Efficacy and safety of imiquimod for verruca planae: A systematic review

Objective: To assess the efficacy and safety of imiquimod for treating verruca planae. Methods: We searched the Pubmed, Cochrane Register of Controlled Trials, EMbase, CBM, CNKI and Wanfang databases (Chinese) to collect randomized controlled trials (RCTs). We screened the retrieved studies according to the predefined inclusion and exclusion criteria, evaluated the quality of include studies, and performed meta-analyses using the Cochrane Collaboration’s RevMan 5.1. Software. Results: Twenty-six RCTs involving 2169 patients with verruca planae were included and assessed. At the end of the 6th and ≥8th week, the effective rate of topical imiquimod was obviously higher than that of control [ RR=1.42, 95%CI (1.27, 1.60), P <0.00001; RR=1.43, 95%CI (1.22,1.67), P<0.00001]. The effective rate of imiquimod cream was higher than tretinoin cream, tazarotene gel and other antiviral drugs. [RR=1.41, 95%CI (1.25, 1.59), P <0.00001; RR=1.76, 95%CI (1.48, 2.10), P<0.00001; RR=1.71, 95%CI (1.29, 2.26), P =0.0002]. However, the effectiverate of imiquimod cream was lower than 5-ALA-PDT (RR=0.6, 95%CI (0.5, 0.71), P<0.00001). Conclusions: The limited evidence demonstrates that topical imiquimod is safe and efficient. More multiple central RCTs with large samples are required to verify these conclusions. Correspondence to: Rui-qun Qi, MD, PhD, Department of Dermatology, No 1 Hospital of China Medical University, Shenyang 110001, China, Tel: +86 24 8328 2742; Fax: +86 24 8328 2742; E-mail: xiaoqiliumin@163.com Xing-hua Gao, MD, PhD, Department of Dermatology, No 1 Hospital of China Medical University, Shenyang 110001, China, Tel: +86 24 8328 2326; Fax: +86 24 8328 2326; E-mail: gaobarry@hotmail.com


Introduction
Verruca planae are warts caused by the human papilloma virus (HPV), mostly by HPV type3, 10, 28 and 41. They primarily affect children and young adults [1]. The treatment cycle is usually prolonged. Current treatment options are anti-viral, immune-modulation and destruction of the infected tissue.
Imiquimod is a low molecular weight, synthetic immune response modifier which does not exert its antiviral effects directly on virusinfected cells. Imiquimod induces the production of antiviral cytokines that enhance cellular immunity necessary for the control or elimination of HPV infection. Imiquimod is often prescribed for condyloma acuminatum [2]. In recent years, there are reports that it has been used for flat warts and molluscum contagiosum, with satisfactory curative effect [3]. Here we performed a systematic review on the efficacy and safety of imiquimod cream in the treatment of verruca planae in order to provide the evidence for clinical decision.

Eligibility criteria
Inclusion and exclusion criteria were determined before the search was conducted. We included studies comparing the efficacy and safety of Imiquimod with other drugs on patients with verruca planae. Included studies must be randomized controlled trial (RCT). Case reports, reviews and document of incomplete data were excluded. "Systematic review," "Randomized controlled trial," "Treatment").

Study selection
To determine eligibility for inclusion in the review, we searched all titles and abstracts that analyses the efficacy of imiquimod for treating verruca planae with control group. There were no limitations on the study design, participant's age, gender, or nationality. We identified 68 articles in the initial search. Two of them were in English, others in Chinese. Through manual review of the citations from these articles, we removed 39 articles including general reviews, case reports, investigative research, commentaries and other non-clinical trials. We identified 28 original studies that were eligible for inclusion criteria assessment. After reviewing the full text of these 28 studies, we excluded 2 articles of non RCT nature. In the end, we selected 26 studies that met the inclusion criteria for this systematic review . The search processes are presented in chart in Figure 1.

Data extraction
Studies were selected independently by two researchers who used the same criteria. The third researcher was involved in the discussion if there were controversial issues. If the information is not complete or not clear, we contact original author to obtain the information and determine whether the study will be included.

Quality assessment
We used RevMan 5.1 (Review Manager Version 5.1) to analyze the quality of the data, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias ( Figure 2).

Data synthesis and analysis
We analysed the data using RevMan 5.1.Chi square test was used to test for heterogeneity. The degree of heterogeneity between studies was assessed using the I 2 test. And I 2 value >50% was considered there existed substantial heterogeneity. In such a case, random effects model was used. Results were expressed with relative risk (RR) and 95% confidence interval (CI) and the test level α=0.05. Publication bias was displayed graphically by using funnel plots (Figures 1 and 2).

Characteristics of the included publications
The basic characteristics of the included studies were shown in Table 1, including the total number of cases, the number of excluded and the lost, the age, course of disease, the number of effective cases and the intervention measures.

Quality assessment
All included studies were referred to the randomized grouping, and only 4 studies [4,9,10,20] described the details. All the studies were unclear in reporting allocation concealment and blinding. 5 studies [5,7,8,14,29] reported the number of withdraw. Assessment of methodological quality of included studies was presented in Figure 2.

Therapeutic evaluation
Total effect: Twenty six RCTs involving 2169 patients with verruca planae were included and assessed. Results showed that the effective rate of topical imiquimod combined with intramuscular injection or other oral drugs in the treatment of flat wart was obviously higher than using other drugs alone. (RR=1.35 (95% CI 1.181.54.), P<0.00001) (Figure 3), 10 studies [4,[10][11][17][18][20][21]23,27,29] described the efficacy at the end of 4 weeks. As there exist statistical heterogeneity among the studies (P<0.00001, I²=82%), meta-analysis was performed using a random effects model. The results showed that the efficacy of test group was significantly higher than that in control group. The difference had no statistical significance.

