Abstract
Evaluation of: Kwok CS, Gibbs S, Bennett C, Holland R, Abbott R. Topical treatments for cutaneous warts. Cochrane Database Syst. Rev. 9, CD001781 (2012).
Cutaneous warts are common skin lesions caused by human papillomavirus infection. Their treatment is aimed at relieving a patient’s physical and psychological discomfort, and at preventing spread of infection by autoinoculation. The aim of the article under review is to describe the outcome of current therapies for cutaneous warts according to randomized controlled trials. Results from pooled data show that significantly higher remission rates may be expected with salicylic acid and cryotherapy, best if used in combination. Limited data on adverse effects suggest that these are mild, well tolerated and more common with cryotherapy.
Treatment of cutaneous warts (CWs) is aimed at relieving patient’s physical and psychological discomfort, and at preventing the spread of infection by autoinoculation. It is often troublesome, as no specific therapy addressing human papillomavirus (HPV) infection is available so far. Different treatments for warts may be considered, including prescription drugs, over-the-counter medications and physical destructive methods, but as yet no treatment has been proven to be 100% effective in achieving complete remission. Kwok et al. have recently reported the results of an updated systematic review of available randomized controlled trials (RCTs) on CWs Citation[1].
Methods & results
To assess evidence regarding efficacy of topical treatments for CWs, the authors selected all articles published from 1981 to 2011, using systematic electronic searches from multiple databases.
From this search, the authors selected 1106 abstracts related to clinical trials on CWs. However, review of such trials disclosed highly variable methods and quality (with only a few number of placebo RCTs). A total of 85 RCTs (randomized participants: 8815) supported by rigorous trial design were considered. The type of topical interventions was classified into 12 therapeutic categories, as follows: topical salicylic acid (SA), cryotherapy, intralesional bleomycin, intralesional interferons, dinitrochlorobenzene (DNCB), photodynamic therapy, duct tape, pulsed-dye therapy, topical 5-fluorouracil (5-FU), intralesional 5-FU, topical zinc and others (topical imiquimod, formic acid puncture, traditional Chinese medicine, acyclovir cream, hyperthermia, topical Thuja, intralesional mumps, measles and rubella vaccine, and silver nitrate).
Fourteen RCTs demonstrated the efficacy of SA, a keratolytic agent, used with or without lactic acid (LA), with cure rates ranging from 68 to 87%. Data pooled from a meta-analysis of six RTCs showed, that after 6–12 weeks of treatment, there were statistically significant cure rates of SA versus placebo for warts at all sites. Subgroup analysis showed a greater efficacy of SA on the hands (two studies) compared with feet (two studies). The product is generally inexpensive, easy and safe to apply, and adverse effects (local irritation, pruritus and burning) are mild and well tolerated. Only one case of cellulitis was reported after treatment with monochloroacetic acid and 60% SA.
Data from 21 RCTs using cryotherapy, a common destructive method based on the use of liquid nitrogen at -196°C as cryogen, resulted to be somewhat contradictory. A meta-analysis of three RCTs showed no advantage of cryotherapy over placebo or no treatment. Another meta-analysis of four trials comparing cryotherapy versus SA provided no statistically significant difference in cure rates. Trials comparing combined therapy of cryotherapy with SA/LA versus SA/LA (two studies) or cryotherapy alone (two studies), showed that the combination of cryotherapy with SA/LA was significantly better than SA/LA alone, with cure rates ranging from 78 to 87%, whereas cryotherapy alone showed similar results to the combination. Long-term cure rates did not seem to depend on treatment interval (2-, 3- and 4-weekly intervals), whereas an ‘aggressive’ approach (application time up to 30 s) seemed to provide better results than a ‘gentle’ one (application time 10–15 s). Limiting factors included postinflammatory hypo- or hyper-pigmentation, scarring, pain and discomfort, particularly in young children.
Four selected trials out of seven RCTs suggested the efficacy of intralesional bleomycin, a cytotoxic polypeptide synthesized by Streptomyces verticillus, with clinical cure rates ranging from 16 to 94%. It is unclear whether these widely variable results depend on different concentrations, type of delivery systems and total drug amount used. However, in two studies comparing bleomycin with placebo, no advantage was demonstrated, whereas two studies showed superiority to cryotherapy. Results are generally achieved with minimal adverse effects.
Six (out of seven) small RCTs were considered for treatment of refractory warts with intralesional IFN-α, -β or -γ. Pooled data from four of them showed limited advantage over placebo. Moreover, local pain, headache and mild or moderate flu-like symptoms may occur.
Contact immunotherapy with topical sensitizers, such as DNCB, had a better clinical outcome than placebo (80 vs 35%) and cryotherapy (80 vs 50%), with minimal discomfort.
