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Monochloroacetic Acid Application Is an Effective Alternative to Cryotherapy for Common and Plantar Warts in Primary Care: A Randomized Controlled Trial
Department of Public Health and Primary Care (V0-P), Leiden University Medical Center, Leiden, The NetherlandsRadboud University Nijmegen Medical Centre, Department of Primary and Community Care, 117-hag, Nijmegen, The Netherlands
Cryotherapy and salicylic acid (SA) often fail as treatments for skin warts. We examined the effectiveness of monochloroacetic acid (MCA) for patients with common or plantar warts. Consecutive patients aged 4 years and older with one or more newly diagnosed common or plantar warts were recruited in 53 Dutch general practices. We randomly allocated eligible patients to 13-week treatment protocols of office-applied MCA versus liquid nitrogen cryotherapy every 2 weeks for patients with common warts (n=188), and MCA versus cryotherapy combined with daily SA self-application for patients with plantar warts (n=227). The primary outcome was the proportion of patients whose warts were all cured at 13 weeks. In the common wart group, cure rates were 40/92 (43%, 95% confidence interval 34–54) for MCA and 50/93 (54%, 44–64) for cryotherapy (risk difference (RD) -10%, -25–4.0, P=0.16). In the plantar wart group, cure rates were 49/106 (46%, 37–56) for MCA and 45/115 (39%, 31–48) for cryotherapy combined with SA (RD 7.1, 5.9–20, P=0.29). For common warts, MCA is an effective alternative to cryotherapy to avoid pain during the treatment, although pain after the treatment is similar. For plantar warts, office-applied MCA may be preferred over cryotherapy combined with SA, on the basis of comparable effectiveness, less treatment pain, and less treatment burden.
Abbreviations
CI
confidence interval
MCA
monochloroacetic acid
RD
risk difference
SA
salicylic acid
INTRODUCTION
Cutaneous warts are highly prevalent benign papillomas of the skin (
). The 2012 update of the Cochrane Review on the treatments for cutaneous warts did not draw firm conclusions, as data on the effectiveness of cryotherapy and SA remain contradictory (
). However, the review highlighted the apparent difference in response to treatment between common warts (mostly located on hands) and plantar warts (located on the sole of the foot). Our recent randomized controlled trial showed that for common warts cryotherapy is more effective than a wait-and-see policy or SA treatment (
). Nevertheless, cryotherapy did not cure half of all patients with common warts. For plantar warts, the trial showed that both cryotherapy and SA monotreatments were not effective; this was confirmed by another large trial (
In search for more effective treatments, there is some evidence that SA combined with cryotherapy could be more effective than either treatment alone for the treatment of plantar warts (
). Furthermore, several specialized treatments such as pulsed dye laser or intralesional bleomycin are available. Evidence for these treatments is limited, and large-scale use in primary care is not feasible (
). However, an exception may be monochloroacetic acid (MCA), which is a powerful irritant that has been used by dermatologists and podiatrists for several decades (
). A trial from the UK, and two small unpublished pilot studies from the Netherlands, showed promising results of MCA in primary care with a few side effects (
Behandeling van wratten in de huisartspraktijk: Monochloorazijnzuur vs.
in: Salicylzuur [Treatment of warts in general practice: Monochloroacetic acid vs. salicylic acid], Report, Department of General Practice, University Medical Center Groningen, Groningen, The Netherlands2004
Behandeling van voetwratten in de eerste lijn: Cryotherapie vs.
in: Monochloorazijnzuur [Treatment of plantar warts in primary care: Cryotherapy vs. Monochloroacetic acid], Report, Department of General Practice, University Medical Center Groningen, Groningen, The Netherlands2004
). It should be stressed, however, that treatment with MCA should only be administered by experienced health-care professionals.
Therefore, we conducted a multicenter, randomized, parallel-group superiority trial to compare the effectiveness of MCA with the most effective usual treatments—i.e., in common warts compared with cryotherapy and in plantar warts compared with cryotherapy combined with SA. These treatment arms were also compared with cryotherapy, SA monotreatment, and a wait-and-see policy from our previous trial (
Of the 560 initially selected patients with warts, 145 were excluded mainly because they had already been treated in the previous year or they did not want to participate (Figure 1). The remaining 415 patients were stratified into the common wart group (n=188) and the plantar wart group (n=227) before randomization. Within both groups, baseline characteristics did not differ between treatment arms (Table 1). For the common wart group, median age and median duration of warts were higher than in the plantar wart group. In total, the study contained 790 plantar warts and 611 common warts, of which 526 warts (86%) were located on hands and 85 warts (14%) were located on other body sites.
