CED
Clinical dermatology • Original article
Clinical and Experimental Dermatology
Topical praziquantel as a new treatment for perioral dermatitis: results of a randomized vehicle-controlled pilot study M. R. Bribeche,1 V. P. Fedotov,1 A. Jillella,1 V. V. Gladichev2 and D. M. Pukhalskaya2 1 Department of Dermatology and Venereology and 2Department of Drug Chemistry and Technologies, Zaporozhye Medical State University, Zaporozhye, Ukraine
doi:10.1111/ced.12342
Summary
Background. Perioral dermatitis (POD) is a common skin disease, and extending the range of treatments available for this condition is important. Aim. To evaluate the safety, efficacy and tolerability of praziquantel 3% ointment as monotherapy. Methods. This was a single-centre, randomized, single-blind, vehicle-controlled pilot study in adult patients (n = 46) with 4 weeks of treatment and 4 weeks of follow-up. Efficacy was assessed clinically using the Investigator’s Global Assessment (IGA) and the Perioral Dermatitis Severity Index (PODSI). Quality of life (QOL) was determined by the Dermatology Quality of Life Index (DLQI). Results. PODSI was significantly lower in the praziquantel group than in the placebo (vehicle) group, both during treatment and period. Mean IGA score showed a statistically significant therapeutic advantage of praziquantel over placebo at week 4 (P < 0.001). The praziquantel group experienced a greater improvement in mean DLQI. No serious treatment-related adverse events occurred in either group. Conclusions. Praziquantel ointment 3% effectively improves POD symptoms and QOL.
Introduction Perioral dermatitis (POD) is commonly described as an acneiform-like eruption, characterized by erythematous papules, papulopustules and papulovesicules. The aetiology and pathogenesis of POD remain unclear but several factors have been suggested as possibly related, including contact allergy, use of topical or systemic corticosteroids, pregnancy, malabsorption and infective agents (Candida, Demodex, Fusobacterium spirilla). Usually, the first step in therapy includes the avoidance of any topical corticosteroids because of their involvement in the pathogenesis of POD,1 and also any cosmetic products. Topical metronidazole and Correspondence: Dr Mohamed Ridha Bribeche, Department of Dermatology and Venereology, Dermatology Clinic of Zaporozhye University Hospital 67 Kirova street, Zaporozhye, 69063, Ukraine E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 6 January 2014
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Clinical and Experimental Dermatology (2014) 39, pp448–453
erythromycin or systemic tetracyclines have been found to be moderately effective.2 Some authors suggest a ‘watch and wait’ approach, which is difficult for many patients. Topical tacrolimus or pimecrolimus have been used in POD, but there are some reports in the literature of occasional granulomatous eruptions occuring after use of these preparations.3–5 Some authors have reported the use of antiacne topicals6,7 and photodynamic therapy with topical 5-aminolevulinic acid,3 but no double-blind controlled trials have been performed using these therapies. Given the currently limited range of therapeutic options for the treatment of POD, extending this range is important. Praziquantel (PZQ) is an anthelmintic isoquinoline cestocide. Oral PZQ has been available for over 60 years, and has a good safety profile.8 PZQ appears to target the inflammatory aspects of POD by mechanisms that may differ from the conventional drugs that have been used to treat this condition. To our knowledge, there have been no prior studies using topical PZQ in POD. The objective of this study was to
ª 2014 British Association of Dermatologists
Praziquantel in the treatment of perioral dermatitis M. R. Bribeche et al.
evaluate the safety, efficacy, and tolerability of PZQ 3% ointment as monotherapy in the treatment of POD.
