Intralesional Vitamin D Injection May Be an Effective Treatment Option for Warts

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1 602841CMSXXX / Journal of Cutaneous Medicine and SurgeryAktaş et al research-article2015 Basic/Clinical Science Intralesional Vitamin D Injection May Be an Effective Treatment Option for Warts Journal of Cutaneous Medicine and Surgery 1 5 The Author(s) 2015 Reprints and permissions: sagepub.com/journalspermissions.nav DOI: / jcms.sagepub.com Habibullah Aktaş 1, Can Ergin 2, Betül Demir 3, and Özlem Ekiz 4 Abstract Background: Plantar warts are typically resistant to treatment. In recent years, treatments have included administration of intralesional tuberculin; measles, mumps, rubella vaccine; and Candida albicans antigen immunotherapy. To the best of our knowledge, there are no reports of intralesional vitamin D administration for the treatment of warts. Aim: To evaluate the efficacy and safety of intralesional vitamin D treatment for plantar warts. Methods: Twenty patients with single or multiple plantar warts were included in this study. Vitamin D 3 (0.2 ml, 7.5 mg/ml) was injected into the base of the warts after prilocaine (0.1 ml, 20 mg/ml) injection. A maximum of 5 warts were treated in 1 session, with at maximum 2 injections performed at 4-week intervals. Results: In total, 16 of 20 patients (80%) showed complete resolution of warts, and 1 patient showed partial resolution. Three patients failed to show any response. No recurrence or serious adverse effects were observed. Conclusion: Intralesional vitamin D 3 may be an effective treatment option for warts. Résumé Contexte : Les verrues résistent généralement au traitement. Au cours des dernières années, les traitements ont inclus l administration intralésionnelle de tuberculine ou du vaccin rougeole-rubéole-oreillons, ainsi que l immunothérapie aux anticorps de Candida albicans. Au meilleur de notre connaissance, il n existe aucun rapport faisant état d administration intralésionnelle de vitamine D pour le traitement des verrues. Objectif : Vérifier l efficacité et l innocuité du traitement des verrues plantaires par injection intralésionnelle de vitamine D. Méthodologie : Vingt patients porteurs d une ou de plusieurs verrues plantaires ont été recrutés pour cette étude. Après injection de prilocaïne (0,1 ml, 20 mg/ml), on a injecté de la vitamine D 3 (0,2 ml, 7,5 mg/ml) dans la base des verrues. On a traité au plus cinq verrues par séance et on a administré au plus deux injections à quatre semaines d intervalle. Résultats : Chez 16 (80 %) patients sur 20 patients, toutes les verrues sont complètement disparues et chez un autre, elles sont partiellement disparues. Chez trois patients, l injection de vitamine D 3 n a produit aucun effet. Aucune récurrence n a été observée, non plus que d effets secondaires sérieux. Conclusion : L injection intralésionnelle de vitamine D 3 pourrait être un traitement efficace contre les verrues. Keywords viral warts, vitamin D injection, treatment Warts are benign epidermal proliferations of the skin and mucosa caused by human papilloma virus (HPV). Plantar warts are typically refractory to treatment, and multiple treatment sessions are required to clear lesions completely. Warts are usually treated by traditional destructive modalities such as cryotherapy, electrocoagulation, topical salicylic acid, topical 5-fluorouracil, and laser surgery. All of these treatment options can be painful, time consuming, and/or expensive, and none is considered the gold standard. 1-6 In recent years, treatments for warts have included intralesional injections of tuberculin purified protein derivative (PPD); measles, mumps, and rubella (MMR) vaccine; Mycobacterium vaccine; Ksharodaka (an alkaline aqueous solution of Apamarga Kshara); and Candida albicans antigen. While the mechanisms of vaccine and antigen therapy have not been elucidated, it is thought that the host immune system 1 Department of Dermatology, Education and Research Hospital, Karabük University, Karabük, Turkey 2 Department of Dermatology, Dışkapı Yıldırım Beyazıt Education and Research Hospital, Ankara, Turkey 3 Department of Dermatology, Fırat University Hospital, Elazığ, Turkey 4 Department of Dermatology, Faculty of Medicine, Mustafa Kemal University, Hatay, Turkey Corresponding Author: Can Ergin, MD, Dışkapı Yıldırım Beyazıt Education and Research Hospital, Department of Dermatology, Yesilyurt Sok. No: 15/7, Ayrancı, 06660, Ankara, Turkey. drcanergin@hotmail.com

2 2 Journal of Cutaneous Medicine and Surgery is activated to recognize the virus, leading to wart clearance This treatment approach is known as intralesional immunotherapy. Topical vitamin D has been used successfully for wart treatment in some cases The effect of vitamin D derivatives on warts is speculated to be derived from its potential to regulate epidermal cell proliferation and differentiation and to modulate cytokine production. Upregulation of vitamin D receptors in the skin leads to the induction of antimicrobial peptide expression To the best of our knowledge, intralesional vitamin D has not been used for the treatment of warts. Herein, we report the treatment response and adverse effects of intralesional injections of vitamin D 3 for the treatment of recalcitrant plantar warts. Methods A retrospective analysis was conducted on the clinical outcomes of 20 patients with