# Efficacy and Safety of Fire Needle Therapy for Flat Warts: Evidence from 29 Randomized Controlled Trials

Authors: Ying Zhang; Jing-Si Jiang; Le Kuai; Yue Luo; Jia-Le Chen; Yan-Jiao Wang; Rong Xu; Meng Xing; Liu Liu; Xin Li; Bin Li
Journal: Evidence-Based Complementary and Alternative Medicine
 (2021)

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## Abstract

Flat warts are a common and recurrent skin disease that has no specific antiviral treatment. As an alternative or complementary therapy, fire needle therapy has been widely used in the treatment of flat warts. The objective of this study was to systematically evaluate the efficacy and safety of fire needle therapy for flat warts. Using the search terms “flat warts” and “fire needle,” we searched the PubMed, Embase, Cochrane, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, Chinese biomedical (SinoMed) database, and the China Science and Technology Journal databases for studies until March 12, 2020. Randomized controlled trials comparing fire needle therapies with conventional therapies were also included. We calculated the risk ratios (RR) and mean differences with a 95% confidence interval (CI). We analyzed 29 trials involving 2,666 patients. Results showed that the use of fire needle therapy alone may have a higher efficacy rate compared with that of an immunomodulator (RR = 1.11, 95% CI: 1.03 to 1.20,I2 = 0%, P = 0.006; RR = 1.19, 95% CI: 1.03 to 1.37, I2 = 70%, P = 0.02, respectively) or tretinoin (RR = 1.39, 95% CI: 1.25 to 1.55, I2 = 0%, P < 0.00001), with a lower risk of blisters (P = 0.03) or erythema (P = 0.04), but with a higher risk of pigmentation (P = 0.02). We also determined the efficacy rate of fire needle therapy in combination with traditional Chinese medicine (RR = 1.16, 95% CI: 1.10 to 1.23, I2 = 21%, P < 0.00001), immunomodulators (RR = 1.17, 95% CI: 1.07 to 1.28, I2 = 33%, P = 0.0005), imiquimod (RR = 1.21, 95% CI: 1.04 to 1.42, P = 0.02), or as multidrug therapies (RR = 1.15, 95% CI: 1.07 to 1.24, I2 = 0%, P = 0.0001) and found that the combination treatments could reduce recurrence rates (P < 0.00001) and provided a lower risk of desquamation (P = 0.006). In conclusion, fire needle therapy seems to be effective for flat warts, with a reduced incidence of adverse events, such as blisters, erythema, and desquamation, but may increase incidence of pigmentation.


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## Body

## 1. Introduction

Flat warts, which appear as flat, light brown papules, are caused by human papillomavirus (HPV) infection, especially types 3/10 and 28 [1]. Epidemiological surveys have shown that the incidence of flat warts has reached 1.77% in recent years, accounting for 11.4% of facial skin diseases, mainly occurring in children and adolescents [2]. Although 65% to 78% of skin warts may resolve within 2 years, skin warts in adults rarely repair themselves and usually last 5 to 10 years [3, 4], affecting general appearance and mental health, and cause major psychosocial problems.The stratum corneum of the flat wart lesions in the basal layer of the skin was observed to have epidermal thickening and hyperkeratinization [5]. Histopathological analysis showed that many vacuole-like clear cells were found in the upper and granular layers of the spinous layer [6]. The diagnosis of flat warts is usually based on clinical symptoms: apical papules, minimal scale, and a slight elevation of 2 to 4 mm in diameter of the papules [7].The mechanisms linking HPV to flat warts have not yet been identified, but it is generally believed that flat warts are closely related to changes in the human immune system [8]. There is no antiviral treatment specific to HPV; however, cell-mediated immunity against viruses has been reported to have a significant effect on flat warts [9]. Current treatments for flat warts, including salicylic acid, cryotherapy, bleomycin, 5-fluorouracil, and lasers, destroy the wart body, correct abnormal proliferation, and differentiation, and stimulate the local or systemic immune response [10–15]. Although these therapies have been proven effective, treating the adverse effects of warts, including infection, blisters, or scars, requires the development of a formulation with similar therapeutic effects but fewer adverse events [8, 16].In China, fire needle therapy, a type of acupuncture therapy, has been used to treat skin diseases. It is an external treatment method that uses a specific needle that is heated until it burns red and is quickly stabbed into diseased local lesions or acupuncture points. It could stimulate and dredge the meridians and accelerate the flow of Qi and blood thus dissipating nodules. On this basis, the fire needles therapy has been proven to treat nodular prurigo [17], moderate severe acne [18], vitiligo [19]and psoriasis [20, 21]. Recently, fire needle therapy has also been used to treat flat warts, and its possible therapeutic mechanism may be destroying the wart body, improving local circulation, and promoting the local immune response. Additionally, the 2014 British Dermatology Association guidelines recommended acupuncture as a treatment for flat warts on the hands or face [8], and the Chinese fire needle guidelines also recommend acupuncture for flat warts [22].Nevertheless, there is still a lack of systematic reviews comparing the use of fire needle therapy combined with different medications for flat warts. Here, we conducted a systematic review of randomized controlled trials (RCTs) to evaluate the efficacy and safety of fire needle therapy for flat warts.


## 2. Materials and Methods

### 2.1. Materials and Methods for Fire Needle Therapy

After informing the patient of the procedure, a surgeon used 75% alcohol to disinfect his hands and the acupuncture site of the patient. The operation included the following steps:(1)
An alcohol lamp and a disposable sterile fire needle were prepared (Figures1(a) and 1(b)).(2)
The alcohol lamp was lit and was moved continuously from the needle root, along the needle body, to the needle tip (Figure1(c)).(3)
The needle tip and the front of the needle body were heated over the outer flame, and the needle body was moved over the flame until it turned red (Figure1(d)).(4)
The center of the wart body was quickly punctured vertically, and the needle was withdrawn. Small warts only needed to be pricked using one needle; large warts were punctured around the lesion with multiple needles, and the puncture depth did not exceed the base of the lesion.Figure 1
Materials and methods of preparing the fire needle (a–d).
(a)(b)(c)(d)


### 2.2. Registration

This systematic review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Supplementary file 1: TableS1) [23]. The PROSPERO registration number of this study is CRD42020185678.


### 2.3. Search Trials

Two reviewers (Le Kuai and Yue Luo) searched for relevant RCTs published in the following databases: PubMed, Embase, Cochrane, China National Knowledge Infrastructure (CNKI), Wanfang Medical Database, Chinese biomedical (SinoMed) database, and the China Science and Technology Journal Database (VIP), from their inception to March 12, 2020. Furthermore, the clinicaltrials.gov and the China Clinical Trial registry website were thoroughly searched to confirm the availability of relevant unpublished studies. Studies were restricted to the English and Chinese languages. The search strategy is listed in Supplementary File 2: TableS2. A total of 341 articles were retrieved.


### 2.4. Study Selection

We screened the titles, abstracts, and full texts of these 341 trials using the following inclusion criteria: participants, inclusion of patients diagnosed with flat warts, regardless of the age, sex, and disease duration; intervention, fire needle, or combined therapies as the intervention; comparison, control groups of conventional therapies; outcome, standardized therapeutic evaluation (efficacy rate) as the outcome; study design, RCTs. A total of 312 trials were excluded by the following exclusion criteria: case reports, reviews, animal studies, and studies containing fire needle therapy or combined therapies for a control group. The inclusion and exclusion of studies were formulated according to participants, intervention, comparison, outcome, and study design (PICOS) principle (Supplementary File 3: TableS3).


### 2.5. Data Extraction

Two investigators independently scrutinized the full texts of the selected studies. Two authors (Jia-le Chen and Yan-jiao Wang) completed the self-designed data extraction form (Table1), including the general information (i.e., the first author, study design, and year of publication), participant characteristics (i.e., average age, sample size, and disease duration), diagnostic criteria, interventions, duration of treatments, primary or secondary outcomes, adverse events, and recurrence rates.Table 1
Characteristics of the included trials.
StudyAverage course duration of diseaseAverage age (years)Treatment courseSample sizeAdverse eventsECECECECSheng 2019NRNR23.5 (4.5)23.2 (4.4)4 w6060NRNRZhu 2019NRNR25.79 (2.52)25.81 (2.47)4 w4848Itching (1), mild burning (1)Infection (2), itching (2), mild burning (3)Yuan 20198.09 (3.11) m8.25 (3.04) m25.97 (6.78)25.36 (7.36)8 w3939Itching (3), mild burning (5), erythema (2), pigmentation (2)Itching (4), mild burning (4), erythema (3)Li 20199.0 (3.8) m8.8 (3.2) m30.0 (3.9)31.3 (3.6)30 d4040Itching (2)Itching (3)Li2 2019NRNR26.8 (3.2); 26.4 (3.3)26.4 (3.1)4 w40; 4040Scar (1); 0Scar (2), pigmentation (3)Huang  2019NRNRNRNR10 w30; 3030NRNRCui 201921.92 (6.65) m ; 22.75 (6.62) m22.47 (6.74) m26 (5.87); 24 (6.94)25 (6.05)6 w30; 3030NRNRLiang 201819.11 (6.23) m ; 19.43 (5.98) m18.76 (6.01) m26.59 (5.38); 25.55 (5.13)26.30 (4.88)4 w30; 3030NRNRLiao 20173.59 (1.91) y;3.35 (1.87) y3.41 (1.89) y25 (7); 26 (5)25 (8)4 w30; 3030NRNRJia 2017NRNRNRNR4 w5050NRNRRuan 2017NRNR20.520.34 w6060Pigmentation (6)0Jiang 201730.4 (6.45) m24.8 (6.24)8w6055Pain (6)0He 20171.60 y1.53 y28.527.54 w6058Pain (5)0Fan 20161.60 y1.53 y28.527.54 w6058NRNRWang 2016NRNR20.8; 20.520.38 w38; 5236NRNRHuang 20161.8 (1.82) y26.8 (6.4)8 w49460Mild burning (5), desquamation (5)Guo 20161.8 (0.60) y1.70 (0.70) y23.86 (8.92)22.28 (9.35)30 d3838NRNRLiu 20166.9 m7.2 m18.319.74 w3030NRNRShi 201530.03 (16.51) m29.48 (14.18) m26.46 (6.48)25.39 (6.27)30 d3332Infection (2), mild burning (1), pigmentation (4), desquamation (2), isomorphic response (3)Infection (2), mild burning (1), pigmentation (2), isomorphic response (3)He 201419.48 (12.95) m20.24 (13.14) m30.11 (6.47)29.87 (6.30)8 w4646NRNRMa 2014NRNRNRNR10 d3830NRNRXu 20144.8 y4.5 y333130 d3030Pain (5)Pain (3), blister (11)Jin 201332.89 (12.29) m31.89 (12.91) m27.06 (9.15)26.67 (7.89)4 w1818NRNRPu 201118.2 m ; 19.6 m21.5 m23; 27264 w32; 2927Itching (4), desquamation (9), pigmentation (25); itching (4), desquamation (3), pigmentation (11);Itching (6), pigmentation (8), desquamation (12),Zheng 2010NRNRNRNR2 w60; 60600; 0Itching (2)Chen 20094.8 y4.5 y313130 d7248Pigmentation (4), isomorphic response (2)Mild burning (6), erythema (6)Yang 20082.28 (1.92) y1.80 (2.57) y22.75 (7.59)24.03 (5.69)4 w3030NRNRZhang 20073.5 m3.55 m20.321.130 d5257NRNRChen 200730.13 (17.61) m29.59 (14.28) m26.56 (6.58)25.29 (6.37)30 d4848Infection (2), mild burning (2), pigmentation (4), isomorphic response (2)Pigmentation (2), desquamation (8), isomorphic response (1), mild burning (8)StudyFUP (m)RecurrencePatients (M/F)InterventionsMain outcomesECECECSheng 2019NRNRNR19/4125/35Fire needleBCG nucleic acid injectionEfficacy rateZhu 2019341325/2326/225% Imiquimod + fire needle5% ImiquimodEfficacy rate, RER, AEsYuan 201932322/1725/14Fire needle + Isotretinoin Erythromycin GelIsotretinoin Erythromycin GelEfficacy rate + skin lesion scores + IL-2/IL-10/INF-γ, RER, AEsLi 20193NRNR13/2711/29Fire needleTretinoinEfficacy rate, AEsLi2 201934; 01122/18; 23/1725/15Fire needle; fire needle + Xiaoyou DecoctionRecombinant human interferon alpha-2b gelEfficacy rate + skin lesion scores, RER, AEsHuang 2019NR3; 0840/50Fire needle; Fire needle + Polymyosin injectionPolymyosin injectionEfficacy rate, RERCui 2019NRNRNR10/20; 13/1711 /19Fire needle; Fire needle + Taohongsiwu DecoctionTaohongsiwu DecoctionEfficacy rateLiang2018NRNRNR13/17; 14/1615/15Fire needle; Fire needle + Xiaoyou DecoctionXiaoyou DecoctionEfficacy rate + IL-2/IL-10/IFN-γ, DLQILiao 2017NRNRNR11/19; 13/1712/18Fire needle; fire needle + mild moxibustionMild moxibustionEfficacy rateJia 2017371022/2824/26Fire needle + recombinant human interferon alpha 2Recombinant human interferon alpha 2Efficacy rate, RERRuan 2017NRNRNR20/4018/42Fire needle + Chinese medicine inverted filmChinese medicine inverted filmEfficacy rateJiang 2017NRNRNR52/63Fire needleMannan peptideEfficacy rateHe 2017NRNRNR21/3922/36Fire needle + Xiangfu lotionXiangfu lotionEfficacy rateFan 2016NRNRNR21/3922/36Fire needle + Xiangfu lotionXiangfu lotionEfficacy rateWang 20163NRNR15/23; 20/3214/22Fire needle; fire needle + Chinese medicine inverted filmChinese medicine inverted filmEfficacy rateHuang 20163313NRNRFire needle + Chinese medicine inverted film + ImiquimodChinese medicine inverted film + ImiquimodEfficacy rate, RER, AEsGuo 2016NRNRNR22/1620/18Fire needleRecombinant human interferon alpha 2Efficacy rateLiu 2016NRNRNR11/1915/15Fire needle + recombinant human interferon alpha 2Recombinant human interferon alpha 2Efficacy rateShi 201531218/1517/15Fire needleTretinoinEfficacy rate + skin lesion scores, RER, AEsHe 2014NRNRNR25/2122/24Fire needle + Tazarotene gelTazarotene gelEfficacy rateMa 2014NRNRNR23/45Fire needle + Quyou DecoctionQuyou DecoctionEfficacy rateXu 2014NRNRNR10/207/23Fire needleLiquid nitrogen freezingEfficacy rate, AEsJin 20131.5NRNR9/95/13Fire needlePhotodynamicEfficacy rate + skin lesion scores + IL-2/IL-10/INF-γPu 2011NRNRNR16/16; 15/1415/12Fire needle; fire needle + tretinoin + BCG polysaccharide nucleic acidTretinoin + BCG polysaccharide nucleic acidEfficacy rate, AEsZheng 2010610; 0054/126Fire needle; Fire needle + Utlins injectionUtlins injectionEfficacy rate, RER, AEsChen 200932333/3920/28Fire needleTretinoinEfficacy rate, RER, AEsYang 20083139/2112/18Fire needle + decoctionFire needle + decoctionEfficacy rate, RERZhang 2007122419/3320/37Fire needle + tretinoin + BCG polysaccharide nucleic acidTretinoin + BCG polysaccharide nucleic acidEfficacy rate, RERChen 200731223/2520/28Fire needleTretinoinEfficacy rate + skin lesion scores, RER, AEsE: experimental group; C: control group; NR: no report; FUP: follow-up period; M: male; F: female; y: years; m: months; w: weeks; d: days; BCG: Bacillus Calmette–Guerin; RER: recurrence rate; AEs: adverse events; DLQI: Dermatology Life Quality Index; IL-2/10: interleukin-2/10; IFN–γ: interferon-γ. E, experimental group; C, control group; NR, no report; y, years; m, months; w, weeks; d, days.