At 13 weeks, three patients from the common wart group and six patients from the plantar wart group were lost to follow-up because they refused further participation or could no longer be contacted (Figure 1). Of the remaining 406 patients, 106 (26%) did not fully comply with treatment protocol, 92 did not adhere to minimal treatment frequencies, and 14 started other treatment in general practice in addition to the protocol. The cryotherapy combined with the SA arm showed the lowest adherence to treatment protocol (68/115, 59%); the most frequently reported reason was treatment burden such as time-consuming visits to the general practice and daily hassle with SA and tape (Figure 1). During the follow-up, only one patient was referred to a dermatologist, because the wart was growing larger than 1 cm in spite of treatment and the patient had a considerable pain.
Assumption of similarity
Baseline characteristics (Supplementary Table S1 online), as well as the observed effectiveness of cryotherapy in patients with common warts, were comparable between the previous trial and the current trial (cure rates at 13 weeks: 49% (95% confidence interval (CI) 34–64) and 54% (95% CI 44–64), respectively, P=0.60). Therefore, treatment arms of the two trials were also compared with the treatment arms of the previous trial (
For the common wart group, the cure rate at 13 weeks of MCA was 43% (95% CI 34–54), which was comparable to the cure rate of cryotherapy of 54% (95% CI 44–64; risk difference (RD) -10%, 95% CI -25–4.0; RR 0.81, 95% CI 0.60–1.1; P=0.16) (Table 2). Both cryotherapy and MCA were more effective than the wait-and-see policy or SA treatment from the previous trial (Figure 2). Stratification by age or by duration of warts yielded similar findings (Table 2).
Table 2Effectiveness of treatments for patients with common warts (n=185) and patients with plantar warts (n=221)
Variable
Common wart group
Plantar wart group
Difference % (95% CI)
MCA
Cryotherapy
Difference
MCA
Cryotherapy with SA
n/N
% (95% CI)
n/N
% (95% CI)
% (95% CI)
n/N
% (95% CI)
n/N
% (95% CI)
All patients
40/92
43 (34–54)
50/93
54 (44–64)
–10 (–25; 4.0)
49/106
46 (37–56)
45/115
39 (31–48)
7.1 (–5.9; 20)
Age, years
4–12
15/34
44 (29–61)
20/35
57 (41–72)
–13 (–36; 10)
39/57
68 (56–79)
34/59
58 (45–69)
11 (–6.7; 28)
≥12
25/58
43 (31–56)
30/58
52 (39–64)
–8.6 (–27; 9.5)
10/49
20 (11–34)
11/56
20 (11–32)
0.7 (–15; 16)
Duration of warts, months
<6
13/19
68 (46–85)
22/30
73 (56–86)
–4.9 (–31; 21)
30/46
65 (51–77)
34/51
67 (53–78)
–1.4 (–20; 17)
≥6
27/73
37 (27–48)
28/63
44 (33–57)
–7.5 (–24; 9.1)
19/60
32 (21–44)
11/64
17 (10–28)
14 (0.5; 29)
Abbreviations: CI, confidence interval; MCA, monochloroacetic acid; SA, salicylic acid.
Values are numbers of participants cured/number of participants in intention-to-treat analysis at 13 weeks, and percentages of participants cured with 95% CI. A participant was considered cured when all warts present at baseline had disappeared at follow-up.
Figure 2Effectiveness of treatments with 95% confidence intervals of the current trial and the previous trial at 13 weeks for patients with common warts and patients with plantar warts (n=646).
For the plantar wart group, the cure rate at 13 weeks of MCA was 46% (95% CI 37–56), which was comparable to the cure rate of cryotherapy combined with SA of 39% (95% CI 31–48; RD 7.1, 5.9–20; RR 1.2, 95% CI 0.87–1.6; P=0.29) (Table 2). When these treatment arms were compared with the treatment arms of our previous trial (
), all CIs of the active treatment groups of MCA, cryotherapy combined with SA, and cryotherapy and SA monotreatments overlapped (Figure 2). Compared with a wait-and-see policy, MCA for plantar warts was the only treatment reaching the predefined clinically relevant RD (RD 23%, 95% CI 8–39; RR 2.0, 95% CI 1.1–3.6) (Supplementary Table S2 online).
