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Treatment of palmoplantar pustulosis with arotinoid ethylester

European Journal of Dermatology. Volume 19, Number 5, 474-7, September-October 2009, Therapy

DOI : 10.1684/ejd.2009.0727

Summary

Author(s) : Shi-Jun Shan , Yuan-Hong Li , Guowei Zhang, Ting Xiao, Changping Li, Huachen Wei, Hong-Duo Chen , Department of Dermatology, No.1 Hospital of China Medical University, 155 North Nanjing Street, Shenyang 110001, China, Department of Dermatology, Xinqiao Hospital of No.3 Military Medical University, Chongqing, China, Consulting Center of Biomedical Statistics, Academy of Military Medical Sciences, Beijing, China, Department of Dermatology, Dermatology Research Laboratories, The Mount Sinai Medical Center, New York, New York.

Summary : Palmoplantar pustulosis (PPP) is a chronic recurring and refractory pustular dermatosis. To investigate the efficacy and safety of arotinoid ethylester in patients with PPP, sixteen adult subjects with PPP, who had taken no systemic medications for three months, were enrolled. All the subjects received 0.03 mg of arotinoid ethylester once daily as initial dosage. The number of pustules and lesion area index (LAI) were measured pre- and post-treatment. Repeated measures of one factor ANOVA was used to statistically analyze the data. After 3 months of treatment, pustules disappeared completely in all patients (F \= 15.04\; p <\; .0001)\; LAI decreased significantly (F \= 24.54\; p <\; .0001). Complete clearance (100% reduction of LAI and complete disappear of pustules) and near complete clearance (75%-99%) occurred in 6 and 8 patients, respectively\; the other two patients exhibited partial clearance (50%-74%). Side effects were observed in 10 patients, but were mild to moderate and well tolerated. Our study suggested that arotinoid ethylester is an effective therapy for PPP with minimal side effects.

Keywords : arotinoid ethylester, palmoplantar pustulosis, treatment

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ARTICLE

Auteur(s) : Shi-Jun Shan¹, Yuan-Hong Li¹, Guowei Zhang², Ting Xiao¹, Changping Li³, Huachen Wei⁴, Hong-Duo Chen¹

¹Department of Dermatology, No.1 Hospital of China Medical University, 155 North Nanjing Street, Shenyang 110001, China
²Department of Dermatology, Xinqiao Hospital of No.3 Military Medical University, Chongqing, China
³Consulting Center of Biomedical Statistics, Academy of Military Medical Sciences, Beijing, China
⁴Department of Dermatology, Dermatology Research Laboratories, The Mount Sinai Medical Center, New York, New York

accepté le 7 Avril 2009

Palmoplantar pustulosis (PPP), synonymous to localized pustular psoriasis, is a chronic recurring pustular dermatosis localized mainly on the palms and soles. The exact etiology of PPP remains largely unknown. Clinically, crops of sterile pustules are found on palmoplantar skin. Histologically, intraepidermal pustules filled with neutrophils associated with surrounding spongiosis are described [1-5]. Treatment of PPP poses a great challenge to dermatologists, and so far there has been no universally accepted modality for PPP.

Arotinoid ethylester(p-[(E)-2-(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) propenyl]-benzoic acid ethylester), one of the polyaromatic retinoids, has shown potent anti-psoriatic and anti-inflammatory effects [6]. Here we report that arotinoid ethylester is a promising drug in treating PPP.

Methods

Patients

Sixteen patients (12 females and 4 males; mean age of 46.1 years with a range of 23 to 62 years) were enrolled from the dermatology outpatient clinic of No.1 Hospital, China Medical University (1999-2004). All the patients were diagnosed as PPP both clinically and histopathologically (mean duration: 20.6 months, range: 1-96 months). Referring to the study of Erkko et al. [7], all the patients had more than 20 pustules with a diameter ≥ 1 mm. Patients with systematic disorders, pregnancy or lactation and severe xerosis were excluded from the study. Nine patients had used topical triamcinolone or halometasone or emollients before enrollment. All patients had received no systemic medication in the past three months. Informed consents were signed by all participants. This study was approved by the Medical Ethic Committee of China Medical University.

