Journal Pre-proof

Intralesional vitamin D3 injection in the treatment of warts: A systematic review and

meta-analysis

Marvin Chia-Han Yeh, MD PhD, Tsung-Yu Tsai, MD, Yu-Chen Huang, MD

PII: S0190-9622(19)32982-2
DOI: https://doi.org/10.1016/j.jaad.2019.10.059
Reference: YMJD 13959

To appear in: Journal of the American Academy of Dermatology

Received Date: 25 September 2019

Accepted Date: 23 October 2019

Please cite this article as: Chia-Han Yeh M, Tsai T-Y, Huang Y-C, Intralesional vitamin D3 injection in
the treatment of warts: A systematic review and meta-analysis, Journal of the American Academy of
Dermatology (2019), doi: https://doi.org/10.1016/j.jaad.2019.10.059.

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© 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.

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Intralesional vitamin D3 injection in the treatment of warts:

A systematic review and meta-analysis

Marvin Chia-Han Yeh, MD PhD, a Tsung-Yu Tsai, MD, a, b Yu-Chen Huang, MD, a, b, c

a
Department of Dermatology, Wan Fang Hospital, Taipei Medical University, Taipei,

Taiwan
b
Research center of big data and meta-analysis, Wan Fang Hospital, Taipei Medical

University, Taipei, Taiwan

c
Department of Dermatology, School of Medicine, College of Medicine, Taipei

Medical University, Taipei, Taiwan

*Corresponding author:

Yu-Chen Huang

Department of Dermatology, Wan Fang Hospital, Taipei Medical University

E-mail: dhist2002@yahoo.com.tw

Address: No.111, Sec. 3, Xinglong Rd., Wenshan Dist., Taipei City 116, Taiwan

Tel: 886-2-29307930-2980; Fax: 886-2-86621197

Text word count: 499

Figure number: 1

Table number: 1

Number of references: 4

Funding sources: none

Conflict of interest: none

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Intralesional immunotherapy has become more commonly used for treatment of warts.

The direct injection of vaccines or fungal antigens into warts was believed to

stimulate the host cell-mediated immunity and eliminate the infected cells.1 Recently,

vitamin D3 was reported to have comparable treatment effects to other

immunotherapeutic agents. Therefore, a systematic review and meta-analysis was

performed to investigate its efficacy and safety profile.

Database searches were performed on Sep 10, 2019, to include studies reporting the

efficacy of intralesional vitamin D3 injection for warts. The reported response rates

were pooled into different categories: complete, above 50% (including complete) and

below 50% response group. A random effects model was used to calculate the odds

ratio (OR) and pooled remission rate for the treatment responses. A meta-regression

analysis was performed to assess the association between the dose of injection and

treatment responses.

Fourteen studies with 480 patients were included. When all types of warts were

included, intralesional vitamin D3 injection was significantly more effective than the

placebo (complete response, OR: 3.027, 95% confidence interval[CI]: 1.146-7.993, I2:

9.148%; below 50% response, OR: 0.061, 95%CI: 0.009-0.415, I2:68.132%).

However, it was less effective than intralesional purified protein derivative (PPD)

injection (complete response, OR: 0.358, 95%CI: 0.223-0.574, I2:1.390%; above 50%

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response, OR: 0.319, 95%CI: 0.223-0.574, I2: 0.000%). A subgroup analysis including

only patients with common warts and palmoplantar warts showed similar results

(Table 1). No evidence of publication bias was observed in the studies.

The pooling of all studies indicated 59.9% patients (95%CI: 45.5%-72.9%) receiving

intralesional vitamin D3 injection achieved complete resolution, and 77.7% (95%CI:

60.9%-88.6%) achieved more than 50% improvement (Table 1). The meta-regression

analysis showed that vitamin D3 dose was not associated with the treatment response

in patients with all types of warts. However, subgroup analyses revealed that in

patients with common warts and palmoplantar warts, the dose injected per wart, dose

injected in each session, and total dose (Figure 1) were significantly associated with

the rates of complete and above 50% response (all p<0.05), respectively. For all the

studies included, only mild adverse effects were noticed, such as local pain, swelling,

and erythema.

The mechanism of intralesional injection of vitamin D3 in the treatment of warts

remains to be elucidated. It has been proposed that vitamin D could regulate the

proliferation of epidermal cells and stimulate cytokine release by upregulating vitamin

D receptor and hydroxylase gene.2, 3 For example, Abou-Taleb et al. demonstrated an

increased serum interferon-γ level after intralesional vitamin D3 injection.4

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This study was limited by substantial heterogeneity of the included studies, which

may be attributable to various treatment regimens and disease severity (number,

location, and duration of warts) included in the studies.