All sensitivity analyses were in line with primary analysis (Supplementary Table S3 online). The cure rate of cryotherapy combined with SA in the plantar wart group was increased in the per-protocol analysis (60%, 95% CI 48–71), but it remained comparable with the cure rate of MCA (53%, 95% CI 43–63).
Side effects and treatment satisfaction
Pain was the most frequently reported side effect for all treatment arms (Table 3). We found a lower proportion of patients reporting pain during MCA application compared with cryotherapy for both common and plantar wart groups. However, similar proportions of patients reported pain after treatment. MCA showed a pain-free period after MCA application (median 1 hour, IQR 10 minutes-7 hours), whereas the pain during application for cryotherapy was immediately followed by post-application pain. Median duration of pain for all treatment arms was 1 day (IQR 2 hours–3 days). The median overall treatment pain score was lower for MCA than for cryotherapy arms. The most serious side effects reported were blistering and superficial wounds for all four treatment arms (Table 3). In the common wart group, blistering occurred less frequently for MCA (39%, 95% CI 30–49) than for cryotherapy (62%, 95% CI 52–72, P<0.01). The percentage of patients reporting treatment burden was comparable for MCA (34%, 95% CI 25–46) and cryotherapy (37%, 95% CI 27–47, P=0.76). In the plantar warts group, treatment burden was lower for MCA (30%, 95% CI 22–39) than for cryotherapy combined with SA (47%, 95% CI 38–56, P=0.009). The percentage of patients satisfied with their treatment was comparable between treatment arms and between common and plantar groups (overall 64%, 95% CI 59–68).
Table 3Side effects reported during the 13-week follow-up per treatment group (n=406)
This pragmatic randomized controlled trial in primary care showed that for common warts both MCA application and cryotherapy are effective treatments. However, pain caused by MCA starts about 1 hour after application compared with the immediate, more intensive pain caused by cryotherapy. For plantar warts, MCA was the only treatment with a clinically relevant RD (23%) compared with a wait-and-see policy. Cryotherapy combined with SA also seemed effective, especially in patients compliant to the treatment protocol, but it caused considerable side effects and treatment burden.
In line with the recently updated Cochrane review on cutaneous warts, the present trial was separately powered for patients with common warts and patients with plantar warts because of evident differences in response to treatment. However, in that review, MCA was not investigated owing to the insufficient number of trials to include. Apart from a few descriptive studies (
). That study reported that MCA combined with SA treatment resulted in a cure rate of 66% compared with 16% for placebo after 6 weeks in patients with plantar warts; however, only 59 patients were included, and a MCA crystal was taped on the wart for 1 week. We also found two unpublished pilot studies showing that application of MCA-saturated solution every 2 weeks was more effective than SA, and as effective as cryotherapy but with less reported pain. Our data confirm the modest benefit for SA in plantar warts reported by the Cochrane Review, but only significant when pooled. This benefit is probably enhanced when combined with cryotherapy, but the clinical relevance of the RDs compared with a wait-and-see policy remains questionable.
With the pragmatic design in a primary care setting, almost complete follow-up, and intention-to-treat analysis, our findings are directly applicable in daily practice. The similarity of treatment effects between the current trial and our previous trial secured comparison of treatment arms across the two trials. Treatment options did not secure realistic blinding of patients and practices. Research nurses were also not blinded, because during home visits they assessed and discussed side effects, treatment burden, and treatment adherence in addition to outcome. These highly valued home visits resulted in almost complete follow-up. Additional home visits from a second blinded assessor was not feasible, and clinical outcome assessment in which the skin could both be closely inspected and palpated was preferred over assessment of digital images. However, the risk of bias introduced by the protocolled but unblinded outcome assessment is considered low.