Methods This was a single-centre, randomized, single-blind, vehicle-controlled pilot study, which took place in the dermatology clinic of Zaporozhye University Hospital between November 2012 and August 2013. The study protocol was approved by the institutional research commission and received ethical clearance. Enrolled patients were counselled that the 3% PZQ treatment was ‘off label’ and that adverse effects could occur. All subjects gave informed consent before any investigational procedure. The product under study was delivered in the form of an ointment containing 3% PZQ and a preservative consisting of polyethylene glycol-400, poloxamer-268 and propylene glycol. The PZQ ointment was prepared by the fusion method. No specific toxicological analyses were performed on the ointment, as oral PZQ has been given the status of a category B medication by the US Food and Drugs Administration. Adults aged 18 years and older with a diagnosis of POD and having a score of ≥ 4 on the POD Severity Index (PODSI) were eligible for the study. Exclusion criteria included use of systemic antibiotics within
4 weeks prior to and during the baseline study (except for tetracyclines, which were allowed until 2 weeks prior to the baseline study); use of any topical drug within 2 weeks prior to and during the baseline study; use of systemic or topical corticosteroids within 4 weeks prior to and during the study; and use of cytochrome P450 inducers during the study. The following medications were also prohibited: concomitant administration of cytochrome P450 inducers; use of tetracycline family antibiotics at any dose; and use of any POD, acne or rosacea treatments during the course of the study. The final study population consisted of 46 subjects (41 women and 5 men; mean SD age 33.4 5.1 years; range 24–39). Diagnosis and severity of POD was confirmed by the same dermatologist ‘M R Bribeche’ throughout the study. The participants were randomly assigned to one of two groups at a ratio of 1 : 1 (n = 23 in each group). The assignment was carried out in a single-blind manner for safety reasons, with the subjects, but not the investigators, blinded to the treatment allocation. Group 1 received topical 3% PZQ ointment and group 2 (placebo group) received the vehicle ointment without PZQ included. Both ointments were to be applied twice daily as monotherapy for 4 weeks, with participants followed up at weeks 1, 2, 3, 4 and 8. The study flow diagram is shown in Fig. 1. The intent-to-treat population (ITT) Enrolled (n = 46) Randomized (n = 46)
Praziquantel ointment 3% (n = 23)
Vehicle ointment (n = 23)
Received intervention (n = 23)
Received intervention (n = 23)
Discontinued intervention (n = 1) Adverse event (n = 0) Lost to follow up (n = 0) Non compliance (n = 1) Withdrawal by subject (n = 0)
Discontinued intervention (n = 2)
Analysed ITT population (n = 23) PP population (n = 22) Reasons for exclusion from PP population* *Missed > 12 total or 6 consecutive applications of study product (n = 0) *Prohibited medications (n = 1)
Adverse event (n = 0) Lost to follow up (n = 1) Non compliance (n = 1) Withdrawal by subject (n = 0)
Analysed ITT population (n = 23) PP population (n = 21) Reasons for exclusion from PP population* *Missed > 12 total or 6 consecutive applications of study product (n = 1) *Prohibited medications (n = 1)
Figure 1 Study flow diagram.
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Clinical and Experimental Dermatology (2014) 39, pp448–453
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Praziquantel in the treatment of perioral dermatitis M. R. Bribeche et al.
and the safety population included all subjects who were randomized and received the study product. The per-protocol (PP) population excluded subjects from the ITT population who missed > 12 applications in total or > 6 consecutive applications of study, product during the study or who were excluded for major protocol violations. Assessment of quality of life and product safety
The Dermatology Quality of Life Index (DLQI) is widely accepted method of assessing a patient’s QOL,9 which scores on a scale from 0 (no effect on QOL) to 30 (worst effect on QOL). The participants were asked to complete the DLQI questionnaire at each visit, starting from baseline to week 8. For safety assessment, adverse events (AE), local signs (adverse reactions such as facial oiliness, peeling, dryness, and erythema) or any worsening of symptoms from baseline study visit, were monitored throughout the study (graded by the investigator using a fourpoint intensity scale, where 0 = none, 1 = mild, 2 = moderate and 3 = severe). Outcome assessment
The primary end result was improvement in PODSI over the 4 weeks of the trial, starting from baseline. The PODSI included three symptoms (erythema, papules and scaling) to differentiate forms of the disease. During the trial, evaluation of PODSI was performed only on skin lesions untreated for at least 6 h. A PODSI of 0.5–2.5 was interpreted as mild, 3–5.5 as moderate and 6–9 as severe.10 The secondary end point was the proportion of subjects with an improvement from the baseline score of > 2 on the Investigator’s Global Assessment (IGA; a five-point scale, where 0 = clear, 1 = minimal, 2 = mild, 3 = moderate and 4 = severe) and those achieving a reduction of at least 50% from baseline PODSI. Tertiary end points included mean change from baseline in the DLQI at weeks 2, 4 and 8. Statistical analyses
This study was not powered. Continuous categorical effectiveness variables were summarized by mean, median, standard deviation, number and range (minimum to maximum). Baseline IGA, PODSI and DLQI were compared respectively with subsequent IGA, PODSI and DLQI using the Cochran–Mantel–Haenszel (CMH) test. Significance for all hypotheses testing was a = 0.01.
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Clinical and Experimental Dermatology (2014) 39, pp448–453
Results In total, 46 patients were enrolled and dispensed with the PZQ ointment (n = 23) and the placebo ointment (n = 23). The ITT population consisted of all 46 subjects. At the screening visit, six of the enrolled subjects were taking prohibited medications, and thus failed to meet all the inclusion criteria. These subjects underwent a 2-week washout period for the prohibited medication before inclusion in the ITT population. All 46 patients completed the 8-week trial. One patient from each group was disqualified because of non-compliance, and one patient from the placebo group was disqualified because they were lost to follow-up. The PP population therefore consisted of 22 participants from the PZQ and 21 participants from the placebo group. Baseline characteristics including PODSI, IGA, and DLQI scores did not differ significantly between the two groups (Table 1), so we inferred that the treatment groups were well balanced with respect to baseline characteristics. Patients in the PZQ group experienced a continuous decline in mean PODSI all through the 4 weeks of treatment, from 5.4 at baseline to 2.1 at week 4, whereas in the placebo group, this decrease was slower and less marked, reducing from 5.3 at baseline to 2.6 at week 4 (Fig. 2). Decrease in PODSI change from baseline to week 4 was greater in the PZQ group ( 3.2) than the placebo group ( 2.6%) (Fig. 2). Table 1 Patient demographics and baseline characteristics.
