Topical Calcipotriol for the Treatment of Cutaneous Warts: An Assessor-Blind Randomized Placebo-Controlled Trial

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Introduction
Cutaneous warts are benign epidermal proliferations caused by human papillomavirus (HPV) and can be categorized into diferent types, including common (verruca vulgaris), plantar (verruca plantaris), and fat (verruca plana) warts [1].Although approximately 75% of warts can resolve spontaneously within 2 years, patients often seek treatment for cosmetic reasons and pain [2].Te common treatment methods include electrocoagulation, laser, and cryotherapy; however, they are expensive and require a long treatment period with multiple sessions, and lesions can recur [3].Terefore, intralesional immunotherapy has been introduced over the last few years, which is believed to enhance cell-mediated immunity [4,5].
It has been suggested that vitamin D can modulate the immune system by inhibiting the expression of cytokines [6].Te expression of vitamin D receptors and vitamin D 1-hydroxylase genes is upregulated when human macrophages are activated by toll-like receptors.Tis leads to the modulation of innate immunity [7].Intralesional vitamin D has been shown to be safe and efective for the treatment of warts [8][9][10][11].Very few studies have also demonstrated the efcacy of topical vitamin D derivatives in this regard, including a case report and a study on 17 patients [12,13].We aimed to evaluate the safety and efcacy of topical calcipotriol for the treatment of cutaneous warts.

Participants and Study
Design.Tis assessor-blind randomized placebo-controlled trial included patients with cutaneous warts referred to the dermatology clinic of BouAli Hospital, Sari, Iran, from January 21 to March 20, 2020.Te inclusion criteria were the clinical or pathological diagnosis (only for suspicious lesions to confrm diagnosis) of cutaneous warts by an expert dermatologist, age > 2 years, and a maximum of 20 warts.Te exclusion criteria were pregnancy and lactation, facial, inguinal, and genital warts, hypersensitivity to topical vitamin D derivatives, extensive warts requiring other treatments, and receiving any treatments in the past two months.Based on the study by Kareem et al. [14], in which complete improvement occurred in 40% of the intervention and 5% of the control groups, as well as α � 0.05 and β � 0.1, the sample size was calculated as at least 28 in each group.
Te study received ethical approval and complies with the statements of the Declaration of Helsinki.Written informed consent was obtained from the patients or their parents/guardians.Te trial has also been registered at the Iranian Registry of Clinical Trials (IRCT).
First, the general characteristics including age, sex, underlying disease, previous treatments (i.e.cryotherapy, topical salicylic acid preparations, and laser), sites of lesions, disease duration, and severity (based on the number of lesions (<5 mild, 5-10 moderate, and >10 severe) were recorded.Ten, patients were randomized into two groups using block randomization by using the Random Allocation software, with a block size of four.Patients in the calcipotriol group received calcipotriol 0.05% ointment (Caspian Tamin Pharmaceutical Co., Iran) twice a day on the lesions with a uniform thickness of 1 mm.Patients in the control group received a placebo (Vaseline®).Te duration of treatment was two months, which continued for another two months if resolution did not occur.
Te primary outcome was complete response to treatment evaluated four months after the initiation of therapy.Secondary outcomes were the number and size of the warts assessed at 1, 2, and 4 months and adverse events, including erythema, pruritus, burning sensation, and scaling.Te outcomes were evaluated by the same physician blinded to the patient groupings at each visit.

Data
Analysis.We used the Statistical Package for the Social Sciences (SPSS) software (version 25.0, Armonk, NY: IBM Corp., USA) for data analysis.Continuous variables were described using means and standard deviations.Categorical variables were described using frequencies and percentages.Fisher's exact test was used to compare categorical variables, and the independent t-test was used to compare continuous variables between groups.P values <0.05 were regarded as statistically signifcant.