Although MCA has been locally used by podiatrists and dermatologists for the treatment of warts for decades, it is not routinely obtainable in pharmacies (
). However, it could easily become widely available at low costs if the demand increases, because MCA is produced on a large scale for the chemical industry and agriculture (
). When carefully administered on⩽5 warts per patient (< 0.3% of total body surface), MCA is safe for topical use on skin lesions. However, because of the strong corrosive capacity of the acid and the dangers related to contact with a relatively small skin surface area, MCA is not suitable for self-application. MCA should be stored in small quantities, it should always be administered by a trained health-care professional wearing examination gloves, and surrounding skin should always be protected with petroleum jelly (
). In addition to cases of irritation, burning sensation, and itching of the local skin, the most serious side effects that MCA caused in our trial were blistering (36% of patients) and superficial wounds (8% of patients). Wounds were caused by the application of too much MCA or spilling MCA on healthy skin. However, cryotherapy caused even more blistering in common warts and comparable numbers of wounds. Full-thickness chemical burns and joint deformity have been described in case reports when MCA was not carefully applied—i.e., high concentration of MCA with a long application period or large application surface (
). Severe systemic effects such as vomiting, central nervous disturbances, and cardiovascular involvement are possible, especially in children and elderly, when a total body surface of up to 5% is exposed to an 80% solution of the acid (
The present trial establishes MCA as an effective treatment option for both common and plantar warts. For common warts, MCA is an effective alternative to cryotherapy to avoid pain during treatment, although pain after treatment is similar. This might be appealing for treatment in children who often fear the pain during cryotherapy. For plantar warts, MCA may be preferred over cryotherapy combined with SA on the basis of comparable effectiveness, less treatment pain, and less treatment burden. Nevertheless, optimal treatment for both common and plantar warts only cures around 50% of patients. Therefore, subgroups of patients who respond to current treatments need to be identified and other specialized treatments should be investigated. Ultimately, an evidence-based decision tool should be developed that assists physicians in their decision concerning which treatment to use for specific patient groups.
Materials and Methods
Setting and patients
Between September 2009 and September 2010, 53 general practices in the Leiden region of the Netherlands invited all patients aged 4 years and older with one or more newly diagnosed common or plantar warts to participate. We excluded patients who were treated by a physician or dermatologist in the previous year, as well as pregnant, breastfeeding, or immunocompromised patients, and patients with genital warts, seborrheic warts, or warts ≥1 cm in diameter. A trained research nurse visited eligible patients at home, confirmed eligibility, obtained written informed consent (both child and parental consent for patients aged ⩽18 years), provided both verbal and written information on warts and wart treatment, and collected baseline characteristics for a maximum of 10 warts per patient.
Study design and randomization
Patients were assigned to two parallel groups: the plantar wart group (patients with warts on the soles of the feet) or the common wart group (patients with warts on hands or other locations). Patients with both common and plantar warts were assigned according to the type of the majority of warts and, in case of equal numbers, according to the warts causing the most discomfort. After stratification based on the number of warts (< 6 vs.≥6 warts), the research nurses randomly allocated patients to MCA treatment or cryotherapy in the common wart group, and to MCA treatment or cryotherapy combined with SA in the plantar group. All warts of one patient received the allocated treatment irrespective of location. Opaque, sealed envelopes delivered by an independent statistician based on computerized randomization secured concealment of allocation. The study protocol was approved by the Medical Ethical committee of the Leiden University Medical Center.
Treatment protocols
Allocated treatments were reported to patients’ own general practices where the treatments were explained and carried out. In addition to written protocols, one of the authors (PE) trained all participating general practitioners and their practice assistants by visiting the practices and demonstrating all tools and techniques in a 1-hour interactive session. All patients were instructed not to use any treatment other than the allocated treatment during the 13-week protocols.
For topical application of MCA in the common and plantar wart group, the research pharmacy provided practices with a saturated concentration of 76%. The general practitioner or practice assistant applied the MCA every 2 weeks until all warts were completely cured. The removal of callosity and protection of surrounding skin with petroleum jelly preceded each application of MCA solution on the wart with a cotton swab. If not all of the applied MCA was absorbed by the wart, excess MCA was removed with a tissue. After application, the wart was covered with a tape and patients were instructed to keep the wart dry for at least 12 hours. We refer to http://www.youtube.com/watch?v=cTzkPCZaGW8 for an instruction video.
For cryotherapy in the common wart group, three subsequent freeze–thaw cycles were applied after the removal of callosity in the general practice every 2 weeks until all warts were completely cured. One cycle consisted of application of a wad of cotton wool saturated with liquid nitrogen on the wart until a frozen halo of 2 mm around the base of the wart appeared (usually 2–10 seconds per application). For the cryotherapy combined with SA in the plantar wart group, the above protocol for cryotherapy was applied, combined with daily self-administration of petroleum jelly containing 40% SA until all warts were completely cured. Patients were instructed to daily pare softened surface area of the wart with a file, cover the surrounding skin with tape for protection of healthy skin, and apply SA on top of the wart with another piece of tape.
