Background
Verruccae (Warts) are common epidermal proliferations caused by human papillomavirus, an epitheliotropic DNA virus.1 Although spontaneous improvement is seen in 65-78% of cases, the cosmetic disfigurement, recurrent nature and pain (especially on the palms and soles) are frequent reasons for patients seeking treatment.2 Till recently, local destruction was the commonly employed modality through topical keratolytics, electrocoagulation, cryotherapy, surgical excision or laser therapy. These modalities lead to significant tissue destruction, pain and frequent recurrences. Immunotherapy by various antigens is a new promising modality which has shown to clear both treated and distant warts by mounting a delayed hypersensitivity reaction to the viral antigen. Immunotherapy acts by enhancing cell mediated immunity against HPV, thus helping in clearance of both treated and distant warts. 3
Aims and Objectives
The primary objective of this study was to evaluate the efficacy of intralesional vitamin D3 for the treatment of warts .The secondary objectives were to study the side effect profile, correlation of efficacy with the wart subtype, correct dosage and median time of efficacy as well as the time of recurrence(if any).
Procedure
A hospital based prospective interventional study was carried out in the Department of Dermatology of a tertiary care hospital which was followed by per protocol statistical analysis. Data and records of patients (5 – 70 years) with multiple (>/= 2) warts over a period of 2 years from 1st April 2017 to 31st March 2019 were studied. Written informed consent of the patients had been taken. Patients whose data and photographic records were available and who were followed up till 6 months of the last injection were included in the study. Patients receiving any other treatment for warts, pregnant and lactating females and those with history of immunosuppression or hypersensitivity to Vitamin D3 were excluded from the study. The study was approved by the Institutional Ethical Committee. Method of injection and outcome evaluation: Vitamin D3 (0.2 ml, 15 mg/ml) was injected into the base of two warts/per session (largest in size) after injecting lignocaine (0.2 ml, 20mg/ml). Injections were repeated every 2 weeks for a maximum of 4 sessions or until complete clearance, whichever was earlier. Patients were followed up for 6 months after the last injection to study for any side effects or recurrence. Serum calcium levels were monitored. Photographic records and data were recorded at treatment session for resolution of the treated wart and the distant warts, reduction in the size and number of warts and any immediate or delayed complications or side effects. Results were graded as complete clearance, moderate response, mild response and no response by comparing with the baseline clinical photographs. Complete clearance implied clearance of all distant and treated warts, moderate response denoted 50-100% reduction in size and/or number of warts, while mild response indicated 1-50% reduction in size and/or number of warts. Patients showing no reduction in size or number of warts after 4 injections were classified as no response. After completion of the 4 sessions or in case of complete clearance before completion of the sessions, patients were followed up for 6 months (at two monthly interval) to look for recurrence or any delayed complication.
Results
The study included 106 patients including 58 males and 48 females (M: F- 1.2: 1). Patients ranged from 6 – 65 years with a mean of 28.64 years. The number of warts ranged from 2 to 26 warts with a mean of 10.28 warts. Of the 106 patients, 34 (32.08 %) had verruca vulgaris, 30(28.03 %) had palmoplanter warts, 18(16.98 %) had plane warts and 12(11.32%) had genital and filiform warts each.
Figure 1
a,b: Pre treatment plane warts in the face; c,d: post intralesional vitamin D3 showing complete resolution
Figure 2
a: Pre treatment verruca vulgaris on the thumb; b: Post intralesional vitamin D3 showing moderate response
Figure 4
a: Blue arrow shows swelling at the site of intralesional Vitamin D3 injection; b: Green arrow shows hyperpigmentation at the site of intralesional vitamin D3 injection
Table 1
The response of various types of warts to intralesional vitamin D3
Table 2
Comparison of different immunotherapy agents in warts
|
Antigen/Vaccine |
Study |
Number of patients |
Maximum number of sessions |
Interval between sessions |
Clearance rate (%) |
|
Mycobacterium w (indicuspranii) vaccine |
Singh et al 4 |
44 |
10 |
2 weeks |
54.5 |
|
Candida albicans antigen |
Majid et al 5 |
34 |
3 |
3 weeks |
55.9 |
|
MMR vaccine |
Saini et al 6 |
86 |
3 |
3 weeks |
46.5 |
|
PPD |
Saoji et al 7 |
55 |
4 |
2 weeks |
76 |
|
Vitamin D3 |
Our study |
106 |
4 |
2 weeks |
71.7 |
Complete clearance was seen in 76.4 % of verruca vulgaris, 66.6 % of palmoplantar warts, 100 % of plane warts and 50 % of genital and filiform warts each. Moderate response was seen in 13.2% while mild response was seen in 6 patients 5.7 %. No response was seen in 9.4 %. The response of the various types of warts to intralesional vitamin D3 is tabulated in Table 1 (Figure 1, Figure 2, Figure 3).
