavirus (HPV), which is a small deoxyribonucleic acid virus of the papovavirus family. [1] There are more than 150 different types of HPV identified with the majority of verruca vulgaris lesions caused by HPV types 1, 2, 4, 27, or 57 and verruca plana lesions by HPV types 3 or 10. [1] Viruses can be treated with antiviral agents; however, there is often a reliance on the body's defense mechanisms to control the spread and subsequent effects of viruses. Interestingly, there is selective research determining the HPV type for a cutaneous wart before targeting treatment accordingly. [2] Verruca lesions are identified as "recalcitrant" if they were resistant to an initial treatment method, clinically requiring an alternative therapy. [3] In immunocompetent individuals, spontaneous regression of warts is influenced by the rate of resolution, for example, host immunity, HPV type, and site of infection. However, treatment for instant eradication is favored over spontaneous resolution as natural resolution is found to be successful in only 40% of patients within 2 years. [4] The literature has shown that conventional treatments used in everyday practice are uniformly unsuccessful and carry concerns regarding safety. [3] A Cochrane review by Kwok et al. [4] completed a meta-analysis of the topical treatments for cutaneous warts. They found that liquid nitrogen cryotherapy had the same effectiveness as placebo; salicylic acid may be more effective on the hands and feet compared to placebo and no significant difference was found between salicylic acid and cryotherapy on all areas of the body. These findings are concerning for medical practitioners and for patients receiving treatment.
Over the past decade, interest in more sophisticated and focused wart treatments targeting the immune response to HPV has attracted considerable interest compared to the destructive and irritant approaches currently used. [5] Current verruca vulgaris research is focusing on immune-manipulation methods to determine their effectiveness. These include 5-fluorouracil, dinitrochlorobenzene, intralesional bleomycin, intralesional interferon, photodynamic therapy, and intralesional antigen. [4] Many of these new immunotherapy interventions have an unknown mechanism of action; however, these new immunotherapy interventions show positive signs of wart clearance at the site of injection and systemically. [3] This literature review is first to collate relevant articles over 10 years categorized into anatomical locations with recalcitrant and non-recalcitrant warts segregated. This will provide clarity on the effectiveness of treatment modalities for non-venereal wart resolution.

MaterIals and Methods
The following electronic search method was undertaken on March 22, 2017 following the PICO format to answer the question: What are the current treatment modalities for non-anogenital cutaneous warts in immunocompetent individuals and how effective are they?