Sex (%) Female Male Age, years Mean SD Range IGA score (%) 0 = Clear 1 = Minimal 2 = Mild 3 = Moderate 4 = Severe PODSI Mean Range DLQI Mean Range
PZQ ointment as monotherapy (n = 23)
Vehicle ointment as monotherapy (n = 23)
20 (86.4) 3 (13.6)
21 (91.3) 2 (8.7)
37.9 9.4 19–58
38.6 10.2 18–61
0 (0.0) 2 (8.7) 2 (8.7) 10 (43.5) 9 (39.1)
0 (0.0) 3 (13.1) 1 (4.3) 11 (47.8) 8 (34.8)
5.4 1.3 4–9
5.3 1.2 4–8.5
10.6 4–18
11.4 4–19
DLQI, dermatology life quality index; IGA, investigator’s global assessement; PODSI, perioral dermatitis severity index; SD, standard deviation.
ª 2014 British Association of Dermatologists
Praziquantel in the treatment of perioral dermatitis M. R. Bribeche et al.
visit at week 8 showed an insignificant change in mean PODSI from week 4;1.1 at week 8 in the PZQ ointment group and 1.2 in the placebo group (P > 0.01). At baseline, approximately 82% of all patients in both treatment groups were classified as having a moderate or severe POD on the IGA static score (no patients were rated clear and < 11% were rated as minimal). At week 4, an IGA rating of clear or minimal was achieved in a significantly greater proportion of patients in the PZQ group (82%) compared with the placebo group (43%) (P < 0.001) (Table 3). In the placebo group, the decrease in IGA was slower; IGA ranged from 3.2 at baseline in both groups and at week 4 was 2.1 in the placebo group and 1.7 in the PZQ group (Fig. 2). Clinical improvement over time was apparent in the facial photographs of patients in the PZQ group (Fig. 3a–c, Fig. 4a–c). These images are representative of the treatment group as a whole.
3.5 3
IGA score
2.5 2 1.5 1 PZQ ointment
0.5
Vehicle
0 1
2
3
4
Weeks 6 5
PODSI
4 Table 3 Patient IGA and DLQI scores at week 4 (per protocol population).
3
PZQ ointment group at Week 4 (n = 22)
2 1
PZQ ointment Vehicle
0 1
2
3
4
Weeks Figure 2 Mean Investigator’s Global Assessment (IGA) rating
and Perioral Dermatitis Severity Index (PODSI) from baseline to week 4.
During the study, a reduction of at least 50% from the baseline PODSI was achieved for 10 of 22 subjects (45.4%) in the PZQ group at week 1, compared with only 2 of 21 (9.5%) in the placebo group (P < 0.001). At week 4, 16 of 22 (72.7%) in the PZQ group and 11 of 21 (52.3%) in the placebo group (P < 0.001) achieved this reduction (Table 2). The final follow-up Table 2 Patients attending at least 50% of reduction in the Perioral Dermatitis Severity Index (PODSI) during the treatment period (per protocol population). Reduction of PODSI 50% Week Week Week Week
1 2 3 4
PZQ ointment (n = 22) (%) 10 13 15 16
(45.4) (59.1) (68.2) (72.7)
ª 2014 British Association of Dermatologists
Vehicle (n = 21) (%) 2 5 9 11
(9.5) (23.8) (42.8) (52.3)
IGA score (%) 0 = Clear 1 = Minimal 2 = Mild 3 = Moderate 4 = Severe DLQI mean
10 (45.4) 8 (36.4) 4 (18.2) 0 0 3.4
Vehicle ointment group at Week 4 (n = 21)
2 7 10 2 0 4.9
(9.5) (33.3) (47.7) (9.5)
Mean baseline DLQI was 15.8 and 14.6 respectively in the PZQ and placebo groups, and at the end of study was 3.4 for the PZQ group and 4.9 for the placebo group. Patients in the PZQ group experienced statistically significant improvement (P < 0.001) in comparison with the placebo group at week 8. Overall, patients experienced similar rates of AEs in both treatment groups (n = 1 in each group). The reported AEs consisted of trace dryness of mild intensity, which resolved after administration of a moisturizer, and did not result in treatment discontinuation.
Discussion This study is the first to assess the clinical outcome of patients using topical PZQ for treatment of POD. This pilot study shows PZQ to be effective in the treatment of POD, as demonstrated by the significantly greater success with PZQ compared with placebo, based
Clinical and Experimental Dermatology (2014) 39, pp448–453
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Praziquantel in the treatment of perioral dermatitis M. R. Bribeche et al.
(a)
(b)
(c)
Figure 3 (a–c) Female patient treated with topical praziquantel: (a) at baseline; (b) after 1 week of treatment (c) complete clearance of the lesions after 2 weeks of treatments.
