Therapeutic management of cutaneous and genital warts

Transcription

1 Review Eingereicht: Angenommen: Conflicts of interest None. DOI: /ddg Therapeutic management of cutaneous and genital warts Hans Michael Ockenfels Department of Dermatology and Allergology, Medical Center Hanau, Hanau, Germany Summary During their lifetime, at least 10 % of the population will be infected by human papillomaviruses (HPV), clinically characterized by the formation of cutaneous or genital warts. Although warts are ubiquitous, there are no defined treatments. Especially in the first six months, warts frequently resolve without therapeutic intervention. This complicates the interpretation of study data, given that many studies do not differentiate between newly infected patients and those with infections that have persisted for a long time. Similarly, most studies do not take location, size, and thickness of lesions into account, either. The objective of the present review article is to analyze the study data currently available, taking into consideration both subtypes and locations factors exceedingly crucial in clinical practice. In particular, the distinction between new-onset and chronic recalcitrant warts is reflected in a therapeutic algorithm. In the case of genital warts, the algorithm is more clearly determined by the extent of the area affected rather than the longevity of lesions. In immunocompetent individuals, any therapeutic intervention must be aimed at achieving complete resolution. Introduction Considering the prevalence of warts in the general population (7 12 %), infections with human papillomaviruses (HPV) must be considered a widespread disease. More than 170 different types of papillomaviruses have been identified to date. Depending on a patient's immune status, common warts may appear anywhere on the skin. Genital warts condylomata acuminate may occur as solitary lesions or in huge clusters. As regards differential diagnoses, bowenoid papulosis and condylomata lata should be taken into consideration in the genital area; in the case of large verrucous lesion, for example, on the foot, carcinoma should be borne in mind; and in the case of plane warts on the face, syringomas and lichen nitidus. Given the wide range of clinical manifestations of HPV infections, study data with respect to the treatment of warts is very inhomogeneous. There are some publications that describe newly infected patients and those with chronic warts without distinction [1]. Therapeutic success depends on various clinical factors including disease duration as well as thickness and location of the warts. The classification in classic subgroups (subungual, hands, feet), as suggested by Park, is missing in most publications [2]. Some authors even define first-line treatments as those that can be applied by patients themselves [3]. Not all authors define complete resolution (eradication) and lack of recurrence of clinically visible HPV lesions as a clinical objective [4]. Given that clinical improvement using salicylic acid or cryotherapy is always possible, partial remission is, however, an insignificant study result, and (falsely) suggests that the prescribed treatment is of clinical relevance [5]. With regard to the resolution of viral warts without therapeutic intervention, reports have shown markedly varying results. A pediatric study revealed that twothirds of all warts disappeared without treatment after two years [6], however, there is a lack of controlled studies on the (spontaneous) regression of warts in adults. While it is therefore theoretically possible to adopt a wait-and-see approach in the case of asymptomatic warts in non-cosmetic locations, the possibility of dissemination through autoinoculation 892

2 (from scratching, eczema, shaving, hyperhidrosis) should not be neglected [6]. As each infection takes a different course, which means it is impossible to predict in what way warts will develop and spread, we recommend commencing treatment at an early stage. Such an approach may be considered a preventive measure, given that it is able to prevent the condition from becoming chronic or disseminated in at least 50 % of patients affected. Early treatment is also indicated in case of predisposing factors for viral skin infections. In addition to general immunodeficiency, such factors include acrocyanosis with impaired peripheral circulation, palmoplantar hyperhidrosis, and atopic dermatitis associated with impaired skin barrier function. The present review combines articles with the following search items: warts, verruca, plantar, hands, filiform, flat, plane, periungual, condylomata acuminata, recalcitrant, chronic, treatment, management, therapy. Computerized