### 2.6. Risk of Bias Assessment

Two authors (Meng Xing and Rong Xu) independently conducted risk assessments, using the Cochrane bias risk tool [24]. The evaluation items included random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (implementation bias), blinding of result evaluation (monitoring bias), incomplete result data (wear bias), selective reporting (reporting bias), and other biases. We assessed the risk of bias by using the terms “low risk,” “unclear risk,” and “high risk.” When disagreements occurred, the two authors had discussions to address these issues. If differences still existed, a third author, Bin Li, was invited to make a final decision.


### 2.7. Level of Evidence

The level of evidence combines considerations of risk of bias, directness, heterogeneity, precision, and publication bias classified into grades of recommendation, assessment, development, and evaluation working (GRADE) criteria: very low-quality evidence (+), low-quality evidence (++), moderate-quality evidence (+++), and high-quality evidence (++++). The GRADEpro guideline development tool (GDT) platform (https://gradepro.org) was adopted to create a summary of findings tables for Cochrane systematic reviews and assess the level of evidence of the outcomes.


### 2.8. Statistical Analysis

In this meta-analysis, we used RevMan 5.3 software (version 5.3, Cochrane Collaboration) to calculate the risk ratios (RR) and the mean differences (MD) with a 95% confidence interval (CI). Standard mean differences (SMD) were used when the measurement criteria were not the same. Heterogeneity was tested using theI2 statistic. A fixed effect model was used when P > 0.1 and I2 < 50%; otherwise, when I2 > 50%, subgroup analysis was adopted to resolve methodological and clinical heterogeneity. When there was heterogeneity that could not be readily explained, a random effect model was considered. We performed a sensitivity analysis of all indices to test the stability of the results when necessary. Since studies with negative results could remain unpublished, a funnel plot was used to analyze publication bias across the studies.


### 2.9. Outcomes

According to the PICOS principle, we use efficiency rate as an indicator that emphasizes the primary outcome of patients and include secondary outcomes. The primary outcome was divided into the following four categories: cured, defined by complete resolution of the skin lesions; significantly effective, defined by partial resolution of the skin lesions or if the skin lesion scores were ≥70% but <100%; effective, defined by partial resolution of the skin lesions or if the skin lesion scores were ≥30% but <70%; and ineffective, defined by an insignificant resolution of the skin lesions or if the skin lesion scores were <30% [25]. We used the following formula to calculate the total effective rate: total effective rate = (number of “cured” patients + number of “significantly effective” patients + number of “effective” patients)/total number of patients × 100%. The secondary outcomes were skin lesion scores, cytokine levels, Dermatology Life Quality Index (DLQI), recurrence rate, and adverse events.


## 2.1. Materials and Methods for Fire Needle Therapy

After informing the patient of the procedure, a surgeon used 75% alcohol to disinfect his hands and the acupuncture site of the patient. The operation included the following steps:(1)
An alcohol lamp and a disposable sterile fire needle were prepared (Figures1(a) and 1(b)).(2)
The alcohol lamp was lit and was moved continuously from the needle root, along the needle body, to the needle tip (Figure1(c)).(3)
The needle tip and the front of the needle body were heated over the outer flame, and the needle body was moved over the flame until it turned red (Figure1(d)).(4)
The center of the wart body was quickly punctured vertically, and the needle was withdrawn. Small warts only needed to be pricked using one needle; large warts were punctured around the lesion with multiple needles, and the puncture depth did not exceed the base of the lesion.Figure 1
Materials and methods of preparing the fire needle (a–d).
(a)(b)(c)(d)


## 2.2. Registration

This systematic review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Supplementary file 1: TableS1) [23]. The PROSPERO registration number of this study is CRD42020185678.


## 2.3. Search Trials

Two reviewers (Le Kuai and Yue Luo) searched for relevant RCTs published in the following databases: PubMed, Embase, Cochrane, China National Knowledge Infrastructure (CNKI), Wanfang Medical Database, Chinese biomedical (SinoMed) database, and the China Science and Technology Journal Database (VIP), from their inception to March 12, 2020. Furthermore, the clinicaltrials.gov and the China Clinical Trial registry website were thoroughly searched to confirm the availability of relevant unpublished studies. Studies were restricted to the English and Chinese languages. The search strategy is listed in Supplementary File 2: TableS2. A total of 341 articles were retrieved.


## 2.4. Study Selection

We screened the titles, abstracts, and full texts of these 341 trials using the following inclusion criteria: participants, inclusion of patients diagnosed with flat warts, regardless of the age, sex, and disease duration; intervention, fire needle, or combined therapies as the intervention; comparison, control groups of conventional therapies; outcome, standardized therapeutic evaluation (efficacy rate) as the outcome; study design, RCTs. A total of 312 trials were excluded by the following exclusion criteria: case reports, reviews, animal studies, and studies containing fire needle therapy or combined therapies for a control group. The inclusion and exclusion of studies were formulated according to participants, intervention, comparison, outcome, and study design (PICOS) principle (Supplementary File 3: TableS3).


## 2.5. Data Extraction

Two investigators independently scrutinized the full texts of the selected studies. Two authors (Jia-le Chen and Yan-jiao Wang) completed the self-designed data extraction form (Table1), including the general information (i.e., the first author, study design, and year of publication), participant characteristics (i.e., average age, sample size, and disease duration), diagnostic criteria, interventions, duration of treatments, primary or secondary outcomes, adverse events, and recurrence rates.Table 1
Characteristics of the included trials.
StudyAverage course duration of diseaseAverage age (years)Treatment courseSample sizeAdverse eventsECECECECSheng 2019NRNR23.5 (4.5)23.2 (4.4)4 w6060NRNRZhu 2019NRNR25.79 (2.52)25.81 (2.47)4 w4848Itching (1), mild burning (1)Infection (2), itching (2), mild burning (3)Yuan 20198.09 (3.11) m8.25 (3.04) m25.97 (6.78)25.36 (7.36)8 w3939Itching (3), mild burning (5), erythema (2), pigmentation (2)Itching (4), mild burning (4), erythema (3)Li 20199.0 (3.8) m8.8 (3.2) m30.0 (3.9)31.3 (3.6)30 d4040Itching (2)Itching (3)Li2 2019NRNR26.8 (3.2); 26.4 (3.3)26.4 (3.1)4 w40; 4040Scar (1); 0Scar (2), pigmentation (3)Huang  2019NRNRNRNR10 w30; 3030NRNRCui 201921.92 (6.65) m ; 22.75 (6.62) m22.47 (6.74) m26 (5.87); 24 (6.94)25 (6.05)6 w30; 3030NRNRLiang 201819.11 (6.23) m ; 19.43 (5.98) m18.76 (6.01) m26.59 (5.38); 25.55 (5.13)26.30 (4.88)4 w30; 3030NRNRLiao 20173.59 (1.91) y;3.35 (1.87) y3.41 (1.89) y25 (7); 26 (5)25 (8)4 w30; 3030NRNRJia 2017NRNRNRNR4 w5050NRNRRuan 2017NRNR20.520.34 w6060Pigmentation (6)0Jiang 201730.4 (6.45) m24.8 (6.24)8w6055Pain (6)0He 20171.60 y1.53 y28.527.54 w6058Pain (5)0Fan 20161.60 y1.53 y28.527.54 w6058NRNRWang 2016NRNR20.8; 20.520.38 w38; 5236NRNRHuang 20161.8 (1.82) y26.8 (6.4)8 w49460Mild burning (5), desquamation (5)Guo 20161.8 (0.60) y1.70 (0.70) y23.86 (8.92)22.28 (9.35)30 d3838NRNRLiu 20166.9 m7.2 m18.319.74 w3030NRNRShi 201530.03 (16.51) m29.48 (14.18) m26.46 (6.48)25.39 (6.27)30 d3332Infection (2), mild burning (1), pigmentation (4), desquamation (2), isomorphic response (3)Infection (2), mild burning (1), pigmentation (2), isomorphic response (3)He 201419.48 (12.95) m20.24 (13.14) m30.11 (6.47)29.87 (6.30)8 w4646NRNRMa 2014NRNRNRNR10 d3830NRNRXu 20144.8 y4.5 y333130 d3030Pain (5)Pain (3), blister (11)Jin 201332.89 (12.29) m31.89 (12.91) m27.06 (9.15)26.67 (7.89)4 w1818NRNRPu 201118.2 m ; 19.6 m21.5 m23; 27264 w32; 2927Itching (4), desquamation (9), pigmentation (25); itching (4), desquamation (3), pigmentation (11);Itching (6), pigmentation (8), desquamation (12),Zheng 2010NRNRNRNR2 w60; 60600; 0Itching (2)Chen 20094.8 y4.5 y313130 d7248Pigmentation (4), isomorphic response (2)Mild burning (6), erythema (6)Yang 20082.28 (1.92) y1.80 (2.57) y22.75 (7.59)24.03 (5.69)4 w3030NRNRZhang 20073.5 m3.55 m20.321.130 d5257NRNRChen 200730.13 (17.61) m29.59 (14.28) m26.56 (6.58)25.29 (6.37)30 d4848Infection (2), mild burning (2), pigmentation (4), isomorphic response (2)Pigmentation (2), desquamation (8), isomorphic response (1), mild burning (8)StudyFUP (m)RecurrencePatients (M/F)InterventionsMain outcomesECECECSheng 2019NRNRNR19/4125/35Fire needleBCG nucleic acid injectionEfficacy rateZhu 2019341325/2326/225% Imiquimod + fire needle5% ImiquimodEfficacy rate, RER, AEsYuan 201932322/1725/14Fire needle + Isotretinoin Erythromycin GelIsotretinoin Erythromycin GelEfficacy rate + skin lesion scores + IL-2/IL-10/INF-γ, RER, AEsLi 20193NRNR13/2711/29Fire needleTretinoinEfficacy rate, AEsLi2 201934; 01122/18; 23/1725/15Fire needle; fire needle + Xiaoyou DecoctionRecombinant human interferon alpha-2b gelEfficacy rate + skin lesion scores, RER, AEsHuang 2019NR3; 0840/50Fire needle; Fire needle + Polymyosin injectionPolymyosin injectionEfficacy rate, RERCui 2019NRNRNR10/20; 13/1711 /19Fire needle; Fire needle + Taohongsiwu DecoctionTaohongsiwu DecoctionEfficacy rateLiang2018NRNRNR13/17; 14/1615/15Fire needle; Fire needle + Xiaoyou DecoctionXiaoyou DecoctionEfficacy rate + IL-2/IL-10/IFN-γ, DLQILiao 2017NRNRNR11/19; 13/1712/18Fire needle; fire needle + mild moxibustionMild moxibustionEfficacy rateJia 2017371022/2824/26Fire needle + recombinant human interferon alpha 2Recombinant human interferon alpha 2Efficacy rate, RERRuan 2017NRNRNR20/4018/42Fire needle + Chinese medicine inverted filmChinese medicine inverted filmEfficacy rateJiang 2017NRNRNR52/63Fire needleMannan peptideEfficacy rateHe 2017NRNRNR21/3922/36Fire needle + Xiangfu lotionXiangfu lotionEfficacy rateFan 2016NRNRNR21/3922/36Fire needle + Xiangfu lotionXiangfu lotionEfficacy rateWang 20163NRNR15/23; 20/3214/22Fire needle; fire needle + Chinese medicine inverted filmChinese medicine inverted filmEfficacy rateHuang 20163313NRNRFire needle + Chinese medicine inverted film + ImiquimodChinese medicine inverted film + ImiquimodEfficacy rate, RER, AEsGuo 2016NRNRNR22/1620/18Fire needleRecombinant human interferon alpha 2Efficacy rateLiu 2016NRNRNR11/1915/15Fire needle + recombinant human interferon alpha 2Recombinant human interferon alpha 2Efficacy rateShi 201531218/1517/15Fire needleTretinoinEfficacy rate + skin lesion scores, RER, AEsHe 2014NRNRNR25/2122/24Fire needle + Tazarotene gelTazarotene gelEfficacy rateMa 2014NRNRNR23/45Fire needle + Quyou DecoctionQuyou DecoctionEfficacy rateXu 2014NRNRNR10/207/23Fire needleLiquid nitrogen freezingEfficacy rate, AEsJin 20131.5NRNR9/95/13Fire needlePhotodynamicEfficacy rate + skin lesion scores + IL-2/IL-10/INF-γPu 2011NRNRNR16/16; 15/1415/12Fire needle; fire needle + tretinoin + BCG polysaccharide nucleic acidTretinoin + BCG polysaccharide nucleic acidEfficacy rate, AEsZheng 2010610; 0054/126Fire needle; Fire needle + Utlins injectionUtlins injectionEfficacy rate, RER, AEsChen 200932333/3920/28Fire needleTretinoinEfficacy rate, RER, AEsYang 20083139/2112/18Fire needle + decoctionFire needle + decoctionEfficacy rate, RERZhang 2007122419/3320/37Fire needle + tretinoin + BCG polysaccharide nucleic acidTretinoin + BCG polysaccharide nucleic acidEfficacy rate, RERChen 200731223/2520/28Fire needleTretinoinEfficacy rate + skin lesion scores, RER, AEsE: experimental group; C: control group; NR: no report; FUP: follow-up period; M: male; F: female; y: years; m: months; w: weeks; d: days; BCG: Bacillus Calmette–Guerin; RER: recurrence rate; AEs: adverse events; DLQI: Dermatology Life Quality Index; IL-2/10: interleukin-2/10; IFN–γ: interferon-γ. E, experimental group; C, control group; NR, no report; y, years; m, months; w, weeks; d, days.