Referring to the study of Ettler et al. [8], all the patients were treated with arotinoid ethylester at an initial dose of 0.03 mg once daily. Based upon the clinical response, when the patients attained either complete clearance of pustules or over 75% reduction of the lesion area index (LAI), the dosage was reduced to 0.03 mg every other day for 4 weeks, then 0.03 mg once a week for another 4 to 12 weeks until discontinuation of treatment.

According to Erkko et al. [7], the number of pustules and the lesion area index (LAI) were used as parameters for efficacy evaluation. LAI was defined as the percentage of lesion area of palms and soles. Pustule number and LAI were measured at the baseline (M0) and at 1-, 2- and 3- month follow-up visits (M1-3) after the beginning of treatment. Treatment outcome was defined at M3 as complete clearance (CC, 100% reduction of LAI and complete disappearance of pustules), near complete clearance (NCC, 75%-99%), partial clearance (PCC, 50%-74%) and non-responders (less than 50% reduction of LAI and number of pustules). Treatment success was defined as CC and NCC.

Results were reported as median (interquartile range [IQR]). Repeated measures of one factor ANOVA was used to statistically analyze the data. P < .05 was considered significant.

During treatment, mucocutaneous side effects were strictly monitored and documented at follow-up visits. Laboratory tests, including blood and urine routine, liver and renal functions and blood lipid and lipoprotein levels were examined at baseline and M1-3 follow-up visits, respectively. Recurrence of PPP was evaluated at 12 months post the cessation of therapy.

Results

The clinical details and parameters of 16 patients were summarized in table 1. At the baseline, the median number of pustules was 60.5 (IQR, 31-77.5), and decreased to 5 (IQR, 0-15) at M1, 0 (IQR, 0-6) at M2 and 0 (IQR, 0-0) at M3. Repeated measures of one factor ANOVA analysis exhibited statistically significant difference (F = 15.04; p < .0001). The median LAI decreased significantly from 40.0 (IQR, 25.0-55.0) at baseline to 30.0 (IQR, 10.0-35.0) at M1, 10.0 (IQR, 5.0-20.0) at M2 and 1.0 (IQR, 0-7.5) at M3; statistical analysis showed a significant difference (F = 24.54; p < .0001). At M3, six out of 16 patients presented with complete clearance (figures 1A,B), 8 patients with near complete clearance, and two patients with partial clearance. Thus, the success rate of arotinoid ethylester treatment was 87.5% (14 out of 16 patients). At the 1-year follow-up visit, 36% of patients (5 out of 14) relapsed. All relapsing patients responded quite well upon re-initiation of a once daily dose of 0.03 mg arotinoid ethylester.

Adverse events were observed in 10 patients. Elevated triglyceride and low density lipoprotein were the most frequent side effects, and observed in 5 patients at M1. After one month dietary control, only patient 12 had to take gemfibrozil 120 mg twice daily at M2. Blood and urine routine, liver and renal function tests of all 16 patients were within normal limits during the study. Other side effects included mucocutaneous xerosis, dermal thinning, pruritus, transient hair loss, periungual fissure, insomnia, skin exfoliation and slight leg erythema (table 2). All the side effects were well tolerated and recovered fully after medication was discontinued. No patient withdrew from the study.
Table 1 Clinic details and parameters of PPP patients treated with arotinoid ethylester