literature search was performed using Medline and the Cochrane clinical trial register [5], and included publications between 1980 and In the following, a distinction is made between cutaneous and genital warts. Cutaneous warts Prior to treatment initiation, it is recommended to check whether any of the aforementioned risk factors apply. In addition, the local immune status may be stimulated using supplementary measures such as breathable footwear or alternating baths of different temperatures to promote spontaneous resolution. First-line topical therapies Salicylic acid While salicylic acid primarily causes chemical ablation and irritation of HPV-induced hyperkeratoses, it is also supposed to activate the local immune response. The clinically controlled trials conducted between 1984 and 1991, which compared salicylic acid and placebo in the treatment of warts, only showed positive therapeutic effects for the former. A meta-analysis of six trials comparing the exclusive use of salicylic acid to placebo revealed a significantly positive effect (relative risk [RR]: 1.56; 95 % confidence interval [CI] ) [3]. While clearance rates averaged around 50 %, the study populations examined were not uniform (hands, feet, trunk, < 6 months, > 6 months). None of these studies was able to ascertain the ideal treatment duration; this figure varied from six to 17 weeks. Following the general recommendation by other authors, which corresponds to our own, the mean treatment duration comes to twelve weeks [7]. Mulhem and Pinelis recommend treatment according to the protocol shown in Table 1. Table 1 Treatment protocol using salicylic acid. 17 % salicylic acid products such as Guttaplast or Warzweg and others. Warm foot bath for 5 minutes and careful attempt to remove hyperkeratoses. Apply product containing salicylic acid to the wart, repeat this procedure on a daily basis, continue the procedure for 12 weeks, brief interruption if erythema, pain, or bleeding occurs. Mild erythema in the area treated is normal. Do not use salicylic acid on the face due to the risk of hypo- and hyperpigmentation. Cryotherapy Cryotherapy involves the use of liquid nitrogen at a temperature of 196 C to create an area of necrosis below and around the wart. Achieving temperatures down to 70 C, commercially available cryo pens are less effective. Liquid nitrogen can be applied using either a cryo gun or cotton swabs. As virus particles may survive in the cotton swab, patients should use fresh swabs every day. Our review identified 21 clinically controlled trials conducted in recent years that examined cryotherapy in comparison to salicylic acid, some of which were placebo-controlled (3, 6, 8]. These studies showed clearance rates of % after 3 4 treatments. However, given the low degree of comparability of the studies, it was impossible to provide arithmetic proof on the basis of meta-analyses that cryotherapy achieves better results than placebo [8]. Nevertheless, the aforementioned studies did establish that cryotherapy does provide benefits with regard to certain aspects: cryotherapy brings about quicker results than salicylic acid; in general, only 3 4 applications (at 14-day intervals) are necessary. Aggressive cryotherapy (for seconds) achieves a clearance rate roughly 20 % higher than weak cryotherapy [8]. Cryotherapy should continue for at least three months, even if unsuccessful at first; this especially applies when treating hands and feet [9]. Comparing the clearance rates of combination therapy consisting of cryotherapy and salicylic acid, a study by Kwok CS et al. found a 10 % higher clearance rate than with monotherapies [10]. Forming clinical subgroups and comparing cryotherapy on the hands to cryotherapy on the feet revealed that there was a significant benefit from cryotherapy to warts on the hands in comparison to warts on the feet [11]. This shows that the proper implementation of treatment methods as well as the size, chronicity, and thickness of warts are decisive therapeutic criteria. To summarize, it can be established with regard to both cryotherapy and topical salicylic acid therapy that any technique is only as good as its practical 893