## 2.6. Risk of Bias Assessment

Two authors (Meng Xing and Rong Xu) independently conducted risk assessments, using the Cochrane bias risk tool [24]. The evaluation items included random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (implementation bias), blinding of result evaluation (monitoring bias), incomplete result data (wear bias), selective reporting (reporting bias), and other biases. We assessed the risk of bias by using the terms “low risk,” “unclear risk,” and “high risk.” When disagreements occurred, the two authors had discussions to address these issues. If differences still existed, a third author, Bin Li, was invited to make a final decision.


## 2.7. Level of Evidence

The level of evidence combines considerations of risk of bias, directness, heterogeneity, precision, and publication bias classified into grades of recommendation, assessment, development, and evaluation working (GRADE) criteria: very low-quality evidence (+), low-quality evidence (++), moderate-quality evidence (+++), and high-quality evidence (++++). The GRADEpro guideline development tool (GDT) platform (https://gradepro.org) was adopted to create a summary of findings tables for Cochrane systematic reviews and assess the level of evidence of the outcomes.


## 2.8. Statistical Analysis

In this meta-analysis, we used RevMan 5.3 software (version 5.3, Cochrane Collaboration) to calculate the risk ratios (RR) and the mean differences (MD) with a 95% confidence interval (CI). Standard mean differences (SMD) were used when the measurement criteria were not the same. Heterogeneity was tested using theI2 statistic. A fixed effect model was used when P > 0.1 and I2 < 50%; otherwise, when I2 > 50%, subgroup analysis was adopted to resolve methodological and clinical heterogeneity. When there was heterogeneity that could not be readily explained, a random effect model was considered. We performed a sensitivity analysis of all indices to test the stability of the results when necessary. Since studies with negative results could remain unpublished, a funnel plot was used to analyze publication bias across the studies.


## 2.9. Outcomes

According to the PICOS principle, we use efficiency rate as an indicator that emphasizes the primary outcome of patients and include secondary outcomes. The primary outcome was divided into the following four categories: cured, defined by complete resolution of the skin lesions; significantly effective, defined by partial resolution of the skin lesions or if the skin lesion scores were ≥70% but <100%; effective, defined by partial resolution of the skin lesions or if the skin lesion scores were ≥30% but <70%; and ineffective, defined by an insignificant resolution of the skin lesions or if the skin lesion scores were <30% [25]. We used the following formula to calculate the total effective rate: total effective rate = (number of “cured” patients + number of “significantly effective” patients + number of “effective” patients)/total number of patients × 100%. The secondary outcomes were skin lesion scores, cytokine levels, Dermatology Life Quality Index (DLQI), recurrence rate, and adverse events.


## 3. Results

### 3.1. Included Studies and Their Characteristics

We obtained 341 relevant studies from seven databases; after the removal of 221 duplicate reports, 120 reports remained. After title and abstract filtering, 52 records were excluded, and 68 were left. Further, 39 articles were excluded from the full-text screening, and 29 articles that met the criteria were included in this review [2, 26–53]. The study flow is depicted in Figure 2.Figure 2
Flowchart of the search strategy and study selection, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. CNKI: Chinese National Knowledge Infrastructure database, Wanfang: Wanfang Data Knowledge Service Platform, SinoMed: Chinese Biomedical Database, VIP: China Science and Technology Journal Database, and CBM: Chinese Biomedicine Database.Participants: a total of 29 studies were included, with a total of 2,666 patients. All trials met the diagnostic criteria; 20 trials mentioned the diagnostic criteria used [2, 27, 32–40, 42–48, 50, 51, 53], and three were confirmed cases from hospitals [26, 28, 29, 31, 41, 49, 52]. None reported polycentric differentiation or syndrome differentiation, as described by traditional Chinese medicine (TCM).Intervention: this systematic review included 17 interventions (Table1). Seven of the articles included two experimental groups, including fire needle therapy alone and combined therapy, with one control group each [2, 27, 30, 32, 33, 39, 49].Comparison: to present the results of the studies more concisely, we developed subgroups based on the different interventions. Seventeen RCTs used fire needle therapy only [2, 26, 27, 29–33, 36, 37, 39, 41, 43, 46–48, 51, 53], whereas ten studies were in combination with TCM [27, 31–33, 35, 37–39, 45, 51]. Four trials used fire needle therapy in combination with immunosuppressive agents [2, 34, 42, 49], one trial used fire needle therapy in combination with imiquimod [28], one used fire needle therapy and tretinoin [44], and the other four used a multidrug combination [29, 40, 48, 52]. The treatment course ranged from 4 to 10 weeks.Outcome: the primary outcome indicator is efficacy rate. Four trials used the efficacy rate from the skin lesion scores as the outcome indicator [29, 31–33, 43, 53], whereas the other 25 studies used symptom assessment.Study design: all included studies are RCTs.


### 3.2. Risk of Bias Assessment

Fifteen trials reported the generation of random sequences, nine of which used a random number table [2, 26–29, 34, 44, 50, 52], four used a computer random number generator (SAS) [33, 43, 47, 53], and one used a lottery method [31]. One trial used sequential sampling inspection and introduced artificial evaluation to the process of case inclusion, which was then identified as high risk [40]. The other 15 trials mentioned random only, without further explanation; thus, we identified them as unclear. Eight trials used the random concealment method, three of which used sequentially coded opaque envelopes and were thus identified as low-risk [43, 47, 53], whereas five experiments used an open consultation order, which were identified as high risk [28, 33, 36, 44, 46]. Only one study reported the implementation and monitoring of blinding [53]. Since one trial had no explanation regarding the amount of data loss or the reason for data loss, it was considered high risk [43]. Three trials provided detailed protocols and result reports followed by the research plan, and these were identified as low risk [43, 47, 53]. No study described other biases (Figure 3). The risk of publication bias across studies is presented in a funnel plot (Supplementary file 4: Figure S1), implying low-quality methodology and that publication bias related to insufficient sample size may exist.Figure 3
Risk of bias in the included studies for the safety and efficacy of fire needle therapy for flat warts. (a) Risk of bias graph; (b) risk of bias summary.
(a)(b)


### 3.3. Level of Evidence

Based on the GRADE system, the evidence on the safety and efficacy of fire needle therapy for flat warts was evaluated using the GRADEpro GDT platform. The evidence of efficacy rate of fire needle alone compared with control groups was level C (Table2), whereas the evidence of fire needle combined therapies was level B. In addition, the results of secondary indices indicated that the evidence of skin lesion scores and adverse events was level C, and the evidence of cytokine expression levels and recurrence rate was level B. All of them were moderate or weak recommendations.Table 2
Summary of GRADE on the outcomes of the safety and efficacy of fire needle therapy for flat warts.
Certainty assessmentNumber of patientsEffectCertaintyImportanceNumber of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsFire needleControl groupRelative (95% CI)Absolute (95% CI)Efficacy rate of fire needle alone vs. control groups18Randomized trialsSeriousSeriousNot seriousNot seriousNone686/749 (91.6%)424/568 (74.6%)RR 1.18 (1.09 to 1.28)134 more per 1,000 (from 67 more to 209 more)⊕⊕⃝⃝LowImportantEfficacy rate of fire needle combined therapies vs. control groups20Randomized trialsSeriousNot seriousNot seriousNot seriousNone831/863 (96.3%)579/694 (83.4%)RR 1.16 (1.12 to 1.20)133 more per 1,000 (from 100 more to 167 more)⊕⊕⊕⃝ModerateImportantSkin lesions scores9Randomized trialsSeriousSeriousNot seriousNot seriousNone725619—SMD 1 lower (1.43 lower to 0.57 lower)⊕⊕⃝⃝LowImportantCytokine levels2Randomized trialsSeriousNot seriousNot seriousNot seriousNone207162—MD 0.4 higher (0.19 lower to 1 higher)⊕⊕⊕⃝ModerateImportantRecurrence rate14Randomized trialsSeriousNot seriousNot seriousNot seriousNone40/621 (6.4%)72/508 (14.2%)RR 0.44 (0.30 to 0.63)79 fewer per 1,000 (from 99 fewer to 52 fewer)⊕⊕⊕⃝ModerateImportantAdverse events15Randomized trialsSeriousSeriousNot seriousNot seriousNone123/1794 (6.9%)109/1478 (7.4%)RR 0.83 (0.56 to 1.23)13 fewer per 1,000 (from 32 fewer to 17 more)⊕⊕⃝⃝LowImportantCI, confidence interval; RR, risk ratio; SMD, standardized mean difference; MD, mean difference.


