Efficacy and Safety of Intralesional Purified Protein Derivative Versus Vitamin D for the Treatment of Cutaneous Warts: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Cutaneous warts, caused by HPV, are common, and conventional destructive treatments often fail to prevent recurrence. Intralesional immunotherapy offers a promising alternative. Specifically, purified protein derivative (PPD) and vitamin D have demonstrated efficacy; however, a direct comparison of their therapeutic value and safety profiles is needed. This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to compare the efficacy and safety of intralesional PPD versus intralesional Vitamin D for cutaneous warts. Methods: A comprehensive search of PubMed, Scopus, CENTRAL, and Google Scholar was conducted for RCTs up to November 2025. Primary outcomes were the complete and partial clinical response rates of warts. Secondary outcomes included recurrence and adverse events. Risk ratios (RRs) with 95% confidence intervals (CIs) and p-values were pooled using STATA 19.5. Results: Seven RCTs involving 520 patients were included. The analysis found no significant difference in the rate of complete clinical response (RR: 1.07, 95% CI 0.95, 1.21; p = 0.24) or partial clinical response (RR: 0.90, 95% CI 0.56, 1.46; p = 0.68) between the two groups. Also, the two groups showed no significant difference in recurrence rate (RR: 1.14, 95% CI 0.48, 2.68; p = 0.77). Regarding safety, PPD was associated with a significantly higher risk of injection site erythema (RR: 4.76, 95% CI 2.08, 10.93; p < 0.001) and flu-like symptoms/fever (RR: 8.28, 95% CI 1.59, 43.18; p = 0.01). Still, no significant differences were found for injection site pain (p = 0.12) or swelling (p = 0.68). Conclusions: With uncertain evidence, intralesional PPD and vitamin D demonstrate comparable overall efficacy in clearing cutaneous warts. However, PPD carries a higher risk of systemic adverse events (fever) and injection site erythema, with a more effective potential to clear distant warts. The choice between the two agents should be based on the clinical profile and patient preference.