3 implementation allows it to be. If a plantar wart is too large or too thick for salicylic acid or cryotherapy to destroy a sufficient amount of tissue to eliminate all HPV particles in the affected area, the treatment will fail. Cryotherapy is nothing other than tissue destruction induced by freezing. Unlike ablative procedures, it is not immediately apparent whether all keratinocytes have actually been destroyed (frozen). To what extent the inflammatory process resulting from tissue freezing is involved in destroying HPV-infected keratinocytes is pure speculation, and has to date not been scientifically proven. Recommendation: The treatment of warts using salicylic acid and cryotherapy is simple and cost-effective, and should, in most locations, likely be considered the treatment of first choice for small and new-onset warts. Experienced clinicians should nonetheless be aware that the size and chronicity of warts in particular, as well as their location (periungual), are additional decisive factors determining therapeutic success. Energy-based methods (first-/second-line therapy) Depending on the data available and type of wart, energy-based methods may similarly be classified as first-line therapies. Second- or third-line topical treatments will be discussed below. For example, it would be appropriate to remove a filiform wart that has grown out of a nostril in a simple, direct manner by means of electrocautery using a wire loop to prevent recurrence. It is likely better from a cosmetic perspective to excise a large solitary wart on the knee. In this context, surgical excision of warts is, with regard to the risk of autoinoculation from spreading HPV particles, only recommended, however, in the case of clearly demarcated and readily accessible locations using appropriate surgical margins. Alternatives include energy-based methods such as dye lasers, electrocautery, CO 2 lasers, and photodynamic therapy, as these allow for scar-free treatment. Energy-based nonablative/destructive dye laser treatment Of these alternatives, dye lasers have been examined in greatest detail, in particular in the treatment of chronic recalcitrant warts. Dye laser treatment is a nonablative method. The light emitted by the most commonly used dye lasers has a wavelength of around 595 nm. The numerous capillary vessels in the warts rupture under the influence of the relatively short high-energy pulses. Patients experience only mild pain. Correct application of energy is indicated by the occurrence of purpura in the papillary dermis within a few minutes. Marked hyperkeratoses must be removed prior to treatment. With a dose of 7 10 Joule, a spot size of 5 7 mm, and a pulse duration of 500 μs, the depth of penetration is only around 2 mm [7]. The costs of this treatment are currently not borne by statutory health insurance funds in Germany. Eighteen studies, including four prospective studies, revealed clearance rates between 48 % and 93 %, with an average of four treatment cycles [3, 5, 7, 12]. Given that most studies enrolled patients with chromic recalcitrant warts, such clearance rates have to be considered high. In a prospective study conducted in 1995, Kauvar et al. treated 142 patients with 703 chronic recalcitrant warts [13]. In the context of a prospective 2007 study, we were able to achieve complete remission in 89 % of a total of 73 patients [12]. A study of 227 patients, the largest number of patients with recalcitrant warts treated to date, was recently published by Sparreboom et al. [14]. The clearance rate, including the one-year follow-up period, ultimately came to a total of 86 %. The difference between this therapeutic method and electrocautery or CO 2 lasers is that dye lasers allow for scarfree treatment, and the warts do not have to be anesthetized. As these studies were neither placebo-controlled nor did they have a second arm, for example, the exclusive use of salicylic acid, Mulhem and Pinelis categorize laser treatment as efficacy unknown [8]. According to these authors, the same applies to surgical excision, electrocautery, and CO 2 treatment. Considering the data available, by now including more than 1,000 patients with chronic recalcitrant warts treated with dye lasers (some prospectively, some retrospectively), this nonablative method can clearly be removed from the category of efficacy unknown. An average clearance rate of around % reveals the high efficacy of this treatment. For some regions (periungual) or plane warts on the face, we would like to propose dye lasers as first-line therapy (Figure 1). Ablative procedures CO 2 laser and electrocautery Bloody removal of common warts or genital warts is classified among the group of ablative procedures (physical destruction) [3, 7]. Based on the clearance rates reported by various studies, CO 2 laser treatment achieves, on average, complete remission in 75 % of cases [3, 7, 15]. However, some working groups published clearance rates of up to 100 %. In their non-placebo-controlled, non-randomized study (level of evidence 3b), Serour and Somekh, for example, reported a clearance rate of 100 % in 40 children treated with a CO 2 laser [15]; over the course of the one-year follow-up period, none of the children showed signs of recurrence. There have so far been no clinical studies showing the superiority of CO 2 lasers over electrocautery. A clearance rate of 75 % to 88 % in any of these ablative procedures signifies that not 894

