Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2024;14(3):e2024215 1 Comparative Analysis of Intralesional Immunotherapy and Conventional Treatments for Non-Genital Warts: A Systematic Review and Network Meta-Analysis Amr Molla1, Muhammad Tobaiqi2, Hossein Elbadawy3, Raed Jannadi2, Heba Eltahir3, Emad Albadawi4, Naweed Alzaman1, Mohammed Aloufi5, Mekky Abouzied3,6, Muayad Albadrani2 1 Department of Medicine, College of Medicine, Taibah University, Al-Madinah Al-Munawara, Saudi Arabia 2 Department of Family and Community Medicine and Medical Education, College of Medicine, Taibah University, Al-Madinah Al-Munawara, Saudi Arabia 3 Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawara, Saudi Arabia 4 Department of Basic Medical Sciences, College of Medicine, Taibah University, Al-Madinah Al-Munawara, Saudi Arabia 5 Madinah Health Cluster, Al-Madinah Al-Munawara, Saudi Arabia 6 Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt Key Message: Network meta-analysis reveals intralesional immunotherapy, particularly needling and furosemide with digoxin, surpasses conventional treatments for non-genital warts, highlighting a need for broader accessibility and further comparative studies. Key words: intralesional immunotherapy, cryotherapy, HPV, network meta-analysis, non-genital warts Citation: Molla A, Tobaiqi M, Elbadawy H, et al. Comparative Analysis of Intralesional Immunotherapy and Conventional Treatments for Non-Genital Warts: A Systematic Review and Network Meta-Analysis. Dermatol Pract Concept. 2024;14(3):e2024215. DOI: https://doi .org/10.5826/dpc.1403a215 Accepted: July 14, 2024; Published: July 2024 Copyright: ©2024 Molla et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Amr Molla, Department of Medicine, College of Medicine, Taibah University, Al-Madinah Al-Munawara, Saudi Arabia. Tel.: +966 14-8618888, Ext: 3495 Email: amolla@taibahu.edu.sa Introduction: Warts, benign skin growths caused by various human papillomavirus strains, are categorized as genital and non-genital. Non-genital warts often lack noticeable symptoms but can lead to psychological distress due to factors like embarrassment. Traditional treatments, including physical and chemical methods, show limitations, prompting the exploration of novel approaches like intrale- sional immunotherapy. The clinical challenge lies in selecting the most effective modality. Objective: In our study, we used the network meta-analysis (NMA) as a statistical tool to explore the most effective intralesional immunotherapy interventions. ABSTRACT 2 Review | Dermatol Pract Concept. 2024;14(3):e2024215 Introduction Warts are defined as non-cancerous skin growth related to viral infection, mostly associated with various strains of hu- man papillomavirus (HPV) [1,2]. The virus infects the outer layer of the skin as it enters the body from an area where the skin is damaged [3]. Warts are divided into genital and non-genital warts. The non-genital type of warts may be present on different body parts, such as verruca vulgaris, the most common type of wart. There are many other different types, such as plantar warts, flat warts, filiform warts [4], periungual warts [5], and mosaic warts [6]. Typically, these warts do not exhibit noticeable symptoms, although some types, like plantar or subungual warts, may cause tender- ness, especially when fissured [7,8]. Although warts cannot cause mortality directly without developing into a cancerous type, which is higher in genital warts [9], non-genital warts can put a heavy burden on the patients, as these warts can significantly impact an individual’s psychological well-being, leading to a diminished quality of life. This influence is man- ifested through embarrassment, fear of negative judgment from others, and frustration stemming from the persistent recurrence of the warts [1,10,11]. The psychological toll en- compasses emotional aspects such as shame, anxiety about social perception, and the ongoing emotional strain associ- ated with the continual reappearance of the warts [10,12]. Multiple treatment approaches exist for warts, including physical methods like cryotherapy, electrosurgery, ablative la- ser procedures, or surgical removal. Chemical options involve salicylic acid or trichloroacetic acid, while anti-proliferative agents like podophyllin, 5-fluorouracil, or bleomycin [13,14] are also utilized. Regrettably, none of the treatments have demonstrated complete effectiveness as a cure with a 100% cure rate [14,15]. Additionally, these available methods may induce pain, lead to scarring, and are linked to elevated