This clinical trial was conducted in compliance with the Declaration of Helsinki. The study protocol was reviewed and approved by the Research Ethics Committee of the Tehran University of Medical Sciences (approval code: IR.TUMS.VCR.REC.1395.184). This study was registered at the Iranian Registry of Clinical Trials website (IRCT2016092830030N1). After explaining the purpose of the trial to the patient, written informed consent was obtained from each patient.

The ChP oleogel was a mixture of traditional M. chamomilla oil (direct heat method), C. pepo seed oil, and colloidal silicon dioxide (47.5%: 47.5%: 5%). The placebo oleogel consisted of traditional M. chamomilla oil, C. pepo seed oil, silicon dioxide, and liquid paraffin (0.5%: 0.5%: 5%: 94%). The texture, color, and smell of these two formulations were similar.

Traditional chamomile oil was prepared based on the direct heat method, which was standardized in previous studies 2122. In this method, chamomile flower was powdered and boiled in water to achieve an aqueous extract. Then, after filtering the mixture, the aqueous extract was mixed with sesame oil and then boiled to evaporate all water content. The remaining oil is called chamomile oil. Also, standard pumpkin seed oil was purchased from the Giah Essence Phytopharm Co., Iran.

We enrolled 40 patients of both sexes using the eligibility criteria listed in the Table 1.

Table 1

Inclusion criteria	Exclusion Criteria
Diagnosis of mild to moderate plaque-type psoriasis by a dermatologist	Pregnancy or lactation
The presence of at least two symmetric psoriasis plaques	Systemic therapy or phototherapy within the last four months before study
Age between 20 and 60 years	Need to start systemic therapy during the study
Discontinuation of topical treatment for at least two weeks prior to the study	Use of medications that could induce or exacerbate psoriasis during the study
Patient consent to participate in the study	Skin infection or malignancy in the treatment area
	History of allergic reaction to the herbal ingredients of the drug
	The unwillingness of patients to continue treatment

To ensure balance in the treatment side (left or right), block randomization with a 1:1 ratio and block size of four participants was performed. The principal investigator prepared sequentially numbered, sealed, opaque envelopes for allocation of treatment. The investigators and patients remained unaware of treatment allocation. The codes of ChP and placebo were only revealed after the trial was completed.

The patients first signed the written informed consent. Then symmetrical target lesions in each patient were selected to receive ChP or placebo, twice daily for four weeks.

A dermatologist who was blind to randomization scored the severity of erythema, scaling, and induration of plaques with an 8-point scale (0 = none, 2 = mild, 4 = moderate, 6 = severe, 8 = very severe). The response to the treatment was evaluated based on the mean reduction in the erythema, scaling, induration, and PSI scores from baseline. The PSI score is the sum of erythema, scaling, and induration score, and ranges from 0 to 24.

In addition, we used the Physician’s Global Assessment (PGA) scale as follows: worse, no change (0%), mild improvement (0–25%), moderate improvement [25–50%), marked improvement [50–75%), almost clear [75–100%), and completely clear (100%). Photographs of the lesions were taken at baseline and the fourth week.

Patient satisfaction with the ChP and placebo was evaluated using a visual analog scale of 0 (completely dissatisfied) to 10 (completely satisfied). Additionally, the patients were asked to report all treatment-related side effects during the study.

A sample size of 40 was estimated by considering the significance level of 5%, the power of 80%, and a probable 20% drop-out rate. The statistical analysis was performed using SPSS 16. All patients who completed the study were included in the statistical analysis. A Wilcoxon’s matched-pairs signed-ranks test was conducted to establish the difference between the baseline and post-treatment values and the difference between the changes in the ChP and placebo sides. All the statistical tests were two-sided with the significance level of 0.05.

Of the 40 patients enrolled in our study, 37 (20 female and 17 male) completed it. Three patients withdrew from the trial due to local side effects after application of the medications. The recruitment of the patients is shown in the CONSORT flow diagram (Figure 1).

Figure 1

The average age of the patients was 36.8 ± 13.3 years (range, 20–60 years). The mean duration of the psoriasis disease was 12.11 ± 6.2 years (range, 2–31 years) and the mean Psoriasis Area and Severity Index (PASI) score was 6.58 ± 3.22 (range 1.2–10.1).

