Comparison of Cryotherapy and Topical Salicylic Acid in Common Warts: A Systematic Review and Meta-Analysis

. Background . Common warts are most common complaint among children and adults caused by human papillomavirus (HPV). Cryotherapy and topical salicylic acid are common therapies. Objective . To compare the efcacy and safety of cryotherapy and topical salicylic acid in common warts. Methods . Randomized controlled trials (RCTs) comparing cryotherapy and topical salicylic acid treatment in patients with common warts were searched by using PubMed, Embase, Google Scholar, and Cochrane Database of Systematic Reviews up to Oct 20, 2021. Te keywords were “common warts/verruca,” “cryotherapy,” and “salicylic acid.” Te language was restrained to English. No age or gender limitation was conducted. Te outcomes were complete remission of all warts at diferent observation times, recurrence rates, and side efects. Study-specifc efect sizes were pooled by using the fxed-efects model and the Mantel–Haenszel method. I 2 was used to assess heterogeneity of studies. Results . Seven articles involving 976 patients randomized into the cryotherapy group or salicylic acid group were included. Of whom, 487 patients received cryo-therapy, while 489 received salicylic acid treatment. With the fxed-efects model, the pool efect of complete clearance of warts at 12 weeks comparing cryotherapy and salicylic acid was not statistically signifcant (RR � 0.99 (0.84–1.17), I 2 � 0%). Conclusion . Comparable efcacy of cryotherapy and topical salicylic acid was conducted in common wart treatment. More high-quality pieces of evidence with more samples are needed to confrm the results for further recommendations.


Introduction
Common warts are widespread benign skin conditions caused by human papilloma virus (HPV) [1,2].Tey frequently afect the hands as well as feet but also in other sites.Tey are widespread in general population, estimated to afect approximately 7-12% populations worldwide [3].Tere are more than 200 types of HPV identifed, most of which are DNA viruses infecting epithelial cells [4].Tey afect any area on the skin and mucous membrane and are transmitted by direct or indirect contact.Although warts disappear spontaneously without treatment in 15-63% of cases in years [1], patients usually seek treatments to avoid physical discomfort and debilitating appearance.
Tere are several treatment options available for common warts, including cryotherapy, topically applied treatments, surgical curettage, and local hyperthermia [5].Topical salicylic acid is the frst-line treatment choice of common warts, and further treatment with cryotherapy is indicated as second-line therapy without clearance of warts [6].Cryotherapy is usually applied on lesions at intervals of 2-4 weeks by using liquid nitrogen, which works by freezing tissue, damaging intended cells and their vascular supply, and is also expected to stimulate the immune system which leads to resolution of warts [4].Salicylic acid is comparatively cheaper, readily available, and self-applicable topical treatment.It is efective for warts with limited adverse efects but requires daily application for several weeks [4].Local hyperthermia is a patent device held by our team.It destroyed HPV-infected tissue by antigen-presenting cells, Tcells, and natural killer cells at 44 °C [7].Our previous study including 1027 patients showed comparable complete clearance rates of plantar warts by local hyperthermia and cryotherapy (50.9% vs. 54.3%) 3 months after treatment [8].
Several studies reported cryotherapy and topical salicylic acid treatment in common warts.But the results were controversial.Terefore, we conducted the present systemic review and meta-analysis in order to compare the efcacy as well as safety of cryotherapy and topical salicylic acid in common warts.

Methods
Te procedure followed the recommendations for the Preferred Reporting Items for Systematic Review (PRISMA) [9] and the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane Collaboration, 2011).

Search Strategy.
Randomized controlled trials (RCTs) of cryotherapy and topical salicylic acid treatment in common warts of healthy, nonimmunocompromised adults, and/or children were searched by using PubMed, Google Scholar, Embase, and Cochrane Database of Systematic Reviews up to Oct 20, 2021.Te keywords were "common warts/verruca," "salicylic acid," and "cryotherapy."Te language was restrained to English.No age or gender limitation was conducted.

Study Selection and Data Extraction.
All studies with cure rates of both cryotherapy and salicylic acid treatments were selected by screening abstracts or even full text.Studies with recurrent/recalcitrant warts, genital warts, immunocompromised patients (such as agammaglobulinemia), impaired healing (such as diabetics), cold intolerance (such as cold urticaria or Raynaud's syndrome), blood dyscrasias of unknown origin, cryoglobulinemia, cryofbrinogenemia, and connective or autoimmune disease were excluded.Guidelines, review articles, commentary, salicylic acid, or cryotherapy used as adjuvant therapy and treatments other than salicylic acid and cryotherapy were also omitted.Relative data, including the frst author, year of publication, size/number of warts, age/gender of patients, and treatment procedure, were extracted by screening the full text.Two reviewers, Dipika Chaudhary and Anupama Bishwokarma, performed the procedure independently and discussed as well as consulted with a third reviewer, Archana Shrestha, with disagreements.