plantar warts who were treated with intralesional vitamin D 3 in the Dermatology Outpatient Department of our hospital from March 2014 to October The same dermatologist examined all patients, and warts were diagnosed on the basis of clinical findings and dermoscopic examination. All patients had been previously treated with other modalities, including cryotherapy and topical salicylic acid preparations, for more than 6 months without any considerable benefit. Initially, each lesion was injected with 0.1 ml of prilocaine (20 mg/ml). A few minutes later, 0.2 ml of vitamin D 3 (7.5 mg/ml) solution was slowly injected into the base of each wart using a 21-gauge syringe. Injections were performed monthly with a maximum of 2 sessions. A maximum of 5 warts were treated per patient in 1 session. The maximum total amount of vitamin D 3 injected into a patient in 1 session was 7.5 mg. Clinical changes or adverse reactions were recorded every week for the first month and every 2 weeks thereafter. Patients were considered cleared if all warts completely resolved; patients were considered partially responsive if some of the warts remained unchanged. The treatment was considered to have failed if no response was observed in any of the lesions. Patients were followed for 6 months. Informed consent was obtained from all of the participants, and the local ethics committee approved the study. Results In total, 20 patients received vitamin D 3 injections. The study included 13 females and 7 males. The mean age of the patients was 28.6 years (range, years). A total of 102 warts were found on plantar surfaces of the patients. While most of the patients had 1 to 5 warts, 1 patient had 23 warts. The duration of the warts ranged from 1 to 25 years (mean, 4.3 years). The dimensions of the lesions ranged from 2 3 mm to mm. Figure 1. (a) Plantar mosaic wart. (b) The appearance of the lesion 1 month after intralesional vitamin D injection. Complete clearance was seen in 14 (70%) of the 20 patients at 1 month after treatment. (Figure 1). Three patients who had a partial response (<50% decrease in lesion size) were injected a second time. The remaining 3 patients who showed no response declined a second injection. Two months after initial treatment, 2 of the 3 patients who were injected twice showed complete resolution of their lesions. No further healing was observed in the third patient. In total, 16 (80%) of 20 patients showed complete resolution of their warts at the 2-month follow-up. At the 6-month follow-up, no recurrences were observed. The overall cure rate was 80%, and the patients were very satisfied with the results. None of the patients experienced adverse effects such as erythema, swelling, itching, dyspigmentation, ulcer, or scar formation. No allergic or systemic adverse reactions and no sign or symptoms of hypervitaminosis D were observed. The only patient complaints were of minimal to moderate pain during injection. Discussion This study clearly demonstrates that recalcitrant plantar warts can be treated successfully with intralesional vitamin D 3 injection. This treatment caused minimal side effects, and there was no evidence of wart recurrence during the followup period. The exact mechanism of vitamin D activity against warts remains to be elucidated; however, it controls cell proliferation and differentiation and has immunoregulatory activities. Its effects are mediated via the vitamin D receptor (VDR), which is present in keratinocytes, melanocytes, fibroblasts, and immune system cells of the skin. 15 Topical vitamin D has been used in several studies for the treatment of common and anogenital warts. For example, Moscarelli et al 13 successfully treated refractory warts with topical activated vitamin D in a renal transplant recipient. Rind et al 14 reported the successful clearance of an anogenital wart in an infant with topical administration of vitamin D. In both case reports, the effect of vitamin D on warts was speculated to be derived from its potential to regulate

3 Aktaş et al 3 Table 1. Intralesional Treatment Outcomes of Patients With Warts. Study Shaheen et al 7 Lee et al 8 Garg and Baveja 9 Gundeti et al 10 Majid et al 11 (2013) Singh et al 12 Kumar et al 19 Nofal et al 20 Broganelli et al 18 (2012) No. of Patients Type of Wart Treatment Maximum No. of Sessions Adverse Effects Results 10 Common wart PPD 3 NR CR: 60% 10 Common wart MMR vaccine 3 NR CR: 80% 10 Common wart Normal saline 3 NR C 15 Genital wart Bleomycin 6 Severe pain during injection (33%), dyspigmentation (20%), crust formation (66%), atrophic scar (13%) 30 Common and plantar warts Mycobacterium w vaccine 10 Fever (66%), local side effects (33%), myalgia (23%), headache (10%), vomiting (6%), ulceration (6%) CR: 73% PR: 13% R: 13% CR: 93% R: 14% 4 Common and filiform warts Ksharodaka 1 Pain during injection CR: 100% 34 Common warts Candida albicans 3 Pain during injection in majority CR: 56% antigen of patients, fever and myalgia PR: 6% in 3 patients 44 Common, Mycobacterium 10 Intradermal nodule-granuloma CR: 54% palmoplantar, indicus pranii on shoulder (81%), PR: 30% periungual vaccine intralesional nodule (43%), fever (27%), pain on injection (18%), paresthesia (13%), atrophic scar (6%), injection site pustule (2%) 44 Anogenital Topical imiquimod NR No serious adverse effects CR: 59% 45 Anogenital Mycobacterium w NR No serious adverse effects CR: 67% vaccine 