### 3.4. Primary Outcomes

#### 3.4.1. Efficacy Rate

Twenty-six trials used the clinical evaluation criteria of clinical dermatology that defined the reduction of symptoms or scores of more than 30% as effective, and less than 30% as invalid [25]. One study was based on the evaluation criteria for treatment of flat warts given in the Standards for Diagnosis and Treatment of Traditional Chinese Medical Diseases that defines the degree of skin loss of more than 20% as effective, and otherwise invalid [51]. The evaluation criteria for other two studies were unclear [47, 53]. The results of the meta-analysis showed that the efficacy rate of fire needle therapy alone was higher when compared with that of an immunomodulator (RR = 1.19, 95% CI: 1.03 to 1.37, I2 = 70%, P = 0.02; Table 3; Supplementary file 5: Figure S2) or tretinoin (RR = 1.39, 95% CI: 1.25 to 1.55, I2 = 0%, P < 0.00001). Regarding the different subgroups, the efficacy rate of combination of fire needle therapy with other TCMs was significantly higher than that of TCM alone (RR = 1.16, 95% CI: 1.10 to 1.23, I2 = 21%, P < 0.00001; Supplementary file 6: Figure S3). The groups that used fire needle therapy combined with an immunomodulator (RR = 1.17, 95% CI: 1.07 to 1.28, I2 = 33%, P = 0.0005), imiquimod (RR = 1.21, 95% CI: 1.04 to 1.42, P = 0.02), and multidrug therapy (RR = 1.15, 95% CI: 1.07–1.24, I2 = 0%, P = 0.0001) also exhibited statistically significant differences.Table 3
Efficacy rate comparing fire needle and conventional therapies in a quantitative study on the safety and efficacy of fire needle therapy for flat warts.
TrialsComparisonsEffect estimates (95% CI)P value1. Fire needle versus control group1.1.Fire needle versus traditional Chinese medicineWang 2016Fire needle versus traditional Chinese medicineRR1.01 [0.83, 1.23]He 2017Fire needle versus traditional Chinese medicineRR1.12 [1.01, 1.24]Liao 2017Fire needle versus traditional Chinese medicineRR1.79 [1.02, 3.14]Liang 2018Fire needle versus traditional Chinese medicineRR1.00 [0.69, 1.45]Cui 2019Fire needle versus traditional Chinese medicineRR1.09 [0.77, 1.55]Meta-analysisRR1.10 [0.99, 1.21]0.071.2.Fire needle versus immunomodulatorZheng 2010Fire needle versus immunomodulatorRR1.06 [0.92, 1.21]Guo 2016Fire needle versus immunomodulatorRR1.20 [1.00, 1.44]Jiang 2017Fire needle versus immunomodulatorRR1.14 [1.00, 1.29]Huang 2019Fire needle versus immunomodulatorRR1.09 [0.77, 1.55]Li 2019Fire needle versus immunomodulatorRR1.09 [0.89, 1.33]Sheng 2019Fire needle versus immunomodulatorRR1.89 [1.40, 2.55]Meta-analysisRR1.19 [1.03,1.37]0.021.3 Fire needle versus tretinoinChen 2007Fire needle versus tretinoinRR1.48 [1.19, 1.84]Chen 2009Fire needle versus tretinoinRR1.48 [1.20, 1.84]Shi 2015Fire needle versus tretinoinRR1.25 [1.01, 1.56]Li 2019Fire needle versus tretinoinRR1.36 [1.09, 1.68]Meta-analysisRR1.39 [1.25, 1.55]< 0.000011.4.Fire needle versus liquid nitrogen freezingXu 2014Fire needle versus liquid nitrogen freezingRR0.96 [0.83, 1.12]0.641.5 Fire needle versus photodynamicJin 2013Fire needle versus photodynamicRR1.00 [0.85, 1.17]11.6.Fire needle versus multi drug therapyPu 2011Fire needle versus multidrug therapyRR1.20 [0.94, 1.28]0.152. Fire needle combined with conventional therapies versus control group2.1 Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineYang 2006Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.29 [0.99, 1.67]Ma 2014Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.33 [1.06, 1.66]Fan 2016Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.12 [1.01, 1.24]Wang 2016Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.18 [0.95, 1.45]Ruan 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.05 [0.98, 1.14]He 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.12 [1.01, 1.24]Liao 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.19 [0.69, 2.05]Liang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.21 [0.93, 1.57]Cui 2019Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.32 [0.96, 1.80]Meta-analysisRR1.16 [1.10, 1.23]< 0.000012.2.Fire needle combined with traditional Chinese medicine versus immunomodulatorLi 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR1.19 [0.98, 1.44]0.092.3 Fire needle combined with immunomodulator versus immunomodulatorZheng 2010Fire needle combined with immunomodulator versus immunomodulatorRR1.08 [0.97, 1.20]Liu 2016Fire needle combined with immunomodulator versus immunomodulatorRR1.21 [1.00, 1.46]Jia 2017Fire needle combined with immunomodulator versus immunomodulatorRR1.12 [0.96, 1.31]Huang 2019Fire needle combined with immunomodulator versus immunomodulatorRR1.50 [1.05, 2.14]Meta-analysisRR1.17 [1.07, 1.28]0.00052.4.Fire needle combined with tretinoin versus tretinoinHe 2014Fire needle combined with trunnion versus tretinoinRR1.09 [0.99, 1.21]0.072.5.Fire needle combined with imiquimod versus imiquimodZhu 2019Fire needle combined with imiquimod versus imiquimodRR1.21 [1.04, 1.42]0.022.6.Fire needle combined with multidrug therapy versus multidrug therapyZhang 2007Fire needle combined with multidrug therapy versus multidrug therapyRR1.10 [0.98, 1.23]Pu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR1.18 [0.94, 1.49]Huang 2016Fire needle combined with multidrug therapy versus multidrug therapyRR1.13 [0.99, 1.30]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR1.25 [1.06, 1.48]Meta-analysisRR1.15 [1.07, 1.24]0.0001When heterogeneity of the subgroups was observed in the efficacy rate of fire needle therapy compared with an immunomodulator, sensitivity analysis was performed (Supplementary file 7: FigureS4). We excluded studies [26] on the sensitivity analysis that led to a reduction in the heterogeneity of the subgroups (I2 = 0), yet the result was still statistically significant (P = 0.006).


### 3.5. Secondary Outcomes

#### 3.5.1. Skin Lesion Scores

Five trials used skin lesion scores as the criteria to assess disease severity [29, 30, 32, 33, 54], as recommended by the Chinese Dermatology Monograph [25]. The overall skin lesion scores of the fire needle group were similar to those of the control group (P = 0.15; Table 4; Supplementary file 8: Figure S5), whereas the combined groups had lower scores (SMD = −2.66, 95% CI: −4.55 to −0.78, I2 = 97%, P = 0.006; Supplementary file 9: Figure S6). Compared with TCM and tretinoin, the group with fire needle therapy alone had reduced scores with respect to the size (SMD = −1.20, 95% CI: −1.54 to −0.87, I2 = 0%, P < 0.00001), thickness (SMD = −0.94, 95% CI: −1.26 to −0.61, I2 = 0%, P < 0.00001), and itching (SMD = −0.44, 95% CI: −0.75 to −0.13, I2 = 0%, P = 0.006). However, there was no statistically significant difference in the number of warts (P = 0.30), color of the skin lesions (P = 0.57), and isomorphic response (P = 0.23). We conducted a sensitivity analysis of the two subgroups with high heterogeneity, but the result could not be considered significant because there were an insufficient number of trials (Supplementary file 10: Figure S7; Supplementary file 11: Figure S8).Table 4
Skin lesion scores, cytokine levels, recurrence rates, and adverse events comparing fire needle and conventional therapies in a quantitative study on the safety and efficacy of fire needle therapy for flat warts.
TrialsComparisonsEffect Estimates (95% CI)P value1. Skin lesion scores1.1 Fire needle versus control group1.1.1 OverallLiang 2018Fire needle versus traditional Chinese medicineRR−0.05 [−0.67, 0.57]Cui 2019Fire needle versus traditional Chinese medicineRR−4.86 [−5.91, −3.82]Li2 2019Fire needle versus immunomodulatorRR−0.47 [−1.10, 0.16]Meta-analysisRR−1.75 [−4.15,0.64]0.151.1.2 Number of wartsChen 2007Fire needle versus tretinoinRR−1.31 [−1.75, −0.86]Shi 2015Fire needle versus tretinoinRR−0.02 [−0.51, 0.46]Meta-analysisRR−0.67 [−1.93, 0.59]0.31.1.3 SizeChen 2007Fire needle versus tretinoinRR−1.17 [−1.61, −0.74]Shi 2015Fire needle versus tretinoinRR−1.25 [−1.79, −0.72]Meta-analysisRR−1.20 [−1.54, −0.87]<0.000011.1.4 ThicknessChen 2007Fire needle versus tretinoinRR−0.97 [−1.39, −0.55]Shi 2015Fire needle versus tretinoinRR−0.89 [−1.40, −0.38]Meta-analysisRR−0.94 [−1.26, −0.61]< 0.000011.1.5 Skin lesion colorChen 2007Fire needle versus tretinoinRR−0.89 [−1.31, −0.47]Shi 2015Fire needle versus tretinoinRR0.25 [−0.24, 0.74]Meta-analysisRR−0.32 [−1.44, 0.79]0.571.1.6 ItchingChen 2007Fire needle versus tretinoinRR−0.42 [−0.83, −0.02]Shi 2015Fire needle versus tretinoinRR−0.47 [−0.96, 0.03]Meta-analysisRR−0.44 [−0.75, −0.13]0.0061.1.7 Isomorphic responseChen 2007Fire needle versus tretinoinRR0.17 [−0.23, 0.57]Shi 2015Fire needle versus tretinoinRR0.22 [−0.27, 0.71]Meta-analysisRR0.19 [−0.12, 0.50]0.231.2 Fire needle combined with control group versus control group1.2.1 Skin lesions overall scoresLiang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−0.54 [−1.18, 0.09]Cui 2019Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−0.58 [−1.21, 0.05]Li2 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR−9.84 [−11.74, −7.94]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR−1.09 [−1.57, −0.61]Meta-analysisRR−2.66 [−4.55, −0.78]0.0062. Cytokine levels2.1 Fire needle combined with control group versus control group2.1.1 Interleukin-2Liang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR5.56 [3.05, 8.07]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR4.94 [3.17, 6.71]Meta-analysisRR5.15 [3.70, 6.59]<0.000012.1.2 Interleukin-10Liang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−2.48 [−3.71, −1.25]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR−1.41 [−2.26, −0.56]Meta-analysisRR−1.75 [−2.45, −1.05]<0.000012.1.3 Interferon-γLiang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR7.75 [4.24, 11.26]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR7.64 [5.48, 9.80]Meta-analysisRR7.67 [5.83, 9.51]<0.000013 Dermatology Life Quality Index3.1 Fire needle versus control groupLiang 2018Fire needle versus traditional Chinese medicineRR−0.03 [−2.65, 2.59]0.983.1 Fire needle combined with control group versus control groupLiang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−3.82 [−6.32, −1.32]0.0034. Recurrence rate4.1 Fire needle versus control groupChen 2007Fire needle versus tretinoinRR0.50 [0.05, 5.33]Chen 2009Fire needle versus tretinoinRR0.44 [0.08, 2.56]Shi 2015Fire needle versus tretinoinRR0.48 [0.05, 5.09]Zheng 2010Fire needle versus immunomodulatorRR10.67 [0.65, 176.19]Li2 2019Fire needle versus immunomodulatorRR0.33 [0.11, 1.05]Huang 2019Fire needle versus immunomodulatorRR0.38 [0.10, 1.46]Meta-analysisRR0.71 [0.38, 1.31]0.274.2 Fire needle combined with control group versus control groupYang 2008Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR0.33 [0.04, 3.03]Li2 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR0.05 [0.00, 0.80]Huang 2016Fire needle combined with immunomodulator versus immunomodulatorRR0.22 [0.07, 0.71]Huang 2019Fire needle combined with immunomodulator versus immunomodulatorRR0.06 [0.00, 1.00]Zhu 2019Fire needle combined with imiquimod versus imiquimodRR0.31 [0.11, 0.88]Zhang 2007Fire needle combined with multidrug therapy versus multidrug therapyRR0.55 [0.10, 2.87]Jia 2017Fire needle combined with multidrug therapy versus multidrug therapyRR0.70 [0.29, 1.69]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR0.84 [0.15, 4.77]Meta-analysisRR0.34 [0.21, 0.54]<0.000015. Adverse events5.1 Fire needle versus control group5.1.1 InfectionChen 2007Fire needle versus tretinoinRR5.00 [0.25, 101.48]Shi 2015Fire needle versus tretinoinRR0.97 [0.15, 6.47]meta-analysisRR1.55 [0.31, 7.71]0.595.1.2 ItchingZheng 2010Fire needle versus immunomodulatorRR0.10 [0.00, 2.07]Pu 2011Fire needle versus multidrug therapyRR0.54 [0.14, 2.09]Li 2019Fire needle versus tretinoinRR0.67 [0.12, 3.78]Meta-analysisRR0.48 [0.18, 1.32]0.155.1.3 PainXu 2014Fire needle versus liquid nitrogen freezingRR1.67 [0.44, 6.36]He 2017Fire needle versus traditional Chinese medicineRR1−.64 [0.60, 188.18]Jiang 2017Fire needle versus immunomodulatorRR11.93 [0.69, 207.04]Meta-analysisRR3.73 [0.87, 16.06]0.085.1.4 Mild burningChen 2007Fire needle versus tretinoinRR5.00 [0.25, 101.48]Chen 2009Fire needle versus tretinoinRR0.05 [0.00, 0.90]Shi 2015Fire needle versus tretinoinRR0.97 [0.06, 14.85]Meta-analysisRR0.61 [0.04, 8.47]0.725.1.5 ErythemaChen 2009Fire needle versus tretinoinRR0.05 [0.00, 0.90]0.045.1.6 PigmentationChen 2007Fire needle versus tretinoinRR2.00 [0.38, 10.41]Chen 2009Fire needle versus tretinoinRR6.04 [0.33, 109.71]Shi 2015Fire needle versus tretinoinRR1.94 [0.38, 9.86]Pu 2011Fire needle versus multidrug therapyRR2.54 [1.10, 5.86]Li 2019Fire needle versus immunomodulatorRR0.17 [0.01, 4.01]Meta-analysisRR2.19 [1.15, 4.17]0.025.2 Fire needle combined with control group versus control group5.2.1 InfectionZhu 2019Fire needle combined with imiquimod versus imiquimodRR0.20 [0.01, 4.06]0.295.2.2 ItchingZhu 2019Fire needle combined with imiquimod versus imiquimodRR0.50 [0.05, 5.33]Pu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR0.64 [0.17, 2.49]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR0.75 [0.18, 3.13]Meta-analysisRR0.66 [0.27, 1.64]0.375.2.3 Mild burningZhu 2019Fire needle combined with imiquimod versus imiquimodRR0.33 [0.04, 3.09]Huang 2016Fire needle combined with multidrug therapy versus multidrug therapyRR0.09 [0.00, 1.50]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR1.25 [0.36, 4.31]Meta-analysisRR0.48 [0.10, 2.31]0.365.2.4 ErythemaYuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR0.67 [0.12, 3.77]0.655.2.5 PigmentationRuan 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR13.00 [0.75, 225.75]Li2 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR0.10 [0.01, 2.04]Pu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR1.33 [0.51, 3.43]Yuan 2019Fire needle combined with multi drug therapy versus multidrug therapyRR5.00 [0.25, 100.89]Meta-analysisRR1.65 [0.32, 8.48]0.555.2.6 DesquamationPu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR0.24 [0.07, 0.83]Huang 2016Fire needle combined with multidrug therapy versus multidrug therapyRR0.09 [0.00, 1.50]Meta-analysisRR0.21 [0.07, 0.64]0.006


#### 3.5.2. Cytokine Levels

Two studies reported that increased levels of cytokines, including interleukin-2 (IL-2), interleukin-10 (IL-10), and interferon-γ (IFN-γ), were associated with flat warts [29, 33] (Table 4; Supplementary file 10: Figure S9). After combined treatments, the levels of IL-2 (MD = 5.15, 95% CI: 3.70 to 6.59, I2 = 0%, P < 0.00001) or IFN-γ (MD = 7.67, 95% CI: 5.83 to 9.51, I2 = 0%, P < 0.00001) were significantly increased, whereas the level of IL-10 was decreased, compared with that of other drugs (MD = −1.75, 95% CI: −2.45 to −1.05, I2 = 49%, P < 0.00001).