Results
Initially, 65 patients were assessed for eligibility, of whom three did not meet the inclusion criteria and two declined to participate.Te remaining patients were randomized into two equal groups (n � 30).Tereafter, two patients from the calcipotriol group and one from the control group were lost to follow-up.In addition, one patient in the control group discontinued intervention (Figure 1), leaving 28 patients in each group for the fnal analysis.
Patients in both groups were comparable regarding previous treatment, underlying disease, and disease duration (Table 1).However, patients in the control group were older.Also, a higher proportion of patients in the calcipotriol group were male and had warts on their palms and toes.Moreover, a higher percentage of controls had moderate disease.
Te mean number and the size of lesions did not difer between groups before intervention; however, both were signifcantly lower in the calcipotriol group than in controls at 1 st , 2 nd , and 4 th months (Table 2).In addition, complete response to treatment was signifcantly higher in the calcipotriol group (85.7% vs. 16%; P < 0.001).On the other hand, the frequency of adverse events was not diferent between groups (P � 0.352) (Table 3).Figure 2 shows images of patients before and after treatment.

Discussion
In the current study, we found that calcipotriol was efective for the treatment of cutaneous warts in terms of the number and size of lesions as well as the overall response to treatment.Moreover, the frequency of adverse events was comparable between the calcipotriol and control groups.Calcipotriol is a vitamin D3 analogue, assumed to have immunomodulatory efects [6].On the other hand, lower serum vitamin D levels have been reported in patients with viral warts [15,16].
Intralesional vitamin D derivatives have been evaluated for the treatment of warts.Amin et al. compared cryotherapy with intralesional vitamin D3 (5 mg/ml) for warts on the hands and feet and showed similar efcacy for both modalities [10].In another study, Ihsan Mahmoud and Ayyash used 60,000 and 120,000 IU of intralesional vitamin D3 for common warts and found both efective without any signifcant diference [11].Additionally, Kumar and Brar demonstrated that 600,000 IU intralesional vitamin D3 was safe and efective for the treatment of palmoplantar warts [17].Similarly, Kavya et al. showed the safety and efcacy of intralesional vitamin D for multiple cutaneous warts [8].Consistently, Aktas ¸et al. treated single or multiple plantar warts with intralesional vitamin D3 in 20 patients, of whom 2 Dermatologic Terapy 80% showed complete resolution [9].Nevertheless, intralesional vitamin D appears not to be as efective for anogenital warts [18].Topical vitamin D3 (maxacalcitol) was frst successfully used by Imagawa and Suzuki for the treatment of refractory warts in 17 patients, including four adults and 13 pediatric patients.Warts disappeared in all of the patients [13].Tis is in agreement with our results; nonetheless, the resolution of warts in their study occurred after 6 months of treatment, while the maximum treatment duration in our study was four months.Moreover, Rind et al. reported the successful treatment of anogenital warts in an infant [12].
Te major strength of the current study was its superiority to previous studies regarding the sample size.Nevertheless, this study was not without limitations.First, the efects of interventions on the number and size of lesions should have been adjusted for age, sex, site, and severity of lesions as well as preintervention values.Second, although our sample size was higher than that of previous studies, it was still relatively small, which limits the generalizability of our fndings.Finally, the patients were not evaluated after four months; therefore, the long-term efects and the relapse rate could not be assessed.

Conclusions
Response to treatment was signifcantly better with calcipotriol in this study, with comparable adverse events compared to the control group.Terefore, calcipotriol can be considered a safe and efective treatment option for cutaneous warts.However, larger double-blind randomized placebo-controlled trials, potentially including another arm for intralesional vitamin D, are required to confrm these fndings.

Figure 1 :
Figure 1: Details of patient enrollment, intervention allocation, and analysis.

Figure 2 :
Figure 2: Two warts on the palm of a patient (a) before and (b) after treatment with calcipotriol and a wart on the sole of a patient in the placebo group (c) before and (d) after receiving a placebo.

Table 1 :
Comparison of general characteristics between groups.

Table 2 :
Comparison of the number and size of lesions between groups.
Abbreviations: N, number; SD, standard deviation.* Analyzed by the independent t-test.

Table 3 :
Comparison of adverse events and response to treatment after 4 months between groups.