4 use of CO 2 lasers is preferred by many physicians, this is not based on scientific evidence but rather due to their practical application in everyday clinical practice. Lasers are equally capable of cutting quickly and precisely in CW mode and removing individual warts in ultrapulsed mode, with minimal thermal tissue damage. There is a risk of scarring both with CO 2 lasers and electrocautery methods. If the appropriate equipment is available, argon plasma coagulation may also be taken into consideration as an ablative method, especially for condylomata acuminata. However, there have so far been only a few case reports on the use of argon lasers. Photodynamic therapy (PDT) Figure 1 Therapeutic algorithm I. all HPV-infected keratinocytes have been destroyed. In order to achieve a high level of freedom from recurrence and nearly 100 % clearance, it is therefore crucial to maintain the required safety margins, while taking anatomical structures into account. This is the only way to ensure not missing any HPV-infected keratinocytes that are clinically not visible [15]. Although, depending on the location, this is not always achievable, a clearance rate of 85 % especially in the case of recalcitrant warts also argues in favor of employing ablative methods. Arguments against this method include the occurrence of large wounds, long healing times (potentially entailing sick leaves from work), and scarring. For extragenital warts, we therefore initially employ a dye laser prior to selecting an ablative method. However, whenever warts and clusters of warts are so large and in particular so thick that treatment with a dye laser does not appear promising, patients should directly be given the option of having the warts completely removed by means of CO 2 laser or electrocautery. As patients are usually unable to envision the size or depth of the wound, showing them pictures of postoperative wounds on hands and feet caused by the removal of warts is recommended. While, compared to electrocautery, the Since 2008, several studies including randomized double-blind studies have been published on the therapeutic effects of photodynamic therapy in the treatment of common warts [16 18]. Similar to PDT employed in actinic keratoses, the procedure has been modified to account for the clinical characteristics of warts [19]. They are pretreated with salicylic acid for 3 5 days in order to remove hyperkeratoses. The active agent is then under occlusion applied to the wart for 3 5 hours (depending on the study). One noticeable side effect reported by patients is the development of much more severe pain than is the case in the treatment of actinic keratoses. One benefit cited by the authors is that subclinical HPV-infected lesions can also be treated. Complete remission rates range from 43 % (in chronic recalcitrant warts) to 75 %. Two placebo-controlled studies [20] clearly demonstrated the superiority of PDT in comparison to placebo. All studies showing a favorable outcome involved pretreatment with salicylic acid. This should be taken into consideration when employing this therapeutic method. The working group of Li Q et al. [21] were able to show a clearance rate of just under 70 % for multiple plane warts on the face using aminolevulinic acid (ALA) 10 %. There was no significant difference compared to ALA 5 % or ALA 20 %. Given the risk of scarring posed by deep cryotherapy on the face and the fact that salicylic acid potentially leads to hypo- and hyperpigmentation, photodynamic therapy on the face may well be considered a first-line treatment in patients with multiple (> 20) (juvenile) plane warts. Hence, PDT appears twice in the therapeutic algorithm, once as third-line method and once as treatment of first choice (Figure 1). Unfortunately, the costs of PDT for this indication are currently not borne by German statutory health insurance funds. Alternative methods third-line therapy Imiquimod cream Imiquimod 5 % cream has been approved for the treatment of genital warts in adults. It induces the release of interferon- 895