(a)
(b)
(c)
Figure 4 (a–c) Male patient treated with topical praziquantel: (a) at baseline; (b) after 1 week of treatment (c) complete clearance of the lesions after 2 weeks of treatments.
on reduction in IGA, PODSI and mean DLQI at the end of treatment. Compared with the placebo group, a significantly greater number of patients treated with PZQ had minimal or no POD on completion of treatment. However, patients in the placebo group also showed a significant symptomatic improvement in POD, although this occurred only after week 5, which is in accordance with the ‘zero therapy’ recommended by some dermatologists. Treating individuals with PZQ leads to a decrease in the protein CH3L1 (chitinase 3-like 1;11 also called YKL-
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Clinical and Experimental Dermatology (2014) 39, pp448–453
40) which is secreted mainly by inflammatory cells. Furthermore, increased serum levels of YKL-40 have been reported in conditions with inflammation and/or tissue remodelling, such as psoriasis, rheumatoid arthritis, Crohn disease and cancers.12,13 Thus, as POD is considered a chronic inflammatory condition and taking into consideration the therapeutic effect obtained with PZQ in this study, we suggest a didactic hypothesis to explain the mechanism behind the observed effectiveness of topical PZQ. We suggest that the inflammatory biomarker
ª 2014 British Association of Dermatologists
Praziquantel in the treatment of perioral dermatitis M. R. Bribeche et al.
YKL-40 might be associated with POD, and that a potential mechanism of action of PZQ in POD could be related to an anti-inflammatory effect of this biomarker. This new treatment affords the opportunity to target the inflammatory aspects of POD by mechanisms that may differ from those of conventional POD treatment drugs. Clinical improvement during the study of the PZQ-treated patients hints at a possible anti-parasitic property of this antihelmintic drug targeting the mite Demodex folliculorum, which is implicated in the pathogenesis of POD. We therefore postulate that the mechanism of action of topical PZQ in suppressing POD is based on its potential anti-parasitic and anti-inflammatory properties. Future studies will be required and might confirm our deductions. Tolerability of PZQ was good throughout the trial period, and no patient discontinued treatment because of AEs or lack of efficacy.
Conclusion PZQ ointment was effective in treating POD, with a good safety profile. Based on our results, 3% PZQ ointment appears to be a promising therapeutic agent for improving symptoms of POD. Future studies with much larger sample size are required to confirm our findings.
What’s already known about this topic? • Perioral dermatitis is a common skin condition
and the number of patients with this dermatitis appears to be increasing.
What does this study add? • Topical praziquantel enlarges the armamentar-
References 1 Hafeez ZH. Perioral dermatitis: an update. Int J Dermatol 2003; 42: 514–17. 2 Veien NK, Munkvad JM, Nielsen AO et al. Topical metronidazole in the treatment of perioral dermatitis. J Am Acad Dermatol 1991; 24: 258–60. 3 Chamlin SL, Lawley LP. Perioral dermatitis. In: Fitzpatrick’s Dermatology in General Medicine, 7th edn (Wolff K, Goldsmith LA, Katz SI et al.eds). New York: McGraw Hill Medical, 2008; 709–12. 4 Antile C, Wolff K, Goldsmith LA, Katz SI et al. Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. Arch Dermatol 2004; 140:457–60. 5 Goldman D. Tacrolimus ointment for the treatment of steroid induced rosacea: a preliminary report. J Am Acad Dermatol 2001; 44: 995–8. 6 Jansen T. Azelaic acid as a new treatment of perioral dermatitis: results from an open study. Br J Dermatol 2004; 151: 933–4. 7 Jansen T. Perioral dermatitis successfully treated with topical adapalene. J Eur Acad Dermatol Venereol 2002; 16: 175–7. 8 Utzinger J, Keiser J. Schistosomiasis and soil-transmitted helminthiasis: common drugs for treatment and control. Expert Opin Pharmacother 2004; 5: 263–85. 9 Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)—a simple practical measure for clinical routine use. Clin Exp Dermatol 1994; 19: 210–16. 10 Wollenberg A, Oppel T. Scoring of the skin lesions with the perioral dermatitis severity index (PODSI). Acta Derm Venereol 2006; 86: 251–2. 11 Appleby LJ, Nausch N, Bourke CD,et al. Chitinase 3-like 1 protein levels are elevated in Schistosoma haematobium infected children. PLoS Negl Trop Dis 2012; 6: e1898 12 Rathcke CN, Johansen JS, Vestergaard H. YKL-40, a biomarker of inflammation, is elevated in patients with type 2 diabetes and is related to insulin resistance. Inflamm Res 2006; 55: 53–9. 13 Imay I, Tsuda T, Aochi S, et al. YKL-40 (chitinase 3-like-1) as a biomarker for psoriasis vulgaris and pustular psoriasis. J Dermatol Sci 2011; 64: 75–7.
ium against perioral dermatitis. • Topical 3% praziquantel ointment specfically
targets the inflammatory aspects of perioral dermatitis by mechanisms that may differ from those of conventional drugs.