#### 3.5.3. DLQI

One study used DLQI to evaluate the effects of the treatment [33]; it indicated no significant difference when comparing fire needle therapy and TCM (P = 0.98; Table 4). However, when compared to the effects of TCM alone, the combination of fire needle therapy and TCM showed a statistical difference (RR = −3.82, 95% CI: −6.32 to −1.32, P = 0.003).


#### 3.5.4. Recurrence Rates

Twelve trials reported recurrence rates [2, 28, 29, 31, 34, 40, 43, 49–53]. The follow-up period for 10 studies was 3 months, one was 6 months [49], and one was 12 months [52]. The results of the meta-analysis (Table 4; Supplementary file 13: Figure S10) showed that the recurrence rate in the groups that used fire needle therapy alone was similar to that in the control groups (RR = 0.71, 95% CI: 0.38 to 1.31, I2 = 24%, P = 0.27); however, recurrence rates were significantly lower in the combined therapies (RR = 0.34, 95% CI: 0.21 to 0.54, I2 = 12%, P < 0.00001).


#### 3.5.5. Adverse Events

Fourteen trials evaluated the safety of treatment by assessing various types of adverse events [28–31, 35–37, 40, 43, 46, 48–50, 53]. Subgroup analysis (Table 4; Supplementary file 14: Figure S11) showed that patients treated with fire needle therapy were at a reduced risk of erythema (RR = 0.05, 95% CI: 0.00 to 0.90, P = 0.04) and blisters (RR = 0.04, 95% CI: 0.00 to 0.71, P = 0.03), but were more likely to develop pigmentation (RR = 2.19, 95% CI: 1.15 to 4.17, I2 = 0%, P = 0.02). Furthermore, comparisons of desquamation in the fire needle combined with multidrug therapy group and multidrug therapy alone demonstrated a significant difference (RR = 0.21, 95% CI: 0.07 to 0.64, I2 = 0%, P = 0.006; Supplementary file 15: Figure S12). In the sensitivity analysis, the subgroup of mild burning and pigmentation showed high heterogeneity, which may be related to two studies [30, 50], but the conclusion is still valid with statistical significance (Supplementary file 16: Figure S13; Supplementary file 17: Figure S14).


## 3.1. Included Studies and Their Characteristics

We obtained 341 relevant studies from seven databases; after the removal of 221 duplicate reports, 120 reports remained. After title and abstract filtering, 52 records were excluded, and 68 were left. Further, 39 articles were excluded from the full-text screening, and 29 articles that met the criteria were included in this review [2, 26–53]. The study flow is depicted in Figure 2.Figure 2
Flowchart of the search strategy and study selection, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. CNKI: Chinese National Knowledge Infrastructure database, Wanfang: Wanfang Data Knowledge Service Platform, SinoMed: Chinese Biomedical Database, VIP: China Science and Technology Journal Database, and CBM: Chinese Biomedicine Database.Participants: a total of 29 studies were included, with a total of 2,666 patients. All trials met the diagnostic criteria; 20 trials mentioned the diagnostic criteria used [2, 27, 32–40, 42–48, 50, 51, 53], and three were confirmed cases from hospitals [26, 28, 29, 31, 41, 49, 52]. None reported polycentric differentiation or syndrome differentiation, as described by traditional Chinese medicine (TCM).Intervention: this systematic review included 17 interventions (Table1). Seven of the articles included two experimental groups, including fire needle therapy alone and combined therapy, with one control group each [2, 27, 30, 32, 33, 39, 49].Comparison: to present the results of the studies more concisely, we developed subgroups based on the different interventions. Seventeen RCTs used fire needle therapy only [2, 26, 27, 29–33, 36, 37, 39, 41, 43, 46–48, 51, 53], whereas ten studies were in combination with TCM [27, 31–33, 35, 37–39, 45, 51]. Four trials used fire needle therapy in combination with immunosuppressive agents [2, 34, 42, 49], one trial used fire needle therapy in combination with imiquimod [28], one used fire needle therapy and tretinoin [44], and the other four used a multidrug combination [29, 40, 48, 52]. The treatment course ranged from 4 to 10 weeks.Outcome: the primary outcome indicator is efficacy rate. Four trials used the efficacy rate from the skin lesion scores as the outcome indicator [29, 31–33, 43, 53], whereas the other 25 studies used symptom assessment.Study design: all included studies are RCTs.


## 3.2. Risk of Bias Assessment

Fifteen trials reported the generation of random sequences, nine of which used a random number table [2, 26–29, 34, 44, 50, 52], four used a computer random number generator (SAS) [33, 43, 47, 53], and one used a lottery method [31]. One trial used sequential sampling inspection and introduced artificial evaluation to the process of case inclusion, which was then identified as high risk [40]. The other 15 trials mentioned random only, without further explanation; thus, we identified them as unclear. Eight trials used the random concealment method, three of which used sequentially coded opaque envelopes and were thus identified as low-risk [43, 47, 53], whereas five experiments used an open consultation order, which were identified as high risk [28, 33, 36, 44, 46]. Only one study reported the implementation and monitoring of blinding [53]. Since one trial had no explanation regarding the amount of data loss or the reason for data loss, it was considered high risk [43]. Three trials provided detailed protocols and result reports followed by the research plan, and these were identified as low risk [43, 47, 53]. No study described other biases (Figure 3). The risk of publication bias across studies is presented in a funnel plot (Supplementary file 4: Figure S1), implying low-quality methodology and that publication bias related to insufficient sample size may exist.Figure 3
Risk of bias in the included studies for the safety and efficacy of fire needle therapy for flat warts. (a) Risk of bias graph; (b) risk of bias summary.
(a)(b)


## 3.3. Level of Evidence

Based on the GRADE system, the evidence on the safety and efficacy of fire needle therapy for flat warts was evaluated using the GRADEpro GDT platform. The evidence of efficacy rate of fire needle alone compared with control groups was level C (Table2), whereas the evidence of fire needle combined therapies was level B. In addition, the results of secondary indices indicated that the evidence of skin lesion scores and adverse events was level C, and the evidence of cytokine expression levels and recurrence rate was level B. All of them were moderate or weak recommendations.Table 2
Summary of GRADE on the outcomes of the safety and efficacy of fire needle therapy for flat warts.
Certainty assessmentNumber of patientsEffectCertaintyImportanceNumber of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsFire needleControl groupRelative (95% CI)Absolute (95% CI)Efficacy rate of fire needle alone vs. control groups18Randomized trialsSeriousSeriousNot seriousNot seriousNone686/749 (91.6%)424/568 (74.6%)RR 1.18 (1.09 to 1.28)134 more per 1,000 (from 67 more to 209 more)⊕⊕⃝⃝LowImportantEfficacy rate of fire needle combined therapies vs. control groups20Randomized trialsSeriousNot seriousNot seriousNot seriousNone831/863 (96.3%)579/694 (83.4%)RR 1.16 (1.12 to 1.20)133 more per 1,000 (from 100 more to 167 more)⊕⊕⊕⃝ModerateImportantSkin lesions scores9Randomized trialsSeriousSeriousNot seriousNot seriousNone725619—SMD 1 lower (1.43 lower to 0.57 lower)⊕⊕⃝⃝LowImportantCytokine levels2Randomized trialsSeriousNot seriousNot seriousNot seriousNone207162—MD 0.4 higher (0.19 lower to 1 higher)⊕⊕⊕⃝ModerateImportantRecurrence rate14Randomized trialsSeriousNot seriousNot seriousNot seriousNone40/621 (6.4%)72/508 (14.2%)RR 0.44 (0.30 to 0.63)79 fewer per 1,000 (from 99 fewer to 52 fewer)⊕⊕⊕⃝ModerateImportantAdverse events15Randomized trialsSeriousSeriousNot seriousNot seriousNone123/1794 (6.9%)109/1478 (7.4%)RR 0.83 (0.56 to 1.23)13 fewer per 1,000 (from 32 fewer to 17 more)⊕⊕⃝⃝LowImportantCI, confidence interval; RR, risk ratio; SMD, standardized mean difference; MD, mean difference.


## 3.4. Primary Outcomes

### 3.4.1. Efficacy Rate

Twenty-six trials used the clinical evaluation criteria of clinical dermatology that defined the reduction of symptoms or scores of more than 30% as effective, and less than 30% as invalid [25]. One study was based on the evaluation criteria for treatment of flat warts given in the Standards for Diagnosis and Treatment of Traditional Chinese Medical Diseases that defines the degree of skin loss of more than 20% as effective, and otherwise invalid [51]. The evaluation criteria for other two studies were unclear [47, 53]. The results of the meta-analysis showed that the efficacy rate of fire needle therapy alone was higher when compared with that of an immunomodulator (RR = 1.19, 95% CI: 1.03 to 1.37, I2 = 70%, P = 0.02; Table 3; Supplementary file 5: Figure S2) or tretinoin (RR = 1.39, 95% CI: 1.25 to 1.55, I2 = 0%, P < 0.00001). Regarding the different subgroups, the efficacy rate of combination of fire needle therapy with other TCMs was significantly higher than that of TCM alone (RR = 1.16, 95% CI: 1.10 to 1.23, I2 = 21%, P < 0.00001; Supplementary file 6: Figure S3). The groups that used fire needle therapy combined with an immunomodulator (RR = 1.17, 95% CI: 1.07 to 1.28, I2 = 33%, P = 0.0005), imiquimod (RR = 1.21, 95% CI: 1.04 to 1.42, P = 0.02), and multidrug therapy (RR = 1.15, 95% CI: 1.07–1.24, I2 = 0%, P = 0.0001) also exhibited statistically significant differences.Table 3
Efficacy rate comparing fire needle and conventional therapies in a quantitative study on the safety and efficacy of fire needle therapy for flat warts.
TrialsComparisonsEffect estimates (95% CI)P value1. Fire needle versus control group1.1.Fire needle versus traditional Chinese medicineWang 2016Fire needle versus traditional Chinese medicineRR1.01 [0.83, 1.23]He 2017Fire needle versus traditional Chinese medicineRR1.12 [1.01, 1.24]Liao 2017Fire needle versus traditional Chinese medicineRR1.79 [1.02, 3.14]Liang 2018Fire needle versus traditional Chinese medicineRR1.00 [0.69, 1.45]Cui 2019Fire needle versus traditional Chinese medicineRR1.09 [0.77, 1.55]Meta-analysisRR1.10 [0.99, 1.21]0.071.2.Fire needle versus immunomodulatorZheng 2010Fire needle versus immunomodulatorRR1.06 [0.92, 1.21]Guo 2016Fire needle versus immunomodulatorRR1.20 [1.00, 1.44]Jiang 2017Fire needle versus immunomodulatorRR1.14 [1.00, 1.29]Huang 2019Fire needle versus immunomodulatorRR1.09 [0.77, 1.55]Li 2019Fire needle versus immunomodulatorRR1.09 [0.89, 1.33]Sheng 2019Fire needle versus immunomodulatorRR1.89 [1.40, 2.55]Meta-analysisRR1.19 [1.03,1.37]0.021.3 Fire needle versus tretinoinChen 2007Fire needle versus tretinoinRR1.48 [1.19, 1.84]Chen 2009Fire needle versus tretinoinRR1.48 [1.20, 1.84]Shi 2015Fire needle versus tretinoinRR1.25 [1.01, 1.56]Li 2019Fire needle versus tretinoinRR1.36 [1.09, 1.68]Meta-analysisRR1.39 [1.25, 1.55]< 0.000011.4.Fire needle versus liquid nitrogen freezingXu 2014Fire needle versus liquid nitrogen freezingRR0.96 [0.83, 1.12]0.641.5 Fire needle versus photodynamicJin 2013Fire needle versus photodynamicRR1.00 [0.85, 1.17]11.6.Fire needle versus multi drug therapyPu 2011Fire needle versus multidrug therapyRR1.20 [0.94, 1.28]0.152. Fire needle combined with conventional therapies versus control group2.1 Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineYang 2006Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.29 [0.99, 1.67]Ma 2014Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.33 [1.06, 1.66]Fan 2016Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.12 [1.01, 1.24]Wang 2016Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.18 [0.95, 1.45]Ruan 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.05 [0.98, 1.14]He 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.12 [1.01, 1.24]Liao 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.19 [0.69, 2.05]Liang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.21 [0.93, 1.57]Cui 2019Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.32 [0.96, 1.80]Meta-analysisRR1.16 [1.10, 1.23]< 0.000012.2.Fire needle combined with traditional Chinese medicine versus immunomodulatorLi 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR1.19 [0.98, 1.44]0.092.3 Fire needle combined with immunomodulator versus immunomodulatorZheng 2010Fire needle combined with immunomodulator versus immunomodulatorRR1.08 [0.97, 1.20]Liu 2016Fire needle combined with immunomodulator versus immunomodulatorRR1.21 [1.00, 1.46]Jia 2017Fire needle combined with immunomodulator versus immunomodulatorRR1.12 [0.96, 1.31]Huang 2019Fire needle combined with immunomodulator versus immunomodulatorRR1.50 [1.05, 2.14]Meta-analysisRR1.17 [1.07, 1.28]0.00052.4.Fire needle combined with tretinoin versus tretinoinHe 2014Fire needle combined with trunnion versus tretinoinRR1.09 [0.99, 1.21]0.072.5.Fire needle combined with imiquimod versus imiquimodZhu 2019Fire needle combined with imiquimod versus imiquimodRR1.21 [1.04, 1.42]0.022.6.Fire needle combined with multidrug therapy versus multidrug therapyZhang 2007Fire needle combined with multidrug therapy versus multidrug therapyRR1.10 [0.98, 1.23]Pu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR1.18 [0.94, 1.49]Huang 2016Fire needle combined with multidrug therapy versus multidrug therapyRR1.13 [0.99, 1.30]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR1.25 [1.06, 1.48]Meta-analysisRR1.15 [1.07, 1.24]0.0001When heterogeneity of the subgroups was observed in the efficacy rate of fire needle therapy compared with an immunomodulator, sensitivity analysis was performed (Supplementary file 7: FigureS4). We excluded studies [26] on the sensitivity analysis that led to a reduction in the heterogeneity of the subgroups (I2 = 0), yet the result was still statistically significant (P = 0.006).


