Abstract
Introduction
Warts are caused by the human papillomavirus (HPV), of which there are over 100 types. HPV probably infects the skin via areas of minimal trauma. Risk factors include use of communal showers, occupational handling of meat, and immunosuppression. In immunocompetent people, warts are harmless and resolve as a result of natural immunity within months or years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for warts (non-genital)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 17 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic, review we present information relating to the effectiveness and safety of the following interventions: intralesional bleomycin; intralesional candida antigen; contact immunotherapy; cryotherapy; duct tape occlusion; photodynamic treatment; pulsed dye laser; surgical procedures; and topical salicylic acid.
Key Points
Warts are caused by the human papillomavirus (HPV), of which there are over 100 types. HPV probably infects the skin via areas of minimal trauma.
Risk factors include use of communal showers, occupational handling of meat, and immunosuppression.
In immunocompetent people, warts are harmless and resolve as a result of natural immunity within months or years.
For what is such a common condition, there are few large, high-quality RCTs available to inform clinical practice.
Topical salicylic acid increases the cure rate of warts compared with placebo.
Cryotherapy may be as effective at increasing the cure rate of warts as topical salicylic acid, but we don't know about wart recurrence. We found insufficient evidence on the effects of cryotherapy versus placebo.
Contact immunotherapy with dinitrochlorobenzene may increase wart clearance compared with placebo, but it can cause inflammation.
We don't know whether intralesional bleomycin speeds up clearance of warts compared with placebo, as studies have given conflicting results.
We found no systematic reviews or RCTs about the effects of intralesional candida antigens.
We don't know whether duct tape occlusion, pulsed dye laser, photodynamic treatment, or surgery increase cure rates compared with placebo, as few high-quality studies have been found.
We found limited evidence from one small RCT that photodynamic treatment plus topical salicylic acid may increase the proportion of warts cured compared with placebo plus topical salicylic acid; however, it may increase pain or discomfort compared with placebo.
About this condition
Definition
Non-genital warts (verrucas) are an extremely common, benign, and usually a self-limited skin disease. Infection of epidermal cells with the human papillomavirus (HPV) results in cell proliferation and a thickened, warty papule on the skin. There are over 100 different types of HPV. The appearance of warts is determined by the type of virus and the location of the infection. Any area of skin can be infected, but the most common sites are the hands and feet. Genital warts are not covered in this review (see review on Genital warts). We have also excluded RCTs in people with immunosuppression in this review. Common warts are most often seen on the hands and present as skin-coloured papules with a rough 'verrucous' surface. Flat warts are most often seen on the backs of the hands and on the legs. They appear as slightly elevated, small plaques that are skin-coloured or light brown. Plantar warts occur on the soles of the feet and look like very thick callouses.
Incidence/ Prevalence
There are few reliable, population-based data on the incidence and prevalence of non-genital warts. Prevalence probably varies widely between different age groups, populations, and periods of time. Two large population-based studies found prevalence rates of 0.84% in the US and 12.9% in Russia. Prevalence is highest in children and young adults, and two studies in school populations have shown prevalence rates of 12% in 4- to 6-year-olds in the UK and 24% in 16- to 18-year-olds in Australia.
Aetiology/ Risk factors
Warts are caused by HPV, of which there are over 100 different types. They are most common at sites of trauma, such as the hands and feet, and probably result from inoculation of virus into minimally damaged areas of epithelium. Warts on the feet can be acquired from walking barefoot in areas where other people walk barefoot. One observational study (146 adolescents) found that the prevalence of warts on the feet was 27% in those that used a communal shower room and 1.3% in those that used the locker (changing) room. Warts on the hand are also an occupational risk for butchers and meat handlers. One cross-sectional survey (1086 people) found that the prevalence of warts on the hand was 33% in abattoir workers, 34% in retail butchers, 20% in engineering fitters, and 15% in office workers. Immunosuppression is another important risk factor. One observational study in immunosuppressed renal transplant recipients found that, at 5 years or longer after transplantation, 90% had warts.