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Clinical and Experimental Dermatology (2014) 39, pp448–453
453
Clinical dermatology • Original article
Clinical and Experimental Dermatology
Topical praziquantel as a new treatment for perioral dermatitis: results of a randomized vehicle-controlled pilot study M. R. Bribeche,1 V. P. Fedotov,1 A. Jillella,1 V. V. Gladichev2 and D. M. Pukhalskaya2 1 Department of Dermatology and Venereology and 2Department of Drug Chemistry and Technologies, Zaporozhye Medical State University, Zaporozhye, Ukraine
doi:10.1111/ced.12342
Summary
Background. Perioral dermatitis (POD) is a common skin disease, and extending the range of treatments available for this condition is important. Aim. To evaluate the safety, efficacy and tolerability of praziquantel 3% ointment as monotherapy. Methods. This was a single-centre, randomized, single-blind, vehicle-controlled pilot study in adult patients (n = 46) with 4 weeks of treatment and 4 weeks of follow-up. Efficacy was assessed clinically using the Investigator’s Global Assessment (IGA) and the Perioral Dermatitis Severity Index (PODSI). Quality of life (QOL) was determined by the Dermatology Quality of Life Index (DLQI). Results. PODSI was significantly lower in the praziquantel group than in the placebo (vehicle) group, both during treatment and period. Mean IGA score showed a statistically significant therapeutic advantage of praziquantel over placebo at week 4 (P < 0.001). The praziquantel group experienced a greater improvement in mean DLQI. No serious treatment-related adverse events occurred in either group. Conclusions. Praziquantel ointment 3% effectively improves POD symptoms and QOL.
Introduction Perioral dermatitis (POD) is commonly described as an acneiform-like eruption, characterized by erythematous papules, papulopustules and papulovesicules. The aetiology and pathogenesis of POD remain unclear but several factors have been suggested as possibly related, including contact allergy, use of topical or systemic corticosteroids, pregnancy, malabsorption and infective agents (Candida, Demodex, Fusobacterium spirilla). Usually, the first step in therapy includes the avoidance of any topical corticosteroids because of their involvement in the pathogenesis of POD,1 and also any cosmetic products. Topical metronidazole and Correspondence: Dr Mohamed Ridha Bribeche, Department of Dermatology and Venereology, Dermatology Clinic of Zaporozhye University Hospital 67 Kirova street, Zaporozhye, 69063, Ukraine E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 6 January 2014
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Clinical and Experimental Dermatology (2014) 39, pp448–453
erythromycin or systemic tetracyclines have been found to be moderately effective.2 Some authors suggest a ‘watch and wait’ approach, which is difficult for many patients. Topical tacrolimus or pimecrolimus have been used in POD, but there are some reports in the literature of occasional granulomatous eruptions occuring after use of these preparations.3–5 Some authors have reported the use of antiacne topicals6,7 and photodynamic therapy with topical 5-aminolevulinic acid,3 but no double-blind controlled trials have been performed using these therapies. Given the currently limited range of therapeutic options for the treatment of POD, extending this range is important. Praziquantel (PZQ) is an anthelmintic isoquinoline cestocide. Oral PZQ has been available for over 60 years, and has a good safety profile.8 PZQ appears to target the inflammatory aspects of POD by mechanisms that may differ from the conventional drugs that have been used to treat this condition. To our knowledge, there have been no prior studies using topical PZQ in POD. The objective of this study was to
ª 2014 British Association of Dermatologists
Praziquantel in the treatment of perioral dermatitis M. R. Bribeche et al.
evaluate the safety, efficacy, and tolerability of PZQ 3% ointment as monotherapy in the treatment of POD.