rates of wart recurrence [16]. Due to the previous side effects and the problems with physical, surgical, or chemical methods, new methods are required to treat the warts with a higher success rate. Intralesional immunotherapy constitutes a ther- apeutic modality employed recently in wart treatment. This procedure entails the direct injection of immunomodulatory agents into the wart or adjacent tissue, intending to elicit a heightened immune response against the HPV causative agent [17,18]. The overarching objective is the augmentation of the local immune milieu, thereby facilitating the eradica- tion of wart lesions. Objective Choosing among the various modalities poses a clinical chal- lenge when there is a lack of clear evidence favoring one method over another. To fill this knowledge gap, we conduct our study using NMA. This statistical approach facilitates the comparison of multiple treatments, which would fit this type of study that contains multiple interventions [19]. Methods Our network meta-analysis was performed according to the PRISMA statement and the guidelines of the Cochrane Handbook for systematic reviews [20-22]. Searching Databases and Keywords We searched four main databases with the following terms: ((Intralesional OR Injection* OR Inject*) AND (immuno- therap* OR “purified protein derivative” OR “PPD-B” OR “PPD B” OR “PPD-L” OR “PPD L” OR “Purified Protein Derivative” OR PPD OR “PPD-S” OR “PPD-CG” OR “PPD CG” OR “PPD-F” OR “PPD F” OR Trichophyton OR Methods: Comprehensive searches of Web of Science, PubMed, Cochrane, and Scopus databases were conducted until December 2023. Eligible studies were analyzed for outcomes presented as risk ratios (RRs) with 95% confidence intervals (CI). Treatments were ranked using the P-score in an NMA per- formed with R software. Results: We included 68 RCTs in our study. For complete response, needling showed a signifi- cant difference compared to Candida albicans antigen (RR= 0.13, 95% CI [0.02; 0.99]) and Mw (RR= 0.12, 95% CI [0.02; 0.94]). In overall response, both bleomycin and furosemide with digoxin were significant compared to autoimplantation (RR= 0.46, 95% CI [0.24; 0.88]) and (RR= 0.40, 95% CI [0.18; 0.91]) respectively. Similarly, both were significant compared to cryotherapy (RR= 0.45, 95% CI [0.27; 0.76]) and (RR= 0.40, 95% CI [0.19; 0.82]) respectively. Conclusion: This NMA indicates needling, furosemide with digoxin, and PBP antigen stimulants as effective for non-genital warts, surpassing traditional treatments in complete and overall response. Direct comparisons in future research are warranted to confirm their superiority. Review | Dermatol Pract Concept. 2024;14(3):e2024215 3 Trychophyton OR Endodermophyton OR BCG OR “Bacil- lus Calmette Guerin” OR “Calmette’s Vaccine” OR Calmette OR “Calmette Guerin Bacillus” OR “Measles Mumps Rubella” OR “Measles-Mumps-Rubella” OR “Measles, Mumps, Rubella” OR MMR OR “Mumps-Measles-Rubella” OR “Mumps Measles Rubella “ OR “Mumps-Measles- Rubella” OR “Triviraten Berna” OR Priorix OR Trimovax OR Pluserix OR Virivac OR Monilia* OR “Cyberlindnera jadinii” OR Candida OR “Lindnera jadinii” OR “Hansenula jadinii” OR “Pichia jadinii” OR “Saccharomyces jadinii” OR “Torula utilis” OR Mycobacteri* OR “vitamin D” OR Calciferol OR autoinoculate OR autoimplant OR “Coryne- bacterium parvum” OR INF OR interferon OR INF-g OR “Propionibacterium parvum” OR “Propionibacterium acne” OR Vaccin*) AND (Wart OR Verruca OR Verrucas OR “human papilloma virus” OR papillomavirus OR HPV)). The search was done until December 2023. We also did a manual search for the references of the included studies. Eligibility Criteria and Study Selection We included studies that met the following criteria: (1) Pop- ulation: All patients with non-genital warts, either single or multiple. (2) Intervention and comparator arms: Intral- esional immunotherapy compared with any other treat- ment modality including: needling, furosemide and digoxin, polyvalent bacterial protein antigen (PBP Ag) stimulant, purified protein derivative vaccine (PPD) and cryotherapy, bleomycin, Bacille Calmette-Guérin vaccine (BCG), PPD and isotretinoin, ozone gas, multiple PPD, PPD and Candida albicans antigen with MMR, C. albicans antigen, C. albi- cans antigen and cryotherapy, mycobacterium with vaccine (Mw), measles, mumps, and rubella vaccine (MMR), PPD, isotretinoin, photodynamic therapy (PDT), vitamin D3, 5-FU, mumps, Candida or Trichophyton (MCT) antigen and interferon (IFN) α-2b, MMR subcutaneous (SC), autoim- plantation, C. albicans antigen and isotretinoin, zinc sulfate, MMR intradermal (ID), cryotherapy, DPCP, MCT antigen, IFN α-2b and PDL, formic acid 85%, IFN α-2b, PDL, and placebo. (3) Outcomes: Complete response, no or minimal response, overall response, and partial response. (4) Study design: Randomized clinical trials (RCTs) only. Data Extraction We extracted the data related to the following: 1. Summary and baseline characteristics of the included studies; including study arms, site, trial registration, age, male, follow-up duration, type of warts, warts duration, number of sessions, adverse events, recurrence rate, in- clusion criteria, primary endpoints, and conclusion. 