## 3.4.1. Efficacy Rate

Twenty-six trials used the clinical evaluation criteria of clinical dermatology that defined the reduction of symptoms or scores of more than 30% as effective, and less than 30% as invalid [25]. One study was based on the evaluation criteria for treatment of flat warts given in the Standards for Diagnosis and Treatment of Traditional Chinese Medical Diseases that defines the degree of skin loss of more than 20% as effective, and otherwise invalid [51]. The evaluation criteria for other two studies were unclear [47, 53]. The results of the meta-analysis showed that the efficacy rate of fire needle therapy alone was higher when compared with that of an immunomodulator (RR = 1.19, 95% CI: 1.03 to 1.37, I2 = 70%, P = 0.02; Table 3; Supplementary file 5: Figure S2) or tretinoin (RR = 1.39, 95% CI: 1.25 to 1.55, I2 = 0%, P < 0.00001). Regarding the different subgroups, the efficacy rate of combination of fire needle therapy with other TCMs was significantly higher than that of TCM alone (RR = 1.16, 95% CI: 1.10 to 1.23, I2 = 21%, P < 0.00001; Supplementary file 6: Figure S3). The groups that used fire needle therapy combined with an immunomodulator (RR = 1.17, 95% CI: 1.07 to 1.28, I2 = 33%, P = 0.0005), imiquimod (RR = 1.21, 95% CI: 1.04 to 1.42, P = 0.02), and multidrug therapy (RR = 1.15, 95% CI: 1.07–1.24, I2 = 0%, P = 0.0001) also exhibited statistically significant differences.Table 3
Efficacy rate comparing fire needle and conventional therapies in a quantitative study on the safety and efficacy of fire needle therapy for flat warts.
TrialsComparisonsEffect estimates (95% CI)P value1. Fire needle versus control group1.1.Fire needle versus traditional Chinese medicineWang 2016Fire needle versus traditional Chinese medicineRR1.01 [0.83, 1.23]He 2017Fire needle versus traditional Chinese medicineRR1.12 [1.01, 1.24]Liao 2017Fire needle versus traditional Chinese medicineRR1.79 [1.02, 3.14]Liang 2018Fire needle versus traditional Chinese medicineRR1.00 [0.69, 1.45]Cui 2019Fire needle versus traditional Chinese medicineRR1.09 [0.77, 1.55]Meta-analysisRR1.10 [0.99, 1.21]0.071.2.Fire needle versus immunomodulatorZheng 2010Fire needle versus immunomodulatorRR1.06 [0.92, 1.21]Guo 2016Fire needle versus immunomodulatorRR1.20 [1.00, 1.44]Jiang 2017Fire needle versus immunomodulatorRR1.14 [1.00, 1.29]Huang 2019Fire needle versus immunomodulatorRR1.09 [0.77, 1.55]Li 2019Fire needle versus immunomodulatorRR1.09 [0.89, 1.33]Sheng 2019Fire needle versus immunomodulatorRR1.89 [1.40, 2.55]Meta-analysisRR1.19 [1.03,1.37]0.021.3 Fire needle versus tretinoinChen 2007Fire needle versus tretinoinRR1.48 [1.19, 1.84]Chen 2009Fire needle versus tretinoinRR1.48 [1.20, 1.84]Shi 2015Fire needle versus tretinoinRR1.25 [1.01, 1.56]Li 2019Fire needle versus tretinoinRR1.36 [1.09, 1.68]Meta-analysisRR1.39 [1.25, 1.55]< 0.000011.4.Fire needle versus liquid nitrogen freezingXu 2014Fire needle versus liquid nitrogen freezingRR0.96 [0.83, 1.12]0.641.5 Fire needle versus photodynamicJin 2013Fire needle versus photodynamicRR1.00 [0.85, 1.17]11.6.Fire needle versus multi drug therapyPu 2011Fire needle versus multidrug therapyRR1.20 [0.94, 1.28]0.152. Fire needle combined with conventional therapies versus control group2.1 Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineYang 2006Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.29 [0.99, 1.67]Ma 2014Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.33 [1.06, 1.66]Fan 2016Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.12 [1.01, 1.24]Wang 2016Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.18 [0.95, 1.45]Ruan 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.05 [0.98, 1.14]He 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.12 [1.01, 1.24]Liao 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.19 [0.69, 2.05]Liang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.21 [0.93, 1.57]Cui 2019Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR1.32 [0.96, 1.80]Meta-analysisRR1.16 [1.10, 1.23]< 0.000012.2.Fire needle combined with traditional Chinese medicine versus immunomodulatorLi 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR1.19 [0.98, 1.44]0.092.3 Fire needle combined with immunomodulator versus immunomodulatorZheng 2010Fire needle combined with immunomodulator versus immunomodulatorRR1.08 [0.97, 1.20]Liu 2016Fire needle combined with immunomodulator versus immunomodulatorRR1.21 [1.00, 1.46]Jia 2017Fire needle combined with immunomodulator versus immunomodulatorRR1.12 [0.96, 1.31]Huang 2019Fire needle combined with immunomodulator versus immunomodulatorRR1.50 [1.05, 2.14]Meta-analysisRR1.17 [1.07, 1.28]0.00052.4.Fire needle combined with tretinoin versus tretinoinHe 2014Fire needle combined with trunnion versus tretinoinRR1.09 [0.99, 1.21]0.072.5.Fire needle combined with imiquimod versus imiquimodZhu 2019Fire needle combined with imiquimod versus imiquimodRR1.21 [1.04, 1.42]0.022.6.Fire needle combined with multidrug therapy versus multidrug therapyZhang 2007Fire needle combined with multidrug therapy versus multidrug therapyRR1.10 [0.98, 1.23]Pu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR1.18 [0.94, 1.49]Huang 2016Fire needle combined with multidrug therapy versus multidrug therapyRR1.13 [0.99, 1.30]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR1.25 [1.06, 1.48]Meta-analysisRR1.15 [1.07, 1.24]0.0001When heterogeneity of the subgroups was observed in the efficacy rate of fire needle therapy compared with an immunomodulator, sensitivity analysis was performed (Supplementary file 7: FigureS4). We excluded studies [26] on the sensitivity analysis that led to a reduction in the heterogeneity of the subgroups (I2 = 0), yet the result was still statistically significant (P = 0.006).