Methods This was a single-centre, randomized, single-blind, vehicle-controlled pilot study, which took place in the dermatology clinic of Zaporozhye University Hospital between November 2012 and August 2013. The study protocol was approved by the institutional research commission and received ethical clearance. Enrolled patients were counselled that the 3% PZQ treatment was ‘off label’ and that adverse effects could occur. All subjects gave informed consent before any investigational procedure. The product under study was delivered in the form of an ointment containing 3% PZQ and a preservative consisting of polyethylene glycol-400, poloxamer-268 and propylene glycol. The PZQ ointment was prepared by the fusion method. No specific toxicological analyses were performed on the ointment, as oral PZQ has been given the status of a category B medication by the US Food and Drugs Administration. Adults aged 18 years and older with a diagnosis of POD and having a score of ≥ 4 on the POD Severity Index (PODSI) were eligible for the study. Exclusion criteria included use of systemic antibiotics within
4 weeks prior to and during the baseline study (except for tetracyclines, which were allowed until 2 weeks prior to the baseline study); use of any topical drug within 2 weeks prior to and during the baseline study; use of systemic or topical corticosteroids within 4 weeks prior to and during the study; and use of cytochrome P450 inducers during the study. The following medications were also prohibited: concomitant administration of cytochrome P450 inducers; use of tetracycline family antibiotics at any dose; and use of any POD, acne or rosacea treatments during the course of the study. The final study population consisted of 46 subjects (41 women and 5 men; mean SD age 33.4 5.1 years; range 24–39). Diagnosis and severity of POD was confirmed by the same dermatologist ‘M R Bribeche’ throughout the study. The participants were randomly assigned to one of two groups at a ratio of 1 : 1 (n = 23 in each group). The assignment was carried out in a single-blind manner for safety reasons, with the subjects, but not the investigators, blinded to the treatment allocation. Group 1 received topical 3% PZQ ointment and group 2 (placebo group) received the vehicle ointment without PZQ included. Both ointments were to be applied twice daily as monotherapy for 4 weeks, with participants followed up at weeks 1, 2, 3, 4 and 8. The study flow diagram is shown in Fig. 1. The intent-to-treat population (ITT) Enrolled (n = 46) Randomized (n = 46)
Praziquantel ointment 3% (n = 23)
Vehicle ointment (n = 23)
Received intervention (n = 23)
Received intervention (n = 23)
Discontinued intervention (n = 1) Adverse event (n = 0) Lost to follow up (n = 0) Non compliance (n = 1) Withdrawal by subject (n = 0)
Discontinued intervention (n = 2)
Analysed ITT population (n = 23) PP population (n = 22) Reasons for exclusion from PP population* *Missed > 12 total or 6 consecutive applications of study product (n = 0) *Prohibited medications (n = 1)
Adverse event (n = 0) Lost to follow up (n = 1) Non compliance (n = 1) Withdrawal by subject (n = 0)
Analysed ITT population (n = 23) PP population (n = 21) Reasons for exclusion from PP population* *Missed > 12 total or 6 consecutive applications of study product (n = 1) *Prohibited medications (n = 1)
Figure 1 Study flow diagram.
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Clinical and Experimental Dermatology (2014) 39, pp448–453
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Praziquantel in the treatment of perioral dermatitis M. R. Bribeche et al.
and the safety population included all subjects who were randomized and received the study product. The per-protocol (PP) population excluded subjects from the ITT population who missed > 12 applications in total or > 6 consecutive applications of study, product during the study or who were excluded for major protocol violations. Assessment of quality of life and product safety
The Dermatology Quality of Life Index (DLQI) is widely accepted method of assessing a patient’s QOL,9 which scores on a scale from 0 (no effect on QOL) to 30 (worst effect on QOL). The participants were asked to complete the DLQI questionnaire at each visit, starting from baseline to week 8. For safety assessment, adverse events (AE), local signs (adverse reactions such as facial oiliness, peeling, dryness, and erythema) or any worsening of symptoms from baseline study visit, were monitored throughout the study (graded by the investigator using a fourpoint intensity scale, where 0 = none, 1 = mild, 2 = moderate and 3 = severe). Outcome assessment
The primary end result was improvement in PODSI over the 4 weeks of the trial, starting from baseline. The PODSI included three symptoms (erythema, papules and scaling) to differentiate forms of the disease. During the trial, evaluation of PODSI was performed only on skin lesions untreated for at least 6 h. A PODSI of 0.5–2.5 was interpreted as mild, 3–5.5 as moderate and 6–9 as severe.10 The secondary end point was the proportion of subjects with an improvement from the baseline score of > 2 on the Investigator’s Global Assessment (IGA; a five-point scale, where 0 = clear, 1 = minimal, 2 = mild, 3 = moderate and 4 = severe) and those achieving a reduction of at least 50% from baseline PODSI. Tertiary end points included mean change from baseline in the DLQI at weeks 2, 4 and 8. Statistical analyses
This study was not powered. Continuous categorical effectiveness variables were summarized by mean, median, standard deviation, number and range (minimum to maximum). Baseline IGA, PODSI and DLQI were compared respectively with subsequent IGA, PODSI and DLQI using the Cochran–Mantel–Haenszel (CMH) test. Significance for all hypotheses testing was a = 0.01.
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Clinical and Experimental Dermatology (2014) 39, pp448–453
Results In total, 46 patients were enrolled and dispensed with the PZQ ointment (n = 23) and the placebo ointment (n = 23). The ITT population consisted of all 46 subjects. At the screening visit, six of the enrolled subjects were taking prohibited medications, and thus failed to meet all the inclusion criteria. These subjects underwent a 2-week washout period for the prohibited medication before inclusion in the ITT population. All 46 patients completed the 8-week trial. One patient from each group was disqualified because of non-compliance, and one patient from the placebo group was disqualified because they were lost to follow-up. The PP population therefore consisted of 22 participants from the PZQ and 21 participants from the placebo group. Baseline characteristics including PODSI, IGA, and DLQI scores did not differ significantly between the two groups (Table 1), so we inferred that the treatment groups were well balanced with respect to baseline characteristics. Patients in the PZQ group experienced a continuous decline in mean PODSI all through the 4 weeks of treatment, from 5.4 at baseline to 2.1 at week 4, whereas in the placebo group, this decrease was slower and less marked, reducing from 5.3 at baseline to 2.6 at week 4 (Fig. 2). Decrease in PODSI change from baseline to week 4 was greater in the PZQ group ( 3.2) than the placebo group ( 2.6%) (Fig. 2). Table 1 Patient demographics and baseline characteristics.