70 Extragenital MMR vaccine 5 Mild pain during injection (100%), flulike symptoms (12%), itching (6%) erythema (4.6%), edema (1.5%) 280 Recalcitrant cutaneous warts Our study 20 Plantar warts Vitamin D 3 + prilocaine Cidofovir 3.2 Pain and burning sensation during injections; itching, erythema, and postinflammatory hyperpigmentation; no systemic side effects 2 Minimal or moderate pain during prilocaine injection CR: 63% PR: 23% Distant complete response: 74% Distant partial response: 15% R: 4.8% CR: 98% CR: 80% PR: 5% Abbreviations: CR, complete response; MMR, measles, mumps, and rubella; NR, not reported; PPD, purified protein derivative; PR, partial response; R, recurrence. epidermal cell proliferation and differentiation and modulate cytokine production. In addition, Toll-like receptor activation of human macrophages upregulates the expression of VDR and vitamin D 1 -hydroxylase genes, leading to expression and secretion of antimicrobial peptides. 13,14 In a study of 17 patients with recalcitrant warts treated with topical application of maxacalcitol ointment 3 times a day, all warts disappeared within 2 weeks to 6 months. 16 In another case report, 3 immunocompromised patients with recalcitrant warts were treated with topical vitamin D 3 via a half-day occlusive dressing technique. 17 Intralesional therapy for warts has been performed using bleomycin, cidofovir, PPD, C albicans antigen, MMR, and Mycobacterium w vaccine. Bleomycin is an antitumoural, antibacterial, and antiviral agent. Cidofovir is a nucleoside analog of deoxycytidine with potent activity against a broad spectrum of DNA viruses, including HPV. 8,18 These treatments are considered immunotherapy as they are thought to

4 4 Journal of Cutaneous Medicine and Surgery activate the host immune system, leading to viral clearance. Success rates of these treatments range from 54% (Mycobacterium w vaccine) to 98% (cidofovir). The treatment outcomes of different intralesional methods are summarized in Table ,18-20 In this study, 20 patients with plantar warts received intralesional vitamin D 3 treatment, and 16 patients (80%) achieved complete clearance after 2 injections. These results suggest that intralesional vitamin D 3 is more effective than intralesional PPD, bleomycin, and C albicans antigen treatment and is comparable to intralesional MMR and Mycobacterium w vaccine treatments. Intralesional treatment with cidofovir and Ksharodaka (an alkaline substance obtained from a medicinal herb) seems to be superior to that of vitamin D (Table 1). This study had several limitations, including a small number of patients and a lack of a placebo-treated control group. Intralesional saline is generally used as the placebo control for the treatment of warts. Shaheen et al 7 administered intralesional saline as a placebo in wart patients with 0% success rate. However, another study reported a complete response in 75% and 27% of patients after intralesional administration of MMR vaccine and saline, respectively. 21 Spontaneous resolution may occur in warts. Bruggink et al 6 conducted a study of 240 patients with warts and randomly allocated eligible patients to 1 of 3 groups: cryotherapy with liquid nitrogen every 2 weeks, self-application of salicylic acid daily, or a wait-and-see approach. The cure rates were 49% in the cryotherapy group, 15% in the salicylic acid group, and 8% in the wait-and-see group (spontaneous resolution group) at the end of 26 weeks. In contrast, the cure rate in our study was 80% after 2 injections of vitamin D 3 at the end of 8 weeks. Our patients received intralesional prilocaine prior to vitamin D administration. Intralesional local anesthetics have been used in combination with other drugs such as bleomycin and 5-fluorouracil to reduce pain during injection. 22,23 In a prospective, placebo-controlled study, Işçimen et al 22 randomized 76 patients with a total of 315 verrucae to receive either a 5-fluorouracil, lidocaine, and epinephrine (5-FU+LE) mixture or a serum saline injection into paired verrucae in the same patient. A complete response was noted in 70% of the verrucae treated with the 5-FU+LE mixture and 29% of those in the placebo group. A mixture of bleomycin and lidocaine has also been used to reduce the pain of intralesional injection for the treatment of recalcitrant warts. 23 In our study, the serum calcium and parathormone levels of first 5 patients were measured. The results were within normal limits. Unfortunately, we could not measure the serum vitamin D levels of the patients because of technical reasons, which is another limitation of our study. Although no patient experienced any sign or symptom of hypervitaminosis D, it would be safer to measure serum vitamin D and calcium levels before and after intralesional vitamin D treatment to prevent possible hypervitaminosis D. Conclusion Intralesional vitamin D 3 injection may be a new treatment option for warts that are unresponsive to conventional treatments. It is a simple, well-tolerated treatment method that is easy to administer in outpatient clinics. However, the efficacy of this therapy for the treatment of refractory warts requires further evaluation in larger randomized, placebocontrolled, clinical trials. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. References 1. Gibbs S, Harvey I, Sterling J, Stark R. 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