## 3.5. Secondary Outcomes

### 3.5.1. Skin Lesion Scores

Five trials used skin lesion scores as the criteria to assess disease severity [29, 30, 32, 33, 54], as recommended by the Chinese Dermatology Monograph [25]. The overall skin lesion scores of the fire needle group were similar to those of the control group (P = 0.15; Table 4; Supplementary file 8: Figure S5), whereas the combined groups had lower scores (SMD = −2.66, 95% CI: −4.55 to −0.78, I2 = 97%, P = 0.006; Supplementary file 9: Figure S6). Compared with TCM and tretinoin, the group with fire needle therapy alone had reduced scores with respect to the size (SMD = −1.20, 95% CI: −1.54 to −0.87, I2 = 0%, P < 0.00001), thickness (SMD = −0.94, 95% CI: −1.26 to −0.61, I2 = 0%, P < 0.00001), and itching (SMD = −0.44, 95% CI: −0.75 to −0.13, I2 = 0%, P = 0.006). However, there was no statistically significant difference in the number of warts (P = 0.30), color of the skin lesions (P = 0.57), and isomorphic response (P = 0.23). We conducted a sensitivity analysis of the two subgroups with high heterogeneity, but the result could not be considered significant because there were an insufficient number of trials (Supplementary file 10: Figure S7; Supplementary file 11: Figure S8).Table 4
Skin lesion scores, cytokine levels, recurrence rates, and adverse events comparing fire needle and conventional therapies in a quantitative study on the safety and efficacy of fire needle therapy for flat warts.
TrialsComparisonsEffect Estimates (95% CI)P value1. Skin lesion scores1.1 Fire needle versus control group1.1.1 OverallLiang 2018Fire needle versus traditional Chinese medicineRR−0.05 [−0.67, 0.57]Cui 2019Fire needle versus traditional Chinese medicineRR−4.86 [−5.91, −3.82]Li2 2019Fire needle versus immunomodulatorRR−0.47 [−1.10, 0.16]Meta-analysisRR−1.75 [−4.15,0.64]0.151.1.2 Number of wartsChen 2007Fire needle versus tretinoinRR−1.31 [−1.75, −0.86]Shi 2015Fire needle versus tretinoinRR−0.02 [−0.51, 0.46]Meta-analysisRR−0.67 [−1.93, 0.59]0.31.1.3 SizeChen 2007Fire needle versus tretinoinRR−1.17 [−1.61, −0.74]Shi 2015Fire needle versus tretinoinRR−1.25 [−1.79, −0.72]Meta-analysisRR−1.20 [−1.54, −0.87]<0.000011.1.4 ThicknessChen 2007Fire needle versus tretinoinRR−0.97 [−1.39, −0.55]Shi 2015Fire needle versus tretinoinRR−0.89 [−1.40, −0.38]Meta-analysisRR−0.94 [−1.26, −0.61]< 0.000011.1.5 Skin lesion colorChen 2007Fire needle versus tretinoinRR−0.89 [−1.31, −0.47]Shi 2015Fire needle versus tretinoinRR0.25 [−0.24, 0.74]Meta-analysisRR−0.32 [−1.44, 0.79]0.571.1.6 ItchingChen 2007Fire needle versus tretinoinRR−0.42 [−0.83, −0.02]Shi 2015Fire needle versus tretinoinRR−0.47 [−0.96, 0.03]Meta-analysisRR−0.44 [−0.75, −0.13]0.0061.1.7 Isomorphic responseChen 2007Fire needle versus tretinoinRR0.17 [−0.23, 0.57]Shi 2015Fire needle versus tretinoinRR0.22 [−0.27, 0.71]Meta-analysisRR0.19 [−0.12, 0.50]0.231.2 Fire needle combined with control group versus control group1.2.1 Skin lesions overall scoresLiang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−0.54 [−1.18, 0.09]Cui 2019Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−0.58 [−1.21, 0.05]Li2 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR−9.84 [−11.74, −7.94]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR−1.09 [−1.57, −0.61]Meta-analysisRR−2.66 [−4.55, −0.78]0.0062. Cytokine levels2.1 Fire needle combined with control group versus control group2.1.1 Interleukin-2Liang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR5.56 [3.05, 8.07]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR4.94 [3.17, 6.71]Meta-analysisRR5.15 [3.70, 6.59]<0.000012.1.2 Interleukin-10Liang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−2.48 [−3.71, −1.25]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR−1.41 [−2.26, −0.56]Meta-analysisRR−1.75 [−2.45, −1.05]<0.000012.1.3 Interferon-γLiang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR7.75 [4.24, 11.26]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR7.64 [5.48, 9.80]Meta-analysisRR7.67 [5.83, 9.51]<0.000013 Dermatology Life Quality Index3.1 Fire needle versus control groupLiang 2018Fire needle versus traditional Chinese medicineRR−0.03 [−2.65, 2.59]0.983.1 Fire needle combined with control group versus control groupLiang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−3.82 [−6.32, −1.32]0.0034. Recurrence rate4.1 Fire needle versus control groupChen 2007Fire needle versus tretinoinRR0.50 [0.05, 5.33]Chen 2009Fire needle versus tretinoinRR0.44 [0.08, 2.56]Shi 2015Fire needle versus tretinoinRR0.48 [0.05, 5.09]Zheng 2010Fire needle versus immunomodulatorRR10.67 [0.65, 176.19]Li2 2019Fire needle versus immunomodulatorRR0.33 [0.11, 1.05]Huang 2019Fire needle versus immunomodulatorRR0.38 [0.10, 1.46]Meta-analysisRR0.71 [0.38, 1.31]0.274.2 Fire needle combined with control group versus control groupYang 2008Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR0.33 [0.04, 3.03]Li2 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR0.05 [0.00, 0.80]Huang 2016Fire needle combined with immunomodulator versus immunomodulatorRR0.22 [0.07, 0.71]Huang 2019Fire needle combined with immunomodulator versus immunomodulatorRR0.06 [0.00, 1.00]Zhu 2019Fire needle combined with imiquimod versus imiquimodRR0.31 [0.11, 0.88]Zhang 2007Fire needle combined with multidrug therapy versus multidrug therapyRR0.55 [0.10, 2.87]Jia 2017Fire needle combined with multidrug therapy versus multidrug therapyRR0.70 [0.29, 1.69]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR0.84 [0.15, 4.77]Meta-analysisRR0.34 [0.21, 0.54]<0.000015. Adverse events5.1 Fire needle versus control group5.1.1 InfectionChen 2007Fire needle versus tretinoinRR5.00 [0.25, 101.48]Shi 2015Fire needle versus tretinoinRR0.97 [0.15, 6.47]meta-analysisRR1.55 [0.31, 7.71]0.595.1.2 ItchingZheng 2010Fire needle versus immunomodulatorRR0.10 [0.00, 2.07]Pu 2011Fire needle versus multidrug therapyRR0.54 [0.14, 2.09]Li 2019Fire needle versus tretinoinRR0.67 [0.12, 3.78]Meta-analysisRR0.48 [0.18, 1.32]0.155.1.3 PainXu 2014Fire needle versus liquid nitrogen freezingRR1.67 [0.44, 6.36]He 2017Fire needle versus traditional Chinese medicineRR1−.64 [0.60, 188.18]Jiang 2017Fire needle versus immunomodulatorRR11.93 [0.69, 207.04]Meta-analysisRR3.73 [0.87, 16.06]0.085.1.4 Mild burningChen 2007Fire needle versus tretinoinRR5.00 [0.25, 101.48]Chen 2009Fire needle versus tretinoinRR0.05 [0.00, 0.90]Shi 2015Fire needle versus tretinoinRR0.97 [0.06, 14.85]Meta-analysisRR0.61 [0.04, 8.47]0.725.1.5 ErythemaChen 2009Fire needle versus tretinoinRR0.05 [0.00, 0.90]0.045.1.6 PigmentationChen 2007Fire needle versus tretinoinRR2.00 [0.38, 10.41]Chen 2009Fire needle versus tretinoinRR6.04 [0.33, 109.71]Shi 2015Fire needle versus tretinoinRR1.94 [0.38, 9.86]Pu 2011Fire needle versus multidrug therapyRR2.54 [1.10, 5.86]Li 2019Fire needle versus immunomodulatorRR0.17 [0.01, 4.01]Meta-analysisRR2.19 [1.15, 4.17]0.025.2 Fire needle combined with control group versus control group5.2.1 InfectionZhu 2019Fire needle combined with imiquimod versus imiquimodRR0.20 [0.01, 4.06]0.295.2.2 ItchingZhu 2019Fire needle combined with imiquimod versus imiquimodRR0.50 [0.05, 5.33]Pu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR0.64 [0.17, 2.49]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR0.75 [0.18, 3.13]Meta-analysisRR0.66 [0.27, 1.64]0.375.2.3 Mild burningZhu 2019Fire needle combined with imiquimod versus imiquimodRR0.33 [0.04, 3.09]Huang 2016Fire needle combined with multidrug therapy versus multidrug therapyRR0.09 [0.00, 1.50]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR1.25 [0.36, 4.31]Meta-analysisRR0.48 [0.10, 2.31]0.365.2.4 ErythemaYuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR0.67 [0.12, 3.77]0.655.2.5 PigmentationRuan 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR13.00 [0.75, 225.75]Li2 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR0.10 [0.01, 2.04]Pu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR1.33 [0.51, 3.43]Yuan 2019Fire needle combined with multi drug therapy versus multidrug therapyRR5.00 [0.25, 100.89]Meta-analysisRR1.65 [0.32, 8.48]0.555.2.6 DesquamationPu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR0.24 [0.07, 0.83]Huang 2016Fire needle combined with multidrug therapy versus multidrug therapyRR0.09 [0.00, 1.50]Meta-analysisRR0.21 [0.07, 0.64]0.006


### 3.5.2. Cytokine Levels

Two studies reported that increased levels of cytokines, including interleukin-2 (IL-2), interleukin-10 (IL-10), and interferon-γ (IFN-γ), were associated with flat warts [29, 33] (Table 4; Supplementary file 10: Figure S9). After combined treatments, the levels of IL-2 (MD = 5.15, 95% CI: 3.70 to 6.59, I2 = 0%, P < 0.00001) or IFN-γ (MD = 7.67, 95% CI: 5.83 to 9.51, I2 = 0%, P < 0.00001) were significantly increased, whereas the level of IL-10 was decreased, compared with that of other drugs (MD = −1.75, 95% CI: −2.45 to −1.05, I2 = 49%, P < 0.00001).


### 3.5.3. DLQI

One study used DLQI to evaluate the effects of the treatment [33]; it indicated no significant difference when comparing fire needle therapy and TCM (P = 0.98; Table 4). However, when compared to the effects of TCM alone, the combination of fire needle therapy and TCM showed a statistical difference (RR = −3.82, 95% CI: −6.32 to −1.32, P = 0.003).


### 3.5.4. Recurrence Rates

Twelve trials reported recurrence rates [2, 28, 29, 31, 34, 40, 43, 49–53]. The follow-up period for 10 studies was 3 months, one was 6 months [49], and one was 12 months [52]. The results of the meta-analysis (Table 4; Supplementary file 13: Figure S10) showed that the recurrence rate in the groups that used fire needle therapy alone was similar to that in the control groups (RR = 0.71, 95% CI: 0.38 to 1.31, I2 = 24%, P = 0.27); however, recurrence rates were significantly lower in the combined therapies (RR = 0.34, 95% CI: 0.21 to 0.54, I2 = 12%, P < 0.00001).


### 3.5.5. Adverse Events

Fourteen trials evaluated the safety of treatment by assessing various types of adverse events [28–31, 35–37, 40, 43, 46, 48–50, 53]. Subgroup analysis (Table 4; Supplementary file 14: Figure S11) showed that patients treated with fire needle therapy were at a reduced risk of erythema (RR = 0.05, 95% CI: 0.00 to 0.90, P = 0.04) and blisters (RR = 0.04, 95% CI: 0.00 to 0.71, P = 0.03), but were more likely to develop pigmentation (RR = 2.19, 95% CI: 1.15 to 4.17, I2 = 0%, P = 0.02). Furthermore, comparisons of desquamation in the fire needle combined with multidrug therapy group and multidrug therapy alone demonstrated a significant difference (RR = 0.21, 95% CI: 0.07 to 0.64, I2 = 0%, P = 0.006; Supplementary file 15: Figure S12). In the sensitivity analysis, the subgroup of mild burning and pigmentation showed high heterogeneity, which may be related to two studies [30, 50], but the conclusion is still valid with statistical significance (Supplementary file 16: Figure S13; Supplementary file 17: Figure S14).


## 3.5.1. Skin Lesion Scores

Five trials used skin lesion scores as the criteria to assess disease severity [29, 30, 32, 33, 54], as recommended by the Chinese Dermatology Monograph [25]. The overall skin lesion scores of the fire needle group were similar to those of the control group (P = 0.15; Table 4; Supplementary file 8: Figure S5), whereas the combined groups had lower scores (SMD = −2.66, 95% CI: −4.55 to −0.78, I2 = 97%, P = 0.006; Supplementary file 9: Figure S6). Compared with TCM and tretinoin, the group with fire needle therapy alone had reduced scores with respect to the size (SMD = −1.20, 95% CI: −1.54 to −0.87, I2 = 0%, P < 0.00001), thickness (SMD = −0.94, 95% CI: −1.26 to −0.61, I2 = 0%, P < 0.00001), and itching (SMD = −0.44, 95% CI: −0.75 to −0.13, I2 = 0%, P = 0.006). However, there was no statistically significant difference in the number of warts (P = 0.30), color of the skin lesions (P = 0.57), and isomorphic response (P = 0.23). We conducted a sensitivity analysis of the two subgroups with high heterogeneity, but the result could not be considered significant because there were an insufficient number of trials (Supplementary file 10: Figure S7; Supplementary file 11: Figure S8).Table 4
Skin lesion scores, cytokine levels, recurrence rates, and adverse events comparing fire needle and conventional therapies in a quantitative study on the safety and efficacy of fire needle therapy for flat warts.
TrialsComparisonsEffect Estimates (95% CI)P value1. Skin lesion scores1.1 Fire needle versus control group1.1.1 OverallLiang 2018Fire needle versus traditional Chinese medicineRR−0.05 [−0.67, 0.57]Cui 2019Fire needle versus traditional Chinese medicineRR−4.86 [−5.91, −3.82]Li2 2019Fire needle versus immunomodulatorRR−0.47 [−1.10, 0.16]Meta-analysisRR−1.75 [−4.15,0.64]0.151.1.2 Number of wartsChen 2007Fire needle versus tretinoinRR−1.31 [−1.75, −0.86]Shi 2015Fire needle versus tretinoinRR−0.02 [−0.51, 0.46]Meta-analysisRR−0.67 [−1.93, 0.59]0.31.1.3 SizeChen 2007Fire needle versus tretinoinRR−1.17 [−1.61, −0.74]Shi 2015Fire needle versus tretinoinRR−1.25 [−1.79, −0.72]Meta-analysisRR−1.20 [−1.54, −0.87]<0.000011.1.4 ThicknessChen 2007Fire needle versus tretinoinRR−0.97 [−1.39, −0.55]Shi 2015Fire needle versus tretinoinRR−0.89 [−1.40, −0.38]Meta-analysisRR−0.94 [−1.26, −0.61]< 0.000011.1.5 Skin lesion colorChen 2007Fire needle versus tretinoinRR−0.89 [−1.31, −0.47]Shi 2015Fire needle versus tretinoinRR0.25 [−0.24, 0.74]Meta-analysisRR−0.32 [−1.44, 0.79]0.571.1.6 ItchingChen 2007Fire needle versus tretinoinRR−0.42 [−0.83, −0.02]Shi 2015Fire needle versus tretinoinRR−0.47 [−0.96, 0.03]Meta-analysisRR−0.44 [−0.75, −0.13]0.0061.1.7 Isomorphic responseChen 2007Fire needle versus tretinoinRR0.17 [−0.23, 0.57]Shi 2015Fire needle versus tretinoinRR0.22 [−0.27, 0.71]Meta-analysisRR0.19 [−0.12, 0.50]0.231.2 Fire needle combined with control group versus control group1.2.1 Skin lesions overall scoresLiang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−0.54 [−1.18, 0.09]Cui 2019Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−0.58 [−1.21, 0.05]Li2 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR−9.84 [−11.74, −7.94]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR−1.09 [−1.57, −0.61]Meta-analysisRR−2.66 [−4.55, −0.78]0.0062. Cytokine levels2.1 Fire needle combined with control group versus control group2.1.1 Interleukin-2Liang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR5.56 [3.05, 8.07]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR4.94 [3.17, 6.71]Meta-analysisRR5.15 [3.70, 6.59]<0.000012.1.2 Interleukin-10Liang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−2.48 [−3.71, −1.25]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR−1.41 [−2.26, −0.56]Meta-analysisRR−1.75 [−2.45, −1.05]<0.000012.1.3 Interferon-γLiang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR7.75 [4.24, 11.26]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR7.64 [5.48, 9.80]Meta-analysisRR7.67 [5.83, 9.51]<0.000013 Dermatology Life Quality Index3.1 Fire needle versus control groupLiang 2018Fire needle versus traditional Chinese medicineRR−0.03 [−2.65, 2.59]0.983.1 Fire needle combined with control group versus control groupLiang 2018Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR−3.82 [−6.32, −1.32]0.0034. Recurrence rate4.1 Fire needle versus control groupChen 2007Fire needle versus tretinoinRR0.50 [0.05, 5.33]Chen 2009Fire needle versus tretinoinRR0.44 [0.08, 2.56]Shi 2015Fire needle versus tretinoinRR0.48 [0.05, 5.09]Zheng 2010Fire needle versus immunomodulatorRR10.67 [0.65, 176.19]Li2 2019Fire needle versus immunomodulatorRR0.33 [0.11, 1.05]Huang 2019Fire needle versus immunomodulatorRR0.38 [0.10, 1.46]Meta-analysisRR0.71 [0.38, 1.31]0.274.2 Fire needle combined with control group versus control groupYang 2008Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR0.33 [0.04, 3.03]Li2 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR0.05 [0.00, 0.80]Huang 2016Fire needle combined with immunomodulator versus immunomodulatorRR0.22 [0.07, 0.71]Huang 2019Fire needle combined with immunomodulator versus immunomodulatorRR0.06 [0.00, 1.00]Zhu 2019Fire needle combined with imiquimod versus imiquimodRR0.31 [0.11, 0.88]Zhang 2007Fire needle combined with multidrug therapy versus multidrug therapyRR0.55 [0.10, 2.87]Jia 2017Fire needle combined with multidrug therapy versus multidrug therapyRR0.70 [0.29, 1.69]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR0.84 [0.15, 4.77]Meta-analysisRR0.34 [0.21, 0.54]<0.000015. Adverse events5.1 Fire needle versus control group5.1.1 InfectionChen 2007Fire needle versus tretinoinRR5.00 [0.25, 101.48]Shi 2015Fire needle versus tretinoinRR0.97 [0.15, 6.47]meta-analysisRR1.55 [0.31, 7.71]0.595.1.2 ItchingZheng 2010Fire needle versus immunomodulatorRR0.10 [0.00, 2.07]Pu 2011Fire needle versus multidrug therapyRR0.54 [0.14, 2.09]Li 2019Fire needle versus tretinoinRR0.67 [0.12, 3.78]Meta-analysisRR0.48 [0.18, 1.32]0.155.1.3 PainXu 2014Fire needle versus liquid nitrogen freezingRR1.67 [0.44, 6.36]He 2017Fire needle versus traditional Chinese medicineRR1−.64 [0.60, 188.18]Jiang 2017Fire needle versus immunomodulatorRR11.93 [0.69, 207.04]Meta-analysisRR3.73 [0.87, 16.06]0.085.1.4 Mild burningChen 2007Fire needle versus tretinoinRR5.00 [0.25, 101.48]Chen 2009Fire needle versus tretinoinRR0.05 [0.00, 0.90]Shi 2015Fire needle versus tretinoinRR0.97 [0.06, 14.85]Meta-analysisRR0.61 [0.04, 8.47]0.725.1.5 ErythemaChen 2009Fire needle versus tretinoinRR0.05 [0.00, 0.90]0.045.1.6 PigmentationChen 2007Fire needle versus tretinoinRR2.00 [0.38, 10.41]Chen 2009Fire needle versus tretinoinRR6.04 [0.33, 109.71]Shi 2015Fire needle versus tretinoinRR1.94 [0.38, 9.86]Pu 2011Fire needle versus multidrug therapyRR2.54 [1.10, 5.86]Li 2019Fire needle versus immunomodulatorRR0.17 [0.01, 4.01]Meta-analysisRR2.19 [1.15, 4.17]0.025.2 Fire needle combined with control group versus control group5.2.1 InfectionZhu 2019Fire needle combined with imiquimod versus imiquimodRR0.20 [0.01, 4.06]0.295.2.2 ItchingZhu 2019Fire needle combined with imiquimod versus imiquimodRR0.50 [0.05, 5.33]Pu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR0.64 [0.17, 2.49]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR0.75 [0.18, 3.13]Meta-analysisRR0.66 [0.27, 1.64]0.375.2.3 Mild burningZhu 2019Fire needle combined with imiquimod versus imiquimodRR0.33 [0.04, 3.09]Huang 2016Fire needle combined with multidrug therapy versus multidrug therapyRR0.09 [0.00, 1.50]Yuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR1.25 [0.36, 4.31]Meta-analysisRR0.48 [0.10, 2.31]0.365.2.4 ErythemaYuan 2019Fire needle combined with multidrug therapy versus multidrug therapyRR0.67 [0.12, 3.77]0.655.2.5 PigmentationRuan 2017Fire needle combined with traditional Chinese medicine versus traditional Chinese medicineRR13.00 [0.75, 225.75]Li2 2019Fire needle combined with traditional Chinese medicine versus immunomodulatorRR0.10 [0.01, 2.04]Pu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR1.33 [0.51, 3.43]Yuan 2019Fire needle combined with multi drug therapy versus multidrug therapyRR5.00 [0.25, 100.89]Meta-analysisRR1.65 [0.32, 8.48]0.555.2.6 DesquamationPu 2011Fire needle combined with multidrug therapy versus multidrug therapyRR0.24 [0.07, 0.83]Huang 2016Fire needle combined with multidrug therapy versus multidrug therapyRR0.09 [0.00, 1.50]Meta-analysisRR0.21 [0.07, 0.64]0.006