2. Outcomes of Complete response, no or minimal re- sponse, overall response, and partial response. 3. Quality assessment domains. Quality Assessment We employed the Cochrane risk of bias tool (version 1) to evaluate the quality of the interventional studies included in our analysis. This tool is detailed in chapter 8.5 of the Cochrane Handbook for Systematic Reviews of Interven- tions 5.1.0. Statistical Analysis We performed a frequentist network meta-analysis employ- ing random-effects models. Binary data were extracted as risk ratio [RR] and their corresponding 95% confidence in- terval [CI]. All statistical analyses were conducted using R programming through net-meta statistical packages. Hetero- geneity was evaluated across clinical, methodological, and statistical domains. The assessment of statistical heterogene- ity involved the use of I2 statistics. Definitions of the Outcomes Overall response: The proportion of patients who have a partial or complete response to therapy in getting rid of warts. Complete response: The proportion of patients with thorough eradication and absence of not only the targeted central wart that was subjected to injection but also any supplementary lesions situated in close proximity to the treated area. Partial response: This was achieved by calculating the proportion of patients who showed treatment re- sponse (more than 25% but less than complete response). No or minimal response: This was achieved by calculat- ing the proportion of patients who showed either no improvement in the warts or minimal treatment re- sponse (less than 25%). Results After conducting our literature search on various search da- tabases, we found 3,614 records. We found a total of 1,357 duplicates with the use of the endnote system. We excluded and removed these duplicates and excluded 2,109 articles based on title and abstract screening. With a final full-text screening for 148 papers, we finally included 68 studies (Figure 1). 4 Review | Dermatol Pract Concept. 2024;14(3):e2024215 followed by bleomycin, and finally BCG. On the other hand, the 3 interventions with the lowest effect on achieving the complete response according to P-scores are IFN α-2b, pla- cebo, and PDL (Figure 3). Almost all of the highest interventions in results showed significance compared with IFN α-2b, placebo, and PDL. Needling was significant compared to C. albicans antigen as the results were (RR= 0.13, with 95% CI [0.02; 0.99]). Nee- dling was also effective compared to Mw as the results were (RR= 0.12, with 95% CI [0.02; 0.94]). PPD and cryotherapy were significant compared to MMR as the results were (RR= 0.52, with 95% CI [0.28; 0.95]). BCG was substantial com- pared to MMR as the results were (RR= 0.68, with 95% CI [0.47; 0.98]) (Figure 3). Overall Response The top five interventions demonstrating the most sig- nificant effectiveness in achieving an overall response in wart treatment, based on P-scores from our results, are as follows: PBP antigen stimulants followed by furosemide and digoxin followed by bleomycin followed by PPD and Study Characteristics and Quality A total of 68 studies, including 4,996 patients, were included in our study. The included studies were from Egypt, India, the United States, Thailand, Pakistan, Malaysia, Libya, Saudi Arabia, Iran, Korea, Brazil, and the Philippines. The mean age ranged from 20 years to 40 years. The majority of follow-up periods were 3 and 6 months. The plantar warts were the most common type in the included population. A low per- centage of the warts showed recurrence (Supplementary Table 1). Using the ROB tool for the included RCTs, almost all the included studies were of moderate quality. Full details are displayed in (Figure 2). Main Outcomes Complete Response The top 5 interventions demonstrating the most significant effectiveness in achieving a complete response in wart treat- ment, based on P-scores, are as follows: Needling followed by furosemide and digoxin followed by PBP antigen stimulants Figure 1. PRISMA flow chart. Review | Dermatol Pract Concept. 