Photodynamic therapy using a topical photosensitizer has the advantage of being minimally invasive with mild adverse reactions. Three placebo RCTs (out of five trials) showed limited results with cure rates of 56% in one study. However, several factors, including widely variable trial design, as well as use of different photosensitizing agents, dyes and light sources, hampered data pooling.
The results of duct tape application versus placebo, reported in three RCTs, were considered limited, mainly because of trial methodology variability. Only one of them showed higher resolution rates versus cryotherapy (71 vs 46%). Adverse effects included erythema, eczema and pain.
Among destructive methods, pulsed-dye laser therapy is a relatively new option. However, it should be considered as an alternative treatment, as the cure rates from three RCTs were not statistically significant when compared with cryotherapy or cantharidin. In addition, the procedure is generally expensive and painful. Hypopigmentation and scarring may also frequently occur.
The efficacy of topical 5-FU, a chemotherapeutic agent, was evaluated in seven RCTs. Cure rates superior to placebo were reported in three RCTs, whereas no significant difference with SA was found. If used for periungual warts, it may cause onycholysis. When intralesional 5-FU was compared with placebo (two RCTs), higher cure rates were obtained in the 5-FU group (64–70 vs 29–35%, respectively). Disadvantages included inflammation and pigmentation at the injection site.
One placebo trial and one RCT evaluated the efficacy of topical zinc. Higher cure rates (44%) than placebo were obtained when higher zinc concentrations (10–20%) were used, whereas comparison with SA showed similar results in both groups (36%). Adverse effects included acute dermatitis, pain and hypopigmentation.
For resistant and recurrent CWs, a wide range of alternative options were taken into consideration. In general, they are off-label, reserved to experienced physicians and supported by limited evidence and a few controlled studies. Available RCTs include the following: one on 80% phenol versus cryotherapy (63 vs 68%), one on smoke exposure from burnt Populus euphratica versus cryotherapy (53 vs 43%), one single-blind study on silver nitrate versus placebo (43 vs 11%), one double-blind study on α-lactalbumin-oleic acid versus placebo (45 vs 15%) and one on 5% imiquimod versus placebo (12 vs 2.9%). Among intralesional treatments, one comparative study on antigen injection with Candida, mumps or Trichophyton antigens, with or without interferon, was identified (22 vs 10%). No controlled trials or RCTs were found for the following agents: glutaraldehyde, formaldehyde, podophyllotoxin, cantharidin, diphencyprone and squaric acid dibutylester. Finally, commonly utilized physically destructive methods (curettage and excision) were anecdotally reported and were associated with a relatively high recurrence rate.
Discussion & significance
The results of the pooled data showed that significantly higher remission rates may be expected with cryotherapy and SA only, especially when used in combination. Occurrence of adverse effects, such as pain, blistering and scarring, are limited and not consistently reported, and are probably more common with cryotherapy than SA. However, they are generally mild and well tolerated. Good quality data for most of the other treatments are still lacking. Topical immunotherapy with DNCB showed some evidence of efficacy in the treatment of refractory warts. Still, the mutagenic potential of this agent, which is not shared by other contact sensitizers, should be considered.
Expert commentary
Little has changed in the field over the past 8 years Citation[2,3]. Treatment decisions should be made on a case-by-case basis, according to evidence-based medicine criteria, but also considering patient preference and physician experience. So far, the use of nonconventional approaches in selected cases of relapsing and refractory warts seems justified, although scientific evidence is still low.
Five-year view
Experience gained in the field of genital HPV disorders should be expanded in order to develop a targeted prophylactic vaccine preventing the spread of cutaneous HPV infections.
Key issues
• Treatment of cutaneous warts is aimed at preventing patient’s discomfort and spread of infection by autoinoculation.
• No treatment for warts has yet been proven to be 100% effective in achieving complete remission.
• Kwok et al. provided an updated systematic review of available randomized controlled trials on cutaneous warts.
• Cryotherapy and salicylic acid, especially when used in combination, showed significantly higher remission rates.
• Good quality data for most of the other medical or physical treatments are still lacking.
• The treatment decision for cutaneous warts should be made on a case-by-case basis, considering patient preference and physician experience.
• The management of relapsing and refractory warts continues to be troublesome; therefore, the use of nonconventional approaches in selected cases seems justified.
• The development of a targeted prophylactic vaccine preventing the spread of cutaneous human papillomavirus infections would be a welcome addition to the effective management of warts.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Kwok CS, Gibbs S, Bennett C, Holland R, Abbott R. Topical treatments for cutaneous warts. Cochrane Database Syst. Rev. 9, CD001781 (2012).
- Micali G, Dall’Oglio F, Nasca MR, Tedeschi A. Management of cutaneous warts: an evidence-based approach. Am. J. Clin. Dermatol. 5(5), 311–317 (2004).
- Dall’Oglio F, D’Amico V, Nasca MR, Micali G. Treatment of cutaneous warts: an evidence-based review. Am. J. Clin. Dermatol. 13(2), 73–96 (2012).