Patient No./Sex/Age, y	Duration, mo	Period of treatment, mo	LAI, %				Number of pustules				Outcome, CC, NCC or PC	Relapse at 1-year follow-up
M0	M1	M2	M3	M0	M1	M2	M3
1/F/52	24	5	40	30	10	5	35	5	0	0	NCC
2/M/49	24	6.5	90	70	10	1	21	0	0	0	NCC	R
3/F/62	1	4	65	30	5	0	78	10	0	0	CC
4/F/48	6	5	20	10	5	5	68	20	7	0	NCC
5/F/44	3	5	10	5	5	0	54	0	0	0	CC
6/F/32	3	6. 5	40	30	20	10	260	60	10	0	NCC	R
7/M/41	12	4.5	40	30	10	0	72	0	0	0	CC
8/F/54	1	4.75	50	30	10	0	230	50	14	0	CC	R
9/M/23	36	5	10	5	1	1	20	0	0	0	NCC
10/F/51	96	6	60	40	30	10	38	5	0	0	NCC	R
11/F/37	12	5	30	10	10	5	67	8	5	0	NCC
12/F/58	48	9.5	50	30	20	10	28	0	0	0	NCC	R
13/F/58	5	7	40	40	20	20	34	10	0	0	PC
14/F/50	36	6	60	40	20	20	97	20	16	0	PC
15/F/48	18	3.5	30	10	5	0	77	0	0	0	CC
16/M/43	7	7	20	5	5	0	24	0	0	0	CC

Table 2 Adverse effects of arotinoid ethylester in PPP treatment

Patient No./Sex/Age	Adverse effects
Blood lipid and lipoprotein levels		Mucocutaneous side effects			Others
	TG	LDLP	Xerosis	Dermal thinning	Pruritus
01/F/52			+			Skin exfoliation
02/M/49		6.7
03/F/62
04/F/48
05/F/44
06/F/32			+		+	Periungual fissure, insomnia, transient hair loss
07/M/41				+	+	Legs erythema
08/F/54			+		+
09/M/23				+
10/F/51
11/F/37	6.50
12/F/58	7.78(M1) 6.25(M2)	5.15(M1) 4.00(M2)	+
14/F/58
13/F/50	5.65
15/F/48
6/M/43		4.15	+

Discussion

PPP is a chronic pustular dermatosis characterized by recurrent sterile pustules on the palms and soles. The disease is resistant to treatment. The treatment principle of PPP largely follows that of generalized pustular psoriasis [9]. Topical calcipotriol and potent corticosteroids are recommended when hyperkeratosis and erythema are predominant. Methotrexate, cyclosporine and retinoids have been proposed for recalcitrant conditions [1, 4]. Among the retinoids, acitretin and etretinate have shown a certain efficacy, but PPP often relapses after discontinuation of treatment. However, prolonged therapy usually results in side effects [10].

Arotinoid ethylester belongs to the third generation of retinoids. It has a potent ability to induce differentiation, inhibit proliferation and suppress inflammation and keratinization. The therapeutic effect of arotinoid ethylester is long lasting for its excretion, and has been demonstrated in Darier’s disease, cutaneous T-cell lymphoma, psoriasis vulgaris and other dermatosis [11-13].

In this study, all the patients exhibited some improvement during the treatment. The results were consistent with previous reports of other retinoids [7, 14]. All the patients improved significantly during M2. Four weeks after the therapy was discontinued, 3 patients relapsed; and at the 1-year follow-up visit, 5 patients had relapsed. The overall relapsing rate is much lower than that of other retinoids previously reported [7]. Once the treatment of arotinoid ethylester was resumed, the subjects responded well again.

It has been reported that the side effects of arotinoid ethylester are milder and less frequent than acitretin. Overall, 10 patients in our study experienced more or less side effects. All the side effects fully recovered after cessation of arotinoid ethylester treatment. As the teratogenicity of arotinoid ethylester has been demonstrated in animal studies [15], it should not be used for pregnant women or females with child-bearing potential.

In conclusion, our pilot study suggested that arotinoid ethylester is an effective medication in the treatment of PPP, with milder side effects and lower recurrence rates than acitretin or etretinate [10]. Because of the limited number of patients and lack of controls in our study, the efficacy and safety of arotinoid ethylester on PPP needs to be further validated in a large scale study in the future.

Acknowledgements

Financial disclosure: none. Conflict of interest: none.

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