Sex (%) Female Male Age, years Mean SD Range IGA score (%) 0 = Clear 1 = Minimal 2 = Mild 3 = Moderate 4 = Severe PODSI Mean Range DLQI Mean Range
PZQ ointment as monotherapy (n = 23)
Vehicle ointment as monotherapy (n = 23)
20 (86.4) 3 (13.6)
21 (91.3) 2 (8.7)
37.9 9.4 19–58
38.6 10.2 18–61
0 (0.0) 2 (8.7) 2 (8.7) 10 (43.5) 9 (39.1)
0 (0.0) 3 (13.1) 1 (4.3) 11 (47.8) 8 (34.8)
5.4 1.3 4–9
5.3 1.2 4–8.5
10.6 4–18
11.4 4–19
DLQI, dermatology life quality index; IGA, investigator’s global assessement; PODSI, perioral dermatitis severity index; SD, standard deviation.
ª 2014 British Association of Dermatologists
Praziquantel in the treatment of perioral dermatitis M. R. Bribeche et al.
visit at week 8 showed an insignificant change in mean PODSI from week 4;1.1 at week 8 in the PZQ ointment group and 1.2 in the placebo group (P > 0.01). At baseline, approximately 82% of all patients in both treatment groups were classified as having a moderate or severe POD on the IGA static score (no patients were rated clear and < 11% were rated as minimal). At week 4, an IGA rating of clear or minimal was achieved in a significantly greater proportion of patients in the PZQ group (82%) compared with the placebo group (43%) (P < 0.001) (Table 3). In the placebo group, the decrease in IGA was slower; IGA ranged from 3.2 at baseline in both groups and at week 4 was 2.1 in the placebo group and 1.7 in the PZQ group (Fig. 2). Clinical improvement over time was apparent in the facial photographs of patients in the PZQ group (Fig. 3a–c, Fig. 4a–c). These images are representative of the treatment group as a whole.
3.5 3
IGA score
2.5 2 1.5 1 PZQ ointment
0.5
Vehicle
0 1
2
3
4
Weeks 6 5
PODSI
4 Table 3 Patient IGA and DLQI scores at week 4 (per protocol population).
3
PZQ ointment group at Week 4 (n = 22)
2 1
PZQ ointment Vehicle
0 1
2
3
4
Weeks Figure 2 Mean Investigator’s Global Assessment (IGA) rating
and Perioral Dermatitis Severity Index (PODSI) from baseline to week 4.
During the study, a reduction of at least 50% from the baseline PODSI was achieved for 10 of 22 subjects (45.4%) in the PZQ group at week 1, compared with only 2 of 21 (9.5%) in the placebo group (P < 0.001). At week 4, 16 of 22 (72.7%) in the PZQ group and 11 of 21 (52.3%) in the placebo group (P < 0.001) achieved this reduction (Table 2). The final follow-up Table 2 Patients attending at least 50% of reduction in the Perioral Dermatitis Severity Index (PODSI) during the treatment period (per protocol population). Reduction of PODSI 50% Week Week Week Week
1 2 3 4
PZQ ointment (n = 22) (%) 10 13 15 16
(45.4) (59.1) (68.2) (72.7)
ª 2014 British Association of Dermatologists
Vehicle (n = 21) (%) 2 5 9 11
(9.5) (23.8) (42.8) (52.3)
IGA score (%) 0 = Clear 1 = Minimal 2 = Mild 3 = Moderate 4 = Severe DLQI mean
10 (45.4) 8 (36.4) 4 (18.2) 0 0 3.4
Vehicle ointment group at Week 4 (n = 21)
2 7 10 2 0 4.9
(9.5) (33.3) (47.7) (9.5)
Mean baseline DLQI was 15.8 and 14.6 respectively in the PZQ and placebo groups, and at the end of study was 3.4 for the PZQ group and 4.9 for the placebo group. Patients in the PZQ group experienced statistically significant improvement (P < 0.001) in comparison with the placebo group at week 8. Overall, patients experienced similar rates of AEs in both treatment groups (n = 1 in each group). The reported AEs consisted of trace dryness of mild intensity, which resolved after administration of a moisturizer, and did not result in treatment discontinuation.
Discussion This study is the first to assess the clinical outcome of patients using topical PZQ for treatment of POD. This pilot study shows PZQ to be effective in the treatment of POD, as demonstrated by the significantly greater success with PZQ compared with placebo, based
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(a)
(b)
(c)
Figure 3 (a–c) Female patient treated with topical praziquantel: (a) at baseline; (b) after 1 week of treatment (c) complete clearance of the lesions after 2 weeks of treatments.
