Intralesional measles, mumps, and rubella vaccine versus vitamin D for treatment of warts: A randomised clinical trial

Introduction

Warts, induced by the various human papillomavirus (HPV) strains, are widespread and upsetting skin growths infecting the outer skin layers and/or mucous membranes.¹ Although the diagnosis can often be made clinically, dermoscopy plays a crucial role in confirming the diagnosis and following up the response to treatment.²

Dermatologists should consider the recurrent and benign nature of warts while establishing the treatment plan.³ Warts were typically treated with destructive methods, such as chemical cautery, electrocautery, or cryotherapy. These methods may cause many side effects, like inflammation, scarring, hypo-, or hyper-pigmentation. Additionally, treatment response is expected in the target wart only. In contrast, intralesional immunotherapy is linked to a lower incidence of adverse effects and works by activating the immune system to identify the virus, resulting in treatment response in all warts.²

Various antigens, such as BCG, PPD, MMR, Candida antigen, and the more recently utilised HBV vaccine, have been injected as immunotherapy for the treatment of warts.¹ The MMR vaccine functions as an immunotherapy by eliciting a Th1 immune response, increasing IL-2, IL-4, IL-5, TNF α, and IFN-γ, and inducing delayed hypersensitivity targeting both MMR viral antigens and HPV.⁴

Nevertheless, vitamin D3 acts by regulating cytokine production and epidermal proliferation, which contributes to its effectiveness over other immunotherapeutic approaches. It suppresses IL-1 α and IL-6 while stimulating toll-like receptors (TLRs) of human macrophages, promoting the production of antimicrobial peptides in both treated and remote warts.⁵ Despite numerous reports regarding the efficacy of intralesional immunotherapy in wart treatment, it remains unapproved by the FDA. So, additional research is needed to compare different antigens and gain a clearer understanding of their relative efficacy.³

The main aim of this randomised clinical trial was to assess the effectiveness of the intralesional measles, mumps, and rubella (MMR) vaccine over vitamin D in treating warts. Moreover, the secondary objectives were to assess their safety and tolerability. Dermoscopy was applied as a tool to confirm the clinical diagnosis of complete improvement.

Methods

The research received approval from the ethics committee of the Faculty of Medicine, Mansoura university hospital, number 2617 dated may 2024. This randomised clinical trial enrolled 112 patients with multiple common, plantar and,/or plane warts, clinically diagnosed and verified through dermoscopic evaluation. All participants were selected from the Dermatology Outpatient Clinic at Mansoura university hospital from April 2022 to October 2023.

Exclusion criteria in the current study were: (i) patients aged < 4 years, (ii) prior diagnosis of asthma, allergic skin conditions, widespread dermatitis, hypersensitivity to vitamin D, or MMR, (iii) pregnant or breastfeeding women, (iv) patients with compromised immune system—(either absolute or relative), and (v) individuals with chronic illnesses, including kidney failure, liver dysfunction, hepatitis, or heart-related conditions. Moreover, participants who had undergone any treatment for warts within the three months preceding the study was excluded.

Prior to their participation in the study, written informed consents were secured from all patients or their caregivers. The CONSORT flow diagram of participants has been illustrated in Figure 1.

Close

Figure 1:

consort flow chart showing the included, excluded and studied groups.

Export to PPT

Each participant underwent a thorough medical history review, along with a comprehensive general and dermatological evaluation to determine the quantity, dimensions, and location of warts, while ruling out any additional skin disorders.

Digital images were captured before injection and during each follow-up visit for each patient using Sony Cyber-shot DSC-W620.

DermLite III device from 3 Gen was utilised for Dermoscopy to confirm wart diagnoses prior to treatment and during every session throughout the study to assess the level of improvement following treatment. Two dermatologists, blinded to the study details, assessed the dermoscopic photomicrographs to assess the clinical and dermoscopic improvement.

Results

The included patients were divided into two groups randomly, with no significant differences in age, gender, or the initial clinical characteristics of the studied warts [Table 1].

Table 2 demonstrates a significantly greater percentage of complete response in MMR (80.4%) relative to the vitamin D group (66.1%). Partial responders were also higher in the MMR (14.3%) than in the vitamin D group (7.1%), while the percentage of poor responders was greater in the vitamin D group (26.8%) than in the MMR group (5.4%) with no significant differences in the average number of required injections (4 sessions) in both groups [Figures 2-5].

Close

Figure 2a:

Male patient aged 25 y in the MMR group with multiple plantar warts, (before treatment).

Export to PPT

Close

Figure 2b:

After five sessions of IL MMR with excellent response, (polarised, 20x).

Export to PPT

Close

Figure 3:

(a) A 10-year old girl in the MMR group with multiple common and periungual wartswarts, (before treatment), (b) Female patient aged 10 years in the vitamin MMR group with multiple common and periungual warts, (before treatment), (c) After three sessions of IL MMR with excellent response, (d) After three sessions of IL MMR with excellent response.

Export to PPT

Close

Figure 4:

(a) A 6-year old boy with multiple common warts, (before treatment), (b) Male patient aged 6 years in the vitamin D group with multiple common warts, (before treatment), (c) A 6-year old boy with multiple common warts, (after treatment), (d) After 3 sessions of IL vitamin D with excellent response.

Export to PPT

Close

Figure 5 a-c:

A 9-years old boy in the vitamin D group with multiple common and periungual warts, (before treatment).