Quality Assessment.
Qualities of all the studies included were evaluated using the revised Cochrane risk-of-bias tool (RoB, version 2) for randomized trials.RoB 2 is designed into a fxed set of domains of bias, aimed at focusing various traits of trial designing, conducting, and reporting.Tere are 5 domains in RoB: biases as a result of the randomization process, biases owing to deviations from intended interventions, biases as a result of missing outcome data, biases in the measurement of the outcome, and bias during selection of the reported result.In each domain, there are a series of questions (signaling questions) focused on obtaining information regarding features of the trial, which are signifcant to the risk of bias.For each domain, a response (yes, probably yes, probably no, no, or no information) was defned according to each study.Ten, the quality was evaluated by the algorithm as a low risk, some concerns, or a high risk [10].

Outcomes.
Complete remission of all warts was described as the complete restoration of normal skin.Te outcomes were complete remission of all warts at diferent observation times, recurrence rates, and side efects.

Statistical Analysis.
All of the statistical analysis was conducted by using R version 4.0.3(the R Foundation for Statistical Computing, Vienna, Austria) [11].Study-specifc efect sizes were pooled by using the fxed-efects model [12] and the Mantel-Haenszel method.I 2 was used to assess heterogeneity of studies.Te forest plot, funnel plot, and pooled relative risk (RR) were conducted by using the "meta" package [13].Robustness was performed by leaveone-out sensitivity analysis in the "metainf" function of the meta package.

Eligible Studies.
A total of 617 studies were retrieved.After screening titles as well as abstracts of the yielded studies, 208 duplicates and 269 studies which failed to meet the inclusion criteria were excluded.Tus, the remaining 140 articles were selected for full-text review.Subsequently, 133 studies with recurrent warts/recalcitrant warts, genital warts, guidelines or review articles, commentary, salicylic acid, or cryotherapy used as adjuvant therapy or treatments other than salicylic acid and cryotherapy were excluded.At last, 7 studies were selected for the following meta-analysis [14][15][16][17][18][19][20] (Figure 1).

Basic Characteristics and Interventions of the Studies
Included.A total of 976 patients with common warts were treated with either cryotherapy or salicylic acid.Teir age ranged from 4 to 79 years old.Sample size ranged from 70 [18] to 240 [14] (Table 1).
A total of 487 patients were treated with cryotherapy, which was performed 4-6 sessions at hospital with an interval of 2-3 weeks.Te other 489 patients were treated with 20-50% salicylic acid, which was applied topically by themselves every day for a maximum of 8-12 weeks.Te follow-up periods were 6 weeks for 1 study [17], 12 weeks for 5 studies [14][15][16][17]19], and 6 months for the other one [20] (Table 2).

Full text articles assessed for eligibility n=140
Studies included in meta analysis n=7 Excluded records (n=477 One study reported the complete remission rate of all warts between cryotherapy and salicylic acid treatment at 6 weeks [17].Te complete remission rate was comparable in the salicylic acid group (66.7%) and the cryotherapy group (56.9%) (p � 0.415).

Complete Remission Rate of All Warts at 12 Weeks.
Four studies compared the complete remission rate of all warts treated by cryotherapy or salicylic acid at 12 weeks [14,16,18,19].With the fxed-efects model, there was not any statistical signifcance between the two groups, RR � 0.99 (0.84-1.17) with a heterogeneity of I 2 � 0% (Figure 3).

Complete Remission Rate of All Warts at 13 Weeks.
One study reported the complete remission rate of all warts between cryotherapy and salicylic acid treatment at 13 weeks [15].Te cure rate was observed to be higher in the cryotherapy group (39%) than that in the salicylic acid group (24%) (p < 0.05).Te relative risk between cryotherapy and salicylic acid was 1.6 (95% CI: 1.0-2.6).

Complete Remission Rate of All Warts at 24 Weeks.
Only 1 study reported the complete remission rate of all warts between cryotherapy and salicylic acid treatment at 24 weeks [20].For common warts in hands, the complete remission rate was 62.5% in the cryotherapy group and 60.5% in the salicylic acid group (p < 0.05); for those in feet, the complete remission rate was 57.7% in the cryotherapy group and 40.9% in the salicylic acid group (p < 0.05).
3.4.6.Side Efects.Two studies reported side efects between cryotherapy and salicylic acid on warts [15,18].In Cockayne's study, patients after cryotherapy sufered from more side efects than those after topical salicylic acid treatment.Te side efects included pain, scarring, blistering, crust, pigmentation, and irritation.A total of 28 adverse events Dermatologic Terapy were reported, including 1 serious one (not related to the treatment in the salicylic acid group) and 27 nonserious ones.For the remaining 27 reported events, 14 were in the cryotherapy group (2 related events of blisters, 7 were unrelated, and 5 unlikely to be related) and 13 were in the salicylic acid group (9 unrelated and 4 unlikely to be related) [18].In Bruggink's study, more patients treated with salicylic acid (54%) reported signifcant treatment burden than those with cryotherapy (31%) (p � 0.040), such as pain, blistering, and scarring [15].