Prognosis
Non-genital warts in immunocompetent people are harmless and usually resolve spontaneously as a result of natural immunity within months or years. The rate of resolution is highly variable and probably depends on several factors, including host immunity, age, HPV type, and site of infection. One cohort study (1000 children in long-stay accommodation) found that two-thirds of warts resolved without treatment within a 2-year period.
Aims of intervention
To eliminate warts, with minimal adverse effects.
Outcomes
Wart clearance (generally accepted as complete eradication of warts from the treated area); reduction in number of warts (if wart clearance not reported); wart recurrence; and adverse effects of treatment.
Methods
Clinical Evidence search and appraisal October 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to October 2013, Embase 1980 to October 2013, and The Cochrane Database of Systematic Reviews 2013, issue 9 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) Database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in the English language, blinded or open label trials, studies of any size of which more than 80% of participants were followed up. There was a minimum follow-up of 4 weeks. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Warts (non-genital).
| Important outcomes | Wart clearance, Wart recurrence | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments for warts (non-genital)? | |||||||||
| 6 (486) | Wart clearance | Topical salicylic acid versus placebo or no treatment | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for weak methods; directness points deducted for inclusion of co-interventions and trial heterogeneity |
| 2 (80) | Wart clearance | Contact immunotherapy (dinitrochlorobenzene) versus placebo or no treatment | 4 | –2 | 0 | –1 | +1 | Low | Quality points deducted for sparse data and inclusion of abstract in analysis; directness point deducted for unclear length of follow-up in 1 RCT; effect-size point added for RR >2 |
| 4 (247) | Wart clearance | Cryotherapy versus placebo or no treatment | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for weak methods; directness points deducted for no statistical analyses between groups in 1 RCT and for unclear length of follow-up in 1 RCT |
| 2 (42) | Wart clearance | Cryotherapy versus photodynamic treatment | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results; directness point deducted for inclusion of co-interventions |
| 5 (900) | Wart clearance | Cryotherapy versus topical salicylic acid | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for weak methods |
| 1 (240) | Wart recurrence | Cryotherapy versus topical salicylic acid | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for no statistical analysis between groups and for inclusion of plantar warts only |
| 2 (318) | Wart clearance | Cryotherapy plus salicylic acid versus salicylic acid alone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for unspecified blinding in 1 RCT; directness point deducted for inclusion of hand warts only in 1 RCT |
| 2 (328) | Wart clearance | Cryotherapy plus salicylic acid versus cryotherapy alone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for unspecified blinding in 1 RCT; directness point deducted for inclusion of hand warts only in 1 RCT |
| 4 (592) | Wart clearance | Aggressive versus gentle cryotherapy | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for weak methods; directness points deducted for different definitions of aggressive and gentle between RCTs, and inclusion of co-interventions |
| 3 (313) | Wart clearance | Interval between cryotherapy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for weak methods; directness point deducted for differences in populations |
| 2 (57) | Wart clearance | Photodynamic treatment versus placebo photodynamic treatment | 4 | –2 | 0 | –1 | 0 | Very low | Quality point deducted for sparse data and incomplete reporting of results; directness point deducted for inclusion of co-interventions |
| 1 (56) | Wart clearance | Different types of photodynamic treatment versus each other | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results; directness point deducted for no statistical analysis between groups |
| 4 (133) | Wart clearance | Intralesional bleomycin versus placebo | 4 | –1 | –1 | –2 | 0 | Very low | Quality point deducted for sparse data; consistency point deducted for conflicting results; directness points deducted for combined control group, and randomising by people but analysing by warts |
| 1 (26) | Wart clearance | Different concentrations of intralesional bleomycin | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, exclusion of warts that spontaneously regressed from the analysis, and a high withdrawal rate in people receiving intralesional bleomycin 0.25% |
| 2 (117) | Wart clearance | Intralesional bleomycin versus cryotherapy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for no statistical analysis between groups in 1 RCT |
| 2 (193) | Wart clearance | Duct tape occlusion versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for age differences between populations |
| 1 (17) | Wart recurrence | Duct tape occlusion versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for subgroup analysis |
| 1 (61) | Wart clearance | Duct tape occlusion versus cryotherapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and poor outcome assessment |
| 1 (37) | Wart clearance | Pulsed dye laser versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and not specifying number of warts per treatment group at baseline |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Contact immunotherapy
Contact sensitisers such as dinitrochlorobenzene, diphencyprone, and squaric acid dibutyl ester result in allergic dermatitis, which stimulates an immune reaction in close proximity to the wart.