5 alpha and other cytokines that suppress viral replication. To date, only two clinical studies have been published that provide evidence of the efficacy of imiquimod 5 % cream in the treatment of recalcitrant extragenital warts [22, 23]. Success rates were only somewhere between 37 % and 30 %. Diphenylcyclopropenone An obligate contact allergen, diphenylcyclopropenone (DPCP) is usually employed in the treatment of alopecia areata. Following application (on the nape of the neck) at a concentration of 1 %, it triggers contact dermatitis when applied again after 4 weeks. From 1999 to 2007, five studies on the treatment of chronic extragenital warts were published, which described remission rates between 60 % and 92 % following twice-a-week application [3]. The only side effects were the known local reactions such as erythema and a burning sensation. This response rate was, however, not achieved until a period around six months later. The mechanism of action involved is best described as an immunomodulatory effect caused by a type IV contact allergic response in the viral lesion [24]. Immunomodulators In 2001, intralesional injections of Candida albicans antigen for chronic, nongenital warts were described for the first time [25]. With respect to the use of mumps, candida, and trichophyton antigens in the treatment of chronic warts, there have been three clinical studies showing clearance rates between 60 % and 85 %. Adverse effects included fever and arthralgia. A recent review article by Na et al. described a retrospective two-year study of 136 patients that resulted in complete resolution in 51.5 % of cases [1]. In a study population of 70 adult patients with recalcitrant warts, Nofal et al. reported complete remission in 63 % of cases [26]. Bleomycin and 5-fluorouracil injections There are a few studies on intralesional injections of bleomycin, an agent that inhibits DNA synthesis by preventing thymidine incorporation. In this method, U/ ml of bleomycin is injected into the chronic wart. As the procedure is quite painful, a local anesthetic is also added. Depending on the study, intralesional bleomycin injections achieve clearance rates of %. Overall, Dall'Oglio et al. found six randomized, controlled studies, some of which were also double-blind [3]. The clearance rates using intralesional bleomycin injections averaged 85 % but were only around 20 % superior to the placebo arm. Data obtained with 5-fluorouracil is similar to that reported for bleomycin [3, 5]. Cidofovir, intralesional A nucleoside analogue markedly effective against a wide range of DNA viruses, cidofovir has been approved for cytomegalovirus (CMV)-induced retinitis in HIV patients and is also effective against herpes simplex virus type 1 and 2, Epstein-Barr virus, papillomavirus and others. In 2012, Broganelli et al. published a retrospective analysis of 280 patients who had been treated with intralesional cidofovir over the period from 2003 to 2008 [27]. The maximum daily dose came to 140 mg for each site of infiltration. Two hundred seventy-six cases saw 100 % clearance, with no recurrence observed over a twelve-month period. There are, however, currently no more recent studies on the use of cidofovir. Individual case reports With respect to other experimental therapeutic measures, there are only individual case reports available. One exception could be treatment of plane warts using isotretinoin. In addition to an open-label trial involving 20 patients (1987), there is a recent 2012 study by Al-Hamamy et al. [28]. Patients received a dose of 0.5 mg/kg over a period of two months, with a complete clearance rate on the face of 73 %. Treatment was administered to 31 male and female patients aged between 5 and 35 years. Both the risk of early closure of the epiphyseal plate in younger individuals as well as the known teratogenicity places, in our opinion, limitations on the indication for this form of treatment in routine clinical practice. It has to date not been possible to provide evidence for the clinical benefit of various commonly used mono- and combination preparations made from various inorganic and organic acids such as lactic acid, oxalic acid, acetic acid and copper, chloroacetic acid and the combination of salicylic acid, fluorouracil 0.5 %, and dimethyl sulfoxide (DMSO 8 %) in comparison to placebo or monotherapy with salicylic acid. This likewise applies to the extemporaneous formulation (popular in Germany) of an ointment consisting of anthralin (dithranol) 1 % and salicylic acid 25 %. The flowchart (Figure 1) on the treatment of extragenital warts is based on the randomized clinical studies available, the clearance rates from open clinical studies, and the requirements of efficacy, acceptability, practicability, and clinical experience. Genital warts Until a few years ago, the only treatment of condylomata acuminata consisted of combined or sequential treatment with podophyllotoxin, cryotherapy, and laser ablation. Since then, new pharmacological agents and methods have broadened 896