Verruca vulgaris and verruca plantaris treatment: 34 articles
There were 19 Level II randomized control trials comparing varying treatment methods for verruca vulgaris lesions, as summarized in Table 1. Khozeimeh et al. [6] compared intralesional Candida albicans antigen and liquid nitrogen cryotherapy. There was a statistical significance in wart resolution with immunotherapy more successful. Shaheen et al. [7] found that purified protein derivative (PPD) and measles, mumps, and rubella (MMR) vaccine were statistically more effective than a saline injection for wart eradication; however, there was no statistical significance between PPD and MMR groups. Bruggink et al., [8] in a study of 406 participants, compared monochloroacetic acid (MCA) with cryotherapy on common warts and cryotherapy plus 50% salicylic acid on plantar warts. The study found no significant difference between the treatments for common or plantar warts; however, 212 participants did not adhere to the study protocol. A previous study by Bruggink et al. [9] found that cryotherapy was more effective for common warts than salicylic acid and the "wait-and-see" policy, but there was no difference in wart eradication between these treatments with plantar warts. Zamanian et al. [10] compared intralesional MMR vaccine and normal saline finding a statistical difference in the second and third visits with fewer lesions in the interventional group. However, 30% of the MMR group had influenza type side effects. A similar study by Nofal et al. [11] compared intralesional MMR and saline finding a statistical significance in therapeutic response with MMR being more effective. However, this was not the case with recalcitrant warts. Mohamad et al. [12] compared the MMR vaccine to saline in plantar warts with a statistical significance found for MMR having significant clearance. Cockayne et al. [13] compared cryotherapy and salicylic acid for plantar wart treatment finding no group more effective with relatively low clearance rates. Soni et al. [14] compared intralesional bleomycin and saline finding a statistical significance in resolution rate at 12 weeks in the intervention group. Dhar et al. [15] compared intralesional bleomycin and cryotherapy and found that bleomycin was significantly more effective than cryotherapy. Another previous study by Adalatkhah et al. [16] compared bleomycin and cryotherapy noting that bleomycin intralesional injection was more effective than cryotherapy. Akhyani et al. [17] compared pulsed dye laser (PDL) with cryotherapy and found no statistical significance between both interventions for complete remission. Huo et al. [18] studied local hyperthermia on plantar warts finding a statistical significant difference in cure rates for the local hyperthermia compared to a sham red dot without heat. Aksakal et al. [19] studied sublesional interferon-α injection in common warts finding a statistical significance between the intervention and the placebo as well as a statistical significance in response rate of a single wart more responsive than multiple lesions. Banihashemi et al. [20] compared cryotherapy and 80% phenol solution noting no statistical difference between the treatments. Yazdanfar et al. [21] compared 5-fluorouracil, lidocaine and epinephrine (5-FU+LE) against the placebo of normal saline finding a statistical significance in complete resolution for the intervention group. Ebrahimi et al. [22] compared 10% silver nitrate solution to black ink and found a statistical significant difference in cure rates in the intervention group as well as a statistical significant cure rate in females over males. Wenner et al. [23] compared duct tape occlusion therapy to placebo moleskin and found no statistical difference between the groups. Khattar et al. [24] compared topical zinc oxide and a combination of salicylic acid and lactic acid. They found no statistical difference between the groups for cure rates.
Three Level III-2 prospective cohort studies were noted. Kaçar et al. [25] compared topical CPS (1% cantharidin, 5% podophyllotoxin, 30% salicylic acid) and cryotherapy for plantar warts noting that topical CPS was significantly more effective than cryotherapy for resolution. Choi et al. [26] compared DCP (1% diphencyprone) to cryotherapy noting a statistical significance in clearance rate in the DCP group at 12 months. Bohlooli et al. [27] compared Fig  Tree latex and cryotherapy finding cryotherapy to be more effective for wart reduction.
Twelve Level IV experimental design studies with a one-arm intervention or retrospective experimental studies were analyzed. These research studies were conducted without a control group. These treatments included PPD, MMR vaccine, Candida antigen, Nd:YAG, mycobacterium w (Mw) vaccine, intralesional injection of photodynamic therapy, adapalene, CO 2 laser, and homologous autoimplantation.

Recalcitrant verruca vulgaris and verruca plantaris treatment: 14 articles
Four Level II randomized control trials were analyzed, as summarized in Table 2. Dhakar et al. [28] compared Mw vaccine and cryotherapy noting no statistical significance between the two groups. Amirnia et al. (2015) [29] compared intralesional PPD, liquid nitrogen cryotherapy, and saline placebo. They found a statistical No: compared to salicylic acid + lactic acid significance in clearance between PPD and the control. Togsverd-Bo et al. [30] compared intense pulsed light (IPL) and paring alone finding no statistical significant difference in clearance rate at 6 weeks. López-García et al. [31] compared oral zinc sulfate and starch placebo finding no significant difference in clearance rates between the two groups.
A Level III-2 non-randomized control trial compared PDL and Nd:YAG for warts eradication finding no statistical significance between the two groups.
Nine Level IV experimental design studies with a one-arm intervention or retrospective experimental studies were analyzed. These studies did not include a control group. The treatments included cantharidin/ podophyllotoxin/salicylic acid, MMR vaccine, Mw vaccine, C. albicans antigen, PDL, autowart injection, photodynamic therapy, and retinoid.

Pediatric verruca vulgaris treatment: 3 articles
Gladsjo et al., [33] in a Level II randomized controlled trial, compared 5% 5-fluorouracil cream with duct tape occlusion applied once a day to the same treatment applied twice a day. They found no significant difference in resolution rate between the two groups [ Table 3].
Bruggink et al., [34] in a Level III-2 prospective cohort study, analyzed the "wait-and-see" policy finding 50% of warts were gone in 1 year. Maronn et al. (2008), [35] in a Level IV retrospective experimental study on 170 patients with no control group, found that 87% had complete resolution with C. antigen injection.

Recalcitrant pediatric verruca vulgaris treatment: 3 articles
Two Level IV retrospective experimental studies with no control groups were found. Sethuraman et al. [36] with no control group found a 75% overall clearance rate using PDL. Fernández-Guarino et al. [32] found a 76.4% resolution rate with 3% topical Cidofovir applied twice daily without occlusion.
A nonrated case study (Kellis 2011) [37] found hypnosis for 6 weeks resolved the warts within 1 week with no recurrence.