- Cryotherapy
A destructive treatment based on the targeted freezing of tissue using liquid nitrogen, dimethyl ether propane, or carbon dioxide snow. Liquid nitrogen achieves the lowest temperatures and is now the most commonly used agent.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Photodynamic treatment
Combines the application of a photosensitising substance (usually aminolaevulinic acid) to the wart and subsequent irradiation with wavelengths of light that are absorbed by the photosensitising substance and lead to destruction of the target tissue.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Genital warts
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Steven King-fan Loo, Hong Kong Adventist Hospital, , Hong Kong SAR.
William Yuk-ming Tang, , , Hong Kong SAR.
References
- 1.Johnson ML, Roberts J. Skin conditions and related need for medical care among persons 1–74 years. US Department of Health Education and Welfare Publication 1978;1660:1–26. [PubMed] [Google Scholar]
- 2.Beliaeva TL. The population incidence of warts. Vestn Dermatol Venerol 1990;2:55–58. [PubMed] [Google Scholar]
- 3.Williams HC, Pottier A, Strachan D. The descriptive epidemiology of warts in British schoolchildren. Br J Dermatol 1993;128:504–511. [DOI] [PubMed] [Google Scholar]
- 4.Kilkenny M, Merlin K, Young R, et al. The prevalence of common skin conditions in Australian school students: 1. common, plane and plantar viral warts. Br J Dermatol 1998;138:840–845. [DOI] [PubMed] [Google Scholar]
- 5.Johnson LW. Communal showers and the risk of plantar warts. J Fam Pract 1995;40:136–138. [PubMed] [Google Scholar]
- 6.Keefe M, al-Ghamdi A, Coggon D, et al. Cutaneous warts in butchers. Br J Dermatol 1995;132:166–167. [DOI] [PubMed] [Google Scholar]
- 7.Leigh IM, Glover MT. Skin cancer and warts in immunosuppressed renal transplant recipients. Recent Results Cancer Res 1995;139:69–86. [DOI] [PubMed] [Google Scholar]
- 8.Massing AM, Epstein WL. Natural history of warts. Arch Dermatol 1963;87:303–310. [DOI] [PubMed] [Google Scholar]
- 9.Kwok CS, Gibbs S, Bennett C, et al. Topical treatments for cutaneous warts. In: The Cochrane Library, Issue 9, 2013. Chichester, UK: John Wiley & Sons, Ltd. Search date 2011. 22972052 [Google Scholar]
- 10.Wilson P. Immunotherapy v cryotherapy for hand warts; a controlled trial (abstract). Scot Med J 1983;28:191. [Google Scholar]
- 11.Rosado-Cancino MA, Ruiz-Maldonado R, Tamayo L, et al. Treatment of multiple and stubborn warts in children with 1-chloro-2,4-dinitrobenzene (DNCB) and placebo. Dermatol Rev Mex 1989;33:245–252. [Google Scholar]
- 12.Yu YE, Kuohung V, Gilchrest BA, et al. Photodynamic therapy for treatment of hand warts. Dermatol Surg 2012;38:818–820. [DOI] [PubMed] [Google Scholar]
- 13.Stender IM, Lock-Anderson J, Wulf HC. Recalcitrant hand and foot warts successfully treated with photodynamic therapy with topical 5-aminolaevulinic acid: a pilot study. Clin Exp Dermatol 1999;24:154–159. [DOI] [PubMed] [Google Scholar]
- 14.Cockayne S, Curran M, Denby G, et al; EVerT team. EVerT: cryotherapy versus salicylic acid for the treatment of verrucae – a randomised controlled trial. Health Technol Assess 2011;15:1–170. [DOI] [PubMed] [Google Scholar]
