Abstract
Introduction
Warts are caused by the human papillomavirus (HPV), of which there are over 100 types, which 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 June 2008 (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 12 systematic reviews, RCTs, or observational 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; cimetidine; contact immunotherapy; cryotherapy; duct tape occlusion; formaldehyde, glutaraldehyde; homeopathy; photodynamic treatment; pulsed dye laser; surgical procedures; topical salicylic acid; and zinc sulphate.
Key Points
Warts are caused by the human papillomavirus (HPV), of which there are over 100 types, which 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 complete wart clearance compared with placebo.
Cryotherapy may be as effective at increasing wart clearance as topical salicylic acid, but studies have been small and have given inconclusive results. We found insufficient evidence on the effects of cryotherapy versus placebo.
Photodynamic treatment may increase the proportion of warts cured compared with placebo, although RCTs were small. It may increase pain or discomfort compared with 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 don't know whether cimetidine, formaldehyde, glutaraldehyde, homeopathy, duct tape occlusion, pulsed dye laser, surgery, or oral zinc sulphate increase cure rates compared with placebo, as few high-quality studies have been found.
About this condition
Definition
Non-genital warts (verrucas) are an extremely common, benign, and usually 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). 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. One systematic review (search date 2005; 60 RCTs) comparing local treatments with placebo found that 48% of people using placebo (range 10%–54%) had no warts at between 6 weeks and 18 months after initiation of therapy.
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 June 2008. We have reported complete wart clearance where possible; however, some RCTs reported outcomes such as number of warts cured or loss of single warts. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2008, Embase 1980 to June 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials, 2008, Issue 2 (1966 to date of issue). An additional search was carried out of the NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language and with more than 80% of patients followed up. We included trials of any size. A minimum length of follow-up for inclusion was 4 weeks. We included studies described as "open", "open label", or not blinded. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (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)? | |||||||||
| 5 (322) | 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 |
| 2 (69) | Wart clearance | Cryotherapy versus placebo or no treatment | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and weak methods. Directness point deducted for inclusion of different types of wart (some resistant to treatment) |
| 1 (30) | 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 |
| 2 (320) | Wart clearance | Cryotherapy versus topical salicylic acid | 2 | –1 | 0 | –1 | 0 | Low | Quality point deducted for weak methods. Directness point deducted for inclusion of co-interventions |
| 4 (592) | Wart clearance | Aggressive versus gentle cryotherapy | 4 | –1 | +1 | –2 | 0 | Low | Quality point deducted for weak methods. Consistency point added for evidence of dose effect. Directness points deducted for different definitions of aggressive and gentle between RCTs, and inclusion of co-interventions |
| 3 (at least 313) | Wart clearance | Interval between freezes | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for weak methods. Directness point deducted for differences in populations |
| 2 (112) | Wart clearance | Photodynamic treatment versus placebo photodynamic treatment | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. 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% |
| 1 (44) | Wart clearance | Intralesional bleomycin versus cryotherapy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (163) | Wart clearance | Cimetidine versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for different regimens |
| 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 |
| 2 (241) | Wart clearance | Homeopathy versus placebo | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for lack of comparators and no statistical follow-up in 1 RCT |
| 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, Social Hygiene Service, Centre for Health Protection, Department of Health, , Hong Kong SAR.
William Yuk-ming Tang, Shatin International Medical Centre, Union Hospital, , Hong Kong SAR.
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