6 Table 2 HPV types in condylomata acuminata. Low risk Intermediate risk High risk 6, 11, 42, 43, 44, 53, 57, 81, 84 31, 33, 35, 45, 51, 52, 55, 56, 58, 59, 68 the spectrum of therapeutic options. The present review attempts to provide an overview of all treatments for genital warts currently available and to translate the significance/ usefulness of novel treatment options into a therapeutic algorithm. More than 30 subtypes of HPV are able to infect the genital mucosa, with types 6 and 11 found in 90 % of individuals affected (Table 2) [29]. Genital HPV are transmitted through sexual contact, however, in few cases vertical transmission and autoinoculation have also been described. Seventy percent of individuals develop clinically apparent HPV-positive condylomata acuminata within the first three weeks to eight months following contact. As in the case of extragenital warts, % of infections resolve without therapeutic intervention. Depending on the extent and size of condylomata acuminata, topical treatment should first be recommended to patients [29, 30]. Large clusters of condylomata acuminata would constitute an exception to this, as in the case of Buschke-Löwenstein tumor (giant condyloma acuminatum). In such cases, surgical removal, subsequently combined with immunomodulatory agents, ought to be recommended. Topical therapeutic agents 16, 18 Podophyllotoxin: Podophyllotoxin is a substance obtained from the rootstock of the mayapple plant. Its mode of action in the topical treatment of genital warts was first described in Podophyllotoxin not only results in local reactions (erythema, edema, erosions) but may also cause bone marrow suppression, hepatic dysfunction, neurological symptoms, hallucinations, psychoses, epistaxis, and similar symptoms [30]. If applied over a large area, systemic absorption, with subsequent occurrence of the aforementioned adverse effects, is possible. Podophyllotoxin is applied once a week, and shows complete resolution in up to 93 % of cases, with recurrence rates of 22 % [31, 32]. Given the adverse effects associated with podophyllotoxin, it can only be considered an alternative (third-line therapy) [32]. Imiquimod: Five placebo-controlled studies can be found on imiquimod. Unlike podophyllin, imiquimod is not caustic. It is an immunomodulatory substance that induces a large number of cytokines, including from macrophages. One of the most frequently induced cytokines is interferon-alpha. Applied as a cream three times a week for 16 weeks, imiquimod achieves clearance rates between 16 % and 50 %. The most common adverse effects include local erosions, erythema, and a burning sensation. While the recently approved imiquimod 3.75 % cream demonstrates less pronounced local reactions in comparison to the 5 % cream, is also less effective [29, 33, 34]. Sinecatechin/polyphenon E 15 %: Sinecatechin/ polyphenon E 15 % (Veregen ) is obtained from a green tea (Camellia sinensis) extract and has been approved for the treatment of genital warts since It is applied three times a week. Side effects are comparable to those caused by imiquimod 5 %, namely erythema, erosion, edema, burning sensation, pain, and occasionally blistering. Several international, prospective double-blind studies have shown an average clearance rate of 50 % following 16-week treatment [29]. In this context, it should be noted that the rate of spontaneous resolution (placebo vehicle) came to 35.3 %! As in the case of extragenital warts, a study design that excludes patients with new-onset condylomata acuminata would be useful in this respect. Prior to treatment with sinecatechin/polyphenon E 15 %, or with imiquimod and podophyllotoxin, a pregnancy test should be performed if pregnancy is suspected. As a general rule, these topical therapeutic agents should only be used if therapeutic effects might actually outweigh the potential risk to the fetus [34]. Energy-based methods Cryotherapy: Similar to the treatment of extragenital warts, the simplest ablative treatment method is cryotherapy. Appropriate for the treatment of solitary genital warts, cryotherapy induces clearance rates between 80 % and 88 %, depending on the publication consulted. At the same time, there is a high rate of recurrence of %, even after multiple treatments. Cryotherapy is performed every other week over a period of twelve weeks [3, 29, 34, 35]. Electrocautery: Electrosurgical ablation with a wire loop is simple to perform and, according to the studies available, on a par with lasers. The average clearance rate stands at 85 %, the rate of recurrence at % [3, 24, 35, 36]. However, these studies do not take into consideration that large clusters of condylomata acuminata have to be treated multiple times within 2 3 months, and attempts to treat, for example, an area of 30 cm² with hundreds of condylomata acuminata in a single session (using a laser or electrocautery) are usually unsuccessful and lead to recurrence. Such cases either require multiple treatments, or, following clinical resolution, combination therapy, for example, with imiquimod is recommended. CO 2 lasers: CO 2 lasers are easier to handle than electrocautery devices, and cause less bleeding, especially at doses resulting in vaporization. In this indication, CO 2 lasers are best used with a dose of 2 10 Watt. As is the case with extragenital warts, there is no study documenting the 897