Export to PPT

Close

Figure 5 d-f:

After 4 sessions of IL vitamin D with excellent response

Export to PPT

Regarding the adverse effects, the MMR group showed a significantly higher percentage of mild pain (96.4%) and injection site itching (12.5%) than the vitamin D group. Vitamin D group patients reported no injection site reactions. Severe pain, erythema, oedema, and symptoms resembling influenza were recorded in the MMR group more than in the Vitamin D group, though these differences were not statistically significant [Table 3].

According to our results, in the MMR group, complete response occurred significantly with smaller size warts (mean = 3.8 mm) compared to larger warts [Table 4]. Conversely, in the vitamin D group, complete response was significantly more common in patients with plantar warts compared to other subgroups [Table 4].

After six months of follow-up, the recurrence rates revealed no significant difference between the two groups, with two cases (3.6%) in the MMR group versus three cases (5.4%) in the vitamin D group developing recurrence.

Discussion

In this study, 80.4% of participants from the MMR group experienced a complete response, while partial and no responses were observed in 14.3% and 54%, respectively. These results are consistent with Nofal and Nofal,⁶ Shaldoum et al.,⁴ and Mohammed et al.⁷ However, Awal and Kaur,⁸ Nofal et al.,⁹ Grawal et al.,¹⁰ Rezk et al.,¹¹ and Mohamed and ElGhareeb¹² reported lower response rates [Table 5]. This discrepancy may be owed to differences in sample sizes, ethnic backgrounds, doses, or intervals between sessions.

It is supposed that the MMR vaccine, having three different antigens (measles, mumps, and rubella), may elicit an enhanced immune response to HPV by stimulating the release of multiple cytokines, including IL-2, IL-4, IL-5, and tumour necrosis factor-α.⁸)

In the present investigation, the administration of intralesional vitamin D injections led to a complete response in 66.1% of participants, while 7.1% exhibited a partial response, and 26.8% showed no improvement. These outcomes resemble those recorded by Shaldoum et al.,⁴ Rezk et al.¹³ and Mohta et al.¹⁴ However, Aktaş et al.,¹⁵ Kavya et al.,¹⁶ Raghukumar et al.,¹⁷ and Al-Sabak et al.¹⁸ reported higher response rates in contrast to Abou-Taleb et al.¹⁹ who reported lower response rates [Table 5]. The variation between these studies may be explained by using different concentrations, doses, and intervals. Additionally, to ensure accuracy and to minimise the potential for error associated with clinical examination alone, we verified the complete resolution of warts through dermoscopic evaluation.

The response of warts to intralesional MMR (80.4%) was significantly higher than to vitamin D (66.1%), aligning our study with prior research.^4,5,14,20 The superior response in the MMR group can be explained by the synergistic effect of its three antigens, which generate a stronger immunogenic response.

In this study, both groups demonstrated a similar number of sessions needed to achieve a complete response (4). This finding indicates that injections should be discontinued if no improvement is observed by the fourth session. These results are consistent with those of previous studies.^5,14 However, Shaldoum et al.⁴ reported significantly fewer sessions with vitamin D (2.9) compared to the MMR group (5.4), and this fast cure could be attributed to the injection of every wart with vitamin D in their study. Also, Naresh Babu et al.²¹ reported a slightly lower number of sessions in the vitamin D group than in the MMR group, and this might be related to the administration of elevated vitamin D doses.

Regarding adverse effects, the MMR group showed a notably increased proportion of mild pain (96.4%), and injection site itching (12.5%) compared to the vitamin D group. Vitamin D group patients reported no injection site reactions. Severe pain, erythema, oedema, and symptoms resembling influenza were recorded in MMR more than in the vitamin D group, with no significant results. These results are similar to those of Shaldoum et al.⁴ and Jartarkar et al.,⁵ but contrasting with Mohta et al.¹⁴ and Jain et al.²² who reported injection site itching exclusively in the Vitamin D group.

According to our results, complete response was significantly associated with smaller-sized warts (mean=3.8) in the MMR group, compared to those with partial or no response cases. In contrast, complete response was significantly related to plantar warts in the vitamin D group. Shaldoum et al.⁴ reported no correlation between the clinical characteristics of warts and the clinical response. Joshi et al.²³ reported a significant inverse correlation between the length of time for which warts persisted and the response rate in the two groups.

Upon follow-up of patients for 6 months after cure, recurrence rates revealed no significant differences between the two groups, with three cases (5.4%) in the vitamin D group vs. two cases (3.6%) in the MMR group, which agrees with the results of Jain et al.²² In contrast, Mohta et al.¹⁴ reported no recurrences in the MMR group versus two (6.5%) patients in the vitamin D group, who had initially shown partial improvement. Shaldoum et al.⁴, Jartarkar et al.,⁵ and Babu et al.²¹ reported no recurrence in either group. Joshi et al.²³ reported higher recurrence rates in the Vitamin D (14%) versus the MMR group (16%).

Limitations

This is a clinical study, and we did not assess viral types nor measured the serum levels of any involved cytokine pre and post treatment. Further studies are necessitated to assess the effect of these injections on the serum level of different cytokines.

Conclusion

Both intralesional MMR and vitamin D are efficacious, safe, and cost effective therapeutic modalities for warts with low recurrence rates. Therefore, immunotherapy may be used for multiple, disseminated, and recalcitrant warts.