Imiquimod cream vs. Tretinoin cream:
A total of 8 studies [4][5][6][7][8][9][10][11] were included, of which 3 studies [4][5][6] of the test group is imiquimod cream combined with BCG -PSN, the control group is tretinoin cream combined with BCG-PSN, 3 studies [7][8][9] of the test group was imiquimod cream only, the control group was tretinoin cream only. The 2 studies [10,11] of test group was imiquimod cream combined with tretinoin cream once a day each, the control group was only tretinoin cream once per day; results showed that the effective rate in imiquimod group was significantly higher than tretinoin cream group (RR=1.41, 95%CI (1.25, 1.59), P<0.00001); the effective rate of imiquimod combined with BCG-PSN group was higher than that of tretinoin cream combined with BCG-PSN group (RR=1.56, 95%CI (1.27, 1.91), P<0.0001); the effective rate of imiquimod alone or in combination with tretinoin cream group was higher than that of tretinoin cream alone group (RR=1.32, 95%CI (1.14, 1.54), P =0.0003) ( Figure 5A

Imiquimod cream vs. Tazarotene gel:
A total of 4 studies [12][13][14][15] were included, of which the test group was imiquimod cream combined with tazarotene gel once a day each, the control group was tazarotene gel alone once per day. The results showed the effective rate in test group was higher than tazarotene group (RR=1.76, 95%CI (1.48, 2.10), P<0.00001) ( Figure 5A.3.1.2.). One study [16] reported that the effective rate in imiquimod group was higher than that of adapalene group.

Imiquimod Cream vs. Other antiviral medications:
A total of 2 studies [25,26] were included, of which the test group was imiquimod cream alone or combined with pidotimod powder. Pidotimod powder alone served as control group. The results showed that the effective ratein imiquimod group was higher than in control group (RR=1.71, 95%CI (1.29, 2.26), P=0.0002) ( Figure 5A.3.1.3.).

Imiquimod Cream vs. ALA-PDT:
A total of 3 studies [27][28][29] were included, of which of the test group was imiquimod cream alone once every other day and ALA-PDT in the control group. The results showed that the effective rate of imiquimod group was lower than that of ALA-PDT group (RR=0.6, 95%CI (0.5, 0.71), P<0.00001) ( Figure 5A.3.1.4.).

Imiquimod Cream Combined with Other Drugs vs. Others drugs:
A total of 9 studies [16][17][18][19][20][21][22][23][24] were included, of which the test group was imiquimod cream alone or in combination with adapalene, BCG-PSN, famciclovir, transfer factor, Alpha 2 b interferon cream , ALA-PDT and placebo. And adapalene, BCG-PSN, famciclovir, transfer factor, Alpha 2b interferon cream and ALA-PDT were in the control groups, correspondingly. Results show that the effective rate of imiquimod (or in combination with other drugs) was higher than that of the control groups (RR=1.46, 95% CI (1.20, 1.78), P=0.0002) ( Figure  5B). The heterogeneity is significant due to the different intervention measures for each of the control groups.

Publication bias
Funnel plot analysis showed that the figure was basically symmetrical upside down funnel, and there was no significant publication bias ( Figure 6).

Follow up
8 studies reported the follow-up. Lium [5] followed the patients for 2 months. There was no recurrence in the cured patients in the test group, and 2 cases who significantly improved also cured. Some of the patients in the control group had increase in the lesions. Huangm [6] followed the patients for a month, test group had 2 recurrent cases, control group had 7 recurrent cases. Tang [24] closely observed the cured patients in both groups for 3 months. The recurrence cases in the test group in 1, 2, 3 months were less than those in the control group, the difference was statistically significant (P<0.05), Wang [4] followed up for 3 months then observed both groups showed no recurrence. Su [28] followed up the cured patients for 3 months; there were no cases of recurrence. Jiang [29] followed up for half a year, the test group and the control group had no recurrence. Liu [25] followed up for 2 months the results showed no recurrence, Wu [26] followed up for six months, 2 recurrent cases occurred in the treatment group (5.71%) and 4 in the control group (12.5%).

Discussion
During the search, we found that many articles reported that imiquimod cream alone or in combination with other drugs could make a good effect on treatment of verruca planae. But there was no systematic review about efficacy and safety of imiquimod cream on the verruca planae. This systematic review included all RCT on verruca planae. The meta-analysis results showed that the effective rate of imiquimod cream in the treatment of flat wart was higher than other treatments. We found that the effective rate of ALA-PDT in treatment of verruca planae was more effective than imiquimod. However, the report about ALA-PDT use was limited.
The review made the conclusion that imiquimod was efficacy and safe on verruca planae based on the limited evidence. First, owing to the studies of imiquimod on verruca planae was investigated mostly by Chinese, we included a total of 26 randomized controlled trials that all come from China which may cause language bias. Second, quality of the included studies was not high, only 1 study described exclusion or losses of follow up. All studies did not mention the blinding and allocation concealment which may cause selection bias, performance bias and measurement bias. Third, the intervention measures in the test group and the control group were different, and it was difficult to extract and combine the data. Fourth, each of the intervention measures included in the studies was relatively small. Therefore, the results of these articles need to be confirmed and re-evaluated by more RCTs with high quality, large scale and multicenteral.