## 3.5.2. Cytokine Levels

Two studies reported that increased levels of cytokines, including interleukin-2 (IL-2), interleukin-10 (IL-10), and interferon-γ (IFN-γ), were associated with flat warts [29, 33] (Table 4; Supplementary file 10: Figure S9). After combined treatments, the levels of IL-2 (MD = 5.15, 95% CI: 3.70 to 6.59, I2 = 0%, P < 0.00001) or IFN-γ (MD = 7.67, 95% CI: 5.83 to 9.51, I2 = 0%, P < 0.00001) were significantly increased, whereas the level of IL-10 was decreased, compared with that of other drugs (MD = −1.75, 95% CI: −2.45 to −1.05, I2 = 49%, P < 0.00001).


## 3.5.3. DLQI

One study used DLQI to evaluate the effects of the treatment [33]; it indicated no significant difference when comparing fire needle therapy and TCM (P = 0.98; Table 4). However, when compared to the effects of TCM alone, the combination of fire needle therapy and TCM showed a statistical difference (RR = −3.82, 95% CI: −6.32 to −1.32, P = 0.003).


## 3.5.4. Recurrence Rates

Twelve trials reported recurrence rates [2, 28, 29, 31, 34, 40, 43, 49–53]. The follow-up period for 10 studies was 3 months, one was 6 months [49], and one was 12 months [52]. The results of the meta-analysis (Table 4; Supplementary file 13: Figure S10) showed that the recurrence rate in the groups that used fire needle therapy alone was similar to that in the control groups (RR = 0.71, 95% CI: 0.38 to 1.31, I2 = 24%, P = 0.27); however, recurrence rates were significantly lower in the combined therapies (RR = 0.34, 95% CI: 0.21 to 0.54, I2 = 12%, P < 0.00001).


## 3.5.5. Adverse Events

Fourteen trials evaluated the safety of treatment by assessing various types of adverse events [28–31, 35–37, 40, 43, 46, 48–50, 53]. Subgroup analysis (Table 4; Supplementary file 14: Figure S11) showed that patients treated with fire needle therapy were at a reduced risk of erythema (RR = 0.05, 95% CI: 0.00 to 0.90, P = 0.04) and blisters (RR = 0.04, 95% CI: 0.00 to 0.71, P = 0.03), but were more likely to develop pigmentation (RR = 2.19, 95% CI: 1.15 to 4.17, I2 = 0%, P = 0.02). Furthermore, comparisons of desquamation in the fire needle combined with multidrug therapy group and multidrug therapy alone demonstrated a significant difference (RR = 0.21, 95% CI: 0.07 to 0.64, I2 = 0%, P = 0.006; Supplementary file 15: Figure S12). In the sensitivity analysis, the subgroup of mild burning and pigmentation showed high heterogeneity, which may be related to two studies [30, 50], but the conclusion is still valid with statistical significance (Supplementary file 16: Figure S13; Supplementary file 17: Figure S14).


## 4. Discussion

This systematic review included 29 trials comparing the effectiveness of fire needle therapy alone and combined treatments for flat warts. We found evidence to support that fire needle therapy showed significantly better therapeutic potential than immunomodulators or tretinoin, especially in terms of wart size, thickness, and itching. The reason for this may be related to the mechanism of high temperature directly destroying warts and degenerative proteins and killing viruses in epidermal spinous processes, which are possibly the most common methods of inducing cell death and antigen exposure [8, 40, 55]. Based on the high heterogeneity in the efficacy rate of the subgroup that received fire needle therapy compared with that of the immunomodulator, we found that the intervention frequency might be the determining factor responsible for the differences. The results of the sensitivity analysis resolved the heterogeneity and proved that the results are still significant. However, the efficacy rate between fire needle therapy and liquid nitrogen or photodynamic therapy did not significantly differ, but the evidence was insufficient because each of the comparisons was made using only one study. Furthermore, our results showed that the total efficacy rate of fire needle therapy alone was as effective as TCM, whereas combination therapies significantly improved effectiveness.In terms of combined therapies, the total efficacy rates of TCM, immunomodulators, imiquimod, or multi drug therapy were significantly improved after using fire needle therapy, with lower skin lesion scores. The mechanism of fire needle combination therapy is still unclear and may be related to thermal effects that improve microcirculation and enhance drug absorption [35, 40]. Additionally, local or systemic cellular immune responses generated by natural killer (NK) cells have been reported as an important mechanism of fire needle therapy for flat warts [2]. In this meta-analysis, we found that groups that received fire needle therapy combined with tretinoin or TCM treatment were more likely to have decreased IL-10 and increased IL-2 or IFN-γ levels after peripheral blood testing. Consistent with this result, an experiment confirmed that HPV infection inhibits NK cell activation by fluorescence quantitative polymerase chain reaction (PCR) and western blot analysis of lesion tissues and peripheral blood samples. The peripheral blood of infected patients analyzed using enzyme-linked immunosorbent assays revealed that IL-2 and IFN-γ protein levels were significantly lower than those in normal subjects, whereas the IL-10 levels of the patients were higher [54]. The expression levels of IFN-γ and IL-2 mRNA were correlated with wart remission, as evidenced by real-time PCR of select punch biopsy specimens, and IL-2 or IFN-γ mRNA levels were significantly increased in tissues of effectively treated viral warts [56]. Treatments of flat warts that regulate the levels of these cytokines have been reported, including retinoids [57]. Fire needle therapy may assist retinoids in enhancing this effect, increasing IL-2 and IFN-γ expression and enhancing cell-mediated immune responses. The levels of IL-2 or IFN-γ were positively correlated with promoting the activation of NK cells and removing the target cells infected with viruses [58]. As a cell synthesis inhibitor, IL-10 can directly inhibit IFN-γ synthesis, thereby reducing their ability to eliminate toxins [59]. The result of the reduction of IL-10 was consistent with the hypothesis of immunosuppression in infected patients [54].Combined medication significantly reduced the clinical recurrence rate of flat warts. In addition to their destructive effects, the reduction of recurrence rates through fire needle therapy may be related to the regulation of immune function. According to previous reports, the recurrence rate of flat warts after combined therapy was lower than that of fire needle therapy alone, and it is recommended that, after fire needle treatment, antiviral therapy be commenced to further reduce the recurrence rates [29].Regarding adverse events, we found that patients were less likely to have blisters and erythema when they were treated with fire needle therapy alone, and desquamation was less likely to occur in groups that received combined therapy. The main adverse events caused by the treatment of flat warts were irritating cautery, hypertrophic scar formation, local or systemic infection, itching, allergies, and increased sensitivity to pain [60–62]. Skin lesions, including pigmentation, scar formation, erythema, desquamation, and blistering, were also common [8]. This study included only 10 adverse events. Blisters have been reported as adverse events in cryotherapy, and erythema and desquamation have been reported as adverse events of squaric acid dibutyl ester or diphencyprone therapy [8]. We demonstrated that, to a limited extent, fire needle therapy can be used as an alternative or complementary therapy to avoid these adverse events. Pigmentation was the main adverse reaction to fire needle therapy alone, whereas our results showed that using combined therapies may lower this risk. Furthermore, some preventive measures for pigmentation have been proposed and implemented clinically. For example, the use of asiaticoside ointment could significantly relieve the pigmentation caused by fire needle therapy [63].The present study is the first systematic review of the efficacy of fire needle treatment for flat warts that follows the PRISMA statement and is formulated according to the PICOS framework. The heterogeneity of each index factor was evaluated using sensitivity analysis to test the stability of the approach. The GRADE system was adopted to evaluate the level of evidence and make the results more credible. Evidence from 29 clinical trials illustrates that using fire needle therapy could significantly improve the efficacy rate with fewer side effects. This article provides evidence and guidance for the clinical practice of fire needles in flat warts.However, this study had some limitations. First, the quality of trials was not very good; only fourteen trials reported specific randomization, and only nine mentioned allocation concealment. Only one trial reported blinding, and no studies reported other biases. Second, we did not distinguish between flat warts on the hands and faces. Third, flat warts from children and adults were discussed together; the difference among them requires further research.


## 5. Conclusion

In conclusion, fire needle therapy seems to be more effective against flat warts when compared with an immunomodulator or tretinoin and can reduce adverse events, such as blisters and erythema, but may cause pigmentation. Using fire needle therapy in combination with conventional therapies could significantly improve the treatment efficacy rate and lower the risk of desquamation. However, the quality of the included literature was not good, and large multicenter studies with a large number of samples and high-quality RCTs should be conducted to confirm the efficacy and safety of fire needle therapy in the treatment of flat warts.



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*Source: 9513762-2021-01-18.xml*