Safety and Efficacy of Intralesional Vitamin D3 in Cutaneous Warts: An Open Uncontrolled Trial

INTRODUCTION

Warts or verrucae are benign epidermal proliferations of the skin and mucosa caused by human papillomavirus (HPV). Although spontaneous resolution occurs within 2 years in 65%–78% of warts, most patients seek treatment of warts as they are cosmetically disfiguring and sometimes painful, especially on the soles.[1] Local destruction of warts is a commonly employed treatment modality performed by using either topical keratolytics, electrocoagulation, cryotherapy or laser therapy.[2345] All these modalities of treatment can be painful and may be associated with scarring and frequent recurrences. In addition, destructive modalities are not suitable for the treatment of multiple and refractory warts as they clear only treated lesions and not the distant ones. Hence, to overcome these shortcomings, immunotherapy is being tried widely for the treatment of warts over the last few years. It acts on the basic principle of enhancing the cell-mediated immunity for the clearance of warts.[6] Various antigens have been tried including measles, mumps, rubella (MMR); tuberculin purified protein derivative (PPD); Mycobacterium w vaccine and Candida antigen.[78910]

Few studies have been published showing the efficacy of topical Vitamin D3 derivatives in the treatment of warts.[1112] However, intralesional Vitamin D3 injection was tried first time by Aktas et al. for the treatment of plantar warts and reported encouraging results.[13] Herein, we report the treatment response of intralesional Vitamin D3 injections for the treatment of cutaneous warts.

MATERIALS AND METHODS

The study was conducted from August 2015 to November 2016 in the Department of Dermatology and Venereology of our institute. The study was approved by the institute Ethical Committee. A total of 42 patients were enrolled in the study and were available for analysis.

RESULTS

A total of 42 patients received Vitamin D3 injections. The demographic and clinical data of 42 patients are shown in Table 1.

Table 1 Summary of the demographic and clinical data

The study included 27 males and 15 females. Age of the patients ranged from 12 to 66 years, with a mean of 20 years. The duration of warts ranged from 1 month to 96 months, with a mean of 6 months. The number of warts ranged from 2 to <30. Twenty-three patients had palmoplantar warts, one patient had filiform wart over face and 18 patients had verruca vulgaris. Multiple non-contiguous sites were involved in 16 patients (38.09%).

The mean number of intralesional injections required for complete clearance which was seen in 33 patients was 3.

Complete clearance was seen in 19 (82.60%) out of 23 patients with palmoplantar warts and 14 (77.77%) of 18 patients with verruca vulgaris. Representive patients showing complete response are depicted in [Figures 1–4]. Six patients (14.28%) i.e., three each in palmoplantar and verruca vulgaris group showed moderate response. One each in all subtypes of warts showed improvement which ranged from 1 to <50%. The response rate of various types of warts is shown in Table 2.

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Figure 1

(a) Multiple palmar warts before treatment. (b) Complete clearance after three injections

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Figure 2

(a) Verruca vulgaris before treatment. (b) Complete clearance after two injections

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Figure 3

(a) Verruca vulgaris before treatment. (b) Complete clearance after two injections

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Figure 4

(a) Palmar and periungual wart before treatment. (b) Complete clearance after four injections

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Table 2 Treatment response according to type of wart

Adverse effects were seen in 34 (80%) patients, but all were minor with no life-threatening complications. Swelling at the site of injection was the most common adverse effect seen in 33 (78.57%) patients which resolved without any treatment in 4 weeks [Figure 5]. Dyspigmentation was seen in one patient [Figure 6].

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Figure 5

Swelling at the injection site

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Figure 6

Pigmentation after clearance

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Recurrence was observed in one patient with palmoplantar wart during 6-month follow-up period.

DISCUSSION

Treatment of multiple warts especially palmoplantar warts is difficult and it needs multiple sittings by destructive methods such as cryotherapy and electrocautery. These destructive procedures are usually associated with scarring and pigmentation. In addition, some warts are resistant to these treatments and recurrence rate is also high. Hence, immunotherapy is the best available option in treating warts as it boosts the immune system to HPV virus leading to clearance of both treated and untreated warts. Recurrence rate is also low when compared to destructive methods.[1234] Immunotherapy has been tried with various antigens and vaccines such as bleomycin, PPD, MMR, Candida albicans and Mycobacterium w vaccine.[91015161718] In this present study, we used intralesional Vitamin D3 which was a relatively new treatment option for warts. Several studies have been published showing the efficacy of topical Vitamin D for the treatment of warts. Refractory wart in a 41-year-old renal transplant patient was treated successfully with calcitriol solution by Moscarelli et al.[19] Rind et al.[11] reported complete clearance of anogenital wart in an infant by calcipotriene ointment. In both case reports, the effect of Vitamin D3 derivatives on warts was speculated to be derived from its potential to regulate epidermal cell proliferation and differentiation and to modulate cytokine production. Recently, it was observed that there is toll-like receptor activation of human macrophages which upregulated the expression of Vitamin D receptor (VDR) and Vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide.[20]

Aktas et al. used intralesional Vitamin D3 for plantar warts. Twenty patients were included in the study, and 7.5 mg of Vitamin D3 injection was given at monthly intervals for a maximum of 2 sessions. They reported complete clearance in 80% of patients at the end of 8 weeks.[13] The results were similar with our study as shown in Table 3.

Table 3 Comparison with select study with intralesional Vitamin D3

The exact mechanism of action of Vitamin D in the clearance of warts is not known. Experimental evidence suggests that it has immunomodulatory effects by inhibiting the expression of interleukin-6 (IL-6), IL-8, tumour necrosis factor (TNF)-α and TNF-γ mediated through VDR-dependent pathway.[21]

Various other antigens/vaccines used for immunotherapy and their response rate are shown in Table 4. The response rate achieved in our study was 78.57% in maximum of 4 sessions which was superior to the results achieved with PPD, Bleomycin, MMR vaccine, C. albicans antigen and Mycobacterium indicus pranii vaccine. However, treatment with Mycobacterium w vaccine was superior to that of Vitamin D3, but the number of sessions was more i.e., 10 as compared to our study which was 4. Hence, higher response rate i.e., 93% reported in the Garg and Baveja study[9] can be attributed to more number of sessions. Furthermore, they reported systemic and local complications such as high-grade fever and redness, swelling, induration and ulcer formation at the injection site. Hence, compared to these adverse effects, we did not experience any serious systemic and local complications which needed medications hence it is very safe procedure than Mycobacterium w vaccine.

Table 4 Response rate of various antigens/vaccine

CONCLUSION

Intralesional Vitamin D3 injection is an innovative approach for the treatment of warts. It is inexpensive, safe and special value to treat multiple warts in developing countries. Although our study is limited by its small sample size and lack of randomisation, the results are encouraging. Well-designed, large randomised placebo-controlled studies are required in future to confirm the efficacy of intralesional Vitamin D3 injection for the treatment of multiple warts in clinical practice.