Forty symmetrical target lesions were selected, in which 16 pairs were located on upper extremities and 24 pairs were located on lower extremities.

Four weeks after treatment, the average PSI score decline in the ChP group (4.09 ± 2.24) was significantly (p = 0.000) greater than the placebo group (0.48 ± 1.39). The mean values of the erythema, scaling, induration, and PSI scores at baseline and four weeks after treatment are summarized in Table 2.

Table 2

Item	Group	Baseline (n=37) mean± SD	4th week (n=37) mean± SD	Pa
Erythema score	ChP	3.44 ± 1.36	2.44 ± 1.21	0.000
	placebo	3.34 ± 1.25	3.21 ± 1.22	0.052
Scaling score	ChP	4.09 ± 1.38	2.28 ± 1.55	0.000
	placebo	3.80 ± 1.30	3.63 ± 1.34	0.170
Induration score	ChP	3.46 ± 0.93	2.17 ± 0.96	0.000
	placebo	3.27 ± 0.95	3.09 ± 0.99	0.039
PSI score	ChP	11 ± 2.64	6.90 ± 3.04	0.000
	placebo	10.42 ± 2.71	9.94 ± 2.56	0.019

^{Pa : P value of analysis in each group from baseline to four weeks after treatment}

The mean ± SD decrease in the erythema, scaling, and induration scores were 1 ± 1, 1.80 ± 1.1, and 1.28 ± 1.03 in the ChP group, respectively, and 0.13 ± 0.48, 0.17 ± 0.87, and 0.17 ± 0.58 in the placebo group, respectively. In between group comparisons, these changes were significantly (p < 0.05) in favor of ChP treatment.

Regarding the Physician’s Global Assessment, 50% or greater improvement at week four was seen in 35% (13/37) of the ChP treated plaques versus 0% of the placebo-treated plaques. Of the 40 plaques treated with ChP, 54% showed moderate to marked improvement, and 14% became almost or completely clear. In the placebo group, 41% and 16% of the plaques found respectively mild and moderate improvement (Figure 2). The clinical effectiveness of the ChP is shown in figure 3 (Figure 3).

Figure 2

Figure 3

The overall patient satisfaction score on a 0–10 VAS was 4.77 ± 2.22 in the ChP group and 1.92 ± 1.13 in the placebo group.

Safety was assessed by recording adverse drug reactions and patient withdrawal from the study. During the first week of treatment, three of the forty subjects enrolled experienced itching and irritation of contralateral plaques which was more severe in the ChP treated side. These symptoms resolved 24 hours after discontinuation of the treatments, but these patients were excluded due to an unwillingness to continue the trial. In the remaining 37 patients, the ChP was well tolerated without any side effect.

Topical therapy is an important part of psoriasis management especially in mild to moderate cases. Unfortunately, conventional topical drugs have side effects, which limit their long-term use 23. Developing new anti-psoriasis drugs from medicinal plants could be a promising option. In this regard, we assessed the clinical efficacy of a topical preparation (ChP) containing chamomilla oil and pumpkin seed oil on mild to moderate plaque psoriasis. Because psoriasis is a multifactorial disease, we chose an intra-patient method to decrease the possible effect of variables such as sex, age, BMI, lifestyle habits, etc. on therapeutic response. This pilot study revealed that four weeks of treatment with ChP significantly improved erythema, scaling, thickness, and PSI scores compared with the placebo.

Psoriasis is an immune -mediated inflammatory skin disease with a complex pathogenesis that is not completely understood. Complex interactions among keratinocytes, activated T cells, macrophages, neutrophils, and dendritic cells are involved in the development of this disease 24. Reactions of these immune cells in skin layers induce inflammatory mediators release, reactive oxygen species (ROS) production, and cellular damage. All of these inflammatory reactions lead to keratinocyte hyperproliferation and psoriatic lesion formation 25.