2024;14(3):e2024215 5 No or Minimal Response Based on P-scores from our results, the top five interventions demonstrating the lowest response in wart treatment are as follows: Placebo followed by IFN α-2b followed by KOH 5% followed by MMR ID followed by zinc sulfate. Furose- mide and digoxin mix was significant when compared with placebo, IFN α-2b, KOH 5%, MMR ID, and zinc sulfate as the results were (RR= 0.03, with 95% CI [0.00; 0.35]), (RR= 0.04, with 95% CI [0.00; 0.53]) (RR= 0.03, with 95% CI [0.00; 0.69]), (RR= 0.04, with 95% CI [0.00; 0.72]), and (RR= 0.05, with 95% CI [0.40; 0.70]). PPD and isotretinoin mix was significant when compared placebo, and IFN α-2b (RR= 0.08, with 95%CI [0.01; 0.54]), and (RR= 0.09, with 95%CI [0.01; 0.88]). C. albicans antigen was significant when compared to placebo, and IFN α-2b (RR= 0.16, with 95% CI [0.09; 0.28]), and (RR= 0.17, with CI [0.04; 95%, 0.71]) respectively (Figure 5). Partial Response Based on P-scores from our results, the top 5 interventions demonstrating partial response in wart treatment are 5-FU, bleomycin, PDT, DPCP, and formic acid 85%. On the other hand, the lowest 3 interventions in achieving the partial re- sponse according to P-scores are needling, furosemide and digoxin, and MMR ID. MMR ID was significantly lower in partial response when compared with 5-FU, bleomycin, and PDT (RR= 0.01, with 95% CI [0.00; 0.32]), (RR= 0.02, with 95% CI [0.00; 0.54]), and (RR= 0.06, with 95% CI [0.01; 0.48]) (Figure 6). Discussion To the best of our knowledge, our NMA included all the avail- able treatment interventions for non-genital warts. We set our comparison based mainly on efficacy outcomes for treating warts at the place of injection and the distantly related warts. Our results revealed that the most efficacious interventions yielding complete response encompassed needling, the com- bination of furosemide and digoxin, and PBP antigen stim- ulants. Conversely, IFN α-2b, PDL, and formic acid 85% exhibited a lower complete response rate. The combination of furosemide with digoxin, PBP antigen stimulants, and bleo- mycin were among the top interventions yielding overall re- sponses. Nevertheless, KOH 5%, MMR ID, and cryotherapy exhibited comparatively lower efficacy in achieving overall re- sponse. Regarding the outcome of no or minimal response, in- terventions with the lowest efficacy included IFN α-2b, KOH 5%, and MMR ID. Meanwhile, the least interventions in this outcome were the mix of furosemide and digoxin, PBP anti- gen stimulants, and the combination of PPD and isotretinoin. The partial response outcome mirrored the trends observed isotretinoin and finally 5-FU. On the other hand, the low- est three interventions in achieving the complete response according to P-scores are KOH 5%, placebo, and MMR ID (Figure 4). Both bleomycin intervention and the mix of furosemide and digoxin were significant when compared with auto- implantation as the results were (RR= 0.46, with 95% CI [0.24; 0.88]), and (RR= 0.40, with 95%CI [0.18; 0.91]) re- spectively. Additionally, both bleomycin intervention and the mix of furosemide and digoxin were significant when com- pared with cryotherapy as the results were (RR= 0.45, with 95% CI [0.27; 0.76]), and (RR= 0.40, with 95% CI [0.19; 0.82]) respectively. PPD and Isotretinoin and 5-FU were sig- nificant when compared with cryotherapy as the results were (RR= 0.54, with 95% CI [0.29; 0.99]), and (RR= 0.62, with 95% CI [0.40; 0.95]) respectively (Figure 4). Figure 2. Risk of bias summary graph of the included randomized control trials. 6 Review | Dermatol Pract Concept. 2024;14(3):e2024215 immunotherapy [24]. Our finding aligns with a previous meta-analysis that investigated the efficacy of cryotherapy for plantar warts [25]. Although intralesional immunotherapy would result in better results than traditional methods, ad- verse events may present as localized immunologic or irritant reactions or systemic and constitutional symptoms, including fever and flu-like manifestations. While pain at the injection site was a prevalent observation in most studies, it was sel- dom of extended duration [13,26]. Traditional treatments designed with a destructive mechanism for warts may sim- ilarly exhibit efficacy in addressing prominent lesions [27]. It is crucial to acknowledge that the availability and feasibility of these treatments in clinical practice may vary in the no response category, with needling, the mix of furose- mide and digoxin, and MMR ID