(a)
(b)
(c)
Figure 4 (a–c) Male patient treated with topical praziquantel: (a) at baseline; (b) after 1 week of treatment (c) complete clearance of the lesions after 2 weeks of treatments.
on reduction in IGA, PODSI and mean DLQI at the end of treatment. Compared with the placebo group, a significantly greater number of patients treated with PZQ had minimal or no POD on completion of treatment. However, patients in the placebo group also showed a significant symptomatic improvement in POD, although this occurred only after week 5, which is in accordance with the ‘zero therapy’ recommended by some dermatologists. Treating individuals with PZQ leads to a decrease in the protein CH3L1 (chitinase 3-like 1;11 also called YKL-
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40) which is secreted mainly by inflammatory cells. Furthermore, increased serum levels of YKL-40 have been reported in conditions with inflammation and/or tissue remodelling, such as psoriasis, rheumatoid arthritis, Crohn disease and cancers.12,13 Thus, as POD is considered a chronic inflammatory condition and taking into consideration the therapeutic effect obtained with PZQ in this study, we suggest a didactic hypothesis to explain the mechanism behind the observed effectiveness of topical PZQ. We suggest that the inflammatory biomarker
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Praziquantel in the treatment of perioral dermatitis M. R. Bribeche et al.
YKL-40 might be associated with POD, and that a potential mechanism of action of PZQ in POD could be related to an anti-inflammatory effect of this biomarker. This new treatment affords the opportunity to target the inflammatory aspects of POD by mechanisms that may differ from those of conventional POD treatment drugs. Clinical improvement during the study of the PZQ-treated patients hints at a possible anti-parasitic property of this antihelmintic drug targeting the mite Demodex folliculorum, which is implicated in the pathogenesis of POD. We therefore postulate that the mechanism of action of topical PZQ in suppressing POD is based on its potential anti-parasitic and anti-inflammatory properties. Future studies will be required and might confirm our deductions. Tolerability of PZQ was good throughout the trial period, and no patient discontinued treatment because of AEs or lack of efficacy.
Conclusion PZQ ointment was effective in treating POD, with a good safety profile. Based on our results, 3% PZQ ointment appears to be a promising therapeutic agent for improving symptoms of POD. Future studies with much larger sample size are required to confirm our findings.
What’s already known about this topic? • Perioral dermatitis is a common skin condition
and the number of patients with this dermatitis appears to be increasing.
What does this study add? • Topical praziquantel enlarges the armamentar-
References 1 Hafeez ZH. Perioral dermatitis: an update. Int J Dermatol 2003; 42: 514–17. 2 Veien NK, Munkvad JM, Nielsen AO et al. Topical metronidazole in the treatment of perioral dermatitis. J Am Acad Dermatol 1991; 24: 258–60. 3 Chamlin SL, Lawley LP. Perioral dermatitis. In: Fitzpatrick’s Dermatology in General Medicine, 7th edn (Wolff K, Goldsmith LA, Katz SI et al.eds). New York: McGraw Hill Medical, 2008; 709–12. 4 Antile C, Wolff K, Goldsmith LA, Katz SI et al. Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. Arch Dermatol 2004; 140:457–60. 5 Goldman D. Tacrolimus ointment for the treatment of steroid induced rosacea: a preliminary report. J Am Acad Dermatol 2001; 44: 995–8. 6 Jansen T. Azelaic acid as a new treatment of perioral dermatitis: results from an open study. Br J Dermatol 2004; 151: 933–4. 7 Jansen T. Perioral dermatitis successfully treated with topical adapalene. J Eur Acad Dermatol Venereol 2002; 16: 175–7. 8 Utzinger J, Keiser J. Schistosomiasis and soil-transmitted helminthiasis: common drugs for treatment and control. Expert Opin Pharmacother 2004; 5: 263–85. 9 Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)—a simple practical measure for clinical routine use. Clin Exp Dermatol 1994; 19: 210–16. 10 Wollenberg A, Oppel T. Scoring of the skin lesions with the perioral dermatitis severity index (PODSI). Acta Derm Venereol 2006; 86: 251–2. 11 Appleby LJ, Nausch N, Bourke CD,et al. Chitinase 3-like 1 protein levels are elevated in Schistosoma haematobium infected children. PLoS Negl Trop Dis 2012; 6: e1898 12 Rathcke CN, Johansen JS, Vestergaard H. YKL-40, a biomarker of inflammation, is elevated in patients with type 2 diabetes and is related to insulin resistance. Inflamm Res 2006; 55: 53–9. 13 Imay I, Tsuda T, Aochi S, et al. YKL-40 (chitinase 3-like-1) as a biomarker for psoriasis vulgaris and pustular psoriasis. J Dermatol Sci 2011; 64: 75–7.
ium against perioral dermatitis. • Topical 3% praziquantel ointment specfically
targets the inflammatory aspects of perioral dermatitis by mechanisms that may differ from those of conventional drugs.
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