Leave-One Out Sensitivity Analysis.
Te leave-one out sensitivity analysis was conducted by eliminating one study at a time in sequential order, pooled RR was recalculated for the remaining studies, and the efect of removing each study based on the I 2 statistic was evaluated.It showed how an individual study afected the overall estimate of the rest ones [21].Te pooled RRs did not change signifcantly, ranging from 1.0487 (95% CI: 0.9183; 1.1976) to 1.1455 (95% CI: 0.9694; 1.3536).I 2 indicated small heterogeneity among studies, varied from 0.0% to 20.3% (Table 3).

Publication Bias.
Te publication bias of the 7 studies was shown in the funnel plot (Figure 4).Te points were few but scattered symmetrically, which indicated lower publication bias.We could not use Egger's test to evaluate the potential publication bias because fewer studies were involved in meta-analysis (<10) [22].

Discussion
Cryotherapy commonly uses liquid nitrogen with a temperature of −196 °C, which works by either necrotic destruction of HPV-infected keratinocytes or local infammation triggering cell-mediated response [6].Te efcacy varies in mode of application, treatment intervals, and freeze times.Increased efcacy is conducted by aggressive cryotherapy, accompanied with higher risks of side efects, such as pain, scarring, blistering, crust, pigmentation, and irritation [23].Hyperpigmentation or hypopigmentation may occur, especially in dark-skinned patients [18].Moreover, side efects are more common in treatment regimens with a shorter interval.Terefore, preventive measures must be taken during application of cryotherapy adjacent to the cutaneous nerves, nail apparatus, and tendons, as well as in patients with arterial or venous circulation impairment.Topical salicylic acid is a keratolytic agent which gradually destroys the epidermis infected by virus, and the mild irritation may activate an immune response.Te concentration preparation may vary from 10% to 60%.Te available preparations over the counter are 17% salicylic acid combined with a fexible collodion base or as 20%, 40%, and 50% in Vaseline ointment [6].Before each application of topical salicylic acid, warts should be soaked in warm water for approximately 5 minutes, and then, the dead tissues should be removed using a fle.Patients should be very careful when paring in order to avoid abrading the adjacent normal skin, as it may spread the disease.
Both treatments are destructive therapy.As we know, there were 4 studies with meta-analysis reported the comparison of efectiveness and cost between cryotherapy and topical salicylic acid in common warts.All of them showed no signifcant diference in efcacy [4,24,25].Our fndings were consistent with those of previous ones, but the number of patients and studies included were more than theirs.Nowadays, topical salicylic acid is frst-line therapy, while cryotherapy is second-line therapy for common warts [18].Terefore, we suggest that both topical salicylic acid and cryotherapy should be the frst choice for common warts according to the present results.
Furthermore, salicylic acid is convenient and cheap but requires daily application up to 8 weeks.Terefore, patient compliance plays a major role.Moreover, all salicylic acid can cause chemical burns so it should not be applied to poor healing areas such as neuropathic feet, except for few very low-strength ones.Tus, they are forbidden to apply on the face because of risk of irritant burning [26].Since both salicylic acid and cryotherapy have a higher probability of adverse reactions and recurrence, photodynamic therapy might be a better choice with better efcacy, fewer adverse reactions, and lower recurrence rates [27].Te mechanism might be associated with antiviral activity, local immunity, and reactive oxygen species [28].Terefore, patients could choose either treatment as their convenience.
However, there were some limitations in this review.On the one hand, although the funnel plot was symmetrically distributed, it was difcult to conclude that publication bias was absent because only 7 RCTs were included.On the other hand, the individual study quality assessment indicated a high risk of publication bias, except for one.Terefore, we acknowledge that our metaanalysis could have been afected by publication bias, with inclusion of disproportionately higher number of studies with hypothesized outcomes.Moreover, topical salicylic acid was self-administered by patients themselves so it was bound to have some variations in compliance, as it would reduce the efcacy compared to treatments applied by health professions.

Conclusion
Te present study concluded a comparable efcacy of cryotherapy and topical salicylic acid for the treatment of common warts.More pieces of evidence with higher qualities and sample sizes are needed to confrm the results for further recommendations.Figure 4: Publication bias of the included studies.Te funnel plot was generated using the "meta" package of R. Te vertical axis represents the standard error, and the horizontal axis represents the risk ratio of all the included studies.

Figure 2 :
Figure 2: Quality assessments of the included studies.

Table 1 :
Basic characteristics of the included studies.

Table 2 :
Interventions and outcomes of the included studies.
Comparison of complete clearance of common warts at 12 weeks between cryotherapy and salicylic acid.Te forest plot was generated using the "meta" package of R.

Table 3 :
Leave-one out sensitivity analysis.