The effect of externally applied chamomilla preparations was investigated in several inflammatory skin conditions. In a study on patients with inflammatory dermatoses, the clinical efficacy of Kamillosan cream (containing German chamomilla extract) was equivalent to hydrocortisone and superior to diflucortolone and bufexamac 26. In another study on peristomal skin lesions, the mean time for healing with a topical chamomilla solution was significantly greater than hydrocortisone 27. These therapeutic effects of chamomilla could be attributed to biological ingredients including flavonoids (apigenin, luteolin, and quercetin) and terpenoids (α-bisabolol, chamazulene). These compounds exert anti-inflammatory effects through different mechanisms including anti-oxidant activities 2829303132, and inhibitory effects on the production of inflammatory mediators such as LTB₄, PGE2, IL-1β, IL-6, TNF-α, and nitric oxide 3334353637. Also, sesame oil (used as a vehicle for chamomilla oil preparation) has compounds with anti-proliferative 38, anti-inflammatory 3940 and anti-oxidant properties 41. Additionally, both sesame oil 42 and pumpkin seed oil 43 are rich in linoleic acid (LA) which is an essential fatty acid in the stratum corneum (SC) barrier structure. Recent studies revealed the relationship between skin barrier disruption and psoriasis pathogenesis 44. Any defect in the SC barrier could result in keratinocyte hyper-proliferation and cytokine release 45. The SC consists of corneocytes embedded in an intercellular matrix. The presence of a lipid matrix rich in ceramides, cholesterol, and fatty acids is necessary for maintaining skin barrier function 46. LA is the predominant fatty acid in the SC and is the main precursor of ceramides 47. LA has a major role in preserving skin barrier integrity, and one of its metabolites named 13-hydroxyoctadecadienoic acid has antiproliferative properties 48.

In addition to LA, pumpkin seed oil has a high content of tocopherols, Selenium, β carotene, and phenolic compounds, all of which provide antioxidant effects 49.

In most of the patients, ChP was well tolerated, and no serious adverse event was reported. Three patients experienced bilateral irritation of plaque psoriasis and dropped out from the study. These side effects could be due to an allergic reaction to one of the herbal ingredients of the ChP and placebo. Chamomile is listed as GRAS (generally recognized as safe) by the FDA and has been used as a topical treatment in different dermatologic conditions for centuries 50. Sesame seed oil is widely used in cosmetic products and the Cosmetic Ingredient Review (CIR) Expert Panel has confirmed its safety 51. Although not common, allergic reactions after the topical use of Chamomile525354555657 and sesame oil 585960 were documented in several case reports. Therefore, this formulation should be used with caution in patients with a history of allergic reaction to these herbs.

We acknowledge some limitations of our study including lack of comparison with a conventional topical anti-psoriasis drug (e.g. corticosteroid) and short-term follow-up period.

This is the first study to evaluate the efficacy of a herbal formulation containing chamomile and pumpkin seed oil in the treatment of plaque psoriasis. Our findings suggest that ChP could be a safe and effective therapeutic option in mild to moderate plaque psoriasis. This therapeutic response could be related to the anti-inflammatory and antioxidant properties of the ChP ingredients. Further clinical trials with larger sample size and longer observation are needed to confirm our results and to compare the effectiveness of ChP with conventional anti-psoriasis drugs.

The authors state no conflict of interest.

Sima Kolahdooz: study design, data acquisition, data analysis, and manuscript preparation

Mehrdad Karimi: Study design, manuscript preparation

Nafiseh Esmaili: patient recruitment and selection

Arman Zargaran: drug formulation, review and revise the manuscript

Gholamreza Kordafshari: patient recruitment

Nikoo Mozafari: patient recruitment and selection and data interpretation

Mohammad. Hossein Ayati: data analysis

All authors read the final version of article and approved it.

ChP: Chamomile-pumpkin oleogel

CIR: Cosmetic Ingredient Review

GRAS: Generally recognized as safe

ITM: Iranian Traditional medicine

LA: Linoleic acid

PASI: Psoriasis Area and Severity Index

PGA: Physician’s Global Assessment‌

PSI: Psoriasis Severity Index‌

ROS: Reactive oxygen species

SC: Stratum corneum

TM/CAM: Traditional, complementary, and alternative medicine

VAS: Visual analog scale‌

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