7 benefits of CO 2 lasers in comparison to placebo [35]. The only study that can be found in this context is a comparison to electrocautery. As mentioned above, however, there are no significant benefits from the use of a CO 2 laser in comparison to conventional electrocautery. Complete remission rates of 90 % are achieved [29]. Photodynamic therapy Similar to extragenital warts, a number of studies can be found that provided evidence of the positive effects of photodynamic therapy using 5-aminolevulinic acid. Liang et al. published the first larger study in which 91 patients were treated with photodynamic therapy (ALA 20 %) [37], achieving a clearance rate of 100 %. Wang et al. applied ALA 10 % gel to the cervix for four hours and subsequently used a 635 nm laser (100 Joule/cm²) as light source for excitation [38]. The 56 patients treated showed a clearance rate of just under 100 % (98.2 %). Lu et al. performed a total of 3 PDT sessions at two-week intervals; all 40 patients exhibited complete resolution, with a recurrence rate of only 15 % after three months [39]. Although none of these studies was placebo-controlled, but merely prospective, they do suggest interesting approaches that have encouraged us to employ photodynamic therapy, especially in case of recurrent condylomata acuminata in the anal region. As this treatment is very well tolerated and does not lead to bleeding and/or scarring, as is the case with other ablative interventions, it is at the very least a good third-line therapy /alternative (Figure 2). Vaccination Vaccination, especially with the quadrivalent vaccine against HPV 6, 11, 16, and 18 approved in 2006, prevents 90 % of infections with these HPV subtypes. It has also been debated whether vaccination might also have positive effects in patients already infected. Scheinfeld summarizes five studies that provide evidence that vaccination with the vaccines currently approved does not have any positive effects on clearance rates or recurrent-free intervals [35]. By contrast, Abeck et al. recently reported on the positive effects of such vaccination in children [40]. Conclusion The clinical algorithm (Figure 2) for genital warts is less complex than the one for extragenital warts. With respect to the latter, the clinical course of action is characterized to a greater extent by the location affected, as well as the extent and chronicity of the lesions. The two algorithms presented herein are intended to assist experienced clinicians in their therapeutic decisions. Only when evidence-based studies show Figure 2 Therapeutic algorithm II. one of these measures or future methods to be therapeutically significantly superior will it be possible to issue binding recommendations. Correspondence to Prof. Dr. med. Hans Michael Ockenfels Department of Dermatology and Allergology Medical Center Hanau Leimenstraße Hanau, Germany klinik@professor-ockenfels.de References 1 Na Ch, Choi H, Song SH et al. Two-year experience of using the measles, mumps and rubella vaccine as intralesional immunotherapy for warts. Clin Exp Dermatol 2014; 39(5): Park HS, Choi WS. Pulsed dye laser treatment for viral warts: a study of 120 patients. J Dermatol 2008; 35(8): Dall'oglio F, D Amico V, Nasca MR, Micali G. Treatment of cutaneous warts: an evidence-based review. Am J Clin Dermatol 2012; 13(2): Vender R, Bourcier M, Bhatia N, Lynde C. Therapeutic options for external genital warts. J Cutan Med Surg 2013; 17( Suppl 2): S Kwok CS, Gibbs S, Bennett C et al. Topical treatments for cutaneous warts. Cochrane Database Syst Rev 2012; 9: CD Lynch MD, Cliffe J, Morris-Jones R. Management of cutaneous viral warts: an evidence-based review. Am J Clin Dermatol 2012; 13(2):