demonstrating the highest efficacy and lowest partial response. At the same time, 5-FU, bleomycin, and PDT exhibited the most increased occurrence of partial response in the participants. Recently, there has been a notable increase in the promi- nence and utilization of intralesional immunotherapy meth- ods due to their promising results compared to traditional methods for treating warts [23,24]. Our results suggest that cryotherapy is not a superior intervention in the treat- ment of non-genital warts despite the widespread utilization of cryotherapy. According to our findings, it demonstrates lower effectiveness and inferiority compared to intralesional Figure 3. Complete response: (A) Network graph showing direct evidence between the evaluated interventions. (B) A forest plot comparing all interventions. (C) The league table represents the network meta-analysis estimates for all interventions’ comparisons. Review | Dermatol Pract Concept. 2024;14(3):e2024215 7 Our study has several strengths as we included all the interventions of intralesional immunotherapy that are used and available. We have high numbers of RCTs with high number of population. We also compared all the available in- terventions, assessing the most effective treatments through NMA. Our main limitation was the heterogeneity of the included studies regarding the final outcome and inclusion criteria and severity of warts. Nevertheless, Our study is lim- ited by the lack of head-to-head studies between treatments and the sparse literature available for certain types of treat- ments. This may affect the generalizability of our findings. Also, the number of warts can significantly impact treatment decisions and outcomes. While our study did not specifically significantly. For instance, treatments that showed high ef- ficacy in our study might not be universally accessible due to factors such as cost, infrastructure requirements, and re- gional disparities. Similarly, treatments that demonstrated lower complete response rates, might be more readily avail- able in certain regions or healthcare settings. Therefore, while our study provides valuable insights into the compar- ative efficacy of various treatments, the real-world imple- mentation of these findings will require further research and strategic planning to overcome these practical challenges. This includes exploring cost-effective alternatives, strength- ening healthcare infrastructure, and advocating for equitable healthcare policies Figure 4. Overall response: (A) Network graph showing direct evidence between the evaluated interventions. (B) A forest plot comparing all interventions. (C) The league table represents the network meta-analysis estimates for all interventions’ comparisons. 8 Review | Dermatol Pract Concept. 2024;14(3):e2024215 PBP antigen stimulants proved the highest efficacy in com- plete response. Conversely, IFN α-2b, PDL, and formic acid had the lowest complete response rates. Top choices for over- all responses included furosemide with digoxin, PBP anti- gen stimulants, and bleomycin. For no or minimal response, the mix of furosemide and digoxin, PBP antigen stimulants, and PPD with isotretinoin were the least groups achieving minimal response, which indicates high effectivity. Needling, furosemide with digoxin, and MMR ID were highly effective in partial responses. Meanwhile, 5-FU, bleomycin, and PDT showed the highest partial response rates. Overall, we can conclude that both furosemide with digoxin and PBP antigen stimulants showed the best results. However, direct compari- son studies are required to prove the superiority. stratify patients based on single or multiple warts due to lim- itations in the included studies, we recognize that the treat- ment approach for warts can vary significantly depending on whether the patient presents with single or multiple lesions. We encourage future research to consider stratifying anal- yses based on wart count to provide more tailored clinical guidance. Moreover, we need more head-to-head studies be- tween the most effective treatments. Conclusion Our comprehensive NMA evaluated different treatment mo- dalities for non-genital warts, focusing on efficacy outcomes. Needling, the combination of furosemide and digoxin, and Figure 5. No or minimal response: (A) Network graph showing direct evidence between the evaluated interventions. (B) A forest plot com- paring all interventions. (C) The league table represents the network meta-analysis estimates for all interventions’ comparisons. 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