Verruca plana treatment: 2 articles
Vali and Ferdowsi, [38] in a Level II randomized control trial, found that 50% citric acid solution was statistically significant in clearance rate as compared with 0.05% tretinoin lotion; however, no significant difference was noted in the onset of action [ Table 4].
A nonrated case study (Bhushan et al. 2014) [39] concluded that 200-mg hydroxychloroquine that was applied twice daily had complete resolution in 40 days.

Recalcitrant verruca plana treatment: 1 article
Kartal Durmazlar et al., [40] in a Level IV experimental design with a one-arm intervention, noted that all patients had clinical cure within 16 weeks using 0.7% cantharidin solution in acetone solution.

Periungual verruca treatment: 1 article
AlGhamdi and Khurram, [41] in a Level IV experimental design with a one-arm intervention, found that 86.6% had complete clearance with 1 mL bleomycin at 6 months after treatment.

Recalcitrant periungual verruca treatment: 2 articles
Espana et al., [42] in a Level IV retrospective experimental study, concluded that 50% of patients had complete clearance with Cidofovir cream application.

dIscussIon
Numerous wart treatment modalities have been researched with the aim to identify the most effective treatment for wart resolution. Of the studies each has its own intervention concentration, method protocol, and comparison. Determining the exact effectiveness of these treatments is made difficult with these varying parameters and absent comparison between each intervention.
Appreciating the meta-analysis findings on cutaneous wart treatments, Kwok et al. [4] highlighted the neutral comparison between cryotherapy and salicylic acid to placebo providing a basis for our analysis. This literature review discovers immunotherapy injections for treatment of verruca vulgaris and verruca plantaris lesions as more superior to the conventional methods. The immunotherapy treatments studied in randomized controlled trials considered to be effective include C. albicans antigen, PPD, MMR vaccine, and bleomycin. Interferon-α and 5-FU+LE are considered effective treatments against placebo; however, it is unknown how effective they are as compared to other treatment methods. Treatments found not to be effective include PDL, phenol, duct tape occlusion, and zinc oxide. Furthermore, when treating recalcitrant verruca vulgaris and verruca plantaris lesions there is no welldemonstrated effective treatment.
Pediatric populations still appear to greatly benefit from the "wait-and-see" policy with all other treatment modalities in an experimental phase. Recalcitrant and non-recalcitrant verruca plana and periungual lesions are still in experimental stages with potentially effective citric acid and tretinoin applications.
Interestingly, clinical practice has been known to encompass the use of surgical removal or electrosurgery for treatment of verruca lesions. However, this literature review was unable to appreciate the effectiveness of this modality with the absence of this method published during our search strategy. This is similar to potassium hydroxide, used in the pediatric verruca population, which was also not mentioned in the results.
The findings align with the study purpose of collating systematically searched literature on treatment modalities for wart resolution over the past 10 years. The findings also support the previous systematic review noting liquid nitrogen cryotherapy and salicylic acid treatments no more superior than placebo. [4] This literature review has highlighted a variety of treatments for non-venereal warts shown to be effective. In this instance where optimal evidence-based treatments are not available, clinical experience determines the clinical practice. This can include conventional treatments if the deemed necessary even though the current evidence does not clearly support their practice. From this study, we gain a greater insight of the effective treatment modalities for anatomical location, population group, and recalcitrant status. Even though the majority of the research into immunotherapy drugs is still in an experimental stage with varied methods, there is still continued evidence demonstrating their effectiveness. The prediction is that the shift to these experimental treatments will take place in the near future, once formal guidelines and further research is available.
The limitations of this study manifest from the limited optimal evidence (Level II NHMRC hierarchy) currently available on wart treatments. There is a vast availability of experimental studies; however, they do not have a control group to provide any comparison of their effectiveness.

Future dIrectIons
Larger, prospective controlled trials of non-venereal wart treatments including immunotherapy injections are required to determine the most effective practice and shape evidence based guidelines. The prediction is that future clinical practice will require the HPV type for each wart to target treatment accordingly;

Financial support and sponsorship
Nil.

Conflicts of interest
There are no conflicts of interest.