8 7 Ockenfels HM, Hammes S. Laser in der Therapie der Warzen. Hautarzt 2008: 59: Mulhem E, Pinelis S. Treatment of nongenital cutaneous warts. Am Fam Physician 2011; 84: Berth-Jones J, Hutchinson PE. Modern treatment of warts. Br J Dermatol 1992; 127(3): Kwok CS, Holland R, Gibbs S. Efficacy of topical treatments for cutaneous warts: a meta-analysis and pooled analysis of randomized controlled trials. Br J Dermatol 2011; 165(2): Berth-Jones J, Bourke J, Eglitis H et al. Value of a second freeze thaw cycle in cryotherapy of common warts. Br J Dermatol 1994; 131(6): Schellhaas U, Gerber W, Hammes S, Ockenfels HM. Pulsed dye laser treatment is effective in the treatment of recalcitrant viral warts. Derm Surg 2008: 34: Kauvar AN, McDaniel DH, Geronemus RG. Pulsed dye laser treatment of warts. Arch Fam Med 1995; 4: Sparreboom EE, Luijks HG, Luiting-Welkenhuyzen HA et al. Pulsed-dye laser treatment for recalcitrant viral warts: a retrospective case series of 227 patients. Br J Dermatol 2014; 171(5): Serour F, Somekh E. Successful treatment of recalcitrant warts in pediatric patients with carbon dioxide laser. Eur J Pediatr Surg 2003; 13: Stender IM, Na R, Fogh H et al. Photodynamic therapy with 5-aminolaevulinic acid or placebo for recalcitrant foot and hand warts: randomised double-blind trial. Lancet 2000; 355: Fabbrocini G, Di Costanzo MP, Riccardo AM et al. Photodynamic therapy with topical delta-aminolaevulinic acid for the treatment of plantar warts. J Photochem Photobiol B 2001; 61: Lu YG, Wu JJ, He Y et al. Efficacy of topical aminolevulinic acid photodynamic therapy for the treatment of verruca planae. Photomed Laser Surg 2010; 28: Vogel S, Ruzicka T, Berking C. Subluminescence photodynamic therapy of recalcitrant foot warts. Br J Dermatol 2015; 172(3): Gibbs S, Harvey I. Topical treatments for cutaneous warts. Cochrane Database Syst Rev 2006(3): CD Li Q, Jiao B, Zhou F et al. Comparative study of photodynamic therapy with 5 %, 10 % and 20 % aminolevulinic acid in the treatment of generalized recalcitrant facial verruca plana: a randomized clinical trial. J Eur Acad Dermatol Venereol 2014; 28(12): Ahn CS, Huang WW. Imiquimod in the treatment of cutaneous warts: an evidence-based review. Am J Clin Dermatol 2014; 15: Grussendorf-Conen EI, Jacobs S, Rübben A et al. Topical 5 % imiquimod long-term treatment of cutaneous warts resistant to standard therapy modalities. Dermatol 2002; 205(2): Suh DW, Lew BL, Sim WY. Investigations of the efficacy of diphenylencyclopropenone immunotherapy for the treatment of warts. Int J Dermatol 2014; 53(12): e Johnson SM, Roberson PK, Horn TD. Intralesional injection of mumps or Candida Skin test antigens: a novel immunotherapy for warts. Arch Dermatol 2001; 137(4): Nofal A, Nofal E, Yosef A et al. Treatment of recalcitrant warts with intralesional measles, mumps, an rubella vaccine: a promising approach. Int J Dermatol 2015; 54(6): Broganelli P, Chiaretta A, Fragnelli B, Bernengo MG. Intralesional cidofovir for the treatment of multiple and recalcitrant cutaneous viral warts. Dermatol Ther 2012; 25(5): Al-Hamamy HR, Salman HA, Abdulsattar NA. Treatment of plane warts with a low-dose oral isotretinoin. ISRN Dermatol 2012; 2012: Scheinfeld N, Lehmann DS. An evidence-based review of medical and surgical treatments of genital warts. Dermatol Onl Journ 2006; 12(3): Claesson U, Lassus A, Happonen H et al. Topical treatment of venereal warts: a comparative open study of podophyllotoxin cream versus solution. Int J STD AIDS 1996; 7: Stone KM, Becker TM, Hadqu A, Kraus SJ. Treatment of external genital warts: a randomized clinical trial comparing podophyllin, cryotherapy, and electrodesiccation. Genitourin Med 1990; 66(1): Lacey CJN, Goodall RL, Rangarson Tennvall G et al. Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts. Sex Transm Infect 2003; 79: Wu J, Feldman R, Barry GT et al. Pharmacokinetics of daily self-application of imiquimod 3.75 % cream in adult patients with external anogenital warts. Clin Pharmacol 2012; 52(6): Leszczyszyn J, Lebski I, Lysenko L et al. Anal warts (condylomata acuminate) current issues and treatment modalities. Ady Clin Exp Md 2014; 23(2): Scheinfeld N. Update on the treatment of genital warts. Dermatol Online J 2013; 19(6): Hawkins MG, Winder DM, Ball SL et al. Detection of specific HPV subtypes responsible for the pathogenesis of condylomata acuminata. Virol J 2013; 10: Liang J, Lu XN, Tang H et al. Evaluation of photodynamic therapy using topical aminolevulinic acid hydrochloride in the treatment of condylomata acuminata: a comparative, randomized clinical trial. Photodermatol Photoimmunol Photomed 2009; 25(6): Wang HW, Zhang LL, Miao F et al. Treatment of HPV infection-associated cervical condylomata acuminata with 5-aminolevulinic acid-mediated photodynamic therapy. Photochem Photobiol 2012; 88(3): Lu YG, Yang YD, Wu JJ et al. Treatment of perianal condylomata acuminata with topical ALA-PDT combined with curettage: outcome and safety. Photomed Laser Surg 2012; 30(3): Abeck D, Fölster-Holst R. Quadrivalent human papillomavirus vaccination: A promising treatment for recalcitrant cutaneaous warts in children. Acta Derm Venereol 2015 Mar 31. [Epub ahead of print]. 899