- 15.Bruggink SC, Gussekloo J, Berger MY, et al. Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial. CMAJ 2010;182:1624–1630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Connolly M, Basmi K, O'Connell M, et al. Cryotherapy of viral warts: a sustained 10-s freeze is more effective than the traditional method. Br J Dermatol 2001;145:554–557. [DOI] [PubMed] [Google Scholar]
- 17.Bourke JF, Berth-Jones J, Hutchinson PE. Cryotherapy of common viral warts at intervals of 1, 2 and 3 weeks. Br J Dermatol 1995;132:433–436. [DOI] [PubMed] [Google Scholar]
- 18.Stender IM, Na R, Fogh H, et al. Photodynamic therapy with 5-aminolaevulinic acid or placebo for recalcitrant foot and hand warts: randomised double-blind trial. Lancet 2000;355:963–966. [DOI] [PubMed] [Google Scholar]
- 19.Veien NK, Genner J, Brodthagen H, et al. Photodynamic inactivation of Verrucae vulgares II. Acta Derm Venereol 1977;57:445–447. [PubMed] [Google Scholar]
- 20.Bunney MH, Nolan MW, Buxton PK, et al. The treatment of resistant warts with intralesional bleomycin: a controlled clinical trial. Br J Dermatol 1984;111:197–207. [DOI] [PubMed] [Google Scholar]
- 21.Rossi E, Soto JH, Battan J, et al. Intralesional bleomycin in Verruca vulgaris Double-blind study. Dermatol Rev Mex 1981;25:158–165. [Google Scholar]
- 22.Munkvad M, Genner J, Staberg B, et al. Locally injected bleomycin in the treatment of warts. Dermatologica 1983;167:86–89. [DOI] [PubMed] [Google Scholar]
- 23.Perez Alfonzo R, Weiss E, Piquero Martin J. Hypertonic saline solution vs intralesional bleomycin in the treatment of common warts. Dermatol Venez 1992;30:176–178. [Google Scholar]
- 24.Hayes ME, O'Keefe EJ. Reduced dose of bleomycin in the treatment of recalcitrant warts. J Am Acad Dermatol 1986;15:1002–1006. [DOI] [PubMed] [Google Scholar]
- 25.Adalatkhah H, Khalilollahi H, Amini N, et al. Compared therapeutic efficacy between intralesional bleomycin and cryotherapy for common warts: a randomized clinical trial. Dermatol Online J 2007;13:4. [PubMed] [Google Scholar]
- 26.Dhar SB, Rashid MM, Islam A, et al. Intralesional bleomycin in the treatment of cutaneous warts: a randomized clinical trial comparing it with cryotherapy. Indian J Dermatol Venereol Leprol 2009;75:262–267. [DOI] [PubMed] [Google Scholar]
- 27.Wenner R, Askari SK, Cham PM, et al. Duct tape for the treatment of common warts in adults: a double-blind randomized controlled trial. Arch Dermat 2007;143:309–313. [DOI] [PubMed] [Google Scholar]
- 28.de Haen M, Spigt MG, van Uden CJ, et al. Efficacy of duct tape vs placebo in the treatment of verruca vulgaris (warts) in primary school children. Arch Pediat Adol Med 2006;160:1121–1125. [DOI] [PubMed] [Google Scholar]
- 29.de Haen M, Spigt MG, van Uden CJ, et al. Duct tape or placebo? Treatment of warts in primary school children. Huisarts en Wetenschap 2007;50:416–421. 17088514 [Google Scholar]
- 30.Focht DR, Spicer C, Fairchok MP. The efficacy of duct tape vs cryotherapy in the treatment of Verruca vulgaris (the common wart). Arch Pediatr Adolesc Med 2002;156:971–974. [DOI] [PubMed] [Google Scholar]
- 31.Passeron T, Sebban K, Mantoux F, et al. [595 nm pulse dye laser therapy for viral warts: a single-blind randomized comparative study versus placebo]. Ann Dermatol Vener 2007;134:135–139. [In French] [DOI] [PubMed] [Google Scholar]