Outcome assessment
Independently of the treating physician, trained research nurses assessed outcomes during home visits at 4 and 13 weeks of follow-up. The visit at 4 weeks was mainly to verify and support adherence to the treatment protocol. The 13-week follow-up allowed sufficient time for treatment plus additional time to assure sustained clearance (
). For quality control, 5% of the assessments were supervised by experienced general practitioners (JE and PE) with no difference in evaluation. The primary outcome measure was the proportion of patients with all common and plantar warts cured at 13 weeks. A wart was considered cured if it was no longer visible (skin color and skin lines reestablished) and could not be palpated any more. Secondary outcome measures included reported side effects, treatment adherence, treatment burden, and treatment satisfaction. We considered adherence adequate if patients did not use treatments other than the allocated treatment, had received MCA at least every 3 weeks and kept the wart dry at least 8 hours after applications, had received cryotherapy at least every three weeks, and had self-administered SA at least 3 days a week. Patients rated treatment burden (yes vs. no) and treatment satisfaction on a 5-point scale (1=very unsatisfied, 5=very satisfied); those with a score of 4 or 5 reported to be satisfied. Research nurses, general practitioners, and participants were not blinded to treatment allocation.
Statistical analysis
We calculated sample sizes for the common wart and plantar wart group separately, which would provide 80% power at a significance level of 5% to detect a clinically relevant absolute increase in cure rate of 20% for the MCA arms. We chose this clinically relevant difference in line with the Cochrane Review on topical treatments for cutaneous warts (
), warranting potential side effects in the treatment of a minor ailment with a benign natural course. Considering a 50% cure rate in the cryotherapy arm of the common wart group and a 30% cure rate of a wait-and-see policy in the plantar wart group (
), 91 patients were required per treatment arm for each wart group. Assuming a loss-to-follow-up of 10%, we needed 200 patients for the common wart group and 200 patients for the plantar wart group.
In the primary analysis, we calculated cure rates including 95% CI to compare treatment arms. For the common wart group, MCA and cryotherapy arms were compared, and for the plantar wart group the arms MCA and cryotherapy combined with SA were compared.
These treatment arms of the current trial were also directly compared with the treatment arms in the respective groups of patients from our previous trial (
). This randomized three-arm trial with patient inclusion criteria, study design, and outcome assessment identical to current trial compared cryotherapy, salicylic acid, and a wait-and-see policy. The underlying assumption for comparing the treatment arms between trials was that treatment effects of both trials is similar based on their identical study design. We examined this assumption of similarity of treatment effects comparing patient characteristics and the cure rates of cryotherapy in common warts between the two trials (
In addition, we compared the secondary outcomes (percentages of patients with side effects, considerable treatment burden, and the percentages of patients satisfied with treatment) between arms by using the two-sided χ2 test. Furthermore, subgroup analyses on the effectiveness were pre-planned for age clusters (4–12 years vs. ≥12 years), number of warts per participant, and duration of warts (⩽6 months vs. >6 months). In sensitivity analyses, we compared cure rates between treatments arms per wart group (a) with patients lost to follow-up considered not cured, (b) by using per-protocol analysis based on adequate treatment adherence, (c) after excluding patients who had both plantar and common warts, (d) only including the warts on the hands in common wart group, and (e) with individual warts instead of patients as unit of analysis. Data were analyzed with SPSS Version 17.0 (IBM, The Netherlands).
ACKNOWLEDGMENTS
We thank all the participating patients and family practices from the Leiden Primary Care Research Network (LEON), the research nurses Corrie Vlieland and Irene Barnhorn-Bakker for collecting data during home visits, and Anita Pannekoek for her administrative support. We also thank Jan Meulenbelt, Professor of Clinical Toxicology/Director Dutch Poisons Information Centre, for critically reviewing the manuscript on MCA toxicity. This study was funded by the Netherlands Organisation for Health Research and Development (ZonMW). The organization did not have any influence on the study design, the collection, analysis, or interpretation of data, the writing of the report, or the decision to submit the paper for publication. All authors were independent from funder. Dutch trial registration: NTR1771.
Behandeling van wratten in de huisartspraktijk: Monochloorazijnzuur vs.
in: Salicylzuur [Treatment of warts in general practice: Monochloroacetic acid vs. salicylic acid], Report, Department of General Practice, University Medical Center Groningen, Groningen, The Netherlands2004
Behandeling van voetwratten in de eerste lijn: Cryotherapie vs.
in: Monochloorazijnzuur [Treatment of plantar warts in primary care: Cryotherapy vs. Monochloroacetic acid], Report, Department of General Practice, University Medical Center Groningen, Groningen, The Netherlands2004
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