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 (Figures 1(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 (Figure 1(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 (Figure 1(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.

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.

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 (Table 1). 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.

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.

Disclosure

The funders had no role in study design, data collection, analysis, decision to publish, or manuscript preparation.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

YZ and JSJ conceived this study. XL and BL designed this study. LK and YL performed the searches. JLC and YJW extracted the data. MX and RX assessed the quality of the trials. MX and LL analyzed the data. YZ and JSJ wrote the original draft. YZ, LK, YL, XL, and BL contributed to the revision of the manuscript. All authors have read and approved the final manuscript. Ying Zhang and Jing-si Jiang contributed equally to this work.