Of the 76 patients showing complete clearance, 56 required 4 sessions of Vitamin D3, 16 required 3 sessions while 4 patients required only 2 sessions of Vitamin D3 injections. The average number of injections required for complete clearance was 3.68.
Complications were seen in 23 patients (18.8%), which included swelling at the site of injection in 16 patients (15.09%) and hyperpigmentation after injection in 4 patients (3.8%) (Figure 4). Swelling subsided in 2 -3 weeks without any treatment.
Recurrence was not seen in any patient during the 6 month follow up period. There was no increase in serum calcium level above the normal reference range in any of the patients during the entire study period.
Discussion
Local destructive procedures are the commonly available treatment modality for warts which include electrocautery, lasers or cryotherapy. However, all these procedures are tedious and painful and not practical in case of multiple warts. These also cause destruction of the surrounding tissue and hence may lead to scarring. Moreover, there can be recurrence of warts even after complete removal by these procedures. Hence immunotherapy by use of various agents is a good option for treatment of warts. Immunotherapy acts by boosting immunity to HPV virus as a result of which both treated and distal warts are cleared.8 Various agents have been used for immunotherapy such as Mycobacterium w vaccine, 4 Candida albicans antigen, 5 MMR (measles, mumps, rubella) vaccine, 6 Purified Protein Derivative (PPD) etc. 7 The advantage with immunotherapy is its low recurrence rate compared to the normal destructive procedures.
In the present study, we have used Vitamin D3 for immunotherapy for the treatment of multiple warts. The exact mechanism of action of Vitamin D3 as an immunomodulator is not known. Studies suggest that it can regulate proliferation and differentiation of keratinocytes and hence modulates cytokine production. It inhibits the expression of tumor necrosis factor (TNF)-α, TNF-γ, interleukin-6 (IL-6) and IL-8, mediated through Vitamin D receptor (VDR)-dependent pathway. 9 Hence topical Vitamin D3 has been used in the treatment of warts in various studies. 10, 11
Kavya et.al. used intralesional vitamin D3 for the treatment of palmoplantar and common warts. 2 A total of 42 patients were included in the study and maximum of 4 injections were given at 2 weekly interval. They achieved a clearance of 78.6% with recurrence in 2.38% patients. Similarly, Raghukumar et.al. studied the effect of Vitamin D3 in verruca vulgaris, palmoplantar, filiform and plane warts. 12 Sixty patients were included in the study and a maximum of 4 sessions of Vitamin D3 injections intralesionally were given at 2 weekly interval. Ninety percent of the patients responded while recurrence was seen in 3.33%. The results of both the studies were similar to our study as shown in the following table.
Various other antigens and vaccines have been used as immunotherapy and the response of these are compared in Table 2.
The response rate achieved in our study was 71.7 % in maximum of 4 sessions which was superior to the results achieved with Mycobacterium w vaccine, Candida albicans and MMR vaccine. However, treatment with PPD was superior to that of Vitamin D3, but the complications and side effects during injection were more in the form of pain, severe swelling, eczematous changes, constitutional symptoms like fever and bodyache. However, in our study we did not experience any major systemic or local side effects requiring any form of treatment. Also, there was no recurrence seen in our study during the 6 month follow up period.
Conclusion
Intralesional Vitamin D3 injection is cheap and effective approach for treatment of multiple warts. Our study concludes its high efficacy in plane warts followed by verruca vulagaris. It is safe as compared to other immunotherapy agents with no major local or systemic side effects. It can be easily used in children as it is safe and painless compared to other locally destructive procedures.
The limitations of this study were its lack of a control group. However, the results are encouraging. Large well designed, randomised case control study is required to confirm the efficacy of intralesional Vitamin D3 in the treatment of multiple warts.
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