In summary, intralesional vitamin D3 injection is an effective and safe treatment

option for warts, but it is less effective than intralesional PPD injection. Moreover, a

higher vitamin D3 dosage correlates with a better treatment response in patients with

common and palmoplantar warts. Further studies are required to investigate the

dose-response relationship and determine an optimal regimen.

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Reference

1. Thappa DM , Chiramel MJ. Evolving role of immunotherapy in the treatment of

refractory warts. Indian Dermatol Online J 2016;7:364-70.

2. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR et al. Toll-like receptor

triggering of a vitamin D-mediated human antimicrobial response. Science

2006;311:1770-3.

3. Osborne JE , Hutchinson PE. Vitamin D and systemic cancer: is this relevant to

malignant melanoma? Br J Dermatol 2002;147:197-213.

4. Abou-Taleb DAE, Abou-Taleb HA, El-Badawy O, Ahmed AO, Thabiet Hassan AE ,

Awad SM. Intralesional vitamin D3 versus intralesional purified protein derivative in

treatment of multiple warts: A comparative clinical and immunological study.

Dermatol Ther 2019:e13034.

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1 Abbreviations

2 CI, confidence interval

3 OR, odds ratio

4 PPD, purified protein derivative

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6 Figure legends

7 Figure 1. Scatter plot. Significant association between the treatment response and

8 vitamin D3 dose in patients with common warts and with palmoplantar warts.

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14 Table 1

Table 1. Results of meta-analysis

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Treatment Study/patient Effect size Effect estimate (95% CI) P I

Vitamin D3 vs PPD
All warts
100% response 5/282 OR 0.358 (0.223-0.574) <0.001 1.390
>50% responsea 5/282 OR 0.332 (0.195-0.564) <0.001 0.000
<50% response 5/282 OR 2.227 (0.987-5.028) 0.054 12.693
Common warts and
palmoplantar warts
100% response 4/202 OR 0.319 (0.190-0.533) 0.001 0.000
>50% responsea 4/202 OR 0.350 (0.200-0.668) 0.001 19.466
<50% response 4/202 OR 3.091 (1.359-7.028) 0.007 0.000

Vitamin D3 vs placebo
All warts
100% response 3/152 OR 3.027 (1.146-7.993) 0.025 9.148
b
<50% response 3/152 OR 0.061 (0.009-0.415) 0.004 68.132

Vitamin D3 group
All warts

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100% response 14/480 Pooled 59.9% (45.4%-72.9%) 86.117

remission
rate
>50% responsea 14/480 Pooled 77.7% (60.9%-88.6%) 88.568
remission
rate
<50% response 14/480 Pooled 13.7% (8.8%-20.7%) 65.245
remission
rate
Common warts and
palmoplantar wart
100% response 13/413 Pooled 59.9% (45.4%-72.9%) 87.754
remission
rate
>50% responsea 13/413 Pooled 78.5% (59.8%-90.0%) 87.279
remission
rate
<50% response 13/413 Pooled 10.8% (5.2%-18.2%) 63.021
remission
rate
Common warts
100% response 8/193 Pooled 63.7% (40.1%-82.2%) 84.547

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remission
rate
>50% responsea 8/193 Pooled 83.2% (49.4%-96.2%) 87.477
remission
rate
<50% response 8/193 Pooled 11.5% (4.9%-24.8%) 19.815
remission
rate
Palmoplantar wart
100% response 9/177 Pooled 74.0% (55.5%-86.7%) 73.141
remission
rate
>50% responsea 9/177 Pooled 86.2% (70.5%-94.2%) 65.459
remission
rate
<50% response 9/177 Pooled 10.6% (4.6% - 22.5%) 54.301
remission
rate
Periungual warts
100% response 4/12 Pooled 49.1% (18.7%-80.2%) 12.815
remission
rate

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>50% responsea 4/12 Pooled 73.3% (26.9%-95.3%) 37.280 15

remission 16
rate 17
<50% response 4/12 Pooled 26.7% (4.7%-73.1%) 37.280 18
remission 19
rate 20
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CI, confidence interval; OR, odds ratio 22
a
Above 50% response including 100% response, b Above 50% was not reported as the response group in the original
articles cannot be merged to form this group

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23 Figure 1

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25 Supplementary materials available at doi: 10.17632/z9z5w93tb6.1

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